Allogeneic Disc Progenitor Cells Safely Increase Disc Volume and Improve Pain, Disability, and Quality of Life in Patients With Lumbar Disc Degeneration-Results of an FDA-Approved Biologic Therapy Randomized Clinical Trial.

BACKGROUND: Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and efficacy results of a US Food and Drug Administration-approved clinical trial of these cells for the treatment of symptomatic degenerative disc disease. METHODS: Sixty patients with symptomatic single-level lumbar degenerative disc disease (mean age 37.9 years, 60% men) were enrolled in a randomized, double-blinded, placebo-controlled Phase I/Phase II study at 13 clinical sites. They were randomized to receive single intradiscal injections of either low-dose cells (N = 20), high-dose cells (N = 20), vehicle alone (N = 10), or placebo (N = 10). The primary endpoint was mean visual analog scale (VAS) pain improvement >30% at 52 weeks. Disc volume was radiologically assessed. Adverse events (AEs), regardless of whether they were related to treatment, were reported. Patients were assessed at baseline and at 4, 12, 26, 52, 78, and 104 weeks posttreatment. RESULTS: At week 52, the high-dose group had a mean VAS percentage decrease from baseline (-62.8%, P = 0.0005), achieving the endpoint of back pain improvement >30%; the mean change was also significantly greater than the minimal clinically important difference of a 20-point decrease (-42.8, P = 0.001). This clinical improvement was maintained at week 104. The vehicle group had a smaller significant decrease in VAS (-52.8%, P = 0.044), while the low-dose and placebo groups showed nonsignificant improvements. Only the high-dose group had a significant change in disc volume, with mean increases of 249.0 mm3 (P = 0.028) at 52 weeks and 402.1 mm3 (P = 0.028) at 104 weeks. A minority of patients (18.3%) reported AEs that were severe. Overall, 6.7% of patients experienced serious AEs, all in the vehicle (n = 1) or placebo (n = 3) groups, none treatment related. CONCLUSIONS: High-dose allogeneic disc progenitor cells produced statistically significant, clinically meaningful improvements in back pain and disc volume at 1 year following a single intradiscal injection and were safe and well tolerated. These improvements were maintained at 2 years post-injection. CLINICAL TRIAL REGISTRATION: NCT03347708-Study to Evaluate the Safety and Preliminary Efficacy of Injectable Disc Cell Therapy, a Treatment for Symptomatic Lumbar Intervertebral Disc Degeneration.

Effect of age on outcomes after allogeneic disc tissue supplementation in patients with chronic discogenic low back pain in the VAST trial.

Aim: To explore the effects of viable allogeneic disc tissue supplementation in younger patients with discogenic chronic low back pain (CLBP). Patients & methods: VAST was a randomized placebo-controlled trial of disc allograft supplementation in 218 patients with discogenic CLBP. We conducted a post hoc analysis of change from baseline to 12 months in Oswestry Disability Index (ODI) and visual analog scale for pain intensity scores stratified by patient age. Results: Patients aged <42 years receiving allograft experienced greater improvement in ODI (p = 0.042) and a higher ODI response rate (≥10-, ≥15- and ≥20-point reductions in ODI) than those receiving saline (p = 0.001, p = 0.002 and p = 0.021, respectively). Conclusion: Young patients with discogenic CLBP may have significant functional improvement following nonsurgical disc allograft supplementation.

The VAST trial evaluated a new treatment for patients with chronic back pain resulting from one or two degenerated spinal discs. The treatment consists of a single injection of disc tissue supplement. A total of 218 adults participated in the study; most received the active treatment, while a smaller number (39 patients) received an injection of saline. In this paper we explain what happened over the 12 months after the injections. Patients who were younger (<42 years old) experienced more functional benefits (i.e., ability to perform daily tasks) after active treatment compared with those who received the saline injection, as measured by disability score. In contrast, older patients (≥42 years old) experienced functional benefits with both active and saline treatments, with no differences between the groups. There were more side effects in both age groups in those who received the active treatment compared with those who received saline, but almost all of the side effects were temporary and not serious. Clinical Trial Registration number: NCT03709901 (ClinicalTrials.gov).

Treatment of chronic axial back pain with 60-day percutaneous medial branch PNS: Primary end point results from a prospective, multicenter study.

BACKGROUND: The objective of this prospective, multicenter study is to characterize responses to percutaneous medial branch peripheral nerve stimulation (PNS) to determine if results from earlier, smaller single-center studies and reports were generalizable when performed at a larger number and wider variety of centers in patients recalcitrant to nonsurgical treatments. MATERIALS & METHODS: Participants with chronic axial low back pain (LBP) were implanted with percutaneous PNS leads targeting the lumbar medial branch nerves for up to 60 days, after which the leads were removed. Participants were followed long-term for 12 months after the 2-month PNS treatment. Data collection is complete for visits through end of treatment with PNS (primary end point) and 6 months after lead removal (8 months after start of treatment), with some participant follow-up visits thereafter in progress. RESULTS: Clinically and statistically significant reductions in pain intensity, disability, and pain interference were reported by a majority of participants. Seventy-three percent of participants were successes for the primary end point, reporting clinically significant (≥30%) reductions in back pain intensity after the 2-month percutaneous PNS treatment (n = 54/74). Whereas prospective follow-up is ongoing, among those who had already completed the long-term follow-up visits (n = 51), reductions in pain intensity, disability, and pain interference were sustained in a majority of participants through 14 months after the start of treatment. CONCLUSION: Given the minimally invasive, nondestructive nature of percutaneous PNS and the significant benefits experienced by participants who were recalcitrant to nonsurgical treatments, percutaneous PNS may provide a promising first-line neurostimulation treatment option for patients with chronic axial back pain.

Use of Bone Marrow Concentrate to Treat Pain and Musculoskeletal Disorders: An Academic Delphi Investigation.

BACKGROUND: Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. OBJECTIVES: The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. STUDY DESIGN: Delphi panel technique. SETTING: The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. METHODS: An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. RESULTS: Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. LIMITATIONS: The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. CONCLUSIONS: There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.

Percutaneous Peripheral Nerve Stimulation of the Medial Branch Nerves for the Treatment of Chronic Axial Back Pain in Patients After Radiofrequency Ablation.

OBJECTIVE: Lumbar radiofrequency ablation is a commonly used intervention for chronic back pain. However, the pain typically returns, and though retreatment may be successful, the procedure involves destruction of the medial branch nerves, which denervates the multifidus. Repeated procedures typically have diminishing returns, which can lead to opioid use, surgery, or implantation of permanent neuromodulation systems. The objective of this report is to demonstrate the potential use of percutaneous peripheral nerve stimulation (PNS) as a minimally invasive, nondestructive, motor-sparing alternative to repeat radiofrequency ablation and more invasive surgical procedures. DESIGN: Prospective, multicenter trial. METHODS: Individuals with a return of chronic axial pain after radiofrequency ablation underwent implantation of percutaneous PNS leads targeting the medial branch nerves. Stimulation was delivered for up to 60 days, after which the leads were removed. Participants were followed up to 5 months after the start of PNS. Outcomes included pain intensity, disability, and pain interference. RESULTS: Highly clinically significant (≥50%) reductions in average pain intensity were reported by a majority of participants (67%, n = 10/15) after 2 months with PNS, and a majority experienced clinically significant improvements in functional outcomes, as measured by disability (87%, n = 13/15) and pain interference (80%, n = 12/15). Five months after PNS, 93% (n = 14/15) reported clinically meaningful improvement in one or more outcome measures, and a majority experienced clinically meaningful improvements in all three outcomes (i.e., pain intensity, disability, and pain interference). CONCLUSIONS: Percutaneous PNS has the potential to shift the pain management paradigm by providing an effective, nondestructive, motor-sparing neuromodulation treatment.

Cervical disc degeneration and neck pain.

Cervical intervertebral disc has long been considered a common source of neck pain. However, the pain caused by the disc itself has not been clearly defined so far, and its diagnosis and treatment has always been controversial. Degenerative cervical disc has a rich supply of nerve fibers, is prone to inflammatory reactions, and is susceptible to pain that can be provoked by disc stimulation or distention, and can be eliminated by block. Overwhelming clinical evidence demonstrates that neck pain in patients with degenerative cervical radiculopathy or myelopathy can be subsided rapidly by anterior cervical surgery, further indicating that this neck pain stems from the pathology of cervical disc itself. Cervical discography is advocated as the only test that connects disease to symptoms, but the procedure remains controversial. If strict criteria and technique are maintained, discography can discriminate painful, symptomatic discs from nonpainful, asymptomatic discs. Discogenic neck pain alone without cervical disc herniation or cervical spondylosis accounts for a large proportion of chronic neck pain. For these patients who continue to have refractory neck pain and fail to respond to conservative treatment, anterior cervical fusion surgery or artificial cervical disc replacement may be a better choice, and preoperative cervical discography can guarantee the excellent surgical results. Existing basic and clinical studies have scientifically shown that cervical intervertebral disc degeneration can lead to neck pain.

Cellular supplementation technologies for painful spine disorders.

Low back pain affects more than 80% of adults. A proportion of these adults develops chronic low back pain (CLBP) and becomes disabled by their condition. CLBP is expensive to diagnose and treat and in terms of associated loss of productivity in the work place setting by affected individuals. Although challenging, the source of CLBP can be identified. Contemporary literature contains several studies that have established prevalence estimates for various structural sources of CLBP. In young adults, the intervertebral disk is a common source of CLBP, once it incurs annular injury that heals incompletely. Effective treatment for painful disks currently is an unmet clinical need. In older adults, the facet and sacroiliac joints are more commonly responsible for CLBP. Although certain minimally invasive techniques do exist for these painful joints, an effective restorative intervention has yet to be established. Annular injury precipitates a physiologic response that can lead to a catabolic state within the disk that impairs disk restoration. Cell loss is a feature of this process as well as the pathophysiology associated with painful facet and sacroiliac joints. Cellular supplementation is an attractive treatment strategy to initiate the repair of an injured lumbosacral structure. The introduction of exogenous cells may lead to increased extracelluar matrix production and reduced pain and disability in diskogenic CLBP. Compelling data in animal studies have been produced, stimulating Food and Drug Administration-regulated trials in humans. Numerous questions remain regarding cell viability and sufficient native nutrients to support these cells. Clinical research protocols have focused predominantly on diskogenic CLBP, and very few have addressed painful facet and/or sacroiliac joints.

An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy.

BACKGROUND CONTEXT: The objective of the North American Spine Society's (NASS) Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy is to provide evidence-based recommendations to address key clinical questions surrounding the diagnosis and treatment of lumbar disc herniation with radiculopathy. The guideline is intended to reflect contemporary treatment concepts for symptomatic lumbar disc herniation with radiculopathy as reflected in the highest quality clinical literature available on this subject as of July 2011. The goals of the guideline recommendations are to assist in delivering optimum efficacious treatment and functional recovery from this spinal disorder. PURPOSE: To provide an evidence-based educational tool to assist spine specialists in the diagnosis and treatment of lumbar disc herniation with radiculopathy. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This guideline is a product of the Lumbar Disc Herniation with Radiculopathy Work Group of NASS' Evidence-Based Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. A literature search addressing each question and using a specific search protocol was performed on English-language references found in Medline, Embase (Drugs and Pharmacology), and four additional evidence-based databases to identify articles. The relevant literature was then independently rated using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were developed via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Level I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Twenty-nine clinical questions were formulated and addressed, and the answers are summarized in this article. The respective recommendations were graded by strength of the supporting literature, which was stratified by levels of evidence. CONCLUSIONS: The clinical guideline has been created using the techniques of evidence-based medicine and best available evidence to aid practitioners in the care of patients with symptomatic lumbar disc herniation with radiculopathy. The entire guideline document, including the evidentiary tables, suggestions for future research, and all the references, is available electronically on the NASS Web site at http://www.spine.org/Pages/PracticePolicy/ClinicalCare/ClinicalGuidlines/Default.aspx and will remain updated on a timely schedule.

Comparison of four different analgesic discogram protocols comparing the incidence of reported pain relief following local anesthetic injection into concordantly painful lumbar intervertebral discs.

OBJECTIVE: To compare the incidence of pain relief following injection of local anesthetic (LA) into lumbar discs that caused concordant pain during provocation testing. DESIGN: Prospective collected data review from two centers and compare with published results. OUTCOME MEASURES: We compared subjective reported pain relief following provocative testing using the following protocols at three separate facilities: 23 patients undergoing routine provocative discography using contrast alone (PD); 47 patients undergoing provocative discography performed using an equal combination of LA and contrast (CPD); 120 patients injected with LA following routine PD (ADPD); 33 patients undergoing stand-alone analgesic discography (SAAD); and 28 patients injected with LA through a catheter (FAD) placed during provocative discogaphy testing. RESULTS: Pressure-controlled PD showed a positive response rate of 34% per disc in patients with a clinical diagnosis of discogenic pain. None of the PD group without LA had pain relief and less than 10% of the CPD group reported pain relief. Forty percent of the SAAD group with positive pain reproduction reported ≥50% relief and 20% reporting ≥80% relief. Forty-six percent of the ADPD group reported ≥50% relief and 30% reporting ≥80% relief. The FAD group had a greater 80% patients reporting ≥50% pain relief although fewer 26% reporting more convincing ≥80% relief. CONCLUSIONS: If the criterion standard to confirm painful annular tears is concordant pain provocation and 80% or greater pain relief following LA injected into lumbar discs, the SAAD, ADPD, and FAD protocols show statistically similar 20% to 30% prevelance.

Spine osteoarthritis.

Osteoarthritis of the spine develops as a consequence of the natural aging process and is associated with significant morbidity and health care expenditures. Effective diagnosis and treatment of the resultant pathologic conditions can be clinically challenging. Recent evidence has emerged to aid the investigating clinician in formulating an accurate diagnosis and in implementing a successful treatment algorithm. This article details the degenerative cascade that results in the osteoarthritic spine, reviews prevalence data for common painful spinal disorders, and discusses evidence-based treatment options for management of zygapophysial and sacroiliac joint arthrosis.

Multivariable analysis of the relationship between pain referral patterns and the source of chronic low back pain.

BACKGROUND: Discogenic, facet joint, and sacroiliac joint mediated axial low back pain may be associated with overlapping pain referral patterns into the lower limb. Differences between pain referral patterns for these three structures have not been systematically investigated. OBJECTIVE: To examine the individual and combined relationship of age, hip/girdle pain, leg pain, and thigh pain and the source of internal disc disruption (IDD), facet joint pain (FJP), or sacroiliac joint pain (SIJP) in consecutive chronic low back pain (CLBP) patients. DESIGN: Retrospective chart review. SETTING: Community based interventional spine practice. PATIENTS: 378 cases from 358 consecutive patients were reviewed and 157 independent cases from 153 patients who underwent definitive diagnostic injections were analyzed. METHODS: Charts of consecutive low back pain patients who underwent definitive diagnostic spinal procedures were retrospectively reviewed. Patients underwent provocation lumbar discography, dual diagnostic medial branch blocks, or intra-articular diagnostic sacroiliac joint injections based on clinical presentation. Some subjects underwent multiple diagnostic injections until the source of their chronic low back pain (CLBP) was identified. MAIN OUTCOME MEASUREMENTS: Based on the results of diagnostic injections, subjects were classified as having IDD, FJP, SIJP, or other. The mean age/standard deviation and the count/percentage of patients reporting hip girdle pain, leg pain, or thigh pain were estimated for each diagnostic group and compared statistically among the IDD, FJP, SIJP, and other source groups. Next, the 4 predictor variables were simultaneously modeled with a single multinomial logistic regression model to explore the adjusted relationship between the predictors and the source of CLBP. RESULTS: The mean age was significantly different among the source groups. IDD cases were significantly younger than FJP, SIJP, and other source groups and FJP cases were significantly younger than other sources. The age by thigh pain interaction effect was statistically significant (P = 0.021), indicating that the effect of age on the source of CLBP depends on thigh pain, and similarly, that the effect of thigh pain on the source of CLBP depends on age. LIMITATIONS: Retrospective study design. CONCLUSIONS: The presence or absence of thigh pain possesses a significant correlation on the source of CLBP for varying ages, whereas the presence of hip/girdle pain or leg pain did not significantly discriminate among IDD, FJP, or SIJP as the etiology of CLBP. Younger age was predictive of IDD regardless of the presence or absence of thigh pain.

Multivariable analyses of the relationships between age, gender, and body mass index and the source of chronic low back pain.

OBJECTIVE: To examine the combined relationships between age, gender, and body mass index (BMI) and the specific source of chronic low back pain. DESIGN: Retrospective chart review. SETTING: University spine center. PATIENTS: Charts from 378 cases from 358 consecutive patients were reviewed and 157 independent cases from 153 patients who underwent definitive diagnostic injections were analyzed. INTERVENTIONS: Discography, dual diagnostic facet joint blocks, sacroiliac joint injections, anesthetic interspinous ligaments/opposing spinous processes/posterior fusion hardware injections, percutaneous augmentation. OUTCOME MEASURES: Chronic low back pain source was the primary outcome variable. Predictor variables included age at initial presentation, gender, and BMI. RESULTS: Age, gender, and BMI were each significantly associated with the source of chronic low back pain, after controlling for the effects of each other. Increases in age were associated with significant decreases in the odds of internal disc disruption (IDD) vs facet joint pain (FJP), sacroiliac joint pain (SIJP), and other sources and decreases in the odds of FJP and SIJP vs other sources. Being female was associated with significant increases in the odds of SIJP vs IDD, FJP, and other sources. Increased BMI was associated with significant increases in the odds of FJP vs SIJP. CONCLUSIONS: These findings suggest a significant relationship among gender, age, and BMI and structural causes of chronic low back pain. Lumbar IDD is more prevalent in young males while FJP is more prevalent in females with increased BMI. Female gender and low BMI are associated with SIJP.

Is the history of a surgical discectomy related to the source of chronic low back pain?

BACKGROUND: Recurrent or persistent low back pain (LBP) after surgical discectomy (SD) for intervertebral disc herniation has been well documented. The source of low back pain in these patients has not been examined. OBJECTIVE: To compare the distribution of the source of chronic LBP between patients with and without a history of SD. STUDY DESIGN: Retrospective chart review. SETTING: Academic spine center. PATIENTS: Charts from 358 consecutive patients were reviewed. Charts noting the absence/presence of SD in patients who subsequently underwent diagnostic injections to determine the source of chronic LBP were included resulting in 158 unique cases for analysis. METHODS: Patients underwent either dual diagnostic facet joint blocks, intra-articular diagnostic sacroiliac joint injections, provocation lumbar discography, or anesthetic injection into putatively painful interspinous ligaments/opposing spinous processes/posterior fusion hardware. If the initial diagnostic procedure was negative, the next most likely structure in the diagnostic algorithm was interrogated. Subsequent diagnostic procedures were not performed after the source of chronic LBP was identified. OUTCOME: The source of chronic LBP was diagnosed as discogenic pain (DP), facet joint pain (FJP), sacroiliac joint pain (SIJP), or other sources of chronic LBP. RESULTS: Based on a Fisher's exact test, there was marginal evidence the distribution of the source of chronic LBP differed for those with and without a history of SD (P = 0.080). Post-hoc comparisons suggested that patients with a history of SD have a higher probability of DP compared to those without a history of SD (82% versus 41%; P = 0.011). Differences in the probability of FJP, SIJP, or other sources between the SD history groups were not significant. LIMITATIONS: Small sample size, restrospective design, and possible false-positive results. CONCLUSIONS: This is the first published investigation of the tissue source of chronic LBP after SD. It appears that DP is the most common reason for chronic LBP after SD. If more rigorous study confirms our findings, future biologic treatments may hold value in repairing symptomatic annular fissures after SD.