Intervertebral Disc Repair

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member

Title XVIII of the Social Security Act, §1862(a)(1)(D) addresses services that are determined to be investigational or experimental

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, §10 General Exclusions from Coverage

This is a non-coverage policy for all injections for Intervertebral Disc Repair.

Low back pain secondary to degenerative disc disease is the most prevalent musculoskeletal complaint among the adult population, affecting up to 80% of people and costing the United States (U.S.) healthcare system between $19.6 and $118.8 billion per year.¹ Degenerative disc disease can lead to changes in the spinal vertebrae that can destabilize the anterior spinal column and cause radiculopathy due to nerve compression. The normal intervertebral disc serves as a "shock absorber" between each vertebra. The intervertebral disc consists of a gelatinous mucoid center and the nucleus pulposus (NP) that is covered by the annulus fibrosus, a band of fibrous tissue. When an individual is upright, weight causes the nucleus of each vertebra to expand, but the annulus fibrosis holds it in place. A degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral disc, influenced by genetic, nutritional and mechanical factors.² As the degeneration cascade progresses, production of pro-inflammatory molecules such as tumor necrosis factor (TNF)–α and interleukins increases. Furthermore, endplate calcification impairs nutrient flow and exacerbates the hypoxic acidic environment. Together, nutrient deprivation and inflammatory environment accelerates the cell death within NP. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in loss of elasticity as fibrosis and dehydration of the NP worsen. There is loss of disc height, formation of osseous spurs, and, eventually, extrusion of nucleus tissue.³ Due to its low blood supply, an intervertebral disc has difficulty repairing itself after an injury or age-related dehydration, thus the continuing loss of cushioning function.⁴

Conservative management of back pain is the first-line treatment for most patients. Nonsteroidal anti-inflammatory drugs or other analgesics are used for symptom relief. Duloxetine or tramadol are recommended second-line pharmacologic therapies by the American College of Physicians.⁵ Additionally, modification of activity in conjunction with some form of exercise therapy is frequently prescribed early in the course of symptoms. For patients with persistent non-radicular back pain, guidelines recommend interdisciplinary rehabilitation, which is defined as an integrated approach using physical rehabilitation in conjunction with a psychological or psychosocial intervention. Opioids may also be prescribed. Invasive procedures include spine fusion and recently, spinal arthroplasty.⁴ Spinal fusion is a procedure that unites 2 or more vertebral bodies together. The goal is to restrict spinal motion and remove the degenerated disc (the presumed pain generator) in order to relieve symptoms. However, fusion alters the normal mechanics of the spine and is associated with an increase in long-term degenerative changes in adjacent spine segments. Practice guidelines from the American Pain Society recommend that surgery be presented as an option to patients with persistent (>1 year) disabling non radicular low back pain with discussion of its risks and benefits and with interdisciplinary rehabilitation discussed as similarly effective.⁶ Shared decision-making with regard to surgery should take into account that most patients who undergo surgery will have some residual symptoms.

Although existing surgical treatments may provide better pain relief than nonsurgical interventions,⁷ they do not address the biology of disc degeneration. Most patients respond to conservative management and surgical interventions well initially, yet a sizable number of patients continue to suffer from chronic low back pain. Moreover, these treatments are limited to relieving symptoms, with no attempt to restore the disc’s structure. Artificial disc replacement is a newer alternative to fusion. A theoretic advantage of lumbar disc replacement compared with fusion is that a prosthetic disc could help preserve normal range of motion and spine mechanics. This could reduce the long-term degenerative changes in adjacent vertebral segments that have been observed following spinal fusion. However, the evidence suggests that the efficacy of this approach is similar to that of spinal fusion. These early trials have reported on small sample sizes and clinical applications that are limited by the strict inclusion criteria and/or lack of durability. A key limitation of existing evidence for the role of lumbar disc replacement is the lack of longer-term follow-up to assess efficacy and failure rates necessitating device removal and potential conversion to a fusion procedure. Guidelines from the American Pain Society found insufficient supporting evidence regarding long-term benefits and harms of disc replacement to recommend the procedure.⁸

Regardless of treatment (disc replacement, fusion, or nonsurgical), few patients report complete symptom resolution. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Several clinical trials have evaluated both autologous and allogeneic human cellular/tissue therapies in patients with painful degenerative disc disease and have reported various improvements in pain and function.

Intradiscal Steroid Injection

The efficacy of intradiscal steroid injections was assessed in 4 systematic reviews (3 included meta-analysis).^9-12 Randomized controlled trials (RCTs) were included in all these reviews.^13-20 Additionally, 2 evidence synthesis^9,10 included non-randomized studies of an intervention (NRSI).^21-23 Changes in patient-reported pain intensity and disability (functional status) were primary outcomes in all the reviews. The certainty of the evidence was reduced by the small number of studies, methodologic limitations (e.g., high risk of bias), imprecision, and inconsistent results between studies.

Miller, et al. (2024) performed a systematic review of 6 RCTs and 3 NRSI.⁹ Data was analyzed for 603 adult participants diagnosed with chronic low back pain attributed to disc or vertebral end plate pathology, as evidenced by positive provocation discography or inflammatory end plate changes (Modic 1 or 2) on magnetic resonance imaging (MRI). Fluoroscopically guided or computed tomography (CT)–guided intradiscal corticosteroid injection (IDCI) was compared to sham/placebo procedures (intradiscal saline, anesthetic, discography alone) or other active treatment. Pain intensity and disability outcomes were assessed at 1, 3, 6, and 12 months post-intervention. IDCI was found to reduce pain and disability for 1–6 months in those with Modic 1 and 2 changes but not in those selected by provocation discography. IDCI showed no difference with comparators in pain or disability at 12 months. The main reported limitation of this review was the overall low certainty of evidence, as determined by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) appraisal methods.²⁴

Mu, et al. (2023) systematically reviewed and meta-analyzed the efficacy and safety of intradiscal steroid injection (prednisolone acetate or betamethasone) versus a placebo or no control group in adults with non-specific chronic low back pain and Modic type 1 change.¹⁰ The review included 434 participants obtained from 4 RCTs and 3 NRSI. Outcomes were measured between 6-24 months. The meta-analysis revealed a significant difference in pain intensity after intradiscal steroid injection compared to before treatment [Standardized Mean Difference (SMD): 3.09, 95% Confidence Interval (CI): 1.60-4.58; p<0.01]; however, no between-group analysis was performed. The pooled result detected a significant difference in patients’ self-reported improvement between intradiscal steroid injection and control groups (Odds Ratio (OR): 11.41, 95% CI: 3.39 - 38.41; p=0.05). None of the secondary outcomes (return to work, utilization of additional medical treatment, serious adverse events (AEs)) showed statistically significant differences between groups. In addition to not performing a comparative analysis for the primary outcome (pain intensity), this review had several limitations. Risk of bias was unclear for 3 of the 4 RCTs. There was serious imprecision; RCT sample sizes ranged between 15 and 68, and 3 observational studies had sample sizes ranging between 12 and 40. Some indirectness was present due to the ages of the individuals included in these studies, which ranged between 32 and 64 years. Serious inconsistency (heterogeneity) was observed for the primary outcomes (pain = I² 93.8% and self-assessed improvement = I² 60.9%). Additionally, outcomes were not reported by timing to follow-up, which likely contributed to inconsistent results. The authors noted publication bias was likely. Overall, the certainty of evidence was rated as very low.

In a systematic review with meta-analysis, Riegger, et al. (2023) evaluated data from 626 participants in 7 RCTs.¹¹ Participants with discogenic low back pain of any age and duration, diagnosed by a combination of clinical examination and MRI scan, received either intradiscal glucocorticoid injection (IGI), or a sham/placebo injection. Pain intensity and functional outcomes using validated patient-reported tools were assessed in the short-term (1 week to <3 months), intermediate-term (3 to <6 months), and long-term (6 to 24 months). The authors concluded that IGI reduces discogenic low back pain intensity and improves physical function effectively at short-term follow-up and continues to improve physical function at intermediate term. However, 6 months post-treatment, outcomes were similar in comparison to the control groups. The type of Modic change does not appear to be related with the response to IGI. The studies included in this review had several important limitations. All studies were rated as having a high risk of bias or some concerns about bias. There was serious imprecision, i.e., short- and intermediate-term pain results ranged from no benefit to large effects, and intermediate-term functional results ranged from no benefit to large effects. Inconsistency was detected among the included studies due to statistical heterogeneity. The limited number of studies available did not permit assessment of publication bias. The certainty of evidence was rated as very low.

Daste, et al. (2021) included 5 RCTs involving 436 adult participants with non-specific chronic low back pain who were assigned to receive either IGI or a control intervention (placebo or intradiscal anesthetic).¹² Pain intensity and functional outcomes using validated patient-reported tools were assessed in the short-term (1 week to <3 months), intermediate-term (3 to <6 months), and long-term (6 to 24 months). At short-term, IGI was associated with improved low back pain outcomes [SMD (95% CI) for IGI for low back pain intensity and activity limitations were −1.33 (−2.34; −0.32) and −0.76 (−1.85; 0.34)], respectively. Positive effects on pain and function were not sustained in the intermediate-term [−2.22 (−5.34; 0.90) and −1.60 (−3.51; 0.32)] or in the long-term [−1.11 (−2.91; 0.70) and −0.63 (−1.68; 0.42)]. ORs (95% CI) for serious and minor AEs with IGI were 1.09 (0.25; 4.65) and 0.97 (0.49; 1.91). Limitations reported by the authors included high heterogeneity and a moderate-low methodological quality across studies. Additionally, there was serious imprecision. Pain (short-term) results ranged from non-clinically significant to large effects. Intermediate- and long-term pain ranged from unfavorable to large effects. Short- intermediate- and long-term disability results ranged from unfavorable to large effects. The overall certainty of evidence was rated as very low.

In a prospective, parallel-group, double-blind, randomized, controlled study, Nguyen and colleagues²⁵ evaluated the effectiveness of a single glucocorticoid intradiscal injection (GC-IDI) in patients with chronic low back pain with active discopathy on MRI. A total of 135 patients 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 low back pain intensity less than 40 on an 11-point numeric rating scale (NRS) (0 [no pain] to 100 [maximum pain] in 10-point increments) in the previous 48 hours and at 1 month after the intervention. The main secondary outcomes were low back pain intensity and persistent active discopathy on MRI at 12 months and spine-specific limitations in activities, health-related quality of life, anxiety and depression, employment status, and use of analgesics and non-steroidal anti-inflammatory drugs 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 (low back pain 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 low back pain intensity at 12 months and in most secondary outcomes at 1 and 12 months. The authors concluded that in chronic low back pain associated with active discopathy, a single GC-IDI reduced low back pain at 1 month but not at 12 months.²⁵

A prior study¹³ found that, in patients with degenerative disc disease who did not respond to epidural steroid injection, intradiscal steroid injection was superior to discography alone only in the subgroup of patients with vertebral bone marrow signal intensity seen on MRI, but outcomes were poorly reported. Two earlier trials of patients with MRI evidence of degenerative disc disease and a positive response to discography found no difference between intradiscal steroid and control injection (saline or local anesthetic).^26,27 Based on these studies, the American Pain Society guideline recommends against IGI for chronic low back pain.⁸ The North American Spine Society guideline states there is insufficient evidence that intradiscal steroids provide improvements in pain or function in patients with discogenic low back pain.²⁸

Intradiscal Tumor Necrosis Factor (TNF) Blocker

TNF-alpha has been implicated in the pathogenesis of radiculopathy and discogenic back pain with the theory that biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disc homeostasis to favor regeneration.²⁹ However, a small pilot study showed that intradiscal injections of etanercept (a drug which interferes with TNF-alpha) did not improve pain or disability scores for patients with lumbosacral radiculopathy or chronic discogenic low back pain.³⁰ This study was limited by a small sample size (n=8) with a short follow up of 1 month. An article in UpToDate³¹ suggests not performing anti-TNF treatments for chronic low back pain (Grade 2C).

Intradiscal Methylene Blue (MB)

Methylene blue (MB) is a compound used as a dye or stain and has been studied for various therapeutic purposes; results of trials evaluating intradiscal MB injections are mixed. As examples, in a double blind, multicenter randomized trial including 72 patients with discography-positive, presumed discogenic back pain, intradiscal MB injection was associated with large improvements in pain (about 40 points on a 100-point pain scale) and function (about 35 points on the 0 to 100 Oswestry Disability Index (ODI)) compared with a placebo intradiscal injection; there were no AEs such as increased pain, radiculopathy, or infection.³² This study was limited by small sample size, and short follow up duration. However, in a subsequent randomized trial that replicated the design of the previous trial, studying 81 patients with similar inclusion criteria, there were no differences between intradiscal MB versus placebo in pain intensity, likelihood of >30% improvement in pain, function, quality of life, or function through 6 months.³³ This study was limited by small sample size, short duration of follow up and limited applicability of MB injection. These researchers were unable to confirm that intradiscal MB injections were better capable of significantly reducing pain in patients with chronic discogenic low back pain 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.³³ The authors concluded that these findings did not support the recommendation of using intradiscal MB injections for patients with degenerative disc disease.

Zhang and associates³⁴ conducted an observational study in 33 patients with low back pain to evaluate clinical outcomes and MRI changes of intradiscal MB injection for the treatment of low back pain. A total of 33 patients were evaluated using ODI and NRS at baseline, 3, 6, and 12 months. The mean apparent diffusion coefficient and T2 value were significantly higher at 6 and 12 months after treatment as compared to baseline. Authors concluded in patients with low back pain, intradiscal MB injection might be an effective therapy. This study is limited by study design, small sample size and short term follow up.

Guo and colleagues³⁵ performed a meta-analysis to evaluate the effects of intradiscal MB injection on discogenic low back pain. A total of 5 studies were included, and significant differences were reported when evaluating Visual Analog Scale (VAS) or NRS and ODI in effects of intradiscal MB injection between pre-operation and post-operation on discogenic low back pain. Authors concluded that intradiscal MB injection may reduce pain severity and improve the ODI score in individuals with discogenic low back pain. Authors further state although their results suggest it is beneficial, larger studies are needed to establish safety and efficacy. This study is limited by including small sample sizes, varying evaluation criteria and poor study design.

The North American Pain Society states there is insufficient evidence to make a recommendation for or against the use of intradiscal MB in patients with discogenic low back pain.²⁸

An article in UpToDate³¹ suggests not performing MB treatments for chronic low back pain (Grade 2C).

Intradiscal Platelet Rich Plasma (PRP)

Intradiscal injections of biologic agents such as platelet rich plasma (PRP) are theorized to have regenerative properties and have gained increasing interest as a treatment; however, the evidence supporting their use in clinical practice is not yet well-defined. Six systematic reviews^36-41 (3 with meta-analysis) and a single RCT⁴² not included in any evidence synthesis, were identified. The primary studies included in the reviews ranged from 3 to 13, with the total numbers of participants ranging from 89-427.^20,43-58 In general, most studies reported favorable effects for PRP intradiscal injections. However, most primary studies were non-comparative (single arm) designs, which limited conclusions about efficacy. Studies with comparative designs did not consistently demonstrate clinically relevant treatment effects. The body of evidence for PRP intradiscal injection was judged to be of very low certainty.

Machado, et al. (2023) performed a systematic review that included 427 participants (7 RCTs) with low back pain.³⁶ PRP intradiscal injection was compared to placebo (saline) or an active therapeutic agent (corticosteroid, ozone). Pain, function, and AE outcome data were obtained at 8 weeks, 6 months, and 1 year. While the authors noted positive results were found in most studies and the number of AEs was small, a closer assessment of the data did not support the effectiveness of PRP intradiscal injections. At 8 weeks, a single trial showed an absolute difference of 0.99 on the VAS, which was not clinically significant. A clinically relevant benefit (1.89 on VAS) favoring platelet-rich fibrin compared to PRP was reported in a single RCT at 6 months. Two studies reported non-significant results between PRP, and betamethasone, or placebo at 12 months follow-up. At 8 weeks, a single trial showed an absolute difference of 6.46 on the Functional Rating Index, which was not clinically significant. At 12 weeks, a clinically relevant benefit of 12.7 points on the ODI favoring platelet-rich fibrin compared to PRP was reported in a single RCT. Another RCT reported non-significant results (0.5 points on the Roland-Morris Questionnaire) between PRP and placebo at 12 months follow-up. Limitations of this review included very serious imprecision, with only a single small RCT assessed for outcomes at 8 weeks and 6 months. High heterogeneity (inconsistent between-study results) was noted due to variability in the protocols used for PRP preparation. There was insufficient reporting of participant characteristics to assess indirectness. In sum, the certainty of evidence was judged to be very low.

In a systematic review and meta-analysis, Peng, et al. (2023) included 3 RCTs and 3 prospective single-arm trials of participants (mean age 33.3-47.5 years) with discogenic low back pain receiving intradiscal injections of PRP.⁴¹ Pain intensity and disability outcomes were measured at 1, 2, and 6 months follow-up. According to this meta-analysis, pain scores decreased by >30% and >50% from baseline, with incidence rates of 57.3%, 50.7%, and 65.6%, and 51.0%, 53.1%, and 51.9%, respectively, after 1, 2, and 6 months of treatment. The ODI scores decreased by >30% with an incidence rate of 40.2% and by >50% with an incidence rate of 53.9% from baseline after 2 and 6 months, respectively. Pain scores decreased significantly after 1, 2, and 6 months of treatment (SMD: 1 month, −1.04, P = 0.02; 2 months, −1.33, P = 0.003; and 6 months, −1.42, P = 0.0008). There was no significant change (P > 0.05) in the pain scores and the incidence rate when pain scores decreased by >30% and >50% from baseline between 1 and 2 months, 1 and 6 months, and 2 and 6 months after treatment. No significant adverse reactions occurred in any of the 6 included studies. According to the authors, this review was limited by the quantity and quality of the included studies. A critical limitation was the lack of comparative analyses, as only within-group pre/post results were reported. Therefore, no conclusions about efficacy can be drawn. Additionally, the pooled results for all outcomes showed very serious imprecision, with CIs crossing the line of no-effect. Inconsistent results across studies were present (heterogeneity >50%) for pain at all time points and for incidence rates at 1 and 2 months. Some indirectness was present due to the younger age of participants. In aggregate, the certainty of evidence was found to be very low.

Muthu, et al. (2022) conducted a systematic review and meta-analysis of 317 patients diagnosed with lumbar disc disease who received either PRP intradiscal injection or placebo or no comparator.³⁷ A total of 13 studies (2 RCTS, 11 NRSI) were included in the review. Outcomes were measured after a minimum of 6 months post-intervention. The authors reported pain relief was noted in patients undergoing an intradiscal injection of PRP based on outcomes like VAS score (p < 0.001) and pain component of the Short Form (SF)-36 questionnaire (p = 0.003), although significant heterogeneity was noted among the included studies. No functional improvements based on the ODI score (p = 0.071), the physical component of the SF-36 questionnaire (p = 0.130), or structural improvement based on MRI signal changes (p = 0.106) were observed in patients undergoing intradiscal injection of PRP. No procedure-related additional AEs were noted among the included studies (p = 0.662). The primary limitation of the current meta-analysis was that it involved single-arm trials, which need further validation by large double-blinded double-arm RCTs. The authors judged 9 of 11 studies to have a moderate or high risk of bias. Small sample sizes resulted in imprecise results. There was also significant heterogeneity among the outcomes measures between the studies included. The practical limitation of the included studies involves the utilization of devices from multiple manufacturers to prepare the PRP used among the studies analyzed. The certainty of evidence was judged to be very low.

A systematic review authored by Schneider, et al. (2022) included 1 RCT and 3 NRSI comprising 100 patients with discogenic low back pain confirmed by lumbosacral provocation discography or correlating clinical and imaging findings.³⁸ Participants received PRP intradiscal injection, placebo injection, or there was no control study arm. Outcomes were measured at 6 months. The primary outcome was the proportion of responders (>50% reduction in pain), while the secondary outcome was the proportion of improvement (>30% improvement). All studies with available categorical data in aggregate reported that 23/42 (54.8%, 95% CI: 40%−70%) participants achieved >50% relief of low back pain following intradiscal injection of PRP with a minimum follow-up of 6 months. Limitations included a high risk of bias in the 1 RCT due to failure to include all participants in the analysis. There was very serious imprecision due to the small sizes of included studies. A meta-analysis was not performed due to a high degree of study heterogeneity. The authors employed the GRADE methodology for rating the certainty of the evidence. They concluded, “There is very low-quality evidence that PRP effectively reduces pain and disability in patients with discogenic low back pain.”

Chang, et al. (2021) performed a systematic review and meta-analysis that included a total of 89 participants from 1 RCT and 2 NRSI.³⁹ Interventions included PRP intradiscal injection, placebo injection, or no comparator. Pain intensity outcomes were meta-analyzed at 1, 2, and 6 months post-treatment. The meta-analysis of the changes in pain scores showed the reduction after 1 month was not significant (SMD = −0.661, 95% CI = −1.346 to 0.023, P = 0.058). However, pain scores significantly reduced 2 and 6 months after intradiscal PRP injection (2 months: SMD = −0.837, 95% CI = −1.158 to −0.516, P < 0.001; 6 months: SMD = −1.430, 95% CI = −2.209 to −0.652, P < 0.001). The analysis of the changes in ODI scores revealed that disability was significantly reduced 6 months after intradiscal PRP injection (SMD = −0.964, 95% CI = −1.885 to −0.043, P = 0.040). No AEs were reported in all 3 included studies. There were significant limitations in this review. The baseline quality was “low” due to the non-comparative study designs included in the meta-analysis. The meta-analysis calculated treatment effect as SMDs. Since all studies used the same pain and disability scales, mean differences would have provided more explicit information about the clinical relevance of the results. There was very serious imprecision due to the small size of individual studies and pooled data. The overall certainty of evidence was judged to be very low.

Hirase, et al. (2020) performed a best-evidence synthesis (systematic review) that evaluated the effects of PRP intradiscal injection compared to placebo or no control in patients with degenerative disc disease.⁴⁰ One RCT and 4 NRSI (N=90) were included in the review. Intradiscal injection of PRP for degenerative disc disease resulted in a statistically significant improvement in VAS for pain intensity at 6 months following intradiscal PRP injection (p<0.01). However, only 2 studies (32 patients) reported individual data to allow a direct comparison of the change in VAS scores with previously reported thresholds for minimally clinically important difference (MCID), substantial clinical benefit (SCB), and patient acceptable symptom state (PASS). Of the 2 studies, only 19 patients (59.4%) met MCID, and 12 patients (37.5%) met SCB and PASS. This demonstrates that though the procedure resulted in statistically significant improvement, a large portion of the patients did not achieve a clinically meaningful improvement in outcomes. The reviewers noted significant limitations. Four of the 5 articles were non-comparative study designs, which limited the strength of the results. Study heterogeneity and nature of evidence (mostly retrospective, non-comparative) precluded meta-analysis. The certainty of evidence was determined to be very low.

Navani, et al. (2024) performed a multicenter, crossover, RCT that investigated intradiscal PRP injection compared with saline trigger point injection or intradiscal bone marrow concentrate (BMC) injection.⁴² A total of 57 participants were randomized, with 40 (70%) included in the analysis. Outcomes measured were pain, function, hospitalizations, and surgery rate at 1, 3, 6, and 12 months post-treatment. The authors reported all the placebo patients reported <50% pain relief and crossed to the active arm. Both PRP and BMC demonstrated similar statistically significant improvement in pain and function. However, prior to crossover (3 months), there was no significant difference in the change in pain (VAS) scores between the PRP and placebo groups, -3.00 and -2.99 points, respectively. Results for functional outcomes were also non-significant at 3 months. None of the patients had any adverse effects, hospitalization, or surgery up to 12 months post-treatment. This RCT was judged to have a high risk of bias as 30% of participants were not included in the analysis. The authors noted additional limitations including the small number of patients and open-label nature of the study.

Although these results for various PRP products are promising, further studies are needed to define the subset of participants most likely to respond to biologic intradiscal treatment and the ideal cellular characteristics of the intradiscal PRP injectate.

The North American Spine Society states there is insufficient evidence to make a recommendation for or against the use of intradiscal PRP in patients with discogenic low back pain.²⁸ The American Society of Interventional Pain Physicians guidelines concluded that there is Level III evidence for intradiscal injections of PRP.⁵⁹

GelStix

GelStix is a device composed of hydrolyzed polyacrylonitrile that is injected into the intradiscal space. Theoretically this injection acts as a reservoir of hydration and increases pH, since a low pH is associated with degeneration and inflammation.⁶⁰ A pilot study which was designed in Switzerland as a parallel group, randomized sham-controlled double-blind, multicenter trial to assess whether the GelStix device is superior to sham in reducing pain intensity in patients with chronic discogenic low back pain. The study was conducted in 2 regional hospitals in Europe. Seventy-two participants were randomized in a 1:1 ratio. The primary outcome was the change in pain intensity between preoperative baseline and at 6 months postintervention. Secondary outcomes were disability, quality of life, the patient’s global impression of change scale, the use of pain medication and the disc degeneration process assessed by means of MRI. Results have not been published.

A retrospective study⁶¹ evaluated 29 patients from 2013 to 2017. All patients were evaluated using the ODI and a 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 the 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. This study was also limited by retrospective design, small sample size and heterogeneity of subjects.

Gelified Ethanol (DiscoGel)

Sayhan and associates⁶² stated that radiopaque gelified ethanol 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 conducted 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 quality of life 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, and short-term follow-up.

Kuhelj and co-workers⁶³ 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, patient’s satisfaction with the treatment results and patient's willingness to repeat the treatment were also evaluated. A total of 59 patients responded to the 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 for 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. The authors stated that the main drawback of this study was that the number of patients included, especially in cervical group (n = 16) was low; larger cohort might show different results. In addition, more than one-fourth of patients did not respond to the questionnaire, so these investigators were able to follow-up with 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.

A clinical assessment was conducted by ECRI which concluded that the evidence was inconclusive due to being very low quality data.⁶⁴ The report compared DiscoGel to other treatment options with a focus on safety and efficacy. There were no RCTs that compared DiscoGel with other treatment options.

Papadopoulos and associates⁶⁵ conducted a RCT to assess 36 patients with discogenic pain. A total of 18 patients were assigned to receive intradiscal DiscoGel (Group A) and 18 were treated with DiscoGel plus pulsed radiofrequency (Group B). The primary outcome was pain score (VAS 0–10) taken at baseline, 1, 3, 6, and 12 months. Secondary outcomes included functional ability (based on the Roland-Morris Disability Questionnaire (RDQ)), the neuropathic characteristics of the pain (Lanss scale), the quality-of-life score (EQ-5D scale), and the need to use analgesics. A significant difference with improved pain scores was reported in group B at 6 and 12 months follow up. Group B also had significant improvements when considering secondary outcomes. This study was limited by short duration of follow up and small sample size which may impact the estimated effect of treatment.

Hashemi and associates⁶⁶ conducted a prospective cohort study comprised of 72 subjects with unilateral or bilateral radicular pain, secondary to lumbar intervertebral disc herniation. Subjects were followed for 12 months after undergoing either an intradiscal injection of DiscoGel or percutaneous laser disc decompression (PLDD). A significant difference in mean NRS from total cohort baseline was 8.0 and was reduced to 4.3 in the DiscoGel group and 4.2 in the PLDD group. A significant reduction in ODI score was 81.25% and was reduced to both treatments DiscoGel (41.14%) and PLDD (52.86%). No statistically significant differences were reported between groups. Limitations include lack of generalizability, lack of comparison group, study design, small sample size and duration of follow up.

Houra and colleagues⁶⁷ conducted a prospective of 29 patients in 3 medical centers to evaluate the safety of intervertebral disc chemonucleolysis and to report the effectiveness of a percutaneous, minimally invasive treatment for contained herniated intervertebral discs in the lumbar spine using the recently marketed radiopaque gelified ethanol. The verbal numeric scale (VNS) and the RDQ for defined periods of 0–6, 6–12, 12–18, 18–24, and 24–30 months. Authors conclude that gelified ethanol may reduce pain and the material is safe and easy to manage. This study is limited by study design, small sample size, lack of control group, and short duration of follow up.

La Torre, et al.⁶⁸ assessed functional outcomes in a consecutive series of 94 consecutively enrolled patients with symptomatic lumbar disc herniation in a single-center observational study. Patients underwent a percutaneous intradiscal injection of DiscoGel. Quality of life outcomes were assessed at 1, 6, 12, 48, and 60 months following surgery. Pain relief was achieved in 90.6% and 88.8% of patients at 1 and 4 year follow up, respectively. A satisfactory result or above was achieved in 92.5% of patients at final follow up. Authors concluded that DiscoGel was effective in appropriately selected patients. Limitations of this study include study design, small sample size, selection bias, lack of control group and moderate duration of follow up.

AEs are associated with DiscoGel including death,⁶⁹ footdrop,⁷⁰ epidural leakage,^67,71 surgical therapy following treatment,⁶³ temporary mild transitory sensory-motor deficit and acute radicular pain.⁶⁸

Retrospective studies^71,72 were reviewed but not summarized.

Intradiscal Bone Marrow Concentrate (BMC)

Three systematic reviews^38,40,73 and a single RCT⁴² evaluated the efficacy and safety of intradiscal BMC injections. The body of evidence was mainly comprised of single-arm, non-comparative trials. These preliminary studies showed a favorable trend for patient-important outcomes (pain and function). However, the overall certainty of evidence was rated as very low.

Her, et al. (2022) systematically reviewed evidence from 9 NRSI that included the intradiscal injection of bone marrow aspirate concentrate (BMAC).⁷³ Participants (N=513) were diagnosed with cervical or lumbar discogenic pain. One study compared BMAC with PRP intradiscal injections.⁵⁵ A second study compared BMAC with posterior spinal chain injections.⁷⁴ The remaining 7 studies did not include placebo or active comparators.^75-81 The reviewers appraised the evidence using the GRADE approach. The authors concluded participants with lumbar intradiscal injection experienced improved pain and function with significantly decreased opioid use. More than 70% of the participants did not undergo spine surgery throughout follow-up for 6 years. Similarly, participants with cervical intradiscal injection reported improved pain and function at 24 months of follow-up. Post-intervention Pfirrmann imaging grade results were inconsistent across studies. The overall level of certainty for the potential associations made in this systematic review is low because there is very low-quality GRADE evidence to support these injection therapies. Adding to the very low certainty of evidence was serious indirectness. The analysis combined studies that used autologous bone marrow aspirate that was either non-concentrated, concentrated, or further processed to obtain culture-expanded bone marrow mesenchymal stromal cells (BM-MSCs) for intradiscal injection.

A systematic review produced by Schneider, et al. (2022) reported on the effects of BMAC in patients with chronic discogenic low back pain.³⁸ The review included 4 non-comparative NRSI.^75-77,81 Outcomes focused on categorical results, i.e., the proportion of responders (>50% reduction in pain/disability) and the proportion of improvement (>30% improvement). Categorical data from 2 studies showed the proportion of responders (>50% reduction in pain) at 6 months ranged from 23.5%–73%, and 38.9%–61.5% at 12 months. Functional outcomes were reported in a single study.⁸¹ Patients reported at least 50% improvement in ODI scores at 6 months (12.1%, 95% CI: 1.0%−23.3%) and at 12 months (21.2%, 95% CI: 7.3%−35.2%). These findings showed that a larger proportion of individuals did not respond favorably to BMAC injections. Limitations of this review included the non-comparative design of the primary studies, which did not permit conclusions about efficacy. There was also very serious imprecision due to the small number of studies and aggregate participants. Overall, the certainty of evidence was rated as very low.

Hirase, et al. (2020) conducted a systematic review that evaluated the effects of intradiscal injection of BMC in patients with lumbar disc degeneration after the failure of non-interventional management.⁴⁰ Six non-comparative case series^77,82-86 and a single RCT⁸⁷ were included in the analysis. The reporting of outcomes ranged from 12 to 72 months. The reviewers concluded intradiscal injection of BMC for lumbar disc degeneration resulted in a statistically significant improvement in VAS (pain) and ODI (function) with low re-injection and complication rates for the reported studies. The mean VAS decreased by 41.2 mm, 45.7 mm, 45.1 mm, and 48.8 mm at 3, 6, 12, and 24 months following the intradiscal BMC injection, respectively. The mean ODI decreased by 26.9, 27.1, 25.3, and 26.1 at 3, 6, 12, and 24 months following the intradiscal BMC injection, respectively (all p < 0.001 vs. baseline). The authors noted several important limitations among the studies included in this review. Six of the 7 articles were level IV evidence (non-comparative case series), which limits the strength of the results. None of the studies used a double-blinded approach, producing potential bias. The assimilation of heterogeneous low methodological quality studies with VAS and ODI is a significant limitation. Additionally, significant heterogeneity in BMC sources (age difference, specifically) may have affected the quality of mesenchymal stem cells (MSCs). Very serious imprecision due to the small size of the included studies was an additional limitation. Overall, the certainty of evidence was rated as very low.

Navani, et al. (2024) performed a multicenter, crossover, RCT that investigated intradiscal PRP injection compared with saline trigger point injection or intradiscal BMC injection.⁴² A total of 57 participants were randomized, with 40 (70%) included in the analysis. Outcomes measured were pain, function, hospitalizations, and surgery rate at 1, 3, 6, and 12 months post-treatment. The authors reported all the placebo patients reported <50% pain relief and crossed to the active arm. Both PRP and BMC demonstrated similar statistically significant improvement in pain and function. However, prior to crossover (3 months), there was no significant difference in the change in pain (NRS) and function (ODI) scores between the BMC and placebo groups, -0.99 and -1.00 points, respectively. None of the patients had any adverse effects, hospitalization, or surgery up to 12 months post-treatment. This RCT was judged to have a high risk of bias as 30% of participants were not included in the analysis. The authors noted additional limitations including the small number of patients and open-label nature of the study.

Mesenchymal Stem Cells (MSCs)

Three systematic reviews^38,88,89 synthesized data from 12 primary studies.^{32,75-77,82,83,85-87,90-92} Single-arm, non-comparative studies provided all or much of the data in 2 reviews.^38,88 All the reviews assessed pain and functional (disability) outcomes, with follow-up intervals extending at least 12 months. All the reviews reported imprecise results, largely due to small sample sizes.

Soufi, et al. (2023) systematically reviewed published studies and trials in-progress to assess the potential role for stem cell regenerative therapy as a treatment for degenerative disc disease and low back pain.⁸⁸ The authors included 1 RCT, 10 NRSI, and 11 abstracts of trials in-progress. Six of the full-text studies were single-arm, with participants receiving MSC intradiscal injection. The RCT control group received a sham injection. Most studies showed clinically relevant improvement in pain and functional scores at 6 months and 1 year. The exception was the RCT, which showed no significant improvement in pain at 12 months and worsening function at 6 and 12 months. Limitations included the non-comparative design of most studies and imprecision due to small sample sizes (N= 12-72). The certainty of evidence was rated as very low.

Schneider, et al. (2022) performed a systematic review of intradiscal biologics for discogenic low back pain.³⁸ A single phase I trial of combined MSC and hyaluronic acid intradiscal injection assessed treatment response at 1, 6, and 12 months. Greater than 50% reduction of pain was achieved in 3/10 (30%, 95% CI: 2%−58%) participants at 1 month and 7/10 (70% 95% CI: 42%−98%) at 6 months and 12 months. Secondary outcomes included >30% reduction in disability (ODI), which was achieved in 7/10 (70%, 95% CI: 42%−98%) participants at 6 months and 8/10 (80%, 95% CI: 55%−100%) at 12 months. Significant limitations included the study’s non-comparative design, which did not permit conclusions about efficacy. There was indirectness due to the inability to assess the discrete effects of MSC intradiscal injections. Additionally, there was very serious imprecision. Data was obtained from a single study, with a sample size of 10. The certainty of evidence was determined to be very low.

A systematic review and meta-analysis authored by Xie, et al (2021) included 3 RCTs comprising 104 patients with degenerative disc disease.⁸⁹ Participants were randomized to receive the intervention (intradiscal injection of MSC) or active control (intradiscal injection of hyaluronic acid injection or mepivacaine). The analysis of VAS (pain) scores with a fixed-effect model showed MSC therapy could significantly decrease VAS scores at 3 months (SMD = -0.62, 95% CI = -0.99 ~ -0.24, P = 0.001), 6 months (SMD = -0.46, 95% CI = -0.83 ~ -0.09, P = 0.01), 12 months (SMD = -0.46, 95% CI = -0.84 ~ -0.08, P = 0.02), and ≥24 months (SMD = -0.49, 95% CI = -0.79 ~ -0.18, P = 0.002). A fixed-effect model evaluated the statistical significance of minimally important change (MIC) and clinically significant change (CSC) responders in patient-reported pain intensity. Pooled analysis showed MSC therapy had a high ratio of patients at most thresholds, especially in MIC (change ≥30% from baseline) (OR = 2.16, 95% CI = 1.43 - 3.25, P = 0.0002) and CSC (change ≥50% from baseline) (OR = 2.18, 95% CI = 1.44 - 3.31, P = 0.0002) thresholds. Disability outcomes were analyzed using a fixed-effect model. The pooled effects showed MSC therapy could significantly decrease ODI scores at ≥24 months (SMD = −0.43, 95% CI = −0.74 ~ −0.12, P = 0.006) in patients with degenerative disc disease. However, no statistical differences were found at 3, 6, and 12 months follow-up. The pooled analysis of MIC and CSC for self-reported disability showed MSC therapy had a high ratio of patients at most thresholds, especially in MIC (change ≥ 10 − point ODI from baseline) (OR = 2.06, 95% CI = 1.37 - 3.10, P = 0.0005) and CSC (change ≥ 15 − point ODI from baseline) (OR = 2.01, 95% CI = 1.33 - 3.05, P = 0.001) thresholds. A meta-analysis was performed on the occurrence of AEs. The results showed that AEs or treatment-emergent adverse events (TEAE) (OR = 1.11, 95 % CI = 0.40 - 3.07, P = 0.84), back pain (OR = 1.23, 95% CI = 0.55 - 2.76, P = 0.62), arthralgia (OR = 0.63, 95% CI = 0.19 - 2.11, P = 0.45), and muscle spasms (OR = 2.11, 95% CI = 0.40 - 11.01, P = 0.38) were not statistically significant between groups. However, further statistical analysis showed MSC therapy may induce AE or TEAE related to study treatment (OR = 3.05, 95% CI = 1.11 - 8.40, P = 0.03). Limitations included the small number (3) of analyzed studies resulting in very serious imprecision. All studies included small samples. Pain outcomes ranged from large to small effects at 3 months, and large to trivial at 6 and 12 months. Disability outcomes ranged from moderated to trivial negative effects at 3, 6, and 12 months. At 24 months, disability measures ranged from moderate to trivial effects. Additionally, all RCTs had a high risk of bias.

The American Society of Interventional Pain Physicians guidelines⁵⁹ stated that there is Level III evidence (Fair: evidence obtained from at least 1 relevant high quality non-randomized trial or observational study with multiple moderate or low-quality observational studies) for intradiscal injections of MSCs.

Allogenic Cellular/Tissue-Based Product

VIA Disc Matrix (Vivex Biomedical) is an injectable allograft supplement to NP tissues in the intervertebral disc. It is composed of human disc tissue donated from cadavers with viable cells. It is composed of intervertebral disc tissue particulate and spine derived cells. It is theorized that this provides a scaffold for additional water absorption capacity through its glycosaminoglycan (GAG) content which is expected to translate into increased hydrostatic pressure on the disc. It consists of a NP allograft suspension that is mixed with a minimum of 6 X 106 cryopreserved cells. Utilizing fluoroscopy, a spinal needle is inserted through Kambin’s safe triangle into the NP of the intervertebral disc. The Via Disc is then delivered. The cell source and method of processing has not been disclosed.

A search for relevant research evidence yielded only a single study. Beall, et al.⁹³ conducted a fair quality study known as the Visible Allograft Supplemented Disc Regeneration in the Treatment of Patients with Low Back Pain with or Without Disc Herniation (VAST). The VAST trial was a prospective, multicenter, blind, RCT for patients with single-level or 2-level degenerative lumbar disc disease. This multicenter trial was completed in outpatient surgical centers and office injection suites. Outcomes of the trial were based on assessment of primary and secondary endpoints 6 and 12 months after transplant of supplementary allograft compared with placebo or sustained conservative care, non-surgical management (NSM) in subjects who have discogenic pain attributable to disc degeneration as judged by MRI scoring, physical examination, and subject-reported pain.

The primary objective of the study was to assess safety and improvement from baseline in 2 clinical endpoints at 12 months. A total of 218 patients with chronic low back pain secondary to single-level or 2-level degenerative disc disease were enrolled. Primary exclusion criteria included radicular pain, symptomatic spinal stenosis, disc protrusion >5 mm, spondylolisthesis >5 mm at any level, and body mass index >35. Inclusion criteria included pretreatment VAS of pain intensity ≥40 mm, ODI score ≥40 and symptoms present longer than 6 months. Patients were blinded and randomized to receive intradiscal injections of either viable disc allograft or normal saline. Patients randomized to the NSM group continued existing treatment. Patients were assessed at 6 and 12 months. AEs were continually assessed. There were 2 coprimary endpoints including back pain as measured by the VAS and function as measured by the ODI. There was an option for the NSM patients to crossover to the allograft treatment group at the 3 month time point, and all subjects elected to cross over to allograft treatment.

At the 6 and 12 month time points the ODI improved from 53.73, 49.25, and 55.75 in the allograft, placebo, and NSM subjects, respectively, to 18.47, 28.75, and 19.0 at 6 months, and to 15.67, 9.33, and 11.0 at 12 months. MRI evaluation showed anatomic improvement of the disc and enhanced nucleus signal. In the allograft group, 11 safety AEs occurred in 141 patients (3.5%) and there were no persistently symptomatic AEs.

There was not a statistically significant difference between reduction in pain intensity (co-primary outcome) in patients receiving Via Disc NP and patients receiving saline at 12 months. There was not a statistically significant difference noted between the proportion of patients achieving a ≥50% average reduction in VAS pain intensity score at 12 months follow-up between patients receiving Via Disc NP and patients receiving saline (62.5% vs. 53.3%, respectively). A statistically significant difference favored Via Disc NP over saline injections in the proportion of patients achieving a reduction of at least 15 points on the ODI. Responder analysis demonstrated 76.5% of patients randomized to allograft were responders (P = 0.03) compared to 56.7% in the saline group. A responder group characterized by a ≥20-point reduction in pain at 12 months achieved a statistically significant reduction in pain compared to the saline group (P = 0.022). There was no statistically significant difference between improvement in function (co-primary outcome) in patients receiving Via Disc NP and patients receiving saline injections. Overall, there were no statistically significant differences between Via Disc NP and placebo (saline) treatment groups achieved in improvements in pain intensity, function, or the proportion of patients achieving response on the VAS for pain intensity at ≤12 months.

Limitations of this study include a comparison to saline that has been shown to be more representative of an active comparator as opposed to a placebo. Saline intradiscal injections may elicit clinical responses in excess of those seen with placebo. In addition, a significant number of patients were lost to follow-up (36); this loss resulted in the saline and NSM/crossover groups being smaller than the predetermined group size to have an appropriately powered analysis. Moreover, the study was limited to 2 levels and cannot be extrapolated to individuals with more than 2 levels.

A review of full-text systematic reviews suggests no/unclear support for the use of Via Disc NP (Vivex Biologics Inc.) for relief of symptoms associated with intervertebral disc degeneration. A review of full-text clinical practice guidelines and position statements showed no relevant or related guidelines that confer support for the use of Via Disc NP (Vivex Biologics Inc.) for relief of symptoms associated with intervertebral disc degeneration.

There is insufficient certainty of evidence of efficacy for any intradiscal injection therapy (product) as a treatment of individuals diagnosed with discogenic low back pain. The certainty of evidence for different intradiscal injection therapies was rated as very low. Studies lacked tools to assess treatment heterogeneity depending on patient characteristics, co-intervention, or other factors. While few serious AEs were reported, sample sizes were inadequate to detect AEs, particularly those considered to be rare. The main limitations were high risk of bias across most studies, serious to very serious imprecision resulting from data obtained from small sample sizes, and inconsistent effects between studies due to high heterogeneity. Additionally, uncertainty about the clinical relevance of reported outcomes, applicability of findings and durability of positive effects were frequent limitations in the body of evidence. Further research with rigorous studies with larger patient sample sizes and long-term outcomes are required to demonstrate safety and efficacy.

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• Creation of Uniform LCDs With Other MAC Jurisdiction

• Intervertebral Disc Repair