Electrical Stimulation for Pain
Number: 0011
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses electrical stimulation for pain.
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Medical Necessity
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Transcutaneous Electrical Nerve Stimulators (TENS)
Aetna considers transcutaneous electrical nerve stimulators (TENS) medically necessary durable medical equipment (DME) when used as an adjunct or as an alternative to the use of drugs either in the treatment of acute post-operative pain in the first 30 days after surgery, or for certain types of chronic, intractable pain not adequately responsive to other methods of treatment including, as appropriate, physical therapy and pharmacotherapy. See 'Experimental, Investigational, or Unproven' section for exclusions.
Note: When TENS is used for acute post-operative or chronic intractable pain, Aetna considers use of the device medically necessary initially for a trial period of at least 1 month but not to exceed 2 months. The trial period must be monitored by the physician to determine the effectiveness of the TENS unit in modulating the pain. After this 1-month trial period, continued TENS treatment may be considered medically necessary if the treatment significantly alleviates pain and if the attending physician documents that the patient is likely to derive significant therapeutic benefit from continuous use of the unit over a long period of time. The physician's records must document a reevaluation of the member at the end of the trial period, must indicate how often the member used the TENS unit, the typical duration of use each time, and the results. The physician ordering the TENS unit must be the attending physician or a consulting physician for the disease or condition resulting in the need for the TENS unit. If the TENS unit produces incomplete relief, further evaluation with percutaneous electrical nerve stimulation (PENS) may be indicated. This clinical policy is consistent with Medicare DME MAC guidelines.
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Form-Fitting Conductive Garment
Aetna considers a form-fitting conductive garment medically necessary DME only when it has been approved for marketing by the FDA, has been prescribed by a doctor for delivering TENS for one of the medically necessary indications listed above, and any of the following criteria is met:
- The member can not manage without the conductive garment due to the large area or the large number of sites to be stimulated, and the stimulation would have to be delivered so frequently that it is not feasible to use conventional electrodes, adhesive tapes, and lead wires; or
- The member has a medical need for rehabilitation strengthening following an injury where the nerve supply to the muscle is intact; or
- The member has a skin problem or other medical conditions that precludes the application of conventional electrodes, adhesive tapes, and lead wires; or
- The member requires electrical stimulation beneath a cast to treat disuse atrophy, where the nerve supply to the muscle is intact.
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Percutaneous Electrical Nerve Stimulation (PENS)
Aetna considers percutaneous electrical nerve stimulation (PENS) medically necessary DME for:
- Up to a 30-day period for the treatment of members with chronic low back pain secondary to degenerative disc disease when PENS is used as part of a multi-modality rehabilitation program that includes exercise; or
- Treatment of members with diabetic neuropathy or neuropathic pain who failed to adequately respond to conventional treatments including three or more of the following groups of agents: anti-convulsants (e.g., pregabalin), anti-depressants (e.g., amitriptyline, and duloxetine), opioids (e.g., morphine sulphate and tramadol), and other pharmacological agents (e.g., capsaicin and isosorbide dinitrate spray).
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Peripherally Implanted Nerve Stimulators
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Aetna considers peripherally implanted nerve stimulators (e.g., StimRouter System, Nalu Peripheral Nerve Stimulation System) medically necessary DME for treatment of members with intractable neuropathic pain when all of the following criteria are met. See "Experimental, Investigational, or Unproven" section for exclusions:
- Member has chronic intractable pain, refractory to other methods of treatment (e.g., analgesics and other medications (including TCAs, SSRIs, SNRIs and antiseizure medications, where appropriate), physical therapy (in-person for at least 6 weeks in the past year), local injection, surgery); and
- Member is not addicted to drugs (per American Society of Addiction Medicine guidelines); and
- There is no psychological contraindication to peripheral nerve stimulation; and
- There is objective evidence of pathology (e.g., electromyography/nerve conduction studies and diagnostic blocks of the specific affected nerve(s)); and
- Trial of percutaneous stimulation was successful (resulting in at least a 50 % reduction in pain for a minimum of 3 days). Note: If a peripheral nerve stimulation trial fails, a repeat trial is not medically necessary unless there are extenuating circumstances that lead to trial failure. Trials will be limited to four leads with maximum of 16 contacts.)
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Revision/replacement of a previously implanted stimulator is medically necessary for any of the following reasons:
- Lead malfunction (e.g., fracture or migration); or
- Prior device removal for infection with consult from an infectious disease specialist to confirm infection has been eradicated; or
- If member has a documented need for an MRI-compatible device due to contraindications to CT/myelography or other immediate need and the device was providing pain relief previously.
Note: No more than two services of 64555-(Percutaneous implantation of neurostimulator electrodes; peripheral nerve [excludes sacral nerve]) may be billed per 365 days.
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Experimental, Investigational, or Unproven
The following durable medical equipment (DME) and supplies are considered experimental, investigational, or unproven because the effectiveness of these approaches for the specified indication(s) has not been established (not an all-inclusive list):
- Transcutaneous Electrical Nerve Stimulators (TENS)
Aetna considers TENS experimental, investigational, or unproven for acute pain (less than 3 months duration) other than post-operative pain. TENS is also considered experimental, investigational, or unproven for any of the following (not an all-inclusive list) because there is inadequate scientific evidence to support its efficacy for these specific types of pain:
- Acute and chronic headaches
- Adhesive capsulitis (frozen shoulder)
- Carpal tunnel syndrome pain
- Cervicalgia (e.g., by means of the Quell device)
- Chemotherapy-induced peripheral neuropathy
- Chondromalacia patellae and patellofemoral disorders
- Chronic low back pain
- Deep abdominal pain
- Fibromyalgia
- Hip fracture pain
- Migraine
- Musculoskeletal pain in hemophilia
- Neuropathic pain
- Pain management in burn persons
- Pelvic pain
- Peripheral arterial disease
- Phantom pain
- Post-total knee arthroplasty pain
- Rotator cuff disease (e.g., calcific tendinitis, rotator cuff tendinitis, and subacromial impingement syndrome)
- Stump pain
- Suprascapular nerve entrapment
- Temporomandibular joint (TMJ) pain;
- Stellate ganglion blockade using TENS;
- TENS with low level laser therapy (LLLT) (e.g., the Neurolumen device) for the treatment of Morton’s neuroma and all other indications;
- Interferential stimulation (e.g., RS-4i Sequential Stimulator) for the reduction of pain and edema and all other indications;
- Percutaneous Electrical Nerve Stimulation (PENS) for all of the following (not an all-inclusive list) because its effectiveness for these indications, or approach, has not been established:
- For the management of opioid withdrawal, treatment of chronic neck pain, and all other indications
- Combined PENS and dorsal root ganglion stimulation for the treatment of back pain
- IB-Stim for the treatment of irritable bowel syndrome, and treatment of nausea and abdominal pain secondary to irritable bowel syndrome;
- Percutaneous neuromodulation therapy (e.g., Vertis PNT, BiowavePRO) for pain and other indications;
- Peripheral subcutaneous field stimulation (PSFS) or peripheral nerve field stimulation (PNFS) (e.g., the Freedom PNS System, the Sprint PNS System, the StimQ PNS System) for the treatment of chronic pain, hemiplegic shoulder pain, and other indications (e.g., angina, notalgia paraesthetica);
- Accelerated recovery performance (ARP) wave therapy for the treatment of lumbar spondylosis/back pain;
- Peripheral nerve stimulation (e.g., StimRouter System, Nalu Peripheral Nerve Stimulation System) for all indications other than intractable neurogenic pain (as noted above), including the following:
- Post-herpetic neuralgia
- Suprascapular nerve entrapment
- Peripheral nerve stimulation of the cluneal nerve for treatment of sacroiliac joint-mediated pain, back pain and other indications
- Chronic abdominal pain
- Occipital neuralgia and other headache types
- Genicular nerves for knee pain (all indications)
- Medial branch nerve stimulation;
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H-WAVE Type Stimulators for diabetic peripheral neuropathy and for any of the following indications (not an all-inclusive list):
- To accelerate healing; or
- To reduce edema; or
- To reduce pain from causes other than chronic diabetic peripheral neuropathy; or
- To treat chronic pain due to ischemia;
- Intramuscular stimulation for the management of members with soft-tissue or neuropathic pain and all other indications;
- Electroceutical Therapy (also known as bioelectric nerve block) for the treatment of acute pain or chronic pain (e.g., back pain, diabetic pain, joint pain, fibromyalgia, headache, and reflex sympathetic dystrophy) or other indications;
Note: Other terms used to refer to electroceutical therapy devices include "non-invasive neuron blockade" devices, "electroceutical neuron blockade" devices, and "bioelectric treatment systems." - Electro-Acuscope, Myopulse, and Equiscope Therapy System for the treatment of pain and tissue damage and all other indications;
- Electro-Analgesia Treatment (EAT) using the Synaptic electrical stimulator with or without peripheral nerve blocks for peripheral neuropathy and all other indications;
- Electrical stimulation of the sacral nerve roots or lumbosacral plexus for the treatment of chronic pelvic, abdominal pain, or other indications;
- Electrical stimulation of the posterior tibial nerve for the treatment of neuropathic pain associated with polyneuropathy;
- Electro-therapeutic point stimulation (also known as microcurrent point stimulation) for the treatment of chronic pain and other indications;
- Electrotherapy for the treatment of adhesive capsulitis (frozen shoulder);
- Freedom Peripheral Nerve Stimulator System for the treatment of chronic pain;
- Microcurrent Electrical Nerve Stimulation (MENS) Therapy (including, but not limited to, Algonix, Alpha-Stim 100, Electro-Myopulse 75L, electro-Lyoscope 85P, KFH Energy, MENS 2000-D, MICROCURRENT or Myopulse 75C) for the treatment of chronic back pain and all other indications;
- Frequency-specific microcurrent therapy for the treatment of back and neck pain;
- Scrambler Therapy/The Calmare Therapy Device (also known as transcutaneous electrical modulation pain reprocessing (TEMPR)) for the treatment of cancer pain, chronic pain, Dejerine-Roussy syndrome, neuropathic pain associated with chemotherapy-induced peripheral neuropathy, post-mastectomy pain, and other indications;
- Non-Invasive Interactive Neurostimulation (e.g., the InterX 1000 neurostimulator device) for the treatment of chronic pain and other indications (e.g., ankle fracture, knee osteoarthritis and neck pain);
- Non-invasive/No-Incision Pain Procedure (NIP) Device for the treatment of chronic pain (arthritis, cancer pain, cervical pain, fibromyalgia, joint pain, low back pain, migraines, post-operative pain, and sciatica; not an all-inclusive list) and all other conditions (e.g., anxiety, depression and insomnia; not an all-inclusive list);
- Pulsed Electrical Stimulator (PES)/transcutaneous electrical joint stimulation devices (e.g., the BioniCare device, Jstim 1000) for the treatment of knee osteoarthritis, soft-tissue injuries (e.g., ankle sprain) and all other indications;
- Pulse Stimulation (e.g., the P-STIM device) for the treatment of cervicalgia, cervical radiculopathy, cervical spasm, chronic neck pain, failed back syndrome, lumbago, lumbar muscle spasm, lumbosacral myofasciitis, lumbosacral radiculopathy, osteoarthritis of the knee, post-herpetic neuralgia, or other conditions;
- Auricular electrical stimulation (e.g., DyAnsys auricular electrical nerve stimulator) for the treatment of headache, low-back pain, neuropathic pain, and all other indications
- Cefaly transcutaneous electrical stimulator headband for migraine headache prevention and treatment and all other indications;
- Galvanic stimulation or other types of electrical stimulation for the treatment of peripheral arterial disease;
- Intravaginal electrical stimulation, percutaneous tibial nerve stimulation, and respiratory-gated auricular vagal afferent nerve stimulation for the treatment of chronic pelvic pain;
- Multifidus muscle stimulation (e.g., Reactiv8 device) for the treatment of chronic low back pain;
- Neurogenx 4000PRO device for the treatment of Achilles tendonitis and all other indications;
- Quell device;
- Reduced impedance non-invasive cortical electrostimulation (RINCE) for the treatment of chronic pain;
- SENSUS transcutaneous electrical nerve stimulation for diabetic neuropathy and other indications;
- Sprint (peripheral subcutaneous field stimulation) for the treatment of complex regional pain syndrome, low back pain, nerve root and plexus disorders;
- Sympathetic therapy (Dynatronics Corporation, Salt Lake City, UT);
- Trigeminal nerve stimulation for the treatment of trigeminal neuralgia;
- Ultrasound-guided percutaneous stimulation of the femoral nerve for post-operative analgesia following anterior cruciate ligament reconstruction;
- Ultrasound-guided percutaneous stimulation of the sciatic nerve for post-operative analgesia following ambulatory foot surgery;
- Variable muscle stimulators;
- Combined high frequency electrical stimulation with peripheral nerve block or injections of vitamins and micronutrients (also referred to as combination electrochemical therapy, combination electrochemical treatment, or CET) for all indications - see CPB 0729 - Diabetic Neuropathy: Selected Treatments;
- Combined PENS and spinal cord stimulation for back pain and other indications - see CPB 0194 - Spinal Cord Stimulation;
- Combination stimulation devices for all indications:
- Interferential current stimulation (ICS) and muscle stimulator (e.g., RS-4i sequential stimulator, EMSI TENS/EMS-14); or
- InTENsity Select Combo electrical stimulator for all indications; or
- ManaFlexx 2 combination stimulation device; or
- TENS with ICS; or
- TENS with NMES (e.g., Empi Phoenix, QB1 System); or
- TENS with ultrasound device; or
- Transcranial direct current stimulation and breathing-controlled electrical stimulation for the treatment of neuropathic pain after spinal cord injury.
- Transcutaneous Electrical Nerve Stimulators (TENS)
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Related CMS Coverage Guidance
This Clinical Policy Bulletin (CPB) supplements but does not replace, modify, or supersede existing Medicare Regulations or applicable National Coverage Determinations (NCDs) or Local Coverage Determinations (LCDs). The supplemental medical necessity criteria in this CPB further define those indications for services that are proven safe and effective where those indications are not fully established in applicable NCDs and LCDs. These supplemental medical necessity criteria are based upon evidence-based guidelines and clinical studies in the peer-reviewed published medical literature. The background section of this CPB includes an explanation of the rationale that supports adoption of the medical necessity criteria and a summary of evidence that was considered during the development of the CPB; the reference section includes a list of the sources of such evidence. While there is a possible risk of reduced or delayed care with any coverage criteria, Aetna believes that the benefits of these criteria – ensuring patients receive services that are appropriate, safe, and effective – substantially outweigh any clinical harms.
This CPB is being used to supplement the Medicare NCD and LCD on peripheral nerve stimulators (NCD 106.7, Electrical Stimulators; LCD L37360, Peripheral Nerve Stimulation and accompanying Article A55531, Billing and Coding: Peripheral Nerve Stimulation). This CPB is used to define indications for which peripheral nerve stimulators are proven to be safe and effective (see, e.g., Deer, et al., 2016; Gilmore, et al., 2019; Rauck, et al., 2014; Helm, et al, 2021; Char, et al., 2022). This will better ensure that beneficiaries receive peripheral nerve stimulation for conditions proven to be responsive to this form of therapy and avoid the use of this procedure for conditions for which peripheral nerve stimulators have not been proven to be safe and effective (see, e.g., Eldabe, et al., 2016; Parker & Cameron, 2015; Slavin, 2011). We believe the clinical benefits of avoiding unnecessary and potentially harmful care outweighs any potential risks in delayed or reduced access to care.
Code of Federal Regulations (CFR):
42 CFR 417; 42 CFR 422; 42 CFR 423.
Internet-Only Manual (IOM) Citations:
CMS IOM Publication 100-02, Medicare Benefit Policy Manual; CMS IOM Publication 100-03 Medicare National Coverage Determination Manual.
Medicare Coverage Determinations:
Centers for Medicare & Medicaid Services (CMS), Medicare Coverage Database [Internet]. Baltimore, MD: CMS; updated periodically. Available at: Medicare Coverage Center. Accessed November 7, 2023.
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Related Policies
Below is a list of CPBs that address other types of electrical stimulation:
- CPB 0175 - Pulsed Electromagnetic Stimulation
- CPB 0191 - Vagus Nerve Stimulation
- CPB 0194 - Spinal Cord Stimulation
- CPB 0208 - Deep Brain Stimulation
- CPB 0223 - Urinary Incontinence
- CPB 0302 - Xerostomia: Selected Treatments
- CPB 0327 - Infertility - discusses electroejaculation
- CPB 0343 - Bone Growth Stimulators
- CPB 0398 - Idiopathic Scoliosis - discusses surface electrical muscle stimulation
- CPB 0406 - Tinnitus Treatments - discusses the use of TENS
- CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation
- CPB 0545 - Electrothermal Arthroscopy
- CPB 0676 - Electrical Stimulation for Nausea, Vomiting, and Motion Sickness (PrimaBella and ReliefBand) and Other Selected Indications
- CPB 0677 - Functional Electrical Stimulation and Neuromuscular Electrical Stimulation - discusses Bell’s palsy, cerebral palsy, diaphragmatic pacing, neurogenic bladder, spinal cord injury, and stroke
- CPB 0678 - Gastric Pacing / Electrical Stimulation and Gastric Per Oral Endoscopic Myotomy
- CPB 0679 - Levator Syndrome Treatments
- CPB 0680 - Electrical Stimulation for Chronic Ulcers
- CPB 0707 - Headaches: Invasive Procedures - discusses electrical stimulation of the occipital nerve for occipital neuralgia
- CPB 0729 - Diabetic Neuropathy: Selected Treatments - discusses percutaneous electrical stimulation for the treatment of diabetic neuropathy.
Background
The following are brief descriptions of various types of electrical stimulation discussed in this CPB, and a summary of available evidence:
Transcutaneous Electrical Nerve Stimulator (TENS)
A TENS is a device which utilizes electrical current delivered through electrodes placed on the surface of the skin to decrease the patient's perception of pain by inhibiting the transmission of afferent pain nerve impulses and/or stimulating the release of endorphins. A TENS unit must be distinguished from other electrical stimulators (e.g., neuromuscular stimulators) which are used to directly stimulate muscles and/or motor nerves. Transcutaneous electrical nerve stimulation is characterized by biphasic current and selectable parameters such as pulse rate and pulse width. In theory, TENS stimulates sensory nerves to block pain signals; it also stimulates endorphin production to help normalize sympathetic function. Most TENS units produce current of 1 to 80 microampere (mA), 9 V (average), 2 to 1000 Hz, with a pulse width of 250 to 400 microseconds (mS).
Transcutaneous electrical nerve stimulation has been widely used in the treatment of various types of pain. It has been shown that TENS is highly effective in alleviating pain and reducing analgesic medications following cesarean section, orthopedic and thoracic operations as well as mixed surgical procedures (AHCPR, 1992). Moreover, TENS has been found to be beneficial also to those who suffer from acute musculoskeletal pain (Long, 1991). On the other hand, the use of TENS in the treatment of chronic malignant pain is sparse and its effectiveness remains unproven. Studies by Ventafridda and colleagues (1979) reported that of the 159 cancer patients who experienced short-term pain relief with TENS therapy, 58 % of them found the treatment ineffective by day 10, and only 35 % of these subjects continued its use after 1 month. In another group of 37 patients, pain was markedly reduced in 96 % of them during the first 10 days of TENS treatment. However, pain reduction was found only in 33 % of the subjects during the second 10 days, and to only 11 % during the third 10 days. Physical mobility was improved initially in 76 % of patients but dropped to 19 % by the end of 1 month (Ventafridda et al, 1979). The Canadian Coordinating Office for Health Technology Assessment evaluated the clinical value of TENS in pain management and concluded that there is little evidence of the effectiveness of TENS in treating chronic pain (1995).
On June 8, 2012, the Centers for Medicare & Medicaid Services (CMS) rendered a decision memo for TENS for chronic low back pain. It states that TENS is not reasonable and necessary for the treatment of chronic low back pain. The CMS will only cover TENS if individuals are enrolled in an approved clinical study meeting specific requirements.
The Centers for Medicare & Medicaid Services (2012) has issued a decision memorandum concluding that TENS not reasonable and necessary for the treatment of chronic low back pain. For purposes of the decision memorandum, chronic low back pain was defined as an episode of low back pain that has persisted for three months or longer; and is not a manifestation of a clearly defined and generally recognizable primary disease entity. For example, there are cancers that, through metastatic spread to the spine or pelvis, may elicit pain in the lower back as a symptom; and certain systemic diseases such as rheumatoid arthritis and multiple sclerosis manifest many debilitating symptoms of which low back pain is not the primary focus. The CMS decision memorandum stated that the evidence demonstrates that the use of TENS for chronic low back pain as defined within the scope of this analysis does not produce a clinically meaningful improvement in any of the considered health outcomes The decision memorandum stated that it is apparent that sham (placebo) TENS produces equivalent analgesia as active TENS.
- TENS is not recommended for the treatment of chronic LBP (Level A), and
- TENS should be considered in the treatment of painful diabetic neuropathy (Level B). They stated that further research into the mechanism of action of TENS is needed, as well as more rigorous studies for determination of efficacy.
Guidelines on treatment of LBP from the National Collaborating Centre for Primary Care (Savigny et al, 2009) found insufficient evidence for the use of TENS in LBP and recommended against its use for that indication.
In a Cochrane review, Mulvey et al (2010) evaluated the analgesic effectiveness of TENS for the treatment of phantom pain and stump pain following amputation in adults. These investigators searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycINFO, AMED, CINAHL, PEDRO and SPORTDiscus (February 2010). Only randomized controlled trials (RCTs) investigating the use of TENS for the management of phantom pain and stump pain following an amputation in adults were included. Two review authors independently assessed trial quality and extracted data. It was planned that where available and appropriate, data from outcome measures were to be pooled and presented as an overall estimate of the effectiveness of TENS. No RCTs that examined the effectiveness of TENS for the treatment of phantom pain and stump pain in adults were identified by the searches. The authors concluded that there were no RCTs on which to judge the effectiveness of TENS for the management of phantom pain and stump pain. The published literature on TENS for phantom pain and stump pain lacks the methodological rigor and robust reporting needed to confidently assess its effectiveness. They stated that further RCT evidence is needed before such a judgment can be made.
Johnson et al (2015) updated of a Cochrane review published in 2010 on TENS for phantom pain and stump pain following amputation in adults. The authors concluded that there were no RCTs to judge the effectiveness of TENS for the management of phantom pain and stump pain. The published literature on TENS for phantom pain and stump pain lacks the methodological rigor and robust reporting needed to confidently assess its effectiveness. They stated that further RCT evidence is needed before an assessment can be made. Since publication of the original version of this review, these investigators have found no new studies and their conclusions remain unchanged.
Zeng et al (2015) examined the effectiveness of different electrical stimulation (ES) therapies in pain relief of patients with knee osteoarthritis (OA). Electronic databases including MEDLINE, Embase and Cochrane Library were searched through for RCTs comparing any ES therapies with control interventions (sham or blank) or with each other. Bayesian network meta-analysis was used to combine both the direct and indirect evidence on treatment effectiveness. A total of 27 trials and 6 types of ES therapies, including high-frequency TENS (h-TENS), low-frequency TENS (l-TENS), neuromuscular electrical stimulation (NMES), interferential current (IFC), pulsed electrical stimulation (PES), and noninvasive interactive neurostimulation (NIN), were included. Interferential current is the only significantly effective treatment in terms of both pain intensity and change pain score at last follow-up time-point when compared with the control group. Meanwhile, IFC showed the greatest probability of being the best option among the 6 treatment methods in pain relief. These estimates barely changed in sensitivity analysis. However, the evidence of heterogeneity and the limitation in sample size of some studies could be a potential threat to the validity of results. The authors conclude that IFC seems to be the most promising pain relief treatment for the management of knee OA. However, evidence was limited due to the heterogeneity and small number of included trials. Although the recommendation level of the other ES therapies is either uncertain (h-TENS) or not appropriate (l-TENS, NMES, PES and NIN) for pain relief, it is likely that none of the interventions is dangerous.
Cheing and Luk (2005) examined the clinical effectiveness of high-frequency (HF) TENS for reducing hyper-sensitivity of the hand in patients with neuropathic pain. A total of 19 patients suffering from hand hyper-sensitivity were randomly assigned into either a treatment or a placebo group. A visual analog scale (VAS) and the Downey Hand Center Hand Sensitivity Test were used to measure the tactile tolerance of the hand. Grip strength was assessed by a grip dynamometer. Daily applications of electrical stimulation were provided for 2 weeks. Significantly lower pain scores were found in the treatment group than in the placebo group by day 7 and day 11. The ranking of 10 dowel textures of the Downey Hand Center Hand Sensitivity Test in the treatment group was significantly higher than in the placebo group by day 7 and day 11. However, no significant inter-group difference was found in grip strength.
The Ad hoc Committee of the Croatian Society for Neurovascular Disorders and the Croatian Medical Association's recommendations for neuropathic pain treatment (Demarin et al, 2008) stated that damage to the somatosensory nervous system poses a risk for the development of neuropathic pain. Such an injury to the nervous system results in a series of neurobiological events resulting in sensitization of both the peripheral and central nervous system. The diagnosis of neuropathic pain is based primarily on the history and physical examination finding. Although monotherapy is the ideal approach, rational polypharmacy is often pragmatically used. Several classes of drugs are moderately effective, but complete or near-complete relief is unlikely. Anti-depressants and anti-convulsants are most commonly used. Opioid analgesics can provide some relief but are less effective than for nociceptive pain; adverse effects may prevent adequate analgesia. Topical drugs and a lidocaine-containing patch may be effective for peripheral syndromes. Sympathetic blockade is usually ineffective except for some patients with complex regional pain syndrome. TENS was not mentioned as a therapeutic option.
Norrbrink (2009) assessed the short-term effects of HF and low-frequency (LF) TENS for neuropathic pain following spinal cord injury (SCI). A total of 24 patients participated in the study. According to the protocol, 50 % of the patients were assigned to HF (80 Hz) and 50 % to LF (burst of 2 Hz) TENS. Patients were instructed to treat themselves 3 times daily for 2 weeks. After a 2-week wash-out period, patients switched stimulation frequencies and repeated the procedure. Results were calculated on an intent-to-treat basis. No differences between the 2 modes of stimulation were found. On a group level, no effects on pain intensity ratings or ratings of mood, coping with pain, life satisfaction, sleep quality, or psychosocial consequences of pain were seen. However, 29 % of the patients reported a favorable effect from HF and 38 % from LF stimulation on a 5-point global pain-relief scale. Six of the patients (25 %) were, at their request, prescribed TENS stimulators for further treatment at the end of the study. The authors concluded that TENS merits consideration as a complementary treatment in patients with SCI and neuropathic pain. The mild benefits observed -- 29 % of subjects in the HF group and 38 % of subjects in the LF group could be a placebo effect.
Moharic and Burger (2010) examined if TENS improves small fiber function diminished because of painful diabetic neuropathy. A total of 46 patients with painful diabetic neuropathy were treated with TENS 3 consecutive hours a day for 3 weeks. Treatment effect was evaluated with cold, warm, cold pain and heat pain thresholds, vibration perception thresholds and touch perception thresholds. In all patients, thermal-specific and thermal pain sensitivity determination showed quantitative and qualitative abnormalities in all the measured spots. After the TENS therapy, no statistically significant changes in cold, warm, cold pain, heat pain, vibratory perception and touch perception thresholds were observed in the stimulated area. TENS did not alter C, Aδ nor Aβ fiber-mediated perception thresholds. The authors noted that the observed changes at thenar were probably because of central mechanisms. In general, analgesic mechanisms of TENS are likely to be complex.
Jin et al (2010) evaluated the effectiveness of TENS on diabetic peripheral neuropathy (DPN). Randomized controlled trials (RCTs) comparing TENS with routine care, pharmacological interventions or placebo devices on patients with symptomatic DPN, were identified by electronic and manual searches. Studies were selected and available data were extracted independently by 2 investigators. Meta-analysis was performed by RevMan 4.2.8 software. A total of 3 RCTs involving 78 patients were included in this study. The reductions in mean pain score were significantly greater in TENS group than in placebo TENS group in 4 weeks and 6 weeks follow-up [4 weeks, standard mean difference (SMD) -5.37, 95 % confidence interval [CI]: -6.97 to -3.77; 6 weeks, SMD-1.01, 95 % CI: -2.01 to -0.01)], but not in 12 weeks follow-up [SMD-1.65, 95 % CI: -4.02 to 0.73]. TENS therapy was associated with significantly subjective improvement in overall neuropathic symptoms in 12 weeks follow-up [WMD-0.18, 95 % CI: -0.32 to -0.051]. No TENS-related adverse events were registered in TENS group. The authors concluded that TENS therapy may be an effective and safe strategy in treatment of symptomatic DPN. They stated that due to small sample and short-term treatment duration, large multi-center RCTs are needed to further evaluate the long-term effect of TENS on DPN.
Johnson and Bjordal (2011) stated that the management of neuropathic pain is challenging, with medication being the first-line treatment. Transcutaneous electrical nerve stimulation is a non-invasive, self-administered technique that is used as an adjunct to medication. Clinical experience suggested that TENS is beneficial providing it is administered at a sufficiently strong intensity, close to the site of pain. At present, there are too few RCTs on TENS for neuropathic pain to judge effectiveness. The findings of systematic reviews of TENS for other pain syndromes are inconclusive because trials have a low fidelity associated with inadequate TENS technique and infrequent treatments of insufficient duration. The use of electrode arrays to spatially target stimulation more precisely may improve the efficacy of TENS in the future.
In a systematic review, Abou-Setta (2011) reviewed the benefits and harms of pharmacological and non-pharmacological interventions for managing pain after hip fracture. A total of 25 electronic databases (January 1990 to December 2010), gray literature, trial registries, and reference lists, with no language restrictions were searched. Multiple reviewers independently and in duplicate screened 9,357 citations to identify RCT); non-RCTs; and cohort studies of pain management techniques in older adults after acute hip fracture. Independent, duplicate data extraction and quality assessment were conducted, with discrepancies resolved by consensus or a third reviewer. Data extracted included study characteristics, inclusion and exclusion criteria, participant characteristics, interventions, and outcomes. A total of 83 unique studies (64 RCTs, 5 non-RCTs, and 14 cohort studies) were included that addressed nerve blockade (n = 32), spinal anesthesia (n = 30), systemic analgesia (n = 3), traction (n = 11), multi-modal pain management (n = 2), neurostimulation (n = 2), rehabilitation (n = 1), and complementary and alternative medicine (n = 2). Overall, moderate evidence suggested that nerve blockades are effective for relieving acute pain and reducing delirium. Low-level evidence suggested that pre-operative traction does not reduce acute pain. Evidence was insufficient on the benefits and harms of most interventions, including spinal anesthesia, systemic analgesia, multi-modal pain management, acupressure, relaxation therapy, TENS, and physical therapy regimens, in managing acute pain. The authors concluded that nerve blockade seems to be effective in reducing acute pain after hip fracture. Sparse data preclude firm conclusions about the relative benefits or harms of many other pain management interventions (including TENS) for patients with hip fracture.
In a Cochrane review, Page et al (2014) examined the available evidence regarding the benefits and harms of electrotherapy modalities, delivered alone or in combination with other interventions, for the treatment of adhesive capsulitis (frozen shoulder). These investigators searched CENTRAL, MEDLINE, EMBASE, CINAHL Plus and the ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) clinical trials registries up to May 2014, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials to identify any other potentially relevant trials. They included RCTs and controlled clinical trials using a quasi-randomized method of allocation that included adults with adhesive capsulitis and compared any electrotherapy modality to placebo, no treatment, a different electrotherapy modality, or any other intervention. The 2 main questions of the review focused on whether electrotherapy modalities are effective compared to placebo or no treatment, or if they are an effective adjunct to manual therapy or exercise (or both). The main outcomes of interest were participant-reported pain relief of 30 % or greater, overall pain, function, global assessment of treatment success, active shoulder abduction, quality of life, and the number of participants experiencing any adverse event. Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment, and assessed the quality of the body of evidence for the main outcomes using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. A total of 19 trials (1,249 participants) were included in the review; 4 trials reported using an adequate method of allocation concealment and 6 trials blinded participants and personnel. Only 2 electrotherapy modalities (low-level laser therapy (LLLT) and pulsed electromagnetic field therapy (PEMF)) have been compared to placebo. No trial has compared an electrotherapy modality plus manual therapy and exercise to manual therapy and exercise alone. The 2 main questions of the review were investigated in 9 trials. Low-quality evidence from 1 trial (40 participants) indicated that LLLT for 6 days may result in improvement at 6 days; 81 % (16/20) of participants reported treatment success with LLLT compared with 10 % (2/20) of participants receiving placebo (risk ratio (RR) 8.00, 95 % CI: 2.11 to 30.34; absolute risk difference 70 %, 95 % CI: 48 % to 92 %). No participants in either group reported adverse events. These researchers were uncertain whether PEMF for 2 weeks improved pain or function more than placebo at 2 weeks because of the very low quality evidence from 1 trial (32 participants); 75 % (15/20) of participants reported pain relief of 30 % or more with PEMF compared with 0 % (0/12) of participants receiving placebo (RR 19.19, 95 % CI: 1.25 to 294.21; absolute risk difference 75 %, 95 % CI: 53 % to 97 %). Fifty-five per cent (11/20) of participants reported total recovery of joint function with PEMF compared with 0 % (0/12) of participants receiving placebo (RR 14.24, 95 % CI: 0.91 to 221.75; absolute risk difference 55 %, 95 % CI: 31 to 79). Moderate quality evidence from 1 trial (63 participants) indicated that LLLT plus exercise for 8 weeks probably resulted in greater improvement when measured at the 4th week of treatment, but a similar number of adverse events, compared with placebo plus exercise. The mean pain score at 4 weeks was 51 points with placebo plus exercise, while with LLLT plus exercise the mean pain score was 32 points on a 100-point scale (mean difference (MD) 19 points, 95 % CI: 15 to 23; absolute risk difference 19 %, 95 % CI: 15 % to 23 %). The mean function impairment score was 48 points with placebo plus exercise, while with LLLT plus exercise the mean function impairment score was 36 points on a 100-point scale (MD 12 points, 95 % CI: 6 to 18; absolute risk difference 12 %, 95 % CI: 6 to 18). Mean active abduction was 70 degrees with placebo plus exercise, while with LLLT plus exercise mean active abduction was 79 degrees (MD 9 degrees, 95 % CI: 2 to 16; absolute risk difference 5 %, 95 % CI: 1 % to 9 %). No participants in either group reported adverse events; LLLT's benefits on function were maintained at 4 months. Based on very low quality evidence from 6 trials, these investigators were uncertain whether therapeutic ultrasound, PEMF, continuous short-wave diathermy, Iodex phonophoresis, a combination of Iodex iontophoresis with continuous short-wave diathermy, or a combination of therapeutic ultrasound with TENS were effective adjuncts to exercise. Based on low or very low quality evidence from 12 trials, these researchers were uncertain whether a diverse range of electrotherapy modalities (delivered alone or in combination with manual therapy, exercise, or other active interventions) were more or less effective than other active interventions (e.g., glucocorticoid injection). The authors concluded that based upon low quality evidence from 1 trial, LLLT for 6 days may be more effective than placebo in terms of global treatment success at 6 days. Based upon moderate quality evidence from 1 trial, LLLT plus exercise for 8 weeks may be more effective than exercise alone in terms of pain up to 4 weeks and function up to 4 months. It is unclear whether PEMF is more or less effective than placebo, or whether other electrotherapy modalities are an effective adjunct to exercise. They stated that further high quality RCTs are needed to establish the benefits and harms of physical therapy interventions (that comprise electrotherapy modalities, manual therapy and exercise, and are reflective of clinical practice) compared to interventions with evidence of benefit (e.g., glucocorticoid injection or arthrographic joint distension).
TENS for Pain Management in Burn Persons
In a pilot study, Perez-Ruvalcaba and colleagues (2015) examined the effect of continuous and intermittent TENS on the perception of pain in patients with burns of different types. This study was conducted in 14 patients (aged 30.9 ± 7.5 years) with 2nd- and 3rd-degree burns of different types. The burn types included electrical, fire/flame, and chemical. All patients received continuous and intermittent TENS sessions 3 times per week for 4 weeks; each session had a duration of 30 minutes. A pair of electrodes were placed around the burn. The primary effectiveness endpoint was the perception of pain assessed by a VAS at baseline and at the 30th day. A significant reduction of pain perception was reported (8.0 ± 1.7 versus 1.0 ± 0.5; p = 0.027) by all patients after TENS therapy. There were no reports of adverse events during the intervention period. The authors concluded that TENS could be a potential non-pharmacological therapeutic option for pain management in burn patients. These preliminary findings need to be validated by well-designed studies.
TENS for Peripheral Arterial Disease
- one group received high-frequency TENS; and
- (the 2nd group received low-frequency TENS.
Measures taken were initial claudication distance, functional claudication distance and absolute claudication distance. The McGill Pain Questionnaire (MPQ) vocabulary was completed at the end of the intervention and the MPQ-Pain Rating Index score was calculated. Four participants were excluded from the final analysis because of non-completion of the experimental procedure. Median walking distance increased with high-frequency TENS for all measures (p < 0.05, Wilcoxon signed rank test, all measures). Only absolute claudication distance increased significantly with low-frequency TENS compared with placebo (median of 179 to 228; Ws = 39; z = 2.025; p = 0.043; r = 0.48). No difference was observed between reported median MPQ-Pain Rating Index scores: 21.5 with placebo TENS and 21.5 with active TENS (p = 0.41). The authors concluded that TENS applied to the lower limb of the patients with PAD and IC was associated with increased walking distance on a treadmill; but not with any reduction in pain. They stated that TENS may be a useful adjunctive intervention to help increase walking performance in patients with IC.
TENS for Post-Total Knee Arthroplasty Pain
Chughtai and associates (2016) noted that despite technological advances in total knee arthroplasty (TKA), management of post-operative muscle weakness and pain continue to pose challenges for both patients and health care providers. Non-pharmacologic therapies, such as neuromodulation in the form of NMES and TENS, and other modalities, such as cryotherapy and pre-habilitation, have been highlighted as possible adjuncts to standard-of-care pharmacologic management to treat post-operative pain and muscle weakness. These researchers discussed existing evidence for neuromodulation in the treatment of pain and muscular weakness following TKA and shed light on other non-invasive and potential future modalities. The review of the literature demonstrated that NMES, pre-habilitation, and some specialized exercises are beneficial for post-operative muscle weakness and TENS, cooling therapies, and compression may help to alleviate post-TKA pain. However, there are no clear guidelines for the use of these modalities. The authors concluded that further studies should be aimed at developing guidelines or delineating indications for neuromodulation and other non-pharmacologic therapies in the management of post-TKA pain and muscle weakness.
TENS for Rotator Cuff Disease
In a Cochrane review, Page and colleagues (2016) synthesized available evidence regarding the benefits and harms of electrotherapy modalities for the treatment of people with rotator cuff disease. These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), Ovid Medline (January 1966 to March 2015), Ovid Embase (January 1980 to March 2015), CINAHL Plus (EBSCOhost, January 1937 to March 2015), ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to March 2015, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. They included RCTs and quasi-randomized trials, including adults with rotator cuff disease (e.g., calcific tendinitis, rotator cuff tendinitis, and subacromial impingement syndrome), and comparing any electrotherapy modality with placebo, no intervention, a different electrotherapy modality or any other intervention (e.g., glucocorticoid injection). Trials investigating whether electrotherapy modalities were more effective than placebo or no treatment, or were an effective addition to another physical therapy intervention (e.g., manual therapy or exercise) were the main comparisons of interest. Main outcomes of interest were overall pain, function, pain on motion, patient-reported global assessment of treatment success, quality of life and the number of participants experiencing adverse events. Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. These researchers included 47 trials (2,388 participants). Most trials (n = 43) included participants with rotator cuff disease without calcification (4 trials included people with calcific tendinitis); 16 (34 %) trials investigated the effect of an electrotherapy modality delivered in isolation. Only 23 % were rated at low risk of allocation bias, and 49 % were rated at low risk of both performance and detection bias (for self-reported outcomes). The trials were heterogeneous in terms of population, intervention and comparator, so none of the data could be combined in a meta-analysis. In 1 trial (61 participants; low quality evidence), pulsed therapeutic ultrasound (US) (3 to 5 times a week for 6 weeks) was compared with placebo (inactive US therapy) for calcific tendinitis. At 6 weeks, the mean reduction in overall pain with placebo was -6.3 points on a 52-point scale, and -14.9 points with US (MD -8.60 points, 95 % CI: -13.48 to -3.72 points; absolute risk difference 17 %, 7 % to 26 % more). Mean improvement in function with placebo was 3.7 points on a 100-point scale, and 17.8 points with US (MD 14.10 points, 95 % CI: 5.39 to 22.81 points; absolute risk difference 14 %, 5 % to 23 % more); 91 % (29/32) of participants reported treatment success with US compared with 52 % (15/29) of participants receiving placebo (RR 1.75, 95 % CI: 1.21 to 2.53; absolute risk difference 39 %, 18 % to 60 % more). Mean improvement in quality of life with placebo was 0.40 points on a 10-point scale, and 2.60 points with US (MD 2.20 points, 95 % CI: 0.91 points to 3.49 points; absolute risk difference 22 %, 9 % to 35 % more). Between-group differences were not important at 9 months. No participant reported adverse events. Therapeutic US produced no clinically important additional benefits when combined with other physical therapy interventions (8 clinically heterogeneous trials, low quality evidence). The authors were uncertain whether there were differences in patient-important outcomes between US and other active interventions (manual therapy, acupuncture, glucocorticoid injection, glucocorticoid injection plus oral tolmetin sodium, or exercise) because the quality of evidence is very low; 2 placebo-controlled trials reported results favoring LLLT up to 3 weeks (low quality evidence), however combining LLLT with other physical therapy interventions produced few additional benefits (10 clinically heterogeneous trials, low quality evidence). These researchers were uncertain whether TENS was more or less effective than glucocorticoid injection with respect to pain, function, global treatment success and active range of motion (ROM) sooner because of the very low quality evidence from a single trial. In other single, small trials, no clinically important benefits of PEMF, MENS, acetic acid iontophoresis and microwave diathermy were observed (low or very low quality evidence). No adverse events of therapeutic US, LLLT, TENS or microwave diathermy were reported by any participants. Adverse events were not measured in any trials investigating the effects of PEMF, MENS or acetic acid iontophoresis. The authors concluded that based on low quality evidence, therapeutic US may have short-term benefits over placebo in people with calcific tendinitis, and LLLT may have short-term benefits over placebo in people with rotator cuff disease. They stated that further high quality placebo-controlled trials are needed to confirm these results. In contrast, based on low quality evidence, PEMF may not provide clinically relevant benefits over placebo, and therapeutic US, LLLT and PEMF may not provide additional benefits when combined with other physical therapy interventions. The authors were uncertain if TENS is superior to placebo, and whether any electrotherapy modality provides benefits over other active interventions (e.g., glucocorticoid injection) because of the very low quality of the evidence. They stated that practitioners should communicate the uncertainty of these effects and consider other approaches or combinations of treatment. The authors stated that further trials of electrotherapy modalities for rotator cuff disease should be based upon a strong rationale and consideration of whether or not they would alter the conclusions of this review.
Desmeules et al (2016) performed a systematic review on the effectiveness of TENS for the treatment of rotator cuff tendinopathy in adults. A literature search was conducted in 4 databases (CINAHL, Embase, PubMed and PeDRO) for RCTs published from date of inception until April 2015, comparing the effectiveness of TENS for the treatment of rotator cuff tendinopathy with placebo or any other intervention. Risk of bias was evaluated using the Cochrane risk of bias tool; results were summarized qualitatively. A total of 6 studies were included in this review. The mean methodological score was 49 % (standard deviation 16 %), indicating an overall high risk of bias. One placebo-controlled trial reported that a single TENS session provided immediate pain reduction for patients with rotator cuff tendinopathy, but did not follow the participants in the short-, medium- or long-term. Two trials that compared US therapy with TENS reported discrepancy and contradictory results in terms of pain reduction and shoulder ROM. Corticosteroid injections were found to be superior to TENS for pain reduction in the short-term, but the differences were not clinically important. Other studies included in this review concluded that TENS was not superior to heat or pulsed radiofrequency. The authors concluded that due to the limited number of studies and the overall high risk of bias of the studies included in this review, no conclusions can be drawn on the effectiveness of TENS for the treatment of rotator cuff tendinopathy. They stated that more methodologically sound studies are needed to document the effectiveness of TENS; until then, clinicians should prefer other evidence-based rehabilitation interventions proven to be effective to treat patients with rotator cuff tendinopathy.
TENS for Chemotherapy-Induced Peripheral Neuropathy
- active or
- (placebo stimulation.
All patients were evaluated for pain, numbness/tingling, frequency of symptoms, and quality of life. The TENS device was applied daily with modulating frequencies ranging between 7-Hz and 65-Hz in distal limb regions during 3 cycles of chemotherapy (45 days). The other stimulation parameters were: pulse duration of 200 μsec, intensity at the highest tolerable level, and increases in intensity when it diminished. The data showed no difference between active or placebo groups in terms of pain, numbness/tingling, frequency of symptoms or impact on daily life activities. The authors concluded that these results suggested that TENS applied in the frequency variation mode was not proven to be effective to improve the symptoms of CIPN during chemotherapy cycles. There was no worsening of symptoms in subsequent cycles of the onset of symptoms of the disease.
In a systematic review, Wang et al (2022) examined the best available evidence regarding the use of non-invasive neuromodulation techniques for the management of patients with CIPN. These investigators carried out a systematic literature search of the following databases from their inception to October 17, 2021; and was updated on March 2, 2022: AMED via Ovid, CINAHL via the EBSCO Host, Cochrane Library, Embase, PEDro, PubMed, and Web of Science; RCTs and quasi-experimental studies examining the safety, feasibility, and effectiveness of non-invasive neuromodulation techniques for managing established CIPN were identified. Narrative synthesis was used to analyze data collected from the included studies. A total of 9 RCTs and 9 quasi-experimental studies were included. A variety of non-invasive peripheral and central neuromodulation techniques were examined in those studies, including scrambler therapy, electrical stimulations, photo-biomodulation, magnetic field therapy, therapeutic US, neurofeedback, and repetitive tMS. Non-invasive neuromodulation techniques for the management of established CIPN are generally safe and feasible. The effectiveness of peripheral neuromodulation techniques such as scrambler therapy and TENS was mostly unsatisfactory, while central neuromodulation techniques such as neurofeedback and repetitive tMS were promising. The authors concluded that the use of non-invasive neuromodulation techniques for managing CIPN is still in its infancy. Non-invasive central neuromodulation techniques have significant potential for relieving chronic pain and neuropathic symptoms related to CIPN, warrant further investigation.
Puskulluoglu et al (2022) noted that patients with malignancies experience pain and CIPN. These researchers carried out a systematic review to find research examining the effect of TENS on these 2 common symptoms decreasing the QOL in cancer patients. PubMed, the Cochrane Central Register of Controlled Trials and Embase were searched. Original studies, namely RCTs, quasi-RCTs and controlled clinical trials, published between April 2007 and May 2020, were considered. The quality of the selected studies was examined. A total of 7 studies (260 patients) were incorporated in a qualitative synthesis. The studies varied in terms of design, populations, endpoints, quality, treatment duration, procedures and follow-up period. Based on the results, no strict recommendations concerning TENS usage in the cancer patient population could be issued. However, the existing evidence allowed these investigators to state that TENS is a safe procedure that may be self-administered by the patients with malignancy in an attempt to relieve different types of pain. Moreover, these researchers stated that there is a need for randomized, multi-center studies with a good methodological design and adequate sample size to be performed.
TENS for Fibromyalgia
In a Cochrane review, Johnson and colleagues (2017) evaluated the effectiveness and adverse events of TENS alone or added to usual care (including exercise) compared with placebo (sham) TENS; no treatment; exercise alone; or other treatment including medication, electro-acupuncture, warmth therapy, or hydrotherapy for fibromyalgia in adults. These investigators searched the following electronic databases up to January 18, 2017: CENTRAL (CRSO); Medline (Ovid); Embase (Ovid); CINAHL (EBSCO); PsycINFO (Ovid); LILACS; PEDRO; Web of Science (ISI); AMED (Ovid); and SPORTDiscus (EBSCO). They also searched 3 trial registries. There were no language restrictions. These researchers included RCTs or quasi-randomized trials of TENS treatment for pain associated with fibromyalgia in adults. They included cross-over and parallel-group trial designs. They included studies that evaluated TENS administered using non-invasive techniques at intensities that produced perceptible TENS sensations during stimulation at either the site of pain or over nerve bundles proximal (or near) to the site of pain. The authors included TENS administered as a sole treatment or TENS in combination with other treatments, and TENS given as a single treatment or as a course of treatments. Two review authors independently determined study eligibility by assessing each record and reaching agreement by discussion. A 3rd review author acted as arbiter. These researchers did not anonymize the records of studies before assessment. Two review authors independently extracted data and assessed risk of bias of included studies before entering information into a “Characteristics of included studies” table. Primary outcomes were participant-reported pain relief from baseline of 30 % or greater or 50 % or greater, and Patient Global Impression of Change (PGIC). These investigators assessed the evidence using GRADE and added “Summary of findings” tables. The authors included 8 studies (7 RCTs, 1 quasi-RCT, 315 adults (299 women), aged 18 to 75 years): 6 used a parallel-group design and 2 used a cross-over design. Sample sizes of intervention arms were 5 to 43 subjects. Two studies, 1 of which was a cross-over design, compared TENS with placebo TENS (82 participants), 1 study compared TENS with no treatment (43 subjects), and 4 studies compared TENS with other treatments (medication (2 studies, 74 participants), electro-acupuncture (1 study, 44 participants), superficial warmth (1 cross-over study, 32 subjects), and hydrotherapy (1 study, 10 participants)). Two studies compared TENS plus exercise with exercise alone (98 participants, 49 per treatment arm). None of the studies measured participant-reported pain relief of 50 % or greater or PGIC. Overall, the studies were at unclear or high risk of bias, and in particular all were at high risk of bias for sample size. Only 1 study (14 participants) measured the primary outcome participant-reported pain relief of 30 % or greater; 30 % achieved 30 % or greater reduction in pain with TENS and exercise compared with 13 % with exercise alone. One study found 10/28 participants reported pain relief of 25 % or greater with TENS compared with 10/24 participants using superficial warmth (42 °C). These researchers judged that statistical pooling was not possible because there were insufficient data and outcomes were not homogeneous. There were no data for the primary outcomes participant-reported pain relief from baseline of 50 % or greater and PGIC. There was a paucity of data for secondary outcomes. One pilot cross-over study of 43 subjects found that the mean (95 % CI) decrease in pain intensity on movement (100-mm VAS) during one 30-min treatment was 11.1 mm (95 % CI: 5.9 to 16.3) for TENS and 2.3 mm (95 % CI: 2.4 to 7.7) for placebo TENS. There were no significant differences between TENS and placebo for pain at rest. One parallel group study of 39 participants found that mean ± standard deviation (SD) pain intensity (100-mm VAS) decreased from 85 ± 20 mm at baseline to 43 ± 20 mm after 1 week of dual-site TENS; decreased from 85 ± 10 mm at baseline to 60 ± 10 mm after single-site TENS; and decreased from 82 ± 20 mm at baseline to 80 ± 20 mm after 1 week of placebo TENS. The authors of 7 studies concluded that TENS relieved pain but the findings of single small studies are unlikely to be correct. One study found clinically important improvements in Fibromyalgia Impact Questionnaire (FIQ) subscales for work performance, fatigue, stiffness, anxiety, and depression for TENS with exercise compared with exercise alone. One study found no additional improvements in FIQ scores when TENS was added to the first 3 weeks of a 12-week supervised exercise program. No serious adverse events were reported in any of the studies although there were reports of TENS causing minor discomfort in a total of 3 participants. The quality of evidence was very low. These investigators downgraded the GRADE rating mostly due to a lack of data; thus, they had little confidence in the effect estimates where available. The authors concluded that there was insufficient high-quality evidence to support or refute the use of TENS for fibromyalgia. They found a small number of inadequately powered studies with incomplete reporting of methodologies and treatment interventions.
TENS for Musculoskeletal Pain in Hemophilia
- pharmacologic management,
- physical medicine and rehabilitation, and
- intra-articular injections.
As for pharmacologic management, NSAIDs (ibuprofen, diclofenac, celecoxib, robecoxib) are better than paracetamol. The advantages of tramadol or tramadol/paracetamol and non-tramadol opioids are scanty. With respect to physical medicine and rehabilitation, there is insufficient confirmation that a brace has supplementary favorable effect compared with isolated pharmacologic management. Land-based curative exercise and watery exercise have at the minimum a tiny short-run benefit. Curative ultrasound can be helpful (poor quality of evidence). The effectiveness of TENS for pain mitigation has not been proven. Electrical stimulation treatment can procure notable ameliorations. With respect to intra-articular injections, viscosupplementation appears to be a useful method for pain alleviation in the short-run (months). The short-run (weeks) advantage of intra-articular corticosteroids in the treatment of joint pain has been shown.
Interferential Stimulation
Interferential stimulation (IFS) is characterized by 2 alternating-current sine waves of differing frequencies that "work" together to produce an interferential current that is also known as a beat pulse or alternating modulation frequency. One of the 2 currents is usually held at 4,000 Hz, and the other can be held constant or varied over a range of 4,001 to 4,100 Hz. Interferential currents reportedly can stimulate sensory, motor, and pain fibers. Because of the frequency, the interferential wave meets low impedance when crossing the skin to enter the underlying tissue. This deep tissue penetration can be adjusted to stimulate parasympathetic nerve fibers for increased blood flow. According to proponents, interferential stimulation differs from TENS because it allows a deeper penetration of the tissue with more comfort (compliance) and increased circulation.
- pain and use of pain medications,
- edema and inflammation, and
- healing time, as well as in improving range of motion, and activity levels, and quality of life.
- active ET plus active US;
- active ET plus dummy US;
- dummy ET plus active US;
- dummy ET plus dummy US; or
- no adjuvants.
Additionally, they received a maximum of 12 sessions of exercise therapy in 6 weeks. Measurements at baseline, 6 weeks and 3, 6, 9, and 12 months later were blinded for treatment. Outcome measures: recovery, functional status, chief complaint, pain, clinical status, and range of motion. At the 6th-week, 7 patients (20 %) without adjuvants reported very large improvement (including complete recovery), 17 (23 %) and 16 (22 %) with active and dummy ET, and 19 (26 %) and 14 (19 %) with active and dummy US. These proportions increased to about 40 % at the 3rd-months, but remained virtually stable thereafter. The authors concluded that neither ET nor US proved to be effective as adjuvants to exercise therapy for soft tissue shoulder disorders. Jarit et al (2003) concluded that home IFS may help reduce pain, pain medication taken, and swelling while increasing range of motion in patients undergoing knee surgery. This could result in quicker return to activities of daily living and athletic activities. Drawbacks of this study were as follows:
- while placebo subjects did consume more medications at all time points, the difference was only at some points, and
- a functional assessment scale was not used.
The findings of this study need to be validated by further investigation. Furthermore, a technology assessment by the California Technology Assessment Forum (CTAF, 2005) concluded that interferential stimulation does not meet CTAF’s assessment criteria.
A review on non-pharmacological therapies (including IFS) for acute and chronic LBP by the American Pain Society and the American College of Physicians (Chou et al, 2007) concluded that therapies with good evidence of moderate efficacy for chronic or sub-acute LBP are cognitive-behavioral therapy, exercise, spinal manipulation, and inter-disciplinary rehabilitation. For acute LBP, the only therapy with good evidence of efficacy is superficial heat.
Guidelines on treatment of LBP from the National Collaborating Centre for Primary Care (Savigny et al, 2009) found insufficient evidence for the use of interferential stimulation in LBP and recommended against its use for that indication.
In a systematic review and meta-analysis, Fuentes et al (2010) analyzed the available information regarding the efficacy of IFS in the management of musculoskeletal pain. Randomized controlled trials were obtained through a computerized search of bibliographic databases (i.e., CINAHL, Cochrane Library, EMBASE, MEDLINE, PEDro, Scopus, and Web of Science) from 1950 to February 8, 2010. Two independent reviewers screened the abstracts found in the databases. Methodological quality was assessed using a compilation of items included in different scales related to rehabilitation research. The mean difference, with 95 % confidence interval (CI), was used to quantify the pooled effect. A chi-square test for heterogeneity was performed. A total of 2,235 articles were found. A total of 20 studies fulfilled the inclusion criteria; 7 articles assessed the use of IFS on joint pain; 9 articles evaluated the use of IFS on muscle pain; 3 articles evaluated its use on soft tissue shoulder pain; and 1 article examined its use on post-operative pain. Three of the 20 studies were considered to be of high methodological quality, 14 studies were considered to be of moderate methodological quality, and 3 studies were considered to be of poor methodological quality. Fourteen studies were included in the meta-analysis. The authors concluded that IFS as a supplement to another intervention seems to be more effective for reducing pain than a control treatment at discharge and more effective than a placebo treatment at the 3-month follow-up. However, it is unknown whether the analgesic effect of IFS is superior to that of the concomitant interventions. Interferential current alone was not significantly better than placebo or other therapy at discharge or follow-up. Results must be considered with caution due to the low number of studies that used IFS alone. In addition, the heterogeneity across studies and methodological limitations prevent conclusive statements regarding analgesic efficacy.
Percutaneous Electrical Nerve Stimulation (PENS)
Percutaneous electrical nerve stimulation uses acupuncture-like needles as electrodes. These needles are placed in the soft tissues or muscles at dermatomal levels corresponding to local pathology (needles are usually inserted above and below and into the central area of pain). A 5-Hz frequency with a pulse width of 0.5 mS is usually used. If relief is not attained within 15 minutes, the frequency may be lowered to 1 Hz. According to PENS proponents, the main advantage of PENS over TENS is that it bypasses the local skin resistance and delivers electrical stimuli at the precisely desired level in close proximity to the nerve endings located in soft tissue, muscle, or periosteum of the involved dermatomes.
- define the intervention,
- collect evidence,
- synthesize results,
- make recommendations based on the research, and
- grade the strength of the recommendations.
Outpatient adults with low back, knee, neck, or shoulder pain without vertebral disk involvement, scoliosis, cancer, or pulmonary, neurological, cardiac, dermatological, or psychiatric conditions were included in the review. To prepare the data, systematic reviews were performed for low back, knee, neck, and shoulder pain. Therapeutic exercise, massage, transcutaneous electrical nerve stimulation, thermotherapy, ultrasound, electrical stimulation, and combinations of these therapies were included in the literature search. Studies were identified and analyzed based on study type, clinical significance, and statistical significance. The authors concluded that the Philadelphia Panel guidelines recommend continued normal activity for acute, uncomplicated LBP and therapeutic exercise for chronic, subacute, and post-surgical LBP; TENS and exercise for knee osteoarthritis; proprioceptive and therapeutic exercise for chronic neck pain; and the use of therapeutic ultrasound in the treatment of calcific tendonitis of the shoulder.
Weiner and Ernst (2004) reviewed common complementary and alternative treatment modalities for the treatment of persistent musculoskeletal pain in older adults. A critical review of the literature on acupuncture and related modalities, herbal therapies, homeopathy, and spinal manipulation was carried out. Review included 678 cases within 21 randomized trials and 2 systematic reviews of herbal therapies: 798 cases within 2 systematic reviews of homeopathy; 1,059 cases within 1 systematic review of spinal manipulation for LBP, and 419 cases within 4 randomized controlled trials for neck pain. The review of acupuncture and related modalities was based upon a paucity of well-controlled studies combined with the authors' clinical experience. Insufficient experimental evidence exists to recommend the use of traditional Chinese acupuncture over other modalities for older adults with persistent musculoskeletal pain. Promising preliminary evidence exists to support the use of percutaneous electrical nerve stimulation for persistent LBP. The authors noted that while the use of complementary and alternative modalities for the treatment of persistent musculoskeletal pain continues to increase, rigorous clinical trials examining their effectiveness are needed before definitive recommendations regarding the application of these modalities can be made.
A Cochrane review on electrotherapy for mechanical neck disorders (Kroeling et al, 2005) evaluated if electrotherapy relieves pain or improves function/disability in adults with mechanical neck disorders (MND). For the pain outcome, there was limited evidence of benefit, i.e., pulsed electromagnetic field (PEMF) therapy resulted in only immediate post-treatment pain relief for chronic MND and acute whiplash (WAD). Other findings included unclear or conflicting evidence (galvanic current for acute or chronic occipital headache; iontophoresis for acute, subacute WAD; TENS for acute WAD, chronic MND; PEMF for medium- or long-term effects in acute WAD, chronic MND); and limited evidence of no benefit (diadynamic current for reduction of trigger point tenderness in chronic MND, cervicogenic headache; permanent magnets for chronic MND; electrical muscle stimulation (EMS) for chronic MND). The authors concluded that in pain as well as other outcomes, the evidence for treatment of acute or chronic MND by different forms of electrotherapy is either lacking, limited, or conflicting.
The National Institute for Health and Clinical Excellence’s assessment on “Percutaneous electrical nerve stimulation for refractory neuropathic pain” (NICE, 2013) stated that “Current evidence on the safety of percutaneous electrical nerve stimulation (PENS) for refractory neuropathic pain raises no major safety concerns and there is evidence of efficacy in the short term. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit”.
Fraser and Woodbury (2017) stated that fibromyalgia and complex regional pain syndrome (CRPS) are both chronic pain syndromes with pathophysiologic mechanisms related to autonomic nervous system (ANS) dysregulation and central sensitization. Both syndromes are considered difficult to treat with conventional pain therapies. These investigators described a female veteran with fibromyalgia and a male veteran with CRPS, both of whom failed multiple pharmacologic, physical and psychological therapies for pain, but responded to percutaneous electrical neural field stimulation (PENFS) targeted at the auricular branches of the cranial nerves. The authors concluded that while PENFS applied to the body has been previously described for treatment of localized pain, PENFS effects on cranial nerve branches of the ear was not well-known, particularly when used for regional and full-body pain syndromes such as those described here. They stated that PENFS of the ear is a minimally-invasive, non-pharmacologic therapy that could lead to improved quality of life (QOL) and decreased reliance on medication. However, they stated that further research is needed to guide clinical application, particularly in complex pain patients.
Percutaneous Neuromodulation
Percutaneous neuromodulation therapy (PNT) is a variation of PENS, but utilizes different electrical impulses than PENS; it utilizes an alternating low and high frequency current at varying pulse impulses (Washington State Department of Labor and Industries, 2004). The electrical stimulation is delivered via needle-like electrodes which is purported to allow the stimulation to reach the deep tissue. Examples of this type of device include, but may not be limited to, the Vertis PNT System and the BioWavePRO Neuromodulation Pain Therapy System. The Vertis PNT is for treatment of back pain; the BioWavePRO, however, is not limited to the spine but may also be used in other painful areas in the body. These devices are not for home use, but must be used by a healthcare provider, such as a physician or physical therapist, in a clinic or office setting.
Kang, et al. (2007) reported on a single-blinded pilot randomized controlled trial in 70 patients with knee osteoarthritis who were randomized to a BioWave Deepwave percutaneous neuromodulation device or to sham administered in a clinic over 30 minutes. Seven subjects assigned to sham were lost to follow-up. Pain intensity difference was the primary measure of efficacy in this trial. Pain intensity difference was defined as the difference in visual analog pain scale noted at pretreatment (baseline) versus the visual analog pain scale noted at each post-treatment period. The active group's pain intensity difference was statistically significantly greater than the sham group’s pain intensity difference by 9.5 mm immediately after treatment. The active group's pain intensity difference was also greater than the sham group's pain intensity difference by 5.0 mm, 9.0 mm, and 7.0 mm for the 6-, 24-, and 48-hour post-treatment periods, respectively, although the pain intensity difference was not statistically significant at these time points. Additionally, a nonsignificant trend was noted in improvement of the pain intensity difference in the live group as compared to the sham group 48 hours post-treatment. Limitations of this pilot study include single blinding, lack of testing of adequacy of blinding, and lack of intention-to-treat analysis. The authors concluded: "The results from this pilot phase may be used to design a broader multicenter study that will be powered to provide greater data points leading to broader conclusions as to the treatment efficacy of the percutaneous Deepwave device."
Peripherally Implanted Nerve Stimulation
In this particular treatment, an electrical current is transmitted via an electrode that has been implanted around the selected peripheral nerve. This electrical current purports to block or disrupt the normal transmission of pain signals. The electrodes are connected by a wire to the peripherally implanted neurostimulator (also known as an implantable subcutaneous target stimulator). An external generator (similar to a remote control device) controls the degree of stimulation the individual receives.
In an industry funded study, Deer, et al. (2016) reported on a crossover study of 94 patients with pain of peripheral origin were implanted and then randomized to the treatment with peripheral nerve stimulation (45) or the control group (49). The primary efficacy endpoint was response rate, defined as a 30 percent decrease in a numerical rating scale, with no upward titration in the patient's medication regimen, three months months after randomization to treatment. The investigators reported that patients receiving active stimulation achieved a statistically significantly higher response rate of 38% versus the 10% rate found in the control group (p = 0.0048). Improvement in pain was statistically significant between the randomized groups, with the treatment group achieving a mean pain reduction of 27.2% from baseline to month 3 compared to a 2.3% reduction in the control group (p < 0.0001). During the partial crossover period, patients again demonstrated statistically significant improvement in pain relief with active stimulation compared to baseline. Further, the treatment group had significantly better improvement than the control group in secondary measures including but not limited to quality of life and satisfaction. Safety, assessed throughout the trial and with follow-up to one year, demonstrated no serious adverse events related to the device. The investigators reported that all device-related adverse events were minor and self-limiting. Additional studies confirming these benefits are needed.
Shimada et al (2006) examined the ability to relieve shoulder pain by implanting ceramic-case versions of radiofrequency microstimulators (RFM) in paralyzed shoulder muscles. A 66-year old man, who had left-sided chronic hemiplegia due to a stroke 5 years previously, had developed shoulder subluxation resulting in pain. Two RFM devices were implanted, 1 next to the axillary nerve and 1 at the motor point of the middle deltoid muscle. Electrical stimulation at both sites was commenced 2 weeks after implantation for a 6-month period. Evaluation of the effectiveness of the RFM devices was carried out by measuring pain (using the VAS), ROM at the shoulder, strength of the deltoid muscle, degree of shoulder subluxation, and muscle atrophy. Following commencement of stimulation, follow-up evaluations were performed at 1,2, 3, 4, and 6 weeks, 3 and 6 months, and after 6 months of no stimulation. During the treatment period of 6 months of stimulation, the patient's pain had reduced from 70 to 0 on the VAS. At 6 months after completion of the treatment, pain relief and effective evoked muscle contraction have remained. The authors concluded that although these results suggested that the feasibility of using RFM devices implanted both epineurally to the axillary nerve and next to the muscle motor point in this 1 patient, to relieve pain and elicit contraction, further investigation is needed to demonstrate the clinical feasibility of using RFMs for treating post-stroke shoulder pain.
In a case-report, Nguyen et al (2015) described the 1st participant treated with a fully implantable, single-lead PNS system for refractory hemiplegic shoulder pain. During the 6-week trial stage, a temporary lead was placed percutaneously near the terminal branches of the axillary nerve to the deltoid. The primary outcome measure was the Brief Pain Inventory-Short Form Question 3, a 0 to 10 pain numeric rating scale (NRS). The participant experienced 75 % pain reduction and proceeded to the implantation stage, where he received a single-lead, implantable pulse generator. After 3 weeks, the participant became pain-free. However, 7 weeks after implantation, the system was turned off because of an unrelated acute medical illness. Hemiplegic shoulder pain re-emerged with a Brief Pain Inventory-Short Form Question 3 score of 9. After 11 weeks of recovery, PNS was re-initiated and the participant became pain-free through the 9-month follow-up. At 12 months, Brief Pain Inventory-Short Form Question 3 score was 1. The authors concluded that this case-report demonstrated the feasibility of a single-lead, fully implantable PNS system for refractory hemiplegic shoulder pain.
Wilson et al (2018) examined the feasibility and safety of a single-lead, fully implantable PNS system for the treatment of chronic shoulder pain in stroke survivors. Subjects had moderate-to-severe shoulder pain not responsive to conservative therapies for 6 months. During the trial phase, which included a blinded sham introductory period, a percutaneous single-lead PNS system was implanted to stimulate the axillary nerve of the affected shoulder. After a 3-week successful trial, subjects received an implantable pulse generator with an electrode placed to stimulate the axillary nerve of the affected shoulder. Outcomes included pain, pain interference, pain-free external rotation ROM, QOL, and safety; subjects were followed-up for 24 months. A total of 28 subjects underwent trial stimulation and 5 participants received an implantable pulse generator. Subjects who received the implantable generator experienced an improvement in pain severity (p = 0.0002). All 5 subjects experienced a 50 % or greater pain reduction at 6 and 12 months, and 4 experienced at least a 50 % reduction at 24 months. There was an improvement in pain interference (p < 0.0001). There was an improvement in pain-free external ROM (p = 0.003). There were no serious adverse event (AE) related to the device or to the procedure. The authors concluded that this case series demonstrated the safety and efficacy of a fully implantable axillary PNS system for chronic hemiplegic shoulder pain. Subjects experienced reduction in pain, reduction in pain interference, and improved pain-free external rotation ROM. There were no serious AEs associated with the system or the procedure.
Peripheral Subcutaneous Field Stimulation
Subcutaneous stimulation (peripheral nerve field stimulation/PNFS) is a novel neuromodulation modality that has increased in its utilization during the past decade. It consists of introducing a lead in the subdermal level to stimulate the small nerve fibers in that layer. Unlike other neuromodulation techniques including direct peripheral nerve stimulation, spinal cord stimulation (SCS), or deep brain stimulation, the precise target is not identified. Falco et al (2009) stated that relief of regional, non-appendicular pain, particularly LBP, through SCS has proven challenging. Recently, peripheral nerve stimulation (PNS), also known as PNFS depending on the stimulation area, has demonstrated efficacy for the treatment of well-localized, small areas of pain involving the abdomen, inguinal region, pelvis, face, occipital area, and low back. More widespread application of PNFS has been limited by its narrow field of coverage in a larger group of patients with diffuse or poorly localized pain.
McRoberts and Roche (2010) described a novel approach for the treatment of severe, chronic knee joint pain following total knee arthroplasty utilizing peripheral subcutaneous field stimulation (PSFS) and discussed the role of this treatment modality in patients with symptoms that are refractory to conventional pharmacologic, surgical, and physical therapies. These researchers presented 2 case reports of patients with chronic intractable knee pain where PNS via a permanent neurostimulating implant was introduced successfully. Both patients presented with persistent knee pain, for greater than 1 year, after having had total knee arthroplasty. Their symptoms failed to be alleviated by a variety of interventions including NSAIDS, oral anti-depressants, membrane stabilizers, opioids, physical therapy, surgical revisions, manipulation under anesthesia, local anesthetic patches, and TENS. In each case, direct stimulation of the knee was achieved utilizing a peripheral nerve stimulator via a peri-articular approach. Neuromodulation daily has produced both significant pain relief and functional improvement. Significant decreases in VAS pain scores and improvement in functional capacity were observed during the stimulation trial and during the follow-up after permanent implantation. The mean VAS score changed dramatically. The authors concluded that introduction of PSFS directly to the painful knee area is a novel and simple procedure that was extremely effective for the relief of pain and may provide a breakthrough in the treatment of chronic intractable knee pain following total knee arthroplasty. The peri-articular approach has several advantages, including only small incisions over the lateral and medial knee, proximal thigh and abdomen resulting in minimal strain on the lead array with flexion and extension contributing to overall stability of this system.
Yakovlev and Resch (2010) presented a case report describing application of PSFS to a patient with chronic intractable atypical facial pain (ATFP) that conventional treatment failed to ameliorate. The patient underwent an uneventful PSFS trial with percutaneous placement of 2 temporary 8-electrode leads (Medtronic Inc, Minneapolis, MN) placed subdermally over the left mandible. After experiencing excellent pain relief over the next 2 days, the patient was implanted with permanent leads and rechargeable generator 2 and a half weeks later and reported sustained pain relief at 12-month follow-up visit. Peripheral subcutaneous field stimulation provides an effective treatment option for patients suffering from chronic ATFP who have failed conservative treatment. The authors concluded that PSFS offers an alternative treatment option to select patients with intractable ATFP.
In a retrospective study, Yakovlev et al (2010) evaluated the effectiveness of PSFS for the treatment of chronic hip pain after total hip arthroplasty (THA) and greater trochanteric bursectomy (GTB). A total of 12 patients with chronic post-operative pain after THA and GTB underwent an uneventful PSFS trial with percutaneous placement of 2 temporary 8-electrode leads positioned in the subcutaneous tissue in the area of greatest pain, parallel to post-operative scar over the affected upper lateral thigh. After experiencing excellent pain relief over the next 2 days, the patients were implanted with permanent leads and rechargeable or non-rechargeable generator 2 to 4 weeks later. They reported sustained pain relief at 12-month follow-up visits. The authors concluded that PSFS provided an effective alternative treatment option for select patients with chronic post-operative pain after THA and GTB who have failed conservative treatment.
Ricciardo et al (2010) presented a case study to exemplify the application of PSFS in the treatment of recalcitrant notalgia paraesthetica. The patient was a 60-year old woman with severe and disabling notalgia paraesthetica. The itch persisted despite the use of several medications -- topical and oral. Following a successful trial of PSFS with a temporary electrode, 2 subcutaneous electrodes were inserted into the affected area with a battery implanted subcutaneously in her right buttock. The patient was reviewed at 5 months post-implantation. She reported a greater than 85 % improvement in her itch. She also reported a major improvement in her quality of life, with particular improvement in her ability to sleep through the night. This case illustrated the possible utilization of PSFS in the treatment of notalgia paraesthetica, which is a common yet poorly understood and treated condition. The authors stated that replication and controlled studies are needed to determine the general applicability of this approach.
Desai et al (2011) presented a novel approach to the treatment of thoracic radiculitis following Brown-Sequard syndrome with peripheral nerve field stimulation (PNFS). In addition, these investigators examined the role of PNFS in the management of refractory neuropathic pain conditions including post-traumatic and post-surgical neuropathy especially with regards to the post-surgical spine. They discussed the case of a 57-year-old man with history of thoracic microdiscectomy resulting in Brown-Sequard syndrome, who presented with chronic post-operative thoracic radicular pain radiating to the abdomen, refractory to conservative management. The patient underwent 3 intercostal nerve blocks from T7 to T9 with transient symptomatic relief. The patient's options were limited to chemo-modulation, neuromodulation, or selective intercostal nerve surgical neurectomy. He subsequently underwent a PNFS trial and reported greater than 75 % pain reduction. Permanent percutaneous PNFS electrodes were implanted subcutaneously over the right T7 and T9 intercostal nerves and replicated the trial results. Neuromodulation produced pain relief with greater than 90 % improvement in pain compared with baseline both during the trial and following permanent implantation of the PNFS system. The authors concluded that chronic radicular pain may be difficult to manage in the post-surgical patient and often requires the use of multiple therapeutic modalities. In this case, these researchers successfully used PNFS as it showed greater technical feasibility when compared with dorsal column stimulation and repeat surgery; thus, it may be considered for the management of post-surgical neuropathy. Moreover, these researchers stated that further controlled studies are needed to evaluate the effectiveness of PNFS as a therapeutic option.
Goroszeniuk et al (2012) reported the use of an alternative approach to neuromodulation of anginal pain using subcutaneous leads placed at the site of pain. In this case series, 5 patients with refractory angina received successful treatment with subcutaneous target stimulation -- peripheral subcutaneous field stimulation. This technique was able to provide good analgesia in 2 patients that had had poor pain relief from existing spinal cord stimulators. All 5 patients achieved significant pain relief with a reduction in symptoms and a decrease in the use of pain medication.
Burgher et al (2012) performed a retrospective review of consecutive patients evaluated from August 2009 to December 2010 who had undergone trial of subcutaneous (SQ) PNS with inter-lead stimulation for axial spine pain. Patients proceeding to implant were followed post-operatively with routine clinical visits and a survey form at last follow-up. Ultrasound was used intra-operatively to ensure placement of electrodes at the appropriate depth in patients with larger body mass index. Primary outcome was patient-reported pain relief at last follow-up. Literature review was conducted by searching MEDLINE (1948 to present) and through an unstructured review by the authors. A total of 10 patients underwent trial of SQ PNS and 6 proceeded to permanent implantation; 3 of the 6 (50 %) implanted patients preferred neurostimulation programming that included inter-lead stimulation ("cross-talk"). Average duration of post-operative follow-up was 4.5 months (range of 2 to 9 months). Average patient-reported pain relief at last follow-up was 45 % (range of 20 to 80 %). One patient required re-operation for migration. Patients not proceeding to implant had paresthesia coverage but no analgesia. The authors concluded that SQ PNS is a promising therapy for axial neck and back pain based on a small cohort of patients. Ultrasound was useful to assist with electrode placement at the most appropriate depth beneath the skin. While inter-lead stimulation has been preferred by patients in published reports, these investigators did not find it clearly influenced pain relief. The authors stated that future investigations should include a randomized, controlled study design, as well as defined implantation technique and neurostimulator programming algorithms.
In a retrospective, multi-center, open label, uncontrolled pilot study, Miranda and Taca (2018) examined the effects of the BRIDGE, a non-invasive, percutaneous electrical nerve field stimulator, on withdrawal scores during the induction phase of opioid withdrawal therapy; and the percentage of subjects who successfully transitioned to medication assisted therapy (MAT). Adult patients treated with the BRIDGE during medically supervised withdrawal were included in this study. The clinical opioid withdrawal scale (COWS) scores were prospectively recorded at different intervals (20, 30, and 60 mins) and analyzed; a subset of patients had scores recorded 5-days post-BRIDGE. Participants who returned to the clinic and received their 1st dose of maintenance medication were considered to be successfully transitioned. In this cohort (n = 73; age greater than or equal to 18 years), 65 % were men. The mean COWS score before BRIDGE placement was 20.1 (± 6.1); 20 mins after BRIDGE placement, the mean score was reduced to 7.5 (± 5.9) (62.7 % reduction, p < 0.001). The scores were further reduced after 30 mins 4.0 (± 4 .4) and 60 mins 3.1 (± 3.4) (84.6 % reduction, p < 0.001). No rescue medications were given during this period. The mean withdrawal score on day 5 was 0.6 (97.1 % reduction, n = 33; p < 0.001). Overall, 64/73 patients (88.8 %) successfully transitioned to MAT. The authors concluded that neurostimulation with the BRIDGE was associated with a reduction in opioid withdrawal scores; and this effect persisted during the induction period and allowed for effective transition to MAT. These preliminary findings from a pilot study need to be validated by well-designed studies.
The authors stated that drawbacks of this study included the uncontrolled, retrospective study design, and the relatively small sample size (n = 73). While randomized, placebo-controlled trials have the highest level of validity, most participants in this study presented in moderate-to-severely moderate withdrawal. The concern of using a placebo or sham device in such a vulnerable population must be taken into consideration in future studies. While the data in this study were collected retrospectively, the objective and subjective COWS scores were all recorded prospectively during intervals of clinical care. This eliminated recall bias and helped establish the temporal relationship of the findings. Another drawback of this study was that the potential presence of psychiatric disorders other than opioid dependence and more precise drug use patterns could not be included in the analysis. Studies suggested that perhaps the types of drugs used or the presence of other psychiatric disorders could influence treatment outcomes. Although a large percentage of subjects successfully transitioned to MAT, the study took place in an out-patient setting, therefore, it did not allow the researchers to record withdrawal scores or the use of adjunct medications between day 1 and day 5. Finally, the study design did not allow for long-term follow-up, which was also an important drawback.
H-Wave Stimulation
H-Wave stimulation is a form of electrical stimulation that differs from other forms of electrical stimulation in terms of its waveform. The H-wave produces low frequency muscle stimulation and high frequency pain control. H-wave stimulation has been purported for use in pain control for conditions such as complex regional pain syndrome (reflex sympathetic dystrophy), muscle sprains, temporomandibular joint dysfunctions or treatment of diabetic neuropathy.
H-wave stimulation delivers electrical stimulation in the form of milliamperage. H-wave stimulation is intended to emulate the H waveform found in nerve signals (Hoffman Reflex) and therefore enables greater and deeper penetration of a low frequency current, while using significantly less power than other machines. This allegedly makes H-Wave stimulation much safer, less painful and more effective than other forms of electrotherapy to date. The H-wave signal is a bipolar, exponential decaying waveform that supposedly overcomes the disadvantages of other electrotherapy machines. It allows the therapist to apply 2 treatments at the same time:
- low-frequency muscle stimulation and
- high-frequency deep analgesic pain control (a "TENS" effect).
Note: H-wave stimulation must be distinguished from the H-waves that are a component of electromyography.
- H-wave stimulation, or
- sham treatment.
The authors reported that H-wave treated patients exhibited greater symptomatic relief than their sham-treated counterparts. Moreover, it has also been shown that H-wave stimulation may be a useful adjunctive modality when combined with pharmacotherapy (e.g., amitriptyline) to augment symptomatic relief in patients with diabetic peripheral neuropathy (Julka et al, 1998; McDowell et al, 1999).
On the other hand, H-wave stimulators have not been shown to be effective in reducing pain from causes other than chronic diabetic peripheral neuropathy, or in reducing edema or swelling. In particular, H-wave stimulation has not been demonstrated to be effective in treating chronic pain due to ischemia. In the study by Kumar and Marshall (1997), patients with significant peripheral vascular disease were excluded from the trial. Furthermore, in a randomized controlled study (n = 112), McDowell et al (1995) reported that H-wave stimulation was not effective in reducing experimental ischemic pain.
A systematic evidence review concluded that H-wave stimulation had a moderate to strong effects in relieving pain, reducing pain medication use and increasing functionality in patients with chronic soft tissue inflammation or neuropathic pain (Blum et al, 2008). A critique of this systematic evidence review by the Centre for Reviews and Dissemination (CRD, 2009) concluded that "it is not possible to determine whether the results of this review are reliable" given its significant methodologic limitations. In particular, very limited details of the included studies were given in the review; in particular it was unclear which studies were randomized, no control interventions were detailed, and there were insufficient details on the outcome measures used. Although a validity assessment was performed, the results were not presented. "Given these omissions, it is difficult to assess either the internal or external validity of the results." The CRD noted that the authors of the systematic evidence review used meta-analysis to combine the results, but different measures of effect appeared to be combined in a single effect size. Insufficient details on the outcome measures used in the included studies meant that it was not possible to determine if this was appropriate or not. The CRD critique noted that, in addition to four authors of the systematic evidence review being independent consultants for Electronic Waveform Lab (the makers of the H-Wave device), 2 authors were members of the research groups responsible for conducting the primary studies.
Intramuscular Stimulation
Intramuscular stimulation can be considered as a variation of acupuncture. It has been claimed to promote long-term relief in chronic neuropathic pain. Intramuscular stimulation utilizes the same sized needles as in acupuncture; they are inserted into the part of a shortened muscle where a nerve may be entrapped. This most often causes some local pain as the needle is re-inserted several times to release the nerve and lengthen the muscle. In general, treatments are administered once or twice weekly for 3 to 6 weeks. However, the clinical value of this invasive procedure has not been validated by randomized controlled studies.
Sympathetic Therapy (Dynatron)
Many chronic pain syndromes/conditions (e.g., peripheral neuropathies and reflex sympathetic dystrophy) are "sympathetically biased" and have no identifiable underlying cause(s).
Sympathetic Therapy is a non-invasive treatment protocol advocated for the symptomatic relief of patients with chronic pain. It is a patented method of delivering electrostimulation via peripheral nerves to create a "special" form of stimulation of the sympathetic nervous system. It incorporates dual interfering waveforms with specific electrode placement on the upper and lower extremities (8 electrodes/treatment). Electrodes are placed bilaterally over dermatomes, thus accessing the autonomic nervous system via the peripheral nervous system.
The treatment plan for Sympathetic Therapy includes clinical treatments followed by home therapy. Electrostimulation is administered by means of the Dynatron STS (a clinical unit) or the Dynatron STS Rx (a home unit). A software program is included with the clinical Dynatron unit to help doctors with electrode placement and to record patient progress. According to the manufacturer, electrostimulation delivered by the Dynatron is different from that provided by TENS. The key difference is in its application -- Dynatron applied within the Sympathetic Therapy protocol supposedly treats systemically while TENS treats transcutaneously at or near the primary pain location. Daily therapy sessions are needed to establish effectiveness of the treatment and to ascertain the most effective protocol for individual patients (20 or more sessions may be needed to complete this process). Each treatment session lasts about 60 mins. If the patient responds to treatment and the optimal protocol has been established, a home Dynatron unit may be prescribed to facilitate treatments over an extended period of time and, in most cases, indefinitely. If necessary, the patient may return to the clinic periodically for a follow-up visit to adjust the protocol or receive additional guidance in administering home therapy.
Guido (2002) reported on the effects of Sympathetic Therapy on 20 patients with chronic pain and peripheral neuropathies. Subjects were treated daily with the Dynatron STS for 28 days. At the beginning of the study, 11 of 15 patients reported being in moderate to severe pain, whereas by the end of treatment, 5 of 15 patients defined their pain as being moderate to severe. For these 15 patients, mean cumulative VAS for multiple locations of pain decreased significantly, from 107.8 to 45.3. (The authors stated, without further explanation, that self-reports of pain severity were unavailable for 5 of the 20 patients.) However, because the study did not include a randomized masked control group, placebo effects and other biases could affect results. In addition, the lack of data on pain severity in a quarter of the patients included in this study may have significantly biased the results. There are no published randomized controlled clinical trials of the effectiveness of Sympathetic Therapy in the management of patients with chronic intractable pain. Randomized controlled trials are needed to ascertain the clinical benefits of this treatment protocol in these patients.
An assessment (2003) conducted by the Washington State Department of Labor and Industries concluded that insufficient evidence exists to determine Dynatron STS’ effectiveness in the treatment of chronic pain.
Guidelines on management of chronic pain from the Work Loss Data Institute (2008) considered, but did not recommend, sympathetic therapy for chronic pain.
Electroceutical Therapy
Electroceutical therapy is a noninvasive device that uses a variety of electrical modalities as a proposed treatment for acute and chronic pain. The device is similar to TENS, except electroceutical treatments use higher electrical frequencies, altering the electric current to mimic the human bioelectric system. This therapy may also be referred to as bioelectric nerve block, noninvasive neuron blockade, electroceutical neuron blockade and bioelectric treatment system. An example of this is the Hako-Med Pro Elect DT 2000.
Electroceutical medicine entails the use of various electrical modalities. While certain "low-strength" electrical treatments such as transcutaneous electrical nerve stimulation (TENS) units may be safely used at home, electroceutical treatments use much higher electrical frequencies than TENS units (ranging from 1 to 20,000 Hz compared to 0.5 to 100 Hz used in TENS) and may only be prescribed and administered under the supervision of a healthcare provider experienced in this method of treatment.
- stimulatory class in which repetitive action potentials are induced in excitable cells (depolarization and repolarization activity), and
- multi-facilitory class that produces biophysical effects without repetitive action potential propagation.
The proper electroceutical class, dosage, regimen duration and anatomical placement of electrodes are determined by the individual patient's diagnosis. Proponents of electroceutical therapy claim that its use has resulted in significant relief of pain and elimination or drastic reductions in patients' pain medication requirements, such that patients are able to resume their daily activities. However, there is a lack of scientific evidence to substantiate these claims. Guidelines from the Work Loss Data Institute (2008) considered, but did not recommend, electroceutical therapy for chronic pain. Well-designed, randomized controlled clinical studies are needed to determine the usefulness of electroceutical therapy in the treatment of patients with acute or chronic pain.
Transcutaneous Electrical Joint Stimulation and Pulsed Electrical Stimulation
Transcutaneous electrical joint stimulation is also known as pulsed electrical stimulation; and the Bionicare device uses this type of electrical stimulation. Zizic et al (1995) evaluated the safety and effectiveness of pulsed electrical stimulation for the treatment of osteoarthritis (OA) of the knee (n = 78). Patients were treated 6 hours/day for 4 weeks. The investigators reported that patients treated with the active devices showed significantly greater improvement than the placebo group for all primary efficacy variables in comparisons of mean change from baseline to the end of treatment. Improvement of greater or equal to 50 % from baseline was shown in at least 1 primary efficacy variable in 50 % of the active device group, in 2 variables in 32 %, and in all 3 variables in 24 %. In the placebo group improvement of greater or equal to 50 % occurred in 36 % for one, 6 % for 2, and 6 % for 3 variables. Mean morning stiffness decreased 20 mins in the active device group and increased 2 mins in the placebo group (p < 0.05). No statistically significant differences were observed for tenderness, swelling, or walking time. The authors concluded that improvements in clinical measures for pain and function found in this study suggest that pulsed electrical stimulation is effective for treating OA of the knee. The investigators noted, however, that studies of the durability of results are warranted.
In a Cochrane review on pulsed electric stimulation for the treatment of OA (Hulme et al, 2002), the authors stated that current evidence suggests that electrical stimulation therapy may provide significant improvements for knee OA, but further studies are required to confirm whether the statistically significant results shown in these trials confer clinically significant and durable benefits.
A systematic evidence review by McCarthy et al (2006) concluded that pulsed electromagnetic field therapy is unlikely to benefit patients with knee osteoarthritis. The systematic evidence review identified 5 RCTs of pulsed electromagnetic field therapy for knee osteoarthritis: 2 RCTs scored 5 points for validity, 1 scored 4 and 2 scored 3. The investigators found that none of the individual studies reported a statistically significant difference between treatments for pain. Only 1 study (n = 83) with a low quality score of 3 reported a statistically significant difference between treatments in function (standardized mean difference -0.58, 95 % CI: -1.02 to -0.14). For all studies combined, there was no significant difference between interventions in pain (weighted mean difference -0.66, 95 % CI: -1.67 to 0.35) or function (weighted mean difference -0.70, 95 % CI: -1.92 to 0.52).
Fary and colleagues (2008) stated that OA of the knee is one of the main causes of musculoskeletal disability in the western world. Current available management options provide symptomatic relief (exercise and self-management, medication and surgery) but do not, in general, address the disease process itself. Moreover, adverse effects and complications with some of these interventions (medication and surgery) and the presence of co-morbidities commonly restrict their use. There is clearly a need to investigate treatments that are more widely applicable for symptom management and which may also directly address the disease process itself. The authors described the protocol of a double-blind, randomized, placebo-controlled, repeated measures trial to examine the effectiveness of pulsed electrical stimulation in providing symptomatic relief for people with OA of the knee over 26 weeks. A total of 70 subjects will be recruited and information regarding age, gender, body mass index and medication use will be recorded. The population will be stratified for age, gender and baseline pain levels. Outcome measures will include pain (100 mm VAS and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] 3.1), function (WOMAC 3.1), stiffness (WOMAC 3.1), patient global assessment (100 mm VAS) and quality of life (Medical Outcomes Study Short-Form 36 [SF-36]). These outcomes will be measured at baseline, 4, 16 and 26 weeks. Activity levels will be measured at baseline and 16 weeks using accelerometers and the Human Activity Profile questionnaire. A patient global perceived effect scale (11-point Likert) will be completed at 16 and 26 weeks.
In a double-blind, randomized, placebo-controlled, repeated-measures study, Fary et al (2011) determined the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of OA of the knee. A total of 70 participants with clinical and radiographically diagnosed OA of the knee were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm VAS. Other measures included pain on the WOMAC, function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the SF-36 health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). Thirty-four participants were randomized to PES and 36 to placebo. Intent-to-treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95 % CI: -11.7 to 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95 % CI: -14.9 to 3.6], -1.9 [95 % CI: -9.7 to 5.9], and 3.7 [95 % CI: -6.0 to 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95 % CI: -1.5 to 4.8] and 1.2 [95 % CI: -2.9 to 5.4], respectively), patient's global assessment of disease activity (-2.8 [95 % CI: -13.9 to 8.4]), or activity measures; 56 % of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44 % of controls (12 % [95 % CI: -11 % to 33 %]). The authors concluded that in this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.
Mendel et al (2010) noted that high-voltage pulsed current (HVPC), a form of electrical stimulation, is known to curb edema formation in laboratory animals and is commonly applied for ankle sprains, but the clinical effects remain undocumented. In a multi-center, randomized, double-blind, placebo-controlled trial, these investigators examined if, as an adjunct to routine acute and subacute care, subsensory HVPC applied nearly continuously for the first 72 hours after lateral ankle sprains affected time lost to injury. Data were collected at 9 colleges and universities and 1 professional training site. A total of 50 intercollegiate and professional athletes were included in this study. Participants were given near-continuous live or placebo HVPC for 72 hours post-injury in addition to routine acute and subacute care. Main outcome measure was time lost to injury measured from time of injury until declared fit to play. Overall, time lost to injury was not different between treated and control groups (p = 0.55). However, grade of injury was a significant factor. Time lost to injury after grade I lateral ankle sprains was greater for athletes receiving live HVPC than for those receiving placebo HVPC (p = 0.049), but no differences were found between groups for grade II sprains (p = 0.079). The authors concluded that application of subsensory HVPC had no clinically meaningful effect on return to play after lateral ankle sprain.
Electro-Acuscope Myopulse/Electro-Equiscope
The Electro-Acuscope Myopulse Therapy System is an electronic device that has been used for a wide range of neuromuscular conditions. The Acuscope uses electricity to treat pain by stimulating the nervous system without puncturing the skin. The Myopulse, a companion instrument to the Acuscope, stimulates muscles, tendons and ligaments, reducing spasm, inflammation and strengthening tissue damaged by traumatic injury. This form of therapy purportedly helps the body heal itself by stimulating the supply of blood and oxygen to the involved area. The Electro-Equiscope is an advanced combined version of preceding technologies - Electro-Acuscope and Myopulse. The Electro-Acuscope Myopulse Therapy System has been used in the treatment of pain and many types of tissue damage including swelling, inflammation, and soreness. However there is insufficient scientific evidence to support its effectiveness.
Sacral Nerve Root and Lumbosacral Plexus Stimulation
Electrical stimulation of the sacral nerves (sacral neuromodulation) or lumbosacral plexus has been used for painful conditions resulting from chronic abdominal, pelvic, genital, and anal pain syndromes (Kim, 2004). Specific conditions that have been treated include pain from interstitial cystitis, coccydynia, pyelonephritis, pancreatitis, rectal fugax, and vulvodynia.
Procedures allowing access to sacral and lumbosacral nerves include a retrograde (cephalocaudad) epidural approach and a sacral transforaminal approach. The transforaminal approach is mainly used for the treatment of urge urinary incontinence and urinary retention, while the retrograde approach has been used primarily for the treatment of pelvic pain.
Evidence for sacral nerve root and lumbosacral plexus stimulation is limited to case reports and small case series. Alo and colleagues (1999) reported that lumbar and sacral nerve root stimulation through the retrograde approach resulted in adequate paresthesia and effective pain relief as reflected by VAS scores in 5 patients with chronic pain (e.g., ilioinguinal neuralgia, discogenic LBP, failed back syndrome, and vulvodynia). These investigators concluded that further clinical trials are needed to assess the safety and long-term success rates of lumbar/sacral nerve root stimulation in the management of patients with chronic pain.
Anterograde sacral nerve root stimulation (SNRS) through the sacral hiatus is another method that has been tried for the treatment of pelvic pain. In a case report study, Falco et al (2003) found that anterograde SNRS provided good pain relief (as indexed by VAS scores) in a patient with chronic pelvic (rectal, coccygeal, and perineal) pain. The authors concluded that further investigation is needed before any conclusions can be rendered regarding the reliability of SNRS in the treatment of theses disorders.
Siegel and colleagues (2001) examined the effectiveness of transforaminal sacral nerve stimulation in patients with chronic intractable pelvic pain. After successful percutaneous trial stimulation, a neuroprosthetic sacral nerve stimulation device was surgically implanted in 10 patients with chronic intractable pelvic pain. Leads were placed in the S3 and S4 foramen in 8 and 2 cases, respectively. Patients were evaluated throughout the study using a patient pain assessment questionnaire on a scale of 0 (absence of pain) to 5 (excruciating pain). Pain was assessed at baseline, during test stimulation, and 1, 3 and 6 months after implantation of surgical lead. An additional long-term assessment was done at a median follow-up of 19 months. Of the 10 patients with the implant, 9 had a decrease in the severity of the worst pain compared to baseline at a median follow-up of 19 months. The number of hours of pain decreased from 13.1 to 6.9 at the same follow-up interval. There was also an average decrease in the rate of pain from 9.7 at baseline to 4.4 on a scale of 10 (always having pain) to 0 (never having pain). At a median of 19 months, 6 of 10 patients reported significant improvement in pelvic pain symptomatology. The authors concluded that these data imply that transforaminal sacral nerve stimulation can have beneficial effects on the severity and frequency of chronic intractable pelvic pain. They further stated that future clinical studies are necessary to determine the long-term effectiveness of this therapy.
The available evidence on sacral nerve root and lumbosacral plexus stimulation is insufficient to draw reliable conclusions about the effect of these interventions on chronic pelvic and abdominal pain.
Microcurrent Therapy
Microcurrent electrical nerve stimulation (MENS) devices are also non-invasive devices in which precise, tightly controlled electrical current is applied to specific points on the body. These specific points correspond with classical acupuncture points. MENS is also referred to as microelectrical therapy (MET) or microelectrical neuro-stimulation. Examples of this type of device include, but may not be limited to, Algonix, Alpha-Stim 100, Electro-Lyoscope 85P, Electro-Myopulse 75L, KFH Energy, MENS 2000-D, MICROCURRENT and Myopulse 75C.
Microcurrent therapy (MCT), also known as low-voltage microampere stimulation, is characterized by sub-sensory current that acts on the body’s naturally occurring electrical impulses to decrease pain and facilitate the healing process. It uses microamperage instead of milliamperage to drive its current into the injured site. Microcurrent therapy uses current between 1 and 1,000 microA at a voltage of 10 to 60 V, and a frequency of 0.5 to 100 Hz. It differs from TENS in that it uses a significantly reduced electrical stimulation. While TENS blocks pain, MCT acts on the naturally occurring electrical impulses to decrease pain by stimulating the healing process.
Koopman et al (2009) stated that MCT is a novel treatment for pain syndromes. The MCT patch is hypothesized to produce stimuli that promote tissue healing by facilitating physiologic currents. Solid evidence from randomized clinical trials is lacking. To assess the effectiveness of MCT in treating non-specific, chronic LBP, these researchers conducted a double-blind, randomized, cross-over, pilot trial. A total of 10 succeeding patients presenting with non-specific, chronic LBP were included. Patients started with 2, 9-day baseline period followed by a 5-day treatment periods. During the treatment periods, either a placebo or MCT (verum) patch was randomly assigned. Mean and worst pain scores were evaluated daily by a VAS. Furthermore, analgesic use, side effects, and quality of life were assessed after each period. Differences between the last 4 days of a treatment period and the baseline period were calculated. Differences between verum and placebo periods per patient were compared using paired-t tests. A 20-mm VAS score reduction was considered clinically relevant. The VAS score was lower during verum treatment, with a reduction (95 % CI) of -0.43 (-1.74; 0.89) in mean and -1.07 (-2.85; 0.71) in worst pain. Analgesic use decreased during verum treatment, except for non-steroid anti-inflammatory drug use, which increased. Quality of life improved during verum treatment. However, none of the findings was statistically significant. A positive trend in MCT use for aspecific, chronic LBP was reported. The authors stated that further investigations are needed to evaluate the significance and relevance of these findings.
Furthermore, the American Pain Society's clinical practice guideline on non-surgical interventional therapies for LBP (Chou et al, 2009) concluded that few non-surgical interventional therapies for LBP have been shown to be effective in randomized, placebo-controlled trials.
Zuim et al (2006) evaluated the effect of microcurrent electrical nerve stimulation (MENS) and compared with occlusal splint therapy in temporo-mandibular disorders (TMD) patients with muscle pain. A total of 20 TMD patients were divided into 4 groups. One received occlusal splint therapy and MENS (I); other received splints and placebo MENS (II); the third, only MENS (III) and the last group, placebo MENS (IV). Sensitivity derived from muscle palpation was evaluated using a VAS. Results were submitted to analysis of variance (p < 0.05). There was reduction of pain level in all groups: group I (occlusal splint and MENS) had a 47.7 % reduction rate; group II (occlusal splint and placebo MENS), 66.7 %; group III (MENS), 49.7 % and group IV (placebo MENS), 16.5 %. In spite of that, there was no statistical difference (analysis of variance/p < 0.05) between MENS and occlusal splint therapy regarding muscle pain reduction in TMD patients after 4 weeks.
In a placebo-controlled, single-blinded, and randomized study, Gossrau et al (2011) evaluated the effect of micro-TENS in reducing neuropathic pain in patients with painful diabetic neuropathy (PDN). A total of 22 diabetic patients have been treated with a micro-TENS therapy and 19 patients have been treated with a placebo therapy. Treatment duration was 4 weeks with 3 therapeutic settings per week. Standardized questionnaires (Pain Disability Index [PDI], neuropathic pain score [NPS], Center for Epidemiologic Studies Depression Scale [CES-D]) were used to assess pain intensity, pain disability, as well as quality of life at baseline at the end of the treatment period and 4 weeks after treatment termination. Patients with a minimum of 30 % reduction in NPS were defined as therapy responders. After 4 weeks of treatment, 6/21 (28.6 %) patients in the verum group versus 10/19 (52.6 %) patients in the placebo group responded to therapy. The median PDI score after 4 weeks of treatment showed a reduction of 23 % in the verum versus 25 % in the placebo group. The differences did not reach statistical significance. The authors concluded that the pain reduction with the applied transcutaneous electrotherapy regimen is not superior to a placebo treatment.
Scrambler Therapy/The Calmare Therapy Device
Scrambler therapy (also known as transcutaneous electrical modulation pain reprocessing) is an electro-cutaneous nerve stimulation device that interferes with pain signal transmission by mixing a ''non-pain'' information into the nerve fibers. It consists of a multi-processor apparatus capable of simulating 5 artificial neurons that send out signals identified by the central nervous system as "no pain" via the application of surface electrodes on skin in the pain areas.
Marineo (2003) examined the effects of the Scrambler therapy in the treatment of drug-resistant oncological pain of the visceral/neuropathic type. A total of 11 terminal cancer patients (3 pancreas, 4 colon, 4 gastric) suffering from elevated drug resistant visceral pain were included in this study. The trial program was related to the first 10 treatment sessions. Subsequently, each patient continued to receive treatment until death. Pain measures were performed using the VAS before and after each treatment session and accompanied by diary recordings of the duration of analgesia in the hours following each single application. Any variation in pain-killing drug consumption was also recorded. All patients reacted positively to the treatment throughout the whole reference period. Pain intensity showed a significant decrease (p < 0.001), accompanied by a gradual rise both in the pain threshold and the duration of analgesia; 9 (81.8 %) of the patients suspended pain-killers within the first 5 applications, while the remaining 2 (18.2 %) considerably reduced the dosage taken prior to Scrambler therapy. No undesirable side effects were observed. Compliance was found to be optimal. The authors concluded that these preliminary results obtained using Scrambler therapy were extremely encouraging, both in terms of enhanced pain control after each treatment session and in view of the possible maintenance of effectiveness over time.
Sabato et al (2005) assessed the effectiveness of the Scrambler therapy in the treatment of neuropathic pain. A total of 226 patients, all suffering from intense drug-resistant neuropathic pain, were recruited for this trial. Inclusion criteria included neuropathic pain, very high baseline VAS. Exclusion criteria included pacemaker users, neurolithic blocks or neurolesive pain control treatment. The treated neuropathic pain syndromes were: failed back surgery syndrome (FBSS), post-herpetic neuralgia (PHN), trigeminal neuralgia, post-surgery nerve lesion neuropathy, pudendal neuropathy, brachial plexus neuropathy, LBP, and others. The trial program entailed 1 to 6 therapy sessions of 5 treatments, each one lasting 30 mins. Pain intensity was evaluated using VAS before and after each treatment. The statistical significance of VAS was measured using the paired t-test. The total results showed 80.09 % of responders (pain relief greater than 50 %), 10.18 % of partially responders (pain relief from 25 % to 49 %) and 9.73 % of no responders (patients with pain relief less than 24 % or VAS greater than 3). The authors concluded that the Scrambler therapy produced a statistically significant (p < 0.0001) pain relief in all treated neuropathies.
In a pilot study, Marineo et al (2012) compared guideline-based drug management with Scrambler therapy. A clinical trial with patients randomized to either guideline-based pharmacological treatment or Scrambler therapy for a cycle of 10 daily sessions was performed. Patients were matched by type of pain including post-surgical neuropathic pain, PHN, or spinal canal stenosis. Primary outcome was change in VAS pain scores at 1 month; secondary outcomes included VAS pain scores at 2 and 3 months, pain medication use, and allodynia. A total of 52 patients were randomized. The mean VAS pain score before treatment was 8.1 points (control) and 8.0 points (Scrambler). At 1 month, the mean VAS score was reduced from 8.1 to 5.8 (-28 %) in the control group, and from 8 to 0.7 points (-91 %) in the Scrambler group (p < 0.0001). At 2 and 3 months, the mean pain scores in the control group were 5.7 and 5.9 points, respectively, and 1.4 and 2 points in the Scrambler group, respectively (p < 0.0001). More relapses were seen in polyradicular pain than monoradicular pain, but re-treatment and maintenance therapy gave relief. No adverse effects were observed. The authors concluded that in this pilot randomized trial, Scrambler therapy appeared to relieve chronic neuropathic pain better than guideline-based drug management.
In a pilot study, Smith et al (2010) evaluated the impact on chemotherapy-induced peripheral neuropathy (CIPN) associated with the MC5-A Calmare therapy device. A total of 18 patients from 1 center received 1-hour interventions daily over 10 working days. Of 18 patients, 16 were evaluable. The mean age of the patients (4 men and 14 women) was 58.6 years and the duration of CIPN was 3 months to 8 years. The most common drugs used by these subjects were taxanes, platinum, and bortezomib. At the end of the study (day 10), a 20 % reduction in numeric pain scores was achieved in 15 of 16 patients. The pain score fell 59 % from 5.81 +/- 1.11 before treatment to 2.38 +/- 1.82 at the end of 10 days (p < 0.0001 by paired t-test). A daily treatment benefit was seen with a strong statistically significant difference between the pre- and post-daily pain scores (p < 0.001). Four patients had their CIPN reduced to zero. A repeated-measures analysis using the scores from all 10 days confirmed these results. No toxicity was seen. Some responses have been durable without maintenance. The authors concluded that patient-specific cutaneous electro-stimulation with the MC5-A Calmare device appears to dramatically reduce pain in refractory CIPN patients with no toxicity. They stated that further studies (determining effectiveness compared with sham or placebo treatment, and the need for maintenance therapy) are underway to define the benefit, mechanisms of action, and optimal schedule. The preliminary findings of this pilot study need to be validated by well-designed studies. There is a phase II clinical trial that examines the effectiveness of the MC5-A Scrambler therapy in reducing peripheral neuropathy caused by chemotherapy.
Ricci et al (2012) evaluated the effectiveness of an innovative neuromodulative approach to the treatment of chronic pain using electrical stimulus integrated with pharmacological support. The MC5-A Calmare is a new device for patient-specific cutaneous electro-stimulation which, by "scrambling" pain information with "no pain" information, aims to reduce the perception of pain intensity. These researchers prospectively treated 73 patients with cancer-related (n = 40) and non-cancer-related (n = 33) pain whose pain management was unsatisfactory. The primary objective of the study was to assess efficacy and tolerability of the device. Pain intensity was assessed daily with a NRS for the duration of treatment (2 weeks) and then on a weekly basis for the 2 weeks of follow-up. Mean pain value at T0 (pre-treatment value) was 6.2 [+/- 2.5 SD], 1.6 (+/- 2.0) (p < 0.0001) at T2 (after the 10th day of treatment), and 2.9 (+/- 2.6) (p < 0.0001) at T4 (after the second week of follow-up, i.e., 1 month after the beginning of treatment). Response after the second week of treatment showed a clear reduction in pain for both cancer (mean absolute delta of the reduction in NRS value = 4.0) and non-cancer (mean delta = 5.2) patients. The pain score had decreased by 74 % at T2. On the basis of pre-established response criteria, there were 78 % of responders at T2 and 81 % at T4. No side effects were reported. The authors concluded that these preliminary results suggested that cutaneous electro-stimulation with the MC5-A Calmare can be hypothesized as part of a multi-modality approach to the treatment of chronic pain. They stated that further studies on larger numbers of patients are needed to assess its efficacy, to quantify the effects of inter-operator variability, and to compare results obtained from the active device versus those from a sham machine.
Smith and Marineo (2018) noted that post-herpetic neuropathy (PHN) is common, severe, and often refractory to treatment. These investigators treated 10 patients with refractory PHN using Scrambler therapy, a neurocutaneous stimulation device that delivers "non-pain" information with surface electrodes. Scrambler therapy was given as 30-minute sessions daily for 10 days. Pain was recorded before and after treatment. The average pain score rapidly diminished from 7.64 ± 1.46 at baseline to 0.42 ± 0.89 at 1 month, a 95 % reduction, with continued relief at 2 and 3 months. Patients achieved maximum pain relief with less than 5 treatments. The authors concluded that the Scrambler therapy appeared to have a promising effect on PHN, with prompt and continued relief and no side effects. They stated that further research is warranted.
Pachman et al (2014) stated that chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with multiple chemotherapeutic agents. CIPN may have a detrimental impact on patients' quality of life and functional ability, as well as result in chemotherapy dose reductions. Although symptoms of CIPN can improve with treatment completion, symptoms may persist. Currently, the treatment options for CIPN are quite limited. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has the most evidence supporting its use in the treatment of CIPN. Other agents with potential benefit for the treatment of established CIPN include gabapentinoids, venlafaxine, tricyclic antidepressants, and a topical gel consisting of the combination of amitriptyline, ketamine, and baclofen; none of these, however, has been proven to be helpful and ongoing/future studies may well show that they are not beneficial. The use of these agents is often based on their efficacy in the treatment of non-CIPN neuropathic pain, but this does not necessarily mean that they will be helpful for CIPN-related symptoms. Other non-pharmacologic interventions including acupuncture and Scrambler therapy are supported by positive preliminary data; however, further larger, placebo-controlled trial data are needed to confirm or refute their effectiveness.
In a double-blinded, randomized controlled trial, Starkweather et al (2015) evaluated the effects of Calmare, a non-invasive neurocutaneous electrical pain intervention, on lower back pain intensity as measured by the "worst" pain score and on pain interference using the Brief Pain Inventory-Short Form, on measures of pain sensitivity assessed by quantitative sensory testing, and on mRNA expression of pain sensitivity genes. A total of 30 participants were randomized to receive up to 10 sessions of Calmare® treatment (n = 15) or a sham treatment (n = 15) using the same device at a non-therapeutic threshold. At 3 weeks after conclusion of treatment, compared with the sham group, the Calmare® group reported a significant decrease in the "worst" pain and interference scores. There were also significant differences in pain sensitivity and differential mRNA expression of 17 pain genes, suggesting that Calmare® can be effective in reducing pain intensity and interference in individuals with persistent low back pain by altering the mechanisms of enhanced pain sensitivity. The authors stated that further study of long-term pain outcomes, particularly functional status, analgesic use and health care utilization, is warranted.
Pachman et al (2015) stated that CIPN, a common side effect of chemotherapy, needs better effective treatments. Preliminary data support the use of Scrambler therapy, a device which treats pain via noninvasive cutaneous electrostimulation, for the treatment of CIPN. The current manuscript reported data from a pilot trial, performed to investigate the effect of Scrambler therapy for the treatment of established CIPN. Eligible patients had CIPN symptoms of greater than or equal to 1 month duration with tingling and/or pain greater than or equal to 4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area(s) for up to 10 daily 30-min sessions. Symptoms were monitored using a neuropathy questionnaire consisting of numerical analog scales ranging from 0 to 10, daily before therapy as well as weekly for 10 weeks after therapy. Descriptive summary statistics formed the basis of data analysis. A total of 37 patients were enrolled; 25 patients were treated primarily on their lower extremities while 12 were treated primarily on their upper extremities. There was a 53 % reduction in pain score from baseline to day 10; a 44 % reduction in tingling; and a 37 % reduction in numbness. Benefit appeared to last throughout 10 weeks of follow-up. There were no substantial adverse events. The authors concluded that preliminary data support that Scrambler therapy may be effective for the treatment of CIPN; they stated that a prospective placebo-controlled clinical trial should be performed.
In a single-center, case-series study, Notaro et al (2016) examined the effectiveness of Scrambler therapy in reducing cancer pain induced by skeletal and visceral metastases after failure of standard treatments, including pharmacological therapies and radiation therapy. A total of 25 consecutive patients underwent Scrambler therapy individually delivered by MC5-A Calmare for 10 daily sessions each of 30 to 40 mins. Pain was measured by a numeric rating scale at baseline, as well as before and after each treatment session; 100 % of patients reached a pain relief of greater than or equal to 50 %. Pain score was reduced from 8.4 at baseline to 2.9 after treatment, with a mean pain relief of 89 %. The sleeping hours improved from 4.4 ± 1.2 to 7.5 ± 1.1. The duration of pain control by Scrambler therapy was 7.7 ± 5.3 weeks. No adverse events were observed. The authors concluded that Scrambler therapy did not present toxicity and allowed opioids dosage reduction, and it is also a repeatable treatment. They stated that present novel data support that Scrambler therapy appeared to be effective for the treatment of cancer pain; further evaluation in RCTs is needed to confirm these findings.
Majithia et al (2016) evaluated what is known regarding the mechanisms and mechanics of Scrambler therapy and investigated the preliminary data pertaining to the effectiveness of this treatment modality. The PubMed/Medline, SCOPUS, Embase, and Google Scholar databases were searched for all articles published on Scrambler therapy prior to November 2015. All case studies and clinical trials were evaluated and reported in a descriptive manner. To-date, 20 reports, of varying scientific quality, have been published regarding this device; all but 1 small study, published only as an abstract, provided results that appeared positive. The authors concluded that the positive findings from preliminary studies with Scrambler therapy support that this device provides benefit for patients with refractory pain syndromes. Moreover, they stated that larger, randomized studies are needed to further evaluate the effectiveness of this approach.
Smith and colleagues (2017) stated that chronic post-mastectomy pain (cPMP), including post-lumpectomy pain, is common with no established ways of treatment. These researchers treated 3 consecutive patients referred with cPMP with Scrambler therapy. Treatment was given across the area of pain following the dermatomes for 45 minutes daily, for several consecutive days until relief, and then was repeated as needed. The Scrambler therapy MC5A device synthesized 16 different waveforms that resemble action potentials, delivered to the surface receptors of the c-fibers, to send "non-pain" information along the damaged pathways to reduce central sensitization. All 3 had marked (over 75 %) and sustained (months) reduction of allodynia, hyperalgesia, and pain. All reported marked improvements in their quality of life and normal function. One woman was able to stop chronic opioid use. No side effects were observed. The authors concluded that Scrambler therapy is a promising way to relieve cancer and other types of neuropathic pain, and may be helpful in cPMP. They stated that further prospective clinical trials are needed.
In a randomized, single-blind, sham-controlled trial, Mealy and colleagues (2020) examined if Scrambler therapy is an effective and feasible treatment of persistent central neuropathic pain in patients with neuromyelitis optica spectrum disorder (NMOSD) and examined the effect of Scrambler therapy on co-occurring symptoms. This trial entailed patients with NMOSD who had central neuropathic pain using Scrambler therapy for 10 consecutive week-days. Pain severity, pain interference, anxiety, depression, and sleep disturbance were assessed at baseline, at the end of treatment, and at the 30- and 60-day follow-up. A total of 22 patients (11 each in the treatment and sham groups) were enrolled in and completed this trial. The median baseline NRS pain score decreased from 5.0 to 1.5 after 10 days of treatment with Scrambler therapy, whereas the median NRS score did not significantly decrease in the sham arm. Depression was also reduced in the treatment arm, and anxiety was decreased in a subset of patients who responded to treatment. These symptoms were not affected in the sham arm. The safety profiles were similar between groups. The authors concluded that the Scrambler therapy was a safe and effective intervention for central neuropathic pain in patients with NMOSD. These researchers stated that decreasing pain with Scrambler therapy may additionally improve depression and anxiety.
The authors stated that this study had several drawbacks. First, the design of this study was single-blinded due to the fact that the technician knew whether treatment or sham was being delivered by necessity. To mitigate the bias this potentially introduced, measurement tools and survey data were collected by an unrelated study coordinator. Second, although patients were recruited with the use of a randomized block design to mitigate the risk of confounding effects from pain medication class on the basis of previous data that reported that the type of medication may be predictive of response to Scrambler therapy, this trial was not powered to sufficiently compare efficacy results across classes of pain medications because patients were often on multiple medications. The effect that modifying pain through Scrambler therapy had on co-occurring symptoms was also limited by the sample size. Lastly, while it was encouraging that a difference was detected between the Scrambler-treated and sham arms, this study was not powered to effectively examine sustainability of treatment through the 60-day follow-up period. The practicality of using Scrambler increases if the effect is sustained. The trend toward significance at 60 days suggested that a larger study that includes 29 patients per arm may uncover sustained effect. Furthermore, re-emergence of pain in treatment of both central and peripheral pain conditions has been described, and pain has been shown to be amenable to subsequent booster treatments, often with fewer Scrambler treatment sessions needed. Anecdotally, 1 complete responder from the current study was subsequently treated when pain began to re-emerge after study completion and remained pain-free months later. Therefore, adapting the protocol to include subsequent booster treatments when pain emerges should be considered for future studies. Overall, the safety and effectiveness profiles these investigators reported support the need for a larger, phase-III clinical trial to further examine the effect of Scrambler on pain, reduction of analgesic medication use, co-occurring symptoms, and QOL in a larger NMOSD patient cohort.
Christo and associates (2020) stated that Dejerine-Roussy syndrome or central thalamic pain can be devastating, and treatment with drugs and even DBS can be unsatisfactory. Scrambler therapy is a form of neuromodulation that uses external skin electrodes to send a “non-pain” signal to the brain, with some success in difficult-to-treat syndromes such as NMOSD. These researchers used Scrambler therapy to treat a patient with 6 years of disabling Dejerine-Roussy syndrome pain. A 56-year old man received multiple daily then monthly treatments with electrode pairs placed just above the area of distal pain. Each treatment was for 40 mins. His allodynia and hyperalgesia resolved within 10 mins, and his pain score fell to almost 0 after 30 mins. Months later, he resumed normal activity and was off all his pain medications. No side effects were noted. The authors concluded that Scrambler therapy appeared to reverse 6 years of disabling pain safely and economically, and continued to be effective. These researchers stated that further multi-institutional trials are needed for this rare syndrome.
Non-Invasive Interactive Neurostimulation (e.g., the InterX 1000 Neurostimulator Device)
The InterX 1000 neurostimulator appears to be a hand-held, personal device for home use. It delivers interactive, high amplitude, high density stimulation to the cutaneous nerves, activating the body's natural pain relieving mechanisms (segmental and descending inhibition). However, there is insufficient evidence regarding its effectiveness for the treatment of chronic pain.
In a randomized, sham-controlled, pilot study, Selfe et al (2008) examined the effects of non-invasive interactive neurostimulation used as an adjunct to usual care, on pain and other symptoms in adults with OA of the knee. A total of 37 adults with knee OA (based on American College of Rheumatology diagnostic criteria) were included in this study. Subjects received 17 non-invasive interactive neurostimulation (active or sham) sessions over 8 weeks with a week 12 follow-up. Outcome measures included 11-point numeric rating scale for weekly pain; WOMAC, patient global assessment, and SF-36 completed at baseline and weeks 4, 8, and 12. For the main outcome, pain, the differences between the groups over time did not reach statistical significance (all p > 0.05). However, a clinically important reduction in pain (defined as a 2-point or 30 % reduction on an 11-point numeric rating scale) was maintained at week 12 by the active non-invasive interactive neurostimulation group (2.17 points, 34.55 % reduction) but not the sham group (1.63, 26.04 % reduction). Pain improved over time in participants regardless of group membership (numeric rating scale average pain, p = 0.002; numeric rating scale worst pain, p < 0.001; and WOMAC pain, p < 0.001), as did WOMAC function, WOMAC stiffness, and WOMAC total score (all p < 0.001). Repeated measures ANOVA revealed a statistically significant difference between the groups over time for the SF-36 Vitality scale, F (3, 105) = 3.54, p = 0.017. In addition, the active device group improved on the patient global assessment from baseline to week 8 compared to the sham device group, F (1, 35) = 4.025, p = 0.053. The authors concluded that in this pilot study, clinically important reductions in knee pain were maintained at week 12 in the active, but not the sham, non-invasive interactive neurostimulation group. They stated that further study of this non-invasive therapy is needed.
Gorodetskyi et al (2010) undertook a trial with 60 patients who had undergone operative reduction and internal fixation of bimalleolar, AO type B2 ankle fractures with comminution. Patients were randomized into 2 groups, one of which received post-operative treatment using a non-invasive interactive neurostimulation device (InterX) and the other with a sham device. The trial was designed to test the hypothesis that incorporation of non-invasive interactive neurostimulation into the rehabilitation protocol would result in reduced pain, increased range of motion (ROM), reduced edema, and reduced consumption of pain medication, in comparison with the sham therapy group. Outcome measurements included the patient's subjective assessment of level of pain, ROM, and the extent of edema in the involved ankle, and the use of ketorolac for post-operative control of pain. The authors concluded that these results showed significantly better results in the patients receiving treatment with active neurostimulation (repeated measures analysis of variance, p < 0.001).
In a Cochrane review, Lin and colleagues (2012) evaluated the effects of rehabilitation interventions following conservative or surgical treatment of ankle fractures in adults. The authors concluded that there is limited evidence supporting early commencement of weight-bearing and the use of a removable type of immobilization to allow exercise during the immobilization period after surgical fixation. Because of the potential increased risk of adverse events, the patient's ability to comply with the use of a removable type of immobilization to enable controlled exercise is essential. There is little evidence for rehabilitation interventions during the immobilization period after conservative orthopedic management and no evidence for stretching, manual therapy or exercise compared to usual care following the immobilization period. Furthermore, they stated that small, single studies showed that some electrotherapy modalities may be beneficial. They stated that more clinical trials that are well-designed and adequately-powered are needed to strengthen current evidence.
Teodorczyk-Injeyan et al (2015) evaluated the effect of treatment with a novel non-invasive interactive neurostimulation device (InterX5000) on the production of inflammatory biomarkers in chronic and recurrent mechanical neck pain (NP) syndrome. This study represented pilot biological data from a RCT. A total of 25 NP patients and 14 asymptomatic subjects included for baseline comparison only completed the study. The patients received 6 InterX5000 or placebo treatments within 2 weeks, and pre-treatment and post-treatment blood samples were collected for in-vitro determination of biomarker production. Whole blood cell cultures were activated by lipopolysaccharide or by the combination of lipopolysaccharide and phytohemagglutinin for 24 to 48 hours. The levels of tumor necrosis factor-alpha (TNFα) and its soluble type II receptor (sTNFR II), interleukin (IL) 1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, and monocyte chemotactic protein (CCL2/MCP-1) were determined by specific immunoassays. Compared with asymptomatic subjects, baseline production levels of all pro-inflammatory mediators (TNFα, IL-1β, IL-6, and CCL2/MCP-1) were significantly augmented or trended higher (p = 0.000 to 0.008) in patients with NP. Of the anti-inflammatory markers, only IL-1RA was significantly elevated (p = 0.004). The increase in IL-10 and TNF receptor II levels did not reach statistical significance. Neither InterX5000 nor placebo therapy had any significant effect on the production of the inflammatory mediators over the study period. The authors concluded that this investigation determined that inflammatory cytokine pathways are activated in NP patients but found no evidence that a short course of InterX5000 treatment normalized the production of inflammatory biomarkers.
Electro Therapeutic Point Stimulation
Electro-therapeutic point stimulation (ETPS), also known as microcurrent point stimulation (MPS), employs a non-invasive device to administer low-frequency direct current to acupuncture points, motor/trigger points, and contracted muscle bands. The device (known as called the ETPS 1000) has an enhanced point finder that detects treatment points on the skin and applies brief, concentrated electrical microstimulation in short bursts. This modality/approach combines the principles of acupuncture, massage, physical therapy and microcurrent stimulation. The treatment can be self-administered by the patient at home. There is insufficient peer-reviewed evidence to support the safety and effectiveness of ETPS/MPS.
Aliyev and Geiger (2012) examined the effects of cell-stimulation therapy of lateral epicondylitis with frequency-modulated low-intensity electric current. Patients with lateral epicondylitis were subjected to a 12-week cell-stimulation therapy with low-intensity frequency-modulated electric current in addition to routine therapy. Patients in the control group received the same routine therapy and sham stimulation (the therapeutic apparatus was not energized). The effectiveness of MPS was estimated by comparing medical indices before therapy and at the end of a 12-week therapeutic course using a 10-point pain severity numeric rating scale (NRS) and Roles-Maudsley pain score. The study revealed high therapeutic efficiency of cell-stimulation with low-intensity electric current resulting probably from up-regulation of intracellular transmitters, interleukins, and prostaglandins playing the key role in the regulation of inflammation. The findings of this study need to be validated by well-designed studies with long-term follow-up.
Pulsed Stimulation (e.g., P-Stim)
In a pilot study, Sator-Katzenschlager et al (2003) tested the hypothesis that auricular electro-acupuncture (EA) relieves pain more effectively than conventional manual auricular acupuncture. These researchers studied 21 chronic cervical pain patients without radicular symptoms with insufficient pain relief (VAS greater than 5) treated with standardized analgesic therapy. All patients received disposable acupuncture needles on the dominant side on the following acupuncture points: cervical spine, shen men, and cushion. In 10 patients, needles were continuously stimulated (2-mA constant current, 1 Hz monophasic) by using the electrical point stimulation device P-STIM. In 11 control patients, no electrical stimulation was administered. All needles were withdrawn 48 hours after insertion. Acupuncture was performed once a week for 6 weeks. Patients had to complete a questionnaire assessing pain intensity, psychological well-being, activity, sleep, and demand for rescue medication (lornoxicam and tramadol). The reduction in pain scores was significant in the EA group. Similarly, psychological well-being, activity, and sleep were significantly improved in patients receiving EA, and consumption of rescue medication was significantly less. These results demonstrated that continuous electrical stimulation of auricular acupuncture points by using the new point stimulation device P-STIM improves the treatment of chronic cervical pain in an outpatient population. The authors concluded that continuous electrical stimulation of auricular acupuncture points by using the new point stimulation device P-STIM significantly decreases pain intensity and significantly improves psychological well-being, activity, and sleep in chronic cervical pain patients. This was a pilot study with small number of subjects with short-term follow-up.
In a prospective, randomized, double-blind, controlled study, Sator-Katzenschlager et al (2004) tested the hypothesis that auricular EA relieves pain more effectively than conventional manual auricular acupuncture (CO) in chronic LBP patients with insufficient pain relief (VAS greater than or equal to 5) treated with standardized analgesic therapy. Disposable acupuncture needles were inserted in the auricular acupuncture points 29, 40, and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear. Patients were randomized into group EA (n = 31) with continuous low-frequency auricular EA (1 Hz biphasic constant current of 2 mA) and group CO (n = 30) without electrical stimulation (sham-EA). Treatment was performed once-weekly for 6 weeks, and in each group needles were withdrawn 48 hours after insertion. During the study period and a 3-month follow-up, patients were asked to complete the McGill questionnaire. Psychological well-being, activity level, quality of sleep, and pain intensity were assessed by means of VAS; moreover, analgesic drug consumption was documented. Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO. Similarly, psychological well-being, activity, and sleep were significantly improved in group EA versus group CO, the consumption of analgesic rescue medication was less, and more patients returned to full-time employment. Neuropathic pain in particular improved in patients treated with EA. There were no adverse side effects. These results were the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic LBP in an out-patient population. The authors concluded that continuous electrical stimulation of auricular acupuncture points using the new point stimulation device P-Stim significantly decreases pain intensity and improves psychological well-being, activity, and sleep in chronic LBP patients. This was a small study with a short-term follow-up.
Sator-Katzenschlager and Michalek-Sauberer (2007) stated that acupuncture is now accepted as a complementary analgesic treatment. Auricular acupuncture is a distinct form of acupuncture. Electrical stimulation of acupoints (EA) increases the effects of acupuncture. Recently, an auricular EA device, the P-Stim, has become available. Clinical studies in outpatients have investigated the P-Stim in chronic musculo-skeletal pain and its use for minor surgery. In chronic cervical or LBP, auricular EA was more effective than conventional auricular acupuncture. The results in acute pain were controversial. Auricular EA reduced pain and remifentanil consumption during oocyte aspiration when compared with conventional auricular acupuncture or a sham treatment. However, after third molar tooth extraction, auricular EA and auricular acupuncture failed to reduce either postoperative pain or analgesic consumption. The authors concluded that further large-scale studies are needed to evaluate the analgesic efficacy of auricular EA.
Michalek-Sauberer et al (2007) examined the effects of auricular EA on pain and analgesic drug consumption in the first 48 hours after unilateral mandibular third molar tooth extraction under local anesthesia in a prospective, randomized, double-blind, placebo-controlled study in 149 patients. Patients received either auricular acupuncture with electrical stimulation (AE, n = 76) or without (AA, n = 37) electrical stimulation at an alternating frequency of 2/100 Hz or a sham AE with metal plates instead of needles and no electrical stimulation, no-needle (NN, n = 36) at the AA points 1 (tooth), 55 (Shen men) and 84 (mouth) during the entire study period. Regularly rated pain intensity (5-point verbal rating scale), consumption of acetaminophen 500-mg tablets and additional rescue medication with 500-mg mefenamic acid were assessed. The median fraction of time when pain was rated as moderate or worse (upper and lower quartile): AE: 33 % (12 %, 64 %), AA: 22 % (6 %, 56 %), NN: 30 % (7 %, 53 %) did not differ significantly among the treatment groups. There were no significant differences in mean number of acetaminophen 500-mg tablets (range): AE: 5.2 (0 to 12), AA: 4.6 (0 to 11), NN: 5.4 (0 to 10) or percentage of patients requiring additional mefenamic acid: AE: 19 %, AA: 18 %, NN: 19 %. The authors concluded that neither AE nor AA alone reduce either pain intensity or analgesic consumption in a molar tooth extraction model of acute pain.
Wang (2007) reported the successful treatment of a patient with post-herpetic neuralgia (PHN) using traditional pharmacology in combination with acupuncture. A 13-year old girl developed PHN following a severe attack of varicella zoster. Despite a 1-week course of intravenous acyclovir initiated at the onset of symptoms, the patient developed persistent left facial pain and constant nausea after lesions were healed. A comprehensive pain treatment regimen, consisting of a stellate ganglia block, medications, transcutaneous electrical nerve stimulation and hypnosis, was administered, but the patient did not gain any incremental pain relief. The acupuncture service was consulted to provide assistance with this patient's pain management. A combination of body and auricular acupuncture as well as related techniques, including acupressure and transcutaneous acupoint electrical stimulation, was added to the pain treatment regimen. After 10 complementary acupuncture treatments over a 2-month period, the patient's nausea disappeared. Her left facial pain continued to decline from a maximum of 10 to 0 as assessed by a VAS over a period of 4 months following self-administered treatments of acupressure and transcutaneous acupoint electrical stimulation. The patient was then gradually weaned off all her medications and the complementary acupuncture treatment. She was discharged from the pediatric pain clinic after 5 months of the combined therapy. The author concluded that acupuncture and its related techniques may be an effective adjunctive treatment for symptoms associated with PHN and deserved further study.
Holzer et al (2011) examined the effects of electrical auricular acupuncture (AA) on post-operative pain in patients undergoing laparoscopy with an emphasis on patient-blinding and the exclusion of therapist-patient interactions. With institutional review board approval and written informed consent, these investigators included 40 female patients undergoing laparoscopy. Patients were randomly assigned to receive AA (shen men, thalamus and 1 segmental organ-specific point) or electrodes only and an electrical stimulation device. All patients received this intervention under general anesthesia guaranteeing patient blinding and excluding therapist-patient interactions. Needles and devices were removed 72 hours post-operatively. Post-operatively, patients received 1,000-mg paracetamol every 6 hours. Additional piritramide was given on demand. A blinded observer obtained the VAS scores at 0, 2, 24, 48, and 72 hours as well as the post-operatively administered doses of piritramide. There was no difference in VAS scores or the consumption of piritramide during the first 72 hours post-operatively between groups (acupuncture versus placebo: 2.32 [1.40 to 3.25] versus 2.62 [1.89 to 3.36] average pain on VAS 0-10; 15.3 [12.0 to 18.6] mg versus 13.9 [10.5 to 17.3] mg piritramide). Values are expressed as mean CI. The authors concluded that the findings of this study showed no reduction in post-operative pain or an opioid sparing effect of auricular acupuncture in women undergoing laparoscopic procedures. Because the authors emphasized blinding of the patients and the exclusion of therapist-patient interactions, this study suggested that electrical auricular acupuncture has no effect on post-operative pain.
In a double-blind, randomized, placebo-controlled, repeated-measures trial, Fary and colleagues (2011) examined the effectiveness of sub-sensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee. A total of 70 participants with clinical and radiographically diagnosed OA of the knee were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm VAS. Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes SF-36 health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). Thirty-four participants were randomized to PES and 36 to placebo. Intent-to-treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95 % CI: -11.7 to 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95 % CI: -14.9 to 3.6], -1.9 [95 % CI: -9.7 to 5.9], and 3.7 [95 % CI: -6.0 to 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95 % CI: -1.5 to 4.8] and 1.2 [95 % CI: -2.9 to 5.4], respectively), patient's global assessment of disease activity (-2.8 [95 % CI: -13.9 to 8.4]), or activity measures; 56 % of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44 % of controls (12 % [95 % CI: -11 5 to 33 %]). The authors concluded that in this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.
Neurolumen Device
The Neurolumen is a portable machine that consists of a control unit, 4 wrap assemblies and a battery charger. Each wrap contains 2 laser diodes, 4 light emitting diodes and 1 or 2 electrolytic nerve stimulation gel pads. Once the wraps are in place, the control unit provides up to 30 mins of simultaneous TENS, low-level laser (LLLT) and light-emitting diode (LED) therapy.
However, there is a lack of evidence regarding the effectiveness of the Neurolumen device for the treatment of Morton’s neuroma or any other indications. An UpToDate review on “on Peripheral Nerve Tumors” (Gilchrist and Donahue, 2013) states that “Morton neuroma is a subject of controversy regarding its nomenclature, pathology, and appropriate treatment. Abnormalities ascribed to Morton neuroma are typically located between the metatarsals of the third and fourth toes or at the bifurcation of the fourth plantar digital nerve. The lesions look like a traumatic neuroma grossly, and are comprised of degenerated and/or demyelinated axons, vascular hyalinization, and fibrosis. Clinical manifestations can include pain and tenderness, but similar lesions are common in patients who are asymptomatic. Surgical removal is advocated by some authors for those who fail conservative measures, but data are limited regarding the effectiveness of surgical and nonsurgical interventions for Morton neuroma”. Furthermore, an UpToDate review on “Overview of running injuries of the lower extremity (Callahan, 2013) does not mention the use of electrical stimulation or laser therapy as therapeutic options for Morton’s neuroma.
Non-Invasive/No-Incision Pain Procedure (NIP) Device
According to the FixPain website, the NIP Procedure refers to “Non-Invasive, or No-Incision Pain” Procedure. It is FDA-cleared/certified for various types of chronic pain (arthritis, cancer pain, cervical pain, fibromyalgia, joint pain, low back pain, migraines, post-operative pain, and sciatica) and other conditions (e.g., anxiety, depression and insomnia). The microchip NIP Procedure™ device is placed behind the ear of the patient, the acupuncture in corresponding points and the pulses are transmitted through the stimulating needle. With the help of the NIP Procedure™ device, the patients are receiving continuous treatment for 4 to 5 days. It is recommended that therapies be applied for up to 9 weeks.
However, there is a lack of evidence regarding the effectiveness of the NIP Procedure device for the treatment of chronic pain or any other indications.
Electro-Analgesia Treatment (EAT)
Electro-Analgesia Treatment (EAT) has been described as nerve block injections followed by electrical stimulation administered with the Synaptic device, and has been used as a treatment for diabetic peripheral neuropathy. The combination of nerve block therapy and electrical stimulation is referred to as Electro-Analgesia Treatment or EAT. The manufacturer states that the Synaptic 4000 treatment is controlled by the patient using a joystick.
According to the manufacturer, electrical stimulation with the Synaptic device is different from other forms of electrical stimulation: “The Synaptic technology is unique and stands apart from all other electrical neuro-stimulation devices such as TENS, EMS, functional electrical stimulation (FES), sacral nerve stimulation (SNS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), spinal cord stimulation (SCS) and cochlear and ocular implants.” The manufacturer explains: “The frequency range is from 40,000 to 400 Hertz. Conventional modalities have a frequency range of only 500-180 Hertz and begin their activity at the low end of the range increasing to their maximum as controls are elevated. In contrast, Synaptic begins its frequency sweep at the maximum (40,000 Hertz) and as the remote is advanced the frequency decreases to the minimum (400 Hertz). This cycle may be repeated during each of the ten intensity levels.”
The manufacturer states that the waveform of the Synaptic is also unique. “Also protected are the A-waveform, the unique mechanism for SEA energy delivery as well as the method of patient-controlled treatment using a joystick. The waveform developed for SEA technology mimics a biological process. It simulates the action potential responsible for producing electrical activity in the neuron using a fast rise time and a slow decay, reproducing the action potential in humans.”
There are a lack of peer-reviewed published studies of Electro-Analgesia Treatment or of the Synaptic electrical stimulation device.
Variable Muscle Stimulators (VMS)
Variable muscle stimulators (VMS), like TENS units, produce bi-phasic waves. However, TENS units produce asymmetric bi-phasic waves, whereas VMS units produce symmetrical bi-phasic waves. Unlike TENS, VMS is used to do FES. However, there is a lack of evidence regarding the clinical effectiveness of VMS.
Cefaly
The Cefaly transcutaneous supraorbital nerve stimulator, classified as a transcutaneous electrical nerve stimulator, has an FDA approved indication which is limited to the prophylactic treatment of episodic migraine in individuals 18 years of age or older. Cefaly is a plastic, battery-powered transcutaneous electrical nerve stimulator worn like a headband with reusable self-adhesive electrodes placed on the forehead to cover the supratrochlear and supraorbital nerves (branches of the trigeminal nerve). The device purportedly works through neuromodulatory effects on those nerves, thereby blocking pain signals.
Piquet et al (2011) stated that transcutaneous neurostimulation (TNS) at extra-cephalic sites is a well-known treatment of pain. Thanks to recent technical progress, the Cefaly device now also allows supraorbital TNS. During observational clinical studies, several patients reported decreased vigilance or even sleepiness during a session of supraorbital TNS. These researchers examined in more detail the potential sedative effect of supraorbital TNS, using standardized psychophysical tests in healthy volunteers. They performed a double-blind, cross-over, sham-controlled study on 30 healthy subjects. Subjects underwent a series of 4 vigilance tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale, d2 test). Each subject was tested under 4 different experimental conditions: without the neurostimulation device, with sham supraorbital TNS, with low frequency supraorbital TNS and with high frequency supraorbital TNS. As judged by the results of 3 tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale) there was a statistically significant (p < 0.001) decrease in vigilance and attention during high frequency TNS, while there were no changes during the other experimental conditions. Similarly, performance on the d2 test was impaired during high frequency TNS, but this change was not statistically significant. The authors concluded that supraorbital high frequency TNS applied with the Cefaly device decreased vigilance in healthy volunteers. They stated that additional studies are needed to determine the duration of this effect, the underlying mechanisms and the possible relation with the stimulation parameters. Meanwhile, this effect opened interesting perspectives for the treatment of hyperarousal states and, possibly, insomnia.
In a double-blinded, randomized controlled trial (RCT), Schoenen et al (2013) examined the safety and efficacy of trigeminal neurostimulation with a supraorbital transcutaneous stimulator (Cefaly, STX-Med., Herstal, Belgium) in migraine prevention. This trial was conducted at 5 Belgian tertiary headache clinics. After a 1-month run-in, patients with at least 2 migraine attacks/month were randomized 1:1 to verum (n = 34) or sham (n = 33) stimulation, and applied the stimulator daily for 20 mins during 3 months. Primary outcome measures were change in monthly migraine days and 50 % responder rate. A total of 67 patients were randomized and included in the intention-to-treat analysis. Between run-in and third month of treatment, the mean number of migraine days decreased significantly in the verum (6.94 versus 4.88; p = 0.023), but not in the sham group (6.54 versus 6.22; p = 0.608). The 50 % responder rate was significantly greater (p = 0.023) in the verum (38.1 %) than in the sham group (12.1 %). Monthly migraine attacks (p = 0.044), monthly headache days (p = 0.041), and monthly acute anti-migraine drug intake (p = 0.007) were also significantly reduced in the verum but not in the sham group. There were no AEs in either group. The authors concluded that supraorbital transcutaneous stimulation with the device used in this trial was safe and effective as a preventive therapy for migraine. The therapeutic gain (26 %) was within the range of those reported for other preventive drug and non-drug anti-migraine treatments. Moreover, they stated that adequate studies are needed to disentangle the precise mode of action. This study provided Class III evidence that treatment with a supraorbital transcutaneous stimulator was safe and effective as a preventive therapy for migraine.
The authors noted that despite methodologic precautions including concealed allocation, partial un-blinding may have occurred in this trial. It was difficult to blind peripheral neurostimulation trials because the effective electrical stimulation produces intense paresthesia. These investigators doubted, however, that un-blinding markedly influenced their results for the following reasons. The sham response was within the range of that found in other trials with neurostimulation devices. Compared to the ONSTIM trial of occipital nerve stimulation, it was even higher for the 50 % responder rate: 6 % in ONSTIM, 12.8 % in PREMICE. Un-blinding could thus have been twice more pronounced in ONSTIM than in PREMICE, if one assumed that it was inversely proportional to the percentage of responders in a sham group. The rather small difference (7.3 %) in compliance rates between verum and sham groups also did not favor massive un-blinding. If this were the case, one would expect a much lower compliance in the sham group. Another possible weakness of this trial appeared when data from the different centers were analyzed: patients in the verum group were on average younger than those in the sham group and the duration of their migraine was somewhat shorter. On post-hoc statistical analyses these researchers were unable, however, to detect an influence of age or of disease duration on treatment outcome. In the ONSTIM trial, the difference in mean age between the effectively stimulated patients and the smaller “ancillary” group was 9 years. Overall, both patient groups in PREMICE were well in the age range of migraine patients included in other trials. These researchers stated that beyond statistics, the question whether the results of the PREMICE trial were clinically relevant merits consideration. Besides the therapeutic gain for 50 % responders, other outcome measures suggested that STS could be of benefit to migraine patients. It decreased significantly consumption of acute anti-migraine drugs, which is a pharmaco-economical advantage. In addition, more than 70 % of effectively stimulated patients were satisfied with the treatment. The patients recruited for PREMICE were not the most disabled migraineurs. Having 4 migraine attacks or 7 migraine days per month, they were similar, however, to those included in topiramate trials and representative of the majority of migraine patients in the general population who are in need of preventive treatment according to international recommendations. Whether STS treatment is effective in patients with more frequent attacks or with chronic migraine remains to be determined.
Russo and Tessitore (2015) noted that transcutaneous supraorbital neurostimulation (tSNS) has been recently found superior to sham stimulation for episodic migraine prevention in a randomized trial. These researchers evaluated both the safety and efficacy of a brief period of tSNS in a group of patients with migraine without aura (MwoA). They enrolled 24 consecutive patients with MwoA experiencing a low frequency of attacks, which had never taken migraine preventive drugs in the course of their life. Patients performed a high frequency tSNS and were considered “compliant” if they used the tSNS for greater than or equal to 2/3 of the total time expected. For this reason, 4 patients were excluded from the final statistical analysis. Primary outcome measures were the reduction migraine attacks and migraine days per month (p < 0.05). Furthermore, these investigators evaluated the percentage of patients having at least 50 % reduction of monthly migraine attacks and migraine days. Secondary outcome measures were the reduction of headache severity during migraine attacks and HIT-6 (Headache Impact Test) rating as well as in monthly intake of rescue medication (p < 0.05). Finally, compliance and satisfaction to treatment and potential adverse effects related to tSNS have been evaluated. Between run-in and 2nd month of tSNS treatment, both primary and secondary end-points were met. Indeed, these researchers observed a statistically significant decrease in the frequency of migraine attacks (p < 0.001) and migraine days (p < 0.001) per month. They also demonstrated at least 50 % reduction of monthly migraine attacks and migraine days in respectively 81 % and 75 % of patients. Furthermore, a statistically significant reduction in average of pain intensity during migraine attacks (p = 0.002) and HIT-6 rating (p < 0.001) and intake of rescue medication (p < 0.001) has been shown. All patients showed good compliance levels and no relevant AEs. The authors concluded that in patients experiencing a low frequency of attacks, significant improvements in multiple migraine severity parameters were observed following a brief period of high frequency tSNS. Thus, tSNS may be considered a valid option for the preventive treatment of migraine attacks in patients who cannot or are not willing to take daily medications, or in whom low migraine frequency and/or intensity would not require pharmacological preventive therapies.
The authors stated that this study had several drawbacks. First, these researchers did not use a tSNS sham device and, therefore, they could not rule-out the possible role of a placebo-effect on primary and secondary outcomes in this study. In particular, several factors may contribute to the remedial efficacy of tSNS in these patients such as alternative form of medical therapy, patients naïve to preventive treatment and observation period limited to no more than 2 months. However, the placebo-effect appeared to have a lower impact in the prophylactic treatment than in the acute treatment of migraine attacks. This could be due to the inherent variability in response measured over a period of months compared with one measured over a period of hours. Moreover, the effective tSNS superiority respect to sham stimulation for the prevention of migraine headaches has been extensively demonstrated in a previous RCT in a large cohort of patients with migraine. Nevertheless, in partial disagreement with these findings, Schoenen and colleagues (2013) did not show statistically significant effect on migraine attacks at 2 months, although ameliorating effect on migraine severity vanished in sham treated patients and amplified in effectively treated patients at this time of the study. These investigators suggested that a greater migraine severity (i.e., frequency of migraine per month and disease duration) and, probably, previous pharmacological anti-migraine preventive therapies may cause a different impact on pain pathways in the 2 migraine populations and consequent different response to the tSNS treatment. Second, the lack of blinding may weaken the results of the present study. However, empirical evidence showed that although double-blind RCTs are the gold standard for proving efficacy of a therapeutic procedure, they often suffer from lack of generalizability. Therefore, the authors believed that these data, in addition to the previous effectiveness and safety results of double-blind RCTs (Schoenen and colleagues, 2013) could provide additional information which may be useful in everyday clinical practice. Finally, although these findings were consistent with previous studies, the sample size was relatively small (n = 20 available for final analysis). Thys, they stated that further studies are needed to corroborate these findings and to explore tSNS efficacy and tolerability in patients with migraine compared with preventive treatments used in clinical practice.
Magis et al (2017) noted that a recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention. However, its mechanism of action remains unknown. These researchers performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs. A total of 28 individuals were recruited: 14 with MO and 20 healthy volunteers (HVs). HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly) and after 3 months of treatment (uncontrolled study). The frequency of migraine attacks significantly decreased in compliant patients (n = 10). Baseline FDG-PET revealed a significant hypo-metabolism in fronto-temporal areas, especially in the orbito-frontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients. This hypo-metabolism was reduced after 3 months of eTNS treatment. The authors concluded that the findings of this study suggested that OFC and rACC are hypo-metabolic in MO patients at rest. After a 3-month treatment with eTNS, this hypo-metabolism was reduced and the changes were associated with a significant decrease of migraine attack frequency. It is known that neurostimulation can modulate OFC and rACC activity. Like cluster and medication overuse headache, MO appeared to be associated with dysfunction of medial frontal cortex areas involved in affective and cognitive dimensions of pain control. Because this study was under-powered and had no sham arm, these researchers were unable to formally attribute the metabolic changes to the non-invasive neurostimulation treatment. Nonetheless, the observed effect was likely similar to that found with invasive neurostimulation of peri-cranial nerves, such as pONS. These researchers stated that further trials are needed to confirm these findings.
The authors stated that this study had several drawbacks. Because of the small number of evaluable patients (n = 14), the results must be taken with caution. As discussed, the study design did not allow assessing a direct causal effect of eTNS on brain metabolism since a sham condition is missing. These investigators found sham stimulation for 3 months would be unethical knowing that there is evidence for eTNS efficacy from an RCT. The compliance rate with eTNS therapy was rather low. For preventive drug treatments, adherence varies from 48 % to 94 % between studies. Neurostimulation was more time consuming (20 mins daily in this study), which provoked lower compliance. In the PREMICE trial, patients had a compliance rate of 62 %, while participants renting the eTNS Cefaly device via the internet used it on average 58 % of the recommended time. In this study, the authors considered patients who performed at least 30 % of the sessions as “compliant”; this threshold was chosen on an empirical basis and experience from clinical practice showing that patients may benefit from eTNS with non-daily use of the device. However, the minimal time of use to obtain a clinical improvement in migraine is unknown, and may vary between patients. Although the headache diaries allowed monitoring global intake of acute medications for each patient, they did not allow these researchers to determine the precise proportion of drugs taken within each of the pharmacological classes, analgesics, NSAIDs, triptans, nor its possible change after eTNS. I t is unlikely, however, that such a change would have influenced brain metabolism.
Russo et al (2017) examined the functional re-organization of the pain processing network during trigeminal heat stimulation (THS) after 60 days of eTNS in migraine without aura (MwoA) patients between attacks. Using whole-brain BOLD-fMRI, functional response to THS at 2 different intensities (41 and 51°C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly device. These researchers calculated the percentage of patients having at least a 50 % reduction of monthly migraine attacks and migraine days between baseline and the last month of eTNS. Secondary analyses evaluated associations between BOLD signal changes and clinical features of migraine. Before eTNS treatment, there was no difference in BOLD response between MwoA patients and healthy controls (HC) during low-innocuous THS at 41°C, whereas the perigenual part of the right anterior cingulate cortex (ACC) revealed a greater BOLD response to noxious THS at 51°C in MwoA patients when compared to HC. The same area demonstrated a significant reduced BOLD response induced by the noxious THS in MwoA patients after eTNS (p = 0.008). Correlation analyses showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS. Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found. The authors concluded that the findings of this study suggested that eTNS treatment with the Cefaly® device induced a functional anti-nociceptive modulation in the ACC that is involved in the mechanisms underlying its preventive anti-migraine efficacy. Nevertheless, these researchers stated that further observations to confirm whether the observed fMRI effects of eTNS are both related to clinical improvement and specific to anti-nociceptive modulation in migraine patients are mandatory.
The authors noted that this study had several drawbacks. First, these investigators did not use an eTNS sham device and, therefore, they could not rule out the possible role of a placebo effect in imaging and clinical data. However, the superiority of effective eTNS respect to sham stimulation for the prevention of migraine headaches has already been demonstrated in a randomized, sham-controlled trial. Second, the HC did not undergo eTNS treatment, thus, the authors could not determine if the eTNS-induced changes in ACC activation by THS were specific to migraineurs. By corollary, these researchers could not exclude that these changes could be due to the clinical improvement of patients after eTNS, rather than to the neurostimulation treatment itself.
An UpToDate review on “Preventive treatment of migraine in adults” (Bajwa and Smith, 2018) states that “Transcutaneous nerve stimulation -- Although data are limited, the findings of a controlled trial conducted at 5 tertiary headache centers in Belgium suggest that treatment with a supraorbital transcutaneous electrical nerve stimulator is beneficial for patients with episodic migraine. The trial randomly assigned 69 adults with migraine (with or without aura) to active or sham stimulation for 20 minutes daily for three months. Exclusion criteria included the use of preventive treatment for migraine in the 3 months prior to enrollment. At 3 months of treatment, the responder rate, defined as the percentage of subjects with a ≥ 50 % reduction in migraine days per month, was significantly higher for the active stimulation compared with the sham stimulation group (38.2 versus 12.1 %), as was the mean reduction in monthly migraine days (-2.1 versus +0.3 days). There were no adverse events in either group. Limitations to this trial include small effect size, low patient numbers, and uncertainty in concealing treatment allocation, given that active stimulation causes intense paresthesia. The device used in this trial is approved for marketing in the United States, Canada, Europe, and several additional countries … Non-pharmacologic measures that may be beneficial for migraine headache prevention include aerobic exercise, biofeedback, other forms of relaxation training, cognitive-behavioral therapies, acupuncture, and transcutaneous electrical nerve stimulation”.
Furthermore, an UpToDate review on “Preventive treatment of migraine in children” (Mack, 2018) does not mention “Cefaly / supraorbital transcutaneous electrical nerve stimulation” as a management option.
Quell Device
A recently FDA-cleared device, the Quell device, is the first electrical stimulator to receive approval for use during sleep. The device consists of a band worn around the upper calf to theoretically provide systemic relief of chronic pain and is controlled by an individual’s smartphone or tablet. Like a TENS unit, the electrode strip sends electrical signals that trigger one’s body's own pain relief mechanisms. The Quell is an FDA-approved Class II medical device for symptomatic relief and management of chronic pain. It is available without a prescription.
An UpToDate review on “Management of non-radicular neck pain in adults” (Isaac, 2020) states that “Transcutaneous electrical nerve stimulation -- Although transcutaneous electrical nerve stimulation (TENS) is widely used in the management of musculoskeletal pain syndromes, the evidence of its efficacy is uncertain. In a systematic review including 7 trials of TENS in the treatment of chronic neck pain, no definitive conclusions could be drawn due to the heterogeneity in study interventions and measured outcomes. Even when including only the 2 trials comparing TENS with placebo (sham TENS treatment) for neck pain, there was very low certainty evidence for similar short-term pain outcomes … We do not routinely recommend the use of cervical collars, low-level laser light therapy (LLLT), cervical traction, botulinum toxin injections, transcutaneous electrical nerve stimulation (TENS), electromagnetic therapy, or surgery for the treatment of non-radicular neck pain”.
Combination Therapies
A more recent approach to electrical stimulation has been development of devices that may use a combination of different stimulation modalities, such as combining TENS with ICS, TENS with ultrasound, TENS with low level laser therapy (LLLT) or TENS with neuromuscular stimulation (NMES). Examples of combination devices include, but may not be limited to, the Neurolumen device (combines TENS with LLLT and light-emitting diode (LED) therapy) or the Empi Phoenix and QB1 System (combination TENS with NMES devices).
Additionally, combined ICS and muscle stimulation utilize ICS for pain and muscle stimulation to treat underlying muscle conditions. Examples of this type of device are the RS-4i sequential stimulator and the EMSI TENS/EMS-14.
In combined therapy which consists of high frequency electrical stimulation and peripheral nerve block (also referred to as combination electrochemical therapy, combination electrochemical treatment, or CET), it is purported to treat peripheral neuropathy by first injecting the peripheral nerve with a local anesthetic, followed by a high frequency electrical stimulation.
In a sham-controlled, single-blinded, single-center, cross-over study, Li and co-workers (2018) examined if transcranial direct current stimulation (tDCS) augments the analgesic effect of breathing-controlled electrical stimulation (BCES) in patients with spinal cord injury (SCI) who have chronic neuropathic pain. This trial included 12 participants with incomplete SCI. The treatment protocol included a 20-min tDCS (sham or active), followed by a 20-min BCES to the median nerve on the dominant side. The treatment session with sham or control tDCS was given on different days in a randomized order; VAS was used to assess neuropathic pain at baseline, 10 mins after tDCS, and 10 mins after BCES. Subjects were blinded to the status of tDCS. Of the 12 subjects, 10 completed sessions of both sham and active tDCS, while the other 2 completed only active tDCS and BCES treatment. Of the 12 subjects, 7 showed analgesic effects after active tDCS, while sham tDCS produced some analgesic effects in 4 of 10 subjects. At the group level, there was no difference between active and sham tDCS treatment. All except 1 subject responded positively to BCES in all sessions; VAS score for pain decreased significantly after BCES combined with either active tDCS or sham tDCS treatment. The authors concluded that the immediate analgesic effect of BCES was confirmed. However, this effect was not augmented after 1 session of tDCS treatment.
SENSUS Device
The SENSUS device uses transcutaneous electromagnetic nerve stimulation to purportedly treat individuals with diabetic peripheral neuropathy.
Galvanic Stimulation for Peripheral Arterial Disease
Williams et al (2017) noted that PAD is common and symptoms can be debilitating and lethal. Risk management, exercise, radiological and surgical intervention are all valuable therapies, but morbidity and mortality rates from this disease are increasing. Circulatory enhancement can be achieved using simple medical electronic devices, with claims of minimal adverse side effects. The evidence for these is variable, prompting a review of the available literature. Embase and Medline were interrogated for full text articles in humans and written in English. Any external medical devices used in the management of PAD were included if they had objective outcome data. A total of 31 papers met inclusion criteria, but protocols were heterogeneous. The medical devices reported were intermittent pneumatic compression (IPC), NMES or EMS, and galvanic electrical dressings. In patients with intermittent claudication, IPC devices increase popliteal artery velocity (49 to 70 %) and flow (49 to 84 %). Gastrocnemius EMS increased superficial femoral artery flow by 140 %. Over 4.5 to 6 months IPC increased intermittent claudication distance (ICD) (97 to 150 %) and absolute walking distance (AWD) (84 to 112 %), with an associated increase in quality of life; NMES of the calf increased ICD and AWD by 82 % and 61 to 150 % at 4 weeks, and 26 % and 34 % at 8 weeks. In patients with critical limb ischemia (CLI), IPC reduced rest pain in 40 to 100 % and was associated with ulcer healing rates of 26 %; IPC had an early limb salvage rate of 58 to 83 % at 1 to 3 months, and 58 to 94 % at 1.5 to 3.5 years. No studies have reported the use of EMS or NMES in the management of CLI. The authors concluded that there is evidence to support the use of IPC in the management of claudication and CLI. There is a building body of literature to support the use of electrical stimulators in PAD, but this is low level to date. Devices may be of special benefit to those with limited exercise capacity, and in non-reconstructable CLI. Moreover, they stated that galvanic stimulation is not recommended.
Electrical Stimulation for the Treatment of Chronic Pelvic Pain
Fuentes-Marquez and colleagues (2018) summarized the available scientific evidence on physiotherapy interventions in the management of chronic pelvic pain (CPP). These researchers carried out a systematic review of RCTs. An electronic search of Medline, CINAHL, and Web of Science databases was performed to identify relevant randomized trials from 2010 to 2016. Manuscripts were included if at least 1 of the comparison groups received a physiotherapy intervention. Studies were assessed in duplicate for data extraction and risk of bias using the Physiotherapy Evidence Database scale PEDro; 8 of the studies screened met the inclusion criteria -- 4 manuscripts studied the effects of electrotherapy including intravaginal electrical stimulation, short wave diathermy, respiratory-gated auricular vagal afferent nerve stimulation, percutaneous tibial nerve stimulation, and sono-electro-magnetic therapy with positive results; 3 studies focused on manual assessing the efficacy of myofascial versus massage therapy in 2 of them and ischemic compression for trigger points. The authors concluded that although physiotherapy interventions showed some beneficial effects, evidence could not support the results. They stated that heterogeneity in terms of population phenotype, methodological quality, interpretation of results, and operational definition resulted in little overall evidence to guide treatment.
Electrical Stimulation of the Posterior Tibial Nerve for the Treatment of Neuropathic Pain associated with Polyneuropathy
Dabby and associates (2018) stated that peripheral neuropathic pain (PNP) is caused by neuronal damage to the peripheral nervous system (PNS) and usually affects the distal extremities. In an open-label study, these researchers examined the effect of short-term PNS on individuals with PNP due to polyneuropathy. A total of 12 patients (mean age of 63.0 ± 10.0 years, 41.7 % men) with daily bilateral PNP for at least 6 months (mean duration of neuropathic pain of 7.4 ± 7.8 years) received a total of 6 direct electrical stimulation therapies to the posterior tibial nerve at 3 to 4-day intervals; 8 patients completed the study and were included in the efficacy analysis. The average pain at baseline was 36.6 ± 3.80 estimated by the Short-Form McGill Pain Questionnaire. After the last stimulation, pain was significantly reduced by 85.5 % to 4.88 ± 3.1 (p = 0.008); 6 patients (75 %) had over 50 % decrease in pain after the first stimulation therapy and 99.2 % after the final stimulation therapy. The patients also reported statistically significant decreases in pain level (measured by VAS), ranging from 54.85 % to 87.50 % after each of the stimulations as compared to the pain experienced prior to the stimulations. The authors concluded that the procedure was safe without any serious AEs; PNS has shown excellent efficacy and improvement of PNP symptoms. Moreover, they stated that further studies in larger patient populations and longer duration are needed.
The authors stated that this study’s drawbacks included its small sample size (n = 8), short duration of treatment (6 months), and 33 % patient drop-out.
Reduced Impedance Non-Invasive Cortical Electrostimulation (RINCE) for the Treatment of Chronic Pain
O'Connell and colleagues (2018) provided an update on the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), tDCS, transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE). These investigators evaluated the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain. For this update, they searched CENTRAL, Medline, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017. Randomized and quasi-randomized studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of 3 months' duration or more, and measured pain as an outcome were selected for analysis. Outcomes of interest were pain intensity measured using VAS or NRS, disability, QOL and adverse events (AEs). These investigators included an additional 38 trials (involving 1,225 randomized participants) in this update, making a total of 94 trials in the review (involving 2,983 randomized participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, 2 RINCE and 2 tRNS; 1 study evaluated both rTMS and tDCS. These investigators judged only 4 studies as low-risk of bias across all key criteria. The authors concluded that there is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and QOL; but multiple sources of bias existed that may have influenced the observed effects. These researchers did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES were effective for reducing pain intensity in chronic pain. They noted that the broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation.
Scrambler Therapy for Neuropathic Pain Associated with Chemotherapy-Induced Peripheral Neuropathy
Tomasello and colleagues (2018) noted that chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy in need of effective treatment. Preliminary data supported the efficacy of scrambler therapy (ST), a non-invasive cutaneous electrostimulation device, in adults with CIPN. These researchers examined the safety, efficacy, and durability of ST for neuropathic pain in adolescents with CIPN. They studied 9 pediatric patients with cancer and CIPN who received ST for pain control. Each patient received 45-min daily sessions for 10 consecutive days as a first step, but some of them required additional treatment. Pain significantly improved comparing NRS after 10 days of ST (9.22 ± 0.83 versus 2.33 ± 2.34; p < 0.001) and at the end of the optimized cycle (EOC) (9.22 ± 0.83 versus 0.11 ± 0.33, p < 0.001). The improvement in QOL was significantly reached on pain interference with general activity (8.67 ± 1.66 versus 3.33 ± 2.12, p < 0.0001), mood (8.33 ± 3.32 versus 2.78 ± 2.82, p < 0.0005), walking ability (10.00 versus 2.78 ± 1.22, p < 0.0001), sleep (7.56 ± 2.24 versus 2.67 ± 1.41, p < 0.001), and relations with people (7.89 ± 2.03 versus 2.11 ± 2.03, p < 0.0002; Lansky score 26.7 ± 13.2 versus 10 days of ST 57.8 ± 13.9, p < 0.001; 26.7 ± 13.2 versus EOC 71.1 ± 16.2, p < 0.001). The authors concluded that based on these preliminary data, ST could be a good choice for adolescents with CIPN for whom pain control is difficult; ST caused total relief or dramatic reduction in CIPN pain and an improvement in QOL, durable in follow-up. It resulted in no detected side effects, and could be re-trained successfully. Moreover, these researchers stated that further larger studies are needed to confirm these promising preliminary data in pediatric patients with cancer.
Transcutaneous Electrical Nerve Stimulation for the Treatment of Migraine
Tao and colleagues (2018) stated that migraine is now ranked as the 2nd most disabling disorder worldwide reported by the Global Burden of Disease Study 2016. As a non-invasive neuro-stimulation technique, TENS has been applied as an abortive and prophylactic treatment for migraine recently. These investigators conducted this meta-analysis to analyze the safety and effectiveness of TENS on migraineurs. They searched Medline (via PubMed), Embase, the Cochrane Library and the Cochrane Central Register of Controlled Trials to identify RCTs, which compared the effect of TENS with sham TENS on migraineurs. Data were extracted and methodological quality assessed independently by 2 reviewers. Change in the number of monthly headache days, responder rate, painkiller intake, adverse events and satisfaction were extracted as outcome. A total of 4 studies were included in the quantitative analysis with 161 migraine patients in real TENS group and 115 in sham TENS group. These researchers found significant reduction of monthly headache days (SMD: -0.48; 95 % CI: -0.73 to - 0.23; p < 0.001) and painkiller intake (SMD: -0.78; 95 % CI: -1.14 to - 0.42; p < 0.001). Responder rate (RR: 4.05; 95 % CI: 2.06 to 7.97; p < 0.001) and satisfaction (RR: 1.85; 95 % CI: 1.31 to 2.61; p < 0.001) were significantly increased compared with sham TENS. The authors concluded that the findings of this meta-analysis suggested that TENS may serve as an effective and well-tolerated alternative for migraineurs. However, they stated that the low quality of evidence prevented them from reaching definitive conclusions; future well-designed RCTs are needed to confirm and update the findings of this analysis.
Transcutaneous Electrical Nerve Stimulation for the Treatment of Chronic Pain Following Ankylosing Spondylitis
Chen and colleagues (2018) examined the effect of TENS for the treatment of patients with chronic pain after ankylosing spondylitis (AS). A total of 72 eligible patients with chronic pain following AS were included. All included patients received exercise and were assigned to a treatment group and a control group equally. In addition, patients in the treatment group also underwent TENS therapy. All patients were treated for a total of 6 weeks. The primary outcome of pain intensity was measured by VAS. The secondary outcomes included degree of functional limitation, as assessed by Bath Ankylosing Spondylitis Functional Index (BASFI); and QOL, as evaluated by Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire. All outcomes were assessed before and after 6 weeks treatment. Furthermore, adverse events were also recorded. After 6-week treatment, patients in the treatment group did not show more promising outcomes in pain reduction, as measured by VAS (p = 0.08); functional evaluation, as evaluated by BASFI (p = 0.19); as well as QOL, as assessed by ASQOL (p = 0.18), compared with patients in the control group; no AEs occurred in both groups. The authors concluded that this study did not exert encouraging outcomes in patients with chronic pain following AS after 6-week treatment.
Transcutaneous Electrical Nerve Stimulation (TENS) for the Treatment of Carpal Tunnel Syndrome Pain
In a randomized, pilot study, Casale et al (2013) compared laser versus TENS in reducing pain and paresthesia; and in improving motor and sensory median nerve conduction parameters in mild-to-moderate carpal tunnel syndrome (CTS). Patients and staff administered treatments and outcome measures were blinded. A total of 20 symptomatic CTS patients were included in this trial; 15 sessions of 100-Hz TENS (30 mins; rectangular waves; 80 ms width, intensity below muscle contraction); combined 830 to ,1064 nm laser (radiating dose: 250 J cm-2 delivered to the skin overlying the course of the median nerve at the wrist for 100 s at 25 W (18 W [1,064 nm] + 7 W [830 nm]) via a fiber-optic probe with a spot size of approximately 1 cm2). Outcome measures were VAS for pain and paresthesia; median nerve motor distal latency (mMDL) and median sensory nerve conduction velocity (mSNCV). Laser improved both positive and negative sensory symptoms; TENS induced clinical improvement but this was not statistically significant and was limited to pain reduction. Laser, but not TENS, favorably modified the neurophysiological parameters. The authors concluded that high-intensity combined laser wavelengths of 830 nm and 1,064 nm, which produced a better transparency with less scattering and a high energy transfer, were better than TENS in improving both pain and paresthesia as well as neurophysiological parameters in CTS.
In a RCT, Koca et al (2014) examined the effectiveness of interferential current (IFC) and TENS therapies in the management of CTS compared with splint therapy. This was a prospective, single-blinded, single-center, randomized, 3-group parallel intervention study of 3 weeks duration. Efficacy was examined in the 3rd week after the end of treatments. Subjects were randomly assigned to 1 of the 3 groups: group I patients received splint therapy, group II patients received TENS applied on the palmar surface of the hand and the carpal tunnel, and group III patients underwent IFC therapy applied on the palmar surface of the hand and the volar surface of the forearm. TENS and ICF treatments were applied 5 times weekly for a total of 15 sessions. Group 1 patients were stabilized with volar wrist splints for 3 weeks. The efficacy of the therapies was assessed before initiation of therapy and at 3 weeks after completion of therapy using a VAS, a symptom severity scale, the functional capacity scale of the BCTQ, and measurements of mMDL and mSNCV. Groups were compared pair-wise using the Mann-Whitney U test to identify the source of differences between groups. The Wilcoxon test was used to analyze changes in variables over time within a group. In the VAS, BCTQ, mMDL, and mSNCV, no significant difference was observed between the groups (p > 0.05). In the VAS, BCTQ, and mSNCV, statistically significant improvements were detected in all groups (p < 0.05). There was no statistically significant difference between TENS and splint therapy with respect to improvement in clinical scores, whereas IFC therapy provided a significantly greater improvement in VAS, mMDL, and mSNCV values than splint therapy (VAS: 4.80 ± 1.18 and 6.37 ± 1.18; p = 0.001, mMDL: 3.89 ± 0.88 and 4.06 ± 0.61; p = 0.001, mSNCV: 41.80 ± 1.76 and 40.75 ± 1.48; p = 0.010). IFC therapy provided a significantly greater improvement in VAS, symptom severity, functional capacity, and mMDL and mSNCV values than TENS therapy (VAS: 4.80 ± 1.18 and 6.68 ± 1.42; p < 0.001, symptom severity: 2.70 ± 1.03 and 3.37 ± 1.21; p = 0.015, functional capacity: 1.90 ± 1.21 and 2.50 ± 0.78; p = 0.039, mMDL: 3.89 ± 0.88 and 4.06 ± 0.88; p = 0.003, and mSNCV: 41.80 ± 1.76 and 41.38 ± 1.78; p = 0.021). The authors concluded that IFC may be considered a new and safe therapeutic option for the treatment of CTS.
In a systematic review, Huisstede et al (2018) examined scientific literature studying the effectiveness of physical therapy and electrophysical modalities for the treatment of CTS. Data sources included the Cochrane Library, PubMed, Embase, CINAHL, and Physiotherapy Evidence Database; 2 reviewers independently applied the inclusion criteria to select potential eligible studies; and 2 reviewers independently extracted the data and assessed the methodologic quality using the Cochrane Risk of Bias Tool. A best-evidence synthesis was carried out to summarize the results of the included studies (2 reviews and 22 RCTs). For physical therapy, moderate evidence was found for myofascial massage therapy versus ischemic compression on latent, or active, trigger points or LLLT in the short-term. For several electrophysical modalities, moderate evidence was found in the short-term (ultrasound [US] versus placebo, US as single intervention versus other non-surgical interventions, US versus corticosteroid injection plus a neutral wrist splint, local microwave hyperthermia versus placebo, iontophoresis versus phonophoresis, pulsed radiofrequency (PRF) added to wrist splint, continuous versus pulsed versus placebo shortwave diathermy, and IFC versus TENS versus a night-only wrist splint). In the mid-term, moderate evidence was found in favor of radial extracorporeal shockwave therapy (ESWT) added to a neutral wrist splint, in favor of ESWT versus US, or cryo-US, and in favor of US versus placebo. For all other interventions studied, only limited, conflicting, or no evidence was found. No RCTs investigating the long-term effects of physical therapy and electrophysical modalities were found. Because of heterogeneity in the treatment parameters used in the included RCTs, optimal treatment parameters could not be identified. The authors concluded that moderate evidence was found for several physical therapy and electrophysical modalities for CTS in the short-term and mid-term. Moreover, these researchers stated that future studies should concentrate on long-term effects and which treatment parameters of physical therapy and electrophysical modalities are most effective for CTS.
Neurogenx 4000PRO Device for the Treatment of Achilles Tendonitis
The Neurogenx 4000PRO (400 to 40,00 Hz) is a FDA-cleared electromedical device used for the treatment of various types of neuropathies and chronic pain conditions including CRPS, fibromyalgia, migraines, neuritis, phantom limb pain, plantar fasciitis, radiculopathy and restless leg syndrome. However, there is a lack of evidence regarding its clinical effectiveness.
Sprint (Peripheral Subcutaneous Field Stimulation)
The SPRINT PNS System consists of open-coil leads implanted percutaneously, typically using ultrasound or fluoroscopic guidance, with stimulation delivered by an external pulse generator for up to 60 days. Patients controlled the intensity of stimulation with a wireless remote, and the leads were removed at the end of the treatment period.
Dunteman (2002) stated that post-herpetic neuralgia (PHN) is a common cause of chronic pain in the elderly. Opioids and adjunctive analgesics such as antidepressants and anticonvulsants effectively reduce discomfort in many patients, while others have pain that remains resistant to all forms of therapy. While SCS has shown promise for severe truncal and extremity PHN, it has no impact on neuralgias of cranial nerve origin. Peripheral nerve stimulation (PNS) has been described for problems such as CRPS; however, it has not been reported for cranial nerve syndromes. The author described the cases in which an 86-year-old man and a 76-year-old woman with intractable PHN of greater than 6 and 4 years, respectively, were effectively treated with PNS of the ophthalmic division of the trigeminal nerve.
Wilson et al (2014) investigated the effectiveness of a specific intervention (PNS) compared to usual care (UC) in stroke survivors experiencing pain. The study aimed to assess pain reduction and overall treatment success over a 16-week period. The study screened 88 stroke survivors, with 35 meeting the inclusion criteria. Ultimately, 25 participants were enrolled, with 13 assigned to the PNS group and 12 to the UC group. The PNS group received a specific pain management intervention, while the UC group received standard care. The primary outcome was measured using the Brief Pain Inventory Short Form (BPI-SF3), assessing pain interference. Secondary outcomes included additional pain measures and global treatment success defined as a 30% reduction in pain maintained at follow-up points (weeks 10 and 16). The study found a significant treatment effect, with the PNS group showing a greater reduction in pain compared to the UC group. Specifically, the PNS group had a higher rate of successful outcomes (30% pain reduction) maintained at all follow-up time points. The authors noted several limitations in their study, including the lack of blinding of study participants. The relatively small sample size (25 participants) may limit the generalizability of the findings. Some participants were lost to follow-up, which could introduce bias in the results. The study had strict exclusion criteria, which may have omitted individuals who could benefit from the intervention. Conducting the study at a single center may affect the diversity of the participant population and the applicability of the results to broader settings. The authors emphasized the necessity for further research to validate their findings. They suggested larger, multi-center trials to confirm the efficacy of PNS in diverse populations, exploration of long-term outcomes and the impact of PNS on quality of life, and investigating the mechanisms behind the observed pain relief to better understand how PNS works in stroke survivors. In conclusion, while the study presents promising results for the PNS intervention in managing pain among stroke survivors, the noted limitations and the call for further research highlight the need for continued investigation in this area.
Wilson et al (2014) investigated the effects of a specific neuromodulation treatment on pain and disability in patients with shoulder-related conditions. The study involved a small cohort of ten participants, with a focus on measuring changes in pain levels, shoulder-related disability, and pain interference over time. The study recruited ten participants, although three did not complete all assessments due to various reasons, including loss to follow-up and withdrawal after corticosteroid injections. Ultimately, seven participants completed all outcome assessments. The study reported a significant reduction in pain levels as measured by the Brief Pain Inventory Short Form (BPI-SF). The results indicated that at the end of treatment (EOT, week 4), pain decreased by 36.6% (p < 0.01). At week 5, pain decreased by 35.4% (p < 0.01). At week 8, pain decreased by 40.2% (p < 0.01). At week 16, pain decreased by 48.8% (p < 0.01). Overall, 60% of participants met the criteria for treatment success, defined as a 2-point or 30% reduction in pain at EOT. The study also found significant improvements in shoulder-related disability, measured by the Disabilities of the Arm, Shoulder, and Hand (DASH) score. At EOT, disability decreased by 45.5% (p < 0.01). At week 5, it decreased by 37.4% (p = 0.01). At week 8, it decreased by 53.7% (p < 0.01). At week 16, it decreased by 47.5% (p < 0.01). There was a significant reduction in pain interference, also measured by the BPI-SF, with the analysis showing a significant decrease in pain interference over the study period. The authors noted several limitations in their study, including a small sample size, which limits the generalizability of the findings. The exploratory nature of the study meant that a formal power analysis was not conducted, which may affect the reliability of the results. The loss of three participants may introduce bias and affect the overall outcomes, and the absence of a control group makes it difficult to attribute the observed improvements solely to the treatment. The authors emphasized the necessity for further research to validate their findings, suggesting that larger, controlled studies are needed to confirm the efficacy of the neuromodulation treatment and to explore its long-term effects on pain and disability in a broader patient population. They highlighted the importance of understanding the mechanisms behind the treatment’s effects to optimize therapeutic strategies for shoulder-related conditions.
Ilfeld and colleagues (2018) noted that percutaneous PNS is an analgesic modality involving the insertion of a lead through an introducing needle followed by the delivery of electric current. This modality has been reported to treat chronic pain as well as post-operative pain the day following knee surgery. However, it remains unknown if this analgesic technique may be used in ambulatory subjects following foot procedures beginning within the recovery room immediately following surgery, and with only short series of patients reported to-date, the only available data are derived from strictly observational studies. In a proof-of-concept study, these researchers examined the feasibility of using percutaneous sciatic nerve PNS to treat post-operative pain following ambulatory foot surgery in the immediate post-operative period and provided the first available data from a randomized controlled study design to provide evidence of analgesic effect. Pre-operatively, an electrical lead (SPRINT; SPR Therapeutics, Inc., Cleveland, OH) was percutaneously inserted posterior to the sciatic nerve between the sub-gluteal region and bifurcation with US-guidance. Following hallux valgus osteotomy, subjects received 5 mins of either stimulation or sham in a randomized, double-masked fashion followed by a 5-min cross-over period and then continuous stimulation until lead removal on post-operative days 14 to 28. During the initial 5-min treatment period, subjects randomized to stimulation (n = 4) experienced a down-ward trajectory in their pain over the 5 mins of treatment, whereas those receiving sham (n = 3) reported no such change until their subsequent 5-min stimulation cross-over. During the subsequent 30 mins of stimulation, pain scores decreased to 52 % of baseline (n = 7); 3 subjects (43 %) used a continuous popliteal nerve block for rescue analgesia during post-operative days 0 to 3. Overall, resting and dynamic pain scores averaged less than 1 on the NRS, and opioid use averaged less than 1 tablet daily with active stimulation. One lead dislodged, 2 fractured during use, and 1 fractured during intentional withdrawal. The authors concluded that this small, pilot, proof-of-concept study demonstrated that percutaneous sciatic nerve PNS was feasible for ambulatory foot surgery and suggested that this modality provided analgesia and decreased opioid requirements following hallux valgus osteotomy procedures. However, lead dislodgement and fracture were concerns. Moreover, they stated that the findings of this pilot study indicated that a subsequent clinical trial is needed.
The authors stated that this study had several drawbacks. Prior experience with percutaneous PNS in post-operative subjects 6 to 97 days following knee arthroplasty suggested that analgesia onset and peak were nearly instantaneous following the introduction of electrical current. Thus, these researchers designed the current randomized, sham-controlled, cross-over portion of this study with only 5-min treatment periods so that subjects randomized to sham initially would have a minimal duration without supplemental analgesia. However, the results of this trial suggested that for acute pain in the immediate post-operative period maximum PNS-induced analgesia requires far longer than 5 mins: pain scores continued to decrease even as subjects emerged from general anesthesia through the 40-min time-point. Unfortunately, no subsequent pain data were collected until the following day, so the duration for maximum analgesic effect remains to be determined. In contrast, these investigators were aware of a “carryover” effect following PNS so that subjects continued to receive a variable duration and degree of analgesia following electrical current discontinuation, possibly due to sustained modification of supra-spinal pain processing. These researchers knew that this carryover effect would make the data of the 5-min sham period for the group who initially received active current difficult or impossible to interpret. However, to keep the double-masked study design, the authors had no choice but to collect the measurements from this 5-min period. Thus, they included the collected data; but presented them in ghost to indicate the uncertainty of its interpretation.
In a prospective, proof-of-concept study, Ilfeld and associates (2019) examined the feasibility of using percutaneous PNS of the femoral nerve to treat pain in the immediate post-operative period following ambulatory anterior cruciate ligament (ACL) reconstruction with a patellar autograft. Pre-operatively, an electrical lead (SPRINT, SPR Therapeutics, Inc., Cleveland, OH) was percutaneously implanted with US-guidance anterior to the femoral nerve caudad to the inguinal crease. Within the recovery room, subjects received 5 mins of either stimulation or sham in a randomized, double-masked fashion followed by a 5-min cross-over period, and then continuous active stimulation until lead removal post-operative day 14 to 28. Statistics were not applied to the data due to the small sample size of this feasibility study. During the initial 5-min treatment period, subjects randomized to stimulation (n = 5) experienced a slight down-ward trajectory (decrease of 7 %) in their pain over the 5 mins of treatment, while those receiving sham (n = 5) reported a slight up-ward trajectory (increase of 4 %) until their subsequent 5-min stimulation cross-over, during which time they also experienced a slight down-ward trajectory (decrease of 11 % from baseline). A majority of subjects (80 %) used a continuous adductor canal nerve block for rescue analgesia (in addition to stimulation) during post-operative days 1 to 3, after which the median resting and dynamic pain scores remained equal or less than 1.5 on the NRS, respectively, and the median daily opioid consumption was less than 1.0 tablet. The authors concluded that the findings of this proof-of-concept study demonstrated that percutaneous femoral nerve stimulation was feasible for ambulatory knee surgery; and suggested that this modality may be effective in providing analgesia and decreasing opioid requirements following ACL reconstruction. These researchers stated that the results of this pilot study indicated that a subsequent clinical trial is needed.
The authors stated that this study had several drawbacks. First, this proof-of-concept study lacked a control group following the initial 10‐min treatment period within the recovery room; and, thus documentation and quantification of analgesia delivery and opioid sparing require additional investigation. Second, the needle could not be withdrawn without deploying the lead. Therefore, instead of withdrawing and re-positioning the needle/lead combination if a first attempt passed the femoral nerve without the desired response, an entirely new lead had to be implanted at a different trajectory. This obviously added greatly to both the required attempts and overall procedure duration since multiple implantation kits and leads had to be prepared. Lastly, these researchers were aware of a “carryover” effect following PNS so that subjects continued to receive a variable duration and degree of analgesia following electrical current discontinuation, possibly due to sustained modification of supra-spinal pain processing. They knew that this carryover effect would make the data of the 5‐min sham period for the group which initially received active current difficult or impossible to interpret. However, to keep the double‐masked study design, the authors had no choice but to collect the measurements from this 5‐min period. Thus, they included the collected data but presented them in ghost to indicate the uncertainty of its interpretation.
Gilmore et al (2019) investigated the efficacy and safety of peripheral nerve stimulation (PNS) for managing residual limb pain (RLP) and phantom limb pain (PLP) in patients with traumatic lower extremity amputations. The study was conducted from March 2015 to March 2018 and included 28 subjects who were randomized into two groups: PNS therapy and placebo control. Participants included 28 subjects with traumatic lower extremity amputations who were assessed for eligibility, with 26 ultimately included in the full analysis set (12 in the PNS group and 14 in the placebo group). The intervention involved subjects in the PNS group receiving active stimulation via implanted leads, while the placebo group received sham stimulation. The therapy period lasted 8 weeks, followed by a 10-month follow-up. The primary efficacy outcome was the proportion of subjects achieving a ≥50% reduction in average pain during the first 4 weeks. Secondary outcomes included pain relief during weeks 5-8, pain interference, global impression of change, and medication usage. The study found that 58% of subjects in the PNS group reported ≥50% pain relief during weeks 1-4, compared to 14% in the placebo group (p=0.037). This trend continued into weeks 5-8, with 67% of the PNS group reporting significant pain relief compared to 14% in the placebo group (p=0.014). A greater proportion of subjects in the PNS group experienced significant reductions in pain interference in daily activities (80% vs. 15%, p=0.003). Among subjects who completed the 12-month follow-up, 80% reported continued substantial pain relief, with an average pain reduction of 76%. The study monitored device-related and procedure-related adverse events, with no significant safety concerns reported. The authors noted several limitations, including a small sample size, uncertainty regarding long-term effects of PNS therapy beyond 12 months, potential bias from subjects identifying their group assignment, and the study not being powered to analyze RLP and PLP separately. The authors concluded that while the results are promising, further research is needed to confirm the efficacy of PNS in larger, more diverse populations and to explore the long-term effects of this intervention, emphasizing the importance of additional studies to better understand the mechanisms of PNS and its potential role in pain management for amputees. Other limitations include lack of testing of the adequacy of blinding.
A 12-month follow-up study by Gilmore et al (2019) investigated the long-term efficacy and safety of peripheral nerve stimulation (PNS) for managing post-amputation pain, specifically residual limb pain (RLP) and phantom limb pain (PLP). The study involved a randomized controlled trial with two groups: one receiving active PNS treatment and the other receiving a placebo for the first four weeks before crossing over to active treatment. The primary outcome was the proportion of participants achieving a ≥50% reduction in average daily pain scores during the first four weeks of treatment. The study reported that 67% of participants in the active treatment group (Group 1) maintained this level of pain relief at the 12-month follow-up, compared to 0% in the placebo group (Group 2) at the end of their placebo period. Several secondary outcomes were assessed, including pain interference and the Patient Global Impression of Change (PGIC). Improvements were noted in both pain interference and PGIC scores, with significant differences favoring the active treatment group at various time points throughout the follow-up period. The study reported no device-related or procedure-related adverse events throughout the 12 months, indicating a favorable safety profile for the PNS treatment. The results suggested that the benefits of PNS could be sustained over a long period, with participants showing significant reductions in both RLP and PLP, as well as improvements in overall function and depression. The authors noted several limitations in their study. Although Group 2 crossed over to receive active stimulation after the placebo period, the proportion of participants reporting substantial pain relief did not significantly increase post-crossover. This may have been influenced by suboptimal lead placements during the initial sham period, as only a few participants had their leads replaced. The small sample size limited the interpretability of some outcomes, particularly regarding trends in pain relief and the statistical significance of secondary analyses. The loss of participants to follow-up could have affected the average pain relief reported at later time points. The study did not specifically assess the neuropathic components of pain, which could provide insights into the differential effects of treatment on various pain etiologies. The authors emphasized the necessity for further research to validate their findings, particularly studies that could address the limitations noted, such as the impact of lead placement on outcomes and the exploration of the neurophysiological mechanisms underlying pain relief in different pain types. They also suggested that future studies should consider larger sample sizes and longer follow-up periods to better understand the long-term efficacy and safety of PNS in diverse patient populations.
Gilmore et al (2020) stated that percutaneous PNS provides an opportunity to relieve chronic LBP and reduce opioid analgesic consumption as an alternative to radiofrequency ablation (RFA) and permanently implanted neurostimulation systems. Traditionally, the use of neurostimulation earlier in the treatment continuum has been limited by its associated risk, invasiveness, and cost. Percutaneous PNS leads (SPRINT MicroLead) were placed bilaterally to target the medial branches of the dorsal rami nerves under image guidance. The percutaneous leads were connected to miniature wearable stimulators (SPRINT PNS System) for the 1-month therapy period, after which the leads were removed. Pain and disability were assessed long-term up to 12 months after lead removal. Substantial, clinically significant reductions in average pain intensity (greater than or equal to 50 % reduction as measured by the Brief Pain Inventory Short Form) were experienced by a majority of subjects (67 %) at end of treatment compared to baseline (average 80 % reduction among responders; p < 0.05, analysis of variance; n = 9). Twelve months after the end of PNS treatment, a majority of subjects who completed the long-term follow-up visits experienced sustained, clinically significant reductions in pain and/or disability (67 %, n = 6; average 63 % reduction in pain intensity and 32-point reduction in disability among responders). No serious or unanticipated AEs were reported. The authors concluded that the findings of this study challenged the long-held notion that a positive trial of PNS should be followed by a permanent implant in responders. These researchers stated that percutaneous PNS may serve as an effective neurostimulation therapy for patients with chronic LBP, and should be considered earlier in the treatment continuum as a motor-sparing means of avoiding opioids, denervation, and permanently implanted neurostimulation systems. They stated that this approach has the potential to significantly influence the care continuum for chronic LBP by providing the benefits of an effective neurostimulation therapy to patients earlier than has been previously possible. These researchers stated that additional studies are needed to confirm these findings in a larger population of patients, including studies that compare the effects of percutaneous PNS to other standard interventional approaches used for patients with chronic LBP. The authors stated that this study had 2 main drawbacks. First, the sample size was small (n = 9) and did not include a control group or examine the placebo effect. Second, because chronic LBP could include a heterogeneous population (e.g., facetogenic, discogenic, arthritic, or myofascial pain) and the selection criteria for inclusion in this study were broad, additional studies and analyses of larger populations, including larger, prospective, multi-center, case-series studies, may determine LBP subtypes or characteristics that are more likely to benefit from percutaneous PNS, as well as if specific types of diagnostic tests or imaging are predictive of success.
In a prospective, multi-center study, Gilmore et al (2021) characterized responses to percutaneous medial branch PNS to examine if results from earlier, smaller single-center studies and reports were generalizable when carried out at a larger number and wider variety of centers in patients recalcitrant to non-surgical treatments. Subjects with chronic axial LBP were implanted with percutaneous PNS leads targeting the lumbar medial branch nerves for up to 60 days, after which the leads were removed. Subjects were followed long-term for 12 months after the 2-month PNS treatment. Data collection was complete for visits through end of treatment with PNS (primary endpoint) and 6 months after lead removal (8 months after start of treatment), with some subject follow-up visits thereafter in progress. Clinically and statistically significant reductions in pain intensity, disability, and pain interference were reported by a majority of subjects; 73 % of subjects were successes for the primary endpoint, reporting clinically significant (greater than or equal to 30 %) reductions in back pain intensity after the 2-month percutaneous PNS treatment (n = 54/74). Whereas prospective follow-up is ongoing, among those who had already completed the long-term follow-up visits (n = 51), reductions in pain intensity, disability, and pain interference were sustained in a majority of subjects through 14 months after the start of treatment. The authors concluded that given the minimally invasive, non-destructive nature of percutaneous PNS and the significant benefits experienced by subjects who were recalcitrant to non-surgical treatments, percutaneous PNS may provide a promising 1st-line neurostimulation therapeutic option for patients with chronic axial LBP. These researchers stated that the main drawbacks of this study included that it was not a randomized trial, did not include a control group, and is not yet complete (i.e., prospective, follow-up beyond 8 months remains ongoing).
Ilfeld et al (2021) stated that percutaneous PNS has been used extensively for chronic pain, but only uncontrolled series have been published for acute post-operative pain. In a randomized, multi-center, sham-controlled, pilot study, these investigators determined the feasibility and optimized the protocol for a subsequent clinical trial; and estimated the treatment effect of percutaneous PNS on post-operative pain and opioid consumption. Pre-operatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Post-operatively, subjects were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were cumulative opioid consumption (in oral morphine equivalents); and mean values of the "average" daily pain scores measured on the 0 to 10 NRS within the first 7 post-operative days. During the first 7 post-operative days, opioid consumption in subjects given active stimulation was a median (IQR) of 5 mg (0 to 30) versus 48 mg (25 to 90) in subjects given sham treatment (ratio of geometric means, 0.20 [97.5 % CI: 0.07 to 0.57]; p < 0.001). During this same period, the average pain intensity in subjects given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5 % CI: -2.6 to -0.9]; p < 0.001). The authors concluded that percutaneous PNS reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery. These researchers stated that the findings of this pilot study confirmed feasibility of a future larger trial and suggested protocol enhancements.
Deer et al (2021) noted that PNS is a promising treatment for axial LBP; however, the use of conventional permanently implanted PNS systems has been limited by the invasiveness of the procedure and is technically challenging because of the lack of dedicated hardware. In a prospective, multi-center study, these researchers examined the potential use of percutaneous PNS as a minimally invasive, non-destructive, motor-sparing alternative to repeat RFA and more invasive surgical procedures. A total of 17 subjects were enrolled as part of the prospective, sub-study of patients with a history of RFA of the lumbar medial branch nerves; however, 2 subjects were later found after enrollment to not meet eligibility criteria and were excluded from this analysis (1 was excluded after it was found that the subject met the exclusion criteria of lumbar scoliosis, and the other was excluded because the duration of time between RFA and enrollment was less than 6 months). Subjects (n = 15) with a return of chronic axial pain after RFA underwent implantation of percutaneous PNS leads targeting the medial branch nerves. Stimulation was delivered for up to 60 days, after which the leads were removed. Subjects were followed-up to 5 months after the start of PNS. Outcomes included pain intensity, disability, and pain interference. Highly clinically significant (greater than or equal to 50 %) reductions in average pain intensity were reported by a majority of subjects (67 %, n = 10/15) after 2 months with PNS, and a majority experienced clinically significant improvements in functional outcomes, as measured by disability (87 %, n = 13/15) and pain interference (80 %, n = 12/15). Five months after PNS, 93 % (n = 14/15) reported clinically meaningful improvement in 1 or more outcome measures, and a majority experienced clinically meaningful improvements in all 3 outcomes (i.e., pain intensity, disability, and pain interference). The authors concluded that clinically significant reductions in pain, disability, and pain interference were reported with percutaneous PNS among subjects with chronic axial LBP following lumbar RFA, although additional studies are needed to further examine the comparative effectiveness of RFA and percutaneous PNS.
Gilmore et al (2021) investigated the efficacy of percutaneous peripheral nerve stimulation (PNS) for patients suffering from chronic axial low back pain (LBP). The study included 166 participants who were screened for eligibility, with 81 ultimately qualifying for the study. Key inclusion criteria required participants to have chronic axial LBP (pain score ≥4 on a 0-10 scale for at least 12 weeks) and to have failed at least two different categories of LBP treatments. Exclusion criteria included conditions such as radicular leg pain, prior lumbar surgery, and significant psychological distress (e.g., a Beck Depression Inventory score >20). Participants underwent implantation of percutaneous PNS leads targeting the medial branch nerves of the lumbar region. The primary endpoint was assessed at 2 months post-treatment, with follow-up assessments at 5, 8, 11, and 14 months. The study reported clinically meaningful reductions in both back pain-related disability (measured by the Oswestry Disability Index) and pain interference (measured by the Brief Pain Inventory) over time. Notably, a significant proportion of participants experienced these reductions, with data indicating sustained improvements through the follow-up period. The authors noted several limitations in their study: there were instances of participants being lost to follow-up, which could affect the robustness of the results; the study’s findings may not be generalizable to all populations with chronic LBP, as the sample was limited to those meeting specific eligibility criteria; while the study provided data up to 14 months, longer-term outcomes were not assessed, leaving questions about the durability of the treatment effects; and the study design did not include a control group, which could introduce bias in interpreting the efficacy of the PNS treatment. The authors emphasized the necessity for further research to validate their findings. They suggested that future studies should include larger, more diverse populations and control groups to better assess the efficacy and safety of PNS for chronic LBP. Additionally, long-term follow-up studies are needed to evaluate the sustainability of treatment benefits and to explore the mechanisms underlying the observed pain relief.
Naidu et al (2022) investigated the effectiveness of a 60-day percutaneous peripheral nerve stimulation (PNS) treatment for pain relief. Conventional neurostimulation trials typically last 7-10 days, but this study explored the benefits of an extended 60-day trial to better identify responders and non-responders to neurostimulation. The study involved anonymized data from 747 patients who underwent temporary PNS lead implantation and provided real-world data throughout the treatment period. The results showed that 30% of patients were early responders, achieving ≥50% pain relief throughout the treatment. Another 31% were delayed responders, initially presenting as non-responders but achieving ≥50% pain relief by the end of the treatment. Conversely, 32% of patients were non-responders throughout the treatment, and 7% were delayed non-responders, initially achieving ≥50% pain relief but falling below this threshold by the end of the treatment. The study suggests that the extended 60-day PNS treatment can help identify delayed responders, potentially providing sustained pain relief and reducing the need for permanent implants. It also highlights the limitations of brief conventional trials, which may not accurately predict long-term outcomes. The novel 60-day PNS system, with fine-wire, open-coil leads designed to reduce infection risk, demonstrated a low infection rate and the potential to improve patient outcomes by allowing a more detailed evaluation of patient responses over a longer period. The study concludes that a longer 60-day PNS treatment period may optimize outcomes and cost-effectiveness by better identifying patients who are likely to benefit from neurostimulation, thereby reducing explant rates and improving access to effective pain management solutions.
Pingree et al (2022) presented findings from a survey conducted on patients who previously received 60-day peripheral nerve stimulation (PNS) treatment for chronic pain. The objective of the study was to gather real-world data regarding the long-term effectiveness of this treatment modality, which has been shown in prospective studies to provide significant pain relief. The study utilized a cross-sectional survey design, targeting patients who had undergone temporary PNS lead implantation for pain management. The survey was distributed to a database of 2028 patients who had received the FDA-cleared SPRINT PNS treatment between March 2018 and December 2020. The survey included validated measures of pain, quality of life, and physical function, allowing for a comprehensive assessment of patient outcomes following the PNS treatment. Results indicated that among the 252 patients who completed the survey and were at least three months post-treatment, a significant majority reported sustained improvements in pain and quality of life. Specifically, 50% of respondents reported at least a 50% reduction in pain or improvement in quality of life compared to baseline. Additionally, 61% of patients who had initially responded positively to the treatment at the end of the 60-day period maintained their improvements at the time of the survey, which ranged from 3 to 30 months post-treatment. The study also highlighted a reduction in the use of analgesic medications among patients. Approximately 35% of those who used opioids before the PNS treatment reported reducing or ceasing their usage, while 32% of patients using anticonvulsants reported similar reductions. This finding underscores the potential of 60-day PNS treatment to not only alleviate pain but also to decrease reliance on pharmacological interventions. The authors noted several limitations in their study. One primary limitation was the cross-sectional nature of the survey, which only captured data at a single time point rather than providing longitudinal assessments of patient outcomes over time. This design limits the ability to draw definitive conclusions about the long-term efficacy of the treatment. Additionally, the survey had a response rate of 17.5%, which raises concerns about potential self-selection bias among respondents. Although the authors compared survey respondents to a larger population of patients who received the treatment, the possibility of bias still exists. The authors emphasized the need for further research to address these limitations. They suggested that future studies should include longitudinal designs to track patient outcomes over multiple time points, which would provide a more comprehensive understanding of the long-term effects of PNS treatment. Additionally, controlled studies could help validate the findings of this survey and further elucidate the effectiveness of 60-day PNS in various pain conditions.
A study by Huntoon et al (2023) was a retrospective review of real-world outcomes following a 60-day peripheral nerve stimulation (PNS) treatment for chronic pain. The study aimed to evaluate the effectiveness of this treatment in routine clinical practice. Anonymized records of 6,160 patients who were implanted with the SPRINT PNS System from August 2019 through August 2022 were reviewed. The primary outcome was the percentage of patients with ≥ 50% pain relief and/or improvement in quality of life, stratified by nerve target. Additional outcomes included average and worst pain scores, patient-reported percentage of pain relief, and patient global impression of change. Overall, 71% of patients were responders, reporting ≥ 50% pain relief and/or improvement in quality of life, with pain relief among responders averaging 63%. The responder rate was consistent across various nerve targets, including the back and trunk, upper and lower extremities, and posterior head and neck. The study noted limitations due to its retrospective nature and reliance on a device manufacturer’s database, which lacked detailed demographic information and measures for pain medication usage and physical function. The study found that the mean average pain score and mean worst pain score were substantially lower at the end of treatment compared to baseline. Among responders, more than 60% reported mild or no pain at the end of treatment. Safety analysis indicated a total medical event rate of 6.0%, with the most frequent event being skin irritation. Serious adverse events were rare, with a rate of 0.03%, and infection was confirmed in 0.1% of patients. Lead dislodgement and fracture were reported in 6.0% and 8.1% of patients, respectively, with most fractures occurring with an older version of the lead.
Gilmore et al (2023) investigated the efficacy of percutaneous peripheral nerve stimulation (PNS) for treating chronic low back pain (CLBP) in patients who have not responded to conventional non-surgical therapies. The study is a prospective, multicenter case series involving patients with CLBP who had previously undergone an average of 5.3 non-surgical treatments without success. Participants received a temporary 60-day percutaneous PNS treatment targeting the medial branch nerves. The primary outcomes included pain intensity, disability, and pain interference, assessed using the Brief Pain Inventory (BPI) and the Oswestry Disability Index (ODI). The results indicated that a significant majority of participants experienced clinically meaningful improvements in pain intensity, disability, and pain interference over a follow-up period of 14 months. Specifically, 91% of participants reported clinically significant reductions in pain intensity, while 79% and 73% reported improvements in disability and pain interference, respectively, at the 2-month mark. These improvements were sustained throughout the follow-up period. The study suggests that percutaneous PNS is a safe and effective treatment option for patients with CLBP, providing substantial pain relief and functional improvement without the need for permanent implantation of devices. The authors noted several limitations in their study. Participants were not randomized to a placebo or another intervention group, which could limit the ability to draw definitive conclusions about the efficacy of PNS compared to other treatments. The study included participants with various diagnoses related to CLBP, including discogenic pain and lumbar spondylosis, as well as those with non-specific pain. The authors did not find significant differences in outcomes based on the specific diagnosis, indicating a need for further research to explore this aspect. As a case series, the findings may not be generalizable to all populations with CLBP, particularly those who have not undergone prior treatments. The authors acknowledged the need for further studies to investigate the relationship between the specific source of back pain and the outcomes of PNS treatment, conduct randomized controlled trials to compare PNS with other treatment modalities to better establish its efficacy and safety profile, and explore long-term outcomes and the potential for PNS to be integrated as a first-line treatment option in the management of CLBP.
Goree et al (2024) investigated the efficacy and safety of percutaneous peripheral nerve stimulation (PNS) for managing chronic pain following total knee arthroplasty (TKA). The study is a randomized controlled trial (RCT) that compares the PNS treatment group with a placebo (sham stimulation) group. A total of 130 subjects were screened, with 56 meeting eligibility criteria and being randomized into either the PNS group or the placebo group. The study included subjects who had undergone primary unilateral TKA. The PNS group received active stimulation targeting the femoral and sciatic nerves, while the placebo group received sham stimulation. The primary endpoint was the proportion of subjects achieving clinically significant pain relief (≥50%) during weeks 5-8 post-treatment. Secondary outcomes included average pain relief, functional outcomes measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), quality of life assessed via the Patient Global Impression of Change (PGIC), and walking ability measured by the 6-minute walk test (6MWT). The PNS group showed significantly greater pain relief compared to the placebo group, with 60% of PNS subjects achieving ≥50% pain relief versus 24% in the placebo group (p = 0.028). Average pain relief was also higher in the PNS group (54% vs. 26%). Improvements in walking ability were noted, with the PNS group showing a mean percentage improvement of 47% in the 6MWT at the end of treatment. The PNS group reported better quality of life scores, with a higher proportion of subjects indicating at least minimal improvement (PGIC ≥1) compared to the placebo group. The authors noted several limitations. The study was limited by a relatively small sample size, which may affect the generalizability of the results. There were early terminations and withdrawals from the study, which could introduce bias in the results. The pandemic affected enrollment and follow-up, potentially influencing the outcomes. The use of imputation methods for missing pain diary scores may introduce inaccuracies in the reported outcomes. Although the study included a control group that received sham stimulation, the study did not describe testing for adequacy of blinding. The authors emphasized the necessity for further research to validate the findings of this study. They suggested that larger-scale studies are needed to confirm the efficacy and safety of PNS in diverse populations and to explore long-term outcomes beyond the three-month follow-up period. Additionally, they indicated that future studies should consider the impact of different types of knee surgeries and the potential for PNS to be integrated into broader pain management strategies.
A clinical study by Chae et al (2025) investigated the effectiveness of intramuscular electrical stimulation (ES) in reducing hemiplegic shoulder pain in chronic stroke survivors. The study was a multi-center, randomized clinical trial involving 61 participants who were experiencing shoulder pain and subluxation due to hemiplegia. Participants in the treatment group received intramuscular electrical stimulation to specific shoulder muscles (supraspinatus, posterior deltoid, middle deltoid, and upper trapezius) for 6 hours a day over 6 weeks, while the control group was treated with a cuff-type sling for the same duration. The primary outcome was measured using the Brief Pain Inventory (BPI) question 12, which is an 11-point numeric rating scale. Secondary measures included pain-related quality of life, subluxation, motor impairment, range of motion, spasticity, and activity limitation. The study found that the electrical stimulation group had a significantly higher success rate in pain reduction compared to the control group (63% vs. 21%, P = 0.001). Statistical analysis revealed significant treatment effects on the primary outcome (BPI question 12) and pain-related quality of life (BPI question 23), with P-values indicating strong significance (F = 21.2, P < 0.001 for BPI question 12; F = 8.3, P < 0.001 for BPI question 23). Other secondary measures did not show significant treatment effects. The authors noted several limitations in their study, including the lack of blinding of study participants and the need for further studies to rule out the possibility of a placebo effect influencing the results, the lack of full accounting for other therapies that participants may have been receiving concurrently, and the absence of defined optimal parameters for the electrical stimulation treatment. Additionally, the underlying mechanisms by which intramuscular electrical stimulation exerts its effects were not elucidated, and the study calls for further research to demonstrate therapeutic benefits beyond the 12-month follow-up period. The study concludes that intramuscular electrical stimulation is effective in reducing hemiplegic shoulder pain, with effects maintained for at least 12 months post-treatment. However, the authors emphasize the necessity for additional research to address the noted limitations and to further explore the treatment’s efficacy and mechanisms.
Gilmore et al (2025) stated that CLBP is a leading cause of healthcare expenditure and long-term disability associated with complex treatment challenges and the need for progressively invasive interventions. Percutaneous 60-day PNS is a minimally invasive neurostimulation that has reported to be effective for the treatment of CLBP, providing sustained improvements via 1 year of follow-up after treatment. These researchers examined the long-term clinical outcomes of percutaneous 60-day PNS for CLBP approximately 4 years after initial treatment. Follow-up surveys were sent to participants from a prior prospective study who reported clinically meaningful reductions in pain, disability, or pain interference 12 months after percutaneous 60-day PNS for LBP. The present long-term follow-up survey evaluated current levels of LBP, disability, pain interference, and PGIC. Use of medications and other interventions for LBP treatment since completing percutaneous 60-day PNS was also surveyed. A total of 23 participants returned completed long-term follow-up surveys. A majority of survey respondents (65 %, n = 15/23) reported sustained, clinically meaningful (30 % or greater) relief of back pain compared with baseline an average of 4.7 years after PNS treatment was initiated. On average, these long-term responders reported clinically substantial (50 % or greater) reductions in pain (average 63 % reduction), as well as clinically meaningful improvements in disability and QOL. In addition, 70 % (n = 16/23) of survey respondents avoided progression to more costly, invasive, and/or destructive LBP pain interventions (i.e., radiofrequency ablation, neurostimulation implant, or lumbar surgery). The authors concluded that percutaneous 60-day PNS provided clinically substantial pain relief and/or improvements in disability and QOL for the majority of surveyed respondents more than 4 years after short-term, percutaneous 60-day PNS treatment. These findings showed that percutaneous 60-day PNS could provide durable outcomes that were sustained for multiple (4+) years in some patients with chronic axial LBP, which may mitigate the need for more invasive treatment interventions; thus, as a minimally invasive therapy, short-term, percutaneous 60-day PNS may provide a promising neurostimulation treatment for patients with chronic axial LBP. It should also be noted that sponsorship for this study and Rapid Service Fee were funded by SPR Therapeutics, Inc.
The authors stated that drawbacks of the initial prospective, multi-center trial have been previously reported; and included the absence of a control group and randomization of enrolled subjects. While this subsequent survey did not have a large sample size (n = 23) and there was a potential for non-response bias or self-selection bias among participants who responded to the long-term follow-up survey, the survey response rate (62 %) was concordant with the equal to or greater than 40 % to 60 % rates that are often reported for survey studies. Furthermore, a comparison of 12-month outcomes between participants who did not respond to the survey (n = 14) and the broader group of all participants who received surveys (n = 37) (12-month Brief Pain Inventory [BPI]-5: 43 % versus 47 %; 12-month ODI: 14.5-point versus 12.9-point; 12-month BPI-9: 44 % versus 45 %, reductions, respectively) suggested that there were no meaningful differences in mean outcomes based on survey response. Additionally, baseline average pain scores did not differ meaningfully between survey respondents and non-respondents (baseline BPI-5: 6.0 versus 6.1, respectively). Taken together, these findings decreased the likelihood that outcomes of this trial were significantly impacted by non-response or selection bias. Furthermore, while this study was sponsored by the device manufacturer, which may introduce the potential for perceived or actual bias, all conflicts of interest relevant to the study have been disclosed; efforts were made to ensure objectivity in study design, analysis, as well as reporting ; and to limit the risk of bias in survey assessment, including multiple attempts by study sites to follow-up with participants, completion of surveys without influence by the device manufacturer or clinical study staff, and use of validated outcome measures in the long-term follow-up survey. Since surveys were completed by participants remotely (i.e., not in clinic), objective functional outcomes were not able to be included to examine functional improvements following percutaneous 60-day PNS in this study, although objective functional improvements corresponding with patient-reported improvements in QOL and pain relief have been documented in a double-blinded RCT of percutaneous 60-day PNS and may be considered in future studies. Moreover, these researchers stated that while the absence of a control group limited direct comparisons, subgroup analyses suggested that the long-term pain relief observed in this cohort was not meaningfully influenced by concurrent treatments. Notably, subjects who avoided additional interventional pain procedures, PT, or opioid medications more frequently reported clinically meaningful pain relief than those who did not; suggesting that the therapeutic benefit observed was attributable to the device intervention rather than to external or adjunctive treatments alone. These investigators stated that these promising results of this survey revealing durable relief of chronic axial LBP that is sustained for multiple (4+) years corroborate and extend the findings of previously published prospective studies of this treatment, substantiated the evidence showing that percutaneous 60-day PNS can mitigate the need for more invasive treatment interventions in some patients.
Vorenkamp et al. (2025) evaluated the long-term outcomes of a 60-day percutaneous peripheral nerve stimulation (PNS) treatment for chronic shoulder pain in a real-world population. In a cross-sectional survey of 489 patients (mean follow-up 21 months, range 6–60 months), 83% reported no need for subsequent radiofrequency ablation, permanent implant, or surgery after the 60-day PNS treatment. Among these, 71% maintained at least 50% pain relief at follow-up, and over half reported substantial improvements in quality of life, physical function, and sleep. For patients who initially sought to avoid surgery (n=265), 81% did not proceed to surgery post-PNS, and 77% of these maintained ≥50% pain relief. These benefits were consistent across different shoulder pain etiologies and durations of follow-up, with durable effects observed up to 5 years post-treatment. The findings suggest that a 60-day PNS protocol can provide sustained pain relief and functional improvement, with a low rate of progression to more invasive interventions, supporting its role as a clinically effective and potentially cost-saving option for chronic shoulder pain management.
The study had a number of drawbacks. First, the study utilized a cross-sectional survey design with retrospective patient self-report, which introduces the potential for recall bias and limits the ability to establish causality. There was no control group or randomization, so the observed outcomes cannot be definitively attributed to the 60-day PNS intervention alone. Second, the study population was derived from patients who had already completed the 60-day PNS treatment and were available for follow-up, raising the possibility of selection bias. Patients with poor outcomes or those lost to follow-up may be underrepresented, potentially inflating the reported rates of durable pain relief and avoidance of surgery. Third, outcomes were based on subjective patient-reported measures (e.g., percent pain relief, quality of life, function, and sleep), without objective clinical or functional assessments. There was also no standardized assessment of medication use or adverse events. Finally, while the study included a relatively large sample and long follow-up (up to 5 years), the generalizability of the findings is limited by the lack of detailed information on patient characteristics, pain etiologies, and concurrent treatments. These limitations are consistent with concerns raised in the broader literature regarding the need for more robust, prospective, and controlled studies to evaluate the long-term efficacy and safety of PNS for chronic shoulder pain.
Dickerson et al. (2025) analyzed the economic impact of initiating chronic pain management with a 60-day percutaneous peripheral nerve stimulation (PNS) treatment compared to the conventional approach of a brief PNS trial followed by possible permanent PNS implantation. Using Centers for Medicare & Medicaid Services (CMS) fee-for-service data and a decision tree model, the study found that the 60-day PNS approach resulted in lower PNS-related costs ($17,344 vs. $24,392 weighted average per patient) and a lower rate of progression to permanent implantation (18% vs. 41%) compared to the conventional brief trial. The cost per successful outcome was also substantially lower for the 60-day PNS cohort ($25,228 vs. $64,502). These findings suggest that, when PNS is indicated for chronic pain, initiating therapy with a 60-day PNS treatment is more cost-effective for payers than the traditional brief trial and permanent implant pathway.
The drawbacks of the study by Dickerson et al. include several key methodological and generalizability concerns. The analysis was retrospective and relied on administrative claims data from the Centers for Medicare & Medicaid Services, which may be subject to coding inaccuracies and lacks granular clinical detail such as pain severity, functional outcomes, or patient-reported quality of life. The study population was limited to patients aged 65 and older, which restricts generalizability to younger populations with chronic pain. Additionally, the economic model used real-world data for the 60-day PNS cohort but relied on assumptions and estimates for some clinical outcomes, such as the probability of progressing to permanent implantation and explant rates. There was no randomization or direct head-to-head comparison of the two treatment pathways, introducing potential selection bias and confounding. The follow-up period, while at least 12 months (median 26.4 months), may not capture long-term costs or late complications. Finally, outcomes such as pain relief and functional improvement were not directly measured in the claims data. The study disclosed that it was funded by SPR Therapeutics, Inc., the manufacturer of the 60-day percutaneous PNS system evaluated in the analysis. Several coauthors disclosed financial relationships with the company.
Sheth et al. (2025) used a decision tree model to estimate the potential cost savings of using a 60-day peripheral nerve stimulation (PNS) treatment as the initial interventional therapy for chronic axial low back pain (CLBP) in patients who had failed conservative management. The model compared two hypothetical cohorts: one starting with 60-day PNS followed by other interventions as needed, and another following standard of care (SOC) pathways without access to 60-day PNS. SOC options included epidural steroid injection, radiofrequency ablation, basivertebral nerve ablation, permanent PNS implant, spinal cord stimulation, and spinal fusion. Treatment efficacy and progression probabilities were based on published data and clinician interviews, and costs were calculated using national Medicare reimbursement rates in the ambulatory surgery center setting. The analysis projected that initial use of 60-day PNS would result in $8,056 (95% CI $6,112–$9,981) lower per-patient costs in the first year compared to SOC, primarily by reducing the need for more invasive and costly procedures such as permanent implants and spinal fusion. Sensitivity analyses supported the robustness of these findings. These results suggest that prioritizing 60-day PNS as a first-line interventional option for CLBP may yield substantial cost savings for Medicare and potentially for commercial payers as well.
Drawbacks of this study include its reliance on a decision tree model using hypothetical patient cohorts rather than real-world or prospective clinical data. The model’s treatment efficacy estimates and progression probabilities were derived from published literature and clinician interviews, which introduces potential bias and may not fully capture the heterogeneity of chronic axial low back pain populations. Cost calculations were based on national Medicare reimbursement rates in the ambulatory surgery center setting, which may not generalize to other payer types or care settings. Additionally, the model only considered direct procedural costs over a 12-month time frame and did not account for indirect costs, long-term outcomes, or quality-of-life measures. The study did not incorporate patient-level data on pain relief, functional improvement, or adverse events, limiting its ability to assess clinical effectiveness alongside economic outcomes. The research was funded by SPR Therapeutics, Inc., the manufacturer of the 60-day peripheral nerve stimulation system evaluated in the economic model, and several coauthors reported financial relationships with the company.
American Society of Pain and Neuroscience (ASPN) consensus guidelines (Gill, et al., 2025) recommend that 60-day PNS therapy, using a temporary, non-implanted percutaneous system, may be selectively offered to patients with chronic pain syndromes, The consensus guidelines provided a narrative review of studies of PNS therapy. As a review of existing evidence, the review is inherently limited by the quality and heterogeneity of the underlying studies it summarizes. As a consensus guideline, it relies on expert opinion and lower levels of evidence. The guidelines acknowledge this limitation by stating that the evidence level for 60-day PNS is Level III or fair, with moderate certainty. One significant limitation is the limited availability of long-term data beyond the 60-day treatment period or even beyond 24 months, particularly regarding the durability of pain relief and long-term adverse events. While some studies show promising sustained results, more extended follow-up data is needed to fully understand the long-term effectiveness and potential risks of this therapy. The consensus statement was funded by the manufacturer, and several of the coauthors disclosed funding from the manufacturer.
IB-Stim for the Treatment of Irritable Bowel Syndrome
Babygirija et al (2017) noted that a non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) has been suggested to modulate central pain pathways. These investigators examined the effects of BRIDGE device on the responses of amygdala and lumbar spinal neurons and the development of post-colitis hyperalgesia. Male Sprague-Dawley rats received intra-colonic trinitrobenzene sulfonic acid (TNBS) and PENFS on the same day. Control rats had sham devices. The visceromotor response (VMR) to colon distension and paw withdrawal threshold (PWT) was recorded after 7 days. A different group of rats had VMR and PWT at baseline, after TNBS and following PENFS. Extracellular recordings were made from neurons in central nucleus of the amygdala (CeA) or lumbar spinal cord. Baseline firing and responses to compression of the paw were recorded before and after PENFS. Sham-treated rats exhibited a much higher VMR (greater than 30 mmHg) and lower PWT compared to PENFS-treated rats (p < 0.05). PENFS decreased the VMR to colon distension and increased the PWT compared to pre-stimulation (p < 0.05). PENFS resulted in a 57 % decrease in spontaneous firing of the CeA neurons (0.59 ± 0.16 versus control: 1.71 ± 0.32 imp/s). Similarly, the response to somatic stimulation was decreased by 56 % (3.6 ± 0.52 versus control: 1.71 ± 0.32 imps/s, p < 0.05). Spinal neurons showed a 47 % decrease in mean spontaneous firing (4.05 ± 0.65 versus control: 7.7 ± 0.87 imp/s) and response to somatic stimulation (7.62 ± 1.7 versus control: 14.8 ± 2.28 imp/s, p < 0.05). The authors concluded that PENFS attenuated baseline firing of CeA and spinal neurons, which may account for the modulation of pain responses in this model of post-inflammatory visceral and somatic hyperalgesia. This was an animal study.
Kovacic et al (2017) stated that drawbacks of this study included a relatively homogenous group of predominantly white, female subjects. The inclusion of several functional abdominal pain disorders rather than one disorder might also limit the generalizability of these findings. The Rome III questionnaire used could have over-estimated the prevalence of abdominal migraine (32 % treatment; 30 % sham) because a timeline for return to baseline health was not specified in Rome III criteria; thus, patients who had periodic intensification of pain (twice in 1 year) along with pallor, anorexia, nausea, vomiting, or headache (of which only 2 are required), will meet Rome III criteria for abdominal migraine. The presence of another functional GI disorder was also not an exclusion criterion; therefore, allowing for overlap and lowering the specificity of abdominal migraine diagnosis. Publication of Rome IV has allowed some of these deficiencies to be addressed by the addition of more specific criteria – e.g., episodes should be separated by weeks to months, and symptoms should be stereotypical in the individual patient. There was also the potential for recall bias with weekly administered measures, although this period was generally accepted as appropriate in the literature. This proof-of concept (POC) study focused on pain reduction based on the FDA-approved indication for this device, and changes in bowel habits for individuals with IBS were not measured. This was an important weakness because patients with diarrhea-predominant or constipation-predominant IBS often indicated that altered bowel habits were their most bothersome symptom. These investigators stated that IBS is a multi-dimensional disorder and improvement in bowel habits (e.g., stool frequency, consistency, or urgency) is considered to be an important co-primary endpoint outlined by FDA and EMA for clinical trials in patients with IBS. However, the overall improvement in disability in adolescents with active treatment suggested that pain was probably the most debilitating symptom in those with IBS. Furthermore, the follow-up period was fairly short (8 to 12 weeks) and a longer assessment period would be preferable. It should be noted that the duration of treatment was selected based on anecdotal experience and might be considered arbitrary. For example, more patients with active stimulation met the FDA criteria for IBS trials of 30 % or greater improvement in pain compared with sham treatment; however, no difference between the groups was reported at follow-up. In addition, in contrast to the pain and disability measures, the global symptom measure was not significantly different between groups at 8 to 12 week follow-up. This difference might suggest that patients had a variable duration of response, and that a longer trial or repeat treatment course could be beneficial for specific patients to achieve more sustained effects. In the clinical setting, the treatment course could be expanded or modified based on severity of symptoms or recurrence after treatment. These researchers stated that the proposed modulation of central pain pathways with this therapy was based on an animal model of visceral hyperalgesia. They stated that future studies using colorectal distention with barostat, and functional MRI could aid in confirming that these mechanisms translate to human beings. Other drawbacks included stratification of patients during randomization, which resulted in uneven number of patients in each group. Additionally, more patients in the sham group left the study than in the PENFS group, resulting in higher number of patients analyzed in the PENFS group.
Kovacic et al (2017) stated that development of safe and effective therapies for pediatric abdominal pain-related functional gastro-intestinal (GI) disorders is needed. A non-invasive, Food and Drug Administration (FDA)-cleared device (Neuro-Stim, Innovative Health Solutions, IN, USA) delivers PENFS in the external ear to modulate central pain pathways. In randomized, double-blind, sham-controlled trial, these researchers examined the efficacy of PENFS in adolescents with abdominal pain-related functional GI disorders. They enrolled adolescents (aged 11 to 18 years) who met Rome III criteria for abdominal pain-related functional GI disorders from a single U.S. outpatient gastroenterology clinic. Patients were randomly assigned (1:1) with a computer-generated randomization scheme to active treatment or sham (no electrical charge) for 4 weeks. Patients were stratified by sex and presence or absence of nausea. Allocation was concealed from participants, caregivers, and the research team. The primary efficacy endpoint was change in abdominal pain scores. These investigators measured improvement in worst abdominal pain and composite pain score using the Pain Frequency-Severity-Duration (PFSD) scale. Participants with less than 1 week of data and those with organic disease identified after enrolment were excluded from the modified intention-to-treat (ITT) population. Between June 18, 2015 and November 17, 2016, a total of 115 children with abdominal pain-related functional GI disorders were enrolled and assigned to either PENFS (n = 60) with an active device or sham (n = 55). After exclusion of patients who discontinued treatment (n = 1 in the PENFS group; n = 7 in the sham group) and those who were excluded after randomization because they had organic disease (n = 2 in the PENFS group; n = 1 in the sham group), 57 patients in the PENFS group and 47 patients in the sham group were included in the primary analysis. Patients in the PENFS group had greater reduction in worst pain compared with sham after 3 weeks of treatment (PENFS: median score 5.0 [inter-quartile range [IQR] 4.0 to 7.0]; sham: 7.0 [5.0 to 9.0]; least square means estimate of change in worse pain 2.15 [95 % CI: 1.37 to 2.93], p < 0·0001). Effects were sustained for an extended period (median follow-up 9.2 weeks [IQR 6.4 to 13.4]) in the PENFS group: median 8.0 (IQR 7.0 to 9.0) at baseline to 6.0 (5.0 to 8.0) at follow-up versus sham: 7.5 (6.0 to 9.0) at baseline to 7.0 (5.0 to 8.0) at follow-up (p < 0.0001). Median PFSD composite scores also decreased significantly in the PENFS group (from 24.5 [IQR 16.8 to 33.3] to 8.4 [3.2 to 16.2]) compared with sham (from 22.8 [IQR 8.4 to 38.2] to 15.2 [4.4 to 36.8]) with a mean decrease of 11.48 (95 % CI: 6.63 to 16.32; p < 0.0001) after 3 weeks. These effects were sustained at extended follow-up in the PENFS group: median 24.5 (IQR 16.8 to 33.3) at baseline to 12 (3.6 to 22.5) at follow-up, compared with sham: 22.8 (8.4 to 38.2) at baseline to 16.8 (4.8 to 33.6) at follow-up (p = 0.018); 10 patients reported side-effects (3 of whom discontinued the study): ear discomfort (n = 6; 3 in the PENFS group, 3 in the sham group), adhesive allergy (n = 3; 1 in the PENFS group, 2 in the sham group), and syncope due to needle phobia (n = 1; in the sham group). There were no serious adverse events (AEs). The authors concluded that the findings of this study suggested that non-invasive PENFS was a safe and effective therapeutic option for adolescents with abdominal pain-related functional GI disorders. These researchers stated that further studies should focus on finding the optimal duration of therapy and establishing the specific patient characteristics that are predictive of clinical response.
In an editorial, van Tilburg (2017) stated that the study by Kovacic et al (2017) offered a new direction for treating visceral hypersensitivity via central pathways. PENFS targets the auricular branches of the vagal nerve, and evidence showed that it modulates the pain matrix in the CNS, such as the amygdala. Findings from Kovacic et al showed that a 4-week treatment of PENFS reduced pain and disability compared with sham, and these effects were sustained 2 to 3 months following treatment. A major benefit of PENFS was that it is non-invasive -- PENFS is administered via the ear and electrical stimulation is below the sensation threshold. As a safe and efficacious treatment, PENFS could be an important addition to the therapeutic options for abdominal pain-related functional GI disorders. However, before recommending PENFS widely, the study results need to be replicated. Kovacic et al found only a small placebo response (29 % versus 41 % on average in other trials). Many treatment trials of abdominal pain-related functional GI disorders have not shown significant differences because of a robust placebo response in patients. Investigation of whether PENFS will remain superior to placebo or sham in the long-term should be scrutinized more closely. Secondly, Kovacic et al did not examine if PENFS changed visceral hypersensitivity, central pain pathways, or both. Nor did they indicate whether pain reduction was more robust in patients with pre-existing visceral hypersensitivity. Data on the mechanism of PENFS in pain reduction would strengthen the findings and ease the worries around a possible low placebo response. Furthermore, such findings would provide important information to target PENFS treatment to the right patient. It is hoped that in the future clinicians could confidently explain why children have abdominal pain-related functional GI disorders and that they will have access to safe and effective therapeutic options. The study by Kovacic et al is a major step in this direction. The editorialist concluded that although more studies are needed, their findings suggested that PENFS is a novel treatment targeting visceral hypersensitivity, which can safely reduce pain and disability in these disorders.
In a retrospective study, Wang et al (2018) examined the safety and effectiveness of neuromuscular electrical stimulation (NMES) as an adjunctive therapy to drotaverine hydrochloride (DHC) in patients with diarrhea-predominant IBS (BP-IBS). A total of 108 patient cases with BP-IBS were included in this study. Of these, 54 cases were assigned to a treatment group and received NMES and DHC, whereas the other 54 subjects were assigned to a control group and underwent DHC alone. All patients were treated for a total of 4 weeks. Primary outcomes were measured by the VAS, and average weekly stool frequency. Secondary outcome was measured by the Bristol scale. In addition, adverse events (AEs) were documented. All outcome measurements were analyzed before and after 4-week treatment. Patients in the treatment group did not show better effectiveness in VAS (p = 0.14), and average weekly stool frequency (p = 0.42), as well as the Bristol scale (p = 0.71), compared with the patients in the control group. Moreover, no significant differences in AEs were found between 2 groups. The authors concluded that the findings of this study showed that NMES as an adjunctive therapy to DHC may be not effective for patients with BP-IBS after 4-week treatment.
Krasaelap et al (2020) noted that pre-clinical studies showed that PENFS modulates central pain pathways and attenuates visceral hyperalgesia. In a randomized, double-blind study, these researchers examined the efficacy of PENFS in adolescents with irritable bowel syndrome (IBS). They analyzed data from pediatric patients with IBS who participated in a double-blind trial at a tertiary care gastroenterology clinic from June 2015 through November 2016. Patients were randomly assigned to groups that received PENFS (n = 27; median age of 15.3 years; 24 female) or a sham stimulation (n = 23; median age of 15.6 years; 21 female), 5 days/week for 4 weeks. The primary endpoint was number of patients with a reduction of 30 % or more in worst abdominal pain severity after 3 weeks. Secondary endpoints were reduction in composite abdominal pain severity score, reduction in usual abdominal pain severity, and improvement in global symptom based on a symptom response scale (-7 to +7; 0 = no change) after 3 weeks. Reductions of 30 % or more in worst abdominal pain were observed in 59 % of patients who received PENFS versus 26 % of patients who received the sham stimulation (p = 0.024). The patients who received PENFS had a composite pain median score of 7.5 (IQR, 3.6 to 14.4) versus 14.4 for the sham group (IQR, 4.5 to 39.2) (p = 0.026) and a usual pain median score of 3.0 (IQR, 3.0 to 5.0) versus 5.0 in the sham group (IQR, 3.0 to 7.0) (p = 0.029). A symptom response scale score of 2 or more was observed in 82 % of patients who received PENFS versus 26 % of patients in the sham group (p ≤ 0.001). No significant side effects were reported. The authors concluded that PENFS is a promising, and now FDA-approved, novel therapy for adolescents with IBS. This study confirmed that auricular neurostimulation via PENFS significantly improved abdominal pain and global symptoms in affected adolescents. Traditionally, therapies targeting FAPDs are approved in adults but used off-label in children. Given the safety profile and the likely mechanisms, it appeared reasonable to also consider its use in adults. Future studies should focus on characterizing short- and long-term responses to PENFS in different IBS subtypes and other functional GI disorders, finding the optimal duration of therapy while also assessing changes in stool pattern. Further mechanistic studies are also needed to help target this therapy to the most appropriate patient population, including adults. Moreover, these researchers stated that although future studies are needed to define appropriate thresholds, its utility for identifying treatment responders, low cost, and ease of administration with an ECG device makes vagal efficiency (VE) a promising neurophysiological biomarker. Identification of patients with reduced VE may ultimately help individualize and target therapy for functional GI disorders, findings not previously described.
The authors stated that drawbacks of this study included short-term study duration and outcome assessment and the lower number of measures available at follow-up, resulting in decrease in power and difficulties assessing long-term impact. Notably, VE did not predict long-term treatment response. This may be due to medications or disease status alterations that were not controlled for long-term. Alternatively, the auricle may provide a portal for vagal stimulation to reduce pain short-term, but a longer treatment course may be necessary for sustained effects. Slight group differences such as longer pain duration and higher rates of depression along with temporary stressors may have influenced results. Furthermore, the small number of males prohibited assessment of sex interactions.
In a RCT, Kovacic et al (2020) examined if pre-treatment vagal efficiency (VE), respiratory sinus arrhythmia, and heart period could predict pain improvement with auricular neurostimulation in pediatric functional abdominal pain disorders (FAPDs). A total of 92 adolescents with FAPDs underwent a 4-week randomized, double-blinded, sham-controlled auricular neurostimulation trial. Electrocardiogram-derived variables at baseline were used to predict pain using mixed effects modeling. A 3-way interaction (95 % confidence intervals [CI]: 0.004 to 0.494) showed that the treatment group subjects with low baseline VE had lower pain scores at week 3. There was no substantial change in the placebo or high VE treatment group subjects. This effect was supported by a significant correlation between baseline VE and degree of pain reduction only in the treatment group. The authors concluded that impaired cardiac vagal regulation measured by VE predicted pain improvement with auricular neurostimulation. Moreover, these researchers stated that although future studies are needed to define appropriate thresholds, its utility for identifying treatment responders, low cost, and ease of administration with an ECG device made VE a promising neurophysiological biomarker. Identification of patients with reduced VE may help individualize and target therapy for functional gastro-intestinal (GI) disorders, findings not previously described. This study did not examine the effectiveness of IB-Stim for the treatment of IBS.
The authors stated that drawbacks of this study included short-term study duration and outcome assessment and the lower number of measures available at follow-up, resulting in decrease in power and difficulties evaluating long-term impact. Notably, VE did not predict long-term treatment response. This may be due to medications or disease status alterations that were not controlled for long-term. Alternatively, the auricle may provide a portal for vagal stimulation to reduce pain short-term, but a longer treatment course may be necessary for sustained effects. Slight group differences such as longer pain duration and higher rates of depression along with temporary stressors may have influenced results. Furthermore, the small number of males prohibited assessment of sex interactions.
Furthermore, an UpToDate review on “Treatment of irritable bowel syndrome in adults” (Wald, 2021) does not mention electrical stimulation as a therapeutic option.
Santucci et al (2022) stated that percutaneous electrical nerve field stimulation (PENFS) improves symptoms in adolescents with functional abdominal pain disorders (FAPDs); however, little is known regarding its impact on sleep and psychological functioning. These researchers examined the effects of PENFS on resting and evoked pain and nausea, sleep and psychological functioning, and long-term outcomes. Patient aged 11 to 19 years with FAPD requiring PENFS as standard care were recruited. Evoked pain was elicited by a Water Load Symptom Provocation Task (WL-SPT) before and after 4 weeks of treatment. Pain, gastro-intestinal (GI) symptoms, sleep, somatic symptoms, and physical and psychological functioning were evaluated. Actigraphy was used to measure daily sleep-wake patterns. A total of 20 patients (14.3 ± 2.2 years old) with FAPD were enrolled. Most patients were females (70 %) and white (95 %). During pain evoked by WL-SPT, visual analog scale (VAS) pain intensity and nausea were lower following PENFS compared with baseline (p = 0.004 and p = 0.02, respectively). After PENFS, resting VAS pain unpleasantness (p = 0.03), abdominal pain (p < 0.0001), pain catastrophizing (p = 0.0004), somatic complaints (0.01), functional disability (p = 0.04), and anxiety (p = 0.02) exhibited significant improvements, and some were sustained long-term. Self-reported sleep improved after PENFS (p < 0.05) as well as actigraphy-derived sleep onset latency (p = 0.03). The authors demonstrated improvements in resting and evoked pain and nausea, sleep, disability, pain catastrophizing, somatic complaints, and anxiety after 4 weeks of PENFS therapy. Some effects were sustained at 6 to 12 months post-treatment, suggesting that PENFS is a suitable alternative to pharmacologic therapy.
The authors stated that this study had several drawbacks including a small sample size (n = 20), a heterogeneous population including functional dyspepsia and irritable bowel syndrome, and lack of a control/sham group. However, these factors were mitigated by a within-subject design that is intrinsically more powerful than a between-subject design. These researchers did not have baseline actigraphy data before PENFS. This would have necessitated additional visits, which would further add challenges to participant recruitment.
In a review on “Neuromodulation and neurostimulation for the treatment of functional gastrointestinal disorders”, Chen (2022) noted that several transcutaneous electrical neural stimulation (TENS) devices have been cleared by the FDA; however, many have limitations in the parameter settings that render them ineffective for patients with functional GI disorders. A recently published study by researchers at the Medical College of Wisconsin showed that a form of taVNS, percutaneous electrical nerve field stimulation, applied externally to the ear can relieve pain associated with IBS in adolescents. Following treatment, the median composite pain score of treated patients was 50 % that of patients who received sham treatment; however, information on its effect on IBS with diarrhea or IBS with constipation (IBS-C) was not examined. This taVNS method is approved for the treatment of IBS pain in adolescents and provides a non-pharmacologic method of pain control. These investigators stated that in nerve stimulation research, some investigators are more focused on pathophysiology and others on symptoms. In some instances, researchers are examining whether devices approved for other disorders have applicability for improving symptoms of IBS. Other research considers the pathophysiology of a disorder and then gradually develops and improves a methodology. Research on transcutaneous neuromodulation, including taVNS and a modality known as transcutaneous electrical acustimulation (TEA), has been ongoing, with the aim of approval for use in the treatment of functional GI disorders.
An UpToDate review on “Functional abdominal pain in children and adolescents: Management in primary care” (Chacko and Chiou, 2022) states that “Unproven interventions -- A number of other interventions are used in adults with pain-predominant FGIDs or have been tried in children with functional abdominal pain but lack clear evidence of benefit in randomized trials. These include rifaximin, linaclotide, lubiprostone, yoga, otilonium bromide (available outside the United States), and iberogast (an herbal therapy available in Germany). In a single randomized sham-controlled trial in 115 adolescents, neurostimulation via percutaneous electric nerve field stimulation (PENFS) of the external ear reduced abdominal pain severity, frequency, and duration with no serious adverse effects in adolescents with FAPDs. Although these findings are promising and the US Food and Drug Administration has granted permission to market the device for relief of functional abdominal pain in 11- to 18-year-old adolescents with IBS, additional studies are necessary to confirm the results, determine the optimal setting and duration of treatment, and determine the optimal target population before PENFS can be recommended for children with FAPDs”.
Furthermore, an UpToDate review on “Treatment of irritable bowel syndrome in adults” (Wald, 2022) does not mention electrical stimulation as a therapeutic option.
El-Chammas et al (2022) noted that neuromodulation has been employed in an increasing range of human diseases as well as GI disorders. The use of neuromodulation for the treatment of pediatric motility and functional disorders is an exciting recent development. These investigators discussed the use of neuromodulation for the treatment of pediatric gastroparesis, constipation, and visceral hyperalgesia. The authors stated that sensory and motor dysfunctions of the GI tract can cause severe symptoms and significantly decrease QOL. Neuromodulation of the GI tract is a new and valuable addition that enriches the armamentarium of therapeutic options. Some of the challenges with neuromodulation entail understanding the precise mechanisms of its actions, identifying the right patient, achieving a beneficial and clinically significant therapeutic endpoint, achieving disease modification in addition to symptomatic improvement, safety, optimizing modulation parameters and location, monitoring effectiveness of modulation, and maintaining its effectiveness long term. These researchers stated that even though results have been promising thus far, further research is needed before there is more widespread acceptance of neuro-stimulation in the treatment of children with sensory-motor disorders of the GI tract.
Santucci et al (2023) noted that standard medical therapy (SMT) in children with functional abdominal pain disorders (FAPD) includes cyproheptadine and amitriptyline. While PENFS has shown benefit, no study has compared outcomes of PENFS to SMT. These investigators examined changes in abdominal pain, nausea, and disability before and after treatment and compared outcomes between treatments. The records of FAPD patients aged 11 to 21 years, treated with 4-week of PENFS, cyproheptadine or amitriptyline were reviewed. Outcomes were evaluated using validated questionnaires [Abdominal Pain Index (API), Nausea Severity Scale (NSS), and the Functional Disability Inventory (FDI)] at baseline and follow-up within 3 months (FU). Of 101 patients, 48 % received PENFS, 31 % cyproheptadine and 21 % received amitriptyline. Median ages were 17 (15 to 19), 16 (15 to 18) and 15 (11 to 16) years, respectively; and the majority were females (75 %, 90 % and 52 %, respectively). In the PENFS group, API (p = 0.001), NSS (p = 0.059) and FDI (p = 0.048) were significantly lower at FU. API (p = 0.034) but not NSS and FDI (p > 0.05) decreased significantly at FU in the amitriptyline group. API, NSS and FDI did not change significantly with cyproheptadine at FU (p > 0.05). FU API scores were lower in PENFS versus cyproheptadine (p = 0.04) but not versus amitriptyline (p = 0.64). The FDI scores were significantly lower in the amitriptyline versus cyproheptadine group (p = 0.03). The authors concluded that treatment with PENFS showed improvements in abdominal pain, nausea, and disability while amitriptyline showed improvements in abdominal pain within 3 months of treatment. PENFS was more effective than cyproheptadine in improving abdominal pain. Amitriptyline improved disability scores more than cyproheptadine and showed promise for treatment. These researchers stated that PENFS may be a good non-pharmacologic alternative for FAPD.
The authors stated that this was the 1st study to compare treatment outcomes of PENFS with SMT. These researchers had a moderate sample size in each group allowing for meaningful comparisons. They used validated, pediatric questionnaires that provided objective assessments however, the modified versions over 1 week were not validated compared to the standard questionnaires assessing symptoms over 2 weeks. Unfortunately, the study design did not allow for evaluating baseline psychological co-morbidities that could theoretically impact treatment outcomes. Similarly, the retrospective study design precluded assessment of other biopsychosocial factors that could contribute to symptoms. Furthermore, data were assessed at 3 months, and it would have been ideal to have a longer follow-up with the entire cohort. These investigators noted that only a prospective, head-to-head study would allow for this longer follow-up since medications are typically discontinued if there are no benefits after proper dose adjustments. These researchers stated that future studies should also include prospective analysis of adverse event (AE) comparisons between PENFS and SMT
Santucci et al (2024) stated that functional dyspepsia (FD) includes post-prandial distress and epigastric pain syndrome. PENFS in addition to behavioral interventions (BI) has shown benefits in children with functional abdominal pain but not specifically in FD. In a retrospective study, these researchers examined the effectiveness of PENFS for treating FD and compared the outcomes with those who received the combination of PENFS + BI. Charts of patients with FD who completed 4 weeks of PENFS were evaluated. A subset of patients received concurrent BI. Demographic data, medical history, and symptoms were documented. Outcomes at different time-points included subjective symptom responses and validated questionnaires collected clinically (API, NSS, FDI, Pittsburgh Sleep Quality Index [PSQI], Children's Somatic Symptoms Inventory [CSSI], Patient-Reported Outcomes Measurement Information Systems [PROMIS] Pediatric Anxiety and Depression scales). Of 84 patients, 61 % received PENFS + BI, and 39 % received PENFS alone. In the entire cohort, API (p < 0.0001), NSS (p = 0.001), FDI (p = 0.001), CSSI (p < 0.0001), PSQI (p = 0.01), PROMIS anxiety (p = 0.02), and depression (p = 0.01) scores improved from baseline to 3weeks and at 3 months. Subjective responses showed nausea improvement (p = 0.01) and a trend for improvement in abdominal pain (p = 0.07) at week 3. Abdominal pain subjectively improved at week 3 and 3 months (p = 0.003 and 0.02, respectively), nausea at week 3 and 3 months (p = 0.01 and 0.04, respectively), and a trend for improvement in sleep disturbances at week 3 and 3 months (p = 0.08 and p = 0.07, respectively) in the PENFS + BI group versus PENFS alone. The authors concluded that abdominal pain, nausea, functioning, somatization, sleep disturbances, anxiety, and depression improved at 3 weeks and 3 months after PENFS in pediatric FD. Subjective pain and nausea improvement were greater in the PENFS + BI group than in the group with PENFS alone, suggesting an additive effect of psychologic therapy. Moreover, these researchers stated that further prospective studies with larger sample sizes are needed to better define the role of integrating BI into PENFS therapy.
The authors stated that this study had several drawbacks, including the retrospective design, which did not allow assessment of symptoms associated with FD other than pain and nausea. Data could not be collected at week 4 after completion of treatment because patients did not return for any clinical visits. Furthermore, the BI was not standardized across groups, and there was variation in the number and the timing of the sessions. To improve the quality of study methods, a future study can better standardize the BI with specific content, duration, and timing of treatments as noted in a treatment manual. Subjective data were collected from the medical chart and thus had some missing data that were handled using the mixed modeling and fitting maximum-likelihood method. These researchers noted that the FDA and the healthcare community have also advocated the generation of clinical data in a real-world setting, outside clinical trials, to monitor post-market safety and effectiveness of drugs and devices. They stated that several small studies have reported benefits of auricular transcutaneous stimulation. These studies include patients with post–COVID-19 symptoms, cognitive impairment, visceral hypersensitivity, and FD.
Chogle et al (2023) noted that disorders of the gut-brain interaction (DGBIs) account for 50 % of pediatric GI consultations. Children with DGBIs have worse QOL than those with organic GI disorders such as inflammatory bowel disease (IBD) and gastro-esophageal reflux disease (GERD). Pediatric DGBIs patients, especially those with chronic abdominal pain (AP), have impaired QoL and increased psychological distress in the form of anxiety and depression. PENFS therapy has been shown to be effective in improving symptoms and functioning in children with DGBIs. The treatment's impact on these patients' QOL is unknown. In a prospective study, these researchers examined changes in QOL, GI symptoms, functional disability, somatization, global health, anxiety, and depression in patients aged 11 to 18 years who received PENFS therapy (IB-stim) for treatment of DGBIs-related pain, once-weekly for 4 consecutive weeks. This study included 31 patients with an average age of 15.7 years (SD = 2); 80.6 % were female. After PENFS therapy, patients reported significant reductions in AP, nausea severity, functional disability, somatization, and anxiety from baseline to week 4 (p < 0.05). Parents reported significant improvement in their child's QOL regarding physical function, psychosocial function, and generic core scale scores (p < 0.05). Parents also noted reduced abdominal pain, functional disability, and somatization. Average scores on the PROMIS Global Health scale significantly improved based on both patient and parent reports (p < 0.05). Patients' QOL was significantly lower than healthy controls at baseline and after treatment (p < 0.05). The authors concluded that the findings of this study showed that PENFS significantly enhanced the QOL of children suffering from DGBIs-related pain, in addition to improvement in GI symptoms, daily functioning, somatization, global health, and psychological comorbidities. These investigators stated that these findings showed the effectiveness of PENFS and its potential to alleviate the suffering of countless children. Moreover, these investigators stated that further research is needed to confirm these findings, elucidate the mechanisms underlying the observed associations, the understanding of the gut-brain axis; and optimize treatment strategies, to provide personalized and effective care for pediatric patients with DGBIs, ultimately improving their QOL and ability to thrive in society.
The authors stated that this study had several drawbacks, including a relatively small sample size (n = 31), and the absence of a sham control group. These investigators stated that future research should employ larger sample sizes, placebo-controlled study designs, and long-term follow-up data to examine the effectiveness of PENFS therapy compared to other treatment modalities and to evaluate the durability of treatment effects and optimal duration of therapy. They also examined the potential need for maintenance therapy or repeated courses of treatment or concurrent treatment with other modalities to ensure sustained improvements in symptomatology and QOL for pediatric patients with DGBIs. It is important to examine the long-term effects of PENFS therapy on pediatric patients.; and future studies should also examine the role of patient-specific factors, such as duration of illness and co-morbidities, in determining treatment response and QoL outcomes.
Furthermore, these researchers noted that considering the observed discrepancies between parent and child-reported outcomes, future research should consider employing more objective measures of improvement, such as changes in grades, participation in extra-curricular activities, or the number of missed events before and after PENFS therapy. Understanding the parent-child dyad and the factors that contribute to discrepancies in their perceptions of therapeutic outcomes could aid in informing the development of more effective communication strategies and tailored interventions that consider both the patient's and the parent's perspectives. This may further enhance the understanding of how both perspectives can be employed in assessing treatment progress and tailoring interventions to the specific needs of pediatric patients with DGBIs. In addition, there has been increasing interest in examining the microbiome of patients with various pain disorders; however, there is a lack of studies in the pediatric population. A recent study examined changes in the microbiome of adolescents with IBS after PENFS treatment, and the microbiome showed decreased Clostridial species and long chain fatty acid (LCFA) microbial pathways post-treatment (Castillo, 2023). A future objective could be to examine the microbiome of children with other DBGIs besides IBS and changes in the microbiota secondary to PENFS.
Castillo et al (2023) noted that IBS is affected by the microbiome. Microbial studies in pediatric IBS, especially for centrally mediated treatments, are lacking. These researchers compared the microbiome between pediatric IBS patients and healthy controls (HC), in relation to symptom severity, and with PENFS, a non-invasive treatment targeting central pain pathways. They collected a stool sample, questionnaires and a 1 to 2 week stool and pain diary from 11 to 18 years patients with IBS. A subset of patients completed 4 weeks of PENFS and repeated data collection immediately after and/or 3 months after treatment. Stool samples were collected from HC. Samples underwent metagenomic sequencing to examine diversity, composition, and abundance of species and MetaCyc pathways. These researchers included 27 cases (15.4 ± 2.5 year) and 34 HC (14.2 ± 2.9 year). A total of 12 species including Firmicutes spp., and carbohydrate degradation/LCFA synthesis pathways, were increased in IBS but not statistically significantly associated with symptom severity; 17 participants (female) who completed PENFS showed improvements in pain (p = 0.012), disability (p = 0.007), and catastrophizing (p = 0.003). Carbohydrate degradation and LCFA synthesis pathways decreased post-treatment and at follow-up (FDR p-value < 0.1). The authors concluded that firmicutes, including Clostridiaceae spp., and LCFA synthesis pathways were increased in IBS patients suggesting pain-potentiating effects. PENFS resulted in marked improvements in AP, functioning, and catastrophizing, while Clostridial species and LCFA microbial pathways decreased with treatment, suggesting these as potential targets for IBS centrally mediated treatments. These researchers stated that future directions can include evaluation of GI histology in conjunction with the microbiome. While these investigators used fecal calprotectin as a measure of intestinal inflammation, evaluating histological markers that are elevated in IBS patients such as mast cells would allow for a more accurate measure of inflammation including by location in the GI tract and types of inflammation. Similarly, given potential differences in the microbiome between direct luminal sampling and stool samples, direct sampling during endoscopy may provide a better representation of the relationship between these IBS measures and the microbiome. Other future directions could include examining the potential link between metabolic pathways with the gut-brain axis as well as neuromodulation and the inclusion of metabolomic analysis. A larger sample would aid in verifying these preliminary findings and expand from these exploratory results. While the changes in microbial pathways lasted up to a few months after PENFS treatment, it would be beneficial to follow the cohort for a longer time to determine the durability of these changes in the microbiome after neuromodulation.
The authors stated that this study was limited by the small sample size (n = 27), especially for the longitudinal data; this may have contributed to the lack of associations between the microbiome and symptom severity and limited the generalizability of these findings. Despite the small numbers, statistically significant findings were noted, and this trial may serve as a useful sample to show feasibility and design for a larger trial to corroborate these findings, and also detect more modest differences between IBS subtypes. There were more females in the IBS group compared to controls which posed a higher risk of selection bias if this is not an accurate reflection. However, these researchers included gender as a model co-variate and still found significant differences in the microbiome between groups, consistent with the approach in recent reports of the microbiome in adults with IBS. Similarly, to provide optimal data with meaningful conclusions, the longitudinal analysis was only reflective of female patients and the authors excluded the sole male subject. Finally, although these investigators excluded patients on probiotics and antibiotics and those receiving formula as the sole source of nutrition, they were unable to control for diet and all medications affecting the microbiome. It would be beneficial in a future study to control for these factors.
Karrento et al (2023) stated that children with cyclic vomiting syndrome (CVS) often suffer from disabling AP and co-morbidities that impair QOL. A non-invasive, auricular PENFS device is shown to be effective for AP in children with DGBIs. In a prospective, open-label study, these investigators examined the effects of PENFS on pain, common co-morbidities, and QoL in pediatric CVS. Children aged 8 to 18 years with drug-refractory CVS were enrolled in this trial; they received 6 consecutive weeks of PENFS. Subjects completed the following surveys at baseline, during/after therapy (week 6), and at extended follow-up approximately 4 to 6 months later: API, State-Trait Anxiety Inventory for Children (STAI-C), PSQI, and PROMIS Pediatric Profile-37. A total of 30 subjects were included. Median (inter-quartile range, IQR) age was 10.5 (8.5 to 15.5) years; 60 % were female. Median API scores decreased from baseline to week 6 (p = 0.003) and to extended follow-up (p < 0.0001). State anxiety scores decreased from baseline to week 6 (p < 0.0001) and to extended follow-up (p < 0.0001). There were short-term improvements in sleep at 6 weeks (p = 0.031) but not at extended follow-up (p = 0.22). QOL measures of physical function, anxiety, fatigue, and pain interference improved short-term, while there were long-term benefits for anxiety. No serious side effects were reported. The authors concluded that this was the 1st study to show the effectiveness of auricular neurostimulation using PENFS for pain and several disabling co-morbidities in pediatric CVS. PENFS improves anxiety, sleep, and several aspects of QOL with long-term benefits for anxiety. These researchers stated that this therapy shows promise as an emerging non-pharmacological and targeted intervention for CVS.
The authors stated that this study had several drawbacks. First, the lack of a sham-controlled study design and placebo effects may have underlined some of the improvement as subjects received weekly attention. Placebo effects may be especially high with non-pharmacological, non-invasive interventions such as the PENFS that are often highly sought by parents of CVS sufferers after failing numerous drug therapies; therefore, bias in the report of symptom improvement may be a factor. Yet, the device placements were carried out by certified research nurses who were not part of the research team and were instructed to refrain from interactions with subjects. The noted long-term improvements were also less likely due to placebo effects. Second, evaluating an episodic illness with standardized patient-reported outcome surveys designed for chronic conditions was problematic. The pain assessment (API), in particular, is a survey of pain symptoms over past week, and long-term improvement in this measure may be less relevant to an episodic illness. However, progressive pain improvement throughout and after the treatment intervention based on several measures coupled with long-term reduction in episode frequency suggested that PENFS therapy influenced the disease course. Third, the inclusion of comprehensive and long-term assessments of several co-morbidities and QoL measures in relation to the CVS episodes lessened this confounder. State anxiety assessment could also be confounded by the assessment at single time-points. The state anxiety or PROMIS anxiety subscales did not show a clear relationship. This could be due to a small sample size and insufficiently powered study. A longer duration of follow-up is likely needed to thoroughly examine the impact on episode frequency. However, anxiety indices were improved on both PROMIS and STAI-C (state) scales, suggesting long-term improvement in this common comorbidity. The authors stated that further investigations of the impact of mental health co-morbidities, including antecedent trauma, would be important for a more comprehensive understanding of this patient cohort. Fourth, that lack of standardization of protocols, the type of stimulation (transcutaneous versus percutaneous), and stimulation parameters limited the generalizability of research in the field of non-invasive neuromodulation. Reliable biomarkers of para-sympathetic activity are needed to optimize stimulation protocols and individualize therapy.
Chakraborty et al (2023) stated that functional abdominal pain disorders (FAPDs) affect up to 25 % of children in the U.S. These disorders are more recently known as disorders of "brain-gut" interaction. The diagnosis is based on the ROME IV criteria, and requires the absence of an organic condition to explain the symptoms. Although these disorders are not completely understood, several factors have been involved in the pathophysiology including disordered gut motility, visceral hypersensitivity, allergies, anxiety/stress, GI infection/inflammation, as well as dysbiosis of the gut microbiome. The pharmacologic and non-pharmacologic treatments for FAPDs are directed to modifying these pathophysiologic mechanisms. These investigators examined the non-pharmacologic interventions used in the treatment of FAPDs including dietary modifications, manipulation of the gut microbiome (nutraceuticals, prebiotics, probiotics, symbiotic, gastric electrical stimulation (GES) and PENFS, as well as fecal microbiota transplant [FMT]) and psychological interventions that addresses the "brain" component of the brain-gut axis (cognitive behavioral therapy [CBT], hypnotherapy, breathing and relaxation techniques). In a survey conducted at a large academic pediatric gastroenterology center, 96 % of patients with functional pain disorders reported using at least 1 complementary and alternative medicine treatment to ameliorate symptoms. The authors concluded that in general, well-conducted pediatric studies for many therapies discussed are lacking and the existing ones were small in sample size making generalizable conclusions difficult. They stated that there is a need for large RCTs to examine their effectiveness and superiority compared to other treatments.
Chen et al (2023) noted that various methods of noninvasive neuromodulation have been applied for the treatment of functional GI diseases (FGIDs) including percutaneous auricular vagal nerve stimulation (paVNS). These researchers stated that further development and research are needed to bring more non-invasive neuromodulation therapies from bench to bedside. Methodologically, optimization of stimulation parameters and treatment regimens is highly recommended. For efferent stimulation, the stimulation parameters should be chosen to enhance para-sympathetic activity. For afferent stimulation, the stimulation parameters should be chosen to inform the brain the nature and location of the disorders, which may benefit from the assessment of the endogenous afferent signal associated with the disorder to be treated. Technologically, advanced wearable devices need to be developed preferably with following features: (i) they should be easy to wear and use, such as having a small size and being wireless (electrodes are imbedded with the stimulators); (ii) they should resemble entertainment gadgets, so that the treatment can be delivered in public; (iii) they should automatically track adherence to the treatment. The authors stated that more RCTs, especially multi-center RCTs, are needed to show the effectiveness of the proposed therapy.
Bora et al (2023) noted that the vagus nerve may affect gut microbiome composition via brain-gut-microbiome signaling. In a prospective, pilot study, these investigators examined gut microbiome alterations by PENFS therapy in adolescent IBS patients. This trial enrolled females with IBS aged 11 to 18 years receiving PENFS therapy for 4 weeks with pre- and post-intervention stool sampling. Outcome surveys completed pre-therapy, weekly, and post-therapy included IBS-Severity Scoring System (IBS-SSS), visceral sensitivity index (VSI), functional disability inventory (FDI), and the global symptom response scale (SRS). Bacterial DNA was extracted from stool samples followed by 16S rRNA amplification and sequencing. QIIME 2 (version 2022.2) was used for analyses of α and β diversity and differential abundance by group. A total of 20 females aged 15.6 ± 1.62 years were included; IBS-SSS, VSI, and FDI scores decreased significantly after PENFS therapy (p < 0.0001, p = 0.0003, p = 0.0004, respectively). No intra- or inter- individual microbiome changes were noted pre- versus post-therapy or between responders and non-responders. When response was defined by 50-point IBS-SSS score reduction, α diversity was higher in responders compared with non-responders at week 4 (p = 0.033). There was higher abundance of Blautia in excellent responders versus non-responders. The authors concluded that there were no substantial microbial diversity alterations with PENFS. Subjects with excellent therapeutic response showed an enrichment of relative abundance of Blautia, which may indicate that patients with specific microbial signature have a more favorable response to PENFS. Moreover, these investigators stated that it is possible that specific microbial signatures indicate IBS patients who are more receptive to this therapy; however, further investigations with large sample sizes are needed to draw major conclusions of these findings.
The authors stated that important limitations of this study included the small sample size (n = 20). And the lack of a control group. When the patients were categorized into IBS subgroups, the sample size was further reduced, resulting in insufficient power to make major inferences of some of the study findings, especially regarding specific subgroups. There were also potential confounding effects of medications and diets, as the study confirmed significant β diversity differences in those on restricted diets. These researchers stated that higher-powered studies are needed to enhance the understanding of gut microbiome alteration in response to auricular neurostimulation in IBS.
Furthermore, an UpToDate review on “Functional abdominal pain in children and adolescents: Management in primary care” (Chacko and Chiou, 2023) states that “In auricular neurostimulation therapy, percutaneous electrical nerve field stimulation (PENFS) is administered through a noninvasive device that is worn behind the ear to target central pain pathways involved in pain amplification. In a randomized sham-controlled trial in 115 adolescents, auricular neurostimulation reduced abdominal pain severity, frequency, and duration with no serious adverse effects in adolescents with FAPDs. In another randomized sham-controlled trial in 50 adolescents with IBS, auricular neurostimulation reduced abdominal pain scores and improved overall well-being. In addition to improvements in self-reported symptoms of abdominal pain and nausea, PENFS has been associated with changes in visceral sensitivity using a water load task, actigraphic and subjective sleep measures, and other psychological factors like catastrophizing and somatic complaints. Although these findings are promising and the US Food and Drug Administration has granted permission to market the device for relief of FAP in 11- to 18-year-old adolescents with IBS, additional studies are necessary to confirm the results, determine the optimal setting and duration of treatment, and determine the optimal target population before PENFS can be routinely recommended for children with FAPDs”.
Zhang et al (2024) stated that FGIDs are common, and they severely impair an individual's QOL. The mechanism of pathogenesis and the effective treatments for FGIDs remain elusive. Neuromodulation, a relatively new treatment, has exhibited a good therapeutic effect on FGIDs, although there are different methods for different symptoms of FGIDs. These researchers employed PubMed to examine the history of neuromodulation for the treatment of FGIDs and reviewed several recently proposed neuromodulation approaches with improved effects on FGIDs. The authors concluded that electro-acupuncture, transcutaneous electro-acupuncture, transcutaneous auricular VNS, SNS (which relies on VNS), and GES (which works through the modulation of slow waves generated by the interstitial cells of Cajal), in addition to the non-invasive neurostimulation alternative approach method of SNS-tibial nerve stimulation and transcutaneous electrical stimulation (which is still in its infancy), are some of the proposed neuromodulation approaches with improved effects on FGIDs. These researchers discussed some critical issues related to the selection of stimulation parameters and the underlying mechanism and attempts to outline future research directions backed by the existing literature.
Chogle et al (2024) noted that (PENFS has shown promise in single-center studies for pediatric abdominal pain-related DGBI. In a multi-center, registry study, these researchers examine the effectiveness of PENFS as standard therapy for DGBI. This was a prospective, open-label registry of children (age of 8 to 18 years) undergoing PENFS for DGBI at 7 tertiary care gastro-enterology clinics. DGBI subtypes were classified by Rome IV criteria. Parents and patients completed API, NSS, and FDI questionnaires before, during therapy, and at follow-up visits up to 1 year later. A total of 292 subjects were included. Majority (74 %) were female with median (IQR age of 16.3 (14.0 to 17.7) years). Most (68 %) met criteria for functional dyspepsia, and 61 % had failed 4 or more pharmacotherapies. API, NSS, and FDI scores showed significant decreases within 3 weeks of therapy, persisting long-term in a subset. Baseline (n = 288) median (IQR) child-reported API scores decreased from 2.68 (1.84 to 3.58) to 1.99 (1.13 to 3.27) at 3 weeks (p < 0.001) and 1.81 (0.85 to 3.20) at 3 months (n = 75; p < 0.001). NSS scores similarly improved from baseline, persisting at 3 months (n = 74; p < 0.001) and 6 months later (n = 55; p < 0.001). FDI scores displayed similar reductions at 3 months (n = 76; p = 0.01) but not beyond. Parent-reported scores were consistent with child reports. The authors concluded that this large, comprehensive, multi-center registry highlighted the effectiveness of PENFS for GI symptoms and functionality for pediatric DGBI. These researchers stated that although limited by a large number of drop-outs, these findings were suggestive of a durable response in at least a subset of patients. Moreover, they stated that further investigations of specific characteristics of treatment responders and duration of optimal therapeutic effects are needed.
The authors stated that while this was a large, multi-center study, it had important drawbacks. First, it is well-known that patients with DGBI have a high placebo response, a limitation that cannot be ignored. On the other hand, the majority of patients had already failed other interventions making a placebo effect less likely, as they were generally followed by the same team. Additional studies indicating that PENFS effects are unlikely solely via placebo included a randomized trial reporting superiority over sham, animal data showing reduced central neuronal firing, altered mechano-sensitivity after PENFS in children with DGBI, and sustained brain connectivity changes after PENFS. Second, as previously noted, this was a complex tertiary care population that may not be generalizable to all DGBI in the general population. Third, many patients did not complete the follow‐up surveys, and it was possible that those that who completed them were more satisfied with treatment and willing to complete questionnaires without being incentivized. Several subjects also dropped out of therapy during the first few weeks, accounting for missing data. It is unclear if some of these, designated as “non-compliance” or “unknown” cause, may have been due to the cosmetic appearance of the device. However, the records indicated that more drop-outs occurred due to treatment success than failure. Further analyses of the subjects lost to follow‐up compared to those retained showed no major differences in demographics, co-morbidities, or baseline survey results. Fourth, while the reliability of the long‐term follow‐up data beyond 6 months can be questioned, the results of the primary outcome, and 3‐month follow‐ups included a fairly large cohort and was highly consistent with previous studies. These findings replicated a previous randomized trial in pediatric DGBI, showing significant treatment effects compared to sham for 2 to 3 months and more recent, open‐label data. Fifth, the results may also be skewed, perhaps under-estimated, since data were not systematically collected after the end of therapy at 4 weeks due to majority not returning to clinic after the 4th device placement. Sixth, these researchers did not control for any other interventions such as medication changes or dosing adjustment that could have been given during PENFS. Seventh, this was a very heterogenous cohorts with several types of DGBI classified based on the current Rome criteria. Predicting outcomes by “symptom‐based criteria” is difficult as demonstrated by the authors’ data showing no differences in outcomes when analyzed by the most common Rome categories. These investigators stated that it is important to continue examining the pathophysiology of these disorders to better predict outcomes to available therapies.
In an opinion article, Miranda (2024) stated that few studies have compared treatments head-to-head; and while the study by Santucci et al (2022) had limitations, the authors should be commended for taking on this task. Until more regarding the impact of anti-depressants on the developing brain, ANS, and immune system, clinicians have a responsibility to prescribe these medications in children judiciously, especially when there is evidence of harmful or detrimental effects in adults. Clearly, there is a role for pharmacotherapy; however, duration of treatment should be discussed as should potential alternatives. These include therapies with proven benefit and few side effects that enhance the body's ability to self-regulate and restore homeostasis such as PENFS or psychological therapies including gut-directed hypnotherapy, cognitive behavioral therapy (CBT), or biofeedback (BFB). Consideration should also be given to peppermint oil, safer over the counter (OTC) medications ,or natural supplements and dietary changes. Clinicians also cannot neglect the benefits of lifestyle modification such as exercise and improved sleep hygiene. Future interventions may also entail artificial intelligence (AI) that could, for example, make general pediatricians and families feel more comfortable with the diagnosis of DGBIs without having to refer to the sub-specialist for additional testing. Furthermore, the use of virtual reality as a treatment modality could potentially help “reset” brain pathways that are involved in pain processing. Miranda stated that physicians have a responsibility to offer the best and safest therapies to the patients and families they care for. The time has come to question and study if prescription, off-label medications are safe in children with DGBIs and how best to use them. Until now, poly-pharmacy with a high anti-cholinergic burden was believed to be a problem isolated to the elderly population. However, it is not uncommon to see children present to clinics on multiple medications that include anti-depressants, alpha 2 delta ligands, mood stabilizers, anti-psychotics, as well as stimulants. While some of these have been major therapeutic break-throughs for patients, the responsibility of pediatricians is to try and minimize poly-pharmacy and above all, limit the potential impact of these medications on the developing brain since it is likely investigators will not know the long-term impact for years to come. This article did not provide any clinical data regarding the effectiveness of PENFS in the treatment of DGBIs. It should also be noted that the author is the Chief Medical Officer for NeurAxis, Inc., which concentrates on neuromodulation therapies for chronic and debilitating conditions including DGBIs.
Furthermore, an UpToDate review on “Functional abdominal pain in children and adolescents: Management in primary care” (Balakrishnan and Chiou, 2024) states that “Auricular ոеսrοѕtimulatiοn therapy -- In auricular ոеսrοѕtimսlatiоո therapy, percutaneous electrical nerve field stimulation (PENFS) is administered through a noninvasive device that is worn behind the ear to target central рaiո pathways involved in pаin amplification. In a randomized sham-controlled trial in 115 аԁοlеѕcеnts with DGBIs, auricular ոеսrοѕtimսlаtiоn reduced abdominal раin severity, frequency, and duration with no serious adverse effects. In another randomized sham-controlled trial in 50 аԁοlеѕϲeոts with ІBS, auricular ոеսrοѕtimսlatiοո reduced abdominal рaiո scores and improved overall well-being. In addition to improvements in self-reported symptoms of abdominal раiո and nausea, PENFS has been associated with changes in visceral sensitivity using a water load task, actigraphic and subjective sleep measures, and other psychological factors like catastrophizing and somatic complaints. Although these findings are promising, and the US Food and Drug Administration has granted permission to market the device for relief of IΒЅ in 11- to 18-year-old аԁοlеѕcеnts, additional studies are necessary to confirm the results, determine the optimal setting and duration of treatment, and determine the optimal target population before PENFS can be routinely recommended for ϲhildrеո with DGBIs”.
Auricular Electrical Stimulation
Liao et al (2019) examined the effect of auricular electrical stimulation (ES) on migraine. Migraine was induced in rats by intra-peritoneal administration of nitroglycerin (NTG, 10 mg/kg) 3 times. Auricular ES pre-treatment was carried out for 5 consecutive days. Migraine behaviors were observed by a video recording. Auricular ES pre-treatment could reverse the decrease of the total time spent on exploratory (2,619.0 ± 113.0 s versus 1,581.7 ± 217.6 s, p= 0.0029) and locomotor behaviors (271.3 ± 21.4 s versus 114.3 ± 19.7 s, p = 0.0135) and also could reverse the increase of the total time spent on resting (19.0 ± 10.6 s versus 154.3 ± 46.5 s, p = 0.0398) and grooming (369.9 ± 66.8 s versus 1302.0 ± 244.5 s, p = 0.0324) behaviors. Auricular ES pre-treatment could increase the frequency of rearing behaviors (38.0 ± 1.8 versus 7.7 ± 3.5, p < 0.0001) and total distance traveled (1,372.0 ± 157.9 cm versus 285.3 ± 85.6 cm, p < 0.0001) and also could increase the percentage of inner zone time (6.0 ± 1.6 % versus 0.4 ± 0.2 %, p = 0.0472). The CGRP, COX-2, TRPV1, and TRPA1 immunoreactive cells in the trigeminal ganglion increased in the NTG group compared with the control group (all p < 0.0001); this increase could, however, be reduced by auricular ES pre-treatment (27.8 ± 2.6 versus 63.0 ± 4.2, p < 0.0001; 21.7 ± 1.2 versus 61.8 ± 4.0, p < 0.0001; 24.3 ± 1.0 versus 36.5 ± 1.7, p = 0.0003; and 20.7 ± 1.9 versus 90.8 ± 6.5, p < 0.0001, respectively). The authors suggested that auricular ES pre-treatment was beneficial for the treatment of migraine and this effect was partly related to CGRP/COX-2/TRPV1/TRPA1 signaling pathways.
The authors stated that this study had several drawbacks. First, more objective methods to examine nociceptive pain are needed, such as von Frey test for nociceptive peri-orbital pain threshold; thus, more evaluations need to be carried out for assessment of migraine except video recordings for associated behavior of migraine in the future. Second, more objective methods to examine emotional behavior is needed, such as forced-swim or tail suspension tests except locomotor activity of open-field test in the future. Third, one experiment was inadequate to conclude the signaling pathway; another genetic modification or molecular technique to examine the signaling is needed in the future. Fourth, the study must be concerning with the emotional data that can be interrupted by physical factor, which is a locomotor behavior in the future.
IB-Stim for the Treatment of Nausea and Abdominal Pain Secondary to Irritable Bowel Syndrome
Paicius et al (2006) noted that spinal cord stimulation (SCS) has become an accepted therapeutic modality for the treatment of intractable pain syndromes, primarily used today in the settings of FBSS, neuropathic back and limb pain . The use of SCS for peripheral nerve field electrostimulation is becoming increasingly recognized as a safe, effective alternative for chronic pain conditions that are refractory to medical management and do not respond to traditional dorsal column stimulation. Advances in technology have allowed for minimally invasive percutaneous placement of multi-polar leads with complex programmable systems to provide patient-controlled relief of pain in precisely targeted regions. With these improvements in hardware, the use of peripheral nerve field stimulation (PNFS) appeared to have an untapped potential for providing patients with pain relief for a wider range of underlying conditions than was previously believed possible. These researchers presented 3 cases, each with a different etiology of chronic abdominal pain: 1 with inguinal neuralgia, 1 with chronic pancreatitis, and 1 with pain following liver transplant. Each patient was refractory to conventional medical approaches. For all 3 patients, PNFS provided significant relief from pain, enabling patients to decrease or discontinue their opioid medications and to enjoy significant improvement in their QOL. The authors concluded that PNFS was a safe, effective and minimally invasive treatment that may be used successfully for a wide variety of indications including chronic abdominal pain. Moreover, these researchers stated that their experience suggested that PNFS has potential as a therapeutic option for chronic abdominal pain, including post-inguinal herniorrhaphy pain, abdominal incisional pain, and pain associated with chronic pancreatitis. They stated that the technique merits further study.
Goroszeniuk and Khan (2011) stated that the management of pain in chronic benign pancreatitis is complex. Celiac plexus neurolysis provides pain relief of variable duration. Neuromodulation of splanchnic nerves with electrodes and an IPG system is an alternative to producing long-term pain relief with minimal complications in selected cases. These investigators presented the case of a 36-year-old woman with intractable abdominal pain for 5 years from chronic benign pancreatitis. Multiple pharmacotherapy regimens, surgery, and interventions produced temporary pain relief of variable duration and intensity. Following a successful trial of celiac plexus stimulation, neuromodulation of the splanchnic nerves was achieved with 2 permanently implanted octo-polar leads at the T11/T12 area connected to an IPG. Eighteen months following the implant, the patient continued to derive satisfactory pain relief without any device-related complications. Her opiate use was significantly reduced from 225 (486 mg morphine per day) to 12.5 (27 mg morphine per day) ug/hour fentanyl patches and the fentanyl lozenges were stopped with an increase in appetite and of more than 8 kg in weight gain. The initial VAS 8 to 9 out of 10 was reduced to VAS 0 out of 10 since implantation. The authors noted that the pain of chronic pancreatitis has both visceral and somatic components as evidenced by the lack of complete pain relief from celiac plexus block alone and the knowledge that in chronic disease, the pathology extends to extra-pancreatic somatic tissues, especially the retroperitoneum. These researchers postulated that the electrical field generated by the dual octrode system extended to include splanchnic nerves and other somatic innervations of the pancreas. The authors concluded that this was the 1st case of a successful long-term neuromodulation of splanchnic nerves with a permanently implanted device. The potential exists for its use in visceral abdominal pain of varied etiologies, once more experience is obtained with this technique.
Zhou et al (2017) noted that chronic abdominal wall pain is a well-documented complication of abdominal surgery. However, abdominal wall CRPS is a rare medical condition. These researchers presented a case of abdominal wall CRPS and its treatment with PNFS. A 34-year-old woman presented with right peri-umbilical pain for 2 years. She developed burning, sharp and stabbing pain with allodynia (extremely sensitive to wind and light touch) and erythema or pallor 2 weeks after an exploratory appendectomy. The extensive evaluation ruled out the underlining pathology. After she failed conservative therapies, she underwent a 7-day trial of thoracic SCS and abdominal wall PNFS. Thoracic SCS failed to provide pain relief; however, PNFS provided significant relief (greater than 90 %) of burning sensation. It has now been 5 years since the PNFS was implanted and she continued to demonstrate substantial pain relief. The authors stated that to the best of their knowledge, PNFS has not been documented for the treatment of abdominal CRPS; PNFS has been used for chronic pain with a promising outcome notably in 3 cases of chronic abdominal pain (Paicius et al, 2006).
Reactiv8 Device for the Treatment of Chronic Low Back Pain
The ReActiv8 Implantable Neurostimulation System includes an implantable pulse generator (IPG), 2 stimulation leads, a magnet, and a wireless remote. The IPG delivers electrical stimulation pulses to certain nerves responsible for activating the lumbar multifudus muscle, the key muscles responsible for stabilizing the lower back. It is intended to help with the management of chronic LBP associated with the muscular weakness of the lumbar multifidus muscle in patients who have failed therapy including pain medications and physical therapy and are not candidates for spine surgery. Before implanting the device, multifudus muscle atrophy and weakness must be shown using magnetic resonance imaging (MRI) or during a physical examination using the prone instability test. It received FDA approval on June 16, 2020 (via PMA).
Currently, there is insufficient evidence to support the use of the Reactiv8 device for the treatment of chronic LBP
In a prospective, single-arm, multi-center clinical trial, Deckers et al (2018) examined restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical LBP (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or SCS. A total of 53 subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was LBP evaluated on a 10-point numerical rating scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of greater than or equal to 2-point in LBP NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and QOL (EQ-5D). For 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58 %. The percentage of subjects at 90 days, 6 months, and 1 year with greater than or equal to MCID improvement in single day NRS was 63 %, 61 %, and 57 %, respectively. Percentage of subjects with greater than or equal to MCID improvement in ODI was 52 %, 57 %, and 60 % while those with greater than or equal to MCID improvement in EQ-5D was 88 %, 82 %, and 81 %. There were no unanticipated AEs or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach. The authors concluded that electrical stimulation to elicit episodic lumbar multifidus contraction is a new therapeutic option for CMLBP; results demonstrated clinically important, statistically significant, and lasting improvement in pain, disability, and QOL.
The authors stated that this study had several drawbacks. First, it did not include a control arm. Second, the primary outcome measure in this study was improvement in pain evaluated with the NRS; however, evaluating changes in multiple outcome measures may be more clinically relevant (e.g., many trials of spine surgery for LBP used a composite outcome measure including assessment of disability). Third, lead issues that resulted in loss of stimulation for a period of time may have negatively impacted the outcomes in the affected subjects. Fourth, outcome data to 1 year were presented. Subjects in this study will continue to be evaluated annually through 5 years as part of a post-market clinical follow‐up study, which will provide information on longer term safety and efficacy. Finally, the data from this trial have not been analyzed to examine patient parameters that could be predictive of outcomes, and further research is needed to more clearly identify the best candidates for this therapy.
Mitchell et al (2021) noted that the objective of the ongoing follow-up of the ReActiv8-A Trial is to document the longitudinal benefits of episodic stimulation of the dorsal ramus medial branch and consequent contraction of the lumbar multifidus in patients with refractory mechanical CLBP. These investigators reported the 4-year outcomes of this study. Eligible patients had disabling CLBP (NRS of greater than or equal to 6; ODI of greater than or equal to 25), no indications for spine surgery or SCS, and failed conventional management including at least physical therapy (PT) and medications for LBP. Fourteen days post-implantation, stimulation parameters were programmed to elicit strong, smooth contractions of the multifidus, and subjects were given instructions to activate the device for 30-min stimulation-sessions twice-daily. Annual follow-up through 4 years included collection of NRS, ODI, and European QOL Score on 5 Dimensions (EQ-5D). At baseline (n = 53) (mean ± SD) age was 44 ± 10 years; duration of back pain was 14 ± 11 years, NRS was 6.8 ± 0.8, ODI 44.9 ± 10.1, and EQ-5D 0.434 ± 0.185. Mean improvements from baseline were statistically significant (p < 0.001) and clinically meaningful for all follow-ups. Patients completing year 4 follow-up, reported mean (± standard error of the mean) NRS: 3.2 ± 0.4, ODI: 23.0 ± 3.2, and EQ-5D: 0.721 ± 0.035. Moreover, 73 % of subjects had a clinically meaningful improvement of greater than or equal to 2 points on NRS, 76 % of greater than or equal to 10 points on ODI, and 62.5 % had a clinically meaningful improvement in both NRS and ODI and 97 % were (very) satisfied with treatment. The authors concluded that in patients with disabling intractable CLBP who receive long-term restorative neurostimulation, treatment satisfaction remains high; pain and disability in the 4‐year completed case cohort were on average 53 % and 50 % lower than baseline, respectively, suggesting that the effects were durable over the long-term. Moreover, these researchers stated that the longitudinal analysis presented was not without limitations. After 4 years, 19/53 (35.9 %) patients were missing data for various reasons. Furthermore, the relatively high lead revision rate that contributed to early attrition may also have impacted reported outcomes.
Provenzano et al (2021) stated that neurostimulation techniques for the treatment of chronic LBP have been rapidly evolving; however, questions remain as to which modalities provide the most effective and durable treatment for intractable axial symptoms. Modalities of SCS, such as traditional low-frequency paresthesia based, high-density or high dose (HD), burst, 10-kHz high-frequency therapy, closed-loop, and differential target multiplexed, have been limitedly studied to determine their efficacy for the treatment of axial LBP. Furthermore, stimulation methods that target regions other than the spinal cord, such as medial branch nerve stimulation of the multifidus muscles and the dorsal root ganglion (DRG) may also be viable therapeutic options. The authors concluded that the minimal invasiveness of neurostimulation remains a compelling reason for patients to seek this therapeutic option for the treatment of axial LBP. Invasive surgical methods (e.g., fusion) that alter the anatomy of the spine with considerable rates of failure and high AEs rates are often considered before neurostimulation. These researchers stated that if neurostimulation is shown to demonstrate long-term effectiveness in appropriately designed RCTs with low complication and explant rates, then neurostimulation therapies may move up in the treatment algorithm for chronic axial LBP and refractory non-surgical LBP.
Gilligan et al (2021) stated that CLBP can be caused by impaired control and degeneration of the multifidus muscles and consequent functional instability of the lumbar spine. Available therapeutic options have limited effectiveness and prognosis is unfavorable. These researchers carried out an international randomized, double-blind, sham-controlled trial at 26 multi-disciplinary centers to determine the safety and effectiveness of an implantable, restorative neurostimulator designed to restore multifidus neuromuscular control and facilitate relief of symptoms. A total of 204 eligible subjects with refractory mechanical CLBP and a positive prone instability test indicating impaired multifidus control were implanted and randomized to therapeutic (n = 102) or low-level sham (n = 102) stimulation of the medial branch of the dorsal ramus nerve (multifidus nerve supply) for 30 mins twice-daily. The primary endpoint was the comparison of responder proportions (greater than or equal to 30 % relief on the LBP-VAS without analgesics increase) at 120 days. After the primary endpoint assessment, subjects in the sham-control group switched to therapeutic stimulation and the combined cohort was evaluated through 1 year for long-term outcomes and AEs. The primary endpoint was inconclusive in terms of treatment superiority (57.1 % versus 46.6 %; difference: 10.4 %; 95 % confidence interval [CI]: -3.3 % to 24.1 %, p = 0.138). Pre-specified secondary outcomes and analyses were consistent with a modest but clinically meaningful treatment benefit at 120 days. Improvements from baseline, which continued to accrue in all outcome measures after conclusion of the double-blind phase, were clinically important at 1 year. The incidence of serious procedure- or device-related AEs (3.9 %) compared favorably with other neuromodulation therapies for chronic pain. The authors concluded that this double-blind, randomized, sham-controlled trial provided important insights and design considerations for future neuromodulation trials. Although the primary endpoint was inconclusive, overall data from the blinded phase of this trial were consistent with a clinically meaningful benefit at 120 days. After unblinding and the switch from sham to therapeutic stimulation in the sham-control group, improvements increased over time out to 1 year in the combined cohort. The incidence of serious procedure- or device-related AEs compared favorably with rates published for other neuromodulation therapies for chronic pain. Follow-up of subjects in this trial will continue for a total of 5 years, providing additional insights into the long-term benefits, risks, and reliability of this device.
The authors stated that several drawbacks need to be addressed when interpreting the findings of this study. First, at the time of trial design, the size and duration of the sham response to this type of treatment in subjects with CLBP was unknown. The statistical design assumptions, derived from a literature review for available CLBP treatments, under-estimated the response to a surgically implanted active sham device. Although the LBP-VAS trajectory suggested that the sham effect may be reversing at 120 days, due to the pre-specified switch of the sham-control group to therapeutic stimulation, these investigators were unable to confirm this longer term. Second, although previous studies had shown that observed improvements with this rehabilitative treatment accrue over time, endpoint timing was set to 120 days for practical and ethical reasons, and the fixed 30 % threshold for pain relief reflected the expected improvement at 120 days rather than the fully accrued long-term treatment effect. Finally, although sham stimulation parameters were set to low amplitude and frequency values, a potential therapeutic effect could not be ruled out and this might have diminished the magnitude of the group differences in the outcome measures.
Thomson et al (2021) noted that LBP impacts most people throughout the course of their lives and contributes significantly to the global burden of disease. In some patients, symptoms resolve with little intervention, while others are amenable to surgical intervention, some cases are intractable to current care paradigms. Restorative neurostimulation is an emerging therapy for chronic mechanical LBP. These researchers carried out a prospective, post-market follow-up of 42 patients treated for longstanding chronic mechanical LBP with restorative neurostimulation. Patients were followed-up at 45, 90, and 180 days and 1 and 2 years following activation of the device. Pain, disability, and health-related QOL (HR-QOL) were recorded. Among the 37 patients completing 2-year follow-up, NRS pain scores improved from 7.0 ± 0.2 to 3.5 ± 0.3 (p < 0.001), ODI scores improved from 46.2 ± 2.2 to 29.2 ± 3.1 (p < 0.001), HR-QOL (measured by the EuroQol 5-Dimension 5-Level questionnaire-EQ-5D-5L) improved from 0.426 ± 0.035 to 0.675 ± 0.030 (p < 0.001). Furthermore, 57 % of patients experienced a greater than 50 % reduction in pain, and 51 % of patients benefited by a greater than 15-point reduction in ODI, both substantial improvements. The authors concluded that this real-world sample of patients showed that restorative neurostimulation could provide substantial and durable benefit to a cohort of patients that have traditionally had few reliable therapeutic options. These researchers stated that these findings supported the continued use of this therapy in well-selected patients.
The authors stated that this study had 2 main drawbacks. First, 5 patients did not complete the 2-year follow-up appointment, and their missing data were imputed using simple LOCF and FOCF, including the 4 patients where the device was explanted for lack of efficacy. Second, the absence of a control group; however, the implanted candidates had exhausted conventional medical management. It should also be noted that sponsorship for this study and Rapid Service Fee was provided by Mainstay Medical.
Ardeshiri et al (2022) stated that neuromuscular instability of the lumbar spine resulting from impaired motor control and degeneration of the multifidus muscle is a known root cause of refractory chronic low back pain (CLBP). An implantable neurostimulation system that aims to restore multifidus motor control by stimulating the L2 medial branch of the dorsal ramus (ReActiv8, Mainstay Medical) and thereby relieving pain and reducing disability has demonstrated clinically significant benefits in the clinical trial setting. These researchers presented 1-year results of a single-center, real-world cohort. A total of 44 consecutive patients with refractory, predominantly nociceptive axial CLB, evidence of multifidus dysfunction and no surgical indications or history of surgical intervention for CLBP were recruited at a single site in Germany. Each patient was implanted with a neurostimulation device. Pain (NRS), disability (ODI) and quality of life (QOL) (EQ-5D-5L) outcomes were collected at baseline, 3-, 6- and 12-months post-activation. Statistically significant improvements in pain, disability, and QOL from baseline were observed at all assessment times-points. At 12 months post-activation, mean (± SE) NRS was reduced from 7.6 ± 0.2 to 3.9 ± 0.4 (p < 0.001), mean ODI (±S E) from 43.0 ± 2.8 to 25.8 ± 3.9 (p < 0.001) and mean EQ-5D-5L (± SE) index improved from 0.504 ± 0.034 to 0.755 ± 0.039 (p < 0001). No lead migrations were observed. One patient required revision due to lead fracture. The authors concluded that restorative neurostimulation is a new therapeutic option for well selected patients with refractory CLBP. The clinically meaningful improvements in pain, disability, and QOL demonstrated in routine clinical practice were consistent with the published results of controlled trials. This was a relatively small study (n = 44) with only 1-year follow-up.
Sayed et al (2022) stated that painful lumbar spinal disorders represent a leading cause of disability in the U.S. and worldwide. Interventional treatments for lumbar disorders are an effective treatment for the pain and disability from LBP. Although many established and emerging interventional procedures are currently available, there exists a need for a defined guideline for their appropriateness, safety and effectiveness. The American Society of Pain and Neuroscience (ASPN) Back Guideline was developed to provide clinicians the most comprehensive review of interventional treatments for lower back disorders. Clinicians should utilize the ASPN Back Guideline to examine the quality of the literature, safety, and effectiveness of interventional treatments for lower back disorders. The ASPN identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations. Experts from the fields of Anesthesiology, Physiatry, Neurology, Neurosurgery, Radiology, and Pain Psychology developed the ASPN Back Guideline. The world literature in English was searched using Medline, Embase, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Scopus, and meeting abstracts to identify and compile the evidence (per section) for back-related pain. Search words were selected based upon the section represented. Identified peer-reviewed literature was critiqued using U.S. Preventive Services Task Force (USPSTF) criteria and consensus points were presented. After a comprehensive review and analysis of the available evidence, the ASPN Back Guideline group was able to rate the literature and provide therapy grades to each of the most commonly available interventional treatments for LBP. The authors concluded that the ASPN Back Guideline represents the 1st comprehensive analysis and grading of the existing and emerging interventional treatments available for LBP. This will be a living document that will be periodically updated to the current standard of care (SOC) based on the available evidence within peer-reviewed literature. There was no specific recommendation regarding “Restorative Neurostimulation / ReActiv8 neurostimulator” in this ASPN Back Guideline.
The National Institute for Health and Care Excellence’ guideline on ”Neurostimulation of lumbar muscles for refractory nonspecific chronic low back pain” (NICE, 2022) stated that evidence on the safety and efficacy of neurostimulation of lumbar muscles for refractory non-specific CLBP is limited in quantity and quality; thus, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
Shaffrey and Gilligan (2023) noted that high-impact CLBP correlates with high healthcare resource utilization. Therapies that can alter impact status may provide beneficial long-term economic benefits. An implantable restorative neurostimulation system (ReActiv8, Mainstay Medical) designed to over-ride multifidus inhibition to facilitate motor control restoration; thus, resolving mechanical LBP symptoms, has shown significant durable clinical effects in moderately and severely impacted patients. These investigators examined changes in high-impact CLBP in patients treated with restorative neurostimulation at 2 years. For this longitudinal sub-analysis, patients were stratified into low-, moderate-, and high-impact CLBP categories using the U.S. Department of Health and Human Services definition comprising pain intensity, duration, and impact on work, self-care, and daily activities. Of 2-year completers (n = 146), 71 % had high-impact CLBP at baseline and this proportion reduced to 10 %, with 85 % reporting no or low impact. This corresponded with measurements of HR-QOL returning to near-population norms. The authors concluded that in addition to clinically meaningful improvements in pain and function with long-term durability, the overwhelming majority of patients transitioned from a high- to a no- or low-impact CLBP state. This was typically associated with significantly lower healthcare-utilization levels. The recovery trajectory was consistent with a restorative mechanism of action and suggested that over the long-term, the improvement in these health states will be maintained.
The authors stated that is analysis demonstrated the impact to drivers of direct and indirect economic costs associated with restorative neurostimulation for CLBP. A drawback of this approach was that it only indirectly assessed the economic impact. Furthermore, presenteeism was evaluated by patient self-report and may have inherent bias; occupation type was also not accounted for. There was also potential for selection bias in the identification of the high-impact cohort; however, this definition is consistent with current descriptions of this pain phenotype. The absence of a long-term control group made it difficult to definitively account for spontaneous recovery, although this was less likely to occur in patients presenting with extensive histories of CLBP that has already manifested as functional and occupational impairments. It should also be noted that the ReActiv8-B study was funded by Mainstay Medical.
Lorio et al (2023) stated that this International Society for the Advancement of Spine Surgery statement has been generated to respond to growing requests for background, supporting literature and evidence, and proper coding for restorative neurostimulation for chronic low back pain (LBP). Chronic LBP (CLBP) describes the diverse experience of a significant proportion of the population. Conservative management of these patients remains the predominant care pathway; however, for many patients, symptom relief is poor. The application of new techniques in patients who have exhausted traditional care paradigms should be undertaken with a detailed understanding of the pathology being treated, the mechanisms involved, and the data supporting effectiveness. This statement on restorative neurostimulation places this technology in the context of the current understanding of the etiology of mechanical LBP and the currently available evidence for this technique. In an appropriately selected cohort with a specific subset of CLBP symptoms, this technique may provide benefit to payers and patients. The authors concluded that restorative neurostimulation for chronic mechanical LBP is supported by several studies that showed robust and durable clinical effects over the pre-treatment condition. The totality of evidence suggested that in a well-selected patient population who have exhausted conventional care paradigms, the potential benefits outweighed the risks and costs. These patients tend to be exposed to multiple therapies with limited durability, resulting in a continuous cycle of high-cost healthcare utilization. These investigators stated that restorative neurostimulation should be considered for clinically appropriate patients who have exhausted reasonable conservative approaches. Moreover, these researchers stated that industry funding is a potential source of bias for the available data reviewed; and only a limited number of studies were available in this review.
Francio et al (2023) noted that CLBP is multi-factorial in nature, with recent research highlighting the role of multifidus dysfunction in a subset of non-specific CLBP. In a scoping review of the literature, these investigators provided a foundational reference that elucidates the pathophysiological cascade of multifidus dysfunction, how it contrasts with other CLBP etiologies and the role of restorative neurostimulation. A total of 194 articles were included, and findings were presented to highlight emerging principles related to multifidus dysfunction and restorative neurostimulation. Multifidus dysfunction is diagnosed by a history of mechanical, axial, nociceptive CLBP and examination showing functional lumbar instability, which differs from other structural etiologies. Diagnostic images may be used to grade multifidus atrophy and evaluate for other structural pathologies. While various treatments exist for CLBP, restorative neurostimulation distinguishes itself from traditional neurostimulation in a way that treats a different etiology, targets a different anatomical site, and has a distinctive mechanism of action. The authors concluded that multifidus dysfunction has been proposed to result from loss of neuromuscular control, which may manifest clinically as muscle inhibition resulting in altered movement patterns. Overtime, this cycle may result in potential atrophy, degeneration and CLBP. Restorative neurostimulation, a novel implantable neurostimulator system, stimulates the efferent lumbar medial branch nerve to elicit repetitive multifidus contractions. This intervention aims to interrupt the cycle of dysfunction and normalize multifidus activity incrementally, potentially restoring neuromuscular control. Restorative neurostimulation has been shown to reduce pain and disability in CLBP, improve quality of life (QOL) and reduce healthcare expenditures.
The authors stated that although they followed the journal’s guidelines on scoping reviews, including the PRISMA-ScR and Peter et al (2020) framework, this scoping review has drawbacks that should be considered when interpreting the discussion of the results section. First, assessment of the quality of the studies was not carried out due to the heterogenicity of included studies. Second, data synthesis and key summary of findings was presented in a descriptive format, rather than a quantitative format since this scoping review highlighted a conceptual framework and did not compare the same intervention and outcomes within the same or populations. Third, it was outside the scope of this study to extensively review procedural techniques, safety profile, and comparative clinical results since other studies have covered these topics in detail. Fourth, selection bias in the extraction process could not be excluded; however, this was mitigated by using a systematic transparent approach following the afore-mentioned guidelines.
Thomson et al (2023) noted that mechanical CLBP is frequently associated with impaired neuromuscular control of the lumbar multifidus muscles. Restorative neurostimulation is a modality for the treatment for this specific subset of patients aimed to facilitate restoration of neuromuscular control by bilateral stimulation of the L2 medial branches. Evidence from both prospective and randomized clinical trials to- date has reported marked improvements in clinical outcomes such as pain, disability, and health-related quality of life (HR-QOL). This trial was a prospective, open-label, follow-up for the treatment of mechanical CLBP of nociceptive origin with restorative neurostimulation using the ReActiv8. Patients completed assessments for pain, disability and HR-QOL. Outcomes were collected at 45, 90 and 180 days, as well as 1, 2 and 3 years after the activation visit. A total of 42 patients were implanted with the device; and 33 (79 %) were available at the 3-year appointment. Patients in this cohort presented with severe CLBP (NRS = 7.0 ± 0.2) and severe disability (ODI 46.6 ± 12.0). The HR-QOL was also severely impacted at baseline (EQ-5D = 0.426 ± 0.061). Changes in pain, disability and QOL at 3-year follow-up showed a statistically significant improvement between baseline and 1, 2 and 3 years. After 3 years of therapy, average NRS scores had reduced to 2.7± 0.3 and mean ODI score to 26.0 ± 3.1 while EQ-5D-5L index improved to 0.707 ± 0.036. The authors concluded that the ongoing follow-up of this post-market cohort continued to show that restorative neurostimulation provided a statistically significant, clinically meaningful, and durable response across pain, disability and QOL scores for patients suffering mechanical CLBP that has been refractory to conventional management. The authors stated that the main drawback of this study was that at the 3-year timepoint, 9 patients (21 %) had left the study or missed follow-up appointments for various reasons.
Gilligan et al (2023a) noted that impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory CLBP. An implantable restorative-neurostimulator system could override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided safety and effectiveness evidence for this device, and all subjects received therapeutic stimulation from 4 months onward. These researchers examined the 2-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. Open-label follow-up of 204 subjects implanted with a restorative neurostimulation system (ReActiv8) was carried out. Pain intensity (VAS), disability (ODI), QOL (EQ-5D-5L), and opioid intake were examined at baseline, 6 months, 1 year, and 2 years after activation. At 2 years (n = 156), the proportion of subjects with greater than or equal to 50 % CLBP relief was 71 %, and 65 % reported CLBP resolution (VAS less than or equal to 2.5 cm); 61 % had a reduction in ODI of greater than or equal to 20 points, 76 % had improvements of greater than or equal to 50 % in VAS and/or greater than or equal to 20 points in ODI, and 56 % had these substantial improvements in both VAS and ODI. A total of 87 % of subjects had continued device use during the 2nd year for a median of 43 % of the maximum duration, and 60 % (34 of 57) had voluntarily discontinued (39 %) or reduced (21 %) opioid intake. The authors concluded that at 2 years, 76 % of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provided evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction.
The authors stated that the main drawback of this study was the absence of a long-term comparator because of therapy activation in the sham-control group after conclusion of the blinded phase at 4 months. Furthermore, studies with long follow-up durations will inherently have to account for missing data, especially those for chronic pain conditions. Indiscriminate use of last observation carried forward has been criticized as a source of systematic bias in chronic pain trials, and more appropriate methods have been recommended.
In a prospective, observational, follow-up study, Gilligan et al (2023) reported the 3-year safety and effectiveness of the ReActiv8 neurostimulator in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. This study included 204 implanted trial participants with LBP; VAS, ODI, EuroQol quality of life survey, and opioid intake were assessed at baseline, 6 months, and 1, 2, and 3 years after activation. The mixed-effects model repeated measures approach was employed to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. Data were collected from 133 participants, and 16 patients missed their 3-year follow-up because of coronavirus disease restrictions but remained available for future follow-up. A total of 62 % of participants had a 70 % or greater VAS reduction, and 67 % reported CLBP resolution (VAS of 2.5 cm or less); 63 % had a reduction in ODI of 20 or more points; 83 % had improvements of 50 % or more in VAS and/or 20 points or more in ODI, and 56 % had these substantial improvements in both VAS and ODI. A total of 71 % (36/51) participants on opioids at baseline had voluntarily discontinued (49 %) or reduced (22 %) opioid intake. The attenuation of effectiveness in the imputed (n = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remained favorable, and no lead migrations have been observed to-date. The authors concluded that at 3 years, 83 % of participants experienced clinically substantial improvements in pain, disability, or both..
Gilligan et al (2024) noted that adults with refractory, mechanical chronic LBP associated with impaired neuromuscular control of the lumbar multifidus muscle have few therapeutic options that provide long-term clinical benefit. These researchers hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology. In a prospective, 5-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (n = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic LBP, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. LBP intensity (10-cm VAS), disability (ODI), and QOL (EuroQol’s “EQ-5D-5L” index) were compared with baseline and following the ITT principle, with a supporting mixed-effects model for repeated measures that accounted for missing data. At 5 years (n = 126), LBP VAS had improved from 7.3 to 2.4 cm (-4.9; 95 % CI: -5.3 to -4.5 cm; p < 0.0001), and 71.8 % of participants had a reduction of 50 % or more. The ODI improved from 39.1 to 16.5 (-22.7; 95 % CI: -25.4 to -20.8; p < 0.0001), and 61.1 % of participants had reduction of 20 points or more. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95 % CI: 0.195 to 0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions, and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a 5-year visit, 46 % discontinued, and 23 % decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed. The authors concluded that over a 5-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic LBP associated with multifidus muscle dysfunction.
The authors stated that potential drawbacks of this trial included that owing to elective cross-over to therapeutic stimulation for ethical and trial-practical considerations, the sham-control group could not be maintained during the long-term follow-ups. This has been elaborated in an earlier publication. Device removals for various reasons, including 18 participants who underwent elective removals for resolution of symptoms (i.e., success), contributed to participant withdrawals and subsequent missing data. Although direct correlations with objective device usage and multifidus structure and function were not included in this follow-up, their importance is focus for future investigation.
Ardeshiri et al (2024) stated that data on the Medicare-aged population showed that older patients are major consumers of LBP interventions. An effective approach for patients with mechanical LBP that has been refractory to conservative management is restorative neurostimulation. The effectiveness o. restorative neurostimulation has been shown in multiple prospective studies, with published follow-up over 4 years, showing a consistent durable effect. To further examine the effect of restorative neurostimulation in an older demographic, data from 3 clinical studies were aggregated: ReActiv8-B prospectively followed 204 patients, ReActiv8-C study prospectively followed 87 patients, and ReActiv8-PMCF prospectively followed 42 patients. A total of 261 patients were identified with complete 2-year follow-up and divided into cohorts of equal size based of age quartiles. At 2 years from device activation, patients in either cohort were classified by change in disability (ODI) or change in pain score(NRS/VAS) and assessed as proportion of patients per group at each time-point. Furthermore, health-related quality of life (HRQoL) (EQ5D[1]5L) was longitudinally compared with baseline. Differences in proportions were assessed using χ2 and continuous variables by repeated measures analysis of variance. The oldest quartile (n = 65) had a median age of 60 (56 to 82) years compared with the entire population (n = 261) who had a median age of 49 (22 to 82) years. The completer analysis on patients with 2 years of continuous data showed improvement of a 50 % in pain was achieved by 62 % and 65 % and a 15-point ODI improvement in 48 % and 60 % in the oldest quartile and entire population, respectively. HRQoL (EuroQol 5-Dimension) improved from baselines of 0.568 and 0.544 to 0.763 and 0.769 in the oldest quartile and entire population, respectively. All age quartiles improved statistically and clinically over baseline. The authors concluded that this aggregate analysis of 3 independent studies provided insight into the performance of restorative neurostimulation in an older population. Patients derived significant and clinically meaningful benefit in disability, pain and HRQoL. When compared with a similarly indicated cohort of younger patients, there were no statistically or clinically significant differences. These researchers stated that further studies should focus on the use of restorative neurostimulation in older patients suffering from mechanical chronic LBP as a therapy to address this underlying condition as it appeared to show statistically significant reduction in pain, and increase in activity in this population with lasting durability.
The authors stated that drawbacks of this trial included the small cohort of patients identified in the upper age group, and the retrospective identification of the cohorts. Pain was collected differently between studies enabling a responder rate analysis only and no direct assessment of mean change from baseline. The inclusion and exclusion criteria for the various studies used in this analysis did vary slightly, however, the identification of these patients was achieved by applying the minimum requirements for inclusion for all patients.
Copley, et al. (2024) reported a systematic evidence review and metanalysis of electrical stimulation of the medial branch of the lumbar dorsal rami for the treatment of chronic low back pain. A total of six studies met inclusion criteria for the review, including the randomized clinical trial by Gilligan, et al. (2021) described above and five uncontrolled prospective clinical studies. The weighted pooled mean effect was a reduction in pain intensity (0–10 scale) of 2.9 units (95% CI: 2.1–3.7). Among the limitations is that it pooled the results of the only randomized controlled trial available at the time of the analysis, which failed to demonstrate statistical significance for its prespecified primary endpoint, with open label studies that are at high risk of bias for this pain intervention.
Schwab et al. (2025) reported on a randomized controlled clinical trial investigating the efficacy of the ReActiv8 stimulation therapy compared to optimal medical management in patients suffering from refractory mechanical chronic low back pain associated with multifidus muscle dysfunction. The objective was to evaluate the effectiveness of ReActiv8 stimulation therapy in improving pain and function in patients with chronic low back pain who have not responded adequately to conventional treatments. The study was designed as a randomized controlled trial involving multiple sites, with participants assigned to either the ReActiv8 therapy group or the optimal medical management group. Adults with chronic low back pain, specifically those with multifidus muscle dysfunction, were included in the study. A total of 203 patients, average age 47 years, and with an average 11-year history of low back pain, were included in the analysis. The study demonstrated that patients receiving ReActiv8 stimulation therapy experienced significant improvements in pain and function compared to those receiving optimal medical management. The primary endpoint was a statistically significant demonstration of a clinically relevant mean improvement in the Oswestry Disability Index (ODI) between restorative neurostimulation and OMM arms: ODI (−19.7 ± 1.4 vs. −2.9 ± 1.4; p < 0.001). Additionally, improvements in both the numeric rating scale (NRS) (−3.6 ± 0.2 vs.−0.6 ± 0.2; p < 0.001) and EuroQol Five-Dimension (EQ-5D-5L) (0.155 ± 0.012 vs. 0.008 ± 0.012; p < 0.001) were statistically and clinically significant in the restorative neurostimulation arm compared to the OMM arm. The authors stated that the therapy was well-tolerated, with a favorable safety profile reported. The authors acknowledged that the sample size may limit the generalizability of the findings, and a larger cohort could provide more robust data. They noted that the follow-up period may not be sufficient to assess the long-term effects and durability of the treatment outcomes. There was also a potential for bias in the reporting of outcomes due to the study being funded by Mainstay Medical, although the authors adhered to rigorous clinical trial standards. Additionally, the specific inclusion criteria may limit the applicability of the results to broader populations with chronic low back pain. The authors emphasized the necessity for additional studies to validate the findings in larger and more diverse populations, explore the long-term efficacy and safety of ReActiv8 stimulation therapy, investigate the mechanisms underlying the observed benefits of the therapy, and compare the ReActiv8 therapy with other emerging treatments for chronic low back pain. The open label nature of the study of this pain intervention introduces a significant risk of bias. Also, the comparison "optimal medical management" was not standardized and was left to the discretion of the treating physician.
Frequency Specific Microcurrent Therapy for the Treatment of Back and Neck Pain
In a retrospective case-control study, Shetty et al (2020) examined the effectiveness of adjuvant frequency-specific microcurrent (FSM) application on pain and disability in patients treated with physical rehabilitation for mechanical LBP and neck pain (NP). Pre- and post-treatment numerical pain rating scale (NPRS) score, ODI score, neck disability index (NDI) score, disability categories, and treatment outcome categories were compared between 213 patients in the FSM group (167 patients with LBP, 46 patients with NP) and 78 patients in the control group (61 patients with LBP, 17 patients with NP). In LBP patients, mean post-treatment NPRS score was significantly lower (p = 0.02) and a significantly higher percentage of patients were in the less than or equal to 3 NPRS score (p = 0.02), in the minimal disability (p = 0.01), and the full success (p = 0.006) categories post-treatment in the FSM group when compared to the control group. In NP patients, there was no significant difference in the post-treatment pain intensity, disability or treatment outcome when the 2 groups were compared. The authors concluded that the use of adjuvant FSM application in patients treated with physical rehabilitation for LBP significantly improved pain and disability when compared to patients in the control group. These researchers stated that FSM could be a useful adjuvant in the rehabilitation treatment of patients with LBP. This was a retrospective, case-control study, which did not find FSM to be useful for the treatment of neck pain; but could be helpful for the treatment of LBP. These preliminary findings need to be validated by well-designed studies.
Furthermore, UpToDate reviews on “Management of non-radicular neck pain in adults” (Isaac, 2021), “Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment” (Chou, 2021a), “Subacute and chronic low back pain: Nonsurgical interventional treatment” (Chou, 2021b), and “Treatment of acute low back pain” (Knight et al, 2021) do not mention frequency specific microcurrent as a management / therapeutic option.
Peripheral Nerve Stimulation of the Cluneal Nerve for the Treatment of Sacroiliac Joint-Mediated Pain
Calvillo et al (1998) noted that mild-to-moderate sacroiliac joint (SIJ) pain can be managed conservatively with analgesics, anti-inflammatory drugs, and physical therapy (PT). Severe SIJ pain can be incapacitating and more challenging to manage. Fluoroscopically-guided intra-articular (IA) local anesthetic-steroid injections, followed by joint manipulation, can be effective; and intra-capsular injections of glycerin, glucose, and phenol also may be beneficial in some patients. The use of neuroaugmentation to manage pain of synovial origin has not been reported previously. Sacral nerve root stimulation in particular has been used to manage urinary bladder dysfunction and pain, but not SIJ pain. These researchers reported 2 cases of severe SIJ pain that were resistant to conventional management techniques. Both patients had undergone lumbar fusion, which appeared to be a predisposing factor. These investigators defined the source of pain in these patients by performing a series of diagnostic blocks under fluoroscopic guidance to examine if these patients were candidates for neuroaugmentation. A total of 2 patients with severe SIJ pain were treated by implanting a neuro-prosthesis at the 3rd sacral nerve roots. Subjects had undergone lumbar fusion for back pain that developed as a result of work-related injuries. Stimulation was tried for 1 week with bilateral, percutaneously implanted, cardiac pacing wires at the 3d sacral nerve roots. Both patients experienced relief of approximately 60 % of their pain during the trial period; thus, a neuro-prosthesis was implanted permanently bilaterally at the 3rd sacral nerve root in both patients. The use of analgesics was reportedly the same after implantation, but significantly more effective, and the patients' activities of daily living (ADL) were more tolerable. The authors concluded that 2 cases of refractory SIJ pain were reported that were managed with permanently implanted neuro-prostheses at the 3rd sacral nerve roots. These researchers suggested that neuroaugmentation could be a reasonable option in selected patients with refractory SIJ pain.
Guentchev et al (2015) stated that SIJ pain affects older adults with a prevalence of up to 20 % among patients with chronic LBP. While pain medication, joint blocks and denervation procedures achieve pain relief in most patients, some cases failed to improve. These researchers examined the effectiveness of SIJ PNS in patients with severe conservative therapy-refractory SIJ pain. They presented 12 patients with severe conservative therapy-refractory pain receiving SIJ PNS. Patient satisfaction, pain, and QOL were assessed using the International Patient Satisfaction Index (IPSI), VAS, and ODI using standard questionnaires. For stimulation, these investigators placed an 8-pole peripheral nerve electrode parallel to the SIJ. Two weeks post-operatively, subjects reported an average ODI reduction from 57 % to 32 % and VAS from 9 to 2.1; IPSI was 1.1. After 6 months, the therapy was rated as effective in 7 of 8 patients reporting at that period. The average ODI was low at 34 % (p = 0.0006), while the VAS index rose to 3.8 (p < 0.0001) and IPSI to 1.9. Twelve months after stimulation, 6 of 7 patients considered their treatment a success with an average ODI of 21 % (p < 0.0005), VAS 1.7 (p < 0.0001), and IPSI 1.3. The authors concluded that SIJ stimulation was a promising therapeutic strategy in the treatment of intractable SIJ pain. Moreover, these researchers stated that further studies are needed to determine the precise target group and long-term effect of this novel treatment method.
Chakrabortty et al (2016) noted that as many as 62 % LBP patients could have SIJ pain. There is limited-to-poor evidence regarding long-term pain relief with therapeutic IA injections and/or conventional (heat or pulsed) radiofrequency ablations (RFAs) for SIJ pain. These investigators reported their pain-clinic experience with peripheral nerve field stimulation (PNFS) for 2 patients of intractable SIJ pain. They had reported absence of long-term pain relief (pain relief greater than 50 % for at least 2 weeks post-injection and at least 3 months post-RFA) with SIJ injections and SIJ RFAs. Two parallel permanent 8-contact subcutaneous stimulating leads were implanted under the skin overlying their painful SIJ. Adequate stimulation in the entire painful area was confirmed. For IPG placement, a separate subcutaneous pocket was made in the upper buttock below the iliac crest level ipsilaterally. During the pain-clinic follow-up period, the patients had reduced their pain medications requirements by 50 % with an additional report of more than 50 % improvement in their functional status. The 1st patient passed away 2 years after the PNFS procedure due to medical causes unrelated to his chronic pain. The 2nd patient has been comfortable with PNFS-induced analgesic regimen during her pain-clinic follow-up during last 5 years. The authors concluded that PNFS could be an effective last resort for SIJ pain when conventional interventional pain techniques have failed, and analgesic medication requirements are escalating or causing unwarranted side-effects.
Guentchev et al (2017) noted that they recently (2015) demonstrated that 86 % of the patients treated with PNS for therapy-refractory SIJ pain were satisfied with the result after 1 year of treatment. These investigators examined the long-term (up to 4 years) response rate of this novel treatment. A total of 16 consecutive patients with therapy-refractory SIJ pain were treated with PNS and followed for 4 years in 3 patients, 3 years in 6 patients, and 2 years in 1 patient; QOL, pain, and patient satisfaction were assessed using the ODI 2.0, VAS, and IPSI. Patients reported a pain reduction from 8.8 to 1.6 (VAS) at 1 year (p < 0.001), and 13 of 14 patients (92.9 %) rated the therapy as effective (IPSI score of less than or equal to 2). At 2 years, average pain score was 1.9 (p < 0.001), and 9 of 10 patients (90.0 %) considered the treatment a success. At 3 years, 8 of 9 patients (88.9 %) were satisfied with the treatment results, reporting an average VAS of 2.0 (p < 0.005). At 4 years, 2 of 3 patients were satisfied with the treatment results. The authors concluded that they had shown for the first time that PNS is a successful long-term therapy for SIJ pain.
In a retrospective study, Goroszeniuk (2019) examined the longer-term results of peripheral neuromodulation in 12 patients with significant chronic SIJ pain who had previously failed multiple conservative and interventional pain therapies. To allow for the assessment of meaningful longer-term outcome, implants for all 12 patients had been in place for a minimum of 18 months to a maximum of 36 months prior to the formal review. Compared to the pre-implantation baseline, the longer-term follow-up revealed a significant and sustained reduction in VAS pain scores from 8.7T 1.1 to 1.1T 1.0 (p < 0.001), with a 75 % reduction in analgesia requirement, and improvement in pain impact on ADL from 94.1 % +/- 5.9 % to 5.8 % +/- 6.0 % (p < 0.001). The authors concluded that this initial case series had highlighted that SIJ neuromodulation resulted in the reduction in pain intensity and improved functionality in patients who had already failed conventional medical management and interventional techniques, including RF denervation. Moreover, these researchers stated that these preliminary findings merit a prospective, randomized trial of peripheral neuromodulation.
Peripheral Nerve Stimulation and Transcutaneous Electrical Nerve Stimulation for the Treatment of Suprascapular Nerve Entrapment
Leider et al (2021) noted that suprascapular nerve entrapment syndrome (SNES) is an often-overlooked etiology of shoulder pain and weakness. Treatment varies depending on the location and etiology of entrapment, which can be described as compressive or traction lesions. In some cases, treating the primary cause of impingement (i.e., rotator cuff tear, ganglion cyst, etc.) is sufficient to relieve pressure on the nerve. In other cases where impingement is caused by dynamic microtrauma (as observed in overhead athletes and laborers), treatment is often more conservative. Conservative 1st-line therapy includes rehabilitation programs, non-steroidal anti-inflammatory drugs (NSAIDs), and lifestyle modification. Physical therapy is targeted at strengthening the rotator cuff muscles, trapezius, levator scapulae, rhomboids, serratus anterior, and deltoid muscle(s). If non-operative treatment fails to relieve suprascapular neuropathy, minimally invasive treatment options exist, such as suprascapular nerve injection, neurostimulation, cryo-neurolysis, and pulsed radiofrequency (PRF). Multiple treatment modalities are often used synergistically due to variations in shoulder anatomy, physiology, pain response, and pathology as a sole therapeutic option does not appear successful for all cases. Often patients can be treated with non-invasive measures alone; however, injuries refractory to conservative treatment may require either arthroscopic or open surgery, especially if the patient has an identifiable and reversible cause of nerve compression. Indications for invasive treatment include, but are not limited to, refractory to non-operative treatment, have a space-occupying lesion, or show severe signs and symptoms of muscle atrophy. Open decompression has fallen out of favor due to the advantages inherent in the less invasive arthroscopic approach.
Vij et al (2022) stated that the prevalence of suprascapular neuropathy is higher than previously estimated. Recent literature highlighted a myriad of therapeutic options ranging from conservative treatment and minimally invasive options to surgical management; however, there are no comprehensive review articles comparing these treatment modalities. In a systematic review, these investigators examined the available evidence on suprascapular nerve entrapment and compared minimally invasive treatments to surgical treatments. They carried out a literature search in Mendeley; search fields were varied redundant. All articles were screened by title and abstract and a preliminary decision to include an article was made. A full-text screening was carried out on the selected articles. Any question regarding the inclusion of an article was discussed by 3 authors until an agreement was reached. Recent studies have elucidated the pathoanatomy and described several risk factors for entrapment ranging. A total of 4 studies met inclusion criteria regarding PNS with good pain and clinical outcomes; 2 studies met the inclusion criteria regarding PRF and showed promising pain and clinical outcomes; 1 study met the inclusion criteria regarding TENS and showed good results that were equivalent to PRF. Surgical treatment has shifted to become nearly all arthroscopic and surgical outcomes remain higher than minimally invasive treatments. The authors concluded that conservative therapy (NSAIDs and PT) may be successful in some patients; however, there are limited outcome studies regarding their effectiveness; PRF, PNS, and TENS may be effective in treating patients with SNES. Surgical treatment has shifted to become nearly all arthroscopic and remains the gold-standard in patients with nerve entrapment syndrome refractory for treatment.
Furthermore, an UpToDate review on “Overview of upper extremity peripheral nerve syndromes” (Rutkove, 2022) does not mention peripheral nerve stimulation, and transcutaneous electrical nerve stimulation as management / therapeutic options.
Nalu Peripheral Nerve Stimulation
Nalu peripheral nerve stimulation entails a 3-step process: wear experience, therapy trial, and permanent implantation. It is used for the management of chronic pain.
Knotkova et al (2021) noted that neuromodulation is an expanding area of pain medicine that incorporates an array of non-invasive, minimally invasive, and surgical electrical therapies. These investigators focused on SCS therapies discussed within the framework of other invasive, minimally invasive, and non-invasive neuromodulation therapies. These therapies include DBS and motor cortex stimulation (MCS), PNS, and the non-invasive treatments of rTMS, transcranial direct current stimulation, and tDCS. Although methods devoid of paresthesia (e.g., high frequency) should theoretically allow for placebo-controlled trials, few have been carried out. There is low-to-moderate quality evidence that SCS is superior to re-operation or conventional medical management for FBSS, and conflicting evidence as to the superiority of traditional SCS over sham stimulation or between different SCS modalities. Peripheral nerve stimulation technologies have also undergone rapid development and become less invasive, including many that are placed percutaneously. There is low-to-moderate quality evidence that PNS is effective for neuropathic pain in an extremity, low quality evidence that it is effective for back pain with or without leg pain, and conflicting evidence that it can prevent migraines.
Kalia et al (2022) stated that PNS is an established treatment modality for chronic neuropathic pain. In the past 10 years, with the advent of innovative devices and delivery platforms, PNS has evolved from invasive open surgeries to image-guided, minimally invasive percutaneous procedures. These researchers presented a novel device, the Nalu Neurostimulation System (Nalu Medical, CA), which has established its advantages in providing predictable and reliable PNS therapy for chronic neuropathic pain management. The authors stated that this novel device is effective in treating chronic pain conditions such as post-herniorrhaphy pain syndrome, intercostal neuralgia, post-laminectomy syndrome, and CRPS and holds great promise for the treatment of peripheral neuropathic pain.
Naidu et al (2022) noted that conventional neurostimulation typically involves a brief (e.g., 10-day or less) trial to evaluate presumed effectiveness before permanent implantation. Low trial conversion rates and high explant rates due to inadequate pain relief highlight the need for improved patient identification strategies. The development of a 60-day percutaneous PNS system enables evaluation of outcomes following an extended temporary treatment period of up to 60 days, that may obviate or validate the need for permanent implant. Ina retrospective study, these investigators provided the 1st real-world evidence regarding patient response throughout a 60-day PNS treatment period. Anonymized data listings were compiled from patients who underwent implantation of temporary percutaneous leads and opted-in to provide real-world data to the device manufacturer during routine interactions with device representatives throughout the 60-day treatment. Overall, 30 % (222/747) of patients were early responders (50 % or more pain relief throughout treatment). Another 31 % (231/747) of patients initially presented as non-responders but surpassed 50 % pain relief by the end of treatment. Conversely, 32 % (239/747) of patients were non-responders throughout treatment. An additional 7 % (55/747) of patients initially presented as responders but fell below 50 % relief by the end of the treatment period. The authors concluded that an extended, 60-day PNS treatment may help identify delayed responders, providing the opportunity for sustained relief and improving access to effective PNS treatment. Compared to a conventionally short trial of 10 days or less, a longer 60-day PNS treatment may also help reduce explant rates by identifying delayed non-responders unlikely to benefit long-term. These scenarios supported the importance of an extended 60-day temporary PNS stimulation period to help inform stepwise treatment strategies that may optimize outcomes and cost-effectiveness. This trial was supported by SPR Therapeutics; and 3 of the authors (Naidu R, Li S, Desai MJ) received research funding from Nalu Medical.
The authors stated that the drawbacks of this trial of included its retrospective nature and the availability of data at irregular intervals across the patient population, although the large sample size in the present analysis nonetheless provided a substantial amount of longitudinal real-world data that enables detailed analysis of patient responses throughout the treatment period. Although recent studies have highlighted the importance of multi-dimensional analysis of patient improvement including pain, medication use, function, and health-related QOL, the present study analyzed percent pain relief and did not have sufficient data to assess subsequent changes in function or QOL. Neuromodulation Appropriateness Consensus Committee (NACC) recommendations suggest that medication use, function, and QOL might be considered as alternate determinants of trial success with conventional stimulation, and it is possible that the early and delayed responder and non-responder rates in the present study could shift (potentially producing more early and delayed responders) with the inclusion of additional outcome dimensions. furthermore, as noted above much of the existing data regarding trial duration and trial outcomes are for SCS and more data are needed on trialing strategies and outcomes using conventional PNS systems. Nonetheless, NACC recommends similar trialing strategies for permanently implanted SCS, DRG, and PNS systems, and similar trends of false positive and false negative trial outcomes were reported in the PNS literature, suggesting that the trends discussed in this trial may have similarities across conventional neurostimulation modalities.
Hoffman et al (2022) described the team approach of an interventional pain management practice, with particular emphasis on advanced practice providers (APPs), in the selection, education, care, and management of PNS patients. These investigators devised an APP guide to PNS based on an in-depth search of multiple databases for studies on neuromodulation, pain management, and APPs. Of 65 articles captured in the search strategy, 3 articles were pertinent to the topic of APP involvement in neuromodulation. More specifically, only 1 of the 3 publications on neuromodulation discussed APP involvement in PNS. This single publication was from 1995 and focused on electrical stimulation of the trigeminal ganglion using a permanent percutaneously placed electrode. The authors concluded that PNS is growing in clinical indication and use for both acute and chronic pain conditions. With the increasing need for APPs in both general and specialty medicine, it is imperative that APPs are well-educated on PNS. These researchers have outlined ways in which APPs can optimize the care of PNS patients and how the skillset of the APP in a PNS practice can potentially improve patient outcomes. Moreover, these investigators stated that more research is needed regarding the optimal stimulation waveforms for PNS and the safety of continuous PNS at various frequencies. It is possible that PNS waveforms could be changed to provide improved relief in patients or potentially used as salvage PNS therapy in those who have lost efficacy. Furthermore, the authors noted that further research is needed regarding the role of APPs related to neuromodulation patient outcomes (i.e., patient satisfaction, post-operative complications, etc.). In addition, analysis of PNS patient outcomes (i.e., pain relief, functional improvement, post-operative complications, etc.) could be further examined to determine if there is a correlation between outcomes and treatment by an APP provider. The first author provided general consulting for SPR Therapeutics and Nalu Medical.
Busch et al (2022) stated that PNS is rapidly increasing in use. This interventional pain treatment modality entails modulating peripheral nerves for a variety of chronic pain conditions. These researchers examined its use specifically in the context of chronic lower extremity pain. Studies continue to elucidate the use of PNS and better define indications, contraindications, as well as short- and long-term benefits of the procedure for the lower extremity. The authors concluded that while large, prospective evidence is still lacking, the quality of evidence for PNS of an individual nerve of the lower extremity appeared to be highest for femoral and sciatic nerve stimulation. Evidence for other individual lower extremity nerves is mostly limited to case reports which is the greatest limitation of this study. These investigators stated that while the technology is certainly promising and potentially under-utilized, further research will better elucidate the short-term and long-term effectiveness of PNS.
Currently, there is a clinical trial entitled “Clinical Study of a Micro-Implantable Pulse Generator For The Treatment of Peripheral Neuropathic Pain (COMFORT)” that is still recruiting participant. This prospective, post-market RCT study is being carried out to document the comparative safety and effectiveness of peripheral nerve stimulation (Nalu Neurostimulation System) plus conventional medical management versus conventional medical management alone in the treatment of chronic, intractable peripheral neuralgia of post-traumatic or post-surgical origin (ClinicalTrials.gov: NCT05287373; last updated March 18, 2022).
Soteropoulos et al (2022) reported on a case involving a 69-year-old woman who presented with axial spine pain, which was inadequately controlled by opioids as she was treated unsuccessfully with hydrocodone and remained to have the pain between 7/10 to 10/10. Peripheral neural stimulation was trialed and then used to control her pain. PNS is a device-based therapeutic option that appeared effective in a subset of patients. It has been effectively employed to treat many different chronic pain syndromes. The patient responded well to the treatment, with her pain intensity going down to between 2/10 and 5/10 on the same scale. She was able to discontinue her use of opioids. The authors concluded that PNS could be a safe and effective treatment in patients who have not responded well to pharmacologic analgesia.
Gill et al (2022) discussed their narrative review of interventional treatments for cluneal neuropathy. This was a systematic, evidence-based narrative, performed after extensive review of the literature to identify all manuscripts associated with interventional treatment of the superior and medial cluneal nerves. A total of 11 manuscripts fulfilled inclusion criteria. Interventional treatment of the superior and middle cluneal nerves included blockade with corticosteroid, alcohol neurolysis, PNS, RF neurotomy, and surgical decompression. The supportive evidence for interventions in cluneal neuropathy is largely lacking due to small, uncontrolled, observational studies with multiple confounding factors. There is no standardized definition of cluneal neuropathy. The authors concluded that limited studies promoted beneficial effects from interventions intended to target cluneal neuropathy. Despite increased emphasis and therapeutic options for this condition, there is little consensus on the diagnostic criteria, endpoints, and measures of therapeutics, or procedural techniques for blocks, RF, and neuromodulation. The authors concluded that it is imperative to delineate pathology associated with the cluneal nerves and perform rigorous analysis of associated therapeutic options.
Cohen et al (2019) stated that chronic pain and reduced function are significant problems for military service members and veterans following amputation; and PNS is a promising therapy. However, PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery. These researchers examined if percutaneous PNS would provide relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads. A review of recent studies and clinical reports found that a majority of patients (18/24, 75 %) reported substantial (50 % or more) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference. The authors concluded that percutaneous PNS could durably reduce pain; thus, enabling improvements in QOL, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. These investigations stated that this therapy fills an unmet need and has the potential to become a standard option to relieve post-amputation pain. Furthermore, they noted that percutaneous PNS may have additional benefit for military service members and veterans with post-surgical or post-traumatic pain.
In a case-series study, Pagan-Rosado et al (2023) examined the effectiveness of PNS in the treatment of phantom limb pain, and provided an alternative method for the treatment of this pain syndrome. These investigators described 3 amputee patients with severe phantom limb pain who obtained substantial analgesia and improvement in physical functionality following implantation of a temporary PNS device. These researchers stated that future studies should evaluate predictors of successful response or poor response to PNS therapy, such as mental health, environmental stressors, coping skills, as well as procedural factors, which may facilitate an individualized approach for each patient to ensure appropriate candidacy for PNS and better prognosis. The authors concluded that considering that patients in this cohort did not achieve long-lasting benefit following removal of temporary PNS, future investigations should examine if patients with phantom limb pain would benefit from permanent PNS, rather than temporary PNS.
In a retrospective, observational study, Kalia et al (2025) characterized real-world healthcare resource utilization (HCRU) and costs in adults with chronic pain of peripheral nerve origin treated with PNS using the micro-IPG. This trial (September 1, 2019 to January 31, 2023) linked patients from the Nalu medical database to the OM1 Real-World Data Cloud (RWDC). Eligible patients received the micro-IPG implant for PNS, were identifiable in both databases, and had 12 months or more of RWDC pre-/post-implantation claims data. Primary outcomes were all-cause HRCU and medical costs (12 months pre- and post-implantation); secondary outcomes were all-cause pharmacy costs, including opioids, over the same time. Patients (n = 122) had a higher mean (standard deviation; SD) number of out-patient visits pre-implantation (5.7 [5.4]) than post-implantation (4.9 [5.7]). Mean (SD) total medical costs were 50 % lower, from $27,493 ($44,756) to $13,717 ($23,278). Median (first-third quartile [Q1 to Q3]) medical costs were 57 % lower, from $11,809 ($4,075 to $31,788) to $5,094 ($1,815 to $13,820). Mean (SD) pharmacy costs (n = 77) were higher post-implantation ($22,470 [$77,203]) than pre-implantation ($20,092 [$64,132]), while median (Q1 to Q3) costs were lower (from $2,708 [$222 to 11,882] to $2,122 [$50 to 9,370]). Post-implantation, the proportion of patients using opioids was 31.4 % lower. The authors concluded that patients with PNS using the micro-IPG had reduced HCRU, costs, and opioid use.
These researchers stated that while this study was an important addition to the limited research on HCRU and costs among patients using PNS therapies; it had several drawbacks. While comparable in size to other evaluations of neurostimulation devices, this trial had a relatively small sample size (n = 122) with no formal statistical testing implemented due to the relatively recent introduction of the micro-IPG to the market in 2019. The small sample size was due primarily to the filtering of patients with fewer than 12 months of medical claims data following the index date. As such, outcomes were more sensitive to individual patient healthcare utilization and needs. Patient cost outliers may have affected the overall cost patterns observed, especially in cases where mean and median patterns diverged, warranting additional research. Furthermore, missing data made it difficult to characterize this population in reference to the general population of patients with severe intractable chronic pain of peripheral nerve origin. Missing data included limits on available race and ethnicity (missing for about 2/3 of patients) insurance type (unknown for about 1/5 of patients), and body mass index (BMI) and smoking status (unknown for 90 % or more subjects). Furthermore, it is also unclear if or to what extent the COVID-19 pandemic influenced patient healthcare utilization; thus, the findings of this trial in 2020 and 2021. Lastly, cost estimates were based on available nominal charge amounts from medical claims, not the actual amount paid, and the cost of implantation, day-of-implant costs, or revisions were not included in the analysis. (It should be noted that this study was funded by Nalu Medical, Inc. Nalu Medical funded the conduct of this study and made the decision to submit this manuscript for publication).
Hatheway et al (2024a) reported the findings from the 1st large, post-market, multi-center RCT examining PNS for the treatment of chronic peripheral pain with a micro-implantable pulse generator (micro-IPG). Subjects meeting eligibility were randomised (2:1) to either the active-arm receiving PNS and conventional medical management (CMM) or the control-arm receiving CMM alone. Treatments were limited to the following areas: lower back, shoulder, knee and foot/ankle. At 6 months, the active-arm group attained an 88 % responder rate with a 70 % average reduction in pain. At the 3-month primary endpoint, the active-arm attained an 84 % responder rate with an average pain reduction of 67 % compared with the control-arm group, which achieved a 3 % responder rate with an average pain reduction of 6 %. Both responder rate as well as pain reduction in the active-arm group were significantly better than in the control-arm group (p < 0.001). A majority of PROs also reached statistical significance. There have been no reports of pocket pain and no serious adverse device effects; 81 % of participants found the external wearable component of the PNS system to be comfortable. The authors concluded that this study successfully reached its primary endpoint -- the active-arm group achieved a statistically significant superior responder rate as compared with the control-arm group at 3 months. The findings of this RCT showed that PNS, with this micro-IPG, was safe and effective. Moreover, these researchers noted that the sponsor and investigators are dedicated to continuing the study and reporting the long-term (3 years) outcomes when available. It should be noted that this study was sponsored by Nalu Medical.
The authors stated that drawbacks of this trial included the fact that the control-arm remained in CMM only for 3 months; a longer period was considered but was thought to be ethically problematic for those participants with significant pain. The prevalence of females over males was unanticipated (70 % females); however, the randomization addressed potential bias, and this reflected the real-world population at the clinical sites.
Hatheway et al (2024b) stated that there is paucity of data from RCTs supporting the use of PNS for the treatment of chronic pain. This study was undertaken, in part, to provide RCT data in support of patient access to appropriate PNS therapy. The COMFORT Trial is the 1st large, post-market, multi-center RCT examining the use of a FDA-cleared micro-IPG for the treatment of chronic pain via PNS therapy. Consented, eligible subjects were randomized to either the active arm, which received PNS and conventional medical management, or the control arm, which received conventional medical management alone and were allowed to cross-over to the active arm, after 3 months. Pain and PROs were captured. Therapy responders were subjects who achieved at least a 50 % reduction in pain scores compared with baseline. These researchers are reporting the 12-month results of this 36-month study. At 12months, the responder rate was 87 % with a 69 % average reduction in pain compared with baseline (7.5 ± 1.2 to 2.3 ± 1.7; p < 0.001). Statistical significance was attained for all PROs. There was an excellent safety profile with no serious AEs or reports of pocket pain. A majority of subjects used unique programming options and found this device easy to use and comfortable to wear. The authors concluded that these 12-month results were consistent with previously reported 6-month outcomes from this study, showing durability of PNS treatment with the micro-IPG system; subjects realized sustained large reduction in pain and improvement in PROs following treatment with this micro-IPG system. These researchers stated that this trial is ongoing, and they will report additional findings as they become available.
The authors stated that drawbacks of this study included the fact that this is not a double-blind study, which could increase the risk of expectation bias (blinding was considered during the initial design phase but not executable given the nature of the device and its programming capabilities). In addition, the control arm was in CMM for 3 months. However, requiring patients to remain in severe pain when it was known that CMM was not effective in the preceding years before the study was problematic, especially when earlier studies pointed to a high likelihood of relief from PNS. Hence, a longer CMM arm was thought to violate the bioethical standard of beneficence. Furthermore, the study did not use a questionnaire to evaluate neuropathic pain, but instead relied on best clinical practice. These instruments are not routinely used in the U.S., are not required by U.S. healthcare policy and did not conform to the pragmatic design of the study. Additionally, not all CMM options were available to participants and were dependent on factors such as physician prescribing practices, patient preference, availability and access to treatment, and more importantly, insurance coverage of prescribed CMM; this reflected the usual CMM care patients receive in the U.S. outside of any study and was not the focus of the study.
Hatheway et al. (2025) examined the long-term pain relief delivered by the Nalu micro-implantable pulse generator (micro-IPG) for peripheral nerve stimulation (PNS). The study analyzed data from a large-scale, real-world patient registry, including 2,273 patients who met the eligibility criteria. The average age of the patients was 68.3 years, with 60% being female. The data were collected an average of 6.6 months post-implantation. The results indicated that most patients experienced notable improvement, with the majority reporting "Very Much Improved" or "Much Improved" outcomes. The consistency of outcomes was observed across different anatomic regions, with high percentages of patients achieving the Minimum Clinically Important Difference (MCID) for the Patient Global Impression of Change (PGIC). The authors acknowledge that different evaluation standards apply when comparing RWD with randomized controlled trial (RCT) data. They note that RWD should be assessed with realistic expectations, considering inherent aspects of real-world practice such as patient adherence and variations in treatment.
Multifidus Stimulation for the Treatment of Low Back Pain
Tieppo Francio et al (2023) stated that CLBP is multi-factorial in nature, with recent research highlighting the role of multifidus dysfunction in a subset of non-specific CLBP. In a scoping review, these investigators provided a foundational reference that elucidated the pathophysiological cascade of multifidus dysfunction, how it contrasted with other CLBP etiologies and the role of restorative neuro-stimulation. A total of 194 articles were included, and findings were presented to highlight emerging principles related to multifidus dysfunction and restorative neuro-stimulation. Multifidus dysfunction is diagnosed by a history of mechanical, axial, nociceptive CLBP and examination showing functional lumbar instability, which differs from other structural etiologies. Diagnostic images may be used to grade multifidus atrophy and evaluate other structural pathologies. While various treatments exist for CLBP, restorative neuro-stimulation distinguishes itself from traditional neuro-stimulation in a way that treats a different etiology, targets a different anatomical site, and has a distinctive mechanism of action. The authors concluded that multifidus dysfunction has been proposed to result from loss of neuromuscular control that may manifest clinically as muscle inhibition leading to altered movement patterns. Over time, this cycle may result in potential atrophy, degeneration, and CLBP. Restorative neuro-stimulation, a novel implantable neurostimulator system, stimulates the efferent lumbar medial branch nerve to elicit repetitive multifidus contractions. This intervention aims to interrupt the cycle of dysfunction and normalize multifidus activity incrementally, potentially restoring neuromuscular control.
The authors stated that one of the drawbacks of this review was that assessment of the quality of the studies was not carried out due to the heterogenicity of included studies. Data synthesis and key summary of findings was presented in a descriptive format, rather than a quantitative format since this scoping review highlighted a conceptual framework and did not compare the same intervention and outcomes within the same or populations.
Carayannopoulos et al (2024) noted that CLBP is a debilitating, painful, and costly condition. Implantable neuromuscular ES targeting the multifidus musculature is growing as a non-pharmacologic option for patients with recalcitrant nociceptive mechanical CLBP who have failed conservative treatments (including medications and PT) and for whom surgery is not indicated.
Wu et al (2024) stated that LBP is a globally prevalent musculoskeletal issue. Repetitive peripheral magnetic stimulation (rPMS) is emerging as a promising modality for managing musculoskeletal pain, while US-guided lumbar facet/multifidus injections are a potential therapeutic option for LBP.
Sornkaew et al (2024) noted that aberrant movement in CLBP is associated with a deficit in the lumbar multifidus (LM) and changes in cortical topography. Anodal transcranial direct current stimulation (a-tDCS) can be used to enhance cortical excitability by priming the neuromuscular system for motor control exercise (MCE); thus, enhancing LM activation and movement control. In a RCT, these researchers examined the effects of a 6-week MCE program combined with a-tDCS on cortical topography, LM activation, movement patterns, and clinical outcomes in individuals with CLBP. A total of 22 individuals with CLBP were randomly allocated to the a-tDCS group (a-tDCS; n = 12) or sham-tDCS group (s-tDCS; n = 10). Both groups received 20 mins of tDCS followed by 30 mins of MCE. The LM and erector spinae (ES) cortical topography, LM activation, movement control battery tests, and clinical outcomes (disability and QOL) were measured pre- and post-intervention. Significant interaction (group × time; p < 0.01) was found in the distance between LM and ES cortical locations. The a-tDCS group reported significantly fewer discrete peaks (p < 0.05) in both ES and LM as well as significant improvements (p < 0.05) in clinical outcomes post-intervention. The s-tDCS group showed a significant increase (p < 0.05) in the number of discrete peaks in the LM cortical topography. No significant changes (p > 0.05) in LM activation were observed in either group; however, both groups reported improved movement patterns. The authors concluded that the findings of this study suggested that combined a-tDCS with MCE could separate LM and ES locations over time while s-tDCS (MCE alone) reduces the distance. This trial did not find superior benefits of adding a-tDCS before MCE for LM activation, movement patterns, or clinical outcomes.
Copley et al (2024) stated that CLBP is often associated with impaired motor control and degeneration of the lumbar multifidus muscles. Several studies have reported on the use of multifidus or medial branch stimulation as a treatment. In a systematic review and meta-analysis, these investigators examined the change in LBP intensity with multifidus stimulation. They carried out a comprehensive literature search from 2010 to 2022 for RCTs or prospective reports in adults with CLBP, treated with multifidus or medial nerve stimulation via implanted or percutaneous device. Mean change (standard error) in pain intensity was extracted and data synthesized using a mixed effects regression with a random intercept for the study to account for repeated time-points. A total of 419 participants were enrolled in 6 studies; there were 25 effects (1 to 6 time-points per study), with follow-ups ranging from 1.5 to 48 months. The weighted pooled mean effect was a reduction in pain intensity (0 to 10 scale) of 2.9 units (95 % CI: 2.1 to 3.7). The 95 % prediction interval was a reduction in pain intensity of 0.6 to 5.2 units. The estimated probability of a reduction in pain of greater than 2 units in a new similar study was 0.84 (0.68 to 0.98). Meta-regression showed that a longer follow-up time was associated with greater reductions in pain (0.25 units [0.16 to 0.34] per 6 months). The authors concluded that medial branch stimulation for the treatment of CLBP demonstrated a high probability of a clinically significant change in pain intensity; and longer duration of stimulation was associated with decreased LBP intensities.
Freedom Peripheral Nerve Stimulator System
The Curonix Freedom Peripheral Nerve Stimulator System (PNS) employs high frequency-electromagnetic coupling (HF-EMC) technology to power the implanted neurostimulator. The device uses pulsed electric current to create an electrical field that acts on peripheral nerves to inhibit the transmission of pain signals to the brain.
Strand et al (2022) presented evidence-based clinical guidelines from the ASPN for the use of implantable PNS in the treatment of chronic pain. These investigators noted that there is limited evidence that PNS alleviates pain in neuropathic pain syndrome involving the trunk and back, including radiculopathy and post-herpetic neuralgia (Level of Evidence = III, Degree of Recommendation = Grade C). They also stated that as a less-invasive modality compared to SCS therapy, PNS may be offered to patients with CRPS Type I/II or peripheral causalgia, and may be associated with modest improvement in pain intensity and functional outcomes; however, high-quality evidence is limited and other neuromodulation interventions such as dorsal root ganglion SCS are recommended (Level III, Grade C). The authors concluded that PNS should be used judiciously as an adjunct for chronic pain following adequate patient screening and positive diagnostic nerve block or stimulation trial. Moreover, these researchers stated that further well-designed studies identifying specific conditions, waveforms, programming, and lead placements are needed to ensure standardization of patient and treatment selection.
Abd-Elsayed et al (2023) stated that chronic pain is a growing problem globally, and in the midst of an opioid epidemic, it is important that alternative therapeutic approaches are identified to aid in alleviating the pain experienced by these patients. Chronic pain greatly affects patients’ QOL and many do not experience adequate relief with conventional treatment measures. In a retrospective analysis, these researchers examined the effectiveness of PNS in adult patients suffering from chronic pain refractory to conventional treatment measures who underwent therapy on various anatomical locations. This study consisted of data collected from electronic health records for 89 patients who underwent PNS therapy. Data collected entailed patient age, sex, weight, height, body mass index (BMI), diagnosis, targeted nerves, follow-up encounters, pain scores from before and after PNS therapy, and duration of improvement. Statistical analysis used SPSS software, version 26 (IBM), using a paired t-test to assess significance between pre- and post-PNS therapy pain scores; “p” values were significant if found to be ≤ 0.05. Further analysis assessed the correlation between age and BMI with VAS pain improvement as well as subjective percentage pain relief. The mean pre-operative (pre-op) pain score before PNS therapy was 6.36 (SD = 2.18, standard error of the mean [SEM] 0.23) and the mean post-operative (post-op) pain score after PNS therapy was 4.19 (SD = 2.70, SEM = 0.29). The mean patient-reported percent improvement in pain following PNS therapy was 49.04 % (SD = 34.79). The improvement in pain scores between pre-op and post-op was statistically significant (mean = 2.17, SD = 2.82, SEM = 0.30, t(88) = 7.26, p < 0.001), 95 % CI: 1.57 to 2.76). The mean duration of improvement for patients was 123 days after therapy initiation (min = 6, max = 683, SD = 126). The authors concluded that the findings of this study revealed the potential role for PNS therapy in improving patient-reported pain levels for various neuropathies, targeting various nerves. Moreover, these researchers stated that with PNS therapy's use as a chronic pain treatment and available research being limited, further investigation is needed to ascertain the effectiveness of PNS therapy for pain management and complications associated with PNS device placements at various locations.
D'Souza et al (2023) noted that low back pain (LBP) is a prevalent condition that is associated with diminished physical function, poor mental health outcomes, and reduced QOL; PNS is an emerging modality that has been used in the treatment of LBP. In a systematic review, these investigators examined the level of evidence on the effectiveness of PNS for the treatment of LBP. A total of 29 articles were included in this systematic review, consisting of 828 total participants utilizing PNS as the primary modality for LBP, and 173 participants using PNS as salvage or adjunctive therapy for LBP after SCS placement. Different modalities of PNS therapy were reported across studies, including conventional PNS systems stimulating the lumbar medial branch nerves, PNFS, and restorative neuromuscular stimulation of the multifidus muscles. All studies consistently reported positive modest-to-moderate improvement in pain intensity with PNS therapy when comparing baseline pain intensity to each study's respective primary follow-up period. There was a very low GRADE quality of evidence supporting this finding. Inconsistency was present in some comparative studies that reported no difference between PNS therapy versus control cohorts (sham or SCS therapy alone); thus, highlighting the potential for placebo effect. The authors concluded that the findings of this systematic review highlighted that PNS, PNFS, and neuromuscular stimulation may provide modest-to-moderate pain relief in patients with LBP, although evidence is currently limited due to risk of bias, clinical and methodological heterogeneity, and inconsistency in data.
McGreevy and McGreevy (2024) stated that lower extremity (LE) pain is one of the most common types of chronic pain and could be very difficult to treat using conservative approaches. In a retrospective study, these researchers examined the management of chronic neuralgias in the LEs via PNS. This trial included 21 patients who received a permanent Curonix Freedom PNS System for the treatment of chronic pain in the LEs. They carried out a retrospective chart review to evaluate the baseline and follow-up parameters. A total of 14 of the patients (67 %) received 1 neurostimulator at either the superficial peroneal or posterior tibial nerve; and 7 patients (33 %) received 2 neurostimulators at either the sural and superficial peroneal, posterior tibial and superficial peroneal, or common and superficial peroneal nerves. The data were collected from electronic medical records, followed by case report forms. Pain scores and complications were reported up to 6 months after permanent implantation; AEs were reported descriptively and classified as serious or non-serious AEs and related or non-related AEs. At the end of the trial visit, 21 of the 21 patients (100 %) reported more than 50 % pain relief, with mean pain scores reducing from 7.29 ± 0.9 to 2.81 ± 0.7 (61 %; p < 0.001). A total of 19 patients completed the long-term follow-up; 14 of those 19 patients (74 %) experienced at least a 50 % improvement in pain. The average NRS score decreased significantly to 3.66 ± 1.8 (50 %; p < 0.001). No complications were observed. The authors concluded that PNS carried out with the Curonix Freedom PNS System was a safe and effective therapy for the treatment of LE neuralgias that fail conservative management. This was a retrospective study with a relatively small sample size (n = 21). Participants were followed-up on for 6 months, and all were implanted to treat LE pain related to different peripheral neuralgias. Moreover, these researchers stated that PNS is an evolving procedure gaining an increasing amount of interest each year; multiple studies are needed to examine all individual nerve targets to evaluate this technique’s safety and effectiveness.
ManaFlexx 2
The ManaFlexx 2 is an FDA-cleared wearable/wireless combination device of NMES and TENS. There is insufficient evidence regarding the effectiveness of this combinational device.
Abd-Elsayed (2020) noted that peripheral neuralgia is a common cause of chronic pain. Treatment might be challenging, and the condition can be resistant to commonly used treatment modalities for chronic pain. In a retrospective, case-series study, these researchers described 5 patients with peripheral neuralgia who were successfully treated using wireless PNS. Subjects in this trial underwent peripheral nerve stimulator placement for the treatment of superior cluneal, sural, ilio-inguinal, and genito-femoral neuralgias. They reported a decline in their NRS pain scores from a mean of 6.4 pre-procedure to a score of 1 following implant (p < 0.05). The authors concluded that patients with peripheral neuralgias resistant to other treatment modalities attained excellent pain relief after PNS. This was a retrospective study with small sample size (n = 5); its findings need to be validated by well-designed studies.
Sprint Peripheral Nerve Stimulation (PNS) System
Gilmore et al (2020) noted that percutaneous PNS provides an opportunity to relieve CLBP and reduce opioid analgesic consumption as an alternative to RFA and permanently implanted neurostimulation systems. Traditionally, the use of neurostimulation earlier in the treatment continuum has been limited by its associated risk, invasiveness, and cost. Percutaneous PNS leads (SPRINT) were placed bilaterally to target the medial branches of the dorsal rami nerves under image guidance. The percutaneous leads were connected to miniature wearable stimulators (SPRINT PNS System) for the 1-month therapy period, after which the leads were removed. Pain and disability were assessed long-term up to 12 months after lead removal. Substantial, clinically significant reductions in average pain intensity (50 % or greater reduction as measured by the Brief Pain Inventory Short Form) were experienced by a majority of subjects (67 %) at end of treatment compared to baseline (average 80 % reduction among responders; p < 0.05, analysis of variance; n = 9). Twelve months after the end of PNS treatment, a majority of subjects who completed the long-term follow-up visits experienced sustained, clinically significant reductions in pain and/or disability (67 %, n = 6; average 63 % reduction in pain intensity and 32-point reduction in disability among responders). No serious or unanticipated AEs were reported. The authors concluded that the findings of this study challenged the long-held notion that a positive trial of PNS should be followed by a permanent implant in responders. Percutaneous PNS may serve as an effective neurostimulation therapy for patients with CLBP and should be considered earlier in the treatment continuum as a motor-sparing means of avoiding opioids, denervation, and permanently implanted neurostimulation systems. These investigators stated that this approach has the potential to significantly influence the care continuum for CLBP by providing the benefits of an effective neurostimulation therapy to patients earlier than has been previously possible.
The authors stated that although the results were promising and consistent with previous studies of percutaneous PNS for other types of pain, this study had drawbacks. In particular, the population size was limited (n = 9) and did not include a control group or examine placebo effect; additional studies could aid in confirming these results in a larger population of patients, including studies that might compare the effects of percutaneous PNS to other standard interventional approaches used for patients with CLBP. Because CLBP could include a heterogeneous population (e.g., facetogenic, discogenic, arthritic, or myofascial pain) and the selection criteria for inclusion in this study were broad, additional studies and analyses of larger populations, including larger, prospective multi-center case series studies, may determine LBP subtypes or characteristics that are more likely to benefit from percutaneous PNS, as well as if specific types of diagnostic tests or imaging are predictive of success.
Gabriel and Ilfeld (2021) stated that US-guided percutaneous PNS may be used for the treatment of acute post-operative pain for various types of surgeries. This modality avoids several limitations of traditional local anesthetic-based peripheral nerve blocks including avoidance of motor blockade and sensory deficits. In this review, these investigators discussed the use of SPRINT neuromodulation system in the setting of acute post-operative pain management. The authors concluded that PNS is a novel modality in regional anesthesia that has much promise in reducing overall opioid use after surgery. Placement of PNS is very similar to that of catheter-based regional anesthesia techniques; US is used to guide the percutaneously placed introducer needle in proximity to the target nerve. There are several benefits of PNS over catheter-based approaches, including: (i) avoidance of motor or sensory blockade; (ii) no medication bag needed to be carried; and (iii) electric leads may be kept in-situ safely for up to 60 days. Moreover, these researchers stated that while several proof-of-concept (POC) studies have been published highlighting its use in various types of surgeries, large, high-quality RCTS are still needed.
Hasoon et al (2021) noted that hemiplegic shoulder pain (HSP) is a common co-morbidity affecting stroke survivors; it could result in chronic pain in a significant portion of patients. Prompt recognition and treatment may result in improved outcomes, although it could be very challenging to treat; PNS has shown significant promise as a treatment modality for HSP. These investigators presented the case of a patient with debilitating HSP that was unresponsive to a variety of medications and prior neuromodulation therapies. The authors reported their experience in using the SPRINT PNS system and the outcomes of a patient with refractory HSP treated with PNS. This was a single-case report; its findings need to be validated by well-designed studies.
Huntoon et al (2023) stated that real-world data could provide important insights into treatment effectiveness in routine clinical practice. Studies have reported that in multiple different pain indications temporary (60-day) percutaneous PNS treatment could produce significant relief; however, few real-world studies have been published. These investigators provided the 1st real-world, retrospective review of a large database depicting outcomes at the end of a 60-day PNS treatment period. Anonymized records of 6,160 patients who were implanted with a SPRINT PNS System from August 2019 through August 2022 were retrospectively reviewed from a national real-world database. The percentage of patients with 50 % or greater pain relief and/or improvement in QOL was evaluated and stratified by nerve target. Additional outcomes included average and worst pain score, patient-reported percentage of pain relief, and patient global impression of change. A total of 71 % of patients (4,348/6,160) were responders with 50 % or greater pain relief and/or improvement in QOL; pain relief among responders averaged 63 %. The responder rate was largely consistent across nerve targets throughout the back and trunk, upper and lower extremities, as well as posterior head and neck. The authors concluded that the findings of this retrospective analysis supported recent prospective studies showing that 60-day percutaneous PNS could provide significant relief across a wide range of nerve targets. These data serve an important role in complementing the findings of published prospective clinical trials.
The authors stated that this study had several drawbacks. First, this review was retrospective in nature and relied on a device manufacturer’s database. Second, treatment-related and outcomes data were originally recorded by device field representatives to inform patient support, such as patient education and compliance, technical troubleshooting, stimulation programming, and treatment optimization as part of routine use of the device. Secondary analyses of the data as in the present study were therefore subject to potential sources of bias in the collection of outcomes, although standardized instruments like average NRS-11 pain score, patient-reported percent pain relief, and PGIC were used to help minimize bias in administration. Third, data collection was not compulsory, and patients were only included in the analysis if both baseline and end of treatment (EOT) data were available. This evaluation of outcomes “as-observed” has the potential to over-estimate response rates. However, based on the sensitivity analysis, even in a worst-case scenario where all those missing EOT data were imputed as non-responders, the overall success rate would still be estimated at 58 %; a reasonable approximation scenario based on the distribution of nerve targets in the missing data suggested consistency with the reported overall success rate of 71 %. Fourth, standardized measures for pain medication usage and physical function were absent. Fifth, detailed demographic information was not available due to the nature of the database, which could enable deeper insights into the effectiveness of PNS treatment in specific subpopulations.
Appendix
TENS Unit Supplies
- A 4-lead TENS unit may be used with either 2 leads or 4 leads, depending on the characteristics of the member's pain. If it is ordered for use with 4 leads, the medical record must document why 2 leads are insufficient to meet the member's needs.
- If 2 TENS leads are medically necessary, then a maximum of 1 unit of a TENS supply allowance (HCPCS Code A4595) would be considered medically necessary per month; if 4 TENS leads are necessary, a maximum of 2 units per month would be considered medically necessary. If the use of the TENS unit is less than daily, medical necessity of the TENS supply allowance is reduced proportionally. Note: A TENS supply allowance (HCPCS code A4595) includes electrodes (any type), conductive paste or gel (if needed, depending on the type of electrode), tape or other adhesive (if needed, depending on the type of electrode), adhesive remover, skin preparation materials, batteries (9 volt or AA, single use or rechargeable), and a battery charger (if rechargeable batteries are used).
- Replacement of lead wires more often than every 12 months is rarely medically necessary.
For ongoing supplies and rental DME items, in addition to information described above that justifies the initial provision of the item(s) and/or supplies, there must be information in the member's medical record to support that the item continues to be used by the member and remains medically necessary.
References
The above policy is based on the following references:
TENS/PENS
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Percutaneous Neuromodulation
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Interferential Current Therapy
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H-WAVE Type Stimulators
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Peripheral Nerve Stimulation
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- Eldabe S, Buchser E, Duarte RV. Complications of spinal cord stimulation and peripheral nerve stimulation techniques: A review of the literature. Pain Med. 2016;17(2):325-336.
- Gilmore C, Ilfeld B, Rosenow J, et al. Percutaneous peripheral nervestimulation for the treatment of chronic neuropathic postamputation pain: A multicenter, randomized, placebo-controlled trial. Reg Anesth Pain Med. 2019;44(6):637-645.
- Goroszeniuk T. The effect of peripheral neuromodulation on pain from the sacroiliac joint: A retrospective cohort study. Neuromodulation. 2019;22(5):661-666.
- Guentchev M, Preuss C, Rink R, et al. Long-term reduction of sacroiliac joint pain with peripheral nerve stimulation. Oper Neurosurg (Hagerstown). 2017;13(5):634-639.
- Guentchev M, Preuss C, Rink R, et al. Technical note: Treatment of sacroiliac joint pain with peripheral nerve stimulation. Neuromodulation. 2015;18(5):392-396.
- Helm S, Shirsat N, Calodney A, et al. Peripheral nerve stimulation for chronic pain: A systematic review of effectiveness and safety. Pain Ther. 2021;10(2):985-1002.
- Kovacic K, Hainsworth K, Sood M, et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: A randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol. 2017;2(10):727-737.
- Kovacic K, Kolacz J, Lewis GF, Porges SW. Impaired vagal efficiency predicts auricular neurostimulation response in adolescent functional abdominal pain disorders. Am J Gastroenterol. 2020;115(9):1534-1538.
- Krasaelap A, Sood MR, Li BUK, et al. Efficacy of auricular neurostimulation in adolescents with irritable bowel syndrome in a randomized, double-blind trial. Clin Gastroenterol Hepatol. 2020;18(9):1987-1994.
- Leak WD, Ansel AE. Neural stimulation: Spinal cord and peripheral nerve stimulation. In: Pain Medicine. A Comprehensive Review. PP Raj, ed. St. Louis, MO: Mosby; 1996; Ch. 32: 327-333.
- Meyerson BA, Hakansson J. Alleviation of atypical trigeminal pain by stimulation of the Gasserian ganglion via an implanted electrode. Acta Neurochir Suppl (Wien). 1980;30:303-309.
- Parker JL, Cameron T. Technology for peripheral nerve stimulation. Prog Neurol Surg. 2015;29:1-19.
- Petersen EA, Slavin KV. Peripheral nerve/field stimulation for chronic pain. Neurosurg Clin N Am. 2014;25(4):789-797.
- Racz GB, Browne T, Lewis R Jr. Peripheral stimulator implant for treatment of causalgia caused by electrical burns. Tex Med. 1988;84(11):45-50.
- Rauck RL, Cohen SP, Gilmore CA, et al. Treatment of post-amputation pain with peripheral nerve stimulation. Neuromodulation. 2014;17(2):188-197.
- Slavin KV. Peripheral nerve stimulation for the treatment of neuropathic craniofacial pain. Acta Neurochir Suppl. 2007;97(Pt 1):115-120.
- Slavin KV. Technical aspects of peripheral nerve stimulation: Hardware and complications. Prog Neurol Surg. 2011;24:189-202.
- Taub E, Munz M, Tasker RR. Chronic electrical stimulation of the gasserian ganglion for the relief of pain. J Neurosurg. 1997;86(2):197-202.
- van Tilburg MAL. Can we treat visceral hypersensitivity in functional abdominal pain? Lancet Gastroenterol Hepatol. 2017;2(10):694-695.
- Wald A. Treatment of irritable bowel syndrome in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2021.
- Wang JK, Liu J. Neuromuscular electrical stimulation as an adjunctive therapy to drotaverine hydrochloride for treating patients with diarrhea-predominant irritable bowel syndrome: A retrospective study. Medicine (Baltimore). 2018;97(29):e11478.
Intramuscular Stimulation
- Chu J, Gozon BS, Schwartz I. Twitch-obtaining intramuscular stimulation in reflex sympathetic dystrophy. Electromyogr Clin Neurophysiol. 2002;42(5):259-266.
- Chu J. Early observations in radiculopathic pain control using electrodiagnostically derived new treatment techniques: Automated twitch-obtaining intramuscular stimulation (ATOIMS) and electrical twitch-obtaining intramuscular stimulation (ETOIMS). Electromyogr Clin Neurophysiol. 2000;40(4):195-204.
- Chu J. The role of the monopolar electromyographic pin in myofascial pain therapy: Automated twitch-obtaining intramuscular stimulation (ATOIMS) and electrical twitch-obtaining intramuscular stimulation (ETOIMS). Electromyogr Clin Neurophysiol. 1999;39(8):503-511.
- Chu J. Twitch-obtaining intramuscular stimulation (TOIMS) in acute partial radial nerve palsy. Electromyogr Clin Neurophysiol. 1999;39(4):221-226.
Sympathetic Therapy (Dynatron)
- Dynatronics Corp. Dynatron Sympathetic Therapy System (STS): Revolutionary Breakthrough in the Treatment of Pain [website]. Salt Lake City, UT: Dynatronics; 2001. Available at: http://www.chronicpainrx.com/dynatron/. Accessed January 14, 2002.
- Guido EH. Effects of sympathetic therapy on chronic pain in peripheral neuropathy subjects. Am J Pain Mgmt. 2002;12:31-34.
- Hord ED, Oaklander AL. Complex regional pain syndrome: A review of evidence-supported treatment options. Curr Pain Headache Rep. 2003;7(3):188-196.
- Rajala Rehab Products. Sympathetic Therapy System [website]. Pleasanton, CA: Rajala; 2001. Available at: http://www.rajala.com/cgi/catalog.pl?Electrotherapy. Accessed January 14, 2001.
- Washington State Department of Labor and Industries, Office of the Medical Director. Dynatron STS. Technology Assessment. Olympia, WA: Washington State Department of Labor and Industries; updated April 30, 2002.
- Work Loss Data Institute. Pain (chronic). Corpus Christi, TX: Work Loss Data Institute; 2008.
Electroceutical Therapy
- Benchmark Integrative Medicine, LLC. Clinical electroceutical medicine [website]. Fayetteville, GA: Benchmark; 2002. Available at: http://www.benchmarkpain.com/page4.html. Accessed May 10, 2002.
- Empire Medicare Services NJ. Facet joint nerve block. Medical Policy Bulletin Freedom of Information. Medicare News Brief - New Jersey (Part B). MNB-NJ-2001-2. New York, NY: Empire; April 2001. Available at: http://www.empiremedicare.com/NJBULL/njb2001-2/s129.htm. Accessed May 22, 2002.
- Empire Medicare Services. Nerve blocks: paravertebral nerve blocks. Medicare Part B Medical Policy. Policy No. YPF# 180, Ysurg #43. New York, NY: Empire; May 1, 1999. Available at: http://www.empiremedicare.com/Newypolicy/policy/YSRG43r2.htm. Accessed May 22, 2002.
- GHI Medicare Division. Nerve blocks/ paravertebral nerve blocks. Local Medical Necessity Policy. Policy No. SUR-1233. New York, NY: GHI Medicare; July 30, 1999. Available at: http://www.ghimedicare.com/lmrp2/sur-1233.html. Accessed May 22, 2002.
- Lake Michigan Medical, Inc. Matrix Biokinetics, Inc. PROGeneSys System Electroceutical Treatment [website]. Chicago, IL: Lake Michigan Medical; 2002. Available at: http://lakemichiganmedical.com.control.interliant.com/Pain_Management9.html. Accessed May 10, 2002.
- Robertson M. Electroceutical nerve block [abstract]. Chronic Pain Solutions, Fall 1998. Available at: http://www.chronicpainsolutions.com/nerveblock.htm. Accessed May 22, 2002.
- Work Loss Data Institute. Pain (chronic). Corpus Christi, TX: Work Loss Data Institute; 2008.
Transcutaneous Electrical Joint Stimulation and Pulsed Electrical Stimulation
- Farr J, Mont MA, Garland D, et al. Pulsed electrical stimulation in patients with osteoarthritis of the knee: Follow up in 288 patients who had failed non-operative therapy. Surg Technol Int. 2006;15:227-233.
- Fary RE, Carroll GJ, Briffa TG, Briffa NK. The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: Results of a double-blind, randomized, placebo-controlled, repeated-measures trial. Arthritis Rheum. 2011;63(5):1333-1342.
- Fary RE, Carroll GJ, Briffa TG, et al. The effectiveness of pulsed electrical stimulation (E-PES) in the management of osteoarthritis of the knee: A protocol for a randomised controlled trial. BMC Musculoskelet Disord. 2008;9:18.
- Garland D, Holt P, Harrington JT, et al. A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2007;15(6):630-637.
- Hulme J, Robinson V, DeBie R, et al. Electromagnetic fields for the treatment of osteoarthritis. Cochrane Database Syst Rev. 2002;(1):CD003523.
- McCarthy CJ, Callaghan MJ, Oldham JA. Pulsed electromagnetic energy treatment offers no clinical benefit in reducing the pain of knee osteoarthritis: A systematic review. BMC Musculoskelet Disord. 2006;7:51.
- Mendel FC, Dolan MG, Fish DR, et al. Effect of high-voltage pulsed current on recovery after grades I and II lateral ankle sprains. J Sport Rehabil. 2010;19(4):399-410.
- NHIC, Corp. Draft LCD for transcutaneous electrical joint stimulation devices. LCD ID No. DL28551. Durable Medical Equipment (DME) Medicare Administrative Carrier (MAC) Jurisdiction A. Hingham, MA: NHIC; 2008.
- Rutjes AWS, Nüesch E, Sterchi R, et al. Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database Syst Rev. 2009;(4):CD002823.
- Zizic TM, Hoffman KC, Holt PA, et al. The treatment of osteoarthritis of the knee with pulsed electrical stimulation. J Rheumatol. 1995;22(9):1757-1761.
Lumbosacral Plexus and Sacral Nerve Root Stimulation
- Alo KM, Yland MJ, Redko V, et al. Lumbar and sacral nerve root stimulation (NRS) in the treatment of chronic pain: A novel anatomic approach and neuro stimulation technique. Neuromodulation. 1999;2(1):23-31
- Falco FJE, Rubbani M, Heinbaugh J. Anterograde sacral nerve root stimulation (ASNRS) via the sacral hiatus: Benefits, limitations, and percutaneous implantation technique. Neuromodulation. 2003;6(4):219-224.
- Kim P. Advanced pain management techniques: An overview of neurostimulation. Expert Column. Medscape Neurol Neurosurg. 2004;6(1). Available at: http://www.medscape.com/viewarticle/473431. Accessed January 6, 2006.
- Siegel S, Paszkievics E, Kirkpatrick C et al. Sacral nerve stimulation in patients with chronic intractable pelvic pain. J Urol . 2001;166(5):1742-1745.
Microcurrent Therapy
- Chou R. Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021a.
- Chou R. Subacute and chronic low back pain: Nonsurgical interventional treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021b.
- Chou R, Atlas SJ, Stanos SP, Rosenquist RW. Nonsurgical interventional therapies for low back pain: A review of the evidence for an American Pain Society clinical practice guideline. Spine. 2009;34(10):1078-1093.
- Gossrau G, Wähner M, Kuschke M, et al. Microcurrent transcutaneous electric nerve stimulation in painful diabetic neuropathy: A randomized placebo-controlled study. Pain Med. 2011;12(6):953-960.
- Issac Z. Management of non-radicular neck pain in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Knight CL, Deyo RA, Staiger TO, Wipf JE. Treatment of acute low back pain. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Koopman JS, Vrinten DH, van Wijck AJ. Efficacy of microcurrent therapy in the treatment of chronic nonspecific back pain: A pilot study. Clin J Pain. 2009;25(6):495-499.
- Shetty GM, Rawat P, Sharma A. Effect of adjuvant frequency-specific microcurrents on pain and disability in patients treated with physical rehabilitation for neck and low back pain. J Bodyw Mov Ther. 2020;24(4):168-175.
- Zuim PR, Garcia AR, Turcio KH, Hamata MM. Evaluation of microcurrent electrical nerve stimulation (MENS) effectiveness on muscle pain in temporomandibular disorders patients. J Appl Oral Sci. 2006;14(1):61-66.
Scrambler Therapy/The Calmare Therapy Device
- Christo PJ, Kamson DO, Smith TJ, et al. Treatment of Dejerine-Roussy syndrome pain with Scrambler therapy. Pain Manag. 2020;10(3):141-145.
- Majithia N, Smith TJ, Coyne PJ, et al. Scrambler therapy for the management of chronic pain. Support Care Cancer. 2016;24(6):2807-2814.
- Marineo G, Iorno V, Gandini C, et al. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: Results of a pilot, randomized, controlled trial. J Pain Symptom Manage. 2012;43(1):87-95.
- Marineo G. Untreatable pain resulting from abdominal cancer: New hope from biophysics? JOP. 2003;4(1):1-10.
- Mealy MA, Kozachik SL, Cook LJ, et al. Scrambler therapy improves pain in neuromyelitis optica: A randomized controlled trial. Neurology. 2020;94(18):e1900-e1907.
- Notaro P, Dell'Agnola CA, Dell'Agnola AJ, et al. Pilot evaluation of scrambler therapy for pain induced by bone and visceral metastases and refractory to standard therapies. Support Care Cancer. 2016;24(4):1649-1654.
- Pachman DR, Watson JC, Loprinzi CL. Therapeutic strategies for cancer treatment related peripheral neuropathies. Curr Treat Options Oncol. 2014;15(4):567-580.
- Pachman DR, Weisbrod BL, Seisler DK, et al. Pilot evaluation of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy. Support Care Cancer. 2015;23(4):943-951.
- Ricci M, Pirotti S, Scarpi E, et al. Managing chronic pain: Results from an open-label study using MC5-A Calmare® device. Support Care Cancer. 2012;20(2):405-12
- Sabato AF, Marineo G, Gatti A. Scrambler therapy. Minerva Anestesiol. 2005;71(7-8):479-482.
- Smith T, Cheville AL, Loprinzi CL, Longo-Schoberlein D. Scrambler therapy for the treatment of chronic post-mastectomy pain (cPMP). Cureus. 2017;9(6):e1378.
- Smith TJ, Coyne PJ, Parker GL, et al. Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage. 2010;40(6):883-891.
- Smith TJ, Marineo G. Treatment of postherpetic pain wth Scrambler therapy, a patient-specific neurocutaneous electrical stimulation device. Am J Hosp Palliat Care. 2018;35(5):812-813.
- Starkweather AR, Coyne P, Lyon DE, et al. Decreased low back pain intensity and differential gene expression following Calmare®: Results from a double-blinded randomized sham-controlled study. Res Nurs Health. 2015;38(1):29-38.
Peripheral Subcutaneous Field Stimulation
- Burgher AH, Huntoon MA, Turley TW, et al. Subcutaneous peripheral nerve stimulation with inter-lead stimulation for axial neck and low back pain: Case series and review of the literature. Neuromodulation. 2012;15(2):100-106; discussion 106-107.
- Desai MJ, Jacob L, Leiphart J. Successful peripheral nerve field stimulation for thoracic radiculitis following Brown-Sequard syndrome. Neuromodulation. 2011;14(3):249-252; discussion 252.
- Falco FJ, Berger J, Vrable A, et al. Cross talk: A new method for peripheral nerve stimulation. An observational report with cadaveric verification. Pain Physician. 2009;12(6):965-983.
- Goroszeniuk T, Pang D, Al-Kaisy A, Sanderson K. Subcutaneous target stimulation-peripheral subcutaneous field stimulation in the treatment of refractory angina: Preliminary case reports. Pain Pract. 2012;12(1):71-79.
- McRoberts WP, Roche M. Novel approach for peripheral subcutaneous field stimulation for the treatment of severe, chronic knee joint pain after total knee arthroplasty. Neuromodulation. 2010;13(2):131-136.
- Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: A multisite, retrospective assessment. Am J Drug Alcohol Abuse. 2018;44(1):56-63.
- Ricciardo B, Kumar S, O'Callaghan J, Boyce Z. Peripheral nerve field stimulation for pruritus relief in a patient with notalgia paraesthetica. Australas J Dermatol. 2010;51(1):56-59.
- Yakovlev AE, Resch BE, Karasev SA. Treatment of intractable hip pain after THA and GTB using peripheral nerve field stimulation: A case series. WMJ.2010;109(3):149-152.
- Yakovlev AE, Resch BE. Treatment of chronic intractable atypical facial pain using peripheral subcutaneous field stimulation. Neuromodulation. 2010;13(2):137-140.
Electro Therapeutic Point Stimulation
- Aliyev RM, Geiger G. Cell-stimulation therapy of lateral epicondylitis with frequency-modulated low-intensity electric current. Bull Exp Biol Med. 2012;152(5):653-655.
- Hocking B. Healing pain with ETPS therapy [website], 2006. Available at: http://www.alaskawellness.com/HockingMayJune2006.htm. Accessed October 19, 2012.
Pulsed Stimulation (e.g., P-Stim)
- Fary RE, Carroll GJ, Briffa TG, Briffa NK. The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: Results of a double-blind, randomized, placebo-controlled, repeated-measures trial. Arthritis Rheum. 2011;63(5):1333-1342.
- Holzer A, Leitgeb U, Spacek A, et al. Auricular acupuncture for postoperative pain after gynecological surgery: A randomized controlled trail. Minerva Anestesiol. 2011;77(3):298-304.
- Michalek-Sauberer A, Heinzl H, Sator-Katzenschlager SM, et al. Perioperative auricular electroacupuncture has no effect on pain and analgesic consumption after third molar tooth extraction. Anesth Analg. 2007;104(3):542-547.
- Sator-Katzenschlager SM, Michalek-Sauberer A. P-Stim auricular electroacupuncture stimulation device for pain relief. Expert Rev Med Devices. 2007;4(1):23-32.
- Sator-Katzenschlager SM, Scharbert G, Kozek-Langenecker SA, et al. The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesth Analg. 2004;98(5):1359-1364,
- Sator-Katzenschlager SM, Szeles JC, Scharbert G, et al. Electrical stimulation of auricular acupuncture points is more effective than conventional manual auricular acupuncture in chronic cervical pain: A pilot study. Anesth Analg. 2003;97(5):1469-1473.
- Wang SM. An integrative approach for treating postherpetic neuralgia -- a case report. Pain Pract. 2007;7(3):274-278.
Neurolumen Device
- Callahan LR. Overview of running injuries of the lower extremity. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2013.
- Gilchrist JM, Donahue JE. Peripheral nerve tumors. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
Synaptic Device
- Synaptic Corp. Drug Free, Non-Invasive Solution to Pain. Synaptic Brochure. Denver, CO: Synaptic; 2010. Available at http://www.assureddrugtesting.com/images/Synaptic-Brochure-2010.pdf. Accessed February 10, 2014.
Electrotherapy for the Treatment of Adhesive Capsulitis (Frozen Shoulder)
- Page MJ, Green S, Kramer S, et al. Electrotherapy modalities for adhesive capsulitis (frozen shoulder). Cochrane Database Syst Rev. 2014;10:CD011324.
Non-Invasive Interactive Neurostimulation (InterX 1000 Neurostimulator Device)
- Gorodetskyi IG, Gorodnichenko AI, Tursin PS, et al. Use of noninvasive interactive neurostimulation to improve short-term recovery in patients with surgically repaired bimalleolar ankle fractures: A prospective, randomized clinical trial. J Foot Ankle Surg. 2010;49(5):432-437.
- Lin CW, Donkers NA, Refshauge KM, et al. Rehabilitation for ankle fractures in adults. Cochrane Database Syst Rev. 2012;11:CD005595.
- Selfe TK, Bourguignon C, Taylor AG. Effects of noninvasive interactive neurostimulation on symptoms of osteoarthritis of the knee: A randomized, sham-controlled pilot study. J Altern Complement Med. 2008;14(9):1075-1081.
- Teodorczyk-Injeyan JA, Triano JJ, McGregor M, et al. Effect of interactive neurostimulation therapy on inflammatory response in patients with chronic and recurrent mechanical neck pain. J Manipulative Physiol Ther. 2015;38(8):545-554.
Cefaly
- Bajwa ZH, Smith JH. Preventive treatment of migraine in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2018.
- Didier HA, Di Fiore P, Marchetti C, et al. Electromyography data in chronic migraine patients by using neurostimulation with the Cefaly® device. Neurol Sci. 2015;36 Suppl 1:115-119.
- Mack KJ. Preventive treatment of migraine in children. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2018.
- Magis D, D'Ostilio K, Thibaut A, et al. Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine. Cephalalgia. 2017;37(9):881-891.
- Magis D, Sava S, d'Elia TS, et al. Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013;14:95.
- No authors listed. A transcutaneous electrical nerve stimulation device (Cefaly) for migraine prevention. Med Lett Drugs Ther. 2014;56(1449):78.
- Piquet M, Balestra C, Sava SL, Schoenen JE. Supraorbital transcutaneous neurostimulation has sedative effects in healthy subjects. BMC Neurol. 2011;11:135.
- Riederer F, Penning S, Schoenen J. Transcutaneous supraorbital nerve stimulation (t-SNS) with the Cefaly(®) device for migraine prevention: A Review of the Available Data. Pain Ther. 2015;4(2):135-147.
- Russo A, Tessitore A, Esposito F, et al. Functional changes of the perigenual part of the anterior cingulate cortex after external trigeminal neurostimulation in migraine patients. Front Neurol. 2017;8:282.
- Russo A, Tessitore A. Transcutaneous supraorbital neurostimulation in “de novo” patients with migraine without aura: The first Italian experience. J Headache Pain. 2015;16:69.
- Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. Neurology. 2013;80(8):697-704.
Galvanic Stimulation
- Williams KJ, Babber A, Ravikumar R, Davies AH. Non-invasive management of peripheral arterial disease. Adv Exp Med Biol. 2017;906:387-406.
IB-Stim for the Treatment of Nausea and Abdominal Pain Secondary to Irritable Bowel Syndrome
- Balakrishnan K, Chiou EH. Functional abdominal pain in children and adolescents: Management in primary care. UpToDate [online serial], Waltham, MA: UpToDate; reviewed January 2025.
- Bora G, Atkinson SN, Pan A, et al. Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: A pilot study. J Dig Dis. 2023;24(5):348-358.
- Castillo DF, Denson LA, Haslam DB, et al. The microbiome in adolescents with irritable bowel syndrome and changes with percutaneous electrical nerve field stimulation. Neurogastroenterol Motil. 2023;35(7):e14573.
- Chacko MR, Chiou EH. Functional abdominal pain in children and adolescents: Management in primary care. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2022; December 2023.
- Chakraborty PS, Daniel R, Navarro FA. Non-pharmacologic approaches to treatment of pediatric functional abdominal pain disorders. Front Pediatr. 2023:11:1118874.
- Chen J. Neuromodulation and neurostimulation for the treatment of functional gastrointestinal disorders. Gastroenterol Hepatol (N Y). 2022;18(1):47-49.
- Chen JD, Zhu Y, Wang Y. Emerging noninvasive neuromodulation methods for functional gastrointestinal diseases. J Transl Int Med. 2023;10(4):281-285.
- Chogle A, El-Chammas K, Santucci N, et al. A multicenter registry study on percutaneous electrical nerve field stimulation for pediatric disorders of gut-brain interaction. J Pediatr Gastroenterol Nutr. 2024;78(4):817-826.
- Chogle A, Visnagra K, Janchoi J, et al. Prospective study of the effect of auricular percutaneous electrical nerve field stimulation on quality of life in children with pain related disorders of gut-brain interaction. Front Pain Res (Lausanne). 2023;4:1223932.
- El-Chammas KI, Santucci NR, Mansi S, Kaul A. Pediatric gastrointestinal neuromodulation: A review. Saudi J Gastroenterol. 2022;28(6):403-412.
- Goroszeniuk T, Khan R. Permanent percutaneous splanchnic nerve neuromodulation for management of pain due to chronic pancreatitis: A case report. Neuromodulation. 2011;14(3):253-257.
- Karrento K, Zhang L, Conley W, et al. Percutaneous electrical nerve field stimulation improves comorbidities in children with cyclic vomiting syndrome. Front Pain Res (Lausanne). 2023;4:1203541.
- Miranda A. Opinion: Percutaneous electrical nerve field stimulation compared to standard medical therapy in adolescents with functional abdominal pain disorders. Front Pain Res (Lausanne). 2024;5:1279946.
- Paicius RM, Bernstein CA, Lempert-Cohen C. Peripheral nerve field stimulation in chronic abdominal pain. Pain Physician. 2006;9(3):261-266.
- Santucci NR, Beigarten AJ, Khalid F, et al. Percutaneous electrical nerve field stimulation in children and adolescents with functional dyspepsia -- Integrating a behavioral intervention. Neuromodulation. 2024;27(2):372-381.
- Santucci NR, King C, El-Chammas KI, et al. Effect of percutaneous electrical nerve field stimulation on mechanosensitivity, sleep, and psychological comorbidities in adolescents with functional abdominal pain disorders. Neurogastroenterology & Motility. 2022;34(8):e14358.
- Santucci NR, Sahay R, El-Chammas KI, et al. Percutaneous electrical nerve field stimulation compared to standard medical therapy in adolescents with functional abdominal pain disorders. Front. Pain Res. 2023;4:1251932.
- Wald A. Treatment of irritable bowel syndrome in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2022.
- Zhang S, Zhang C, Fan M, et al. Neuromodulation and functional gastrointestinal disease. Neuromodulation. 2024;27(2):243-255.
- Zhou L, Chou H, Holder E. Abdominal wall type-I complex regional pain syndrome treated effectively with peripheral nerve field stimulation: A case report. J Surg Case Rep. 2017;2017(1):rjw222.
Reactiv8 Device
- Ardeshiri A, Amann M, Thomson S, Gilligan CJ. Application of restorative neurostimulation for chronic mechanical low back pain in an older population with 2-year follow up. Reg Anesth Pain Med. 2024 Mar 9: [Epub ahead ofprint].
- Ardeshiri A, Shaffrey C, Stein K-P, Sandalcioglu IE. Real world evidence for restorative neurostimulation in chronic low back pain -- a consecutive cohort study. World Neurosurg. 2022:168:e253-e259.
- Chakravarthy K, Lee D, Tram J, et al. Restorative neurostimulation: A clinical guide for therapy adoption. J Pain Res. 2022;15:1759-1774.
- Copley S, Batterham A, Shah A, et al. Systematic review and meta-analysis of stimulation of the medial branch of the lumbar dorsal rami for the treatment of chronic low back pain. Neuromodulation. 2024;27(8):1285-1293.
- Deckers K, De Smedt K, Mitchell B, et al. New therapy for refractory chronic mechanical low back pain-restorative neurostimulation to activate the lumbar multifidus: One year results of a prospective multicenter clinical trial. Neuromodulation. 2018;21(1):48-55.
- Francio VT, Westerhaus BD, Carayannopoulos AG, Sayed D. Multifidus dysfunction and restorative neurostimulation: A scoping review. Pain Med. 2023;24(12):1341-1354
- Gilligan C, Burnside D, Grant L, et al. ReActiv8 stimulation therapy vs. optimal medical management: A randomized controlled trial for the treatment of intractable mechanical chronic low back pain (RESTORE Trial Protocol). Pain Ther. 2023b;12(2):607-620.
- Gilligan C, Volschenk W, Russo M, et al; ReActiv8-B investigators. An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: A randomized sham-controlled clinical trial. Pain. 2021;162(10):2486-2498.
- Gilligan C, Volschenk W, Russo M, et al. Five-year longitudinal follow-up of restorative neurostimulation shows durability of effectiveness in patients with refractory chronic low back pain associated with multifidus muscle dysfunction. Neuromodulation. 2024;27(5):930-943.
- Gilligan C, Volschenk W, Russo M, et al. Three-year durability of restorative neurostimulation effectiveness in patients with chronic low back pain and multifidus muscle dysfunction. Neuromodulation. 2023;26(1):98-108.
- Gilligan C, Volschenk W, Russo M, et al; ReActiv8-B Investigators. Long-term outcomes of restorative neurostimulation in patients with refractory chronic low back pain secondary to multifidus dysfunction: Two-year results of the ReActiv8-B Pivotal Trial. Neuromodulation. 2023a;26(1):87-97.
- Lorio M, Lewandrowski KU, Coric D, et al. International Society for the Advancement of Spine Surgery Statement: Restorative Neurostimulation for Chronic Mechanical Low Back Pain Resulting From Neuromuscular Instability. Int J Spine Surg. 2023;17(5):728-750.
- Mitchell B, Deckers K, De Smedt K, et al. Durability of the therapeutic effect of restorative neurostimulation for refractory chronic low back pain. Neuromodulation. 2021;24(6):1024-1032.
- National Institute for Health and Care Excellence (NICE). Neurostimulation of lumbar muscles for refractory nonspecific chronic low back pain. Interventional procedures guidance 739. London, UK: NICE; September 22, 2022.
- Peters MDJ, Godfrey C, McInerney P, et al. Chapter 11: Scoping Reviews (2020 Version). In: Aromataris E, Munn Z, eds. JBI Manual for Evidence Synthesis. JBI; 2020.
- Provenzano DA, Heller JA, Hanes MC. Current perspectives on neurostimulation for the management of chronic low back pain: A narrative review. J Pain Res. 2021;14:463-479.
- Sayed D, Grider J, Strand N, et al. The American Society of Pain and Neuroscience (ASPN) evidence-based clinical guideline of interventional treatments for low back pain. J Pain Res. 2022;15:3729-3832.
- Schwab F, Mekhail N, Patel KV, et al.; RESTORE investigators. Restorative neurostimulation therapy compared to optimal medical management: A randomized evaluation (RESTORE) for the treatment of chronic mechanical low back pain due to multifidus dysfunction. Pain Ther. 2025;14(1):401-423.
- Shaffrey C, Gilligan C. Effect of restorative neurostimulation on major drivers of chronic low back pain economic impact. Neurosurgery. 2023;92(4):716-724.
- Thomson S, Chawla R, Love-Jones S, et al on behalf of The ReActiv8 PMCF Investigators. Restorative neurostimulation for chronic mechanical low back pain: Results from a prospective multi-centre longitudinal cohort. Pain Ther. 2021;10(2):1451-1465.
- Thomson S, Williams A, Vajramani G, et al. Restorative neurostimulation for chronic mechanical low back pain -- Three year results from the United Kingdom post market clinical follow-up registry. Br J Pain. 2023;17(5):447-456.
Sprint (Peripheral Subcutaneous Field Stimulation)
- Abdi S. Complex regional pain syndrome in adults: Treatment, prognosis, and prevention. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Chae J, Yu DT, Walker ME, et al. Intramuscular electrical stimulation for hemiplegic shoulder pain: A 12-month follow-up of a multiple-center, randomized clinical trial. Am J Phys Med Rehabil. 2005;84(11):832-842.
- Deer TR, Gilmore CA, Desai MJ, et al. Percutaneous peripheral nerve stimulation of the medial branch nerves for the treatment of chronic axial back pain in patients after radiofrequency ablation. Pain Med. 2021;22(3):548-560.
- Dickerson DM, Kalia H, Vorenkamp KE, et al. Cost savings in chronic pain patients initiating peripheral nerve stimulation (PNS) with a 60-day PNS treatment. Pain Ther. 2025;14(1):269-282.
- Dunteman E. Peripheral nerve stimulation for unremitting ophthalmic postherpetic neuralgia. Neuromodulation. 2002;5(1):32-37.
- Gill B, Tidwell C, Hagedorn JM, et al. Consensus Guidelines from the American Society of Pain and Neuroscience for the Use of 60-Day Peripheral Nerve Stimulation Therapy. A NEURON Living Guideline Project. J Pain Res. 2025:;8:3117–3139.
- Gilmore CA, Deer TR, Desai MJ, et al. Durable patient-reported outcomes following 60-day percutaneous peripheral nerve stimulation (PNS) of the medial branch nerves. Interv Pain Med. 2023;2(1):100243.
- Gilmore CA Deer TR, Desai MJ, et al. Four-year follow-up from a prospective, multicenter study of percutaneous 60-day peripheral nerve stimulation for chronic low back pain. Pain Ther. 2025;14(3):1103-1115.
- Gilmore CA, Desai MJ, Hopkins TJ, et al. Treatment of chronic axial back pain with 60-day percutaneous medial branch PNS: Primary end point results from a prospective, multicenter study. Pain Pract. 2021;21(8):877-889.
- Gilmore CA, Ilfeld BM, Rosenow JM, et al. Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med. 2019 Nov 17:rapm-2019-100937.
- Gilmore C, Ilfeld B, Rosenow J, et al. Percutaneous peripheral nerve stimulation for the treatment of chronic neuropathic postamputation pain: A multicenter, randomized, placebo-controlled trial. Reg Anesth Pain Med. 2019;44(6):637-645.
- Goree JH, Grant SA, Dickerson DM, et al. Randomized placebo-controlled trial of 60-day percutaneous peripheral nerve stimulation treatment indicates relief of persistent postoperative pain, and improved function after knee replacement. Neuromodulation. 2024;27(5):847-861.
- Ilfeld BM, Plunkett A, Vijjeswarapu AM, et al. Peripheral nerve stimulation (neuromodulation) for postoperative pain: A randomized, sham-controlled pilot study. Anesthesiology. 2021;135(1):95-110.
- Pingree MJ, Hurdle MF, Spinner DA, et al. Real-world evidence of sustained improvement following 60-day peripheral nerve stimulation treatment for pain: A cross-sectional follow-up survey. Pain Manag. 2022;12(5):611-621.
- Sheth SJ, Mauck WD, Russo DP, et al. Potential cost savings with 60-day peripheral nerve stimulation treatment in chronic axial low back pain. Pain Ther. 2024;13(5):1187-1202.
- Vorenkamp KE, Lee G, Lester DD, et al. Durable shoulder pain relief and avoidance of surgery up to 5 years following 60-day PNS treatment. Pain Ther. Published online May 26, 2025.
- Wilson RD, Gunzler DD, Bennett ME, et al. Peripheral nerve stimulation compared with usual care for pain relief of hemiplegic shoulder pain: A randomized controlled trial. Am J Phys Med Rehabil. 2014;93(1):17-28. Erratum in: Am J Phys Med Rehabil. 2016;95(2):e29.
- Wilson RD, Harris MA, Gunzler DD, et al. Percutaneous peripheral nerve stimulation for chronic pain in subacromial impingement syndrome: A case series. Neuromodulation. 2014;17(8):771-776; discussion 776.
Experimental, Investigational, or Unproven Indications
- Chen FC, Jin ZL, Wang DF. A retrospective study of transcutaneous electrical nerve stimulation for chronic pain following ankylosing spondylitis. Medicine (Baltimore). 2018;97(27):e11265.
- Dabby R, Sadeh M, Goldberg I, Finkelshtein V. Electrical stimulation of the posterior tibial nerve reduces neuropathic pain in patients with polyneuropathy. J Pain Res. 2017;10:2717-2723.
- Fuentes-Marquez P, Cabrera-Martos I, Valenza MC. Physiotherapy interventions for patients with chronic pelvic pain: A systematic review of the literature. Physiother Theory Pract. 2018:1-8.
- Gewandter JS, Chaudari J, Ibegbu C, et al. Wireless transcutaneous electrical nerve stimulation device for chemotherapy-induced peripheral neuropathy: An open-label feasibility study. Support Care Cancer. 2019;27(5):1765-1774.
- Gilmore CA, Kapural L, McGee MJ, Boggs JW. Percutaneous peripheral nerve stimulation for chronic low back pain: Prospective case series with 1 year of sustained relief following short-term implant. Pain Pract. 2020;20(3):310-320.
- Ilfeld BM, Gabriel RA, Said ET, et al. Ultrasound-guided percutaneous peripheral nerve stimulation: Neuromodulation of the sciatic nerve for postoperative analgesia following ambulatory foot surgery, a proof-of-concept study. Reg Anesth Pain Med. 2018;43(6):580-589.
- Ilfeld BM, Said ET, Finneran JJ 4th, et al. Ultrasound-guided percutaneous peripheral nerve stimulation: Neuromodulation of the femoral nerve for postoperative analgesia following ambulatory anterior cruciate ligament reconstruction: A proof of concept study. Neuromodulation. 2019;22(5):621-629.
- Li S, Stampas A, Frontera J, et al. Combined transcranial direct current stimulation and breathing-controlled electrical stimulation for management of neuropathic pain after spinal cord injury. J Rehabil Med. 2018;50(9):814-820.
- Liao C-C, Li J-M, Hsieh C-L. Auricular electrical stimulation alleviates headache through CGRP/COX-2/TRPV1/TRPA1 signaling pathways in a nitroglycerin-induced migraine rat model. Evid Based Complement Alternat Med. 2019;2019:2413919.
- Nguyen VQ, Bock WC, Groves CC, et al. Fully implantable peripheral nerve stimulation for the treatment of hemiplegic shoulder pain: A case report. Am J Phys Med Rehabil. 2015;94(2):146-53.
- O'Connell NE, Marston L, Spencer S, et al. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev. 2018;4:CD008208.
- Shimada Y, Davis R, Matsunaga T, et al. Electrical stimulation using implantable radiofrequency microstimulators to relieve pain associated with shoulder subluxation in chronic hemiplegic stroke. Neuromodulation. 2006;9(3):234-238.
- Tao H, Wang T, Dong X, et al. Effectiveness of transcutaneous electrical nerve stimulation for the treatment of migraine: A meta-analysis of randomized controlled trials. J Headache Pain. 2018;19(1):42.
- Tomasello C, Pinto RM, Mennini C, et al. Scrambler therapy efficacy and safety for neuropathic pain correlated with chemotherapy-induced peripheral neuropathy in adolescents: A preliminary study. Pediatr Blood Cancer. 2018;65(7):e27064.
- Wilson RD, Bennett ME, Nguyen VQC, et al. Fully implantable peripheral nerve stimulation for hemiplegic shoulder pain: A multi-site case series with two-year follow-up. Neuromodulation. 2018;21(3):290-295.
Treatment of Suprascapular Nerve Entrapment
- Leider JD, Derise OC, Bourdreaux KA, et al. Treatment of suprascapular nerve entrapment syndrome. Orthop Rev (Pavia). 2021;13(2):25554.
- Rutkove SB. Overview of upper extremity peripheral nerve syndromes. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2022.
- Vij N, Fabian I, Hansen C, et al. Outcomes after minimally invasive and surgical management of suprascapular nerve entrapment: A systematic review. Orthop Rev (Pavia). 2022;14(3):37157.
Nalu Peripheral Nerve Stimulation
- Busch C, Smith O, Weaver T, et al. Peripheral nerve stimulation for lower extremity pain. Biomedicines. 2022;10(7):1666.
- Cohen SP, Gilmore CA, Rauck RL, et al. Percutaneous peripheral nerve stimulation for the treatment of chronic pain following amputation. Mil Med. 2019;184(7-8):e267-e274.
- Gill B, Cheng DS, Buchanan P, Lee DW. Review of interventional treatments for cluneal neuropathy. Pain Physician. 2022;25(5):355-363.
- Hatheway J, Hersel A, Song J, et al. Clinical study of a micro-implantable pulse generator for the treatment of peripheral neuropathic pain: 3-month and 6-month results from the COMFORT-randomised controlled trial. Reg Anesth Pain Med. 2024a May 31 [Online ahead of print].
- Hatheway J, Hersel A, Engle M, et al; COMFORT Study Group. Clinical study of a micro-implantable pulse generator for the treatment of peripheral neuropathic pain: 12-month results from the COMFORT-randomized controlled trial. Reg Anesth Pain Med. 2024b Nov 20 [Epub ahead of print].
- Hatheway J, Ratino T, Swain AR, et al. Long-term pain relief delivered by micro-implantable pulse generator: Findings from a large-scale, real-world data peripheral nerve stimulation patient registry. Chron Pain Manag. 2025; 9:169.
- Hoffmann CH, D'Souza RS, Hagedorn JM, et al. An advanced practice provider guide to peripheral nerve stimulation. J Pain Res. 2022;15:2283-2291.
- Kalia H, Pritzlaff S, Li AH, et al. Application of the novel Nalu™ Neurostimulation System for peripheral nerve stimulation. Pain Manag. 2022;12(7):795-804.
- Kalia H, Thapa B, Staats P, et al. Real-world healthcare utilization and costs of peripheral nerve stimulation with a micro-IPG system. Pain Manag. 2025 Jan 6: [Online ahead of print].
- Knotkova H, Hamani C, Sivanesan E, et al. Neuromodulation for chronic pain. Lancet. 2021;397(10289):2111-2124.
- Naidu R, Li S, Desai MJ, et al. 60-day PNS treatment may improve identification of delayed responders and delayed non-responders to neurostimulation for pain relief. J Pain Res. 2022;15:733-743.
- Pagan-Rosado R, Smith BJ, Smither FC, et al. Peripheral nerve stimulation for the treatment of phantom limb pain: A case series. Case Rep Anesthesiol. 2023;2023:1558183.
- Soteropoulos C, Pergolizzi J, Nagarakanti S, Gharibo C. Peripheral stimulation for treatment of cluneal neuropathy case study. Cureus. 2022;14(8):e28033.
Multifidus Stimulation
- Carayannopoulos A, Johnson D, Lee D, et al. Precision rehabilitation after neurostimulation implantation for multifidus dysfunction in nociceptive mechanical chronic low back pain. Arch Rehabil Res Clin Transl. 2024;6(2):100333.
- Copley S, Batterham A, Shah A, et al. Systematic review and meta-analysis of stimulation of the medial branch of the lumbar dorsal rami for the treatment of chronic low back pain. Neuromodulation. 2024 Sep 24 [Online ahead of print].
- Sornkaew K, Thu KW, Silfies SP, et al. Effects of combined anodal transcranial direct current stimulation and motor control exercise on cortical topography and muscle activation in individuals with chronic low back pain: A randomized controlled study. Physiother Res Int. 2024;29(3):e2111.
- Tieppo Francio V, Westerhaus BD, Carayannopoulos AG, Sayed D. Multifidus dysfunction and restorative neurostimulation: A scoping review. Pain Med. 2023;24(12):1341-1354.
- Wu W-T, Chang K-V, Ozçakar L. Integrating ultrasound-guided multifidus injections with repeated peripheral magnetic stimulation for low back pain: A feasibility study. J Pain Res. 2024;17:2873-2880.
Peripheral Nerve Stimulator System for Chronic Pain
- Abd-Elsayed A. Wireless peripheral nerve stimulation for treatment of peripheral neuralgias. Neuromodulation. 2020;23(6):827-830.
- Abd-Elsayed A, Keith MK, Cao NN, et al. Temporary peripheral nerve stimulation as treatment for chronic Pain. Pain Ther. 2023;12(6):1415-1426.
- D'Souza RS, Jin MY, Abd-Elsayed A. Peripheral nerve stimulation for low back pain: A systematic review. Curr Pain Headache Rep. 2023;27(5):117-128.
- Gabriel RA, Ilfeld BM. Acute postoperative pain management with percutaneous peripheral nerve stimulation: The SPRINT neuromodulation system. Expert Rev Med Devices. 2021;18(2):145-150.
- Gilmore CA, Kapural L, McGee MJ, Boggs JW. Percutaneous peripheral nerve stimulation for chronic low back pain: Prospective case series with 1 year of sustained relief following short-term implant. Pain Pract. 2020;20(3):310-320.
- Hasoon J, Dalal S, Berger AA, et al. Peripheral nerve stimulation for the treatment of hemiplegic shoulder pain. Orthop Rev (Pavia). 2021;13(2):27362.
- Huntoon MA, Slavin KV, Hagedorn JM, et al. A retrospective review of real-world outcomes following 60-day peripheral nerve stimulation for the treatment of chronic pain. Pain Physician. 2023;26(3):273-281.
- McGreevy K, McGreevy K. Peripheral nerve stimulation uses high-frequency electromagnetic technology to power an implanted neurostimulator with a separate receiver for the treatment of chronic pain in the lower extremities. Pain Physician. 2024;27(4):223-227.
- Strand N, D'Souza RS, Hagedorn JM, et al. Evidence-based clinical guidelines from the American Society of Pain and Neuroscience for the use of implantable peripheral nerve stimulation in the treatment of chronic pain. J Pain Res. 2022;15:2483-2504.
