BACKGROUND/IMPORTANCE:Intrathecal drug delivery (ITDD) is an established intervention for chronic non-cancer pain, cancer pain, and spasticity. However, ITDD is not routinely commissioned for non-cancer pain in some countries, including England. A comprehensive synthesis of its clinical impact and safety profile in this population is lacking. OBJECTIVE:To investigate the clinical outcomes and adverse events (AEs) associated with ITDD in adults with chronic non-cancer pain. EVIDENCE REVIEW:A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and a registered protocol (CRD42024581505). Searches across MEDLINE, EMBASE, CENTRAL, and WikiStim until September 2024 were performed to identify studies reporting pain intensity, function, health-related quality of life (HRQoL), and AEs in ITDD recipients with non-cancer pain. Risk of bias was assessed using National Institutes of Health and Cochrane tools. A random-effects meta-analysis was performed on the pain intensity outcome (0-10 scale equivalent) at the 12-month time point. FINDINGS:39 studies (n=2652) were included; 20 single-arm comparisons contributed to meta-analysis. The pooled mean reduction in pain from baseline was 2.64 (95% CI 2.19 to 3.08). Accounting for between-study heterogeneity in effect size, the 95% prediction interval is 0.734 to 4.54 units. The probability that the change from baseline in a new, similar study would be greater than the minimum clinically important difference of 2 units is 75% (95% CI 68% to 83%). All studies reported improvements from baseline in function and HRQoL. Reporting of AEs or discontinuation of ITDD due to AEs was inconsistent. Risk of bias was moderate or high for cohort studies and pre-post studies, low for two crossover randomized trials and one parallel-arm randomized trial, and high for one parallel-arm randomized trial. CONCLUSIONS:ITDD is associated with meaningful reductions in pain from baseline, and functional and HRQoL improvement in patients with chronic non-cancer pain. However, the certainty of evidence is low for pain and very low for other outcomes due to study limitations. Improved reporting and controlled trials are needed to strengthen the evidence base, with careful consideration of a control intervention that maintains clinical equipoise.

BACKGROUND/IMPORTANCE:Existing systematic reviews and meta-analyses of randomized trials of spinal cord stimulation (SCS) for people with chronic pain have consistently excluded direct comparisons between different types of SCS and are therefore at major risk of publication bias. OBJECTIVE:The aim of this systematic review and network meta-analysis (NMA) was to combine both direct and indirect randomized trial evidence on treatment effects of SCS for pain intensity, physical function, and health-related quality of life (HRQoL). EVIDENCE REVIEW:MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and WikiStim were searched from inception to December 19, 2024 for parallel-arm randomized trials comparing SCS to conventional medical management (CMM), an active intervention (including other types of SCS) or placebo for adults with chronic pain. The measure of treatment effect for the primary outcome (pain intensity) and for secondary outcomes (physical function, HRQoL) was mean difference (MD) and 95% CI, and for responder rate was OR and 95% CI. NMA was performed in a frequentist framework. FINDINGS:23 reports of 16 unique randomized trials were included. All but one trial was assessed as having a high risk of bias. Results of NMA show significant reductions in pain intensity scores (0-10) at last follow-up (within the first 24 months) were observed with all types of SCS compared with CMM, with MD range from -2.37 (95% CI -3.54 to -1.20) to -5.55 (95% CI -7.34 to -3.76; 15 trials, 1479 participants; low certainty evidence). Improvements in physical function (MD range from -0.20, 95% CI -10.24 to 9.85) to -31.04 (95% CI -44.36 to -17.33; 8 trials, 837 participants; low certainty evidence) and HRQoL (MD range from 0.15 (95% CI 0.09 to 0.20) to 0.29 (95% CI 0.20 to 0.37; 8 trials, 942 participants; moderate certainty evidence) were observed for SCS compared with CMM at 6 months. Patients were found to have a higher likelihood to be a responder to treatment (ie, ≥50% reduction in pain intensity) with all forms of SCS in comparison to CMM at last follow-up (OR range from 9.75 (95% CI 4.07 to 23.25) to OR 63.4 (18.76 to 212.55; 13 trials, 1887 participants; very low certainty evidence). Clinically meaningful improvements were observed for pain intensity, HRQoL, and in some comparisons for physical function. CONCLUSIONS:There is low to moderate certainty of evidence that all types of SCS are superior to CMM for the management of chronic pain conditions.

Background:Opioids are prescribed for the management of chronic non-cancer pain, but they have important limitations and evidence does not support long-term use. People taking opioids therefore need support to reduce or stop use. Objectives:The research aimed to inform better practice, pathways and service design to support people to reduce or stop their use of opioids and address inequalities. Our objectives were to evaluate evidence on: effectiveness, safety (including adverse effects, adverse event) and acceptability of interventions to reduce opioid use barriers and facilitators to effective intervention inequalities in access to, acceptability of and benefiting from interventions. Methods:We undertook four systematic reviews of published evidence on effectiveness; safety and acceptability; barriers and facilitators and inequalities. Searches included databases [MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycInfo® (American Psychological Association, Washington, DC, USA)], trial registries (EU-CTR, International Standard Randomised Controlled Trial Number, Australian New Zealand Clinical Trials Register, ClinicalTrials.gov), websites (National Institute for Health and Care Research - be part of research, National Institute for Health and Care Excellence Evidence Search, Health Management Information Consortium, British Pain Society Members area) and repositories (Google Scholar, CORE.ac.uk) up to September 2022. Records were independently assessed for inclusion using prespecified criteria: (1) adults with chronic non-cancer pain, with (2) prescription opioid use of at least 3 months experiencing an (3) intervention aiming reduce or discontinue the use of opioids. Cochrane Risk-of-Bias tool for randomised controlled trials and the appropriate Critical Appraisal Skills Programme tool were used for cohort, case-control and qualitative studies. For the reviews of effectiveness and safety, data were synthesised and presented using tables and narrative synthesis. Meta-analysis was not appropriate. The barriers and facilitators review used thematic synthesis. Results:A total of 44 studies (reported across 52 papers) were included in at least 1 of the reviews: 27 studies were included in the effectiveness, 7 in safety and 16 in the barriers and facilitators reviews. All but two studies provided evidence for the inequalities review. The characteristics of the included studies were heterogeneous with different intervention approaches examined. Fifteen studies reported effects on pain. There was no difference in pain severity between intervention and control groups across seven of eight comparative studies. All but two studies reported change in opioid use. The proportion of patients who ceased opioid use varied across studies and some studies reported evidence of later relapse. Other outcomes, including anxiety and depression and sleep quality, were examined across the included studies but there was no clear pattern of effect. No adverse event studies reported serious adverse event and no participants reportedly withdrew due to adverse event. Few studies examined intervention acceptability. Barriers and facilitators:Eight barriers and eight facilitators were identified. They highlight the complex nature of the tapering process with the potential for multiple interdependent, behavioural, structural and contextual barriers to arise. Inequalities:Most studies reported on PROGnosis RESearch Strategy partnership-Plus categories, but few considered impact. Our findings suggest males and older patients experience poorer tapering outcomes. Conclusions:Evidence to support any specific opioid tapered reduction intervention is mixed and uncertain. Our findings reinforce that service design and delivery require careful consideration of individual-level factors and highlight the potential to widen inequalities. Stakeholders consulted on the evidence suggest valuing relationships, addressing fear and stigma and upskilling in behaviour change techniques are key. Study registration:This study is registered as PROSPERO CRD42020171135. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128842) and is published in full in Health Technology Assessment; Vol. 30, No. 27. See the NIHR Funding and Awards website for further award information.

Background:The long-term use of strong opioids for chronic non-cancer pain puts people at risk of serious harm. Objectives:To test the effectiveness and cost-effectiveness of a multicomponent intervention targeting opioid use for the treatment of chronic pain. Design:A multicentred randomised controlled trial with embedded process evaluation. Setting:Primary care. Participants:Adults using strong opioids for non-malignant chronic. Interventions:Participants were randomised 1 : 1 (using a minimisation programme stratified by geographical locality, baseline pain intensity score and baseline morphine equivalent dose) to either usual care (an educational booklet and relaxation compact disc) or usual care plus the I-WOTCH intervention; 3 day-long group sessions delivered by a nurse and lay facilitator, plus a one-to-one session and ongoing telephone contact from the nurse to support opioid tapering. Main outcome measures:The two primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form (8A), and proportion using no opioids, at 12 months. Results:We randomised 608 people. At 12 months, there was no between-group difference in Patient-Reported Outcomes Measurement Information System Pain Interference Short Form (8A) scores; mean difference, -0.52 (95% confidence interval -1.94 to 0.89). At 12 months, 65/225 (29%) of people in the intervention group and 15/208 (7%) of people in usual-care group reported using no opioids [odds ratio 5.55 (95% confidence interval 2.80 to 10.99)], absolute difference, 21.7% (95% confidence interval 14.8 to 28.6). Over a lifetime horizon, I-WOTCH is on average associated with an incremental cost of £9277 per person, and provides an additional 0.314 quality-adjusted life-years. The deterministic incremental cost per quality-adjusted life-year gained was £29,543. The I-WOTCH intervention may be cost-effective compared to best usual care. The process evaluation suggested group support and shared experience were important to those trying to taper. Limitations:The opioid use analysis is based solely on participant self-report. The findings only apply to people willing to consider opioid reduction and may not apply to a more complex secondary care population. The results may not be applicable to people using very high opioid doses. Conclusions:The I-WOTCH intervention helps substantially more people stop opioids than best usual care without adversely affecting pain interference. Future work:The I-WOTCH intervention should be tested in different healthcare settings and other populations. Trial registration:This trial is registered as Current Controlled Trials ISRCTN49470934. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/224/04) and is published in full in Health Technology Assessment; Vol. 30, No. 35. See the NIHR Funding and Awards website for further award information.

Economic evaluations, which systematically compare the costs and health-related outcomes of health interventions, are essential for informing resource allocation decisions, particularly in the context of financial constraints and limited healthcare budgets. Intrathecal drug delivery (ITDD) systems are widely used for the management of cancer pain, chronic non-cancer pain, and spasticity. However, ITDD involves substantial upfront costs, ongoing maintenance expenses, and potential complications. This article provides an overview of health-related economic evaluation principles and of the evidence on the cost-effectiveness of ITDD systems across cancer pain, chronic non-cancer pain, and spasticity. Published studies include both full and partial economic evaluations, conducted from varying perspectives and in diverse healthcare settings. Most analyses suggest that ITDD is cost-effective compared with conventional management strategies, particularly for cancer-related pain and spasticity. However, the robustness of these findings is limited by methodological heterogeneity and reliance on effectiveness data that are often derived from small or uncontrolled studies. Evidence for chronic non-cancer pain is especially sparse and inconsistent, highlighting the need for further research using rigorous designs and comprehensive cost data. Given the high costs and complexity of ITDD systems, strengthening the evidence base on their clinical and economic value is critical to support informed decision-making by health technology assessment bodies and payers. Future studies should prioritize comparative effectiveness research and long-term economic modeling to address current gaps and uncertainties.

INTRODUCTION:During the last century, many ethics codes have emerged, sometimes embedding legally binding instruments, sometimes encoding good clinical practice for the first time. Apart from the general ethical considerations in use of neuromodulation devices, regulators have tried to shield the patient, implanters, and society from possible risks related to such devices, namely, the protection of the patient's privacy and ensuring enduring manufacturer responsibility for the lifecycle of the device. This review aims to reveal the limits of ethics guidelines, the personal responsibility of the researcher, and the usefulness of the European legal, in addition to the international, ethics and deontology frameworks for clinical investigations in neuromodulation. It also introduces a practical tool, the Chimaera Contemplation Checklist, to support researchers throughout the clinical research cycle. MATERIALS AND METHODS:In this narrative review, the full research cycle for clinical investigations with neuromodulation devices is discussed. Practical advice building on multidisciplinary experience in clinical neuromodulation practice, involving social researchers and legal and ethics advisors, is provided. The review integrates the Chimaera Contemplation Checklist as a structured aid for ethical and legal reflection. RESULTS:The article focuses on common hurdles, namely, patient-centered study designs, obtaining true informed consent, clear contracts between sponsors and research partners, posttrial accessibility and support of the device, usefulness of standards, and expectations with respect to institutional review boards. The Chimaera Contemplation Checklist summarizes these challenges and offers practical prompts for researchers at each stage. DISCUSSION:This review highlights that general ethical guidelines and legislation do not easily translate to the practical needs of neuromodulation research. Addressing this gap is essential to support robust, ethical, and legally compliant research that prioritizes patient well-being. With the growing number of regulations concerning medical devices, raising awareness and fostering a deeper understanding of these guidelines is crucial. Collaboration among experts from diverse fields, including law, information technology, research, medical ethics committees, and policy, will play a key role in shaping the future of clinical trials in neuromodulation. The Chimaera Contemplation Checklist serves as a concrete, multidisciplinary tool to guide this process.