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).

Neurophysiological outcomes that sustained clinically significant improvements over 3 years of physiologic ECAP-controlled closed-loop spinal cord stimulation for the treatment of chronic pain.

INTRODUCTION: A novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements. METHODS: 41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain. RESULTS: The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively). CONCLUSION: The results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Intrathecal drug delivery in the management of chronic pain.

Targeted intrathecal drug delivery (TIDD) has the objective of bringing the drug(s) close to the receptors influencing pain modulation, and thus reducing the dose and the side effects. Intrathecal drug delivery knew its real start with the development of permanent implantation of intrathecal and epidural catheters, combined with internal or external ports, reservoirs, and programmable pumps. TIDD is a valuable treatment for patients with cancer suffering refractory pain. Patients suffering noncancer-related pain should only be considered for TIDD when all other options have been tested, including spinal cord stimulation. Only two drugs are approved by the US Food and Drug Administration for TIDD administration for chronic pain: morphine and ziconotide as monotherapy. In pain management, off-label use of medication and combination therapy is often reported. The specific action of the intrathecal drugs, the efficacy and safety, is described, as well as the modalities for trialing intrathecal drug delivery and the implantation methods.

Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

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.

Multi-waveform Spinal Cord Stimulation with High Frequency Electromagnetic Coupled (HF-EMC) Powered Implanted Electrode Array and Receiver for the Treatment of Chronic Back and Leg Pain (SURF Study).

BACKGROUND: Novel externally powered spinal cord stimulation technology can be fully implanted when trialing the effectiveness of the therapy, since no percutaneous leads are needed, and the trial period lasted 30 days. Multiple tests of different stimulation modalities and parameters are possible, thus improving the chances that the therapy will lead to effective pain reduction. OBJECTIVES: The objective of this study was to analyze the effectiveness of the Freedom Spinal Cord Stimulator System (Stimwave LLC, Pompano Beach, FL) for the treatment of failed back surgery syndrome due to postlaminectomy syndrome utilizing multiple waveforms. STUDY DESIGN: This was a prospective, single cohort study. Patients were enrolled and implanted with up to 2 permanent, 8-contact electrode arrays with receiver, controlled regularly during 6 months of follow-up after a one month trial period. Pain and overall improvement were evaluated at 3 months and 6 months following an initial one-month implanted trial period. SETTINGS: A variety of frequency stimulation waveforms (tonic as well as subthreshold) at frequencies of 10 Hz to 1500 Hz* and 50 to 800 µs pulse width, were provided. (*Note: While 1500 Hz was utilized in the study, Stimwave Technologies is currently only permitted to provide spinal cord stimulation therapy at frequencies below 1500 Hz, therefore pulse rates used in this study are not commercially available on Stimwave Technologies' products). METHODS: Endpoints evaluated included the Visual Analog Scale (VAS) for pain intensity, Oswestry Disability Index (ODI) for functionality, Patient Global Impression of Change (PGIC) for overall health improvement, and quality of life as measured by the European Quality of Life 5 Dimension questionnaire (EQ-5D-5L). RESULTS: Thirty-nine patients completed the study. At 6 months, the responder rate (? 50% reduction VAS for back pain) was 33/39 = 85%. Mean VAS for back pain decreased 62%. The mean ODI decreased 46% from 54 to 29.2, indicating a reduction from severe to moderate disability. The median satisfaction as measured with the PGIC was 6 out of 7. The mean EQ-5D-5L utility score increased from 0.54 to 0.75. At the 6-months endpoint, 44% (17/39) of patients preferred tonic stimulation with a back pain per protocol responder rate of 82%; 41% (16/39) preferred surge with a responder rate of 56%; and 15% (6/39) preferred high density, with a responder rate of 83%. Fifteen patients reported 28 adverse events. Migration of the electrode array (n = 10) was the adverse event most reported. Two serious adverse events related to infection were reported. LIMITATIONS: This study had several limitations. Trial failures were excluded from the analysis, there was a small sample size, and there was a lack of blinding due to the suprathreshold nature of tonic stimulation. CONCLUSION: The study demonstrates that spinal cord stimulation with multiple stimulation patterns demonstrates clinical and functional efficacy when using an externally powered stimulation system.

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.

Atypical opioids and their effect on respiratory drive.

Opioids are an important tool in the treatment of pain, but opioid overdose has become a serious health issue. Most opioid-related deaths are caused by respiratory depression, and the risk of respiratory depression is compounded because of the risks of abuse and diversion, which makes the need for safer opioids even more urgent. However, the atypical opioids (buprenorphine, tramadol, and tapentadol), with mechanisms of action not purely driven by µ-opioid receptor agonism, may be safer than conventional opioids, eg, morphine, oxycodone, and fentanyl. The purpose of this narrative review is to describe the clinical and experimental evidence regarding opioid-induced respiratory depression in the context of the mechanisms of action of the atypical opioids. Among the atypical opioids, tramadol has an advantage of being a Schedule IV drug, and thus having a relatively low abuse potential-but its effects, including its effect on respiratory drive, are dependent on cytochrome P450 2D6 metabolizer status. Tapentadol appears to affect respiratory drive, but this has not been well investigated. Buprenorphine is a Schedule III drug, thus having less abuse potential than the majority of opioids. Experimentally, a ceiling effect on the respiratory depression has been reported with intravenous buprenorphine. In addition, experimental hypercapnic stress in healthy volunteers demonstrated no respiratory depression following the administration of a single dose of the buccal film formulation of buprenorphine when compared with placebo. Overall, the data suggest that atypical opioids may be a safer option than conventional opioids for the treatment of pain.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Conversion of Schedule II Opioids to Buprenorphine Buccal Film: A Retrospective Analysis.

OBJECTIVE: To provide clinical data for the conversion of Schedule II opioids to buprenorphine buccal film and to demonstrate sustained analgesia and a reduction in morphine milligram equivalents after conversion. DESIGN: Retrospective review of electronic medical records. SETTING: Group clinical practice providing outpatient chronic pain management care in Winston-Salem, North Carolina. SUBJECTS: Patients who received opioids for chronic pain between January 1, 2016, and June 30, 2019, were selected for chart review if they were converted to buprenorphine buccal film from a Schedule II opioid. METHODS: Patients who met inclusion criteria were stratified into subgroups on the basis of preconversion morphine milligram equivalents, whether they remained on opioids for breakthrough pain postconversion, and pre- and postconversion numerical rating scale pain scores. Outcomes of interest included the differences between pre- and postconversion numerical rating scale pain scores and daily morphine milligram equivalents for each subgroup. RESULTS: Of 157 patients reviewed, 87.9% were successfully converted to buprenorphine buccal film. Overall, numerical rating scale pain scores were stable after conversion. Statistically significant reductions were demonstrated in the <90 daily morphine milligram equivalent subgroup. Postconversion daily morphine milligram equivalents decreased by 85.4% from baseline. Change in daily morphine milligram equivalents is representative of patients who remained on breakthrough pain medication. CONCLUSIONS: Results demonstrate continued analgesia after conversion to buprenorphine buccal film despite reductions in daily morphine milligram equivalents. Most patients were able to convert directly from their long-acting opioid to buprenorphine buccal film and stabilized without the use of concomitant opioids for breakthrough pain. Aggressive titration strategies were associated with greater success.

Effectiveness and Safety of Intrathecal Ziconotide: Final Results of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND AND OBJECTIVES: The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide. METHODS: The study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit. RESULTS: The registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%). CONCLUSIONS: Final study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

Buprenorphine buccal film for chronic pain management.

Buprenorphine is a Schedule III opioid with unique pharmacodynamic and pharmacokinetic properties that contribute to effective analgesia and fewer safety risks than other opioids. This review article focuses on the buccal film formulation, which is preferable to other buprenorphine formulations on the basis of bioavailability, safety and efficacy. The clinical studies reviewed here confirm that buprenorphine buccal film offers effective and continuous pain relief that is generally well tolerated, with no cases of respiratory depression reported in any of the studies. On the basis of these clinical data and individual patient risk/benefit assessments, clinicians should consider utilizing buprenorphine buccal film as a first-line opioid treatment for chronic pain over other buprenorphine formulations or other opioids.

Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group.

BACKGROUND: The past two decades have witnessed a surge in the use of lumbar facet blocks and radiofrequency ablation (RFA) to treat low back pain (LBP), yet nearly all aspects of the procedures remain controversial. METHODS: After approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, letters were sent to a dozen pain societies, as well as representatives from the US Departments of Veterans Affairs and Defense. A steering committee was convened to select preliminary questions, which were revised by the full committee. Questions were assigned to 4-5 person modules, who worked with the Subcommittee Lead and Committee Chair on preliminary versions, which were sent to the full committee. We used a modified Delphi method, whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chair, who incorporated the comments and sent out revised versions until consensus was reached. RESULTS: 17 questions were selected for guideline development, with 100% consensus achieved by committee members on all topics. All societies except for one approved every recommendation, with one society dissenting on two questions (number of blocks and cut-off for a positive block before RFA), but approving the document. Specific questions that were addressed included the value of history and physical examination in selecting patients for blocks, the value of imaging in patient selection, whether conservative treatment should be used before injections, whether imaging is necessary for block performance, the diagnostic and prognostic value of medial branch blocks (MBB) and intra-articular (IA) injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for a prognostic block, how many blocks should be performed before RFA, how electrodes should be oriented, the evidence for larger lesions, whether stimulation should be used before RFA, ways to mitigate complications, if different standards should be applied to clinical practice and clinical trials and the evidence for repeating RFA (see table 12 for summary). CONCLUSIONS: Lumbar medial branch RFA may provide benefit to well-selected individuals, with MBB being more predictive than IA injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of more false-negatives. Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.

Measuring Opioid Withdrawal in a Phase 3 Study of a New Analgesic, NKTR-181 (Oxycodegol), in Patients with Moderate to Severe Chronic Low Back Pain.

OBJECTIVE: To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist. DESIGN: Phase 3, enriched-enrollment, double-blind, randomized-withdrawal study in patients with chronic low back pain (CLBP). SETTING: Conducted in the United States at multiple sites. METHODS: SUMMIT-07 was comprised of five periods: screening; NKTR-181 open-label titration (100 to 400 mg twice daily); 12-week randomized, double-blind study drug (NKTR-181 or placebo); one-week study drug taper; and two-week safety follow-up. Permitted rescue medication included hydrocodone 5 mg/acetaminophen 300 mg (two tablets daily) for two weeks after randomization, then acetaminophen 1.0 gm daily for the remainder of the trial. Signs and symptoms of drug withdrawal were evaluated using the Clinical Opiate Withdrawal Scale (COWS); Subjective Opiate Withdrawal Scale (SOWS); Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS); and withdrawal-related adverse events. RESULTS: Of 1,190 patients entering titration, one patient had moderate withdrawal (COWS score 13/48 maximum) three days after discontinuing NKTR-181. Of 610 patients randomized (N = 309, NKTR-181; N = 301, placebo), no COWS scores indicating withdrawal at a moderate level or greater (i.e., score ≥13) were observed at any time point. At day 8 after randomization, week 12, and the end of tapering, COWS scores indicating mild withdrawal (<13) were observed in seven (2.4%), one (0.4%), and one (0.5%) placebo patients, respectively, and three (1.0%), one (0.4%), and five (2.3%) NKTR-181 patients, respectively. Mean SOWS scores in both arms were ≤2.8 of 64 possible points at all time points. During the randomized period, of 35 events identified by MADDERS, adjudicators identified 20 possible "withdrawal" events (9 [2.9%] NKTR-181 and 11 [3.7%] placebo). CONCLUSIONS: NKTR-181 exhibited a low rate and severity of opioid withdrawal in SUMMIT-07 patients with CLBP.

Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion.

OBJECTIVE: An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management. METHODS: The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine. RESULTS: The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose. CONCLUSIONS: These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management.

Safety and tolerability of ALO-02 (oxycodone hydrochloride and sequestered naltrexone hydrochloride) extended-release capsules in older patients: a pooled analysis of two clinical trials.

Objective: To assess the impact of age on the safety and tolerability of ALO-02, an abuse-deterrent opioid formulation consisting of oxycodone hydrochloride and sequestered naltrexone hydrochloride, in patients with chronic pain.Methods: Data from two clinical studies in patients with chronic low back pain or chronic non-cancer pain were analyzed. Patients aged ≥18 years who required continuous around-the-clock opioid analgesia for an extended period were grouped into ≥65 years and <65 years age groups. Treatment-emergent adverse events (TEAEs), use of concomitant medications, clinical laboratory measurements, and occurrences of opioid withdrawal using reported adverse events (AEs) and Clinical Opiate Withdrawal Scale (COWS) scores assessed safety. Data pooling was employed for the titration and maintenance phases of both studies.Results: Respectively 805 and 436 patients received ≥1 dose of ALO-02 in the titration and maintenance phases; 121 (15.0%) and 83 (14.6%) patients, respectively, were aged ≥65 years in the titration and maintenance phases. Average doses of ALO-02 were lower in the older patients in both phases. Incidences of TEAEs were comparable between age groups in both phases and generally lower in the maintenance phase. Concomitant medications were taken more often by patients aged ≥65 years. Incidences of potentially clinically significant laboratory results were low in both phases with no clinically important differences between age groups. There were few reports of opioid withdrawal events as assessed by reported AEs and COWS scores. One patient aged ≥65 years experienced an AE of opioid withdrawal.Conclusions: The safety and tolerability of ALO-02 is similar in those aged ≥65 years and those aged <65 years with chronic pain.ClinicalTrials.gov identifiers: NCT01571362, NCT01428583.

Redefining Spinal Cord Stimulation "Trials": A Randomized Controlled Trial Using Single-Stage Wireless Permanent Implantable Devices.

BACKGROUND: "Traditional" spinal cord stimulation (SCS) trials with percutaneous electrodes externalized to a pulse generator (PG) are typically limited in duration due to risk of infection. Newer miniaturized wireless SCS technology eliminates the percutaneous extension (as well as PGs implanted for chronic use), thus facilitating a single-stage implantation after which the device can remain indefinitely. OBJECTIVE: To evaluate fully implanted wireless SCS devices during a 30-day screening trial in subjects with chronic low back pain and leg pain and a history of lumbosacral spine surgery. METHODS: In a randomized controlled trial of single-stage wireless SCS using a wireless percutaneous system, 99 subjects received either 10 kHz high frequency stimulation (HFS) or lower frequency stimulation (LFS) below 1500 Hz (Bolash R, Creamer M, Rauck R, et al. Wireless high frequency spinal cord stimulation (10 kHz) compared to multi-waveform low frequency spinal cord stimulation in the management of chronic pain in failed back surgery syndrome subjects: preliminary results of a multicenter, prospective, randomized controlled study. Pain Med 2019, https://doi.org/10.1093/pm/pnz019). In this report, we assess the 30-day trial success rate (≥50% pain relief from baseline) and complications. RESULTS: The overall trial success rate was 88% (87/99): 92% (46/50) for HFS and 84% (41/49) for LFS (NS). The trial success rate in the 64 subjects with predominant low back pain was 92% (59/64) vs. 80% (28/35) in those with leg pain ≥ low back pain (NS). During the screening trial, one infection occurred (1%) and one subject withdrew and was explanted (1%). Electrode migrations were seen on routine follow-up x-rays in 10 cases (10%). CONCLUSION: Using wireless SCS devices that allow for an extended trial period and evaluation of various waveforms, we observed a high rate trial success rate with both HFS and LFS waveforms, with minimal incidence of infection. Long-term follow-up will address the cost-effectiveness and morbidity associated with this technology, which facilitates single-stage treatment.