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.

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.

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.

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.

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.

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).

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.

Trial protocol for a multicenter randomized controlled trial to assess the efficacy and safety of intravenous ketamine for chronic daily headaches: the "KetHead" trial.

BACKGROUND: Chronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-D-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion. METHODS: A multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg-1 bolus followed by infusion of 1 mg. kg-1. h-1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusion DISCUSSION: Despite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306899. Registered on April 1, 2022.

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.

Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? A systematic review and meta-analyses.

ABSTRACT: Central sensitization (CS) is defined as an increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state associated with noxious inputs (eg, polyarthritis). The concept of CS has recently been adopted in clinical assessments of chronic pain, but its diagnosis in humans may now include a wide range of hypervigilant responses. The purpose of this review is to ascertain whether self-report questionnaires linked with CS are associated with enhanced nociceptive responses or whether they measure sensitivity in a broader sense (ie, emotional responses). According to our published, PROSPERO-registered review protocol (CRD42021208731), a predefined search of studies that involve the Central Sensitization Inventory (CSI) or Pain Sensitivity Questionnaire (PSQ), correlated with either nociceptive sensory tests or emotional hypervigilance was conducted on MEDLINE, PsycINFO, and Web of Science. Correlations between the CSI or PSQ with our primary outcomes were extracted and meta-analysed. A review of 66 studies totalling 13,284 participants found that the CSI (but not the PSQ) strongly correlated with psychological constructs: depression, anxiety, stress, pain catastrophising, sleep, and kinesiophobia. The CSI and PSQ showed weak or no correlations with experimental measures of nociceptive sensitivity: pain thresholds, temporal summation, or conditioned pain modulation. The PSQ did, however, correlate strongly with phasic heat and tonic cold pain tests. The studies reviewed did not provide sufficient evidence that self-report measures reflect a canonical understanding of CS. The CSI more closely reflects psychological hypervigilance than increased responsiveness of nociceptive neurons.

Real-world data and evidence in pain research: a qualitative systematic review of methods in current practice.

The use of routinely collected health data (real-world data, RWD) to generate real-world evidence (RWE) for research purposes is a growing field. Computerized search methods, large electronic databases, and the development of novel statistical methods allow for valid analysis of data outside its primary clinical purpose. Here, we systematically reviewed the methodology used for RWE studies in pain research. We searched 3 databases (PubMed, EMBASE, and Web of Science) for studies using retrospective data sources comparing multiple groups or treatments. The protocol was registered under the DOI:10.17605/OSF.IO/KGVRM. A total of 65 studies were included. Of those, only 4 compared pharmacological interventions, whereas 49 investigated differences in surgical procedures, with the remaining studying alternative or psychological interventions or epidemiological factors. Most 39 studies reported significant results in their primary comparison, and an additional 12 reported comparable effectiveness. Fifty-eight studies used propensity scores to account for group differences, 38 of them using 1:1 case:control matching. Only 17 of 65 studies provided sensitivity analyses to show robustness of their findings, and only 4 studies provided links to publicly accessible protocols. RWE is a relevant construct that can provide evidence complementary to randomized controlled trials (RCTs), especially in scenarios where RCTs are difficult to conduct. The high proportion of studies reporting significant differences between groups or comparable effectiveness could imply a relevant degree of publication bias. RWD provides a potentially important resource to expand high-quality evidence beyond clinical trials, but rigorous quality standards need to be set to maximize the validity of RWE studies.