Intradiscal Procedures
Number: 0602
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses intradiscal procedures.
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Experimental and Investigational
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Aetna considers thermal intradiscal procedures (TIPs) experimental and investigational for relief of discogenic pain or other indications because their effectiveness has not been established. Thermal intradiscal procedures are also known as:
- Annulo-nucleoplasty (The Disc-FX procedure)
- Cervical intradiscal radiofrequency lesioning
- Coblation percutaneous disc decompression
- Intradiscal biacuplasty (IDB)/intervertebral disc biacuplasty/cooled radiofrequency
- Intradiscal electrothermal annuloplasty (IEA)
- Intradiscal electrothermal therapy (IDET)
- Intradiscal pulsed radiofrequency for the treatment of discogenic neck pain
- Intradiscal thermal annuloplasty (IDTA)
- MR-guided percutaneous intradiscal thermotherapy (MRgPIT) for the treatment of lumbar degenerative disc disease (DDD)
- Nucleoplasty (also known as percutaneous radiofrequency thermomodulation or percutaneous plasma diskectomy)
- Percutaneous (or plasma) disc decompression (PDD)
- Percutaneous intradiscal radiofrequency thermocoagulation (PIRFT)/intradiscal radiofrequency thermomodulation/percutaneous radiofrequency thermomodulation
- Radiofrequency annuloplasty (RA)
- Targeted disc decompression (TDD).
Note: TIPs are also identified or labeled based on the name of the catheter/probe that is used (e.g., Accutherm, discTRODE, SpineCath, or TransDiscal electrodes).
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Aetna considers the following intradiscal procedures experimental and investigational because their effectiveness has not been established (not an all-inclusive list):
- Intradiscal glucocorticoid injection for the treatment of low back pain (LBP)
- Intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid for the treatment of discogenic LBP
- Intradiscal implantation of stromal vascular fraction plus platelet-rich plasma for the treatment of degenerative disc disease (DDD)
- Intradiscal infiltration with plasma rich in growth factors for the treatment of LBP
- Intradiscal injection of autologous bone marrow concentrate for the treatment of DDD
- Intradiscal injections of bone marrow aspirate for the treatment for discogenic LBP
- Intradiscal injection of chondroitin sulfate ABC endolyase (condoliase) for lumbar disc herniation
- Intradiscal injection of gelified ethanol (DiscoGel) for the treatment of cervical disc herniations, neck pain, and LBP
- Intradiscal injection of recombinant human growth and differentiation factor-5 for chronic LBP
- Intradiscal injection of hydrogel (GelStix) for the treatment of lumbar DDD
- Intradiscal injection of methylene blue for the treatment of LBP
- Intradiscal injection of platelet-rich plasma for discogenic LBP
- Intradiscal injection of tumor necrosis factor alpha inhibitors and growth factors for the treatment of disc inflammation and back pain
- Silk scaffolds
- Ultra-purified stem cells with an in situ-forming bioresorbable gel for enhancement of intervertebral disc regeneration.
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Policy Limitations and Exclusions
This policy addresses intradiscal electrothermal procedures only and should be distinguished from radiofrequency neuroablation, which is the destruction of nerves using heat.
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Related Policies
Background
Thermal Intradiscal Procedures
Electrothermal intradiscal therapies (also referred to as thermal intradiscal procedures [TIP]) are percutaneous spinal procedures that are designed to treat back pain utilizing heat that is applied to the disc or disc wall (annulus). Several techniques have been introduced.
The evolution of TIPs involved the use of electrical and radiofrequency energy to apply or create heat within the disc to treat discogenic pain. Percutaneous thermocoagulation intradiscal techniques involve the insertion and heating of a catheter/probe in the disc under fluoroscopic guidance (Urrutia et al, 2007). Derby et al (2008) stated, "The goals of thermal disc treatments are to remove unwanted tissue such as herniated discs, create a seal to limit expression of matrix components, shrink collagen tissue, and destroy nociceptors. Although intradiscal heating can be accomplished through a variety of means, including electrocautery, thermal cautery, laser, and radiofrequency energy (RFE), most current intradiscal thermal treatments are performed using RFE." A review of the current literature reveals that the mechanism of non-specific chronic low back pain, as well as the mechanism of action of the thermal intradiscal procedures remain uncertain. There are numerous catheters that have received 510(K) clearance from the FDA for use in thermal procedures. Some catheters have a specific indication for use in the intervertebral disc and many are indicated for the creation of heat lesions for the relief of pain.
Intradiscal electrothermal therapy (IDET), also known as intradiscal electrothermal annuloplasty (IDTA) or IEA, is a minimally invasive surgical procedure that uses a catheter and a flexible electrode that is inserted into the affected disc in order to heat the entire posterior edge of the annulus. This technique has been proposed for the treatment of lower back pain caused by internal disc disruption. IDET was designed to reduce pain via two mechanisms: heat-induced changes in the structure of the collagen within the disc and ablation of the nerve endings in the outer third of the annulus. The procedure is conducted using fluoroscopic guidance in which a heating element is inserted via a catheter into a disc. The disc is heated to 90 degrees Celsius for up to 20 minutes, which may result in the contraction and shrinkage of the fibers that comprise the disc wall. The procedure is suggested to be an alternative to spinal fusion surgery in which the disc is destroyed and the two vertebrae are fused together. An example of a device used for IDET includes, but may not be limited to, the SpineCATH Intradiscal Catheter.
Intradiscal electrothermal therapy is used to treat patients with chronic, nonspecific low back pain attributed to degenerative disc disease and who met the criteria for interbody fusion surgery. The IDET technique is commonly identified with the use of the SpineCath Intradiscal catheter. Original 510(k) clearance was obtained by Oratec Interventions, Inc., (Menlo Park, CA). In 2002 Oratec was acquired by Smith & Nephew. The targeted patients have no clinical or radiologic evidence of significant disc herniation or nerve root compression. The procedure involves placing a thermal catheter within an intervertebral disc via a 17-gauge introducer needle under fluoroscopic guidance and heating the tip to 90°C over 13 minutes and maintaining that temperature for 4 minutes. This thermal therapy is postulated to alleviate discogenic pain by shrinking collagen and denervating nerve endings in the disc annulus. Despite its use at various centers around the country, there are few published clinical studies that assess the efficacy of this procedure. Intradiscal electrothermal therapy would not directly treat sciatica and is not currently recommended by the manufacturer for patients with sciatica. Proponents believe that IDET works best when the painful disc has not collapsed more than 50 %.
However, because of the lack of prospective randomized controlled clinical trials with adequate follow up demonstrating the effectiveness of IDET, the procedure is considered experimental and investigational and is not covered. In addition, there are unresolved issues about the long-term effects of this treatment on the biomechanics of the disc. The disc is a viscoelastic structure and possesses various biomechanical properties that are necessary for proper spinal function. The heat of the probe denatures and alters the collagen within the disc, affecting the biomechanics of the disc. The long-term (after 2 to 5 years) maintenance of good results with IDET is also not known at this point in time. In an editorial accompanying a study reporting on the 2-year outcomes of IDET (Saal and Saal, 2002), Dr. Timothy S. Carey of the University of North Carolina School of Medicine, acknowledged that "patients who undergo IDET do significantly improve over a 2-year period of time." However, because the study did not include a comparison group, "we don't know whether (patients) are doing better or worse than if they would have had another procedure," he told Reuters Health on May 8, 2002. The bottom line, he said, is that more study is needed. "A randomized (comparison) trial is urgently needed before we expose patients to a technique that has not been (rigorously) evaluated," Carey said.
Percutaneous intradiscal radiofrequency thermocoagulation (PIRFT) is a similar technique to IDET. PIRFT, however, uses a radiofrequency probe that is placed into the center of the disc rather than around the annulus. The device is activated for 90 seconds at a temperature of 70 degrees Celsius. PIRFT does not ablate the disc material but instead alters the biomechanics of the disc or destroys nociceptive pain fibers. PIRFT is performed using the Radionics RF Disc Catheter System or the DiscTRODE.
One should note that positive results, similar to IDET, were reported in uncontrolled cohort studies of a similar procedure, percutaneous intradiscal radiofrequency thermocoagulation (PIRFT), also known as percutaneous radiofrequency thermomodulation. However, subsequently performed randomized controlled clinical studies demonstrated that PIRFT had no significant effect compared to placebo (Barendse et al, 2001). Azulay and colleagues (2008) assessed a technique for radiofrequency heating of the lumbar intervertebral disc by a needle placed into the nucleus pulposus. The method was tested in 17 patients according to the criteria used in previous intradiscal radiofrequency studies. Before and after treatment, disability was assessed by the Oswestry disability score. A pain reduction of at least 50 % was considered a success. Fifteen patients were responders at 1 month (88 %), 9 at 3 months (53 %), and 12 at 6 months (70.6 %). No complications were observed. The authors concluded that a new method of providing discal radiofrequency treatment for lower back pain had a substantial clinical benefit in 71 % of the observed patients. Moreover, they stated that a prospective study comparing this new method with placebo should be conducted to confirm these initial results.
The developers of this procedure have commented that long-term studies and randomized controlled clinical trials are needed to validate the effectiveness of IDET (Saal and Saal, 1999): "Further study is necessary to define the mechanism and reasons for clinical improvement. Placebo-controlled trials and histologic and biomechanical studies are needed to answer many of the remaining questions. Additional validation of these positive results in placebo-controlled randomized trials and studies that compare IDET with alternative treatments is needed. ... These positive results should be validated in placebo-controlled randomized trials and studies that compare IDET with alternative treatments."
In a patient information statement, the American Academy of Orthopedic Surgeons has commented on the need for prospective randomized controlled studies of IDET (AAOS, March 2002): "The long-term results of this procedure are still unknown. IDET was introduced in 1997 and case series without controls have reported encouraging results. However, these results need to be confirmed in prospective, randomized trials. Additionally, there is debate about how the procedure actually works."
An American Pain Society Bulletin concluded that "[c]learly, IDET is in its infancy and demands the scrutiny of prospective, double-blinded, placebo-controlled studies" (Arends, 2001). In a recent review, Barndes et al (2002) commented: "IDET is an innovative tool for the treatment of discogenic back pain. Initial reports suggest that IDET is effective in 60 to 70 % of patients with chronic discogenic low back pain who have not improved with a comprehensive non-operative program. Intradiscal electrothermal therapy is minimally invasive and has a low complication rate and therefore might offer advantages over surgery. However, the outcomes and cost of IDET have not been compared with those of fusion and chronic pain management. Validation of the initial reports of IDET in placebo-controlled randomized trials is needed."
Technology assessments from several state agencies have also emphasized the need for prospective randomized controlled clinical studies of IDET. A Minnesota Health Technology Advisory Committee Technology Assessment of IDET (2001) concluded: "While the initial data are promising, large randomized controlled trials are needed to determine safety, cost, effectiveness, and long-term outcome. Published research is limited and unrefined due to small sample size, poor study design, and lack of long-term data. Studies comparing IDET with other standard medical and surgical treatments are needed."
A technology assessment by the Institute for Clinical Systems Improvement (2002) concluded as follows: "There is no convincing evidence that shows the short or long-term clinical efficacy of this procedure. Only subjective outcomes from case series and one non-randomized trial have been reported. Blinded, randomized studies comparing the procedure to a placebo treatment or alternative treatments such as spinal fusion have not been done and are needed to develop any conclusion about efficacy of the procedure... The long-term effects of thermal coagulation of the disk are unknown at this time."
The State of Oregon Workman Compensation System (2001) reached similar conclusions regarding IDET: "IDET is a new procedure that is that is currently being promoted by some medical providers as an effective treatment for chronic low back pain. However, there is significant concern that this procedure has not undergone rigorous scientific investigation and therefore is experimental or unproven. There are no randomized studies of its effectiveness, no animal research regarding the long term effects of disc heating, and no evidence of long-term safety."
The Canadian Coordinating Office of Health Technology Assessment (2003) concluded that the available evidence for IDET is of "poor quality" and that "[t]he long-term safety and effectiveness of IDET, and whether patients will require retreatment to maintain pain relief, is not yet known." A structured evidence review conducted by the BlueCross BlueShield Association Technology Evaluation Center (2004) concluded: "The evidence does not permit conclusions as to whether percutaneous intradiscal radiofrequency thermocoagulation for chronic discogenic low back pain improves health outcomes or is as beneficial as established alternatives."
The California Technology Assessment Forum (CTAF) conducted a technology review (2003) of IDET and concluded that IDET with the Radionics Radiofrequency system and with the Oratec IDET system did not meet CTAF technology assessment criteria.
The National Institute for Clinical Excellence (2004) concluded that "[c]urrent evidence on the safety and efficacy of percutaneous intradiscal electrothermal therapy for lower back pain does not appear adequate" and that "[t]he natural history of this condition, the difficulty in assessing pain and the potential for a placebo effect all present problems when interpreting the evidence on this procedure."
At this time, this surgery is only done in the lumbar region. In the early stages of investigation, IDET appears promising; however, additional prospective, randomized controlled clinical studies are needed to compare efficacy against other intradiscal heating procedures, to determine the precise pathology most successfully treated by the procedure, and to assess the long-term outcomes of this procedure as compared to other more conventional therapies.
A Cochrane systematic review (Gibson, 2005) concluded that the effectiveness of IDET remained unproven.
The European Guidelines for the Management of Chronic Nonspecific Low Back Pain (Airaksinen et al. 2006) reported that the diagnosis of internal disc disruption was surrounded by controversy and that the effect of IDET was not well understood. The authors summarized the evidence as follows:- there is conflicting evidence that procedures aimed at reducing the nociceptive input from painful intervertebral discs using either intradiscal radiofrequency thermocoagulation or IDET, in patients with discogenic low back pain, are not more effective than sham treatments (level C); and
- there is limited evidence that radiofrequency lesioning of the ramus communicans is effective in reducing pain up to 4 months after treatment (level C).
The authors stated, "We cannot recommend the use of intradiscal radiofrequency, electrothermal coagulation or radiofrequency denervation of the rami communicans for the treatment of either nonspecific or "discogenic" low back pain."
ECRI (2007) determined that the evidence base for IEA for discogenic pain was rated low for quantity, quality, consistency and robustness. Adverse events for this technology were not well documented.
In a review on IDET for the treatment of chronic discogenic low back pain, Wetzel et al (2002) stated that the studies published so far suggest that the pain resulting from lumbar disc disease may be diminished by intradiscal electrothermal annuloplasty. All these studies project a positive therapeutic effect. However, all the studies suffer from the same methodologic flaws. A prospective cohort design or a non-randomized prospective design is used with a biased control. The authors stated that a randomized prospective study is needed. Additionally, more investigation into the basic science of the action of intradiscal electrothermal annuloplasty is required.
Pauza and colleagues (2004) from the East Texas Medical Center presented data from a randomized, double-blind, placebo-controlled trial evaluating the efficacy of IDET for the treatment of chronic discogenic low back pain with 6 month outcomes. The investigators reported significant improvement in the visual analog scale (VAS), 36-Item Short Form Health Survey (SF-36), Beck Depression Scale, Oswestry Low Back Pain Disability Questionnaire. The authors concluded, "Nonspecific factors associated with the procedure account for a proportion of the apparent efficacy of IDET, but its efficacy cannot be attributed wholly to a placebo effect. The results of this trial cannot be generalized to patients who do not fit the strict inclusion criteria." This is a small, short-term single-institutional study involving the private practice of a single investigator. Because of unanswered questions about the durability of results and generalization of these findings, this single study is not sufficient to draw conclusions about the effect of IDET on health outcomes.
Freeman et al (2005) reported on 57 patients who were randomized to either IDET (n = 38) or sham (n = 19). The objective of the study was to test the safety of IDET compared with sham treatment for low back pain of at least 3 months duration. Study participants were chosen from consecutive patients of 3 spine surgeons if they satisfied eligibility criteria. Randomization occurred after catheter placement via sealed envelope by an independent technician who was responsible to covertly connect the catheter if the patient was to receive active treatment. All subjects followed a common rehabilitation program. Patient evaluations occurred at 6 weeks and 6 months by an independent investigator. Outcomes measures were recorded at baseline and 6 months and included the VAS, low back pain outcome score (LBOS), Oswestry Disability Index (ODI), SF-36, Zung Depression index, the modified somatic perception questionnaire, sitting tolerance, work tolerance, medication, and the presence of any neurologic deficit. Success was defined a priori as a composite measure: no neurologic deficit resulting from the procedure, an improvement in the LBOS of 7 or more points, and an improvement in the SF-36 subscales of bodily pain and physical functioning of greater than 1 standard deviation from the mean. Sample size was calculated before the study and using a 2:1 allocation with 80 % power, 75 patients were required. The authors reported that no serious adverse events in either arm of the study occurred, without defining serious adverse events. The authors also reported, "Transient radiculopathy (less than 6 weeks) was reported in 4 study participants who underwent IDET and in 1 study participant who underwent the sham procedure." The authors concluded that IDET was no more effective than placebo for the treatment of chronic discogenic low back pain.
An assessment of IDET prepared for the Ohio Bureau of Workers' Compensation (2004) concluded that "[t]he more recent medical literature has not found outcomes as good as those previously reported regardless of the measure used in the study" and that "[a]dditional outcomes studies are needed."
Urrutia et al (2007) conducted a systematic review of the evidence of percutaneous thermocoagulation intradiscal techniques (IDET and PIRFT), which concluded that "available evidence does not support the efficacy or effectiveness of percutaneous thermocoagulation intradiscal techniques for the treatment of discogenic low back pain." The investigators reviewed available databases to identify non-randomized controlled trials and randomized controlled trials on these techniques. The investigators identified 6 studies that met inclusion criteria, involving a total of 283 patients. Two open, non-randomized trials (95 patients) showed positive results for IDET compared with rehabilitation and PIRFT. Results from 2 randomized controlled trials showed no differences between PIRFT and placebo, and between different PIRFT techniques. Two randomized controlled trials compared IDET to placebo. One suggested differences only in pain and disability, while the best quality randomized controlled trial showed no differences.
In a review of the evidence for non-surgical interventional therapies for low back pain (LBP) for the American Pain Society, Chou and colleagues (2009) concluded that there is good or fair evidence that PIRFT is not effective. These investigators also noted that there is insufficient (poor) evidence from randomized trials (conflicting trials, sparse and lower quality data, or no randomized trials) to reliably evaluate IDET and coblation Nucleoplasty.
Intradiscal biacuplasty (also referred to as simply "biacuplasty") is a newer minimally invasive intradiscal radiofrequency technique that is proposed as another treatment for back pain. This technique utilizes the Bialys TransDiscal System. During the procedure, two probes are inserted into each side of the disc. Internally circulated water-cooled radiofrequency energy is delivered between the two probes, which heats the area immediately around them and within the disc. As the RF energy heats the tissue, internally circulating water helps cool the tissue to prevent damaging nearby tissue.
Intradiscal biacuplasty (IDB) (Baylis Medical Inc., Montreal, Canada) is a new minimally invasive transdiscal radiofrequency technique for treatment of back pain. Intradiscal biacuplasty uses two internally water-cooled radiofrequency probes to lesion nociceptors in the intervertebral disc. The bilateral approach is intended to facilitate controlled lesioning between the electrodes in the disc. The Bialys TransDiscal System was cleared by the FDA based on a 510(k) premarket notification. Kapural and Mekhail (2007) reported the treatment of severe axial discogenic pain in a young man using IDB. The investigators reported that there were no intra- and post-operative complications, and significant improvements in patient functional capacity and pain scores were noted. At 6-month follow-up, visual analog scale pain scores decreased from 5 cm to 1 cm, Oswestry disability scores improved from 14 points (28 % or moderate disability) to 6 points (12 % or minimal disability) and SF-36-PF (physical function) score changed from 67 to 82. These findings need to be confirmed by well designed controlled clinical studies.
Kapural and colleagues (2008) stated that IDB is a novel bipolar cooled radiofrequency system for the treatment of degenerative disk disease. These researchers presented the results of a pilot trial with 6-month follow-up. A total of 15 patients, 22 to 55 years old, underwent 1- or 2-level IDB treatment of their painful lumbar discs. All had chronic LBP for greater than 6 months, back pain exceeding leg pain, concordant pain on provocative discography, disc height greater than 50 % of control, and evidence of 1- or 2-level degenerative disc disease (DDD) without evidence of additional changes on magnetic resonance imaging. Intra-discal biacuplasty was performed under fluoroscopy using 2 RF probes positioned bilaterally in the intervertebral disc. Thirteen patients completed follow-up questionnaires at 1, 3, and 6 months. Pain disability was evaluated with Oswestry and Short Form (SF)-36 questionnaires. Median VAS pain scores were reduced from 7 (95 % confidence interval [CI]: 6 to 8) to 4 (2 to 5) cm at 1 month, and remained at 3 (2 to 5) cm at 6 months. The Oswestry improved from 23.3 (SD 7.0) to 16.5 (6.8) points at 1 month and remained similar after 6 months. The SF-36 Physical Functioning scores improved from 51 (18) to 70 (16) points after 6 months, while the SF-36 Bodily Pain score improved from 38 (15) to 54 (23) points. Daily opioid use did not change significantly from baseline: from 40 (95 % CI: 40 to 120) before IDB to 5 (0 to 40) mg of morphine sulfate equivalent 6 months after IDB. No procedure-related complications were detected. The authors concluded that patients showed improvements in several pain assessment measures after undergoing IDB for discogenic pain. Moreover, they stated that a randomized controlled trial (RCT) is needed to address the effectiveness of the procedure.
Kapural et al (2010) reported the effects of intradiscal biacuplasty in the treatment of thoracic discogenic pain in 3 patients. No intra-operative and post-operative complications were reported. Improvements in functional capacity and pain scores were noted in 2 patients. Visual analog scale pain scores changed from 10 to 2 cm and 7 to 3 cm in 2 patients who claimed improvements at 12 months follow-up. In patient 1 VAS went from 7 to 8 cm claiming no improvements after the procedure. In patients 1 and 3, ODI improved from 24 to 8 and 10 points, respectively, and SF-36 physical function score changed from 55 to 80 and 45 to 82, respectively. Patient 2 showed no improvements with ODI (28 to 32) and SF-36 physical function score (50 to 45) at 12 months after intradiscal biacuplasty. Patient 1 stopped using his oxycodone/acetaminophen 5/325 mg that he used previously at 6 tablets a day, patient 3 decreased use of his duragesic patch from 75 microg/hr to 25 microg/hr. Patient 2 continued with significant use of opioids (100 microg/hr of transdermal fentanyl). The authors concluded that intradiscal biacuplasty may be an effective and readily available treatment for thoracic discogenic pain if future comparison studies show benefits of such procedure.
Kallewaard et al (2010) noted that various interventional treatment strategies for chronic discogenic LBP unresponsive to conservative care include reduction of inflammation, ablation of intradiscal nociceptors, lowering intra-nuclear pressure, removal of herniated nucleus, and radiofrequency ablation of the nociceptors. Unfortunately, most of these strategies do not meet the minimal criteria for a positive treatment advice. In particular, single-needle radiofrequency thermocoagulation of the discus is not recommended for patients with discogenic pain. Moreover, there is currently insufficient evidence to recommend intra-discal electrothermal therapy and intradiscal biacuplasty.
In a review on "Effectiveness of thermal annular procedures in treating discogenic low back pain", Helm et al (2012) stated that the evidence is fair for IDET and poor for discTRODE and biacuplasty procedures regarding whether they are effective in relieving discogenic LBP. Since 2 RCTs are in progress on that procedure, assessment of biacuplasty may change upon publication of those studies.
In a randomized, placebo-controlled trial, Kapural et al (2013) compared the effectiveness of IDB with that of placebo treatment for discogenic LBP. Subjects were randomized on a 1:1 basis to IDB and sham groups. Follow-ups were conducted at 1, 3, and 6 months. Subjects and coordinators were blinded to randomization until 6 months. Of the 1,894 subjects screened, 64 subjects were enrolled, and 59 were treated: 29 randomized to IDB and 30 to sham. All subjects had a history of chronic LBP for longer than 6 months. Two cooled RF electrodes placed in a bipolar manner in affected discs to lesion the nociceptive fibers of the annulus fibrosus. The sham procedure was identical to the active treatment except that probes were not directly inserted into the disc space, and RF energy was not actively delivered. The principal outcome measures were physical function, pain, disability, and opioid usage. Patients in the IDB group exhibited statistically significant improvements in physical function (p = 0.029), pain (p = 0.006), and disability (p = 0.037) at 6-month follow-up as compared to patients who received sham treatment. Treatment patients reported a reduction of 16 mg daily intake of opioids at 6 months; however, the results were not statistically different from sham patients. The authors concluded that these findings suggested that the clinical benefits observed in this study were the result of non-placebo treatment effects afforded by IDB; and IDB should be recommended to select the patients with chronic discogenic LBP. There were several drawbacks with this study:- lack of a formal assessment of blinding effectiveness,
- short follow-up period (6 months),
- small sample size (n = 29), and lack of difference in post-intervention daily opioid intake between treatment and control groups.
Furthermore, these investigators stated that additional studies are needed to ascertain the effectiveness of IDB as compared with other treatment modalities such as conservative therapy, other minimally invasive modalities or surgery.
Lu and colleagues (2014) carried out a systematic evaluation of the literature to examine current non-operative management for the treatment of discogenic LBP. PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for clinical studies evaluating non-operative methods of treating discogenic back pain that were published between 2000 to 2012. Only prospective RCTs that compared a non-surgical intervention with sham or placebo therapy were included. After removal of duplicate citations, a total of 226 articles were initially identified from the search terms. From these, these researchers identified 11 RCTs from which data analysis was performed. The 11 RCTs investigated traction therapy, injections and ablative techniques. Results from 5 RCTs investigating methylene blue injection, steroid injection, ramus communicans ablation, IDET and biacuplasty favored intervention over sham therapy. However, results from the study on methylene blue injections have not been replicated in other RCTs. Evaluation of the selection criteria utilized in the studies on ramus communicans ablation and intradiscal biacuplasty and a stratified analysis of results from the RCTs on IDET casted doubt on whether the conclusions from these RCTs can be applied to the general discogenic pain patient population. The authors concluded that there are few high quality studies evaluating non-operative treatments for reducing discogenic LBP. Moreover, they stated that although conclusions from several studies favor intervention over sham, it is unclear whether these interventions confer stable long-term benefit. There is some promise in newer modalities such as biacuplasty; however, more inclusive studies need to be performed.
In a feasiblity study, Dreyfuss and colleagues (2008) examined if single-site, long-duration intradiscal radiofrequency (RF) at 2 different positions could generate adequate heating throughout the intervertebral disc to potentially ablate intradiscal nociceptors. The disarticulated cervical spines from 4 fresh frozen cadavers were studied. Temperature recording was completed from 2 different positions of the RF needle. The needle was either placed in the middle of the disc in 4 discs, or it was inserted in the posterior quarter of the disc, in 8 discs. Thermocouple measurements were made every 2 mins from 3 positions:- middle of the disc,
- postero-lateral aspect of the disc, and
- in the anterior third of the disc.
Intradiscal RF lesioning was carried out in the middle and posterior portion of the cervical disc at 85 degrees C for 10 mins. Outcome measures included local temperature within the disc. Lesioning in either the middle or posterior portion of the disc failed to provide sufficient temperature increases throughout the cervical disc to achieve adequate denervation. The authors concluded that as in the lumbar spine, intradiscal cervical RF provides too focal a thermal profile to effectively denervate the disc even in an ex vivo experiment. Thus, single-site, long-duration cervical intradiscal RF lesioning in vivo can not be recommended.
The Centers for Medicare & Medicaid Services (CMS) has issued a national non-coverage determination for TIPs, after a review of the clinical evidence did not demonstrate that TIPs improved health outcomes. A decision memo on TIPs from the Centers for Medicare & Medicaid Services (2008) concluded, "For TIPs, the mechanisms of action remain theoretical. A thorough review of the empirical evidence on TIPs is adequate to demonstrate the lack of benefit to health outcomes from these procedures. Two randomized controlled trials provided evidence of no benefit to health outcomes and one randomized controlled trial failed to demonstrate confidence of any benefit to the Medicare population. The quality of many of the other studies is disappointing and the lack of sufficient documentation of adverse events and long term outcomes is disconcerting. Therefore, we propose that TIPs are not reasonable and necessary."
Targeted disc decompression (TDD) is a minimally invasive spinal procedure that uses thermal energy to treat herniated discs directly at the site of the actual herniation.A catheter is inserted into the disc and coiled inside it until the catheter lies directly adjacent to the disc herniation. The heat energy applied through the coil causes the disc to shrink, thereby reducing discal pressure. An example of a device used for this procedure is the Acutherm Decompression Catheter, which is used in conjunction with the Electrothermal 20S Spine System. Acutherm uses a shorter catheter than is utilized with IDET.
Disc nucleoplasty (also known as percutaneous radiofrequency thermomodulation, percutaneous plasma discectomy or plasma disc decompression [PDD]) is a minimally invasive procedure to treat individuals with symptomatic low back and leg pain caused by herniated discs. The procedure utilizes a device called the ArthroCare Perc-D SpineWand, which includes the Perc DLR (designed to be used in larger discs), the Perc DLG (used when longer access is needed) and the Perc DC (designed to be used in the cervical portion of the spine). The SpineWand is designed to relieve pressure on spinal nerves adjacent to the disc by removing disc material. This procedure relies on a patented technology referred to as Coblation, in which the SpineWand applies a high-frequency electric current directly to the saline medium inside the disc, generating a tightly focused field of highly energized molecules around the tip of the wand. These particles have sufficient energy to convert soft tissue within the disc into a gas at relatively low temperatures and this gas escapes through the wand. The wand is introduced into the intervertebral disc through a small needle, and is advanced and withdrawn across the diameter of the disc several times, alternately dissolving disc material and thermally coagulating the channels left behind after removal of tissue.
Nucleoplasty (also known as percutaneous radiofrequency thermomodulation or percutaneous plasma diskectomy) is a percutaneous method of decompressing herniated vertebral discs that uses radiofrequency energy (Coblation [ArthroCare Corp., Sunnyvale, CA]) for ablating soft tissue, and thermal energy for coagulating soft tissue, combining both approaches for partial disc removal.
Azzazi and colleagues (2011) evaluated the safety and clinical outcome of Nucleoplasty in well-selected cases. Coblation technology was used in 50 patients, who had radicular leg pain due to contained disc herniation or focal protrusion, from 2005 to 2008. Clinical outcome was assessed by the VAS and Oswestry Disability Index Questionnaire. Reduction in analgesic treatment was also recorded. The procedure was performed under local anesthesia. The mean VAS score decreased from 8.2 to 1.3 at the 1 year evaluation (p = 0.001). The Oswestry Disability Index Questionnaire decreased from 62.2 to 9.6 at the 1 year follow-up (p = 0.001). Analgesic consumption was reduced or stopped in 90 % of cases after 1 year. There was complete resolution of symptoms in 40 patients after 1 year. There were 4 patients who underwent conventional microdiscectomy. Five cases had post-operative discitis that cleared clinically and radiologically within 2 months without sequelae in 4 of them. One patient had to undergo operative instrumental fusion at the affected level. The authors concluded that Nucleoplasty does not require general anesthesia, offers less morbidity and shortens recovery time. Contained herniated disc or focal protrusion are the most important inclusion criteria. Hence this technique is a promising tool in well-selected cases.
Coblation ablates tissue via a low-temperature, molecular dissociation process to create small channels within the disc. While monitoring the patient, a series of channels are created by advancing a catheter (Perc-D Coblation Channeling Wand) into the disc while ablating tissue. After stopping at a pre-determined depth, the catheter is slowly withdrawn. On withdrawal, the channels are thermally treated, producing a zone of thermal coagulation. The catheter is then rotated clockwise, and another channel is created. Approximately 6 channels are created, depending on the desired amount of tissue reduction. The Nucleoplasty procedure is performed on an outpatient basis under local anesthesia and fluoroscopic guidance, with the patient in a lateral or prone position.
Nucleoplasty is designed to avoid the substantial thermal injury risks of Intradiscal Electrothermal Annuloplasty (IDET), because Nucleoplasty produces lower temperatures within the disc annulus. Data from ArthroCare using cadaveric models shows that IDET generates substantially higher tissue temperatures within the nucleus and superior endplates of the vertebral disc than the Nucleoplasty procedure. Increased temperatures play a detrimental role with respect to cartilaginous vertebral endplates and surrounding tissues.
An assessment by the National Institute for Clinical Excellence (2004) concluded: "Current evidence on the safety and efficacy of percutaneous disc decompression using Coblation for lower back pain does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research…. The lack of data makes it difficult to draw conclusions regarding the efficacy of the procedure. The lack of long-term and comparative data also makes it difficult to distinguish between the treatment effect and the natural history of the disease, as well as determine whether the benefits of this procedure are sustained beyond 12 months."
An assessment by the Washington State Department of Labor and Industries (2004) found that no randomized trials have been conducted to study the efficacy of nucleoplasty. The assessment concluded that, because only case series studies have been conducted to examine the efficacy of this procedure, it is considered investigational.
Marin (2005) stated that Nucleoplasty is a promising minimally invasive technique for the treatment of symptoms associated with contained herniated disc. However, randomized controlled studies are required to know with more precision the role of this procedure. Cohen and colleagues (2005) ascertained determine the treatment outcomes of 16 consecutive patients with lumbar radicular pain secondary to a herniated disc who underwent Nucleoplasty as their primary therapy. These investigators concluded that Nucleoplasty is not an effective long-term treatment for lumbar radiculopathy, either alone or with IDET.
A technology assessment by the California Technology Assessment Forum (CTAF, 2002) concluded that Nucleoplasty percutaneous disc decompression does not meet CTAF's assessment criteria.
An assessment of radiofrequency techniques (nucleoplasty, percutaneous thermocoagulation, and electrothermal annuloplasty) by the Institute for Clinical Effectiveness and Health Policy (Lopez et al, 2005) reached the following conclusions: "Radiofrequency techniques are new technologies and little information is published about them. The data come mostly from observational studies of poor-level evidence whose main limitation is lack of comparison against control groups treated using conventional strategies (analgesics and physical therapy). This limitation is particularly significant in pathologies such as low back pain which presents a high rate of spontaneous resolution. This makes it difficult to draw conclusions about the efficacy of the procedures and their mid and long term safety… The evidence currently available on the three techniques does not support the use of these procedures on routine basis beyond the research framework."
Marin (2005) stated that Nucleoplasty may be an effective minimally invasive technique for the treatment of symptoms associated with contained herniated disc. However, randomized controlled studies are needed to ascertain with more precision the role of this procedure.
Bhagia et al (2006) reported the short-term side effects and complications after percutaneous disc decompression utilizing Coblation technology (Nucleoplasty). Following institutional review board approval, consecutive patients who were to undergo percutaneous disc decompression using Nucleoplasty were prospectively enrolled. Patients were questioned pre-operatively, post-operatively, and 24 hours, 72 hours, 1 week, and 2 weeks post-procedure by an independent reviewer regarding 17 possible symptom complications, which included bowel or bladder symptoms, muscle spasm, new pain, numbness/tingling or weakness, fevers/chills, rash/pruritis, headaches, nausea/vomiting, bleeding, and needle insertion site soreness. Statistical analysis was performed using Wilcoxon's signed-rank test. A total of 53 patients enrolled, of whom 4 patients dropped out. Two patients had increased symptoms and opted for surgery. Two patients could not be contacted. The most common side effects at 24 hours post-procedure was soreness at the needle insertion site (76 %), new numbness and tingling (26 %), increased intensity of pre-procedure back pain (15 %), and new areas of back pain (15 %). At 2 weeks, no patient had soreness at the needle insertion site or new areas of back pain; however, new numbness and tingling was present in 15 % of patients. Two patients (4 %) had increased intensity of pre-procedure back pain. There were statistically significant reductions in visual analog scale (VAS) score for back pain and leg pain (p < 0.05). The authors concluded that based on this preliminary data, Nucleoplasty seems to be associated with short-term increased pain at the needle insertion site and increased pre-procedure back pain and tingling numbness but without other side effects.
In a prospective, non-randomized, longitudinal, cohort study, Gerszten et al (2006) assessed pain, functioning, and quality of life (QOL) in patients with radicular leg and back pain who underwent Nucleoplasty-based percutaneous disc decompression. A total of 67 patients (mean age of 41 years) with primarily radicular pain due to a contained disc herniation underwent Nucleoplasty-based decompression in an outpatient setting. Patients completed the Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey, EuroQol 5D (EQ5D), and a VAS for pain pre-operatively, and at 3 and 6 months after surgery. Post-operative QOL differences were assessed using the Wilcoxon signed-rank test. A surgical probe, the Perc-DLE SpineWand, was placed percutaneously into the disc after application of a local anesthetic or induction of general anesthesia to remove part of the disc (i.e., a percutaneous discectomy). Nucleoplasty-treated levels were L2 to L3 (1 case), L3 to L4 (5 cases), L4 to L5 (44 cases), and L5 - S1 (40 cases); there were 22 multiple treatment levels and 42 bilateral treatments. There were no infections or nerve root injuries associated with the procedure. Compared with pre-operative QOL, there was a statistically significant improvement in QOL at 3 months as measured using the SF-36 Physical Component Summary (PCS) scale (mean score improvement 4.4 [p = 0.014]), the EQ5D (mean score improvement 0.22 [p = 0.001]), and the VAS for pain (mean score improvement 0.13 [p = 0.021). Six-month results in 36 patients continued to reflect improvement as measured using the SF-36 PCS (mean score improvement 7.6 [p = 0.002]) and the EQ5D (mean score improvement 0.27 [p = 0.001]). The authors concluded that Nucleoplasty-based percutaneous disc decompression in patients with symptomatic contained disc herniations is safe and improves QOL as measured by the SF-36, EQ5D, and VAS for pain, 3 generic QOL outcome instruments. Nucleoplasty is an effective minimally invasive surgical treatment alternative in patients with symptomatic contained disc herniations. They noted that further follow-up evaluation is underway to determine the durability of QOL improvement after Nucleoplasty.
The National Institute for Health and Clinical Excellence's guideline on percutaneous disc decompression using coblation for LBP (2006) stated that "[c]urrent evidence suggests that there are no major safety concerns associated with the use of percutaneous disc decompression using coblation for lower back pain. There is some evidence of short-term efficacy; however, this is not sufficient to support the use of this procedure without special arrangements for consent and for audit or research....Further research will be useful in reducing the current uncertainty, and clinicians are encouraged to collect long-term follow-up data". The guideline also stated that the Specialist Advisors expressed uncertainty regarding the efficacy of this procedure.
In a retrospective, non-randomized case series, Yakovlev et al (2007) assessed the effect of Nucleoplasty on pain and opioid use in improving functional activity in patients with radicular or axial low back pain secondary to contained herniated discs. A total of 22 patients who had undergone Nucleoplasty were included in the analysis. Patients were evaluated at 1, 3, 6, and 12 months post-operatively, and were asked to quantify their pain using a VAS ranging from 0 to 10. Patients were also surveyed in regards to their pain medication use, and functional status was quantified by a physical therapist who also used patient reports of ability to perform activities of daily living to assess status. Data were compared between baseline and at 1, 3, 6, and 12 months post-treatment. Reported pain and medication use were significantly decreased and functional status was improved at 1, 3, 6, and 12 months following Nucleoplasty (p values less than or equal to 0.0010 for all outcome measures at all time periods). There were no complications associated with the procedure and continued improvements were observed over time. The authors concluded that Nucleoplasty appears to be safe and effective; however, they noted that randomized, controlled studies are needed to further evaluate its long-term effectiveness.
Calisaneller and colleagues (2007) examined the early post-operative radiological changes after lumbar Nucleoplasty and evaluated the short-term effects of this procedure on discogenic LBP and leg pain. A total of 29 patients between the ages of 32 and 59 years (mean of 44.14) were included in the study. Visual analog scale scores of patients were recorded in the pre-operative period and 24 hours, 3 months and 6 months after the procedure. Additionally, pre-operative and post-operative lumbar magnetic resonance imaging (MRI) examinations of these patients were compared. The mean pre-operative VAS score was 6.95 (range of 3.0 to 10.0) and the mean post-operative VAS scores at 24 hours, 3 months and 6 months were 2.46 (range of 0 to 8.0), 4.0 (range of 0 to 10.0) and 4.53 (range of 0 to 10.0), respectively. There were statistically significant reductions (p < 0.001) in VAS scores for all post-operative time points when compared to pre-operative values. Nucleoplasty did not produce obvious changes at least on the early post-operative MRI examination. The authors concluded that although Nucleoplasty appeared to be a safe minimally invasive procedure, the value of this new technique for the treatment of discogenic LBP remains as yet unproven. They stated that further RCTs with longer follow-up are needed to elucidate the effects of Nucleoplasty on discogenic LBP and leg pain.
Freeman and Mehdian (2008) stated that over the past 10 years, there has been a surge of minimally invasive techniques aimed at treating both discogenic LBP and radicular pain. These investigators evaluated the current evidence for 3 such treatments:- IDET,
- percutaneous discectomy, and
- Nucleoplasty.
An electronic search of the literature was performed using the Cochrane Library database (2007) and Medline (1966 to 2007); 77 references relating to IDET, 363 to percutaneous discectomy, and 36 to Nucleoplasty were identified. Two RCTs assessed the effectiveness of IDET; 1 demonstrated a positive effect on pain severity only, whereas the other reported no substantial benefit. Trials of automated percutaneous discectomy suggested that clinical outcomes after treatment are at best fair and often worse when compared with microdiscectomy. Other RCTs reported that Nucleoplasty is ineffective for the treatment of discogenic LBP.
In a systematic review, Gerges et al (2010) examined the clinical effectiveness of the Nucleoplasty procedure for treating back pain from symptomatic, contained disc herniation and to evaluate the methodological quality of the included studies. The relevant literature for Nucleoplasty was identified through a search of the following databases: PubMed, Ovid Medline, and the Cochrane library, and by a review of the bibliographies of the included studies. A review of the literature of the effectiveness of the Nucleoplasty procedure for managing discogenic pain was performed according to the criteria for observational studies using a "Quality Index" scale to determine the methodological quality of the literature. The level of evidence was classified as Level I, II, or III based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF) for therapeutic interventions. Recommendations were based on the criteria developed by Guyatt et al. The main outcome measures evaluated were the percentage of pain relief based on VAS or numeric rating scale (NRS), percentage of patients with more than 50 % reduction in pain, percentage of patients meeting one or more success criteria after Nucleoplasty, and improvement in patient function. Secondary measures noted were reports of complications and the Quality Index scores of each study that was evaluated. The quality of evidence for improvement in pain or function after a Nucleoplasty procedure is Level II-3. The recommendation is 1C/strong for the Nucleoplasty procedure based on the quality of evidence available. The median Quality Index score was 16 (range of 12 to 19), indicating adequate methodological quality of the available literature. None of the studies reported major complications related to Nucleoplasty. The authors concluded that observational studies suggest that Nucleoplasty is a potentially effective minimally invasive treatment for patients with symptomatic disc herniations who are refractory to conservative therapy. The recommendation is a level 1C, strongly supporting the therapeutic efficacy of this procedure. However, the authors stated that prospective, RCTs with higher quality of evidence are needed to confirm effectiveness and risks, and to determine ideal patient selection for this procedure.
Zhu et al (2011) evaluated longer-term efficacy over a 2-year follow-up of coblation Nucleoplasty treatment for protruded lumbar intervertebral disc. A total of 42 cases of protruded lumbar intervertebral disc treated by coblation Nucleoplasty followed-up for 2 years were analyzed. Relief of LBP, leg pain and numbness after the operation were assessed by VAS. Function of lower limb and daily living of patients were evaluated by the ODI. Operations were performed successfully in all cases. Three patients had recurrence within a week of the procedure. Evaluation of the 42 patients demonstrated significant improvement rate of VAS: defined as 66.2 % in back pain, 68.1 % in leg pain, and 85.7 % in numbness at 1-week after the operation; 53.2 %, 58.4 %, 81.0 % at 1-year; and 45.5 %, 50.7 %, 75.0 % at 2-year follow-up. One week after the operation, obvious amelioration occurred in all the patients, but the tendency decreased. Before operation, the mean value of ODI was 68.2 +/- 10.9 %. The value at 1 week was 28.6 +/- 8.2 %; 1-year at 35.8 +/- 6.5 %; and 2-years at 39.4 +/- 5.8 %. The authors concluded that coblation Nucleoplasty may have satisfactory clinical outcomes for treatment of protruded lumbar intervertebral disc for as long as 2-year follow-up, but longer-term benefit still needs verification.
In a narrative review, Helm et al (2009) evaluated the effectiveness of thermal annular procedures (TAPs) in reducing LBP in patients with intradiscal disorders. The literature was evaluated according to Cochrane Review criteria for RCTs and according to the Agency for Healthcare Research and Quality (AHRQ) criteria for observational studies. The level of evidence was classified as Level I, II, or III based on the quality of evidence developed by the USPSTF. Pain relief was the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, and return to work. Short-term effectiveness was defined as 1-year or less and long-term effectiveness was defined as greater than 1-year. Systematic review of IDET identified 2 RCTs and 16 observational studies with an indicated evidence of Level II-2. Systematic review of radiofrequency annuloplasty identified no RCTs but 2 observational studies with an uncertain evidence of Level II-3. Systematic review of IDB identified 1 pilot study. The level of evidence is lacking with Level III. The authors concluded that IDET offers functionally significant relief in approximately 50 % of appropriately chosen chronic discogenic LBP patients. The authors found minimal evidence supporting the use of radiofrequency annuloplasty and IDB. A critique of this systematic evidence review by the Centre for Review and Dissemination (2010) noted that the results were mainly extracted from observational studies in settings where the studied procedure was performed routinely; hence there was a bias risk in favor of the procedure (this limitation was acknowledged by the authors). The critique stated that the conclusions of this systematic evidence review were non-specific. The authors supported the use of thermal annular procedure in selected patients despite the fact that the level of evidence was low.
In a prospective, parallel, randomized and gender stratified, double-blind placebo-controlled study, Kvarstein et al (2009) evaluated the long-term effect and safety aspects of PIRFT with the discTRODE probe. A total of 20 patients with chronic LBP and a positive 1-level pressure-controlled provocation discography were randomized to either intra-annular PIRFT or intra-annular sham treatment. A blinded interim analysis was performed when 20 patients had been followed for 6 months. The 6-month analysis did not reveal any trend towards overall effect or difference between active and sham treatment for the primary endpoint: change in pain intensity (0 tp 10). The inclusion of patients was therefore discontinued. After 12 months, the overall reduction from baseline pain had reached statistical significance, but there was no significant difference between the groups. The functional outcome measures (ODI, and SF 36 subscales and the relative change in pain) appeared more promising, but did not reach statistical significance when compared with sham treatment. Two actively treated and 2 sham-treated patients reported increased pain levels, and in both groups a higher number was unemployed after 12 months. The study did not find evidence for a benefit of PIRFT, although it can not rule out a moderate effect. The authors stated that considering the high number, reporting increased pain in this study, they would not recommend intra-annular thermal therapy with the discTRODE probe.
In a prospective, multi-center, randomized, controlled trial, Gerszten and colleagues (2010) assessed clinical outcomes with percutaneous plasma disc decompression (PDD) as compared with standard care using fluoroscopy-guided trans-foraminal epidural steroid injection (TFESI) over the course of 2 years. A total of 90 patients (18 to 66 years old) who had sciatica (VAS score greater than or equal to 50) associated with a single-level lumbar contained disc herniation were enrolled. In all cases, their condition was refractory to initial conservative care and 1 epidural steroid injection had failed. Participants were randomly assigned to receive either PDD (n = 46) or TFESI (n = 44, up to 2 injections). Patients in the PDD group had significantly greater reduction in leg pain scores and significantly improved ODI and SF-36, physical function, bodily pain, social function, and physical components summary scores than those in the TFESI group. During the 2-year follow-up, 25 (56 %) of the patients in the PDD group and 11 (28 %) of those in the TFESI group remained free from having a secondary procedure following the study procedure (log-rank p = 0.02). A significantly higher percentage of patients in the PDD group showed minimum clinically important change in scores for leg and back pain and SF-36 scores that exceeded literature-based minimum clinically important changes. Procedure-related adverse events, including injection site pain, increased leg or back pain, weakness, and light-headedness, were observed in 5 patients in the PDD group (7 events) and 7 in the TFESI group (14 events). The authors concluded that in patients who had radicular pain associated with a contained lumbar disc herniation, PDD resulted in significantly reduced pain and better quality of life scores than repeated TFESI. In addition, significantly more PDD patients than TFESI patients avoided having to undergo a secondary procedure during the 2-year study follow-up. This study compared plasma disc decompression with trans-foraminal epidural steroid injection, which does not seem to be the same as accepted standard steroid epidural injections.
Helm et al (2012) evaluated the effectiveness of TAPs in treating discogenic LBP and assessed complications associated with those procedures. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria for interventional techniques for randomized trials, and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or poor based on the quality of evidence developed by the U.S. Preventive Services Task Force. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 through December 2011, and manual searches of the bibliographies of known primary and review articles. The primary outcome measure was pain relief of at least 6 months. Secondary outcome measures were improvements in functional status. For this systematic review, a total of 43 studies were identified. Of these, 3 RCTs and 1 observational study met the inclusion criteria. Using current criteria for successful outcomes, the evidence is fair for IDET and poor for discTRODE and biacuplasty procedures regarding whether they are effective in relieving discogenic LBP. Since 2 RCTs are in progress on that procedure, assessment of biacuplasty may change upon publication of those studies. The authors concluded that the evidence is fair for IDET and poor for discTRODE; and biacuplasty is being evaluated in 2 ongoing RCTs. The limitations of this systematic review included the paucity of literature and non-availability of 2RCTs which are in progress for biacuplasty.
Grewal et al (2012) stated that a variety of non-operative interventions are available to treat back pain. Careful assessment, discussion, and planning need to be performed to individualize care to each patient. These researchers discussed good to fair evidence from RCTs that injection therapy, PIRFT, IDET, and prolotherapy are not effective. Evidence is poor from RCTs regarding local injections, Botox, and Coblation nucleoplasty; however, with a focused approach, the right treatment can be provided for the right patient. The authors stated that to be more effective in management of back pain, further high-grade RCTs on safety and effectiveness are needed.
In a systematic review, Manchikanti et al (2013) examined the effectiveness of mechanical lumbar disc decompression with nucleoplasty. The available literature on mechanical lumbar disc decompression with nucleoplasty was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, and limited or poor based on the quality of evidence developed by the USPSTF. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to September 2012, and manual searches of the bibliographies of known primary and review articles. Pain relief and functional improvement were the primary outcome measures. Other outcome measures were improvement of psychological status, reduction in opioid intake, and return to work. Short-term effectiveness was defined as 1 year or less, whereas long-term effectiveness was defined as greater than 1 year. For this systematic review, a total of 37 studies were considered for inclusion. Of these, there was 1 randomized trial and 14 observational studies meeting inclusion criteria for methodological quality assessment. Based on USPSTF criteria, the level of evidence for nucleoplasty is limited to fair in managing radicular pain due to contained disc herniation. The authors concluded that this systematic review illustrated limited to fair evidence for nucleoplasty in managing radicular pain due to contained disc herniation. The main drawback of this review was a paucity of literature with randomized trials.
Ogbonnaya and colleagues (2013) evaluated the effectiveness of nucleoplasty in the management of discogenic radicular pain. The medical notes of 33 patients, admitted for nucleoplasty between June 2006 and September 2007, were reviewed retrospectively. All had radicular pain, and contained herniated disc as seen on MRI of lumbosacral spine. Patients were followed-up at 1 and 3 months post-procedure. The outcome measures employed in this study were satisfaction with symptoms and self-reported improvement. A total of 33 cases were examined (18 males and 15 females); 27 procedures were performed with no complications and 6 were abandoned due to anatomical reasons. There were 18 and 15 cases of disc herniation at L5/S1 and L4/5 levels, respectively. Four weeks following the procedure, 13 patients reported improvement in symptoms, and 14 remained symptomatically the same and subsequently had open microdiscectomy. The authors concluded that nucleoplasty has been shown to be a safe and minimal-access procedure. Less than 50 % of the authors’ selected cohort of patients reported symptomatic improvement at 1-month follow-up. The authors noted that they no longer offer this procedure to their patients.
Ren et al (2015) evaluated the effectiveness of percutaneous nucleoplasty using coblation technique for the treatment of chronic non-specific LBP, after 5 years of follow-up. From September 2004 to November 2006, 172 patients underwent percutaneous nucleoplasty for chronic LBP in the authors’ department; 41 patients were followed-up for a mean period of 67 months. Nucleoplasty was performed at L3/L4 in 1 patient; L4/L5 in 25 patients; L5/S1 in 2 patients; L3/L4 and L4/5 in 2 patients; L4/L5 and L5/S1 in 7 patients; and L3/L4, L4/L5, and L5/S1 in 4 patients. Patients were assessed pre-operatively and at 1 week, 1 year, 3 years, and 5 years post-operatively. Pain was graded using a 10-cm VAS and the percentage reduction in pain score was calculated at each post-operative time-point. The ODI was used to assess disability-related to lumbar spine degeneration, and patient satisfaction was assessed using the modified MacNab criteria. There were significant differences among the pre-operative, 1-week post-operative, and 3-year post-operative VAS and ODI scores, but not between the 3- and 5-year post-operative scores. There were no significant differences in age, sex, or pre-operative symptoms between patients with effective and ineffective treatment, but there were significant differences in the number of levels treated, Pfirrmann grade of intervertebral disc degeneration, and provocative discography findings between these 2 groups. Excellent or good patient satisfaction was achieved in 87.9 % of patients after 1 week, 72.4 % after 1 year, 67.7 % after 3 years, and 63.4 % at the last follow-up. The authors concluded that although previously published short- and medium-term outcomes after percutaneous nucleoplasty appeared to be satisfactory, the long-term follow-up results showed a significant decline in patient satisfaction over time.
In a prospective, randomized, cross-over, multi-center trial , Desai et al (2016) compared the effectiveness of IDB versus conventional medical management (CMM) in the treatment of lumbar discogenic pain. A total of 63 subjects with lumbar discogenic pain diagnosed via provocation discography were randomized to IDB + CMM (n = 29) or CMM-alone (n = 34). At 6-months patients in the CMM-alone group were eligible for cross-over if desired. The primary outcome measure was the change in VAS from baseline to 6-months. Secondary outcome measures included treatment "responders", defined as the proportion of subjects with a 2-point or 30 % decrease in VAS scores. Other secondary measures included changes from baseline to 6-months in:- short form (SF) 36-physical functioning (SF36-PF),
- ODI,
- Beck Depression Inventory (BDI),
- Patient Global Impression of Change (PGIC),
- EQ-5D VAS, and
- back pain-related medication usage.
In the IDB cohort the mean VAS score reduction exceeded that in the CMM cohort (-2.4 versus -0.56; p = 0.02), and the proportion of treatment responders was substantially greater (50 % versus 18 %). Differences in secondary measures favored IDB; no differences in opioid utilization were noted between groups. The authors concluded that superior performance of IDB with respect to all study outcomes suggested that it is a more effective treatment for discogenic pain than CMM-alone. (Level of Evidence: 2)
Streitparth and Disch (2015) stated that over the last decades a number of different minimally invasive interventions have been proposed for the treatment of intervertebral disc herniation and degeneration. All of these interventions aim at relieving pressure from compressed nerve roots by mechanical ablation, chemical dissolution, evaporation or coagulation of disc tissue. Standard treatment is microsurgical sequestrectomy with direct visualization of the spinal canal; while treatment innovations include minimally invasive intradiscal interventions (e.g., chemonucleolysis, manual and automated disc decompression, laser disc decompression, nucleoplasty and thermal anular RF techniques with posterolateral access to the intervertebral disc). In a literature review, these investigators compared the safety and effectiveness of the different minimally invasive procedures to the standard surgical procedure. For patients with disc herniation requiring surgery, microsurgical sequestrectomy is the treatment of choice, while discectomy is obsolete. The authors stated that intradiscal procedures have a low level of evidence while long-term results are still lacking; RCTs are needed to generate evidence-based results.
In a prospective cohort study, McCormick et al (2016) determined long-term outcomes of Dekompressor percutaneous laser disc decompression (PLDD) for discogenic radicular pain. Consecutive patients (12/2004 to 11/2005) with discogenic lumbosacral radicular pain who underwent PLDD with Dekompressor were included in this study; NRS leg pain score and ODI score data were collected at 6 months and 1 year. These 2 measures, 5-point Likert scale patient satisfaction, and surgical rate data were collected at 8 years. A total of 70 patients underwent PLDD; 40 and 25 patients were successfully contacted at 1-year and 8-year follow-up, respectively. Using intention-to-treat analysis, at 1 year and 8 years, NRS leg pain scores were reduced greater than 50 % in 47 % (95 % CI: 35 % to 59 %) and 29 % (95 % CI: 18 % to 40 %) of patients, respectively; ODI score improved greater than 30 % in 43 % (CI: 32 % to 55 %) and 26 % (CI: 19 % to 41 %) of patients, respectively. Of the patients who were followed-up at 8 years, 36 % (CI: 17 % to 55 %) had undergone surgery and the median satisfaction was "4" (interquartile range of 2 to 5). The authors concluded that while limited by loss-to-follow-up, the findings of this study suggested that treatment of discogenic lumbosacral radicular pain with Dekompressor resulted in decreased leg pain and disability and favorable satisfaction at long-term follow-up. Moreover, they stated that further study with adequate follow-up retention is needed to confirm that Dekompressor spares open spinal surgery.
Ong et al (2016) stated that open discectomy remains the standard of treatment for patients with lumbar radicular pain secondary to a prolapsed intervertebral disc. Open discectomy performed in patients with small, contained herniations may result in poor outcomes. The various techniques of PDD have been developed to address this population. These researchers performed a literature search on articles, which address PDD for lumbar radicular pain. Published techniques include chymopapain chemonucleolysis, PLDD, automated percutaneous lumbar discectomy (APLD), Dekompressor, nucleoplasty, and targeted disc decompression (TDD). In addition, the rationale of provocative discography, selective nerve root injections, and intra-op discograms before performing PDD was discussed in detail. Dekompressor and nucleoplasty have the best level of evidence with a score of 2B+. The chymopapain chemonucleolysis has the most publications, but it is also accompanied by the most significant adverse complications and so it is scored as a 2B+/-. The other techniques were supported mainly by observational studies and thus their scores range between 0 and 2B+/-. There was no supporting evidence for provocative discography in patients with lumbar radicular pain. The evidence for a positive selective nerve root injection as an inclusion criteria or the need for an intra-operative discogram showed mixed results. The authors concluded that nucleoplasty and Dekompressor have a weak positive recommendation for the treatment of patients with lumbar radicular pain. There is no role for provocative discography in this group of patients, although the evidence for a selective nerve root injection or an intra-operative discogram is inconclusive.
In a retrospective single-center study, Ceylan and Aşık (2019) assessed the efficacy of percutaneous decompression therapy by using intradiscal navigable electrodes on pain and functional movement index in patients with herniated nucleus pulposus (HNP). A total of 209 patients with protrusive lumbar disc herniation underwent percutaneous ablation decompression treatment using an intradiscal routable electrode (L-Disq) in the authors’ pain clinic; VAS and ODI scores were recorded at the beginning and at the 1st, 3rd, 6th, and 12th months following treatment. Patient satisfaction was evaluated at the 12th month by a patient satisfaction scale (PSS). When compared to initial values, VAS and ODI scores showed statistically significant improvement at the 1st, 3rd, 6th, and 12th months (p < 0.001). Mean VAS scores were 7.28 and 3.03 points (p < 0.001) while mean ODI scores were 32.46 and 20.48 points (p < 0.001) at the beginning and at the 12th month, respectively. Satisfaction rate of all patients was 81 %. These researchers also attempted to treat the existing annular fissure using an ablation method and they believed that treating the herniated disc together with the fissure in the same session increased the success rate. The authors suggested that L-Disq may be considered as an appropriate option with a low risk of complications in pain management in cases of lumbar disc herniation that were resistant to conservative methods. These investigators stated that the most important factors playing a role in these promising results were performance of the procedure by the same experienced physician, giving weight to appropriate patient selection, the advantage of the access technique especially at the L5 to S1 level, the navigable feature of the device, repairing the annular fissure together with the protruding disc, performing the procedure on a second level if detected on MRI, and performing regular follow-up after the procedure. The main drawbacks of this study were its retrospective design and its relative short-term follow-up (12 months).
In a retrospective, single-center study, Park and colleagues (2019) compared the therapeutic success of RF (an intradiscal procedure) and laser annuloplasty (both an intradiscal and extradiscal procedure). This trail included 80 patients and followed them for 6 months. Transforaminal laser annuloplasty (TFLA, 37 patients) or intradiscal RF annuloplasty (IDRA, 43 patients) was performed. The main outcomes included pain scores, determined by the NRS, and ODI, at pre-treatment and at post-treatment months 1 and 6. Participants were grouped according to procedure. In all procedures, NRS and ODI scores were significantly decreased over time. Mean post-treatment pain scores at months 1 and 6 were significantly lower (p < 0.01) in both groups, and between-group differences were not significant. The ODI score was also significantly decreased compared with baseline. Among patients undergoing TFLA, 70.3 % (n = 26) reported pain relief (NRS scores less than 50 % of baseline) at post-treatment 6 months, versus 58.1 % (n = 25) of those undergoing IDRA. There were no statistically significant differences between the groups in ODI reduction of greater than 40 %. The authors concluded that these findings indicated that annuloplasty was a reasonable therapeutic option for carefully selected patients with lower back and radicular pain of discogenic origin, and TFLA might be superior to IDRA in patients with discogenic LBP.
The authors noted that one limitation of this study was that the significant improvements in pain were not corroborated by any secondary outcomes. A second limitation was that the follow-up period was only 6 months, so there were no mid- or long-term follow-up results. A third limitation was that there was no post-procedure MRI. Furthermore, this study was retrospective.
Annulo-Nucleoplasty (The Disc-FX Procedure)
Kumar and colleagues (2014) stated that back pain due to lumbar disc disease is a major clinical problem. The treatment options range from physiotherapy to fusion surgery. A number of minimally invasive procedures have also been developed in the recent past for its management. Disc-FX is a new minimally invasive technique that combines percutaneous discectomy, nuclear ablation and annular modification. Literature on its role in the management of lumbar disc pathology is scarce. These researchers included 24 consecutive patients who underwent the Disc-FX for back pain due to lumbar disc pathology non-responsive to non-operative treatment for a period of at least 6 months. Based on MRI these patients fell into 2 groups:- those with DDD (n = 12) and
- those with a contained lumbar disc herniation (CLDH) (n = 12).
They were evaluated using the VAS, ODI and SF-36 scores pre-operatively and post-operatively. The mean age was 37.9 years (21 to 53 years). There were 17 males and 7 females; 1 patient in each subgroup was excluded from the final evaluation. Significant improvement was seen in all outcome measures. The overall rate of re-intervention for persistent symptoms was 18.18 % (4/22); in the CLDH subgroup, it was 36.36 % (4/11). The authors concluded that early results after the Disc-FX procedure suggested that it is a reasonable treatment option for patients with back pain due to lumbar disc disease, especially for those with DDD who fail conservative treatment. It could be an alternative to procedures like fusion or disc replacement. Moreover, they stated that this study presented level IV evidence; however, longer term prospective studies are needed to prove this and to evaluate its role in the treatment of patients with CLDH.
Intradiscal Procedures
Intradiscal Infiltration with Plasma Rich in Growth Factors for the Treatment of Low Back Pain
In a retrospective, observational, pilot study, Kirchner and Anitua (2016) examined the clinical outcome of plasma rich in growth factors (PRGF-Endoret) infiltrations (1 intradiscal, 1 intra-articular facet, and 1 transforaminal epidural injection) under fluoroscopic guidance-control in patients with chronic LBP. Patients with a history of chronic LBP and DDD of the lumbar spine who met inclusion and exclusion criteria were recruited between December 2010 and January 2012. One intradiscal, 1 intra-articular facet, and 1 transforaminal epidural injection of PRGF-Endoret under fluoroscopic guidance-control were performed in 86 patients with chronic LBP in the operating theater setting. Descriptive statistics were performed using absolute and relative frequency distributions for qualitative variables and mean values and standard deviations for quantitative variables. The non-parametric Friedman statistical test was used to determine the possible differences between baseline and different follow-up time-points on pain reduction after treatment. Pain assessment was determined using a VAS at the 1st visit before (baseline) and after the procedure at 1, 3, and 6 months. The pain reduction after the PRGF-Endoret injections showed a statistically significant drop from 8.4 ± 1.1 before the treatment to 4 ± 2.6, 1.7 ± 2.3, and 0.8 ± 1.7 at 1, 3, and 6 months after the treatment, respectively, with respect to all the time evaluations (p < 0.0001) except for the pain reduction between the 3rd and 6th month whose significance was lower (p < 0.05). The analysis of the VAS over time showed that at the end-point of the study (6 months), 91 % of patients showed an excellent score, 8.1 % showed a moderate improvement, and 1.2 % were in the inefficient score. The authors concluded that fluoroscopy-guided infiltrations of intervertebral discs and facet joints with PRGF in patients with chronic LBP resulted in significant pain reduction assessed by VAS.
This study had several drawbacks:- the absence of a control (placebo) group,
- these investigators did not perform a previous diagnostic block for patients’ selection, and therefore the diagnosis and selection of patients relied on a careful clinical examination,
- the lack of measurement of physical activity levels before and after the treatment, and
- to limit the bias of a single assessment, the self-reported VAS pain scale should have been associated with other health survey questionnaires that encompass pain and functional evaluation.
The authors stated that taking into account of the afore-mentioned drawbacks and in the light of these preliminary data, they stated that a RCT is considered imperative.
Monfett and colleagues (2016) provided an overview of clinical and translational research on intradiscal platelet-rich plasma (PRP) as a minimally invasive treatment for discogenic LBP. These investigators performed a literature review of in-vitro, in-vivo, and clinical studies. They noted that there is strong in-vitro evidence that supports the use of intradiscal PRP for discogenic LBP. There are also promising findings in select pre-clinical animal studies. A clinical study of 29 participants who underwent intradiscal PRP injections for discogenic LBP found statistically and clinically significant improvements in pain and function through 2 years of follow-up. The authors concluded that intradiscal PRP is a safe and a possibly effective treatment for discogenic LBP.
Moreover, they stated that future studies are needed to determine- the best candidates for this treatment,
- what the optimal injectate is, and
- what relationships exist between patient-reported outcomes and radiological findings.
In a prospective, clinical trial, Levi and associates (2016) evaluated changes in pain and function in patients with discogenic LBP after an intradiscal injection of PRP. Patients were diagnosed with discogenic LBP by clinical means, imaging, and exclusion of other structures. Provocation discography was used in a minority of the patients. Patients underwent a single treatment of intradiscal injection of PRP at 1 or multiple levels. Patients were considered a categorical success if they achieved at least 50 % improvement in the VAS and 30 % decrease in the ODI at 1, 2, and 6 months post-treatment. A total of 22 patients underwent intradiscal PRP; 9 patients underwent a single-level injection, 10 at 2 levels, 2 at 3 levels, and 1 at 5 levels. Categorical success rates were as follows: 1 month: 3/22 = 14 % (95 % CI: 0 % to 28 %), 2 months: 7/22 = 32 % (95 % CI: 12 % to 51 %), 6 months: 9/19 = 47 % (95 % CI: 25 % to 70 %). The authors concluded that the findings of this trial demonstrated encouraging preliminary results at 6 month, using strict categorical success criteria, for intradiscal PRP as a treatment for presumed discogenic LBP. They stated that randomized, placebo-controlled trials are needed to further evaluate the effectiveness of this treatment.
The American Society of Interventional Pain Physicians (ASIPP) guidelines on "Responsible, safe, and effective use of biologics in the management of low back pain" (Navani et al, 2019) stated that there is Level III evidence for intradiscal injections of PRP and MSCs.
Intradiscal Implantation of Stromal Vascular Fraction plus Platelet-Rich Plasma for the Treatment of Degenerative Disc Disease
Kristin and colleagues (2017) noted that stromal vascular fraction (SVF) can easily be obtained from a mini-lipoaspirate procedure of fat tissue and platelet rich plasma (PRP) can be obtained from peripheral blood. The SVF contains a mixture of cells including adipose tissue-derived stem cells (ADSCs) and growth factors and has been depleted of the adipocyte population. These researchers evaluated the safety and effectiveness of administering SVF and PRP intradiscally into patients with DDD. A total of 15 patients underwent a local tumescent liposuction procedure to remove approximately 60 ml of fat tissue. The fat was separated to isolate the SVF and the cells were delivered into the disc nucleus of patients with DDD. Subjects were then monitored for adverse events (AE), range of motion (ROM), VAS, present pain intensity (PPI), ODI, BDI, Dallas Pain Questionnaire (DPQ) and SF-12 scores over a 6-month period; safety events were followed for 12 months. No severe AEs (SAEs) were reported during a 12-month follow up period with no incidences of infection. Patients demonstrated statistically significant improvements in several parameters including flexion, pain ratings, VAS, PPI, and SF-12 questionnaires. In addition, both ODI and BDI data were trending positive and a majority of patients reported improvements in their DPQ scores. The authors concluded that patients were pleased with the treatment results. More importantly, the procedure demonstrated a strong safety profile with no SAEs or complications linked to the therapy. While the current study provided encouraging feasibility data regarding intradiscal stem cell treatment and suggested some clinical benefit of the SVF therapy in degenerative disc patients, these investigators stated that a true evaluation of safety and effectiveness would require larger phase II/III studies.
Although the findings of this study suggested that the use of SVF is safe and feasible, the general under-powering of the study coupled with the lack of placebo control necessitated additional studies to determine the true clinical effect of the treatment. In addition, several patients were lost to follow-up that could have created patient bias. Given the encouraging results on this small sample size (n = 15) with statistical significance, large appropriately powered clinical studies blinded to both clinical staff and patients are needed
Intradiscal Glucocorticoid Injection for the Treatment of Low Back Pain
In a prospective, parallel-group, double-blind, randomized, controlled study, Nguyen and colleagues (2017) evaluated the effectiveness of a single glucocorticoid intradiscal injection (GC-IDI) in patients with chronic LBP with active discopathy. A total of 135 patients with chronic LBP with active discopathy on MRI were included in this analysis. Subjects received a single GC-IDI (25 mg prednisolone acetate) during discography (n = 67) or discography alone (n = 68). The primary outcome was the percentage of patients with LBP intensity less than 40 on an 11-point NRS (0 [no pain] to 100 [maximum pain] in 10-point increments) in the previous 48 hours at 1 month after the intervention. The main secondary outcomes were LBP intensity and persistent active discopathy on MRI at 12 months and spine-specific limitations in activities, health-related QOL, anxiety and depression, employment status, and use of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) at 1 and 12 months. All randomly assigned patients were included in the primary efficacy analysis. At 1 month after the intervention, the percentage of responders (LBP intensity less than 40) was higher in the GC-IDI group (36 of 65 [55.4 %]) than the control group (21 of 63 [33.3 %]) (absolute risk difference, 22.1 percentage points [95 % CI: 5.5 to 38.7 percentage points]; p = 0.009). The groups did not differ in LBP intensity at 12 months and in most secondary outcomes at 1 and 12 months. The authors concluded that in chronic LBP associated with active discopathy, a single GC-IDI reduced LBP at 1 month but not at 12 months.
Intradiscal Methylene Blue Injection for the Treatment of Low Back Pain
In an observational study, Zhang and colleagues (2016) examined the clinical outcomes and MRI changes of intradiscal methylene blue injection (MBI) for the treatment of discogenic LBP. A total of 33 subjects were selected to be treated with intradiscal MBI. The clinical outcomes were evaluated by NRS and ODI at pre-treatment, 1month, 3, 6, and 12 months after treatment. The MRI changes of involved intervertebral discs were assessed by apparent diffusion coefficient and T2 values at pre-treatment, 3, 6, and 12 months following treatment. All of the patients were followed-up to 12 months. The mean NRS scores at pre-treatment, 1 month, 3, 6, and 12 months after treatment were 6.54, 2.98, 3.23, 3.66, and 4.72, respectively. There was a minimum of 2 points reduction at 1 month, 3, and 6 months after treatment, but less than 2 points reduction at 12 months. There was at least 50 % improvement on the ODI at 1 month, 3, and 6 months after treatment, but not at 12 months. The mean apparent diffusion coefficient and T2 value were significantly higher at 6 and 12 months following treatment compared to pre-treatment, but there was no significant difference between pre-treatment and 3 months after treatment. The authors concluded that intradiscal MBI might be an effective therapy for discogenic LBP for the short-term and could improve disc degeneration condition to some extent. The main drawbacks of this study were;- it was an observational study,
- relatively small sample size (n = 33), and
- short-term (up to 12 months) follow-up.
These preliminary findings need to be validated by well-designed studies.
In a multi-center, prospective, pilot study, Kallewaard and associates (2016) collected information about safety, effectiveness, and acceptability of intradiscal MBI, gain and burden of outcome measures, and sample size assumptions for a potential following RCT. If this study demonstrated that this treatment is potentially safe and effective, and the methods and procedures used in this study are feasible, a RCT would follow. Patients were selected on clinical criteria, MRI findings, and a positive provocative discogram. The primary outcome measure was mean pain reduction at 6 months. A total of 15 consecutive patients with chronic lumbar discogenic pain enrolled in 2 interventional pain treatment centers in the Netherlands. At 6 months after the intervention, 40 % of the patients claimed at least 30 % pain relief. In patients who responded, physical function improved and medication use diminished. These researchers observed no procedural complications or AEs; predictors for success were Pfirrmann grading of 2 or less and higher QOL mental component scores. The authors concluded that the findings of 40 % positive respondents, and no complications, gave reason to set up a randomized, double-blind, placebo-controlled, trial.
Kallewaard and associates (2019) noted that a study published in PAIN in 2010 showed remarkable effects of intradiscal MB injections compared with placebo on pain intensity in patients with chronic discogenic LBP (CD-LBP). Both groups received lidocaine hydrochloride injections for pain associated with the procedure. In a double-blind, multi-center RCT, these researchers replicated the design of the previously published study to examine if the effects of MB on pain intensity could be confirmed. The primary outcomes were treatment success defined as at least 30 % reduction in pain intensity and the Patients' Global Impression of Change 6 months after the intervention. These investigators included 84 patients with CD-LBP of which 14 (35 %) in the MB plus lidocaine group showed treatment success compared with 11 (26.8 %) in the control group who received placebo plus lidocaine (p = 0.426); 27 % of all subjects treated with MB stated that their overall health improved much or very much (Patients' Global Impression of Change), versus 25.6 % in the placebo group (p = 0.958). These researchers were unable to confirm that intradiscal MB injections were better capable of significantly reducing pain in patients with CD-LBP 6 months after treatment compared with placebo. They observed that over 25 % of patients receiving only lidocaine injections reported treatment success, which was in contrast with the previously published study. The authors concluded that these findings did not support the recommendation of using intradiscal MB injections for patients with CD-LBP.
Guo and co-workers (2019) examined the effects of intradiscal MB injection on discogenic LBP (DLBP). These researchers conducted an electronic search of the PubMed, Ovid, Ovid Medline and Embase databases using the search terms "low back pain" and "methylene blue"; the search was limited to English language articles from database inception to October 2017. In addition, the reference lists of all included studies were manually searched. Two reviewers independently assessed the quality of the studies, extracted data from the included studies, and analyzed the data. A total of 5 studies were included. The results of the meta-analysis indicated that the effects of intradiscal MB injection between pre-operation and post-operation on DLBP were statistically significant based on the 3-month VAS or NRS (weighted mean difference [WMD] = 3.61; 95 % CI: 2.46 to 4.76; p < 0.05) and ODI (WMD = 24.64, 95 % CI: 12.07 to 37.21, p < 0.05), the 6-month VAS or NRS (WMD = 2.95; 95 % CI: 1.20 to 4.71; p < 0.05) and ODI (WMD = 23.21, 95 % CI: 12.89 to 33.53, p < 0.05), and the 12-month VAS or NRS (WMD = 3.19; 95 % CI: 0.99 to 5.40; p < 0.05) and ODI (standard mean difference [SMD] = 29.51, 95 % CI: 20.60 to 38.42, p < 0.05). The authors concluded that intradiscal MB injection could reduce pain severity and improve the ODI score in individuals with discogenic LBP. Moreover, these researchers stated that although intradiscal MB injection appeared to be a safe and effective treatment for discogenic LBP, the clinical benefits for patients with discogenic LBP need to be further appraised in larger samples and more in-depth studies.
Intradiscal Injection of Autologous Platelet-Rich Plasma for the Treatment of Discogenic Low Back Pain
In a preliminary clinical trial, Akeda and colleagues (2017) determined the safety and initial efficacy of intradiscal injection of autologous PRP releasate in patients with discogenic LBP. Inclusion criteria for this study were chronic LBP without leg pain for more than 3 months; 1 or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via MRI; and at least 1 symptomatic disc, confirmed using standardized provocative discography; PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a VAS and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification). Data were analyzed from 14 patients (8 men and 6 women; mean age of 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced AEs or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5 ± 1.3; RDQ, 12.6 ± 4.1) were significantly decreased at 1 month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2 ± 2.4, RDQ; 3.6 ± 4.5 and 12 months: VAS, 2.9 ± 2.8; RDQ, 2.8 ± 3.9; p < 0.01, respectively). The mean T2 values did not significantly change after treatment. The authors concluded that they demonstrated that intradiscal injection of autologous PRP releasate in patients with LBP was safe, with no AEs observed during follow-up. Moreover, they stated that future prospective, double-blinded, randomized, and placebo-controlled studies are needed to determine the efficacy of this treatment.
Intradiscal Oxygen-Ozone Chemonucleolysis for the Treatment of Disc Herniation
In a systematic review and meta-analysis of RCTs, Magalhaes and co-workers (2012) evaluated the therapeutic results of percutaneous injection of ozone for LBP secondary to DH. These investigators performed a comprehensive literature search using all electronic databases from 1966 through September 2011. The quality of individual articles was assessed based on the modified Cochrane review criteria for randomized trials and criteria from the AHRQ. The outcome measure was short-term pain relief of at least 6 months or long-term pain relief of more than 6 months. A total of 8 observational studies were included in the systematic review and 4 randomized trials in the meta-analysis. The indicated level of evidence for long-term pain relief was II-3 for ozone therapy applied intradiscally and II-1 for ozone therapy applied paravertebrally. The grading of recommendation was 1C for intradiscal ozone therapy and 1B for paravertebral ozone therapy. The authors concluded that ozone therapy appeared to yield positive results and low morbidity rates when applied percutaneously for the treatment of chronic LBP. Moreover, the authors stated that the main drawbacks of this review were the lack of precise diagnosis and the frequent use of mixed therapeutic agents; the meta-analysis included mainly active-control trials, and no placebo-controlled trial was found.
In a letter to the editor regarding the afore-mentioned study by Magalhaes et al (2012), Rahimi-Movaghar and Eslami (2012) stated that "In order to investigate the maximum effectiveness of ozone therapy in these different methods, we recommend an accurate, multicenter, double blind, randomized controlled trial be undertaken to achieve the best evidence in patients with herniated intervertebral discs".
Dall'Olio and colleagues (2014) noted that intradiscal oxygen-ozone (O2-O3) chemonucleolysis has been used for the treatment for pain caused by protruding disc disease and nerve root compression due to bulging or herniated disc. The most widely used therapeutic combination is intradiscal injection of an O2-O3 mixture (chemonucleolysis), followed by peri-radicular injection of O2-O3, steroid and local anesthetic to enhance the anti-inflammatory and analgesic effect. The treatment was designed to resolve pain and was administered to patients without motor weakness, whereas patients with acute paralysis caused by nerve root compression undergo surgery 24 to 48 hours after the onset of neurological deficit. These researchers reported on the efficacy of O2-O3 chemonucleolysis associated with anti-inflammatory foraminal injection in 13 patients with LBP and cruralgia, LBP and sciatica and subacute partial motor weakness caused by nerve root compression unresponsive to medical treatment. All patients were managed in conjunction with the authors’ colleagues in the Neurosurgery Unit of Bellaria Hospital and the IRCCS Institute of Neurological Sciences, Bologna. The outcomes obtained were promising: 100 % patients had a resolution of motor weakness, while 84.6 % had complete pain relief. The authors concluded that these preliminary findings suggested that O2-O3 chemonucleolysis may be an additional therapeutic option in this category of patients; however, these promising results await confirmation in future studies on larger patient cohorts.
Hashemi and co-workers (2014) determined the effect of intradiscal ozone injection on pain score and disability in patients with LBP from prolapsed disks. Patients with LBP diagnosed with DH were enrolled in this clinical trial study. After prep and drape, the area and under the fluoroscopy guide (c-arm), intradiscal injection of ozone/oxygen mixture (4 ml, 40 µg/ml) was performed. Pain score and functional ability of the patients according to ODI were measured prior to the injection (baseline) and then at 2 and 4 weeks and then at 3 and 6 months after the injection. A total of 30 patients (17 women, 13 men) with the mean age of 58.6 years (range of 42 to 73 ) enrolled in the study. The mean ± standard deviation (SD) of pain score before intervention was 8.1 ± 0.8. After 2 weeks, it was reduced to 3.2 ± 0.6 (p < 0.001) and finally dropped to 2.0 ± 0.6 6 months after intervention (p = 0.0001). Functional status of ODI was 28.5 ± 2.1 before intervention and showed significant reduction after 2 weeks (with the mean of 12.3), and it was almost sustained till 6th months after intervention, with the mean of 11.4 (p = 0.001). The authors concluded that ozone had significant positive effects on patients with DH unresponsive to other conservative and minimally invasive treatments. Moreover, they stated that the study had several drawbacks, including lack of a control group, or blinding. They stated that future studies with larger sample size are needed to perform a better review of ozone effects on disk LBP.
Yang and associates (2018) presented a case involving a pre-vertebral abscess complicated by a spinal epidural abscess (SEA) secondary to intradiscal O2-O3 chemonucleolysis for treatment of a cervical disc herniation. A 67-year old woman with a history of intradiscal O2-O3 chemonucleolysis developed numbness and weakness in her right upper and bilateral lower extremities followed by urinary retention. Her symptoms did not respond to intravenous antibiotics alone; MRI of the cervical region revealed an extensive SEA anterior to the spinal cord, spinal cord myelopathy due to anterior compression by the lesion, and a pre-vertebral abscess extending from C2 to T1. She underwent surgical drainage and irrigation. The patient was successfully treated with surgical drainage and systemic antibiotic therapy without kyphosis. Streptococcus intermedius was detected within the abscess. All clinical symptoms except for the sensory deficit in the left leg were relieved. The authors concluded that the safety of intradiscal O2-O3 therapy requires further assessment; high-dose intravenous antibiotics should be initiated empirically at the earliest possible stage of pre-vertebral and epidural abscesses. Surgical drainage may be a rational treatment choice for patients with a pre-vertebral abscess complicated by an SEA and spinal cord myelopathy.
In a prospective, multicenter pilot study, Kelekis et al (2022) compared the non-inferiority treatment status and clinical outcomes of intradiscal O2-O3 with microdiscectomy in patients with refractory radicular leg pain due to single-level contained lumbar disc herniations. This trial was carried out in 3 European hospital spine centers. A total of 49 patients (mean age of 40 years, 17 women/32 men) with a single-level contained lumbar disc herniation, radicular leg pain for more than 6 weeks, and resistant to medical management were randomized, 25 to intradiscal O2-O3 and 24 to microdiscectomy; 88 % (43 of 49) received their assigned treatment and constituted the as-treated (AT) population. Primary outcome was overall 6-month improvement over baseline in leg pain. Other validated clinical outcomes, including back NRS, Roland Morris Disability Index (RMDI) and EQ-5D, were collected at baseline, 1 week, 1-, 3-, and 6-months. Procedural technical outcomes were recorded; and AEs were evaluated at all follow-up intervals. O2-O3 treatment performed as outpatient day surgeries, included a one-time intradiscal injection delivered at a concentration of 35 ± 3 μg/cc of O2-O3 by a calibrated delivery system. Discectomies performed as open microdiscectomy inpatient surgeries, were without spinal instrumentation, and not as subtotal microdiscectomies. Primary analyses with a non-inferiority margin of -1.94-point difference in 6-month cumulative weighted mean leg pain NRS scores were conducted using AT)and intent-to-treat (ITT) populations. In post-hoc analyses, differences between treatment groups in improvement over baseline were compared at each follow-up visit, using baseline leg pain as a co-variate. In the primary analysis, the overall 6-month difference between treatment groups in leg pain improvement using the AT population was -0.31 (SE, 0.84) points in favor of microdiscectomy and using the ITT population, the difference was 0.32 (SE, 0.88) points in favor of O2-O3. The difference between O2-O3 and microdiscectomy did not exceed the non-inferiority 95 % confidence lower limit of treatment difference in either the AT (95 % lower limit, -1.72) or ITT (95 % lower limit, -1.13) populations. Both treatments resulted in rapid and statistically significant improvements over baseline in leg pain, back pain, RMDI, and EQ-5D that persisted in follow-up. Between group differences were not significant for any outcomes. During 6-month follow-up, 71 % (17 of 24) of patients receiving O2-O3, avoided microdiscectomy. The mean procedure time for O2-O3 was significantly faster than microdiscectomy by 58 mins (p < 0.0010) and the mean discharge time from procedure was significantly shorter for the O2-O3 procedure (4.3 ± 2.9 hours versus 44.2 ± 29.9 hours, p < 0.001). No major AEs occurred in either treatment group. The authors concluded that intradiscal O2-O3 chemonucleolysis for single-level lumbar disc herniations unresponsive to medical management, met the non-inferiority criteria to microdiscectomy on 6-month mean leg pain improvement. Both treatment groups achieved similar rapid significant clinical improvements that persisted and overall, 71 % undergoing intradiscal o2-O3 were able to avoid surgery. Patients with selected lumbar herniated disc radicular leg pain, unresponsive to conservative management, may be offered O2-O3 treatment as an effective treatment before microdiscectomy.
The authors stated that a potential limitation of the study was that the surgical procedure was left to the discretion of participating surgeons and traditional open microdiscectomy procedures were employed at the sites. However, a review of the literature showed that treatment effectiveness of open microdiscectomy for lumbar disc herniation was similar to more minimally invasive surgical approaches, and that rates of re-operations were often lower. This RCT was not powered to detect AEs and the small study size limited estimates of safety for both treatments. These researchers stated that although a clinically significant surgical avoidance rate for patients with herniated lumbar disc radiculopathy has not been established, confirming the high avoidance rate with intradiscal O2-O3 in this trial with larger, and longer follow-up clinical trials would provide additional valuable information.
Intradiscal Implantation of Combined Autologous Adipose-Derived Mesenchymal Stem Cells and Hyaluronic Acid for the Treatment of Discogenic Low Back Pain
Kumar and colleagues (2017) stated that adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic LBP because of their immunomodulatory functions and capacity for cartilage differentiation. In a single-arm, phase-I clinical trial, these researchers evaluated the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. This study had a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a VAS and disability level of greater than or equal to 30 % on the ODI. Patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, SF-36, and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. No patients were lost at any point during the 1-year clinical study. These researchers observed no procedure or stem cell-related AEs or SAEs during the 1-year follow-up period; VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the 2 groups. Among 6 patients who achieved significant improvement in VAS, ODI, and SF-36, 3 patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. The authors concluded that combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP was safe and tolerable. However, this study was a single-arm, open-label, phase I pilot study, and thus caution should be applied when drawing any conclusions regarding long-term safety and efficacy. Moreover, they stated that large-scale clinical trials assessing the optimal cell source, cell dose, scaffold, and relevant clinical end-points are needed to define the true pathology that will benefit from stem cell therapy and the appropriate therapeutic regimen.
The American Society of Interventional Pain Physicians (ASIPP) guidelines on "Responsible, safe, and effective use of biologics in the management of low back pain" (Navani et al, 2019) stated that there is Level III evidence for intradiscal injections of PRP and MSCs.
Intradiscal Injection of Autologous Bone Marrow Concentrate for the Treatment of Degenerative Disc Disease
Pettine and colleagues (2017) evaluated the safety and feasibility of intradiscal bone marrow concentrate (BMC) injections for the treatment of low back discogenic pain as an alternative to surgery with 3 years minimum follow-up. A total of 26 patients suffering from degenerative disc disease and candidates for spinal fusion or total disc replacement surgery were injected with 2 ml autologous BMC into the nucleus pulposus of treated lumbar discs. Asample aliquot of BMC was characterized by flow cytometry and colony-forming unit-fibroblast (CFU-F) assay to determine progenitor cell content. Improvement in pain and disability scores and 12 month post-injection MRI were compared to patient demographics and BMC cellularity. After 36 months, only 6 patients progressed to surgery. The remaining 20 patients reported average ODI and VAS improvements from 56.7 ± 3.6 and 82.1 ± 2.6 at baseline to 17.5 ± 3.2 and 21.9 ± 4.4 after 36 months, respectively; 1 year MRI indicated 40 % of patients improved one modified Pfirrmann grade and no patient worsened radiographically. Cellular analysis showed an average of 121 million total nucleated cells per ml, average CFU-F of 2,713/ml, and average CD34+ of 1.82 million/ml in the BMC. Patients with greater concentrations of CFU-F (greater than 2,000/ml) and CD34+ cells (greater than 2 million/ml) in BMC tended to have significantly better clinical improvement. The authors concluded that there were no AEs related to marrow aspiration or injection, and this study provided evidence of safety and feasibility of intradiscal BMC therapy. They stated that patient improvement and satisfaction with this surgical alternative supports further study of the therapy.
Intradiscal Pulsed Radiofrequency on Refractory for the Treatment of Discogenic Neck Pain
Kwak and Chang (2018) stated that despite medication, exercise, and medical intervention, many patients complain of persistent discogenic neck pain. To manage discogenic neck pain, these researchers performed intradiscal pulsed radiofrequency (PRF) stimulation in a patient with chronic discogenic neck pain refractory to oral medication and epidural steroid injection. A 26-year old man presented with a NRS score of 7 for chronic neck pain. His pain was worse when the neck was held in one position for a prolonged period. There was no pain in the upper extremities. Discography was positive at C4 to C5. Based on the pain characteristics, and the result of discography, these investigators diagnosed him as having discogenic neck pain originating from C4 to C5. Intradiscal PRF on the C4 to C5 intervertebral disc was performed under C-arm fluoroscopy. The PRF treatment was administered at 2-Hz and a 20-ms pulsed width for 20 minutes at 60 V with the constraint that the electrode tip temperature should not exceed 42° C. At the 2-week, and 1-month follow-up visits, the patient's pain was completely relieved. At 2, and 3 months after intradiscal PRF, the pain was scored as NRS 2. No AEs of intradiscal PRF stimulation were observed. The authors concluded that application of intradiscal PRF appeared to be a safe and effective technique for treating chronic discogenic neck pain. Moreover, the authors noted that this study was limited because it was a single-case study; they stated that further studies involving more number of cases are needed to determine the effects of intradiscal PRF on patients with discogenic neck pain.
Intradiscal Injection of Bone Marrow Aspirate for the Treatment of Discogenic Low Back Pain
Wolff and colleagues (2020) noted that there are an overwhelming number of patients suffering from LBP resulting from disc pathology. Although several strategies are being developed pre-clinically, simple strategies to treat the large number of patients currently affected is still needed. One option is to use concentrated bone marrow aspirate (cBMA), which may be effective due to its intrinsic stem cells and growth factors. A total of 33 patients who received intradiscal injections of cBMA to relieve LBP were followed-up based on NRS, ODI, and SF-36 scores. Patients were also subdivided into those with a pre-injection NRS of greater than 5 and pre-injection NRS of less than or equal to 5. The proportion of patients demonstrating at least 50 % improvement (and 95 % CIs) from baseline at 5 follow-up visits for each outcome was evaluated. At least 50 % improvement in NRS was observed for 13.8, 45.8, 41.1, 23.5, and 38.9 % of patients across five follow-up visits, out to 1 year. When stratified by high (greater than 5) versus low (less than or equal to 5) baseline NRS scores, the values were 14.3, 45.5, 71.4, 22.2, and 44.4 % among those with high baseline pain, and 13.3, 46.2, 20.0, 25.0, and 33.3 % among those with low baseline pain. The 50 % improvement rates across visits were 4.3, 28.6, 30.0, 22.2, and 30.8 % for SF-36, and 4.2, 26.7, 36.4, 55.6, and 30.8 % for ODI. The authors concluded that intradiscal cBMA injections may be an effective approach to reduce pain and improve function; patients with relatively higher initial pain may have potential for greatest improvement.
The authors stated that this retrospective analysis had obvious drawbacks such as the lack of a control group, possible regression to mean, and incomplete patient data at certain time-points. Therefore, the interpretation of these findings should be considered with prudence. Injections of cBMA were offered as a therapeutic option for qualified patients based upon clinical evaluation, the refractory and somewhat degenerative nature of their condition, and the relative absence of effective conservative rehabilitation strategies to avoid surgical intervention. Sub-stratification of internal disc disruption correlating to subjective response was not performed because multiple levels were treated, each with their own respective pathology. These researchers stated that additional studies are needed to identify which subset of patients with discogenic LBP are most likely to experience the highest and most consistent benefits from this minimally invasive autologous therapy, and how effective this therapy is when compared to control therapies.
Furthermore, an UpToDate review on "Subacute and chronic low back pain: Nonsurgical interventional treatment" (Chou, 2020) does not mention bone marrow aspirate as a management option.
Intradiscal Injection of Gelified Ethanol (DiscoGel) for the Treatment of Cervical Disc Herniation, Neck Pain, and Low Back Pain
Sayhan and associates (2018) stated that radiopaque gelified ethanol (RGE; DiscoGel, Gelscom SAS, France) has been employed in the treatment of cervical disc herniations (CDHs), demonstrating the potential efficacy of this substance. In a cross-sectional, single-center study, these investigators examined the long-term safety and effectiveness of DiscoGel in patients with CDH and chronic neck pain. The study was carried out from November 2013 to May 2016 on patients visiting Sakarya University Training and Research Hospital's pain clinic. Each patient was examined before the procedure (baseline) and at 1, 3, 6, and 12 months after the procedure, using the VAS score for pain, the ODI score to measure degree of disability, and estimate QOL for those with pain; this coincided with scores on the Neuropathic Pain Questionnaire (DN4) for differential diagnoses. A total of 33 patients with CDH underwent the same treatment with DiscoGel between November 2013 and May 2016. Significant pain relief was noted, as opposed to pre-operative pain, at 1, 3, 6, and 12 months after the procedure according to each patient's self-evaluation (p = 0.01). Differences in VAS, ODI, and DN4 scores between 1, 3, 6, and 12 months with the same variables were not statistically significant. There were no complications with the procedure. The authors concluded that radiopaque gelified ethanol (DiscoGel) is a potential alternative to surgery for patients with pain at the cervical level; however, prospective studies with larger sample size, and longer follow-up intervals are needed in determining its efficiency. These researchers stated that the main drawbacks of this study were its small sample size (n = 33) as well as its retrospective design, which led to problems in obtaining long-term, follow-up data.
Kuhelj and co-workers (2019) noted that percutaneous image-guided intradiscal injection of gelified ethanol was introduced to treat herniated disc disease lately. These researchers examined the clinical efficacy and durability over a 36-month period. A total of 83 patients (47 men, 36 women, mean age of 48.9 years (range of 18 to 79 years) were treated between May 2014 and December 2015 for 16 cervical and 67 lumbar chronic disc herniations. For pain assessment evaluation, the VAS was used. Physical activity, the use of analgesics, patients' satisfaction with the treatment results and patient's willingness to repeat the treatment were also evaluated. A total of 59 patients responded to questionnaire; 89.8 % had significant reduction in VAS after 1 month (p < 0.001); 76.9 % of patients with cervical symptoms and 93.5 % of patients with lumbar symptoms. In the cervical group it remained stable, while in the lumbar group VAS decreased even more during 36 months (p = 0.012); 1 patient had spinal surgery. Moderate and severe physical disability prior to treatment (96.6 %) was reduced to less than 30 % after 12 months. The majority of active patients returned to their regular job (71.1 %); 78 % needed less analgesics. Only 5.1 % patients were not satisfied with the treatment and 10.2 % would not repeat the treatment if needed. The authors concluded that percutaneous image-guided intradiscal injection of gelified ethanol was a safe, effective and durable therapy for chronic cervical and lumbar herniations. These researchers noted that due to minimal invasiveness and long-lasting benefits, this kind of treatment should be proposed to designated group of patients as 1st-line therapy.
The authors stated that the main drawback of this study was that the number of patients included, especially in cervical group (n = 16) was relatively low; larger cohort might show different results. In addition, more than 1/4 of patients did not respond to questioner, so these investigators were able to follow-up only 59 patients for the designated period. Observational character of the study could also not exclude additional external parameters (such as different techniques for pain reduction including physical activity, exercises, additional or alternative analgesics, acupuncture, etc.) possibly influencing results, especially long-term VAS reduction. These researchers stated that a large, double-blinded, randomized study would be helpful in confirming these findings.
Hashemi and colleagues (2020) stated that LBP secondary to discopathy is a common pain disorder. Multiple minimally invasive therapeutic modalities have been proposed; however, to-date no study has compared PLDD with intradiscal injection of radiopaque gelified ethanol (DiscoGel). These researchers described the 1st study on patient-reported outcomes of DiscoGel versus PLDD for radiculopathy. A total of 72 patients were randomly selected from either a previous strategy of PLDD or DiscoGel, which had been performed in the authors’ center between 2016 and 2017. Subjects were asked regarding their NRS scores, ODI scores, and progression to secondary treatment. The mean NRS scores in the total cohort before intervention was 8.0, and was reduced to 4.3 in the DiscoGel group and 4.2 in the PLDD group after 12 months, which was statistically significant. The mean ODI score before intervention was 81.25 %, which was reduced to 41.14 % in the DiscoGel group and 52.86 % in the PLDD group after 12 months, which was statistically significant. Between-group comparison of NRS scores after 2 follow-ups were not statistically different (p = 0.62); however, the ODI score in DiscoGel was statistically lower (p = 0.001); 6 cases (16.67 %) from each group reported undergoing surgery after the follow-up period, which was not statistically different. The authors concluded that both techniques were equivalent in pain reduction, however, DiscoGel had a greater effect on decreasing disability after 12 months, although the rate of progression to secondary treatments and/or surgery was almost equal in the 2 groups.
The authors stated that this study was carried out in a Persian context, which limited the generalizability of findings since it may not be representative for other settings. In addition, the lack of a comparison group for conservative therapies in the course of symptoms was another drawback for which future multi-center studies with comparison groups are recommended to further ascertain the safety, efficacy, and effectiveness of PLDD and intradiscal injection of DiscoGel in discopathy.
In a randomized, double-blind, clinical study, Papadopoulos and co-workers (2020) compared 2 new techniques, intradiscal DiscoGel (D) and the combination of intradiscal PRF and D (PRF + D), regarding their effectiveness in the treatment of discogenic LBP. The final sample was randomized into group A (n = 18, D) and group B (n = 18, PRF + D). During the procedure, 4 patients from group B were excluded from the study. Groups A and B were evaluated regarding the pain score (VAS; 0 to 10), before the interventional procedures, and 1, 3, 6, and 12 months afterwards. Secondary aims of the study were to compare the 2 groups regarding the results of the Roland Morris Disability Questionnaire (RMDQ), LANSS score, and QOL score (EQ-5D). There was no significant evidence for an overall difference in pain score between the 2 groups (analysis of variance [(ANOVA)], F = 3.24, df = 1, p = 0.084), except for the 6th and 12th months, when group B presented a statistically important difference compared with group A (Wilcoxon test). Group B appeared to be more effective, with a statistically significant difference, compared with group A regarding the secondary objectives of the study. The authors concluded that after rigorous and comprehensive assessment by an independent observer, both DiscoGel alone and DiscoGel in combination with PRF produced tangible improvements in pain, function, QOL, and consumption of analgesics, which were sustained at 12 months. The main drawbacks of this study were its small sample size (n = 18 in the DiscoGel group) and the sort-term follow-up (12 months). These findings need to be validated by well-designed studies with larger sample size and longer follow-up duration.
Furthermore, UpToDate reviews on "Subacute and chronic low back pain: Nonsurgical interventional treatment" (Chou, 2020) and "Management of non-radicular neck pain in adults" (Isaac, 2020) do not mention intradiscal injection of gelified ethanol / DiscoGel as a management option.
Intradiscal Hydrogel (GelStix) for the Treatment of Lumbar Degenerative Disc Disease
Ceylan and colleagues (2019) noted that DDD is one of the main causes of LBP. These researchers examined the effectiveness of percutaneous intradiscal GelStix administration in patients with discogenic pain due to lumbar DDD who were unresponsive to conservative methods. A total of 29 patients were included in the study, which took place between 2013 and 2017. Sedation was performed in the prone position in the operating room, and a C-arm was located so as to provide a lateral view of the surgical field. A 22-G, 3.5-inch needle was inserted into the center of the disc under fluoroscopy guidance, and a percutaneous intradiscal GelStix implantation was performed. All patients were evaluated using the ODI and VAS before and after treatment, and using the Patient Satisfaction Scale at 12 months following treatment. The mean VAS scores were 7.14 ± 0.64 at baseline and 2.48 ± 0.63 at 12 months (p < 0.001). The mean ODI scores were 28.14 ± 1.81 at baseline and 17.35 ± 0.67 at 12 months (p < 0.001). There was a statistically significant decrease in VAS and ODI scores before and after treatment. A total of 86.2 % of the patients rated the procedure as very good or good at 12 months. The authors concluded that the findings of this study suggested that GelStix treatment was useful in pain relief in patients with lumbar DDD from the 1st month of treatment. These preliminary findings need to be validated by well-designed studies.
Furthermore, an UpToDate review on "Subacute and chronic low back pain: Nonsurgical interventional treatment" (Chou, 2020) does not mention hydrogel as a management option.
MR-Guided Percutaneous Intradiscal Thermotherapy (MRgPIT) for the Treatment of Lumbar Degenerative Disc Disease
Leidenberger and colleagues (2020) examined the feasibility of real-time MR-guided intradiscal thermotherapy (MRgPIT) and histological analysis of laser annuloplasty in human ex-vivo intervertebral discs. These researchers evaluated a new MR-compatible applicator system for MRgPIT in an open 1.0-T MRI-system. Needle artefacts and contrast-to-noise ratios (CNR) of 6 interactive sequences (PD-, T1-, T2w TSE, T1-, T2w GRE, bSSFP) with varying echo-times (TE) and needle orientations to the main magnetic field (B0) were analyzed. Additionally, 5 laser protocols (Nd: YAG Laser, 2-6 W) were assessed in 50 ex-vivo human intervertebral discs with subsequent histological evaluation. In-vitro, these investigators found optimal needle artefacts of 1.5 to 5.0 mm for the PDw TSE sequence in all angles of the applicator system to B0. A TE of 20 ms yielded the best CNR. Ex-vivo, ablating with 5 W induced histological denaturation of collagen at the dorsal annulus, correlating with a rise in temperature to at least 60 °C. The MRgPIT procedure was feasible with an average intervention time of 17.1 ± 5.7 mins. The authors concluded that real-time MR-guided positioning of the MRgPIT-applicator in cadaveric intervertebral disc was feasible and precise using fast TSE sequence designs; laser-induced denaturation of collagen in the dorsal annulus fibrosus proved to be accurate.
Cooled Radiofrequency Ablation for the Treatment of Lumbar Facet Joint Pain / Knee Pain
McCormick et al (2019) stated that no previous study has assessed the outcomes of cooled radiofrequency ablation (C-RFA) of the medial branch nerves (MBN) for the treatment of lumbar facet joint pain nor compared its effectiveness with traditional RFA (T-RFA). In a blinded, prospective study, these researchers examined 6-month outcomes for pain, function, psychometrics, and medication usage in patients who underwent MBN C-RFA versus T-RFA for lumbar Z-joint pain. Patients with positive diagnostic MBN blocks (greater than 75 % relief) were randomized to MBN C-RFA or T-RFA. The primary outcome was the proportion of “responders” (greater than or equal to 50 % numeric rating scale (NRS) reduction) at 6 months. Secondary outcomes included NRS, Oswestry Disability Index (ODI), and Patient Global Impression of Change. A total of 43 patients were randomized to MBN C-RFA (n = 21) or T-RFA (n = 22). There were no significant differences in demographic variables (p > 0.05). A greater than or equal to 50 % NRS reduction was observed in 52 % (95 % confidence interval [CI]: 31 % to 74 %) and 44 % (95 % CI: 22 % to 69 %) of subjects in the C-RFA and T-RFA groups, respectively (p = 0.75). A greater than or equal to 15-point or greater than or equal to 30 % reduction in ODI score was observed in 62 % (95 % CI: 38 % to 82 %) and 44 % (95 % CI: 22 % to 69 %) of subjects in the C-RFA and T-RFA groups, respectively (p = 0.21). The authors concluded that when using a single diagnostic block paradigm with a threshold of greater than 75 % pain reduction, treatment with both C-RFA and T-RFA resulted in a success rate of approximately 50 % when defined by both improvement in pain and physical function at 6-month follow-up. While the success rate was higher in the C-RFA group, this difference was not statistically significant. Moreover ,these researchers stated that future study should use the effect size or success rate demonstrated in this prospective study for power calculation.
The authors stated that this study had several drawbacks. The primary drawback was the relatively small sample size; 5 patients dropped-out after being enrolled by prior to randomization; selection bias was possible but not dissimilar to other studies of procedural interventions in which individuals may elect for additional non-invasive care prior to undergoing intervention. Further, subjects were lost to follow-up; of 43 subjects who underwent treatment intervention, 3 (7 %) did not report outcomes for the full 6-month duration of the study. A drop-out effect could have altered the overall outcome of the study. Analysis by conservative worst-case scenario definitions (treating all subjects lost to follow-up as treatment failures) would adjust the treatment success rate to 50 % (95 % CI: 29 % to 71 %) and 59 % (95 % CI: 9 % to 80 %) for pain reduction and functional improvement, respectively, in the C-RFA group. 20-gauge rather than 16-gauge or 18-gauge RFA electrodes were used for conventional ablations; as such, the success rate in the T-RFA group may be lower than would be expected when using larger gauge electrodes. Furthermore, some providers use bi-polar lead placement, longer lesion duration times, higher lesioning temperatures or longer active tips when employing C-RFA, all of which expanded the size of the lesion and may increase the chance of successful MBN capture. A heterogeneous group of 5 faculty members, assisted by Pain Medicine fellows, performed these procedures; difference in experience level with the procedural technique may have influenced patient outcomes, although this heterogeneity did improve generalizability of the reported findings. Finally, RFA represents a treatment that is implemented with the goal of long-term treatment; these investigators measured a primary outcome at 6 months, and did not follow subjects beyond this time period, but future study would ideally capture outcomes at a post-RFA time point of at least 1 year. Indeed, it is conceivable that an inter-group difference may have been observed if outcomes had been examined beyond 6 months.
Davis et al (2019) stated that as a follow-up to the 6-month report, these investigators examined the analgesic effect of C-RFA in patients with knee osteoarthritis (OA) 12 months post-intervention and its ability to provide pain relief in patients who experienced unsatisfactory effects of intra-articular steroid injection (IAS); 78 % (52/67) of patients originally treated with C-RFA were examined at 12 months, while at 6 months post-IAS, 82 % (58/71) of those patients crossed-over to C-RFA and examined 6 months later. At 12 months, 65 % of the original C-RFA group had pain reduction greater than or equal to 50 %, and the mean overall drop was 4.3 points (p < 0.0001) on the NRS; 75 % reported “improved” effects. The cross-over group demonstrated improvements in pain and functional capacity (p < 0.0001). No unanticipated adverse events (AEs) occurred. The authors concluded that the findings of this study demonstrated that analgesia following C-RFA for OA knee pain could last for at least 12 months and could rescue patients who continue to experience intolerable discomfort following IAS.
The authors stated that a limitation of this study was the 1-way cross-over option, from IAS to C-RFA, but not vice versa. This paradigm was consistent with the intention of the study to test C-RFA as a rescue intervention for knee OA, rather than long-standing, conservative IAS. The limitations of this portion of the study were that the remaining IAS group sample size was not large enough to carry out statistical test-based comparisons between the originally treated C-RFA patients and the IAS group members at 12 months, outcomes of the originally treated C-RFA group and those of the crossed-over cohort could not be directly compared at 6 months, because the groups were derived from 2 different study populations, and an effect of C-RFA on opioid use could not be detected, perhaps due to alternate patient conditions that also utilized opioids as therapy. Furthermore, the late addition of the amendment to collect X-rays at the final visit limited the ability to capture data on a large portion of the patients enrolled.
Intradiscal Biacuplasty for the Treatment of Discogenic Lumbar Back Pain
Desai et al (2017) reported the 12-month outcomes of subjects treated with intra-discal biacuplasty (IDB) and conservative medical management (CMM) for chronic low-back pain (LBP) of discogenic origin, and results for subjects who elected to receive IDB + CMM 6 months after CMM-alone. A total of 63 subjects were originally randomized to the IDB + CMM group (n = 29) or CMM-alone (n = 34). Six months following continuous CMM-alone treatment, subjects in this study group were allowed to "cross-over" to IDB + CMM (n = 25); and followed for an additional 6 months. The original IDB + CMM study subjects were followed for a total of 12 months (n = 22). Pain reduction at 12 months was statistically significant and clinically meaningful in the original IDB + CMM group compared to baseline. Functional and disability outcomes were also improved statistically and clinically; 55 % of the IDB + CMM patients responded to treatment with a mean VAS reduction of 2.2 points at 12 months. Furthermore, 50 % and 64 % of subjects reported clinically significant improvements in SF36-PF and in ODI, respectively. There was a 1.7-point reduction (improvement) on a 7-point PGIC scale, and a 0.13-point increase (improvement) in the EQ-5D Health Index; 50 % of cross-over subjects responded to IDB + CMM intervention. Mean outcome scores for cross-over subjects were similar to those of the originally-treated subjects, and functional and disability endpoints were improved statistically and clinically compared to respective baseline values. The authors concluded that these findings suggested that IDB is safe and effective; and indicated that IDB may fill an important niche as a minimally-invasive therapy to treat discogenic LBP in carefully selected patients.
The authors stated that this study had several drawbacks. The sample size of this study was insufficient to constitute a statistically powered CMM-alone group after the first 6 months; therefore, outcome comparisons between IDB + CMM and CMM-alone treatments could not be completed beyond this time-frame. The loss of study subjects in the CMM-alone group was indirectly related to an ethical concern that it was not in the best interest of patients to continue ineffective CMM and suffer from back pain; thus, they were offered an opportunity to cross-over to IDB + CMM as a rescue treatment, which had already demonstrated its effectiveness. Finally, not every eligible member of the IDB + CMM and cross-over study groups provided data at each respective follow-up time-point. Medication diaries were not utilized within the trial and instead, medication intake data reflected the prescription practice of the investigators as prescribed doses of medications were captured. It is common practice to prescribe opioids on an “as needed” basis. For the purpose of analysis, the maximum allowable daily dose for that opioid was calculated and utilized. As a result, specific daily dose changes for “as needed” medications were harder to identify. Furthermore, there were multiple psychosocial influences on the use, misuse, and prescribing habits of opioid medications that could have affected the ability to accurately reflect this variable. Conservative medical management (CMM) was not standardized and the physicians were allowed to treat their patients based on personal clinical preferences. These practices vary from clinic-to-clinic and patient-to-patient, which reflects real-world application, and even in a research setting it is challenging to maintain standardized protocols. In additional, the evaluation tools in the study were externally-validated instruments and the internal validity related to reporting was unknown; however; the multi-variable indicators, both general and back pain specific, were implemented to counter-balance this drawback, and the outcome data demonstrated consistent improvements in pain, function, and quality of life, which provided credibility to these findings. Moreover, the results of the treatment in terms of effect and duration replicated what has been previously shown in other studies.
Intradiscal Injection of Chondroitin Sulfate ABC Endolyase (Condoliase) for Lumbar Disc Herniation
Nakajima et al (2020) noted that intradiscal chondroitin sulfate ABC endolyase (condoliase) injection for LDH is an intermediate between conservative treatment and surgery. This approach can only be performed once in a lifetime; thus, understanding the factors that determine the indication for the use of condoliase and predict outcomes is important. In a retrospective study, these investigators reviewed clinical and imaging findings in patients after intradiscal condoliase injection, and examined the short-term outcomes and factors associated with therapeutic effects. Participants were 42 patients with LDH who underwent intradiscal condoliase injection. Patients with and without a greater than or equal to 50 % improvement from baseline of leg pain at 3 months after injection were defined as responders and non-responders, respectively. Clinical features and radiological findings were compared between these groups. Of the 42 patients, 32 (76.2 %) were responders and 10 (23.8 %) were non-responders. Of 8 patients with a history of discectomy at the same level as LDH, 6 (75.0 %) were responders. Non-responders had a significantly longer time from onset to treatment, smaller herniated volume before treatment, lower percentage reduction of herniated mass, and less intervertebral disc degeneration before treatment. There were no significant differences in LDH types (subligamentous extrusion or transligamentous extrusion types), high-intensity area within the herniation, changes in disc height, and region of condoliase injection between the 2 groups. The authors concluded that intradiscal condoliase injection showed good short-term therapeutic effects in patients with LDH, including transligamentous extrusion-type herniation and revision cases. However, careful consideration is required to determine if this injection should be administered to patients with a longer pain duration, smaller herniated mass volume, and lower intervertebral disc degeneration before treatment, based on the data showing that these were negative predictors for the therapeutic effect, in addition to the uncertain long-term clinical outcome.
The authors stated that this study had several drawbacks. First, it was a retrospective, short-term follow-up study that included only 42 patients and did not include a statistical power analysis. Larger scale population studies are needed to provide further evidence to validate these findings. Second, it was not possible to distinguish with certainty whether the positive therapeutic effect was due to intradiscal condoliase treatment or the natural history of LDH. Third, although the short-term therapeutic effect was sufficient, the long-term clinical outcome and adverse effects are uncertain. In a 10-year matched cohort study, disc puncture and pressurized injection were found to increase the risk of clinical disc problems requiring lumbar surgery, new imaging findings, and prolonged back pain, although another prospective study suggested no acceleration of intervertebral disc degeneration in young patients after a 5-year follow-up. Therefore, further evaluation is needed, especially in patients with advanced intervertebral disc degeneration on MRI.
Funayama et al (2022) stated that although post-operative recurrent LDH (rec-LDH) is uncommon, it is a challenging situation that requires revision surgery when conservative treatment fails. Recently, an agent inducing chemical dissolution of the nucleus pulposus using condoliase has been approved as a novel intradiscal treatment for LDH. To-date, no evidence has been reported regarding its effectiveness in the treatment of post-operative rec-LDH. A 25-year-old man with a history of LDH in L4/L5, who underwent transforaminal full endoscopic lumbar discectomy (FELD) when he was 17 years old, complained of severe pain radiating to his left leg for 1 month. The straight leg-raising test was limited to 25° on the left side. Lumbar T2-weighted MRI showed intracanal, left-sided transligamentous disc herniation at L4/L5 with high-signal intensity. Because the patient has failed conservative treatments with oral analgesics and selective left L5 nerve root block, he requested intradiscal condoliase injection instead of revision surgery. No AEs were observed after the condoliase treatment, and the pain radiating to the left leg improved within 2 weeks. A lumbar MRI performed 2 months after treatment revealed that the disc herniation had significantly decreased in size. The straight leg-raising test examined 3 months after treatment was negative. In this case, the disc herniation was of the transligamentous type and showed a high-signal intensity on T2-weighted MRI that could be suitably treated by condoliase injection therapy. The authors concluded that this case report was the 1st to suggest that intradiscal condoliase injection could be a useful and novel conservative therapeutic option for the treatment of post-operative rec-LDH. These researchers stated that although more findings from comparative studies or large case series including various surgical methods other than transforaminal FELD are needed, the findings of this report suggested that intradiscal condoliase injection could be a useful and novel conservative therapeutic option with a possibility of avoiding the need for revision surgery in post-operative rec-LDH.
Intradiscal Injection of Platelet-rich Plasma for Discogenic Low Back Pain
Schneider et al (2022) noted that there are limited treatments for discogenic LBP. Intradiscal injections of biologic agents such as PRP or SC are theorized to have regenerative properties and have gained increasing interest as a possible treatment; however, the evidence supporting their use in clinical practice is not yet well-defined. In a PRISMA-compliant systematic review, these researchers examined the effectiveness of intradiscal biologics for treating discogenic LBP. Patients with discogenic LBP confirmed by provocation discography or clinical and imaging findings consistent with discogenic pain were included in this review. The primary outcome was the proportion of individuals with greater than or equal to 50 % pain relief after intradiscal biologic injection at 6 months. Secondary outcomes included greater than or equal to 2-point pain score reduction on NRS; patient satisfaction; functional improvement; decreased use of other health care, including analgesics and surgery; and structural disc changes on MRI. These investigators carried out comprehensive literature search in 2018 and updated in 2020. Interventions included were biologic therapies including mesenchymal stem cells (MSCs), PRP, micro-fragmented fat, amniotic membrane-based injectates, and autologous conditioned serum. Any other treatment (sham or active) was considered for comparative studies. Studies were independently reviewed. The literature search yielded 3,063 results, 37 studies were identified for full-text review, and 12 met established inclusion criteria for review. The quality of evidence on effectiveness of intradiscal biologics was very low. A single RCT evaluating PRP reported positive outcomes but had significant methodological flaws. A single trial that examined MSCs was negative. Success rates for PRP injectate in aggregate were 54.8 % (95 % CI: 40 % to 70 %). For MSCs, the aggregate success rate at 6 months was 53.5 % (95 % CI: 38.6 % to 68.4 %), though using worst-case analysis this decreased to 40.7 % (95 % CI: 28.1 % to 53.2 %). Similarly, greater than or equal to 30 % functional improvement was achieved in 74.3 % (95 % CI: 59.8 % to 88.7 %) at 6 months but using worst-case analysis, this decreased to 44.1 % (95 % CI: 28.1 % to 53.2 %). The authors concluded that limited observational data supported the use of intradiscal biologic agents for the treatment of discogenic LBP. According to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) System, the evidence supporting use of intradiscal MSCs and PRP is very low quality. These researchers stated that high quality explanatory trials are needed to better examine the true effectiveness of these treatments.
In a retrospective study, Lutz et al (2022) examined clinical outcomes following intradiscal injections of higher-concentration (greater than 10 ×) PRP in individuals with chronic lumbar discogenic pain and compared outcomes with a historical cohort. This trial included 37 patients who received intradiscal injections of higher-concentration (greater than 10 ×) PRP and had post-procedure outcomes data (visual numerical scale pain score, Functional Rating Index [FRI], and NASS Patient Satisfaction Index). Outcomes were compared to a historical cohort of 29 patients who received intradiscal injections of less than 5X PRP. Pain and FRI scores significantly improved by 3.4 ± 2.5 and 46.4 ± 27.6, respectively, at 18.3 ± 13.3 months following intradiscal injections of great than 10 × PRP (p < 0.001). These improvements were greater than those reported by the historical cohort (1.7 ± 1.6 and 33.7 ± 12.3; p = 0.004 and 0.016, respectively). Furthermore, the satisfaction rate was higher in patients receiving greater than 10 × PRP compared to those receiving less than 5 × PRP (81 % versus 55 %; p = 0.032). The authors concluded that findings from this study suggested that clinical outcomes can be optimized by using PRP preparations that contain a higher concentration of platelets. Moreover, these researchers stated that further studies with larger sample sizes and longer follow-ups are needed to continue to optimize the composition of PRP used to treat patients with lumbar disc disease.
The authors stated that this study had several drawbacks. First, the follow-up durations were variable, due to the retrospective nature of the study. Second, baseline NRS pain and FRI scores in the current greater than 10 × PRP cohort were worse than those in the historical less than 5 × PRP cohort; however, age and gender distributions were similar between cohorts. Third, shorter-term effects were not examined in the study and should be investigated in the future.
Akeda et al (2022) noted that clinical studies of PRP for the treatment of LBP have been reported; however, less is known regarding its long-term effectiveness. This study was a long-term follow-up of a previous prospective clinical feasibility study for the use of PRP releasate (PRPr) to treat discogenic LBP patients. Among 14 patients, 11 patients were recruited for a long-term survey. The effectiveness was examined by VAS for LBP intensity and the Roland-Morris Disability Questionnaire (RDQ) for LBP-related disability. Radiographic disc height was assessed for 7 patients. Improvements in VAS and RDQ were sustained at an average of 5.9 years after the intradiscal injection of PRPr (p < 0.01 versus baseline, respectively). Clinically meaningful improvements (more than 30 % decrease from baseline) in VAS and RDQ were identified in 91 % of patients at final survey. The radiographic measurement of disc height of PRPr-injected discs showed a mild decrease (13.8 % decrease compared to baseline) during the average 5.9 years. The authors concluded that the findings of this small study suggested that the intradiscal injection of PRPr had a safe and effective effect on LBP improvement for more than 5 years following treatment. Moreover, these researchers stated that further large-scale studies are needed to confirm the clinical evidence for the use of PRPr for the treatment of patients with discogenic LBP.
The authors stated that this study had several drawbacks. First, the sample size was small (n = 14); thus, an increased number of patients would be needed for the effectiveness estimation of PRPr treatment. Second, among 14 patients in a previous prospective clinical trial, 11 patients were examined for the LBP intensity and disability, and 7 patients were available for lumbar radiographic evaluation (including 1 patient who received the additional PRPr injection) in this long-term follow-up study. Thus, the attrition bias affecting the validity and reliability of the results did exist in this study. Third, MRIs were not taken for the subjects of the long-term follow-up survey; thus, MRI evaluation would be needed to evaluate the extent of disc degeneration itself. Fourth, this study did not contain control subjects. To precisely evaluate the long-term effectiveness of this treatment, a RCT would be needed.
Intradiscal Injection of Recombinant Human Growth and Differentiation Factor-5 for Chronic Low Back Pain
In a systematic review and meta-analysis, Daste et al (2021) examined the benefits and harms of intervertebral disc therapies (IDTs) in individuals with non-specific chronic LBP (NScLBP). These investigators reviewed randomized trials of IDTs versus placebo interventions, active comparators or usual care. Embase, Medline, CENTRAL and CINHAL databases and conference abstracts were searched from inception to June 2020; 2 independent investigators extracted data. The primary outcome was LBP intensity at short-term (1 week to 3 months), intermediate-term (3 to 6 months) and long-term (after 6 months). Of 18 eligible trials (among 1,396 citations), 5 evaluated glucocorticoids (GCs) IDTs and were included in a quantitative synthesis; 13 examined other products including etanercept (n = 2), tocilizumab (n = 1), methylene blue (n = 2), ozone (n = 2), chymopapaine (n = 1), glycerol (n = 1), stem cells (n = 1), PRP (n = 1) and recombinant human growth and differentiation factor-5 (n = 2); and were included in a narrative synthesis. Standardized mean differences (SMD; 95 % CI) for GC IDTs for LBP intensity and activity limitations were -1.33 (-2.34 to -0.32) and -0.76 (-1.85 to 0.34) at short-term, -2.22 (-5.34 to 0.90) and -1.60 (-3.51 to 0.32) at intermediate-term and -1.11 (-2.91 to 0.70) and -0.63 (-1.68 to 0.42) at long-term, respectively. Odds ratios (OR; 95 % CI) for serious and minor AEs with GC IDTs were 1.09 (0.25 to 4.65) and 0.97 (0.49 to 1.91). The authors concluded that GC IDTs were associated with a reduction in LBP intensity at short-term in individuals with NScLBP; however, positive effects were not sustained. Moreover, IDTs had no effect on activity limitations. These investigators stated that these conclusions were limited by high heterogeneity and a limited methodological quality across studies.Silk Scaffolds
Zhang et al (2021) stated that during the last 10 years, various novel tissue engineering (TE) strategies have been developed to maintain, repair, and restore the biomechanical functions of the musculoskeletal system. Silk fibroins are natural polymers with numerous advantageous properties such as good biocompatibility, high mechanical strength, and low degradation rate; and are increasingly being recognized as a scaffolding material of choice in musculoskeletal TE applications. In a systematic review, these researchers examined the latest research on silk scaffolds in musculoskeletal TE applications within the past decade. Scientific databases searched include PubMed, Web of Science, Medline, Cochrane library, and Embase. The following keywords and search terms were used: musculoskeletal, tendon, ligament, intervertebral disc, muscle, cartilage, bone, silk, and tissue engineering. This review was limited to articles on musculoskeletal TE that were published in English from 2010 to September 2019. The eligibility of the articles was evaluated by 2 reviewers according to pre-specified inclusion and exclusion criteria, after which an independent reviewer carried out data extraction and a 2nd independent reviewer validated the data obtained. A total of 1,120 articles were reviewed from the databases. According to inclusion and exclusion criteria, 480 articles were considered as relevant for the purpose of this systematic review. The authors concluded that tissue engineering is an effective modality for repairing or replacing injured or damaged tissues and organs with artificial materials. This review was intended to reveal the research status of silk-based scaffolds in the musculoskeletal system within the recent decade.
These researchers stated that silk has been employed as sutures for many years. In recent years, due to improved extraction techniques, remarkable biocompatibility, excellent mechanical properties, well-controlled biodegradation rate, and the potential of multitudinous functional modifications, silk has become one of the most prevalent polymeric biomaterials in the regenerative medicine field to-date. However, there are several reasons why there are no clinical applications of silk scaffolds for musculoskeletal systems. First, although silk materials have numerous excellent biological and physical properties, they still cannot meet the requirements of human musculoskeletal system regeneration. For example, in the process of tendon reconstruction, most of the scaffolds still do not reach the mechanical requirements of human daily life and exercise when compared with natural human tendons. Second, the silk scaffolds for different tissues are varied, but the optimal silk scaffold strategy for a particular tissue is still undetermined, which has created considerable obstacles to the clinical applications of silk scaffolds. Third, currently, the research on silk scaffolds is still limited to animal experiments, and even large animals have relatively few studies. In the future, more clinical trials of silk scaffolds with tissue specificity are needed to validate their clinical applications.
Ultra-Purified Stem Cells with an In Situ-Forming Bioresorbable Gel for Enhancement of Intervertebral Disc Regeneration
Ukeba et al (2022) noted that lumbar intervertebral disc (IVD) herniations are associated with significant disability. Discectomy is the conventional therapeutic option for IVD herniations but causes a defect in the IVD, which has low self-repair ability; thus, representing a risk of further IVD degeneration. An acellular, bioresorbable, and good manufacturing practice (GMP)-compliant in situ-forming gel, which corrects discectomy-associated IVD defects and prevents further IVD degeneration had been developed. However, this acellular matrix-based strategy has certain limitations, especially in elderly patients, whose tissues have low self-repair ability. These investigators examined the effectiveness of using a combination of newly-developed, ultra-purified, GMP-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs) and the gel for IVD regeneration following discectomy in a sheep model of severe IVD degeneration. RECs and nucleus pulposus cells (NPCs) were co-cultured in the gel. Furthermore, RECs combined with the gel were implanted into IVDs following discectomy in sheep with degenerated IVDs. Gene expression of NPC markers, growth factors, and extracellular matrix increased significantly in the co-culture compared to that in each monoculture. The REC and gel combination enhanced IVD regeneration following discectomy (up to 24 weeks) in the severe IVD degeneration sheep model. The authors concluded that these findings demonstrated the translational potential of the combination of RECs with an in situ-forming gel for the treatment of herniations in degenerative human IVDs. Moreover, these researchers stated that these findings and strategy need to be validated in clinical settings in future studies, especially in an elderly cohort such as individuals with combined lumbar canal stenosis.
Intradiscal Injection of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) for Reduction of Disc Inflammation
Yuan et al (2023) stated that biological therapies that inhibit inflammation or enhance cell proliferation can alter IVD homeostasis to favor regeneration. Since biological molecules have short half-lives and one molecule may not cover multiple disease pathways, effective treatments may require a combination of growth factors and anti-inflammatory agents delivered in a sustained manner. In a pre-clinical, pilot study, these researchers developed and tested a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disc injury model. Biodegradable microspheres were generated separately to encapsulate tumor necrosis factor alpha (TNFα) inhibitors (etanercept [ETN]) or growth differentiation factor 5 (GDF5) and were embedded into a thermo-responsive hydrogel. Release kinetics and activity of ETN and GDF5 were measured in-vitro. For in-vivo testing, New Zealand White rabbits (n = 12) underwent surgery for disc puncture and treatment with blank-DDS, ETN-DDS, or ETN+GDF5-DDS at levels L34, L45, and L56. Radiographic and MRI of the spines were obtained. The IVDs were isolated for histological and gene expression analyses. ETN and GDF5 were encapsulated into PLGA microspheres and had average initial bursts of 2.4 ± 0.1 μg and 11.2 ± 0.7 μg from DDS, respectively. In-vitro studies confirmed that ETN-DDS inhibited TNFα-induced cytokine release and GDF5-DDS induced protein phosphorylation. In-vivo studies showed that rabbit IVDs treated with ETN+GDF5-DDS had better histological outcomes, higher levels of extracellular, and lower levels of inflammatory gene expression than IVDs treated with blank- or ETN-DDS. The authors concluded that this pilot study showed that DDS can be fabricated to deliver sustained and therapeutic dosages of ETN and GDF5. Furthermore, ETN+GDF5-DDS may have greater anti-inflammatory and regenerative effects than ETN-DDS alone. Therefore, intradiscal injection of controlled release TNF-α inhibitors and growth factors may be a promising treatment to reduce disc inflammation and back pain.
References
The above policy is based on the following references:
Nucleoplasty
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- Saal JA, Saal JS. Intradiscal electrothermal treatment for chronic discogenic low back pain: Prospective outcome study with a minimum 2-year follow-up. Spine. 2002;27(9):966-973; discussion 973-974.
- Saal JS, Saal JA. Management of chronic discogenic low back pain with a thermal intradiscal catheter. A preliminary report. Spine. 2000;25(3):382-388.
- Shah RV, Lutz GE, Lee J, et al. Intradiskal electrothermal therapy: A preliminary histologic study. Arch Phys Med Rehabil. 2001;82(9):1230-1237.
- State of Minnesota, Health Technology Advisory Committee (HTAC). Intradiscal electrothermal annuloplasty for low back pain. Bloomington, MN: HTAC; March 2001.
- State of Oregon Workman's Compensation System Medical Advisory Committee The IDET procedure. Salem, OR: Medical Advisory Committee; March 28, 2001.
- Streitparth F, Disch AC. Interventions on the intervertebral discs. Indications, techniques and evidence levels. Radiologe. 2015;55(10):868-877.
- Tice JA. IDET - Intradiscal electrothermal therapy for treatment of back pain. Technology Assessment. San Francisco, CA: California Technology Assessment Forum (CTAF); October 8, 2003.
- U.S. Food and Drug Administration (FDA), Center for Devices and Radiologic Health (CDRH). Baylis TransDiscal System. 510(k) Summary. 510(k) No. K062937. Rockville, MD: FDA; January 8, 2007.
- Urrutia G, Kovacs F, Nishishinya MB, Olabe J. Percutaneous thermocoagulation intradiscal techniques for discogenic low back pain. Spine. 2007;32(10):1146-1154.
- Washington State Department of Labor & Industries, Office of the Medical Director. Intradiscal heating techniques. Technology Assessment. Washington State Department of Labor & Industries; July 20, 2000.
- Wetzel FT, McNally TA, Phillips FM. Intradiscal electrothermal therapy used to manage chronic discogenic low back pain: New directions and interventions. Spine. 2002;27(22):2621-2626.
Intradiscal Procedures
- Akeda K, Ohishi K, Masuda K, et al. Intradiscal injection of autologous platelet-rich plasma releasate to treat discogenic low back pain: A preliminary clinical trial. Asian Spine J. 2017;11(3):380-389.
- Akeda K, Takegami N, Yamada J, et al. Platelet-rich plasma-releasate (PRPr) for the treatment of discogenic low back pain patients: Long-term follow-up survey. Medicina (Kaunas). 2022;58(3):428.
- Ceylan A, Aşık İ. Percutaneous navigable intradiscal decompression in treatment of lumbar disc herniation: A single-center experience. Turk J Med Sci. 2019;49(2):519-524.
- Ceylan A, Asik I, Ozgencil GE, Erken B. Clinical results of intradiscal hydrogel administration (GelStix) in lumbar degenerative disc disease. Turk J Med Sci. 2019;49(6):1634-1639.
- Chou R. Subacute and chronic low back pain: Nonsurgical interventional treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2020.
- Dall'Olio M, Princiotta C, Cirillo L, et al. Oxygen-ozone therapy for herniated lumbar disc in patients with subacute partial motor weakness due to nerve root compression. Interv Neuroradiol. 2014;20(5):547-554.
- Daste C, Laclau S, Boisson M, et al. Intervertebral disc therapies for non-specific chronic low back pain: A systematic review and meta-analysis. Ther Adv Musculoskelet Dis. 2021;13:1759720X211028001.
- Davis T, Loudermilk E, DePalma M, et al. Twelve-month analgesia and rescue, by cooled radiofrequency ablation treatment of osteoarthritic knee pain: Results from a prospective, multicenter, randomized, cross-over trial. Reg Anesth Pain Med. 2019;44:499–506.
- Desai MJ, Kapural L, Petersohn JD, et al. Twelve-month follow-up of a randomized clinical trial comparing intradiscal biacuplasty to conventional medical management for discogenic lumbar back pain. Pain Med. 2017;18(4):751-763.
- Funayama T, Setojima Y, Shibao Y, et al. A case of postoperative recurrent lumbar disc herniation conservatively treated with novel intradiscal condoliase injection. Case Rep Orthop. 2022;2022:3656753.
- Guo X, Ding W, Liu L, Yang S. Intradiscal methylene blue injection for discogenic low back pain: A meta-analysis. Pain Pract. 2019;19(1):118-129.
- Hashemi M, Dadkhah P, Taheri M, et al. Effectiveness of intradiscal injection of radiopaque gelified ethanol (DiscoGel®) versus percutaneous laser disc decompression in patients with chronic radicular low back pain. Korean J Pain. 2020;33(1):66-72.
- Hashemi M, Poorfarokh M, Mohajerani SA, et al. Injection of intradiscal o2-o3 to reduce pain and disability of patients with low back pain due to prolapsed lumbar disk. Anesth Pain Med. 2014;4(5):e19206.
- Isaac Z. Management of non-radicular neck pain in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2020.
- Kallewaard JW, Geurts JW, Kessels A, et al. Efficacy, safety, and predictors of intradiscal methylene blue injection for discogenic low back pain: Results of a multicenter prospective clinical series. Pain Pract. 2016;16(4):405-412.
- Kallewaard JW, Wintraecken VM, Geurts JW, et al. A multicenter randomized controlled trial on the efficacy of intradiscal methylene blue injection for chronic discogenic low back pain: The IMBI study. Pain. 2019;160(4):945-953.
- Kelekis A, Bonaldi G, Cianfoni A, et al. Intradiscal oxygen-ozone chemonucleolysis versus microdiscectomy for lumbar disc herniation radiculopathy: A non-inferiority randomized control trial. Spine J. 2022;22(6):895-909.
- Kirchner F, Anitua E. Intradiscal and intra-articular facet infiltrations with plasma rich in growth factors reduce pain in patients with chronic low back pain. J Craniovertebr Junction Spine. 2016;7(4):250-256.
- Kristin C, Robert S, Michelle P. Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J Transl Med. 2017;15(1):12.
- Kuhelj D, Dobrovolec A, Kocijancic IJ. Efficacy and durability of radiopaque gelified ethanol in management of herniated discs. Radiol Oncol. 2019;53(2):187-193.
- Kumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther. 2017;8(1):262.
- Kwak SY, Chang MC. Effect of intradiscal pulsed radiofrequency on refractory chronic discogenic neck pain: A case report. Medicine (Baltimore). 2018;97(16):e0509.
- Leidenberger T, Winkel A, Philipp C, et al. MR-guided percutaneous intradiscal thermotherapy (MRgPIT): Evaluation of a new technique for the treatment of degenerative disc disease in cadaveric lumbar spine. Cardiovasc Intervent Radiol. 2020;43(3):505-513.
- Levi D, Horn S, Tyszko S, et al. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: Preliminary results from a prospective trial. Pain Med. 2016;17(6):1010-1022.
- Lutz C, Cheng J, Prysak M, et al. Clinical outcomes following intradiscal injections of higher-concentration platelet-rich plasma in patients with chronic lumbar discogenic pain. Int Orthop. 2022;46(6):1381-1385.
- Magalhaes FN, Dotta L, Sasse A, et al. Ozone therapy as a treatment for low back pain secondary to herniated disc: A systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2012;15(2):E115-E129.
- McCormick ZL, Choi H, Reddy R, et al. Randomized prospective trial of cooled versus traditional radiofrequency ablation of the medial branch nerves for the treatment of lumbar facet joint pain. Reg Anesth Pain Med. 2019;44(3):389-397.
- Monfett M, Harrison J, Boachie-Adjei K, Lutz G. Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain: An update. Int Orthop. 2016;40(6):1321-1328.
- Nakajima H, Kubota A, Maezawa Y, et al. Short-term outcome and predictors of therapeutic effects of intradiscal condoliase injection for patients with lumbar disc herniation. Spine Surg Relat Res. 2020;5(4):264-271.
- Navani A, Manchikanti L, Albers SL, et al. Responsible, safe, and effective use of biologics in the management of low back pain: American Society of Interventional Pain Physicians (ASIPP) guidelines. Pain Physician. 2019;22(1S):S1-S74.
- Nguyen C, Boutron I, Baron G, et al. Intradiscal glucocorticoid injection for patients with chronic low back pain associated with active discopathy: A randomized trial. Ann Intern Med. 2017;166(8):547-556.
- Papadopoulos D, Batistaki C, Kostopanagiotou G. Comparison of the efficacy between intradiscal gelified ethanol (Discogel) injection and intradiscal combination of pulsed radiofrequency and gelified ethanol (Discogel) injection for chronic discogenic low back pain treatment. A randomized double-blind clinical study. Pain Med. 2020;21(11):2713-2718.
- Park CH, Lee KK, Lee SH. Efficacy of transforaminal laser annuloplasty versus intradiscal radiofrequency annuloplasty for discogenic low back pain. Korean J Pain. 2019;32(2):113-119.
- Pettine KA, Suzuki RK, Sand TT, Murphy MB. Autologous bone marrow concentrate intradiscal injection for the treatment of degenerative disc disease with three-year follow-up. Int Orthop. 2017;41(10):2097-2103.
- Rahimi-Movaghar V, Eslami V. The major efficient mechanisms of ozone therapy are obtained in intradiscal procedures. Pain Physician. 2012;15(6):E1007-E1008.
- Sayhan H, Beyaz SG, Ulgen AM, et al. Long-term clinical effects of DiscoGel for cervical disc herniation. Pain Physician. 2018;21(1):E71-E78.
- Schneider BJ, Hunt C, Conger A, et al. The effectiveness of intradiscal biologic treatments for discogenic low back pain: A systematic review. Spine J. 2022;22(2):226-237.
- Ukeba D, Yamada K, Suyama T, et al. Combination of ultra-purified stem cells with an in situ-forming bioresorbable gel enhances intervertebral disc regeneration. EBioMedicine. 2022;76:103845.
- Wolff M, Shillington JM, Rathbone C, et al. Injections of concentrated bone marrow aspirate as treatment for discogenic pain: A retrospective analysis. BMC Musculoskelet Disord. 2020;21(1):135.
- Yang CS, Zhang LJ, Sun ZH, et al. Acute prevertebral abscess secondary to intradiscal oxygen-ozone chemonucleolysis for treatment of a cervical disc herniation. J Int Med Res. 2018;46(6):2461-2465.
- Yuan B, Rudeen K, Li J, et al. Biodegradable microspheres and hydrogel drug delivery system of tumor necrosis factor (TNF) inhibitor and growth differentiation factor 5 (GDF5) reduces disc inflammation in the rabbit model. Spine (Phila Pa 1976). 2023 Apr 17 [Online ahead of print].
- Zhang L, Zhang W, Hu Y, et al. Systematic review of silk scaffolds in musculoskeletal tissue engineering applications in the recent decade. ACS Biomater Sci Eng. 2021;7(3):817-840.
- Zhang X, Hao J, Hu Z, Yang H. Clinical evaluation and magnetic resonance imaging assessment of intradiscal methylene blue injection for the treatment of discogenic low back pain. Pain Physician. 2016;19(8):E1189-E1195.
