Pain Trials Research Articles

Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.

Statistical analysis plan for the Petal trial: the effects of parental touch on relieving acute procedural pain in neonates

Background Infants undergo multiple clinically-required painful procedures during their time in hospital, and there is an increasing desire from both parents and clinical staff to have parents directly involved in their newborn’s pain relief. To avoid biases due to selective analysis and reporting, a clinical trial’s statistical analysis plan (SAP) should be finalised and registered prior to dataset lock and unblinding. Here, we outline the SAP for the Petal trial, which was registered on the ISRCTN registry prior to dataset lock and unblinding. Methods The Petal trial is a multicentre, individually randomised, parallel-group interventional superiority trial. The study involves in-patient neonates born at or after 35+0 weeks gestation with a postnatal age of ≤7 days, in two hospital research sites (John Radcliffe Hospital, Oxford, UK; Royal Devon and Exeter Hospital, Exeter, UK). The primary objective is to investigate the potential efficacy of a non-pharmacological parent-led stroking intervention on reducing the magnitude of neonates’ noxious stimulus-evoked brain activity. The primary outcome is the neonate’s brain activity recorded using electroencephalography (EEG) in response to a heel lance blood sampling procedure. Secondary outcomes include neonatal clinical pain scores and tachycardia, and parental anxiety. The study hypothesis is neonates’ pain responses and parents’ anxiety scores are lower in the intervention group. Randomisation will be via a minimisation algorithm to maintain balance in five prognostic factors. Conclusions Paediatric pain trials have been highlighted by regulatory bodies as an important and challenging topic, with interest increasing in brain imaging outcomes. The Petal trial, to which this SAP relates, is part of a larger effort of establishing a brain-based EEG outcome measure of infant pain for use in clinical trials. This SAP is thus likely to be of interest to those in academia, pharmaceutical companies, and regulatory bodies. Trial registration ClinicalTrials.gov: NCT04901611, 25/05/2021; ISRCTN: ISRCTN14135962, 23/08/2021).

Associations of discomfort intolerance, discomfort avoidance, and cannabis and alcohol use among persons with chronic pain receiving prescription buprenorphine for opioid use disorder

BackgroundChronic pain and non-prescribed substance use are associated with lower retention in opioid use disorder (OUD) treatment. We examined the associations of perceived capacity to tolerate uncomfortable physical sensations (discomfort intolerance and discomfort avoidance) and cannabis and alcohol use among persons with chronic pain receiving prescription buprenorphine for OUD. MethodsThis study utilizes baseline data from 163 persons with chronic pain receiving prescription buprenorphine for OUD enrolled in the Treating Opioid use, Persistent Pain, and Sadness (TOPPS) intervention trial. We used negative-binomial regression models, adjusted for age, education, gender, race/ethnicity, pain interference, depression, generalized anxiety disorder, and average cigarettes smoked/day to estimate the associations of discomfort tolerance and discomfort avoidance with frequency of cannabis and alcohol use. ResultsParticipants (n=163) were on average 45 years old (standard deviation=10.6) and predominantly White (86%, n=141). Forty-one percent (n=66) used cannabis and 24% (n=30) used alcohol use in the past 30 days. In adjusted models, discomfort intolerance was positively associated with days of cannabis use (IRR = 1.11, p =.016) and days of alcohol use (IRR = 1.14, p =.022). Discomfort avoidance was not associated with cannabis or alcohol use. ConclusionIndividuals with chronic pain receiving prescribed buprenorphine for treatment of OUD with lower tolerance for physical discomfort may augment pain management with cannabis and alcohol. Given the intersections between substance use and retention in care for OUD, future work should extend this preliminary work by exploring these relationships over time and in experimental settings.Clinical Trial # NCT03698669

Factors influencing fidelity to guideline implementation strategies for improving pain care at cancer centres: a qualitative sub-study of the Stop Cancer PAIN Trial

BackgroundThe Stop Cancer PAIN Trial was a phase III pragmatic stepped wedge cluster randomised controlled trial which compared effectiveness of screening and guidelines with or without implementation strategies for improving pain in adults with cancer attending six Australian outpatient comprehensive cancer centres (n = 688). A system for pain screening was introduced before observation of a ‘control’ phase. Implementation strategies introduced in the ‘intervention’ phase included: (1) audit of adherence to guideline recommendations, with feedback to clinical teams; (2) health professional education via an email-administered ‘spaced education’ module; and (3) a patient education booklet and self-management resource. Selection of strategies was informed by the Capability, Opportunity and Motivation Behaviour (COM-B) Model (Michie et al., 2011) and evidence for each strategy’s stand-alone effectiveness. A consultant physician at each centre supported the intervention as a ‘clinical champion’. However, fidelity to the intervention was limited, and the Trial did not demonstrate effectiveness. This paper reports a sub-study of the Trial which aimed to identify factors inhibiting or enabling fidelity to inform future guideline implementation initiatives.MethodsThe qualitative sub-study enabled in-depth exploration of factors from the perspectives of personnel at each centre. Clinical champions, clinicians and clinic receptionists were invited to participate in semi-structured interviews. Analysis used a framework method and a largely deductive approach based on the COM-B Model.ResultsTwenty-four people participated, including 15 physicians, 8 nurses and 1 clinic receptionist. Coding against the COM-B Model identified ‘capability’ to be the most influential component, with ‘opportunity’ and ‘motivation’ playing largely subsidiary roles. Findings suggest that fidelity could have been improved by: considering the readiness for change of each clinical setting; better articulating the intervention’s value proposition; defining clinician roles and responsibilities, addressing perceptions that pain care falls beyond oncology clinicians’ scopes of practice; integrating the intervention within existing systems and processes; promoting patient-clinician partnerships; investing in clinical champions among senior nursing and junior medical personnel, supported by medical leaders; and planning for slow incremental change rather than rapid uptake.ConclusionsFuture guideline implementation interventions may require a ‘meta-implementation’ approach based on complex systems theory to successfully integrate multiple strategies.Trial registrationRegistry: Australian New Zealand Clinical Trials Registry; number: ACTRN 12615000064505; data: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspxid=367236&isReview=true.

Unraveling the physiological and psychosocial signatures of pain by machine learning.

Pain is a complex subjective experience, strongly impacting health and quality of life. Despite many attempts to find effective solutions, present treatments are generic, often unsuccessful, and present significant side effects. Designing individualized therapies requires understanding of multidimensional pain experience, considering physical and emotional aspects. Current clinical pain assessments, relying on subjective one-dimensional numeric self-reports, fail to capture this complexity. To this aim, we exploited machine learning to disentangle physiological and psychosocial components shaping the pain experience. Clinical, psychosocial, and physiological data were collected from 118 chronic pain and healthy participants undergoing 40 pain trials (4,697 trials). To understand the objective response to nociception, we classified pain from the physiological signals (accuracy >0.87), extracting the most important biomarkers. Then, using multilevel mixed-effects models, we predicted the reported pain, quantifying the mismatch between subjective level and measured physiological response. From these models, we introduced two metrics: TIP (subjective index of pain) and Φ (physiological index). These represent possible added value in the clinical process, capturing psychosocial and physiological pain dimensions, respectively. Patients with high TIP are characterized by frequent sick leave from work and increased clinical depression and anxiety, factors associated with long-term disability and poor recovery, and are indicated for alternative treatments, such as psychological ones. By contrast, patients with high Φ show strong nociceptive pain components and could benefit more from pharmacotherapy. TIP and Φ, explaining the multidimensionality of pain, might provide a new tool potentially leading to targeted treatments, thereby reducing the costs of inefficient generic therapies. RESC-PainSense, SNSF-MOVE-IT197271.

Mean of Daily Versus Single Week Recall-Based Pain Quality Assessments in Neuropathic Pain Trials: Implications for Assay Sensitivity

Patients with neuropathic pain often present with variable pain and nonpainful sensory qualities that could serve as outcomes in randomized clinical trials (RCTs). This study aimed to investigate the within-participant variability in the severity of these sensory qualities and whether the means of 7 daily pain quality assessments provide better assay sensitivity (ie, more sensitivity to treatment effects) than single-week recall-based assessments. This secondary analysis used data from an RCT of transcutaneous electrical nerve stimulation for chemotherapy-induced peripheral neuropathy (N = 142). Participants rated the severity of painful and nonpainful sensory qualities using 0 to 10 numeric rating scales daily for 1 week (24-hour recall) and 1 time at the end of each week (week recall) at trial baseline and endpoint (after 6 weeks of treatment). For pain quality assay sensitivity analyses, the 2 types of measures were used to 1) define the study sample (ie, how many participants met minimum baseline pain quality severity) and 2) calculate the observed effect sizes (ie, between-group differences in mean pain qualities) using analysis of covariances. The projected sample sizes required to detect the observed effect sizes in future clinical trials for hot/burning pain and cramping were substantially smaller using the daily mean outcome compared with week recall (ie, hot/burning pain: 153 vs 388, cramping: 121 vs 349), and only marginally larger for sharp/shooting pain (22 participants) with the daily mean outcome. Compared with single-week recall-based assessments of pain qualities, the mean of daily assessments may improve RCT assay sensitivity when used to define entry criteria and assess outcomes. PerspectiveThis study suggests that means of daily pain quality assessments may improve assay sensitivity when used to define entry criteria and assess outcomes in clinical trials. This work may inform design of future clinical trials evaluating the intensity of different pain qualities.

Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

Early epidural lead migration in spinal cord stimulator trials: A case series

BackgroundSpinal cord stimulation (SCS) devices are routinely trialed to assess pain and functional improvement before permanent lead implantation. Lead migration is a common complication that may cause a loss of therapeutic effect in patients who may otherwise benefit from SCS. The timing of lead migration during the trial period is currently unknown. ObjectivesWe hypothesize that significant lead migration may occur early in the SCS trial period, such as postoperative day 1 or 2, which may allow for contact stimulation adjustment to prevent false negative trial results. As such, in this study, we aim to evaluate the incidence and distance of lead migration in early thoracic SCS trial period. MethodsWe performed a case series of 27 patients ≥19 years of age who received differential target multiplexed thoracic SCS trials for chronic neuropathic pain from July 1, 2020 to July 1, 2023. Patients with a neuropathic pain diagnosis failing medical treatment, without structural pathology limiting epidural access, and with psychiatric clearance for suitability are eligible for SCS trials at our center. Pre- and post-flexion radiographs taken immediately after implantation and on postoperative day 1 or 2 were examined to assess the distance of lead migration. Clinically significant lead migration was pre-defined as ≥ 10 mm. ResultsThe mean (SD) distances of epidural lead migration on postoperative day 1 or 2 were 18.2 (12.9) mm and 19.1 (13.3) mm for the cephalic and caudal leads, respectively. All migrations were caudad except for one trial. Clinically significant lead migration occurred in 20/27 (74 %) patients. ConclusionClinically significant epidural lead migration occurs in the early SCS trial period.

Increased Thalamocortical Functional Connectivity on Discontinuation of Treatment in Painful Diabetic Peripheral Neuropathy.

Altered functional connectivity has been demonstrated in key brain regions involved in pain processing in painful diabetic peripheral neuropathy (Painful-DPN). However, the impact of neuropathic pain treatment on functional connectivity has not been investigated. Sixteen participants underwent resting state functional MRI (rs-fMRI) when optimally treated for neuropathic pain during their involvement in the OPTION-DM trial and 1-week following withdrawal of treatment. On discontinuation of pain treatment, there was a rise in functional connectivity between the left thalamus and primary somatosensory cortex (S1) and the left thalamus and insular cortex, key brain regions that are involved in cerebral processing of pain. The changes in functional connectivity between scans also correlated with measures of pain (baseline pain severity and neuropathy pain symptom inventory). Moreover, when participants were stratified into higher and lower than average baseline pain sub-groups, the change in thalamic-S1 cortical functional connectivity between scans was significantly greater in those with high baseline pain compared with the lower baseline pain group. This study shows that thalamo-cortical functional connectivity has the potential to act as an objective biomarker for neuropathic pain in diabetes for use in clinical pain trials.

Self-acknowledged limitations in exercise therapy trials for low back pain.

Despite the widespread recommendation to engage in therapeutic exercise for the treatment of low back pain (LBP), there is conflicting evidence regarding clinical outcomes and effectiveness. Poor methodological quality may be to blame for reducing the overall strength of evidence for this intervention, yet little is known about the difficulties researchers encounter when designing and implementing their study methods. The aim of this study was to characterize the extent and type of self-acknowledged limitations (SALs) in exercise therapy trials for LBP to gain a better understanding of challenges encountered when conducting this research. This is a methodological review of clinical trials in which SALs were extracted, categorized by theme and subcategorized within each theme. Counts and prevalence rates were tabulated for the number of SALs in each category and subcategory. There were 914 SALs among the 312 included trials, with a mean of 2.93 (95% confidence interval [CI], 2.77-3.09) per trial. Analysis of the data resulted in the development of 13 distinct categories of limitations, among which were 37 subcategories. The top three categories pertained to statistical power (14.3% of total SALs), study length and/or follow-up (14.3%) and inclusion criteria (14.2%). The top three subcategories were lack of long-term follow-up (13.8% of total SALs), inadequate sample size (13.3%) and inclusion of specific populations (12.3%). Statistical power, study length and/or follow-up, and inclusion criteria were the three most commonly reported categories of SALs in exercise trials for LBP. Lack of long-term follow-up, inadequate sample size and inclusion of specific populations were the most common subcategories. Research protocols recognizing and avoiding these limitations will enhance the overall quality of evidence of exercise therapy trials for LBP.

Learning the art of Scholarly Peer-Review: Insights from the Communication Discipline

Many scholars find the peer-review process to be a puzzling, non-transparent, and subjective exercise. Many emerging scholars also learn about the peer-review and publishing process through painful and time-consuming trial and error while still students or as early-career researchers rather than through formal training or guided supervision. Yet many pitfalls exist in this process for new and veteran scholars alike. With this study, grounded in the communication field, we aim to pull back the curtain on this opaque process and assist scholars in their publishing ambitions while also providing suggestions, primarily for journal editors and those who train future reviewers, about how the peer-review process can be improved for collective benefit. To do so, this grounded theory study reviews a year's worth of reviews from a communication journal to explore which issues reviewers identify within the submitted research, to explore how the reviewer feedback reveals their implicit understanding of their role in the peer-review process, and to identify how clear reviewers and editors are regarding which feedback is most important. Taken together, this allows for an understanding of how reviewers and editors engage in the social construction of research. The results inform the training of communication scholars, reviewers, and editors.

Use of patient-reported global assessment measures in clinical trials of chronic pain treatments: ACTTION systematic review and considerations.

Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fifty-two (54.2%) studies included a global assessment measure. The PGIC was most common (n = 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n = 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n = 9; 17.3%), satisfaction (n = 8; 15.4%), or overall health status/recovery (n = 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n = 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n = 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development.

The reporting quality and spin of randomized controlled trials of endometriosis pain: Methodological study based on CONSORT extension on abstracts.

To assess the reporting quality of published RCT abstracts regarding patients with endometriosis pelvic pain and investigate the prevalence and characteristics of spin in these abstracts. PubMed and Scopus were searched for RCT abstracts addressing endometriosis pelvic pain published from January 1st, 2010 to December 1st, 2023.The reporting quality of RCT abstracts was assessed using the CONSORT statement for abstracts. Additionally, spin was evaluated in the results and conclusions section of the abstracts, defined as the misleading reporting of study findings to emphasize the perceived benefits of an intervention or to confound readers from statistically non-significant results. Assessing factors affecting the reporting quality and spin existence, linear and logistic regression was used, respectively. A total of 47 RCT abstracts were included. Out of 16 checklist items, only three items including objective, intervention and conclusions were sufficiently reported in the most abstracts (more than 95%), and none of the abstracts presented precise data as required by the CONSORT-A guidelines. In the reporting quality of material and method section, trial design, type of randomization, the generation of random allocation sequences, the allocation concealment and blinding were most items identified that were suboptimal. The total score for the quality varied between 5 and 15 (mean: 9.59, SD: 3.03, median: 9, IQR: 5). Word count (beta = 0.015, p-value = 0.005) and publishing in open-accessed journals (beta = 2.023, p-value = 0.023) were the significant factors that affecting the reporting quality. Evaluating spin within each included paper, we found that 18 (51.43%) papers had statistically non-significant results. From these studies, 12 (66.66%) had spin in both results and conclusion sections. Furthermore, the spin intensity increased during 2010-2023 and 38.29% of abstracts had spin in both results and conclusion sections. Overall poor adherence to CONSORT-A was observed, with spin detected in several RCTs featuring non-significant primary endpoints in obstetrics and gynecology literature.

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy – achieving similar function using different components – and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs.

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy - achieving similar function using different components - and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

Successes and lessons learned from a mobile health behavior intervention to reduce pain and improve health in older adults with obesity and chronic pain: a qualitative study.

Chronic pain is a prevalent issue among older adults in the United States that impairs quality of life. Physical activity has emerged as a cost-effective and non-pharmacological treatment for chronic pain, offering benefits such as improved physical functioning, weight loss, and enhanced mood. However, promoting physical activity in older individuals with chronic pain is challenging, given the cyclical relationship between pain and sedentary behavior. The Mobile Intervention to Reduce Pain and Improve Health (MORPH) trial was designed as an innovative, mobile health (mHealth) supported intervention to address this issue by targeting daylong movement, weight loss, and mindfulness to manage pain in older adults with chronic multisite pain. The objective of this paper is to provide the result of a qualitative analysis conducted on post-intervention interviews with MORPH participants. At the conclusion of the MORPH study, 14 participants were interviewed regarding their experience with the program. All interviews were conducted by phone before being transcribed and verified. A codebook of significant takeaways was created based on these accounts. Summaries were further synthesized into themes using the principles of thematic analysis. Three key themes of the MORPH intervention emerged from the qualitative interviews: MORPH technology (smart scales, Fitbit, MORPH Companion App) facilitated program adherence and accountability; MORPH intervention components (food tracking and mindfulness activities) facilitated program adherence and awareness, respectively; and, group meetings provided motivational support and accountability. Mobile health technologies, including a dedicated MORPH app, facilitated self-monitoring strategies, helped to break the cycle of old habits, and provided participants with immediate feedback on successes; however, technical issues required timely support to maintain engagement. Food tracking contributed to adherence and accountability for weight loss. Mindfulness activities increased participants' awareness of anxiety provoking thoughts and pain triggers. Finally, social support via group meetings and connection, played a crucial role in behavior change, but participants noted consistency in the delivery medium was essential to fostering genuine connections. Overall, the study results highlight the key considerations related to program technology, intervention components, and the value of social support that can help to guide the development of future interventions similar to MORPH.

Placebo Control and Blinding in Randomized Trials of Procedural Interventions

Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed. To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm. Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison. Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity. Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020. End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality. Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88). The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

Real-world evaluation of an algorithmic machine-learning-guided testing approach in stable chest pain: a multinational, multicohort study.

An algorithmic strategy for anatomical vs. functional testing in suspected coronary artery disease (CAD) (Anatomical vs. Stress teSting decIsion Support Tool; ASSIST) is associated with better outcomes than random selection. However, in the real world, this decision is rarely random. We explored the agreement between a provider-driven vs. simulated algorithmic approach to cardiac testing and its association with outcomes across multinational cohorts. In two cohorts of functional vs. anatomical testing in a US hospital health system [Yale; 2013-2023; n = 130 196 (97.0%) vs. n = 4020 (3.0%), respectively], and the UK Biobank [n = 3320 (85.1%) vs. n = 581 (14.9%), respectively], we examined outcomes stratified by agreement between the real-world and ASSIST-recommended strategies. Younger age, female sex, Black race, and diabetes history were independently associated with lower odds of ASSIST-aligned testing. Over a median of 4.9 (interquartile range [IQR]: 2.4-7.1) and 5.4 (IQR: 2.6-8.8) years, referral to the ASSIST-recommended strategy was associated with a lower risk of acute myocardial infarction or death (hazard ratioadjusted: 0.81, 95% confidence interval [CI] 0.77-0.85, P < 0.001 and 0.74 [95% CI 0.60-0.90], P = 0.003, respectively), an effect that remained significant across years, test types, and risk profiles. In post hoc analyses of anatomical-first testing in the Prospective Multicentre Imaging Study for Evaluation of Chest Pain (PROMISE) trial, alignment with ASSIST was independently associated with a 17% and 30% higher risk of detecting CAD in any vessel or the left main artery/proximal left anterior descending coronary artery, respectively. In cohorts where historical practices largely favour functional testing, alignment with an algorithmic approach to cardiac testing defined by ASSIST was associated with a lower risk of adverse outcomes. This highlights the potential utility of a data-driven approach in the diagnostic management of CAD.

Meta-analyses of Randomized Clinical Trials in Postsurgical Pain: Verify before Trusting.

Meta-analyses of Randomized Clinical Trials in Postsurgical Pain: Verify before Trusting.

How Reproducible Are Manual Therapy Interventions in Trials for Low Back Pain? A Scoping Review.

OBJECTIVES: To assess the reproducibility of manual therapy interventions used in clinical trials for low back pain (LBP), and summarize knowledge gaps in assessing the reproducibility of manual therapy interventions for LBP. DESIGN: Scoping review. LITERATURE SEARCH: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase were searched for trials from inception through April 2023. STUDY SELECTION CRITERIA: Randomized controlled trials were included if they described the use of manual therapy to treat LBP in adults 18 to 65 years old and were accessible in English. DATA SYNTHESIS: The Consensus on Exercise Reporting Template (CERT) checklist, used for exercise reporting, was previously modified for manual therapy reporting. This 11-item modified CERT was used to extract details of manual therapy reporting in the included trials. Frequency counts were calculated to identify items most and least commonly reported. RESULTS: Of 128 trials, none reported all 11 items of the modified CERT. The most commonly reported items were the description of how the application of manual therapy was decided (n = 113, 88.3%) and a description of adjunct interventions provided (n = 82, 64.1%). The least reported items were the description of an associated home program (n = 27, 21.1%) and a detailed description of the application of manual therapy (n = 22, 17.2%). CONCLUSION: Reporting of manual therapy interventions in trials investigating LBP was poor overall, limiting the reproducibility of these treatments. Using a checklist designed explicitly for manual therapy intervention reporting may improve reproducibility of these interventions and help align clinical outcomes with experimental findings. J Orthop Sports Phys Ther 2024;54(4):1-10. Epub 29 January 2024. doi:10.2519/jospt.2024.12201.