Abstract Background Chronic pelvic pain (CPP) affects up to 26% of women worldwide. While its pathophysiology is poorly understood, disturbances in body perception have been identified in various similar chronic musculoskeletal disorders. The Fremantle Perineal Awareness Questionnaire (FrePAQ) is a novel tool designed to specifically assess disturbed body perception in the pelvic region, but its structural validity and reliability require formal evaluation. Methods Patient partners with lived experience contributed to study design. Participants with (n=417 and without (n=277) chronic pelvic pain completed the FrePAQ at baseline, as well as one week later. We assessed the validity and reliability of the FrePAQ following COSMIN guidelines for Classical Test Theory. Results The validated FrePAQ comprises a two-factor model, with a six-item Distress & Disconnection (D&D) subscale and a two-item Size & Shape (S&S) subscale. Confirmatory analysis showed excellent fit (CFI = .988; RMSEA = .048) and measurement invariance between diagnostic groups. Internal consistency was high (α = .838 CPP; .819 controls). Test–retest reliability was high for D&D (ICC = .863) and acceptable for S&S (ICC = .695). FrePAQ scores showed a weak-moderate correlation with pain scores (r = .234–.255), psychological distress (r = .226–.443), and functional impact (r = .172–.295), particularly for the D&D subscale. Conclusion The FrePAQ is a reliable and valid instrument to measure perineal perceptual disturbances in CPP. Future research will evaluate the tool’s potential to support phenotyping and guide individualised interventions. Improved understanding of body perception disturbance in CPP can enhance diagnosis and treatment precision. Perspective This article validates the Fremantle Perineal Awareness Questionnaire (FrePAQ), the first measure of perineal body perception disturbance in chronic pelvic pain. The findings support body perception disturbance as a clinically relevant feature of chronic pelvic pain and provide a foundation for future research exploring its role in phenotyping, treatment selection, and treatment response.

Chronic pelvic pain (CPP) affects 20% of women worldwide and is associated with substantial disability, yet its mechanisms remain unclear. Alterations in sensory or motor processing, and body perception, have been implicated in chronic pain conditions but the evidence has not been formally synthesised in CPP. This scoping review mapped the evidence for altered sensory function, motor function or body perception disturbance (BPD) in women with CPP. We searched multiple databases (up to April 2025) for studies of any design that explored these elements in women with CPP. We included 175 studies (19,457 participants). Most studies compared sensory and motor function with healthy controls, using quantitative sensory testing to assess sensory function, while a small group indirectly investigated BPD in this population. Pain-evoking sensory tests in the pelvic region consistently demonstrated reduced thresholds in people with CPP. Findings from remote body regions were less consistent, though evidence of widespread hypersensitivity and altered pain modulation suggested potential central involvement. Motor testing was limited and inconsistent. Central nervous system studies showed heterogeneous findings across conditions, including altered brain activity and evidence of altered sensorimotor processing. In qualitative studies, women described disconnection from, altered awareness of, and lack of perceived control over the pelvic region. Across all studies methods varied, with highly variable protocols and incomplete reporting limiting comparisons. Collectively, findings suggest emerging but inconsistent evidence for sensory, motor and body perception alterations in CPP. Future research should establish a theoretical framework, standardise methods and reporting, and integrate sensory, motor, and perceptual domains. Perspective Altered sensory function in the affected region is consistently reported in female CPP. Evidence of enhanced sensitivity in other body regions, motor changes, or changes in central nervous system structure and function is limited and inconsistent. Future research should establish a clearer conceptualisation of BPD, develop standardised methods and reporting.

Introduction Randomised controlled trials (RCTs) investigate the safety and efficacy of interventions. It has become clear however that some RCTs include fabricated data. The INSPECT-SR tool assesses the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. However, where individual participant data (IPD) can be obtained, a more thorough assessment of trustworthiness is possible. Consequently, INSPECT-SR recommends obtaining IPD to resolve uncertainties, though there is no consensus on appropriate methods for forensic analysis of raw data. Our aim is to evaluate IPD checks to establish which are worthwhile, and how they can be implemented in a new tool, INSPECT-IPD (Investigating Problematic Clinical Trials with Individual Participant Data). Methods and analysis Using international expert consensus and empirical evidence, the INSPECT-IPD tool will be developed using five stages: (1) compiling a list of IPD trustworthiness checks, (2) evaluating the usefulness and ease of interpretation of the checks when applying them to a collection of presumed authentic and fabricated IPD datasets, (3) a Delphi survey to determine which checks are supported by expert consensus, (4) a series of consensus meetings for selection of checks to be included in the draft tool and finally (5) prospective testing of the draft tool in: a) the production of systematic reviews, and b) the journal editorial process for RCT submissions, leading to refinement based on user feedback. Ethics and dissemination The University of Manchester ethics decision tool determined that ethical approval was not required (18 June 2024). This project includes secondary research and surveys of healthcare researchers on topics relating to their work. All results will be published as preprints and open-access articles, and the final tool will be freely available. ### Competing Interest Statement JW declares funding from NIHR for the INSPECT-SR (NIHR203568) and INSPECT-IPD projects (NIHR303741). He also declares statistics or methodological editor roles for BJOG, Cochrane Gynaecology and Fertility, Reproduction and Fertility, Journal of Hypertension. He performs integrity investigations for various journals and publishers. CH declares funding from NIHR for the INSPECT-IPD project (NIHR303741). NOC is a member of the Cochrane Central Editorial Board. Between 2020 and 2023 NOC was Co-ordinating Editor of the Cochrane Pain, Palliative and Supportive Care group, whose activities were funded by an infrastructure grant from the UK National Institute of Health and Care Research (NIHR). He has received funding from the Federal Ministry of Education and Research, Germany under the ERA-NET Neuron Co-Fund Scheme. MC is Co-ordinating Editor for the Journal of Evidence Based Medicine, JLL Library and Cochrane Methodology Review Group. He is one of the founding co-convenors of the Cochrane Individual Participant Data Meta-analysis (IPD MA) Methods Group and has worked on (and continues to work on) multiple IPD MA and randomised trials. VB is EiC for AJOG MFM, and associate editor for AJOG. LB is Senior Research Integrity Editor, Cochrane, for which she receives remuneration. ES is a Senior Editor of the Cochrane Database of Systematic Reviews. Previously, through March 2023, she was a Co-ordinating Editor of the Cochrane Injuries Group, whose activities were funded by an infrastructure grant from the UK NIHR. She contributed to the Cochrane Editorial Policy on Managing Potentially Problematic Studies. SL is an editor for the Cochrane Gynaecology and Fertility Group, Fertility and Sterility, Human Reproduction Open, and Trials. FN received funding from the French National Research Agency, the French ministry of health and the French ministry of research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science grant agreement No. 101094725). He is also work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360), funded by the EU. He serves as an academic editor for PLOS One and as an associate editor for Fundamental and Clinical Pharmacology. AA is the trustworthiness editor for AJOG MFM. LP is on the Editorial Board for Journal of Clinical Epidemiology. Paul Bramley is an editor for the journal Anaesthesia. AL is on the editorial board of BMC Medical Ethics. Kylie E Hunter led development of the Individual Participant Data (IPD) Integrity Tool (12). Rui Wang is a Deputy Editor of Human Reproduction Update and Editorial Board Member of BJOG and Cochrane Gynaecology and Fertility Group. He is a co-author of the Individual Participant Data (IPD) Integrity Tool. He is supported by an NHMRC Emerging Leadership Investigator grant (2009767). MvW is Editor-in-Chief of Human Reproduction Update and senior Editor of the Cochrane Database of Systematic Reviews and Co-ordinating Editor of the Cochrane Gynaecology and Fertility Group and Sexually Transmitted Infections Group. BKR, MW, NJLB, EL, IH, EMB, SG, LG, GMK, BK, JAH declare no conflict of interest. ### Funding Statement This study was funded by NIHR Doctoral Research Fellowship (303741) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes See 'Open Sciences Practices' paragraph

OBJECTIVES:To test the agreement and usability of a novel quality appraisal tool: A MeaSurement Tool to Assess systematic Reviews of Prognostic Factor studies (AMSTAR-PF). DESIGN:Observational study. PARTICIPANTS:14 appraisers of varied experience levels and backgrounds, including undergraduate, master's and PhD students, postgraduate researchers, research fellows and clinicians. STUDY PROCEDURE:Eight systematic reviews were rated by all reviewers using AMSTAR-PF. OUTCOME MEASURES:Planned measures included intrapair and inter-pair agreement using Cohen's and Fleiss' kappa, time of use and time to reach consensus. Interrater agreement was an added measure, and Gwet's agreement coefficient was calculated and presented due to its greater stability across agreement levels. The percentage of intrapair agreements identical or one category apart was also presented. RESULTS:Interrater agreement averaged 0.59 (range 0.21-0.90), inter-pair agreement 0.61 (range 0.24-0.91) and intrapair agreement 0.75 (range 0.45-0.95) across the domains, with agreement for the overall rating 0.46 (95% CI 0.30 to 0.62) for interrater agreement, 0.46 (95% CI 0.17 to 0.74) for inter-pair agreement and 0.68 (range of averages 0.22-1.00) for intrapair agreement. The majority (60.7%) of intrapair ratings were identical, with 94.6% of final ratings either identical or only one category different for the overall appraisal. The time taken to appraise a study with AMSTAR-PF improved with use and averaged around 34 min after the first two appraisals. CONCLUSIONS:Despite some variance in agreement for different domains and between different appraisers, the testing results suggest that AMSTAR-PF has clear utility for appraising the quality of systematic reviews of prognostic factor studies.

Complex regional pain syndrome (CRPS) is a disabling pain condition, usually confined to a single limb. Amputation of the affected limb is sometimes performed to improve pain and function for treatment-resistant CRPS. This systematic review evaluated the benefits and harms of amputation for CRPS. Primary studies of adults with CRPS that reported the outcomes of amputation of a CRPS-affected limb were included. Primary outcomes were pain intensity and adverse events. The following databases were searched from inception to 23 September 2024: PubMed, EMBASE, Scopus, CENTRAL, CINAHL, and PsycINFO for published literature, and BASE, Web of Science, OpenMD and MedNar for grey literature. Study methodological quality was assessed using Joanna Briggs Institute critical appraisal tools. Data were synthesised using systematic review without meta-analysis guidance. The review included 67 studies, comprising one comparative study, 24 case series and 42 case studies. Studies included 249 patients who received 263 amputations. Amputation indications included pain relief, functional improvement, infection, fracture, and prosthetic complications. The heterogeneous designs of included studies precluded quantitative estimation of treatment effects. The only included comparative study reported that CRPS patients had lower mean pain intensity scores post-amputation than non-amputated, non-matched control patients. The four studies that assessed pain intensity scores before amputation and at least 6 months post-operatively reported reductions in average pain post-amputation. Adverse events in assessed patients included phantom pain (67%), residual limb pain (66%), and recurrence of CRPS (47%). The critically low quality of included evidence and incomplete reporting greatly reduced confidence in the results. This review found no clear evidence that amputation of a CRPS-affected limb offers greater pain relief than no amputation. High-quality, controlled prospective studies with embedded qualitative research are needed to determine the benefits and harms of amputation for CRPS, as well as the factors that drive patients to seek this permanent intervention that does not guarantee improvement. PERSPECTIVE: This article presents a systematic review of the benefits and harms of amputation for complex regional pain syndrome. The unclear benefits and likely harms can help inform individuals and clinicians considering amputation of the potential outcomes of this intervention.

INTRODUCTION:Most clinical practice guidelines (CPGs) for assessing and managing people's chronic pain focus on specific pain conditions, body sites or life course stages. This creates complexity for clinicians making care choices in the absence of a diagnosis and/or where a person experiences more than one pain condition. Specific to this context is the ICD-11 classification of chronic primary pain where an experience of pain cannot be better accounted for by another condition. CPGs for chronic primary pain, agnostic to condition or body part, may support clinicians towards best pain care since many of the principles of person-centred chronic pain care are transdiagnostic. The two aims of this systematic review are to (1) identify and appraise CPGs for chronic primary pain, relevant across the life course and (2) map the CPG content against a pain care priority framework to evaluate the extent to which the CPG content aligns with the priorities of people with lived chronic pain experience. METHODS AND ANALYSIS:We will systematically search nine scholarly databases, the Epistemonikos database and international and national guidelines clearinghouses. CPGs published within 2015-2025, in any language, that offer recommendations about assessment and/or management of chronic primary pain for people of any age, excluding hospitalised inpatients or institutionalised populations, will be included. Pairs of reviewers will independently screen citations for eligibility and appraise CPG quality and implementation potential using the Appraisal of Guidelines for Research and Evaluation (AGREE)-II and the AGREE-Recommendations Excellence tools, respectively. Data extraction will include the citation and scope characteristics of each CPG, methods used to develop recommendations, verbatim recommendations, guiding principles or practice information and narrative excerpts related to the GRADE Evidence-to-Decision (EtD) considerations (or equivalent). We will use the PROGRESS-PLUS framework as a checklist to identify whether determinants of health equity were considered by guideline developers. CPG recommendations will be organised according to common topics and categorised in a matrix according to strength and direction. Qualitative content analysis will be used to synthesise excerpts relating to GRADE EtD considerations (or equivalent), and we will map extracted data against an established chronic pain care priority framework to determine the extent to which the CPGs align with values and preferences of people with lived experience. Interpretation will be informed by an interdisciplinary Advisory Group, including lived experience partners. ETHICS AND DISSEMINATION:Ethical approval is not required for this systematic review. Results will be disseminated through publication in an open-access peer-reviewed journal, through professional societies, and integrated into education curricula and public-facing resources. Reporting will be consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. PROSPERO REGISTRATION NUMBER:CRD420251000482.

The integrity of evidence synthesis is threatened by problematic randomised controlled trials (RCTs). These are RCTs where there are serious concerns about the trustworthiness of the data or findings. This could be due to research misconduct, including fraud, or due to honest critical errors. If these RCTs are not detected, they may be inadvertently included in systematic reviews and guidelines, potentially distorting their results. To address this problem, the INSPECT-SR (INveStigating ProblEmatic Clinical Trials in Systematic Reviews) tool has been developed to assess the trustworthiness of RCTs. This will allow problematic RCTs to be identified and excluded from systematic reviews. This paper describes the development of INSPECT-SR. The tool and an associated guidance document are presented.

RATIONALE:N-methyl-D-aspartate (NMDA) receptor antagonists are a group of medicines classed according to their mechanism of action. Ketamine and other NMDA receptor antagonists are used to treat chronic pain, despite uncertain benefits and harms. OBJECTIVES:To evaluate the benefits and harms of ketamine and other NDMA receptor antagonists compared to placebo, usual care, or other medicines for adults with chronic non-cancer, non-headache pain. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, and three trial registries (with reference checking, citation searching, and contact with study authors/experts) to identify included studies. The last search was 3 June 2025. ELIGIBILITY CRITERIA:We included randomised controlled trials (RCTs) in adults with chronic pain (≥ 3 months' duration), evaluating ketamine, memantine, dextromethorphan, amantadine, or magnesium versus placebo, usual care, or another medicine. We excluded studies of cancer or headache pain. OUTCOMES:Critical outcomes were pain intensity and adverse events. Important outcomes were disability, depressive symptoms, health-related quality of life, tolerability, and opioid consumption. For adverse events and tolerability, follow-up was until the end of treatment. For all other outcomes, we were interested in treatment effects in the immediate term (48 hours-1 week), short term (> 1 week-3 months), medium term (> 3 months-6 months), and long term (> 6 months). RISK OF BIAS:We assessed risk of bias using the Cochrane Risk of Bias tool for RCTs (RoB 2). SYNTHESIS METHODS:We converted all continuous pain intensity scores to a 0-to-100 scale (0 = no pain; 100 = worst pain). We synthesised results using random-effects meta-analysis where possible, reporting mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, each with its 95% confidence interval (CI). We assessed the certainty of evidence with GRADE. INCLUDED STUDIES:We found 67 RCTs (2309 participants): 30 parallel-group RCTs (1568 participants) and 37 cross-over RCTs (741 participants). Most studies (96%) were from high-income countries. Female participation ranged from 11% to 100%. The interventions were ketamine (39 studies), memantine (10 studies), dextromethorphan (9 studies), amantadine (3 studies), and magnesium (8 studies). Sixty-two studies used placebo comparators. Our quantitative synthesis included 28 studies. SYNTHESIS OF RESULTS:Results are presented for pain intensity (continuous measures, at reported time points) and total adverse events. Ketamine Intravenous ketamine versus placebo There is no clear evidence that intravenous ketamine reduces pain intensity in the immediate term (MD -15.79, 95% CI -32.09 to 0.51; 3 studies, 173 participants; very low certainty), short term (MD -5.32, 95% CI -15.51 to 4.87; 4 studies, 114 participants; low certainty), or medium term (MD -8.70, 95% CI -31.05 to 13.65; 1 study, 19 participants; very low certainty). Intravenous ketamine may increase the risk of adverse events (RR 3.26, 95% CI 1.05 to 10.09; 4 studies, 140 participants; low certainty). Oral ketamine versus placebo There is no clear evidence that oral ketamine reduces pain intensity in the immediate term (MD -2.64, 95% CI -13.42 to 8.14; 2 studies, 46 participants; low certainty) or short term (MD -9.80, 95% CI -23.55 to 3.95; 2 studies, 40 participants; low certainty). No studies reported total adverse events. Topical ketamine versus placebo There is no clear evidence that topical ketamine reduces pain intensity in the immediate term (MD 1.90, 95% CI -18.73 to 22.53; 1 study, 47 participants; very low certainty) or short term (MD 2.82, 95% CI -14.49 to 20.12; 2 studies, 64 participants; low certainty). There is no clear evidence that topical ketamine increases the risk of adverse events (RR 1.14, 95% CI 0.47 to 2.73; 1 study, 47 participants; low certainty). Memantine Oral memantine versus placebo There is no clear evidence that oral memantine reduces pain intensity in the immediate term (MD 4.00, 95% CI -9.93 to 17.93; 1 study, 36 participants; very low certainty), short term (MD -8.69, 95% CI -19.40 to 2.02; 6 studies, 217 participants; very low certainty), or medium term (MD -1.74, 95% CI -43.18 to 39.70; 2 studies, 101 participants; very low certainty). There is no clear evidence that oral memantine increases the risk of adverse events (RR 1.09, 95% CI 0.76 to 1.56; 3 studies, 100 participants; low certainty). Dextromethorphan Oral dextromethorphan versus placebo The evidence is very uncertain about the effect of oral dextromethorphan on pain intensity in the short term (MD -9.00, 95% CI -22.86 to 4.86; 1 study, 40 participants; very low certainty). The evidence is very uncertain about the risk of adverse events with oral dextromethorphan (RR 1.80, 95% CI 0.73 to 4.43; 1 study, 40 participants; very low certainty). Amantadine Oral amantadine versus placebo The evidence is very uncertain about the effect of oral amantadine on pain intensity in the immediate term (MD 6.00, 95% CI -12.45 to 24.45; 1 study, 26 participants; very low certainty). The evidence is very uncertain about the risk of adverse events with oral amantadine (RR 0.86, 95% CI 0.14 to 5.20; 1 study, 26 participants; very low certainty). Magnesium Intravenous magnesium versus placebo There is no clear evidence that intravenous magnesium reduces pain intensity in the immediate term (MD -2.00, 95% CI -14.43 to 10.43; 1 study, 55 participants; low certainty) and short term (MD -3.47, 95% CI -15.25 to 8.31; 2 studies, 82 participants; low certainty). The evidence is very uncertain about the risk of adverse events with intravenous magnesium (0/35 events in intravenous magnesium group versus 0/35 in placebo group; 1 study, 70 participants; very low certainty). Oral magnesium versus placebo There is no clear evidence that oral magnesium reduces pain intensity in the short term (MD -0.55, 95% CI -8.32 to 7.21; 2 studies, 118 participants; low certainty). No studies reported total adverse events. AUTHORS' CONCLUSIONS:Limited low- to very low-certainty evidence limits conclusions about the effects of ketamine, memantine, dextromethorphan, amantadine, and magnesium on pain intensity. Intravenous ketamine may increase the risk of adverse events, but the harms of ketamine and other NMDA receptor antagonists are generally unclear. Adequately powered RCTs are needed to determine the benefits and harms of ketamine and other NMDA receptor antagonists for chronic pain. FUNDING:No dedicated funding. REGISTRATION:Protocol available: doi.org/10.1002/14651858.CD015373.

The personal, social and economic burden of chronic pain is enormous. Tremendous research efforts are being directed toward understanding, preventing, and managing chronic pain. Yet patients with chronic pain, clinicians and the public are sometimes poorly served by an evidence architecture that contains multiple structural weaknesses. These include incomplete research governance, a lack of diversity and inclusivity, inadequate stakeholder engagement, poor methodological rigour and incomplete reporting, a lack of data accessibility and transparency, and a failure to communicate findings with appropriate balance. These issues span pre-clinical research, clinical trials and systematic reviews and impact the development of clinical guidance and practice. Research misconduct and inauthentic data present a further critical risk. Combined, they increase uncertainty in this highly challenging area of study and practice, drive the provision of low value care, increase costs and impede the discovery of more effective solutions.In this focus article, we explore how we can increase trust in pain science, by examining critical challenges using contemporary examples, and describe a novel integrated conceptual framework for enhancing the trustworthiness of pain science. We end with a call for collective action to address this critical issue. Perspective Multiple challenges can adversely impact the trustworthiness of pain research and health research more broadly. We present ENTRUST-PE, a novel, integrated framework for more trustworthy pain research with recommendations for all stakeholders in the research ecosystem, and make a call to action to the pain research community.

The ability to predict the onset or natural history of an illness, or how people may respond to a treatment, guides clinical decision making. These predictions are commonly based on prognostic factors: clinical, patient, or societal variables that are identified as being predictive of a certain future outcome. Prognostic factor research has increased across fields, with a subsequent increase in the number of systematic reviews of prognostic factors studies. Understanding the quality of such prognostic factor reviews is essential for confidence in their findings, but there is no quality appraisal instrument to specifically assess systematic reviews of prognostic factor studies. A MeaSurement Tool to Assess systematic Reviews of Prognostic Factor studies, AMSTAR-PF, has been developed to fill this gap

BACKGROUND:Clinical guidelines recommend bisphosphonates for complex regional pain syndrome (CRPS) despite limited evidence of efficacy. PURPOSE:To determine the efficacy and safety of bisphosphonates compared with placebo for CRPS. DATA SOURCES:MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and 3 trial registries from inception to 16 September 2025. STUDY SELECTION:Randomized controlled trials enrolling adults with CRPS (type I or II) to bisphosphonate treatment or placebo. DATA EXTRACTION:Primary outcomes were pain intensity and adverse events. Data were synthesized with random-effects meta-analyses. Risk of bias and certainty of evidence were assessed using the Cochrane Risk of Bias 2 Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation). DATA SYNTHESIS:Eleven trials (754 participants; CRPS type I, 97%), evaluating alendronate (n = 2), clodronate (n = 1), neridronate (n = 5), pamidronate (n = 1), and zoledronate (n = 2), were included. Bisphosphonates may result in little to no difference in pain intensity in the immediate term (≤4 weeks; 0-to-100 scale; mean difference [MD], -9.1 [95% CI, -19.2 to 1.1]; low certainty). In the short term (>4 weeks to 3 months; primary time point), bisphosphonates may reduce pain intensity (MD, -10.0 [CI, -18.9 to -1.1]; low certainty), and in the medium term (>3 to 6 months), they may result in little to no difference in pain intensity (MD, 8.0 [CI, -15.4 to 31.4]; low certainty). The evidence is very uncertain about the effects of bisphosphonates on pain intensity in the long term (>6 months; MD, -2.5 [CI, -19.6 to 14.6]). Bisphosphonates probably increase risk for adverse events (risk ratio, 1.1 [CI, 1.0 to 1.2]; moderate certainty). LIMITATIONS:High heterogeneity and uncertain medium- and long-term effects. Evidence mostly applies to CRPS type I and includes non-U.S.-approved formulations (neridronate, clodronate). CONCLUSION:Bisphosphonates may reduce CRPS pain intensity in the short term, but treatment is accompanied by adverse events. Future research should resolve uncertainty around which patients with CRPS are most likely to benefit from bisphosphonates. PRIMARY FUNDING SOURCE:None. (PROSPERO: CRD42024559783).

BACKGROUND AND OBJECTIVES:The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool. METHODS:We attempted to apply 72 trustworthiness checks to randomized controlled trials (RCTs) in 50 Cochrane reviews. For each, we recorded whether the check was passed, failed, or possibly failed or whether it was not feasible to complete the check. Following application of the checks, we recorded whether we had concerns about the authenticity of each RCT. We repeated each meta-analysis after removing RCTs flagged by each check and again after removing RCTs where we had concerns about authenticity to estimate the impact of trustworthiness assessment. Trustworthiness assessments were compared to Risk of Bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments in the reviews. RESULTS:Ninety-five RCTs were assessed. Following application of the checks, assessors had some or serious concerns about the authenticity of 25% and 6% of the RCTs, respectively. Removing RCTs with either some or serious concerns resulted in 22% of meta-analyses having no remaining RCTs. However, many checks proved difficult to understand or implement, which may have led to unwarranted skepticism in some instances. Furthermore, we restricted assessment to meta-analyses with no more than five RCTs (54% contained only 1 RCT), which will distort the impact on results. No relationship was identified between trustworthiness assessment and Risk of Bias or GRADE. CONCLUSION:This study supports the case for routine trustworthiness assessment in systematic reviews, as problematic studies do not appear to be flagged by Risk of Bias assessment. The study produced evidence on the feasibility and impact of trustworthiness checks. These results will be used, in conjunction with those from a subsequent Delphi process, to determine which checks should be included in the INSPECT-SR tool. PLAIN LANGUAGE SUMMARY:Systematic reviews collate evidence from randomized controlled trials (RCTs) to find out whether health interventions are safe and effective. However, it is now recognized that the findings of some RCTs are not genuine, and some of these studies appear to have been fabricated. Various checks for these "problematic" RCTs have been proposed, but it is necessary to evaluate these checks to find out which are useful and which are feasible. We applied a comprehensive list of "trustworthiness checks" to 95 RCTs in 50 systematic reviews to learn more about them and to see how often performing the checks would lead us to classify RCTs as being potentially inauthentic. We found that applying the checks led to concerns about the authenticity of around 1 in three RCTs. However, we found that many of the checks were difficult to perform and could have been misinterpreted. This might have led us to be overly skeptical in some cases. The findings from this study will be used, alongside other evidence, to decide which of these checks should be performed routinely to try to identify problematic RCTs, to stop them from being mistaken for genuine studies and potentially being used to inform health care decisions.

Complex regional pain syndrome (CRPS) is a rare and disabling pain disorder. Systematic reviews have identified a critical lack of adequately powered, high quality clinical trial evidence to inform the management of CRPS. There is an urgent need to find solutions to the methodological challenges of undertaking clinical trials in CRPS. The aim of the ‘Optimising clinical trial methods for complex regional pain syndrome’ (OptiMeth-CRPS) network project was to develop a methodological framework for optimising the planning, design, conduct and reporting of future clinical trials in CRPS (OptiMeth-CRPS). We employed an ‘Experience and expertise’ approach to develop a methodological framework. The framework was developed by an international group with expertise in the lived experience of CRPS, CRPS research, clinical trials, CRPS evidence synthesis and rare disease research methods. We used an iterative process of i) online and face-to-face meetings, ii) reviewing and approving meeting notes detailing the group’s discussions and iii) revising draft manuscripts to develop the framework. This white paper presents the discussions and recommendations of the OptiMeth-CRPS network project. The OptiMeth-CRPS methodological framework presents nine key optimisation strategies for improving the planning, design, conduct and reporting of CRPS trials. These include strategies for optimising i) the trial team, ii) research questions, iii) trial governance and management, iv) trial design, v) the trial population, vi) intervention and comparator groups, vii) trial outcomes, viii) data analysis, and xi) openness, transparency and reporting. The OptiMeth-CRPS methodological framework is offered as a tool to support the CRPS research community to undertake high quality clinical trial research and improve the quality of the evidence upon which clinical decisions and guidelines for the management of CRPS are based.

AIM:To describe the prevalence and incidence of pain, identify prognostic factors for pain, determine psychometric properties of tools to assess pain, and evaluate effectiveness of interventions for reducing pain among adults with cerebral palsy (CP). METHOD:Six databases were searched to identify studies published since 1990 in any language that met eligibility criteria defined for each objective. Titles, abstracts, and full texts were screened by two independent reviewers. RESULTS:Sixty-three studies were identified; 47 reporting prevalence, 28 reporting prognostic factors, four reporting psychometric properties, five evaluating intervention effectiveness. Pain prevalence ranged from 24% to 89%. Prevalence was higher among adults with CP than in adults without it. Communication function, sex, and age were prognostic factors for pain prevalence. Numerical, verbal, and pictorial rating scales were valid for assessing pain intensity in adults with CP. Pharmacological and surgical interventions had no effect on pain. An active lifestyle and sports intervention reduced pain in adults with CP compared with usual care. INTERPRETATION:Many adults with CP experience pain, although prevalence estimates vary considerably. The quality of evidence for prognostic factors and interventions is very low to low. There is a lack of evidence about effective pain management among adults with CP.

Complex regional pain syndrome (CRPS) is a rare chronic pain condition characterised by severe pain, sensory, motor, autonomic, and trophic abnormalities. Effective treatment options are limited, and international guidelines rely on low-quality evidence and consensus. Two interventions—memantine, an N-methyl-D-aspartate receptor antagonist, and graded motor imagery, a rehabilitation approach targeting sensorimotor processing—have shown promise in pilot studies but lack definitive evaluation in large-scale trials. MEMOIR aims to evaluate the benefits and harms of memantine and graded motor imagery for CRPS. MEMOIR is a fully decentralised, 2 × 2 factorial, randomised trial comparing memantine with placebo and graded motor imagery with no graded motor imagery in adults with CRPS. A total of 204 participants with CRPS of 6 months to 5 years duration will be randomised to one of four groups: (i) memantine and graded motor imagery, (ii) memantine only, (iii) placebo and graded motor imagery, or (iv) placebo only. Memantine will be administered at 40 mg/day (or maximum tolerated dose); graded motor imagery will be comprised seven 1-h sessions delivered via telehealth. The treatment period is 16 weeks. The dual primary outcomes are pain intensity (11-point numeric rating scale) and PROMIS pain interference assessed at 16 weeks. Secondary outcomes include physical function, fatigue, cognitive function, depressive symptoms, self-efficacy, health-related quality of life, CRPS severity, healthcare use, and adverse events. The follow-up period is 52 weeks. The estimands of interest are the mean effect of memantine compared to placebo and the mean effect of graded motor imagery compared to no graded motor imagery on all outcomes. All analyses will follow the intention-to-treat principle. MEMOIR will be the largest investigator-initiated CRPS trial to date. The 2 × 2 factorial design and decentralised delivery aim to maximise efficiency, accessibility, and equity. If effective, memantine and graded motor imagery represent scalable, low-cost treatments that can be given in clinics or at home, with the potential to transform CRPS management. Australian New Zealand Clinical Trials Registry (ACTRN12621000175875). Registered on 12 February 2021.

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives.