An Implantable Restorative-Neurostimulator for Refractory Mechanical Chronic Low Back Pain

A Randomized Sham-controlled Clinical Trial

Christopher Gilligan; Willem Volschenk; Marc Russo; Matthew Green; Christopher Gilmore; Vivek Mehta; Kristiaan Deckers; Kris De Smedt; Usman Latif; Peter Georgius; Jonathan Gentile; Bruce Mitchell; Meredith Langhorst; Frank Huygen; Ganesan Baranidharan; Vikas Patel; Eugene Mironer; Edgar Ross; Alexios Carayannopoulos; Salim Hayek; Ashish Gulve; Jean-Pierre Van Buyten; Antoine Tohmeh; Jeffrey Fischgrund; Shivanand Lad; Farshad Ahadian; Timothy Deer; William Klemme; Richard Rauck; James Rathmell; Robert Levy; Jan Pieter Heemels; Sam Eldabe

Disclosures

Pain. 2021;162(10):2486-249. 

In This Article

Abstract and Introduction

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.

Introduction

Low back pain is the leading cause of years lived with disability worldwide and often a determinant for chronic opioid use.[43,49,64] In the United States, direct healthcare spending on low back and neck pain is estimated at $87.6 billion and growing at a rate of 6.5% annually,[22] and indirect costs including disability benefits and days of work missed are estimated to be as high as $624.8 billion.[15] Most cases of acute low back pain (LBP) resolve spontaneously without treatment, but chronic LBP (CLBP) is far less likely to resolve on its own.[52] Patients with CLBP often endure impaired quality of life, depression, anxiety, and sleep disturbance.[3,7]

The majority of patients with CLBP have no indication for spine surgery but are suffering from mechanical (musculoskeletal) pain that is predominantly nociceptive.[5,21,36] Although nonsurgical treatments, including physical therapy, chiropractic care, nonopioid and opioid medications, injections, and medial branch rhizotomy, provide modest relief and improved function for some, they are ineffective or provide only transient relief for many.[1,4,8,10,29,63,65,68,72,84] Although spinal cord stimulation is an option to be considered for individuals who have failed multiple other treatments and have disabling symptoms related to neuropathic leg and LBP, it is not considered appropriate for the treatment of mechanical CLBP.[19,80]

Mechanical CLBP is often associated with impaired motor control and degeneration of the multifidus muscles, which play an important role in providing segmental control of functional lumbar spine stability.[37,55,73,79] Acute back pain–induced disruption of proprioceptive signaling is believed to facilitate long-term motor control changes via cortical reorganization.[58] This hypothesis is supported by experimental and clinical findings. For example, experimentally induced disk or nerve root injury reduces multifidus neural drive,[48] and in patients with mechanical CLBP, electromyographic activity and ability to recruit the multifidus muscle is diminished.[16]

Although motor control exercises for mechanical CLBP seem to be more effective in the short-term than other exercises, their long-term effectiveness is limited.[10,74] One possible explanation for this is that isolated muscle activation, which is required to reverse impaired motor control,[47,81] is difficult to achieve voluntarily, especially in the presence of underlying inhibition of the multifidus muscle. Furthermore, the structural changes in the muscle and cortical remodeling observed in patients with mechanical CLBP are likely to require longer treatment duration.[47,82]

Based on these insights, it was proposed that eliciting isolated multifidus activation by electrically stimulating the medial branch of the dorsal ramus nerve could facilitate restoration of segmental control and functional stability, and enable symptom reduction.[66]

Encouraging clinical results from a feasibility study led to the development of an implantable, restorative-neurostimulator (ReActiv8; Mainstay Medical, Dublin, Ireland).[17] A prospective multicenter single-arm clinical study supported European regulatory approval for the system in 2016,[18] and informed the development of the ReActiv8-B pivotal trial, designed to determine the safety and efficacy of this restorative-neurostimulator under an investigational device exemption from the United States Food and Drug Administration (FDA). The primary objective of this trial was to test the hypothesis that at the end of the 120-day blinded phase, there would be a greater proportion of responders in the treatment group that received therapeutic stimulation than in the sham-control group that received low-level sham stimulation.

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