PRECISE trial (Pain RElief Combination Intervention StratEgies): protocol for the clinical trial of a pregabalin-melatonin combination for fibromyalgia.

INTRODUCTION: Fibromyalgia is associated with chronic widespread pain and disturbed sleep. Multidisciplinary, multimodal management often includes pharmacotherapy; however, current drugs used to treat fibromyalgia provide meaningful benefit to only 30-60% of treated individuals. Combining two or more different drugs is common in clinical practice with the expectation of better efficacy, tolerability or both; however, further research is needed to identify which combinations actually provide added benefit. Thus, we are planning a clinical trial to evaluate melatonin (MLT)-pregabalin (PGB) combination in participants with fibromyalgia. METHODS AND ANALYSIS: This will be a single-centre, double-blind, randomised, double-dummy, three-period, crossover trial comparing a MLT-PGB combination to each monotherapy in 54 adult participants satisfying the 2016 American College of Rheumatology criteria for fibromyalgia. Participants will receive maximally tolerated doses of MLT, PGB and MLT-PGB combination for 6 weeks. The primary outcome will be daily pain intensity (0-10); secondary outcomes will include the Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events and other measures. Analysis of the primary and secondary outcomes will involve a linear mixed model with sequence, period, treatment, the first-order carryover and baseline pain score as fixed effects and participant as a random effect to test whether there are any treatment differences among three treatments and to estimate the least square mean of the mean daily pain intensity for each treatment, adjusting for carryover as well as period effects (ie, stability of pain levels). ETHICS AND DISSEMINATION: This trial has been registered with the International Standard Randomised Controlled Trial Number Registry, ISRCTN #18278231, has been granted ethical approval by the Queen's University Health Sciences Research Ethics Board (Queen's HSREB Protocol #6040998) and is currently under review for a Clinical Trial Application to Health Canada Natural and Non-prescription Health Products Directorate. All participants will provide written informed consent prior to trial participation. Following trial completion, results will be disseminated in one or more biomedical journal publications and presented at one or more scientific meetings. TRIAL REGISTRATION NUMBER: This trial has been registered with the International Standard Randomised Controlled Trial Number Registry, ISRCTN18278231.

Postdischarge opioid use after lumbar spine surgery among older adults in Ontario: a population-based cohort study.

BACKGROUND: Prescription opioid use places a considerable economic burden on health care systems. Older patients undergoing surgical procedures for painful conditions commonly receive opioids pre- and postoperatively, and are susceptible to adverse reactions. This study explores predictors of prolonged postoperative opioid use among older patients after lumbar spine surgery and the consequences in terms of health care utilization and costs. METHODS: We conducted a retrospective population-based cohort study using Ontario administrative data from older adults undergoing spine surgery between 2006 and 2017. Data were analyzed from 90 days preoperatively to 1 year after hospital discharge, with last postoperative opioid prescriptions stratified into 90-day increments. We used multivariable ordinal logistic regression to identify predictors of long-term opioid use and generalized linear modelling to examine resource utilization and health care costs (2021 Canadian dollars). RESULTS: Of 15 109 patients included, 40.8% received preoperative opioid prescriptions. Preoperative opioid use strongly predicted prolonged postoperative use (odds ratio [OR] 4.47, 95% confidence interval [CI] 4.16-4.79), with 48.3% of patients who received preoperative opioids continuing to use opioids for longer than 9 months, relative to 12.7% of those without preoperative use. Several other risk factors for prolonged use were identified. Patients receiving long-term postoperative opioids incurred greater health care costs relative to those with opioids prescribed for fewer than 90 days (OR 1.49, 95% CI 1.44-1.54). CONCLUSION: Among older adults undergoing spine surgery, preoperative opioid use was a strong predictor of prolonged postoperative use, which was associated with increased health care costs. These results form an important baseline for future studies evaluating strategies to reduce opioid use targeting older surgical populations.

Prevention of persistent pain with lidocaine infusions in breast cancer surgery (PLAN): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. METHODS: PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1-3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. DISCUSSION: This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Comparative benefits and harms of perioperative interventions to prevent chronic pain after orthopedic surgery: a systematic review and network meta-analysis of randomized trials.

BACKGROUND: Chronic postsurgical pain (CPSP) is common following musculoskeletal and orthopedic surgeries and is associated with impairment and reduced quality of life. Several interventions have been proposed to reduce CPSP; however, there remains uncertainty regarding which, if any, are most effective. We will perform a systematic review and network meta-analysis of randomised trials to assess the comparative benefits and harms of perioperative pharmacological and psychological interventions directed at preventing chronic pain after musculoskeletal and orthopedic surgeries. METHODS: We will search MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to present, without language restrictions. We will include randomised controlled trials that as follows: (1) enrolled adult patients undergoing musculoskeletal or orthopedic surgeries; (2) randomized them to any pharmacological or psychological interventions, or their combination directed at reducing CPSP, placebo, or usual care; and (3) assessed pain at 3 months or more after surgery. Screening for eligible trials, data extraction, and risk-of-bias assessment using revised Cochrane risk-of-bias tool (RoB 2.0) will be performed in duplicate and independently. Our main outcome of interest will be the proportion of surgical patients reporting any pain at ≥ 3 months after surgery. We will also collect data on other patient important outcomes, including pain severity, physical functioning, emotional functioning, dropout rate due to treatment-related adverse event, and overall dropout rate. We will perform a frequentist random-effects network meta-analysis to determine the relative treatment effects. When possible, the modifying effect of sex, surgery type and duration, anesthesia type, and veteran status on the effectiveness of interventions will be investigated using network meta-regression. We will use the GRADE approach to assess the certainty evidence and categorize interventions from most to least beneficial using GRADE minimally contextualised approach. DISCUSSION: This network meta-analysis will assess the comparative effectiveness of pharmacological and psychological interventions directed at preventing CPSP after orthopedic surgery. Our findings will inform clinical decision-making and identify promising interventions for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023432503.

Changes in pain following bilateral intermittent theta-burst, transcranial magnetic stimulation for depression: A retrospective chart review.

Introduction: Pain management in patients with chronic pain and comorbid depression is challenging and understudied. There is interest in intermittent theta-burst stimulation (iTBS), a new modality of repetitive transcranial magnetic stimulation (rTMS). This retrospective review describes changes in pain, anxiety and depression throughout iTBS treatment at the dorsolateral prefrontal cortex (DLPFC). Methods: A retrospective chart review was conducted of patients who underwent their first acute series of iTBS treatments at the DLPFC for depression at a single institution between 2020 and 2023. Data on depression, anxiety, and pain were collected throughout iTBS treatment using the Beck Depression Inventory-II (BDI-II; higher scores indicate worse depression) and visual analogue scale (VAS; 0-100, higher scores indicate worse pain, anxiety, and depression). Nonparametric tests were used for all analyses. Results: Of 104 patients, 52 reported moderate pain at baseline (50.0%). Median BDI-II scores decreased from 38.0 (interquartile range [IQR] = 29.0-44.0) to 24.0 (IQR = 9.0-36.0) from pre- to posttreatment (P < 0.001). Of the 32 patients with both pre- and posttreatment pain scores, there was a significant decrease from 40.0 (IQR = 5.5-71.8) to 15.0 (IQR = 3.5-53.8; P = 0.037). In patients with at least moderate pain at baseline, pain scores decreased from 71.0 (IQR = 55.0-80.0) to 20.0 (IQR = 11.0-71.0; P = 0.004). Ten of 32 patients with available pre- and posttreatment scores reported ≥30% reduction in pain scores (31.2%). Conclusion: These preliminary results, suggesting decreases in pain following iTBS treatment, provide a rationale for future rigorous investigations to evaluate this intervention for depression and comorbid chronic pain.

Introduction: La prise en charge de la douleur chez les patients souffrant de douleur chronique et de dépression comorbide est difficile et sous-étudiée. Il existe un intérêt pour la stimulation thêta-burst intermittente (STBi), une nouvelle modalité de stimulation magnétique transcrânienne répétitive (SMTr). Cette revue rétrospective décrit les changements dans la douleur, l'anxiété et la dépression tout au long du traitement par STBi au niveau de la région du cortex préfrontal dorsolatéral.Un examen rétrospectif des dossiers a été mené pour les patients ayant reçu leur première série intensive de traitements par STBi pour la dépression dans la région du cortex préfrontal dorsolatéral dans un seul établissement entre 2020 et 2023. Les données sur la dépression, l'anxiété et la douleur ont été collectées tout au long des traitements par STBi à l'aide de l'Inventaire de dépression de Beck-II (IDB-II; des scores plus élevés indiquent une dépression plus grave) et de l'échelle visuelle analogique (EVA; 0-100, des scores plus élevés indiquent une aggravation de la douleur, de l'anxiété et de la dépression). Des tests non paramétriques ont été utilisés pour toutes les analyses.Résultats: Parmi les 104 patients inclus dans l'étude, 52 ont déclaré une douleur modérée au départ (50,0 %). Les scores médians de l'IDB-II ont diminué de 38,0 (intervalle interquartile [IQR] = 29,0-44,0) à 24,0 (IQR = 9,0-36,0) avant et après le traitement (P < 0,001). Parmi les 32 patients pour lesquels des scores de douleur avant et après le traitement étaient disponibles, une diminution significative a été constatée, passant de 40,0 (IQR = 5,5-71,8) à 15,0 (IQR = 3,5-53,8 ; P = 0,037). Chez les patients hospitalisés avec une douleur au moins modérée au départ, les scores de douleur ont diminué de 71,0 (IQR = 55,0-80,0) à 20,0 (IQR = 11,0-71,0 ; P = 0,004). Dix des 32 patients pour lesquels des scores avant et après le traitement étaient disponibles ont rapporté une réduction ≥30 % des scores de douleur (31,2 %).Conclusion: Ces résultats préliminaires, qui indiquent une diminution de la douleur après le traitement par STBi, offrent une justification pour la réalisation de futures études rigoureuses afin d'évaluer cette intervention pour la dépression et les douleurs chroniques comorbides.

Effectiveness of dexmedetomidine during surgery under general anaesthesia on patient-centred outcomes: a systematic review and Bayesian meta-analysis protocol.

INTRODUCTION: Dexmedetomidine is a promising pharmaceutical strategy to minimise opioid use during surgery. Despite its growing use, it is uncertain whether dexmedetomidine can improve patient-centred outcomes such as quality of recovery and pain. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis following the recommendations of the Cochrane Handbook for Systematic Reviews. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL approximately in October 2023. We will include randomised controlled trials evaluating the impact of systemic intraoperative dexmedetomidine on patient-centred outcomes. Patient-centred outcome definition will be based on the consensus definition established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC). Our primary outcome will be the quality of recovery after surgery. Our secondary outcomes will be patient well-being, function, health-related quality of life, life impact, multidimensional assessment of postoperative acute pain, chronic pain, persistent postoperative opioid use, opioid-related adverse events, hospital length of stay and adverse events. Two reviewers will independently screen and identify trials and extract data. We will evaluate the risk of bias of trials using the Cochrane Risk of Bias Tool (RoB 2.0). We will synthesise data using a random effects Bayesian model framework, estimating the probability of achieving a benefit and its clinical significance. We will assess statistical heterogeneity with the tau-squared and explore sources of heterogeneity with meta-regression. We have involved patient partners, clinicians, methodologists, and key partner organisations in the development of this protocol, and we plan to continue this collaboration throughout all phases of this systematic review. ETHICS AND DISSEMINATION: Our systematic review does not require research ethics approval. It will help inform current clinical practice guidelines and guide development of future randomised controlled trials. The results will be disseminated in open-access peer-reviewed journals, presented at conferences and shared among collaborators and networks. PROSPERO REGISTRATION NUMBER: CRD42023439896.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Patient engagement in designing, conducting, and disseminating clinical pain research: IMMPACT recommended considerations.

ABSTRACT: In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.

Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial.

ABSTRACT: We compared a combination of the nonsedating antioxidant, alpha-lipoic acid (ALA), with the sedating anticonvulsant, pregabalin, vs each monotherapy to treat neuropathic pain due to peripheral neuropathies. In this randomized, double-blind, 3-period crossover trial, participants received oral ALA, pregabalin, and their combination-each for 6 weeks. The primary outcome was mean daily pain intensity at maximal tolerated doses (MTD); secondary outcomes included quality of life (SF-36), sleep (Medical Outcomes Study-Sleep Scale), adverse effects, drug doses, and other measures. Of 55 participants randomized (20-diabetic neuropathy, 19-small fiber neuropathy, and 16-other neuropathies), 46 completed 2 periods, and 44 completed 3. At MTD, the primary outcome of mean pain intensity (0-10) was 5.32 (standard error, SE = 0.18), 3.96 (0.25), 3.25 (0.25), and 3.16 (0.25) at baseline, ALA, pregabalin, and combination, respectively ( P < 0.01 for ALA vs combination and pregabalin). Treatment differences were similar in subgroups with diabetic neuropathy and with other neuropathies. SF-36 total scores (higher number indicates better quality of life) were 66.6 (1.88), 70.1 (1.88), and 69.4 (1.87) with ALA, pregabalin, and combination ( P < 0.05 for ALA vs combination and pregabalin). At MTD, there were no statistically significant treatment differences in adverse effects or drug doses. This trial demonstrates superiority of pregabalin vs ALA but provides no evidence to suggest added benefit of combining ALA with pregabalin to treat neuropathic pain.

Movement-evoked Pain versus Pain at Rest in Postsurgical Clinical Trials and in Meta-analyses: An Updated Systematic Review.

BACKGROUND: Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous 2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials. METHODS: The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated. RESULTS: Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011). CONCLUSIONS: This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators.

Self-Reported Pain Treatment Practices Among U.S. and Canadian Adults: Findings From a Population Survey.

Background and Objectives: Pain treatments and their efficacy have been studied extensively. Yet surprisingly little is known about the types of treatments, and combinations of treatments, that community-dwelling adults use to manage pain, as well as how treatment types are associated with individual characteristics and national-level context. To fill this gap, we evaluated self-reported pain treatment types among community-dwelling adults in the United States and Canada. We also assessed how treatment types correlate with individuals' pain levels, sociodemographic characteristics, and country of residence, and identified unique clusters of adults in terms of treatment combinations. Research Design and Methods: We used the 2020 "Recovery and Resilience" United States-Canada general online survey with 2 041 U.S. and 2 072 Canadian community-dwelling adults. Respondents selected up to 10 pain treatment options including medication, physical therapy, exercise, etc., and an open-ended item was available for self-report of any additional treatments. Data were analyzed using descriptive, regression-based, and latent class analyses. Results: Over-the-counter (OTC) medication was reported most frequently (by 55% of respondents, 95% CI 53%-56%), followed by "just living with pain" (41%, 95% CI 40%-43%) and exercise (40%, 95% CI 38%-41%). The modal response (29%) to the open-ended item was cannabis use. Pain was the most salient correlate, predicting a greater frequency of all pain treatments. Country differences were generally small; a notable exception was alcohol use, which was reported twice as often among U.S. versus Canadian adults. Individuals were grouped into 5 distinct clusters: 2 groups relied predominantly on medication (prescription or OTC), another favored exercise and other self-care approaches, one included adults "just living with" pain, and the cluster with the highest pain levels employed all modalities heavily. Discussion and Implications: Our findings provide new insights into recent pain treatment strategies among North American adults and identify population subgroups with potentially unmet need for more adaptive and effective pain management.

Patient Expectations and Therapeutic Alliance Affect Pain Reduction Following Lidocaine Infusion in an Interdisciplinary Chronic Pain Clinic.

Pain experience is affected by both ascending nociceptive signals and descending modulation. Expectations can affect pain experience and augment treatment-induced analgesia through descending inhibitory modulation of pain. This open-label, prospective cohort study examined the association between participant expectation ratings and pain reduction in adult participants with chronic pain receiving an intravenous lidocaine infusion. We aimed to explore whether: 1) participants' expectations of treatment efficacy were associated with pain reduction over 8 weeks after infusion; and 2) participants' therapeutic alliance was associated with expectations and/or pain reduction. We recruited 70 participants with chronic pain scheduled for lidocaine infusion. Study measures included pain intensity (pre-treatment, post-treatment, and daily for 8 weeks), treatment expectations (EXPECT), and therapeutic alliance (Trust in Physician and Working Alliance Inventory-Short Revised). Baseline treatment expectations were significantly correlated with pain reduction (r = .42, P < .01). Therapeutic alliance was significantly correlated with expectations (r = .27, P < .05) and pain reduction (r = .38, P < .01). This study quantifies the contribution of: 1) treatment expectations; and 2) therapeutic alliance to the magnitude of lidocaine-induced pain reduction. Results generate the hypothesis that focused efforts to augment treatment expectations and therapeutic alliance could serve to improve pain treatment outcomes. PERSPECTIVE: This study evaluates the relationship between pain reduction and ratings of: 1) treatment expectations; and 2) therapeutic alliance following an intravenous lidocaine infusion. Results generate the hypothesis that focused efforts to augment treatment expectations and therapeutic alliance could serve to improve pain treatment outcomes.

Prevalence of postoperative pain after hospital discharge: systematic review and meta-analysis.

Assessment and management of postoperative pain after hospital discharge is very challenging. We conducted a systematic review to synthesize available evidence on the prevalence of moderate-to-severe postoperative pain within the first 1 to 14 days after hospital discharge. The previously published protocol for this review was registered in PROSPERO. MEDLINE and EMBASE databases were searched until November 2020. We included observational postsurgical pain studies in the posthospital discharge setting. The primary outcome for the review was the proportion of study participants with moderate-to-severe postoperative pain (eg, pain score of 4 or more on a 10-point Numerical Rating Scale) within the first 1 to 14 days after hospital discharge. This review included 27 eligible studies involving a total of 22,108 participants having undergone a wide variety of surgical procedures. The 27 studies included ambulatory surgeries (n = 19), inpatient surgeries (n = 1), both ambulatory and inpatient surgeries (n = 4), or was not specified (n = 3). Meta-analyses of combinable studies provided estimates of pooled prevalence rates of moderate-to-severe postoperative pain ranging from 31% 1 day after discharge to 58% 1 to 2 weeks after discharge. These findings suggest that moderate-to-severe postoperative pain is a common occurrence after hospital discharge and highlight the importance of future efforts to more effectively evaluate, prevent, and treat postsurgical pain in patients discharged from the hospital.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review protocol.

INTRODUCTION: For close to a century opioid administration has been a standard of care to complement anaesthesia during surgery. Considering the worldwide opioid epidemic, this practice is now being challenged and there is a growing use of systemic pharmacological opioid minimising strategies. Our aim is to conduct a scoping review that will examine clinical trials that have evaluated the impact of intraoperative opioid minimisation strategies on patient-centred outcomes and identify promising strategies. METHODS AND ANALYSIS: Our scoping review will follow the framework developed by Arksey and O'Malley. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL from their inception approximately in March 2023. We will include randomised controlled trials, assessing the impact of systemic intraoperative pharmacologic opioid minimisation strategies on patient-centred outcomes. We define an opioid minimisation strategy as any non-opioid drug with antinociceptive properties administered during the intraoperative period. Patient-centred outcomes will be defined and classified based on the consensus definitions established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC group) and informed by knowledge users and patient partners. We will use a coproduction approach involving interested parties. Our multidisciplinary team includes knowledge users, patient partners, methodologists and knowledge user organisations. Knowledge users will provide input on methods, outcomes, clinical significance of findings, implementation and feasibility. Patient partners will participate in assessing the relevance of our design, methods and outcomes and help to facilitate evidence translation. We will provide a thorough description of available clinical trials, compare their reported patient-centred outcome measures with established recommendations and identify promising strategies. ETHICS AND DISSEMINATION: Ethics approval is not required for the review. Our scoping review will inform future research including clinical trials and systematic reviews through identification of important intraoperative interventions. Results will be disseminated through a peer-reviewed publication, presentation at conferences and through our network of knowledge user collaborators. REGISTRATION: Open Science Foundation (currently embargoed).

Combination analgesic development for enhanced clinical efficacy (the CADENCE trial): a double-blind, controlled trial of an alpha-lipoic acid-pregabalin combination for fibromyalgia pain.

ABSTRACT: Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different ( P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.

Prevalence and correlates of prescription opioid use among US adults, 2019-2020.

This study estimates the prevalence of prescription opioid use (POU) in the United States (US) in 2019-2020, both in the general population and specifically among adults with pain. It also identifies key geographic, demographic, and socioeconomic correlates of POU. Data were from the nationally-representative National Health Interview Survey 2019 and 2020 (N = 52,617). We estimated POU prevalence in the prior 12 months among all adults (18+), adults with chronic pain (CP), and adults with high-impact chronic pain (HICP). Modified Poisson regression models estimated POU patterns across covariates. We found POU prevalence of 11.9% (95% CI 11.5, 12.3) in the general population, 29.3% (95% CI 28.2, 30.4) among those with CP, and 41.2% (95% CI 39.2, 43.2) among those with HICP. Findings from fully-adjusted models include the following: In the general population, POU prevalence declined about 9% from 2019 to 2020 (PR = 0.91, 95% CI 0.85, 0.96). POU varied substantially across US geographic regions: It was significantly more common in the Midwest, West, and especially the South, where adults had 40% higher POU (PR = 1.40, 95% CI 1.26, 1.55) than in the Northeast. In contrast, there were no differences by rural/urban residence. In terms of individual characteristics, POU was lowest among immigrants and among the uninsured, and was highest among adults who were food insecure and/or not employed. These findings suggest that prescription opioid use remains high among American adults, especially those with pain. Geographic patterns suggest systemic differences in therapeutic regimes across regions but not rurality, while patterns across social characteristics highlight the complex, opposing effects of limited access to care and socioeconomic precarity. Against the backdrop of continuing debates about benefits and risks of opioid analgesics, this study identifies and invites further research about geographic regions and social groups with particularly high or low prescription opioid use.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.