Diabetic Neuropathy: Selected Treatments

Number: 0729

Policy

Aetna considers percutaneous electrical stimulation medically necessary for the treatment of members with diabetic neuropathy who failed to adequately respond to conventional treatments including anti-convulsants (especially 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).

Note: Use of percutaneous electrical stimulation for more than 4 weeks for diabetic neuropathy is considered not medically necessary.

Aetna considers the following interventions experimental and investigational for the treatment of diabetic neuropathy because their clinical value for this indication has not been established.

• Acupuncture
• Aldose reductase inhibitors
• Angiotensin II type 2 receptor antagonists (e.g., candesartan, irbesartan, losartan, and valsartan)
• Autologous bone marrow (BM)-derived stem cells (including BM-derived mesenchymal stem/stromal cells)
• Botulinum toxin
• Combination electrochemical therapy/treatment (CET)
• Dorsal root ganglion stimulation (see also CPB 194 - Spinal Cord Stimulation) 
• Electroanalgesia (e.g., Sanexas SLV2 and Synaptic 4000)
• Electromagnetic field treatment
• Erythropoietin analogs
• Fulranumab
• Ghrelin
• Infrared therapy
• Interleukin-6
• Lacosamide
• Low-intensity laser / low-level laser
• Mecobalamin (a vitamin B12 analog), alone or in combination with acupuncture
• Monochromatic infrared phototherapy
• Moxibustion
• Ozone therapy
• Peripheral nerve blocks (continuous or single-injection)
• Photo-biomodulation
• Plantar electrical-stimulation
• Plantar mechanical stimulation
• Pulsed magnetic field treatment
• Reiki therapy
• Secretoneurin
• Sodium channel blockers
• Spinal cord stimulation (see CPB 0194 - Spinal Cord Stimulation)
• Surgical decompressionFootnotes for surgical decompression*
• Topical ketamine
• Tumor necrosis factor-alpha inhibitors (e.g., adalimumab, certolizumab, etanercept, golimumab, and infliximab)
• Vibrating insoles.

Background

The natural history of DN is progressive and irreversible loss of sensibility in the feet, and may lead to ulceration and/or amputation.  Studies have reported that surgical decompression of lower extremity peripheral nerves in patients with DN can relieve pain, restore sensation, and prevent ulceration and amputation. 

The American Academy of Neurology (AAN)’s practice advisory on surgical decompression for the treatment of DN (Chaudhry et al, 2006) stated that systemic review of the scientific literature revealed only Class IV studies (uncontrolled studies, case series, case reports, or expert opinion) concerning this approach.  The AAN concluded that surgical decompression for DN is unproven, and stated that prospective, randomized, controlled trials with standard definitions of peripheral neuropathy, functional outcome measures with independent, blinded evaluations are needed to ascertain the clinical value of this intervention.

Halle-Caffee (2000) reported the findings of a series of 58 operations on 36 patients who received decompression of the posterior tibial nerve for the treatment of DN.  Pre-operative symptoms included lack of sensation, pain, or both.  Eleven of the 36 patients had neurotrophic ulcers, which were treated simultaneously.  The operation was found to be effective for relief of pain in 24 of the 28 patients with that complaint (86 %).  Restoration of sensation was less consistent with improvement noted in 18 of the 36 patients (50 %).  The mean follow-up period was 32 months with a range of 12 to 84 months, and 5 patients had some degree of recurrent symptoms.  No patient has developed a new ulcer after nerve decompression.  Wound complications were minimal (12 %), even though ulcers were treated simultaneously.  No patient required surgical treatment for the decompression incision, although 1 subject was hospitalized for treatment of a wound infection.  The author stated that the procedure appeared to be a worthwhile treatment, which should be considered for selected diabetics with symptomatic neuropathy.

Wood and Wood (2003) presented the short-term results of 33 lower extremities treated with external neurolysis of the common peroneal, deep peroneal, and tarsal tunnel nerves.  Mean follow-up was 3 months with a range of 1 to 6 months.  The surgery was performed in an attempt to relieve pain, and to restore normal sensation in the foot.  All procedures were performed under spinal or general anesthesia.  Subjects for the procedure were type 1 or type 2 diabetics with symptomatic somatosensory neuropathy (e.g., pain, burning, tingling, and/or numbness) and pre-operative computer-assisted neurosensory testing that confirmed the presence of elevated nerve threshold levels and axonal degeneration in the foot and leg.  External neurolysis of the involved nerves provided good to excellent results in 90.0 % of those patients with pre-operative neuropathic pain, and restored sensation at good to excellent levels in 66.7 % of those patients with pre-operative neuropathic numbness.  The mean visual analog score (VAS) for pain assessment was 9.0 pre-operatively and 3.2 post-operatively for those patients with pain as a symptomatic complaint (n = 30).  There were 4 complications (12 %) and all were early cases consisting of a non-infected wound dehiscence of the tarsal tunnel incision, which went on to heal without consequence.  These initial short-term results suggested that external neurolysis of the common peroneal, deep peroneal, and tarsal tunnel nerves in selected patients with symptomatic DN and an overlying compression neuropathy as determined by using computer-assisted neurosensory testing appears to be an effective treatment for providing pain relief and restoration of sensation in the foot.

The impact of surgical decompression on the development of ulcers and amputations in both the operated and the contralateral, non-operated limb was evaluated in a retrospective analysis of 50 patients with diabetes a mean of 4.5 years (range of 2 to 7 years) from the date of surgery (Aszmann et al, 2004).  No ulcers or amputations occurred in the index limb of these patients.  In contrast, there were 12 ulcers and 3 amputations in 15 different patients in contralateral limbs (p < 0.001).  The authors concluded that decompression of lower extremity nerves in DN changes the natural history of this disease, representing a paradigm shift in health care costs (Aszmann et al, 2004).

In a prospective study, Valdivia and associates (2005) reported the findings of 100 consecutive patients (60 with diabetes and 40 with idiopathic neuropathy) operated on by 2 surgeons; with the post-operative results reviewed by someone other than these two surgeons.  Each patient had neurolysis of the peroneal nerve at the knee and the dorsum of the foot, and the tibial nerve released in the four medial ankle tunnels.  After at least 1 year of follow-up, 87 % of patients with pre-operative numbness reported improved sensation, 92 % with pre-operative balance problems reported improved balance, and 86 % whose pain level was 5 or greater on VAS from 0 (no pain) to 10 (the most severe pain) before surgery reported an improvement in pain.  These researchers concluded that decompression of compressed lower extremity nerves improves sensation and decreases pain, and should be recommended for patients with DN who have failed to improve with traditional medical treatment.

In a review on the role of surgical decompression for DN, Biddinger and Amend (2004) stated that while some studies reported decreased pain, others showed improved sensory function.  These investigators noted that the role of surgical decompression for treating DN remains controversial.

Karagoz and associates (2008) studied the effect of peripheral nerve decompression on DN on the 1st day and 6 months post-operatively (n = 24).  The common peroneal, the posterior tibial, and the deep peroneal nerves were decompressed.  Pain relief was assessed by the VAS.  Patients were screened with neurosensory testing by means of a Pressure-Specified Sensory Device.  Pre-operative values and values on the 1st day and 6 months post-operatively were compared.   Pain relief was reported to be 80 %  and 85 % at 1st day and 6 months after the surgery, respectively.  Mean 2-point discrimination length improvements were found to be 72.6 % and 89 % at 1st day and 6 months, respectively.  The authors concluded that peripheral nerve decompression can be used effectively in the treatment of patients with DN.

On the other hand, Chaudhry and colleagues (2008) concluded in a Cochrane review that the role of decompressive surgery for diabetic symmetric distal neuropathy is unproven.  These researchers examined the evidence from randomized controlled trials concerning the role of decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy.  They included all randomized or quasi-randomized controlled human trials in which any form of decompressive surgery of the lower limbs nerves had been used to treat diabetic symmetrical distal polyneuropathy (DSDP) compared with no treatment or medical therapy.  Patients with DSDP were included if they had decompression (with or without neurolysis) of at least 2 of the following nerves in both lower limbs, for the treatment of DSDP: the posterior tibial nerve (including calcaneal, medial and lateral plantar nerves), deep peroneal nerve at the ankle, common peroneal nerve at the knee, lateral femoral cutaneous nerve and sural nerves in the posterior calf region.  The primary outcome measure was the change in pain measured by the VAS between the baseline and a follow-up period of greater than 3 months.  A total of 142 publications from the above search strategies were identified.  The 3 authors of this manuscript reviewed abstracts of all papers independently.  Only 8 of these were considered relevant to the question at hand.  The data from these 8 studies were entered onto standardized data extraction forms.  The authors used Review Manager to pool the results from appropriate studies comparing the same treatments; dichotomous outcomes to obtain pooled relative risks (RR); measured outcomes to obtain pooled weighted mean differences; and a fixed-effect analysis unless there was evidence of serious heterogeneity between studies sufficient to justify the use of random-effects analysis.  This review failed to identify a single randomized controlled trial or any other well designed prospective study controlling for the non-operated limb that showed improvements in pre-defined end points after decompressive surgery.

In a randomized, double-blind, placebo-controlled parallel study, Weintraub et al (2009) examined if repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration.  Subjects (n = 225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 hrs/day to feet for 3 months.  Nerve conduction testing was performed serially.  Main outcome measures included pain reduction scores using a VAS, the Neuropathy Pain Scale (NPS), and the Patient's Global Impression of Change (PGIC).  A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification.  Subjects (n = 225) were randomized with a drop-out rate of 13.8 %.  There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44 % versus 31 %; p = 0.04).  There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS.  A total of 27 subjects completed serial biopsies; 29 % of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (p= 0.04).  Increases in distal thigh ENFD were significantly correlated with decreases in pain scores.  The authors concluded that PEMF at this dosimetry was non-effective in reducing NP.  However neurobiological effects on ENFD, PGIC and reduced itching scores suggested that future studies are indicated with higher dosimetry (3000 to 5000 G), longer duration of exposure, and larger biopsy cohort.

The American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Physical Medicine & Rehabilitation, and the AAN's evidence-based guideline on the treatment of painful DN (Bril et al, 2011) stated that pregabalin is established as effective and should be offered for relief of painful DN (Level A).  Amitriptyline, capsaicin, duloxetine, gabapentin, isosorbide dinitrate spray, opioids (e.g., morphine sulfate, and tramadol), valproate, and venlafaxine are probably effective and should be considered for the treatment of painful DN (Level B).  Percutaneous electrical nerve stimulation should be considered for the treatment of painful DN (Level B).  The recommended duration for electrical stimulation is 3 to 4 weeks.

Ites et al (2011) evaluated the effectiveness of interventions used by physical therapists to minimize balance dysfunction in people with DPN.  Currently, no systematic review exists that explores the effectiveness of these interventions.  When conducting this systematic review, these investigators searched the electronic databases CINAHL, EMBASE, Cochrane Review, and Medline using specific search terms for the period from inception of each database to June 2009.  Two independent reviewers analyzed the abstracts obtained to determine whether the article focused on balance interventions that are within the scope of physical therapy practice.  All study designs were eligible for review with the exception of case reports and systematic reviews.  The Delphi criteria was used to assess methodological quality.  This literature search and methods assessment resulted in 2,213 titles, 82 abstracts, and 6 articles, including 1 randomized controlled trial eligible for inclusion.  The 6 articles contained 4 physical therapy interventions including monochromatic infrared energy therapy, vibrating insoles, lower extremity strengthening exercises, and use of a cane.  Upon thorough analysis of outcome measures, statistical significance, and clinical relevance, the intervention of lower extremity strengthening exercises was given a fair recommendation for clinical use in treating balance dysfunction in patients with DPN.  All others had insufficient evidence to either support or refute their effect on balance in this population.

In a randomized, placebo-controlled, double-blind study, Mahoney et al (2012) examined if topical 5 % ketamine cream is effective in reducing the pain of DN.  A total of 17 diabetic patients completed the study.  The Michigan Neuropathy Screening Instrument was used to determine whether the neuropathy was likely caused by the diabetic condition.  Hemoglobin A(1c) levels were measured before treatment.  Patients applied 1 ml of either ketamine cream or placebo cream for 1 month.  The intensity of 7 different pain characteristics was evaluated before and after treatment.  A 2-way repeated analysis of variance design was used to test for differences between treatments and within patients (time).  These investigators found no significant treatment main effect, but pain improved significantly over time in both groups.  There was no statistical interaction effect (treatment × time) in any of the pain characteristics, indicating that pain improved in the 2 treatment groups similarly with time.  The authors concluded that the 5% topical ketamine cream was no more effective than placebo in relieving pain caused by DN.

In a Cochrane review, Hearn et al (2012) evaluated the analgesic efficacy and adverse effects of lacosamide in the management of chronic neuropathic pain or fibromyalgia.  These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register (2011, Issue 4), CENTRAL (2011, Issue 3), MEDLINE (January 2000 to August 2011) and EMBASE (2000 to August 2011) without language restriction, together with reference lists of retrieved papers and reviews.  They included randomized, double-blind studies of 8-week duration or longer, comparing lacosamide with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.  Two review authors independently extracted data for efficacy and adverse events and examined issues of study quality, including risk of bias assessments.  Where possible, they calculated numbers needed-to-treat to benefit from dichotomous data for effectiveness, adverse events and study withdrawals.  They included 6 studies -- 5 (1,863 participants) in painful DN (PDN) and 1 (159 participants) in fibromyalgia.  All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose.  Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to impart major bias where, as here, adverse event withdrawal rates were high.  This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low-quality, with moderate-quality evidence available for some efficacy outcomes for 400 mg lacosamide.  There were too few data for analysis of the 200-mg dose for painful diabetic neuropathy or any dose for fibromyalgia.  In painful DN, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30 % and at least 50 % reduction from baseline in patient-reported pain, respectively) and the patient global impression of change outcome of "much or very much improved".  In each case the extra proportion benefiting above placebo was about 10 %, yielding numbers needed-to-treat to benefit compared with placebo of 10 to 12.  For lacosamide 600 mg, there was no consistent benefit over placebo.  There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response.  The number needed-to-treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600-mg dose.  The authors concluded that lacosamide has limited efficacy in the treatment of peripheral DN.  Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals.  Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant over-estimation of treatment efficacy can result.  It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.

Peripheral nerve blocks (PNBs) entail the injection of corticosteroids, local anesthetics, neurolytic agents and/or sclerosing agents into or near peripheral nerves resulting in the temporary interruption of conduction of impulses in peripheral nerves or nerve trunks (somatic and sympathetic nerves).  Peripheral nerve blocks can either be “single-injection” -- refers to one-time injection of local anesthetic to the target nerve for peri-operative analgesia and/or surgical anesthesia, or “continuous” -- refers to the percutaneous insertion of a catheter directly adjacent to the target peripheral nerve(s).  The latter approach is to provide prolonged nerve block by continuous infusion of local anesthetic for longer procedures, as well as post-operative analgesia.  Continuous PNB (cPNB) is primarily used for inpatient procedures, but can also be used in outpatients (Jeng and Rosenblatt, 2012).

The American Academy of Neurology (AAN), American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation (Bril et al, 2011) developed a scientifically sound and clinically relevant evidence-based guideline for the treatment of PDN.  The basic question that was asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and QOL in patients with PDN"?  A systematic review of literature from 1960 to August 2008 was performed, and studies were classified according to the AAN classification of evidence scheme for a therapeutic article.  Recommendations were linked to the strength of the evidence.  The results indicated that pregabalin is established as effective and should be offered for relief of PDN (Level A).  Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B).  Other treatments have less robust evidence, or the evidence is negative.  Effective treatments for PDN are available, but many have side effects that limit their usefulness.  Few studies have sufficient information on their effects on function and quality of life (QOL).

The South African Expert Panel’s clinical practice guidelines for management of neuropathic pain (Chetty et al, 2012) stated that neuropathic pain (NeuP) is challenging to diagnose and manage, despite ongoing improved understanding of the underlying mechanisms.  Many patients do not respond satisfactorily to existing treatments.  There are no published guidelines for diagnosis or management of NeuP in South Africa.  A multi-disciplinary expert panel critically reviewed available evidence to provide consensus recommendations for diagnosis and management of NeuP in South Africa.  Following accurate diagnosis of NeuP, pregabalin, gabapentin, low-dose TCAs (e.g., amitriptyline) and SSRIs (e.g., duloxetine and venlafaxine) are all recommended as first-line options for the treatment of peripheral NeuP.  If the response is insufficient after 2 to 4 weeks, the recommended next step is to switch to a different class, or combine different classes of agent.  Opioids should be reserved for use later in the treatment pathway, if switching drugs and combination therapy fails.  For central NeuP, pregabalin or amitriptyline are recommended as first-line agents.  Companion treatments (e.g., cognitive behavioral therapy and physical therapy) should be administered as part of a multi-disciplinary approach.  Dorsal root entry zone rhizotomy (DREZ) is not recommended to treat NeuP. 

In an evidence-based guideline on “Neuropathic pain interventional treatments”, Mailis and Taenzer (2012) states that “Based on limited evidence that selective transforaminal nerve root blocks (extraforaminal root injections, periradicular steroid injections, intraforaminal oxygen-ozone injections and epidural perineural autologous conditioned serum injections can provide up to 8 to 12 weeks of relief from lumbar radicular pain, the task force cannot justify a general recommendation, but suggests that these interventions be used with caution depending on the circumstances, with full disclosure to the patient of the limited evidence and potential risks.  Evidence quality: Fair; Certainty: Moderate; Strength of recommendation: Grade C (May recommend depending on circumstances.  At least moderate certainty with small net benefit).

Furthermore, UpToDate reviews on “Treatment of diabetic neuropathy” (Feldman and McCulloch, 2012), “Overview of lower extremity peripheral nerve syndromes” (Rutkove, 2012), and “Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated peripheral neuropathy” (Nardin and Freeman, 2012) do not mention the use of PNBs.

Stein and colleagues (2013) evaluated the effect of treatment with electrical stimulation and electromagnetic fields on pain and sensitivity in patients with painful diabetic neuropathy compared with placebo or another intervention.  These investigators searched the following electronic databases (from inception to April 2012): MEDLINE (accessed by PubMed), LILACS, Physiotherapy Evidence Database (PEDro), EMBASE and Cochrane CENTRAL.  They included randomized trials that compared electrical stimulation or electromagnetic fields with control groups in which the objective was to assess pain and sensitivity in patients with PDN.  Two reviewers independently extracted the data.  A random-effects model was used for the main analysis.  The search retrieved 1,336 articles, of which 12 studies were included.  Reductions in the mean pain score were significantly greater in the TENS (transcutaneous electrical nerve stimulation) group than in the placebo group [-0.44 (95 % confidence interval [CI]: -0.79 to -0.09; I2: 0 %)].  There was no improvement in pain relief when electromagnetic fields were compared with the control group [-0.69 (95 % CI: -1.86 to 0.48; I2: 63 %)].  The authors concluded that TENS improved pain relief in patients with diabetic neuropathy, while no such improvement was observed with the use of electromagnetic field treatment.  Due to the methodological differences between the studies, a meta-analysis for the outcome of sensitivity could not be performed.

Chen and colleagues (2013) performed a systematic review to evaluate the potential benefits and harms of manual acupuncture for DPN to justify its clinical use.  These investigators searched for published and unpublished randomized controlled trials of manual acupuncture for DPN till March 31, 2013.  Revman 5.2 software was used for data analysis with effect estimate presented as RR and mean difference (MD) with a 95 % CI.  A total of 25 trials involving 1,649 participants were included.  The methodological quality of included trials was generally poor.  Meta-analysis showed that manual acupuncture had better effect on global symptom improvement compared with mecobalamin (RR 1.31, 95 % CI: 1.21 to 1.42), vitamin B1 and B12 (RR 1.55, 95 % CI: 1.33 to 1.80), and no treatment (RR 1.56, 95 % CI: 1.31 to 1.85), and that the combination of manual acupuncture and mecobalamin had better effect compared with mecobalamin alone on global symptom improvement (RR 1.56, 95 % CI: 1.28 to 1.90).  Adverse events were not reported in any trials.  The asymmetric funnel plot suggested publication bias.  The authors concluded that despite the number of trials of manual acupuncture for DPN and their uniformly positive results, no clinically relevant conclusions can be drawn from this review due to the trials' high risks of bias and the possibility of publication bias.  They stated that clearly defined and internationally acknowledged outcome measures are needed for future study.  They noted that there remains an urgent need for training Chinese researchers in conducting unbiased trials as well as prospectively registering all initiated Chinese trials to avoid publication bias.

An UpToDate review on “Treatment of diabetic neuropathy” (Feldman and McCulloch, 2014) does not mention combinational electrochemical therapy/treatment (CET) as a therapeutic option.

In a phase II, double-blind, placebo-controlled trial, Wang et al (2014) evaluated the safety and effectiveness of fulranumab, a fully human monoclonal antibody against nerve growth factor (NGF), in patients with diabetic peripheral neuropathic pain (DPNP).  Patients with moderate-to-severe DPNP were randomized to treatments with fulranumab (1, 3, or 10 mg) or placebo administered subcutaneously every 4 weeks.  Because of early study termination (clinical hold) by the U.S. Food and Drug Administration (FDA), 77 (intent-to-treat) of the planned 200 patients were enrolled.  The primary end-point, the mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided).  An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported greater than or equal to 30 % reduction in the average DPNP intensity compared with placebo at week 12 (p = 0.006).  Although not statistically significant, several secondary end-points showed directionally similar results to the primary efficacy dose-response relationship.  During the combined efficacy and safety extension phases, the top 3 treatment-emergent adverse events in the combined fulranumab group were arthralgia (11 %), peripheral edema (11 %), and diarrhea (9 %).  No cases of joint replacement or death were reported.  The authors concluded that despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well-tolerated.  The major drawback of this phase II study was its small sample size because of the FDA clinical hold.  Also, patients who discontinued the study were often lost to follow-up for safety.  Because of the small sample size, these researchers stated that they cannot conclude that there is no risk of joint destruction and/or osteonecrosis, which is a specific safety concern for the anti-NGF class.  Moreover, they stated that long-term trials involving more patients are needed to fully characterize the efficacy, safety, and tolerability of this potentially new class of analgesic drug for the treatment of DPNP.

Bannwarth and Kostine (2014) stated that it is unanimously accepted that there is an unmet need for pain medications that are both safe and effective.  Unfortunately, no really novel analgesics have been approved over the past 3 decades.  In view of both experimental and clinical evidence of a major role for NGF in the generation and maintenance of a wide range of pain states, drug discovery efforts focusing on the development of anti-NGF agents have aroused particular interest.  Several humanized anti-NGF monoclonal antibodies (mAbs) have entered clinical trials as potential analgesics.  In this respect, tanezumab is at an advanced stage of clinical development while fulranumab, fasinumab and ABT-110, previously known as PG110, are in early phases of clinical development.  This Current Opinion article aimed at describing the rationale for targeting NGF for pain, reviewing the analgesic safety and effectiveness of anti-NGF agents based on data from fully published studies, conference abstracts, and the FDA website, and discussing the possible future of these agents in managing chronic pain.  Anti-NGF mAbs produced significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip.  Conversely, studies in non-specific lower back pain generated mixed results; overall, this condition appeared to be less responsive to anti-NGF agents than osteoarthritis.  Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in some types of chronic visceral or neuropathic pain.  Furthermore, these studies raised safety concerns about anti-NGF mAbs.  As a class, these drugs may cause or worsen peripheral neuropathies.  But the most problematic issue -- which prompted the FDA to place studies of these compounds on clinical hold in 2010 -- was rapid joint destruction leading to joint replacement surgery.  The etiologies of these side effects have been much debated and their pathophysiology is poorly understood.  After an Arthritis Advisory Committee meeting held in March 2012, pharmaceutical companies negotiated with the FDA on the conditions for restarting clinical studies.  Although the FDA lifted its clinical hold, there remain many unresolved issues about the long-term safety and effectiveness of anti-NGF mAbs.  The authors concluded that while acknowledging that the future of these drugs is unforeseeable, it appears that they may not be the safe and effective painkillers that have been awaited for decades.

Electro-analgesia treatment (EAT) refers to the combination of nerve block therapy and electrical stimulation.  However, there is a lack of evidence regarding its clinical effectiveness for the treatment of DN.

Slangen et al (2014) stated that painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus.  Unfortunately, pharmacological treatment is often partially effective or accompanied by unacceptable side effects, and new treatments are urgently needed.  Small observational studies suggested that spinal cord stimulation (SCS) may have positive effects.  These researchers performed a multi-center randomized clinical trial (RCT) in 36 PDPN patients with severe lower limb pain not responding to conventional therapy: 22 patients were randomly assigned to SCS in combination with the best medical treatment (BMT) (SCS group) and 14 to BMT only (BMT group).  The SCS system was implanted only if trial stimulation was successful.  Treatment success was defined as greater than or equal to 50 % pain relief during daytime or nighttime or "(very) much improved" for pain and sleep on the patient global impression of change (PGIC) scale at 6 months.  Trial stimulation was successful in 77 % of the SCS patients.  Treatment success was observed in 59 % of the SCS and in 7 % of the BMT patients (p < 0.01).  Pain relief during daytime and during nighttime was reported by 41 % and 36 % in the SCS group and 0 % and 7 % in the BMT group, respectively (p < 0.05).  Pain and sleep were "(very) much improved" in 55 % and 36 % in the SCS group, whereas no changes were seen in the BMT group, respectively (p < 0.001 and p < 0.05).  One SCS patient died because of a subdural hematoma.  The authors concluded that treatment success was shown in 59 % of patients with PDPN who were treated with SCS over a 6-month period, although this treatment is not without risks.

An UpToDate review on “Treatment of diabetic neuropathy” (Feldman and McCulloch, 2015) states that “Spinal cord stimulation -- Spinal cord stimulation is an invasive method involving implantable electrodes that deliver electrical stimulation to the dorsal columns of the spinal cord.  Preliminary data from a small open-label trial suggest that spinal cord stimulation reduces pain for patients with refractory painful diabetic neuropathy affecting the legs.  Further trials are needed to confirm the efficacy of this approach …. Non-glycemic interventions (e.g., multi-factorial risk factor reduction and aldose reductase inhibitors) are under investigation for treating or preventing diabetic neuropathy”.   In addition, this review does not mention electroanalgesia/nerve block as a therapeutic option.

Intiso and associates (2015) stated that the management of neuropathic pain (NP) is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits.  Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people.  Although type A BTX (BTX-A) is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP.  The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization.  Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment.  These investigators addressed the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and PDPN, which are commonly managed in a rehabilitation setting.  Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia.  The authors concluded that the use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective.  However, they stated that large and well-designed RCTs are needed to recommend BTX-A use in the relief of neuropathic pain.

Lakhan and co-workers (2015) noted that recent studies showed a promising analgesic effect using BTX-A for NP.  These investigators performed a meta-analysis of 2studies using BTX-A in the treatment of NP.  Electronic searches of MEDLINE/PubMed, EMBASE, and Cochrane Libraries using the terms "botulinum neurotoxin" and "neuropathic pain" were conducted.  Only class I and class II therapeutic trials, as classified by the AAN were included.  The primary outcome measured was the difference in VAS from pre-intervention and post-intervention after 1 month.  Data were analyzed for biases and heterogeneity following Cochrane and PRISMA guidelines.  Two studies on PDN were analyzed in the meta-analysis showing improvement of 1.96 VAS points (95 % CI: -3.09 to -0.84; Z score = 3.43, p < 0.001) following treatment with BTX-A.  This corresponded to clinically significant improvement of "minimum change in pain".  The adverse effects of infection at injection site was not statistically significant (p = 0.49); BTX-A may be effective for PDN.  The authors concluded that tests for significance, low overall risk of bias, and almost no statistical heterogeneity suggested that there is a correlation between BTX-A and improvement of pain scores in PDN.  Moreover, they stated that further large-scale RCTs are needed.

Ozone Therapy

In a Cochrane review , Liu and colleagues (2015) evaluated the effects of ozone therapy on the healing of foot ulcers in people with diabetes mellitus (DM). In March 2015, these investigators searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), Ovid Medline, Ovid Medline (In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL, Science Citation Index, Chinese Biomedical Literature Database and The Chinese Clinical Registry.  There were no restrictions based on language, date or study setting.  They included RCTs that compared ozone therapy with sham ozone therapy or any other interventions for foot ulcers in people with DM, irrespective of publication date or language.  Two reviewers independently screened all retrieved citations, selected relevant citations and extracted data.  Disagreements were resolved by discussion with a 3rd reviewer.  The methodological quality of included studies and the evidence level of outcomes were assessed using the Cochrane risk of bias tool and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, respectively.  Data were expressed using RR for dichotomous outcomes and MD for continuous outcomes with their 95 % CI.  Review Manager (RevMan) software was used to analyze the data.  A total of 3 studies (212 participants) were included in this review.  The overall risk of bias was high for 2 trials and unclear for 1.  One trial (101 participants) compared ozone treatment with antibiotics for foot ulcers in people with DM.  The study had a follow-up period of 20 days.  This study showed that ozone treatment was associated with a greater reduction in ulcer area from baseline to the end of the study than treatment with antibiotics (MD -20.54 cm(2), 95 % CI: -20.61 to -20.47), and a shorter duration of hospitalization (MD -8.00 days, 95 % CI: -14.17 to -1.83), but did not appear to affect the number of ulcers healed over 20 days (RR 1.10, 95 % CI: 0.87 to 1.40).  No side effects were observed in either group.  The other 2 trials (111 participants) compared ozone treatment plus usual care with usual care for foot ulcers in people with DM.  The meta-analysis results did not show evidence of a difference between groups for the outcomes of reduction of ulcer area (MD -2.11 cm(2), 95 % CI: -5.29 to 1.07), the number of ulcers healed (RR 1.69, 95 % CI: 0.90 to 3.17), adverse events (RR 2.27, 95 % CI: 0.48 to 10.79), or amputation rate (RR 2.73, 95 % CI: 0.12 to 64.42).  The authors concluded that the available evidence was 3 small RCTs with unclear methodology, so they were unable to draw any firm conclusions regarding the effectiveness of ozone therapy for foot ulcers in people with DM.

Spinal Cord Stimulation

Tajti and associates (2016) noted that PDN is a disabling pain condition. Its etiology remains unknown, but a sensitization and neuronal hyperexcitabilty have been suggested.  Only symptomatic pharmacological pain management treatment is currently available.  The origin of PDN is enigmatic, and the evidence-based therapeutic guidelines therefore consist only of anti-depressants and anti-epileptics as 1st-line recommended drugs.  The results of the meta-analysis from the aspect of the effectiveness of amitriptyline, duloxetine, venlafaxine, gabapentin and pregabalin are favorable, but the placebo response rate was relatively high in patients with neuropathic pain.  For personalization of the medication of PDN patients, the optimum dosing, the genotyping of the metabolizing enzymes and optimum biomarkers are needed.  Regarding the future perspectives, specific sodium channel subtype inhibitors acting on peripheral nociceptive neurons or modified T-type voltage-gated calcium channel blockers may be promising targets for pharmaceutical innovations.  Another attractive strategy for the treatment is based on the effects of monoclonal antibodies against nerve growth factor, sodium channels, specific receptor and cytokines.  The authors also stated that botulinum toxin A, capsaicin patch and spinal cord stimulation therapies are the nearest future therapeutic options for the treatment of PDN patients.

Ghrelin

Ueno and colleagues (2017) stated that DPN is the most common complication of diabetes, and its progression significantly worsens the patient's QOL.  Although several drugs are available for DPN, all of these provide only symptomatic relief.  These investigators examined the therapeutic effects of ghrelin for DPN, based on its various physiological functions.  A total of 7 patients with type-2 DM (T2DM) with typical clinical signs and symptoms of DPN were hospitalized.  Synthetic human ghrelin (1.0 μg/kg) was administered intravenously for 14 days.  Motor nerve conduction velocity (MCV) of the posterior tibial nerve improved significantly after the treatment, compared to that at baseline (35.1 ± 1.8 to 38.6 ± 1.8 m/s, p < 0.0001), while the MCV in 6 untreated patients did not change throughout hospitalization.  The subjective symptoms assessed based on the total symptom score also significantly improved (15.6 ± 3.1 to 11.1 ± 2.2, p = 0.047).  Although sensory nerve conduction velocity (SCV) of the sural nerve could not be detected in 3 patients at baseline, it was detected in 2 of the 3 patients after 14 days of ghrelin administration; overall, SCV did not change significantly.  Plasma glucose, but not serum C peptide, levels during a liquid meal tolerance test significantly improved after treatment.  The authors concluded that these findings suggested that ghrelin may be a novel therapeutic option for DPN; however, a double-blind, placebo-controlled trial is needed to examine the effect of ghrelin on DPN as well as its underlying mechanisms.

Interleukin-6

Cox and colleagues (2017) noted that DPN remains one of the most common and serious complications of diabetes.  Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need.  Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration.  IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multi-functional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion.  IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to baseline levels within 4 hours.  Importantly, this kinetic profile is in stark contrast to long-term IL-6 elevation that is associated with pro-inflammatory states.  Given exercise induces IL-6 myokine signaling, and exercise has been shown to elicit numerous beneficial effects for the treatment of DPN, a causal link has been suggested.  These researchers discussed both the clinical and pre-clinical evidence related to the application of IL-6 as a therapeutic strategy for DPN.  In addition, they discussed how IL-6 may directly modulate Schwann and nerve cells to explore a mechanistic understanding of how this treatment elicits a neuro-protective and/or regenerative response.  The authors concluded that  available evidence suggested that IL-6, when administered in a low-dose pulsatile strategy to mimic the body's natural response to exercise, may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN.  They stated that this review provided rationale for continued investigation of IL-6 as a therapeutic option for DPN.

Monochromatic Infrared Phototherapy

Robinson and colleagues (2017) stated that monochromatic infrared energy (MIRE) or phototherapy has been employed to improve plantar sensitivity and pain in lower limbs of patients with diabetic sensorimotor peripheral neuropathy (DSPN), but the available primary results are inconsistent.  These investigators reviewed the effects of MIRE on plantar sensitivity and neuropathic pain in patients with DSPN.  Medline, Embase, Cochrane CENTRAL, and Google Scholar were searched up to September 2016; RCTs addressing the effects of MIRE on plantar sensitivity and neuropathic pain in patients with DSPN were selected.  Study inclusion, risk of bias and quality assessment, and data extraction were completed by 2 independent reviewers.  Of 2,549 records identified, 6 studies met the selection criteria, with 304 patients (594 feet) randomized; MIRE was not associated with improvement in plantar tactile sensitivity (standard mean difference [SMD] = 0.22, 95 % CI: -0.07 to 0.51, low quality of evidence).  Subgroups of studies with short-term (up to 2 weeks) follow-up showed significant improvement in plantar sensitivity (SMD = 0.41, 95 % CI: 0.18 to 0.64).  Neuropathic pain increased significantly in patients who received MIRE (MD = 0.49, 95 % CI: 0.30 to 0.68, low quality of evidence).  The authors concluded that there was limited evidence that MIRE results in short-term improvement of tactile sensitivity probably not sustained over time.  Limited evidence also suggested that MIRE does not provide relief for neuropathic pain.  They stated that as quality of evidence is low, further studies are likely to change the estimated effect.

Plantar Electrical Stimulation

Najafi and colleagues (2017) examined the effectiveness of plantar electrical-stimulation therapy to enhance motor-performance among patients with DPN.  Using a double-blinded model, 28 volunteers with DPN (age of 57.8 ± 10.2 years) were recruited and randomized to either intervention (IG: n = 17) or control (CG: n = 11) group.  Both groups received identical plantar-stimulation devices for 6 weeks of daily use at home; however, only the IG devices were set to deliver stimulation.  Balance (ankle, hip, and center of mass [COM] sway) and gait (stride velocity [SV], stride time [ST], stride length [SL], and cadence) were measured using validated wearable sensors.  Outcomes were assessed at baseline and at 6-week.  Clinical assessment including vascular as measured by ankle-brachial-index (ABI) and plantar-sensation as quantified by vibratory plantar threshold (VPT) were also measured at baseline and 6 weeks.  No difference were observed between groups for baseline characteristics (p > 0.050).  Post-therapy, ankle and COM sway with eyes open were significantly improved (p < 0.05, Cohen's effect size d = 0.67 to 0.76) in the IG with no noticeable changes in CG.  All gait parameters were significantly improved in the IG with highest effect size observed for cadence (d = 1.35, p = 0.000).  Results revealed improvement in VPT (p = 0.004, d = 1.15) with significant correlation with stride velocity improvement (r = 0.56, p = 0.037); ABI was improved in the IG in particulate among those with ABI greater than 1.20 (p = 0.041, d = 0.99).  The authors concluded that the findings of this study suggested that daily home use of plantar electrical-stimulation may be a practical means to enhance motor-performance and plantar-sensation in patients with DPN.

Tumor Necrosis Factor-Alpha Inhibitors

Mu and colleagues (2017) stated that tumor necrosis factor-alpha (TNF-α) is a cell signaling protein involved in systemic inflammation, and is also an important cytokine in the acute phase reaction.  Several studies suggested a possible association between TNF-α and DPN in T2DM patients, but no accurate conclusion was available.  These researchers performed a systematic review and meta-analysis of observational studies to evaluate the association between serum TNF-α levels and DPN in T2DM patients.  They searched PubMed, Web of Science, Embase, and China Biology Medicine (CMB) databases for eligible studies.  Study-specific data were combined using meta-analysis. A total of 14 studies were finally included into the meta-analysis, which involved 2,650 participants.  Meta-analysis showed that there were obviously increased serum TNF-α levels in DPN patients compared with T2DM patients without DPN (SMD = 1.203, 95 % CI: 0.795 to 1.611, p < 0.001).  There were also obviously increased levels of serum TNF-α in diabetic patients with DPN when compared with healthy controls (SMD = 2.364, 95 % CI: 1.333 to 3.394, p < 0.001).  In addition, there were increased serum TNF-α levels in painful DPN patients compared with painless DPN patients (SMD = 0.964, 95 % CI: 0.237 to 1.690, p = 0.009).  High level of serum TNF-α was significantly associated with increased risk of DPN in patients with T2DM (odds ratio [OR] = 2.594, 95 % CI: 1.182 to 5.500, p = 0.017).  Increased serum levels of TNF-α was not associated with increased risk of painful DPN in patients with T2DM (OR = 2.486, 95 % CI: 0.672 to 9.193, p = 0.172).  Sensitivity analysis showed that there was no obvious change in the pooled estimates when omitting single study by turns.  The authors concluded that T2DM patients with peripheral neuropathy have obviously increased serum TNF-α levels than T2DM patients without peripheral neuropathy and healthy controls, and high level of serum TNF-α may be associated with increased risk of peripheral neuropathy independently.  Moreover, they stated that further prospective cohort studies are needed to examine the association between TNF-α and DPN.

Autologous Bone Marrow-Derived Stem Cells (Including Bone Marrow-Derived Mesenchymal Stem/Stromal Cells)

Liu and co-workers (2017) stated that DN is one of the most common and serious complications of diabetes mellitus and metabolic syndrome.  The current therapy strategies, including glucose control and pain management, are not effective for most patients.  Growing evidence suggests that infiltration of inflammation factors and deficiency of local neurotrophic and angiogenic factors contribute significantly to the pathologies of DN.  Experimental and clinical studies have shown that bone marrow-derived stem cells (BMCs) therapy represents a novel and promising strategy for tissue repair through paracrine secretion of multiple cytokines, which has a potential to inhibit inflammation and promote angiogenesis and neurotrophy in DN.  These investigators discussed the clinical practice in DN and the therapeutic effect of BMC.  They subsequently illustrated the functional impairment of autologous BMCs due to the interrupted bone marrow niche in DN.  These researchers anticipated that the functional restoration of BMCs could improve their therapeutic effect and enable their wide applications in DN.  The authors concluded that as evidence grew on the safety of autologous BMC therapy in a number of clinical trials, the potential to translate this therapeutic strategy into a pilot clinical trial for DN is very promising.  However, several steps still need to be completed before that can be a reality.  First, the current knowledge of restoring the proper bone marrow niche micro-environment in patients with diabetes requires more investigation.  The modulation of bone marrow niche is vital to obtain the healthy candidate cells.  In addition, the isolated BMCs need to be functionally modified through genetic engineering and other strategies.

Evangelista and colleagues (2018) evaluated the therapeutic effects of bone marrow-derived mesenchymal stem/stromal cells (MSC) on spinal neuro-inflammation, as well as on ultra-structural aspects of the peripheral nerve in DN-associated sensorial dysfunction.  C57Bl/6 mice were treated with bone marrow-derived MSC (1 × 106), conditioned medium from MSC cultures (CM-MSC) or vehicle by endo-venous route following the onset of streptozotocin (STZ)-induced diabetes.  Paw mechanical and thermal nociceptive thresholds were evaluated by using von Frey filaments and Hargreaves test, respectively.  Morphological and morphometric analysis of the sciatic nerve was performed by light microscopy and transmission electron microscopy.  Mediators and markers of neuro-inflammation in the spinal cord were measured by radioimmunoassay, real-time PCR, and immunofluorescence analyses.  Diabetic mice presented behavioral signs of sensory neuropathy, mechanical allodynia, and heat hypoalgesia, which were completely reversed by a single administration of MSC or CM-MSC.  The ultra-structural analysis of the sciatic nerve showed that diabetic mice exhibited morphological and morphometric alterations, considered hallmarks of DN, such as degenerative changes in axons and myelin sheath, and reduced area and density of unmyelinated fibers.  In MSC-treated mice, these structural alterations were markedly less commonly observed and/or less pronounced.  Moreover, MSC transplantation inhibited multiple parameters of spinal neuro-inflammation found in diabetic mice, causing the reduction of activated astrocytes and microglia, oxidative stress signals, galectin-3, IL-1β, and TNF-α production.  Conversely, MSC increased the levels of anti-inflammatory cytokines, IL-10, and TGF-β.  The authors concluded that the present study described the modulatory effects of MSC on spinal cord neuro-inflammation in diabetic mice, suggesting new mechanisms by which MSC can improve DN.  These preliminary findings need to be further investigated in human subjects.

Xie and colleagues (2019) examined the therapeutic potential of stem cells from human exfoliated deciduous teeth (SHED) for DPN.  The biological characteristics of SHED were identified by flow cytometric study and evaluation of differentiation potential.  Using high-fat feeding, diabetes was induced in GK rats, and SHED were transplanted into the caudal veins of these rats.  Immunohistochemical analysis was used to compare the capillary to muscle fiber ratio and intra-epidermal nerve fiber density (IENFD) between SHED- and saline-treated diabetic rats.  Furthermore, the expressions of angiogenesis-related and neurotrophic factors were quantified by RT-PCR and Western blot.  SHED had a capacity of multiple differentiation and shared typical characteristics of mesenchymal stem cells.  SHED transplantation relieved diabetic neuropathic pain, enabled functional recovery of the peripheral nerves, and increased the capillary to muscle fiber ratio and IENFD compared to the saline group and normal controls.  Real-time PCR results showed that the expressions of CD31, vWF, bFGF, NGF, and NT-3 in the skeletal muscles were higher in the SHED group than in the saline groups.  Western blot results indicated that the levels of the CD31 and NGF proteins were higher in the SHED transplantation group than the saline group.  The authors concluded that SHED transplantation ameliorated DPN in diabetic GK rats.  Thus, systemic application of SHED could be a novel strategy for the treatment of DPN; and the mechanism of its therapeutic effects need to be further examined.  Moreover, these researchers stated that future investigation should compare intravenous injection, local injection, or a combination in order to identify the best therapeutic protocol.

Wang and associates (2019) examined if MSCs or resveratrol (RSV) may improve diabetic hyperglycemia and DN.  These investigators examined the combined effect of MSCs and RSV on DN.  A total of 100 non-obese diabetic mice were divided into the following 6 groups: Normal control, MSCs, RSV, MSCs + RSV, insulin and diabetic control groups.  Following homologous therapy, the levels of blood glucose and C-peptide, islets, nuclear factor (NF)-κB, nerve growth factor (NGF) and myelin basic protein (MBP), and the sciatic nerve structure in each group were examined and evaluated.  Following the administration of therapy, the levels of blood glucose and C-peptide in mice in the MSCs + RSV group were significantly improved when compared with the other diabetic groups, and the dosage of insulin therapy required was the lowest among the 6 experimental groups (p < 0.05).  The levels of NGF, MBP and NF-κB in the MSCs + RSV group were significantly improved compared with the MSCs and RSV groups (p < 0.05).  Furthermore, the diameter of the axon, number of myelinated nerve fibers and the depth of the myelin sheath in the MSCs + RSV group were greatest among the 5 examined groups (excluding the control).  The combination of RSV and MSCs could relieve hyperglycemia and improve DN. The authors concluded that the combination of RSV and MSCs may be a novel therapeutic method for the treatment of DN.

Mao and co-workers (2019) examined the safety and therapeutic effects of autologous bone marrow mononuclear cells (BMMNCs) transplantation on the treatment of refractory DPN.  A total of 168 patients with refractory DPN were recruited and enrolled in the study.  They received intra-muscular injection of BMMNCs and followed at 1, 3, 6, 12, 18, 24, and 36 months after the transplantation.  Clinical data, Toronto Clinical Scoring System (TCSS), and nerve conduction studies (NCSs) were compared before and after the transplantation.  The signs and symptoms of neuropathy were significantly improved after BMMNCs transplantation.  The values of the TCSS scores at 1 month (9.68 ± 2.49 versus 12.55 ± 2.19, p < 0.001) and 3 months (8.47 ± 2.39 versus 12.55 ± 2.19, p < 0.001) after the treatment reduced significantly compared with the baseline value.  This decrement remained persistent until the end of the study.  The conduction velocity and action potential and sensory nerves were significantly improved after transplantation (3 and 12 months after the treatment versus the baseline: motor nerve conduction velocity, 40.24 ± 2.80 and 41.00 ± 2.22 m/s versus 38.21 ± 2.28 m/s, p < 0.001; sensory nerve conduction velocity, 36.96 ± 2.26 and 39.15 ± 2.61 m/s versus 40.41 ± 2.22 m/s, p < 0.001; compound muscle action potential, 4.67 ± 1.05 and 5.50 ± 1.20 μV versus 5.68 ± 1.08 μV, p < 0.001; sensory nerve action potential, 4.29 ± 0.99 and 5.14 ± 1.26 μV versus 5.41 ± 1.14 μV, p < 0.001).  No adverse event (AEs) associated with the treatment was observed during the follow-up period.  The authors concluded that autologous transplantation of BMMNCs may be an effective and promising therapeutic strategy for the treatment of refractory DPN.

The authors stated that this study had several drawbacks. First, these researchers did not set up the control group and only analyzed the differences before and after BMMNCs transplantation.  This study only included patients with refractory DPN, as these patients did not respond to conventional therapies and autologous BMMNCs transplantation may be one of the very few promising therapeutic options.  To determine the efficacy of BMMNCs in patients with DPN, randomized, double-blind, controlled trials may be needed in the future.  Second, without measurements of inflammation and anti-inflammation cytokines, neurotrophic, and angiogenic factors, these investigators were unable to determine the potential mechanisms of BMMNCs in treating neuropathy symptoms.  This study could be strengthened if more analyses were performed.  These researchers stated that although further studies are needed to reveal the mechanism of BMMNCs in the treatment of DPN, they believed that this method provides a promising therapeutic option for patients with DPN.

Dorsal Root Ganglion Stimulation

Eldabe and colleagues (2018) presented a retrospective case series of patients with refractory painful diabetic peripheral neuropathy (PDPN) who underwent electrical stimulation of the dorsal root ganglion (DRG) and reported on changes in their overall perceived pain and complication rates.  A total of 10 diabetic men (mean age of 65.2 [SD 8.8] years) with painful symptoms of the lower limbs were enrolled and trialed with up to 4 quadri-polar percutaneous DRG stimulation leads between L2 and L5 spinal levels.  Patients received a fully implantable neuro-stimulation system (Abbott Laboratories, Sunnyvale, CA) immediately or after a successful trial period (greater than 50 % reduction in pain).  Overall perceived pain was measured by VAS at baseline, 1-week post-implantation and 1-, 3-, 6-, and 12-month follow-up (n = 5).  A total of 10 patients were included in this retrospective study; 7 of these subjects received permanent stimulator implants after successful externalized or intra-operative trials; 2 of those patients subsequently required explantation, due to failure to capture primary pain area (n = 1) and personal reasons (n = 1).  For the 5 subjects that proceeded to clinical follow-ups, baseline VAS was reduced by an average of 63.90 % (SD 21.39; p < 0.001) post-implantation.  For 4 patients with available 12-month follow-up data, mean relative reduction in overall perceived pain averaged 64.16 % (SD 35.8; p < 0.001).  The authors concluded that early findings from this small retrospective case series suggested that DRG was a safe and effective neuromodulation modality to improve painful symptoms in PDPN patients.  Moreover, they stated that future prospective trials are needed to further investigate the use of DRG stimulation for this clinical indication.

Secretoneurin

Theurl and associates (2018) noted that the pathogenesis of DN remains enigmatic.  Damage to the vasa nervorum may be responsible for this disorder.  Recently, these researchers showed that secretoneurin (SN) induced angiogenesis in hind-limb and myocardial ischemia.  Moreover, beneficial effects were observed in wound healing.  Thus, these investigators hypothesized that SN therapy may ameliorate DN.  They used db/db mice as animal model for neuropathy.  Gene therapy was accomplished by intra-muscular injection of SN plasmid along the sciatic nerve.  Sciatic nerve motor and sensory conduction velocities were then measured for 9 weeks.  Nerve conduction velocities showed normal values in heterozygous mice for the observational period, but were severely reduced in homozygous mice in which velocities were significantly improved by SN, but not by control plasmid gene therapy.  The reaction time in the tail-flick test improved significantly in SN-treated animals.  The induction of growth of vasa nervorum appeared to be part of the underlying mechanism.  In addition, SN positively affected Schwann cell function in-vitro and induced activation of important signaling pathways.  The authors concluded that these findings suggested that SN exerted beneficial effects on nerve function in-vivo and on Schwann cells in-vitro; it therefore may be a promising therapeutic option for DN.  These preliminary findings need to be further investigated in human subjects.

Moxibustion

Li and colleagues (2019) stated that the underlying protective mechanism of moxibustion against neuroinflammation remains unclear.  These researchers hypothesized that moxibustion treats diabetic peripheral neuropathy (DPN) by regulating the balance of nuclear factor-2 erythroid-related factor-2 (Nrf2)-nuclear factor-kappa light chain enhancer of B cells (NF-кB).  In-vivo, diabetes was induced in rats by injecting streptozotocin (STZ; 60 mg/kg; intra-peritoneal [i.p.]).  Moxibustion was then applied to "Zusanli" (ST 36), "Guanyuan" (BL 26), and "Yishu" (EX-B 3) acupuncture points.  Nerve conduction was detected.  Serum interleukin (IL)-1β, IL-6, and IL-8 levels were determined through enzyme-linked immunosorbent assay.  NF-κB and Nrf2 proteins were examined through immunoblot analysis.  The mRNA of NF-κB and Nrf2 was evaluated through real-time polymerase chain reaction (RT-PCR).  These researchers found that the conduction velocity and amplitude of the action potentials of sciatic nerve conduction were reduced in the DPN model group but were rescued by moxibustion treatment.  Moxibustion also improved the effect of DPN on other parameters, including ultrastructural changes, NF-κB and Nrf2 expression in the sciatic nerve, and serum IL-1β, IL-6, and IL-8 levels.  The authors concluded that these findings suggested that moxibustion may alleviate neuroinflammation by inhibiting NF-κB and by activating Nrf2; and moxibustion may also provide therapeutic effects for patients with DPN by simultaneously targeting Nrf2 and NF-κB.  These preliminary findings need to be validated by well-designed studies. 

Plantar Mechanical Stimulation

Kang and colleagues (2019) noted that people with DPN have impaired gait and balance performance.  These investigators examined the therapeutic effectiveness of mechanical stimulation through a wearable foot compression device equipped in a shoe insole on vibration perception, balance control and gait performance in people with DPN.  Using a single-arm 4-week intervention study design, these researchers examined effectiveness of daily use of shoes equipped with the foot compression device (Footbeat, AVEX, Grand Junction, CO) on improving vibration perception threshold (VPTmax), skin perfusion pressure (SPP), ankle brachial index (ABI), lower extremities edema (circumferences in the calf and ankle), and motor performance (postural sway with eyes open and closed conditions, and gait performance during normal, dual-task and fast walking).  A total of 30 people with type 2 diabetes and symptoms of PN completed the experimental protocol.  Improvements in VPTmax (before = 27.4 V, after = 23.3 V, p = 0.007, d = 0.33, where d denotes effect size), center-of-mass sway in the mediolateral direction with both eyes open and closed conditions (before = 0.94 cm, after = 0.76 cm, p = 0.020, d = 0.47; before = 1.10 cm, after = 0.83 cm, p = 0.033, d = 0.66, respectively), and stride velocity for normal walking, dual-task walking and fast walking tasks (before = 0.87 m/s, after = 0.96 m/s, p = 0.017, d = 0.41; before = 0.75 m/s, after = 0.91 m/s, p = 0.001, d = 0.77; before = 1.10 m/s, after = 1.20 m/s, p = 0.043, d = 0.33, respectively) were found post-treatment.  There was no significant improvement in SPP, ABI, and circumferences in the calf and ankle.  The authors concluded that these findings suggested the wearable foot compression device may be effective for reducing neuropathic symptoms and enhancing motor performances in people with DPN.

Mecobalamin, Alone or in Combination with Acupuncture

Sawangjit and associates (2020) noted that mecobalamin is an active form of vitamin B12 that has been suggested to be beneficial in improving nerve conduction and neuropathic pain symptoms.  Although it is already widely used in Asia for the treatment of peripheral neuropathies, its efficacy remains unclear.  In a systematic review, these researchers examined the safety and efficacy mecobalamin on peripheral neuropathy.  Relevant electronic data-bases were systematically searched for RCTs examining the safety and efficacy of mecobalamin on peripheral neuropathy, from inception through December 2019.  Study selection, data extraction, and quality assessment were performed independently by 2 reviewers.  The clinical therapeutic efficacy, pain score, neuropathic symptom score, nerve conduction velocities (NCVs), and AEs of mecobalamin were evaluated and were pooled by using a random-effects model.  Heterogeneity was assessed by I2 and Chi-square tests.  A total of 15 studies with 1,707 peripheral neuropathy patients caused by DPN and herpetic neuropathy were included.  Based on Cochrane's risk of bias criteria, most of the included studies (11/15, 73 %) were rated high risk of bias, whereas 20 % and 7 % were rated some concerns and low risk of bias, respectively.  In terms of the proportion of patients achieving clinical therapeutic efficacy, mecobalamin alone (RR = 1.17; 95 % CI: 1.03 to 1.33) and mecobalamin in combination (RR = 1.32; 95 % CI: 1.21 to 1.45) were more effective than active control.  For NCV outcomes, only mecobalamin combination treatment was effective.  Neither mecobalamin alone nor mecobalamin in combination was effective on the pain score and neuropathic symptom outcomes.  No serious AEs associated with mecobalamin were reported during the treatment periods.  The authors concluded that these findings indicated that mecobalamin in combination may be effective in improving clinical therapeutic efficacy and NCV outcomes for peripheral neuropathy patients; however, the evidence was unclear for mecobalamin alone.  These researchers stated that more high-quality studies are needed to confirm this finding.

Duan and colleagues (2020) stated that although previous studies have reported the effectiveness of acupuncture combined mecobalamin (AM) in the treatment of elderly DPN (EDPN), no systematic study has examined its safety and effectiveness.  These investigators noted that this study will examine the safety and effectiveness of AM for the treatment of patients with EDPN.  Bibliographic electronic data-bases will be searched as follows: Cochrane Library, PubMed, Embase, CINAHL, PsycINFO, WANGFANG, and China National Knowledge Infrastructure.  All of them will be searched from each data-base initial to March 1, 2020 without language restrictions.  All study selection, information extracted, and study quality evaluation will be performed by 2 independent authors.  Any disagreements between 2 authors will be resolved by a 3rd author via discussion.  RevMan 5.3 software will be used for data pooling and meta-analysis performance if it is possible.  This study will provide synthesis of current evidence of AM for patients with EDPN through primary outcome of glycemic profile, and secondary of NP intensity, plantar tactile sensitivity, sensory NCV and motor NCV, health-related QOL (HR-QOL), and AEs.  The authors concluded that this study is the 1st one to examine the safety and effectiveness of AM for the treatment of patient with EDPN systematically; and the findings of this study will provide helpful evidence for both clinical practice and future studies.

Photo-Biomodulation

M and colleagues (2020) stated that photo-biomodulation is an emerging therapy for the treatment of DPN of which the management is still a dilemma for clinicians.  Elevated neuron-specific enolase (NSE) is associated with neuropathy.  In a pilot study, these researchers examined the effect of low level laser therapy (LLLT) on serum NSE in T2DM patients with DPN.  Pre-post interventional study was carried out in 50 patients with DPN.  DPN was confirmed using 10-g mono-filament test, VPT and Michigan Neuropathy Screening Instrument.  All patients were provided with LLLT for 9 mins on dorsal and plantar of foot with a dosage of 3.1 J/cm 2 for 10 days.  A blood sample was collected at baseline and 4 weeks after LLLT for NSE estimation.  A significant reduction in serum NSE levels (0.006) after 4 weeks of laser therapy was observed in 42 patients when compared with baseline.  A significant reduction in the VPT (p = 0.003) and numeric pain rating scale (p = 0.004) were observed.  The authors concluded that in this pilot study, they examined the effect of LLLT on serum NSE levels among patients with DPN and showed improved QOL and reduction in serum NSE levels.  Moreover, these researchers stated that these findings should be examined in larger trials.

Pulsed Magnetic Field Treatment

In a rat model of experimental diabetes, Mert and colleagues (2020) examined the possible anti-neuropathic effects of daily pulsed magnetic field (PMF) treatments in streptozotocin-induced (60 mg/kg) 4 weeks diabetic (type-1) Wistar rats (6 to 8 months).  Body mass, blood glucose and thermal and mechanical sensations were evaluated during the PMF treatments or sham-PMF in diabetic or non-diabetic rats (n = 7/group).  After the measurements of motor NCV (MNCV), the levels of several biomarkers for oxidative stress, apoptosis and angiogenesis in spinal cord and sciatic nerve were measured.  Treatments with PMF for 4 weeks significantly recovered the MCNV (96.9 % and 63.9 %) and almost fully (100 %) restored to the latency and threshold.  Treatments with PMF also significantly suppressed the diabetes induced enhances in biochemical markers of both neuronal tissues.  The authors concluded that these findings suggested that PMF treatments might prevent the development of functional abnormalities in diabetic rats due to its anti-oxidative, anti-apoptotic and anti-angiogenic actions in neuronal tissues.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
64555	Percutaneous implantation of neurostimulator electrode array; peripheral nerve (excludes sacral nerve)
64565	Incision for implantation of neurostimulator electrodes; peripheral nerve (excludes sacral nerve) neuromuscular
CPT codes not covered for indications listed in the CPB:
Combination electrochemical therapy/treatment (CET), Secretoneurin, Moxibustion, Plantar Mechanical Stimulation - no specific code :
0552T	Low-level laser therapy, dynamic photonic and dynamic thermokinetic energies, provided by a physician or other qualified health care professional [photo-biomodulation]
38232	Bone marrow harvesting for transplantation; autologous.
38241	Hematopoietic progenitor cell (HPC); autologous transplantation.
63650	Percutaneous implantation of neurostimulator electrode array, epidural
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
63661	Removal of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63662	Removal of spinal neurostimulator electrode plate/paddle(s) placed via laminotomy or laminectomy, including fluoroscopy, when performed
63663	Revision including replacement, when performed, of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63664	Revision including replacement, when performed, of spinal neurostimulator electrode plate/paddle(s) placed via laminotomy or laminectomy, including fluoroscopy, when performed
63685	Insertion or replacement of spinal neurostimulator pulse generator or receiver, direct or inductive coupling
63688	Revision or removal of implanted spinal neurostimulator pulse generator or receiver
64400	Injection, anesthetic agent; trigeminal nerve, any division or branch
64402	Injection, anesthetic agent; facial nerve
64405	Injection, anesthetic agent; greater occipital nerve
64408	Injection, anesthetic agent; vagus nerve
64410	Injection, anesthetic agent; phrenic nerve
64413	Injection, anesthetic agent; cervical plexus
64415	Injection, anesthetic agent; brachial plexus, single
64416	Injection, anesthetic agent; brachial plexus, continuous infusion by catheter (including catheter placement)
64417	Injection, anesthetic agent; axillary nerve
64418	Injection, anesthetic agent; suprascapular nerve
64445	Injection, anesthetic agent; sciatic nerve, single
64446	Injection, anesthetic agent; sciatic nerve, continuous infusion by catheter (including catheter placement)
64447	Injection, anesthetic agent; femoral nerve, single
64448	Injection, anesthetic agent; femoral nerve, continuous infusion by catheter (including catheter placement)
64449	Injection, anesthetic agent; lumbar plexus, posterior approach, continuous infusion by catheter (including catheter placement)
64450	Injection, anesthetic agent; other peripheral nerve or branch
64454	Injection(s), anesthetic agent(s) and/or steroid; genicular nerve branches, including imaging guidance, when performed
64455	Injection(s), anesthetic agent and/or steroid, plantar common digital nerve(s) (eg, Morton's neuroma)
64505	Injection, anesthetic agent; sphenopalatine ganglion
64520	Injection, anesthetic agent; lumbar or thoracic (paravertebral sympathetic)
64624	Destruction by neurolytic agent, genicular nerve branches including imaging guidance, when performed
64702	Neuroplasty; digital, one or both, same digit
64704	nerve of hand or foot
64708	Neuroplasty, major peripheral nerve, arm or leg, open; other than specified
64712	sciatic nerve
64713	brachial plexus
64714	lumbar plexus
64716	Neuroplasty and/or transposition; cranial nerve (specify)
64718	ulnar nerve at elbow
64719	ulnar nerve at wrist
64721	median nerve at carpal tunnel
64722	Decompression; unspecified nerve(s) (specify)
64726	plantar digital nerve
97026	Application of a modality to 1 or more areas; infrared
97810 - 97814	Acupuncture
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
C1767	Generator, neurostimulator (implantable), nonrechargeable
C1778	Lead, neurostimulator (implantable)
C1787	Patient programmer, neurostimulator
C1816	Receiver and/or transmitter, neurostimulator (implantable)
C1820	Generator, neurostimulator (implantable), non high-frequency with rechargeable battery and charging system
C1822	Generator, neurostimulator (implantable), high frequency, with rechargeable battery and charging system
C1883	Adaptor/extension, pacing lead or neurostimulator lead (implantable)
E0745	Neuromuscular stimulator, electronic shock unit
L8680	Implantable neurostimulator electrode, each (not covered for spinal cord stimulation)
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8684	Radiofrequency transmitter (external) for use with implantable sacral root neurostimulator receiver for bowel and bladder management, replacement
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator, replacement only
L8695	External recharging system for battery (external) for use with implantable neurostimulator, replacement only
HCPCS codes not covered for indications listed in the CPB:
Fulranumab, Ozone Therapy, Ghrelin, Interleukin - 6, mecobalamin (a vitamin B12 analog), pulsed magnetic field treatment - no specific code:
A4639	Replacement pad for infrared heating pad system, each
C9254	Injection, lacosamide, 1 mg
E0221	Infrared heating pad system
G0283	Electrical stimulation (unattended), to one or more areas for indication(s) other than wound care, as part of a therapy plan of care
G0295	Electromagnetic therapy, to one or more areas, for wound care other than described in G0329 or for other uses
G0329	Electromagnetic therapy, to one or more areas for chronic stage III and stage IV pressure ulcers and venous stasis ulcers not demonstrating measurable signs of healing after 30 days of conventional care as part of a therapy plan of care
J0135	Injection, adalimumab, 20 mg
J0585	Injection, onabotulinumtoxinA, 1 unit,
J0586	Injection, abobotulinumtoxina, 5 units
J0587	Injection, rimabotulinumtoxinB, 100 units
J0588	Injection, incobotulinumtoxinA, 1 unit
J0717	Injection, certolizumab pegol, 1 mg
J0885	Injection, incobotulinumtoxinA, 1 unit
J0887	Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)
J0888	Injection, epoetin beta, 1 microgram, (for non-ESRD use)
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg, for intravenous use
J1745	Injection, infliximab, excludes biosimilar, 10 mg
Q4081	Injection, epoetin alfa, 100 units (for ESRD on dialysis)
Q5102	Injection, infliximab, biosimilar, 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
S8948	Application of modality (requiring constant provider attendance) to one or more areas; low-level laser; each 15 minutes
ICD-10 codes covered for indications listed in the CPB:
E08.40	Diabetes mellitus due to underlying condition with diabetic neuropathy, unspecified
E08.41	Diabetes mellitus due to underlying condition with diabetic mononeuropathy
E08.42	Diabetes mellitus due to underlying condition with diabetic polyneuropathy
E09.40	Drug or chemical induced diabetes mellitus with neurological complications with diabetic neuropathy unspecified
E09.41	Drug or chemical induced diabetes mellitus with neurological complications with diabetic mononeuropathy
E09.42	Drug or chemical induced diabetes mellitus with neurological complications with diabetic polyneuropathy
E10.40	Type 1 diabetes mellitus with diabetic neuropathy, unspecified
E10.41	Type 1 diabetes mellitus with diabetic mononeuropathy
E10.42	Type 1 diabetes mellitus with diabetic polyneuropathy
E11.40	Type 2 diabetes mellitus with diabetic neuropathy, unspecified
E11.41	Type 2 diabetes mellitus with diabetic mononeuropathy
E11.42	Type 2 diabetes mellitus with diabetic polyneuropathy
E13.40	Other specified diabetes mellitus with diabetic neuropathy, unspecified
E13.41	Other specified diabetes mellitus with diabetic mononeuropathy
E13.42	Other specified diabetes mellitus with diabetic polyneuropathy

The above policy is based on the following references: