Five-Year Longitudinal Follow-up of Restorative Neurostimulation Shows Durability of Effectiveness in Patients With Refractory Chronic Low Back Pain Associated With Multifidus Muscle Dysfunction.

BACKGROUND: Adults with refractory, mechanical chronic low back pain associated with impaired neuromuscular control of the lumbar multifidus muscle have few treatment options that provide long-term clinical benefit. This study hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology. MATERIALS AND METHODS: In this prospective five-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (N = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic low back pain, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. Low back pain intensity (10-cm visual analog scale [VAS]), disability (Oswestry Disability Index), and quality of life (EuroQol's "EQ-5D-5L" index) were compared with baseline and following the intent-to-treat principle, with a supporting mixed-effects model for repeated measures that accounted for missing data. RESULTS: At five years (n = 126), low back pain VAS had improved from 7.3 to 2.4 cm (-4.9; 95% CI, -5.3 to -4.5 cm; p < 0.0001), and 71.8% of participants had a reduction of ≥50%. The Oswestry Disability Index improved from 39.1 to 16.5 (-22.7; 95% CI, -25.4 to -20.8; p < 0.0001), and 61.1% of participants had reduction of ≥20 points. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95% CI, 0.195-0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a five-year visit, 46% discontinued, and 23% decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed. CONCLUSION: Over a five-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic low back pain associated with multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02577354; registration date: October 15, 2016; principal investigator: Christopher Gilligan, MD, Brigham and Women's Hospital, Boston, MA, USA. The study was conducted in Australia (Broadmeadow, New South Wales; Noosa Heads, Queensland; Welland, South Australia; Clayton, Victoria), Belgium (Sint-Niklaas; Wilrijk), The Netherlands (Rotterdam), UK (Leeds, London, Middlesbrough), and USA (La Jolla, CA; Santa Monica, CA; Aurora, CO; Carmel, IN; Indianapolis, IN; Kansas City, KS; Boston, MA; Royal Oak, MI; Durham, NC; Winston-Salem, NC; Cleveland, OH; Providence, RI; Spartanburg, SC; Spokane, WA; Charleston, WV).

Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial.

BACKGROUND: Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward. OBJECTIVE: This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. MATERIALS AND METHODS: Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation. RESULTS: At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake. CONCLUSIONS: At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The study is registered on clinicaltrials.gov with identifier NCT02577354.

Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction.

BACKGROUND: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability. OBJECTIVE: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. MATERIALS AND METHODS: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. RESULTS: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date. CONCLUSION: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02577354.

An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: a randomized sham-controlled clinical trial.

ABSTRACT: Chronic low back pain can be caused by impaired control and degeneration of the multifidus muscles and consequent functional instability of the lumbar spine. Available treatment options have limited effectiveness and prognosis is unfavorable. We conducted an international randomized, double-blind, sham-controlled trial at 26 multidisciplinary centers to determine safety and efficacy of an implantable, restorative neurostimulator designed to restore multifidus neuromuscular control and facilitate relief of symptoms (clinicaltrials.gov identifier: NCT02577354). Two hundred four eligible participants with refractory mechanical (musculoskeletal) chronic LBP and a positive prone instability test indicating impaired multifidus control were implanted and randomized to therapeutic (N = 102) or low-level sham (N = 102) stimulation of the medial branch of the dorsal ramus nerve (multifidus nerve supply) for 30 minutes twice daily. The primary endpoint was the comparison of responder proportions (≥30% relief on the LBP visual analogue scale without analgesics increase) at 120 days. After the primary endpoint assessment, participants in the sham-control group switched to therapeutic stimulation and the combined cohort was assessed through 1 year for long-term outcomes and adverse events. The primary endpoint was inconclusive in terms of treatment superiority (57.1% vs 46.6%; difference: 10.4%; 95% confidence interval, -3.3% to 24.1%, P = 0.138). Prespecified secondary outcomes and analyses were consistent with a modest but clinically meaningful treatment benefit at 120 days. Improvements from baseline, which continued to accrue in all outcome measures after conclusion of the double-blind phase, were clinically important at 1 year. The incidence of serious procedure- or device-related adverse events (3.9%) compared favorably with other neuromodulation therapies for chronic pain.

Durability of the Therapeutic Effect of Restorative Neurostimulation for Refractory Chronic Low Back Pain.

OBJECTIVES: The purpose of the ongoing follow-up of ReActiv8-A clinical trial is to document the longitudinal benefits of episodic stimulation of the dorsal ramus medial branch and consequent contraction of the lumbar multifidus in patients with refractory mechanical chronic low back pain (CLBP). We report the four-year outcomes of this trial. MATERIALS AND METHODS: ReActiv8-A is a prospective, single-arm trial performed at nine sites in the United Kingdom, Belgium, and Australia. Eligible patients had disabling CLBP (low back pain Numeric Rating Scale [NRS] ≥6; Oswestry Disability Index [ODI] ≥25), no indications for spine surgery or spinal cord stimulation, and failed conventional management including at least physical therapy and medications for low back pain. Fourteen days postimplantation, stimulation parameters were programmed to elicit strong, smooth contractions of the multifidus, and participants were given instructions to activate the device for 30-min stimulation-sessions twice daily. Annual follow-up through four years included collection of NRS, ODI, and European Quality of Life Score on Five Dimensions (EQ-5D). Background on mechanisms, trial design, and one-year outcomes were previously described. RESULTS: At baseline (N = 53) (mean ± SD) age was 44 ± 10 years; duration of back pain was 14 ± 11 years, NRS was 6.8 ± 0.8, ODI 44.9 ± 10.1, and EQ-5D 0.434 ± 0.185. Mean improvements from baseline were statistically significant (p < 0.001) and clinically meaningful for all follow-ups. Patients completing year 4 follow-up, reported mean (±standard error of the mean) NRS: 3.2 ± 0.4, ODI: 23.0 ± 3.2, and EQ-5D: 0.721 ± 0.035. Moreover, 73% of participants had a clinically meaningful improvement of ≥2 points on NRS, 76% of ≥10 points on ODI, and 62.5% had a clinically meaningful improvement in both NRS and ODI and 97% were (very) satisfied with treatment. CONCLUSIONS: In participants with disabling intractable CLBP who receive long-term restorative neurostimulation, treatment satisfaction remains high and improvements in pain, disability, and quality-of-life are clinically meaningful and durable through four years.

The identification of preliminary prognostic indicators that predict treatment response for exercise therapy in patients with nonspecific chronic low back pain: A multiple-arm cohort study design.

BACKGROUND: For patients with nonspecific chronic low back pain (CLBP), exercise therapy is stated to be the most effective intervention strategy but it is unclear which kind of exercise therapy is most beneficial. OBJECTIVE: To identify preliminary prognostic indicators that predict outcome for exercise therapy in patients with nonspecific CLBP. METHODS: Patients were recruited in two hospitals and received 18 intervention sessions: stabilization therapy, isometric training therapy or a combination therapy. The primary outcome measure was the change in the Modified Low Back Pain Disability Questionnaire after nine weeks. RESULTS: A total of 59 patients completed the study which represents a statistical power of 90%. In total, 30 patients were categorized as having treatment success and 29 as treatment failure. After using regression analyses to determine the association between standardized examination variables and treatment response status, prognostic indicators were identified for predicting therapy success (positive likelihood ratio [LR], 3.8) and failure (negative LR, 0.19). CONCLUSIONS: The most important variables were the prone instability test, pelvic tilt test, straight leg raise, body weight, visual analogue scale and the short form 36 health survey.

Muscle Control and Non-specific Chronic Low Back Pain.

OBJECTIVES: Chronic low back pain (CLBP) is the most prevalent of the painful musculoskeletal conditions. CLBP is a heterogeneous condition with many causes and diagnoses, but there are few established therapies with strong evidence of effectiveness (or cost effectiveness). CLBP for which it is not possible to identify any specific cause is often referred to as non-specific chronic LBP (NSCLBP). One type of NSCLBP is continuing and recurrent primarily nociceptive CLBP due to vertebral joint overload subsequent to functional instability of the lumbar spine. This condition may occur due to disruption of the motor control system to the key stabilizing muscles in the lumbar spine, particularly the lumbar multifidus muscle (MF). METHODS: This review presents the evidence for MF involvement in CLBP, mechanisms of action of disruption of control of the MF, and options for restoring control of the MF as a treatment for NSCLBP. RESULTS: Imaging assessment of motor control dysfunction of the MF in individual patients is fraught with difficulty. MRI or ultrasound imaging techniques, while reliable, have limited diagnostic or predictive utility. For some patients, restoration of motor control to the MF with specific exercises can be effective, but population results are not persuasive since most patients are unable to voluntarily contract the MF and may be inhibited from doing so due to arthrogenic muscle inhibition. CONCLUSIONS: Targeting MF control with restorative neurostimulation promises a new treatment option.

New Therapy for Refractory Chronic Mechanical Low Back Pain-Restorative Neurostimulation to Activate the Lumbar Multifidus: One Year Results of a Prospective Multicenter Clinical Trial.

OBJECTIVES: The purpose of the international multicenter prospective single arm clinical trial was to evaluate restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical low back pain (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or spinal cord stimulation (SCS). MATERIALS AND METHODS: Fifty-three subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was low back pain evaluated on a 10-Point Numerical Rating Scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of ≥2-point in low back pain NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and Quality of Life (QoL; EQ-5D). RESULTS: For 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58%. The percentage of subjects at 90 days, six months, and one year with ≥MCID improvement in single day NRS was 63%, 61%, and 57%, respectively. Percentage of subjects with ≥MCID improvement in ODI was 52%, 57%, and 60% while those with ≥MCID improvement in EQ-5D was 88%, 82%, and 81%. There were no unanticipated adverse events (AEs) or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach. CONCLUSIONS: Electrical stimulation to elicit episodic lumbar multifidus contraction is a new treatment option for CMLBP. Results demonstrate clinically important, statistically significant, and lasting improvement in pain, disability, and QoL.

The Modified Low Back Pain Disability Questionnaire: Reliability, Validity, and Responsiveness of a Dutch Language Version.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: The goal of this study is to translate the English version of the Modified Low Back Pain Disability Questionnaire (MDQ) into a Dutch version and investigate its clinimetric properties for patients with nonspecific chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Fritz et al (2001) developed a modified version of the Oswestry Disability Questionnaire (ODI) to assess functional status and named it the MDQ. In this version, a question regarding employment and homemaking ability was substituted for the question related to sex life. Good clinimetric properties for the MDQ were identified but up until now it is not clear whether the clinimetric properties of the MDQ would change if it was translated into a Dutch version. METHODS: Translation of the MDQ into Dutch was done in 4 steps. Test-retest reliability was investigated using the intraclass correlation coefficient (ICC) model. Validity was calculated using Pearson correlations and a 2-way analysis of variance for repeated measures. Finally, responsiveness was calculated with the area under the curve (AUC), minimal detectable change (MDC), and the standardized response mean (SRM). RESULTS: A total of 80 completed questionnaires were collected in 3 different hospitals and a total of 43 patients finished a 9 weeks intervention period, completing the retest. Test-retest reliability was excellent with an ICC of 0.89 (95% confidence interval [CI], 0.74-0.95). To confirm the convergent validity, the MDQ answered all predefined hypothesises (r = -0.65-0.69/P = 0.01-0.00) and good results for construct validity were found (P = 0.02). The MDQ had an AUC of 0.64 (95% confidence interval [CI], 0.47-0.81), an MDC of 8.80 points, and a SRM of 0.65. CONCLUSION: The Dutch version of the MDQ shows good clinimetric properties and is shown to be usable in the assessment of the functional status of Dutch-speaking patients with nonspecific CLBP. LEVEL OF EVIDENCE: 3.

Chronic Low Back Pain: Restoration of Dynamic Stability.

OBJECTIVES: Electrical stimulation for multifidus muscle contraction is a novel approach for treating chronic low back pain (CLBP). A multicenter, open-label feasibility study investigated this modality in patients with continuing CLBP despite medical management and no prior back surgery and no known pathological cause of CLBP. METHODS: Twenty-six patients with continuing CLBP despite physical therapy and medication were implanted with commercially-available implantable pulse generators and leads positioned adjacent to the medial branch of the dorsal ramus as it crosses the L3 transverse process such that electrical stimulation resulted in contraction of the lumbar multifidus (LM) muscle. Patients self-administered stimulation twice daily for 20 min. Low back pain (VAS), Oswestry Disability Index (ODI) and Quality of Life (EQ-5D) scores were collected at three and five months and compared to baseline. Stimulation was withdrawn between months 4 and 5 to test durability of effect. RESULTS: At three months, 74% of patients met or exceeded the minimally important change (MIC) in VAS and 63% for disability. QoL improved in 84% of patients (N = 19) and none got worse. Five of the 11 patients on disability for CLBP (45%) resumed work by three months. Half the patients reported ≥50% VAS reduction by month 5. Twenty-one lead migration events occurred in 13 patients, of which 7 patients are included in the efficacy cohort. CONCLUSIONS: Episodic stimulation to induce LM contraction can reduce CLBP and disability, improve quality of life and enable return to work. A dedicated lead design to reduce risk of migration is required.