Pain Trials Research Articles

Sex Differences in Computed Tomography Coronary Stenosis Severity Versus Flow Impairment and Impact on Revascularization, Clinical Events and Health Care Costs: A FORECAST Substudy.

The impact of sex-related differences in coronary atheroma and flow impairment severity on clinical events and costs remains unclear. This is a secondary analysis of patients with stable coronary artery disease who underwent both coronary computed tomography angiography and fractional flow reserve derived from computed tomography as part of the FORECAST (Fractional Flow Reserve Derived From Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain) trial, investigating (1) the relationship between coronary stenosis severity on coronary computed tomography angiography and fractional flow reserve derived from computed tomography FFRCTby sex and (2) the association with revascularization, resource usage, and adverse clinical events. A total of 212 patients (64 female participants [32.1%]) and 1245 vessels were included. There was no significant sex difference in the frequencies of significant coronary artery disease (38.2% of women versus 51.3% of men; P=0.073), but female participants had significantly less coronary flow impairment, according to the presence of at least 1 fractional flow reserve derived from computed tomography≤0.8 (47.0% versus 71.5%; P=0.008). Female subjects underwent fewer revascularization procedures (23.5% versus 42.3%; P=0.014), less coronary artery bypass graft surgery (2.9% versus 13.1%; P=0.025) and were less likely to be on statin treatment (72.0% versus 84.7%; P=0.022) by 9-month follow-up. This resulted in lower overall health care costs for female participants compared with male counterparts (median total cost, £1276 versus £2051; P=0.014). In multivariable Cox analysis the presence of significant coronary artery disease (hazard ratio [HR], 2.91; 95% CI, 1.30-6.51) and having a positive fractional flow reserve derived from computed tomography (HR, 4.11; 95% CI, 1.15-14.69) were independent predictors of major adverse cardiovascular events at 9 months, whereas sex was not statistically significant (p=0.13). There are significant sex differences in the anatomico-functional assessment of coronary artery disease leading to differences in clinical management, costs, and adverse events.

Therapeutic quality of exercise interventions for chronic low back pain: a meta-research study using i-CONTENT tool

ObjectiveTo assess the therapeutic quality of exercise interventions delivered in chronic low back pain (cLBP) trials using the international Consensus on Therapeutic Exercise aNd Training (i-CONTENT) tool and its inter-rater...

Evaluating Treatment Preferences and the Efficacy of Capsaicin 179 mg Patch vs. Pregabalin in a Randomized Trial for Postsurgical Neuropathic Pain in Breast Cancer: CAPTRANE.

Background/Objectives: CAPTRANE evaluated the efficacy and tolerability of high-concentration capsaicin patch (HCCP) vs. oral pregabalin for the treatment of postsurgical neuropathic pain (PSNP) following breast cancer surgery. The study was designed with the aim of demonstrating noninferiority of one HCCP against daily pregabalin. Methods: This was a multicenter, randomized, parallel-arm, open-label study conducted across nine centers in France. The primary endpoint was a change from baseline in the Numeric Pain Rating Scale (NPRS) score after 2 months. Results: Recruitment challenges resulted in the randomization of 140 patients (versus 644 planned); the per-protocol population comprised 107 patients (HCCP: n = 65; pregabalin: n = 42). Baseline characteristics were similar between the two groups. In the per-protocol analysis, the mean (standard deviation) change versus baseline in NPRS score was -1.926 (2.554) with HCCP and -1.634 (2.498) with pregabalin. The prespecified analysis showed that HCCP was not inferior to pregabalin: the lower bound of the 90% confidence interval for the between-arm difference was -0.889 and the upper bound was +0.260 (i.e., below the predefined clinical threshold of +0.4). Patient-reported outcomes showed no statistically significant differences between treatments. The painful area size decreased significantly more with HCCP. Tolerability profiles differed, with HCCP mostly causing application-site reactions. While >50% of patients switched from pregabalin to HCCP, none switched from HCCP to pregabalin. Conclusions: This comparative study in PSNP post breast cancer surgery, evaluating a single treatment of HCCP, shows a noninferior reduction in pain intensity, a superior reduction in painful area size, and a patient preference for HCCP compared with pregabalin. Despite limitations, it contributes valuable initial data for PSNP management in breast cancer care.

'Which treatment do you believe you received?' A randomised blinding feasibility trial of spinal manual therapy

BackgroundBlinding is essential for mitigating biases in trials of low back pain (LBP). Our main objectives were to assess the feasibility of blinding: (1) participants randomly allocated to active or placebo spinal manual therapy (SMT), and (2) outcome assessors. We also explored blinding by levels of SMT lifetime experience and recent LBP, and factors contributing to beliefs about the assigned intervention.MethodsA two-parallel-arm, single-centre, placebo-controlled, blinding feasibility trial. Adults were randomised to active SMT (n = 40) or placebo SMT (n = 41). Participants attended two study visits for their assigned intervention, on average seven days apart. The primary outcome was participant blinding (beliefs about assigned intervention) using the Bang blinding index (BI) at two study visits. The Bang BI is arm-specific, chance-corrected, and ranges from − 1 (all incorrect beliefs) to 1 (all correct beliefs), with 0 indicating equal proportions of correct and incorrect beliefs. Secondary outcomes included factors contributing to beliefs about the assigned intervention.ResultsOf 85 adults screened, 81 participants were randomised (41 [51%] with SMT lifetime experience; 29 [39%] with recent LBP), and 80 (99%) completed follow-up. At study visit 1, 50% of participants in the active SMT arm (Bang BI: 0.50 [95% confidence interval (CI), 0.26 to 0.74]) and 37% in the placebo SMT arm (0.37 [95% CI, 0.10 to 0.63]) had a correct belief about their assigned intervention, beyond chance. At study visit 2, BIs were 0.36 (0.08 to 0.64) and 0.29 (0.01 to 0.57) for participants in the active and placebo SMT arms, respectively. BIs among outcome assessors suggested adequate blinding at both study visits (active SMT: 0.08 [− 0.05 to 0.20] and 0.03 [− 0.11 to 0.16]; placebo SMT: − 0.12 [− 0.24 to 0.00] and − 0.07 [− 0.21 to 0.07]). BIs varied by participant levels of SMT lifetime experience and recent LBP. Participants and outcome assessors described different factors contributing to their beliefs.ConclusionsAdequate blinding of participants assigned to active SMT may not be feasible with the intervention protocol studied, whereas blinding of participants in the placebo SMT arm may be feasible. Blinding of outcome assessors seemed adequate. Further methodological work on blinding of SMT is needed.Trial registration numberNCT05778396.

A scoping review of the effectiveness of underwater treadmill exercise in clinical trials of chronic pain.

The objective of this scoping review was to investigate the available literature on physical and quality of life (QoL) outcomes of underwater treadmill exercise trials in clinical chronic pain samples. A scoping search of studies of the effectiveness of underwater treadmill exercise trials from 1947 to 2024 was conducted using the following databases: EMBASE, MEDLINE, SPORTDiscus, CINAHL, and Cochrane Reviews. To be included, studies were required to have included adult participants living with chronic pain (defined as pain lasting for 3 months or longer) who participated in an active underwater treadmill exercise intervention. No restrictions on pain diagnosis were applied. All clinical trials, including but not limited to randomized controlled trials (RCTs), feasibility trials, and pilot studies, were included in the search. Two independent reviewers determined whether studies met inclusion criteria, and a third reviewer resolved any disagreement on study inclusion. The initial search identified 2,209 studies: 314 articles were removed for duplications, 1,781 were removed because they did not meet inclusion criteria, and 113 were retained for full-text review. The full-text review yielded nine studies, all of which included samples consisting of participants with osteoarthritis. The following variables were investigated in the included studies to varying degrees: pain, QoL, mobility, balance, strength, and changes in gait kinematics. Multiple studies identified significant differences between control groups or pre-intervention groups and underwater treadmill groups or post-intervention groups in chronic pain, balance, mobility, strength, and QoL. Findings suggest that underwater treadmill exercise leads to positive changes in chronic pain, balance, mobility, strength, and QoL. However, more studies, particularly RCTs with larger samples that include individuals with chronic pain conditions other than osteoarthritis, are warranted.

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).

Teletherapy could miss a distinct group among patients with pain and opioid use disorder

The COVID-19 pandemic highlighted a pre-existing issue related to healthcare accessibility, especially for comorbid chronic pain and opioid use disorder (OUD) populations. Though researchers and practitioners have relied on telehealth to address barriers to healthcare, telehealth services remain inaccessible for many. This study explored the effectiveness of strategies used to continue a clinical trial for comorbid chronic pain and OUD during the COVID-19 pandemic. This study involved the transition of in-person group psychotherapy (Self-regulation Therapy for Opioid use disorder and Chronic Pain–STOP) to telehealth. We completed a mixed-method data analysis to assess the differences between the telehealth and in-person administrations. Though the telehealth group showed higher retention, the in-person group reached more diverse samples. Participants who completed the telehealth group had higher education and income, longer periods of stability on medication for opioid use disorder (MOUD) and were more likely to be White compared to participants who completed the in-person group. Individuals from minoritized and underserved groups who lack access to in-person services may fall through the gaps of healthcare in the shift to telehealth. There is a clear need for additional research on how to best support those who lack access to current comorbid chronic pain and OUD treatment modalities. ClinicalTrials.gov record number:17–1849, registered November 2017.

Impact of the COVID-19 pandemic on participants in pragmatic clinical trials for chronic pain: implications for trial outcomes and beyond.

The COVID-19 pandemic had profound effects on society, including those living with chronic pain. This study sought to examine pandemic impacts on individuals enrolled in pragmatic clinical trials focused on nonpharmacological treatments for chronic pain. We evaluated responses to a questionnaire on COVID-19 impacts that had been administered to participants (n=2024) during study enrollment in 3 pragmatic clinical trials for chronic pain treatment. All trials were part of the National Institutes of Health (NIH)-Department of Veterans Affairs (VA)-Department of Defense (DOD) Pain Management Collaboratory. COVID-19-related impacts on access to health care, mental health, finances, ability to meet basic needs, and social support were assessed. Pandemic impacts were found in all domains assessed, including access to health care, mental and emotional health, ability to meet basic needs, finances, and social support. Impacts varied by demographic and clinical characteristics. The participants most negatively impacted by the pandemic were younger, Black or Latino, female, more educated, and unemployed and had screened positive for depression. No impact differences were found with regard to alcohol use disorder screenings or a prior history of COVID-19. Higher levels of pain were associated with worse pandemic impacts, and negative impacts declined over time. Negative impacts of the pandemic on individuals living with chronic pain cut across aspects of life that are also central to effective pain management, including access to health care, social support, and mental and emotional health, with differential impacts found across key demographic and clinical factors. These findings should yield consideration of pandemic impacts in clinical practice and as moderating effects of treatment outcomes in clinical trials conducted during the pandemic.

Adapting the open-source Gen3 platform and kubernetes for the NIH HEAL IMPOWR and MIRHIQL clinical trial data commons: Customization, cloud transition, and optimization

ObjectiveThis study aims to provide the decision-making framework, strategies, and software used to successfully deploy the first combined chronic pain and opioid use data clinical trial data commons using the Gen3 platform. Materials and MethodsThe approach involved adapting the open-source Gen3 platform and Kubernetes for the needs of the NIH HEAL IMPOWR and MIRHIQL networks. Key steps included customizing the Gen3 architecture, transitioning from Amazon to Google Cloud, adapting data ingestion and harmonization processes, ensuring security and compliance for the Kubernetes environment, and optimizing performance and user experience. ResultsThe primary result was a fully operational IMPOWR data commons built on Gen3. Key features include a modular architecture supporting diverse clinical trial data types, automated processes for data management, fine-grained access control and auditing, and researcher-friendly interfaces for data exploration and analysis. DiscussionThe successful development of the Wake Forest IDEA-CC data commons represents a significant milestone for chronic pain and addiction research. Harmonized, FAIR data from diverse studies can be discovered in a secure, scalable repository. Challenges remain in long-term maintenance and governance, but the commons provides a foundation for accelerating scientific progress. Key lessons learned include the importance of engaging both technical and domain experts, the need for flexible yet robust infrastructure, and the value of building on established open-source platforms. ConclusionThe WF IDEA-CC Gen3 data commons demonstrates the feasibility and value of developing a shared data infrastructure for chronic pain and opioid use research. The lessons learned can inform similar efforts in other clinical domains.

How initial perceptions of the effectiveness of mind and body complementary and integrative health therapies influence long-term adherence in a pragmatic trial.

Beliefs and perceptions about pain intervention effectiveness when initiating a therapy may influence long-term engagement. This study examines how early perceived effectiveness of complementary and integrative health therapies impacts long-term engagement in a pragmatic trial context. Veterans with chronic musculoskeletal pain participating in a pragmatic trial of provider-delivered complementary and integrative health therapies (acupuncture, chiropractic care, or massage therapy) used alone compared to combining those therapies with self-care therapies (yoga, Tai Chi/Qigong, or meditation). This analysis focuses on 1713 participants using self-care therapies at baseline. 18 Veterans Healthcare Administration Medical Facilities. Prospective cohort study. Predictors of total self-care complementary and integrative health therapy sessions over a 6-month assessment period were assessed using linear regression to determine how strongly perceptions of initial therapy effectiveness was associated with total utilization. Perception of initial therapy effectiveness was assessed at study entry across four domains (pain, mental health, fatigue, and general well-being). In total, 56% (1032/1713) of Veterans reported a positive perceived effectiveness of their recent complementary and integrative health therapy use at study initiation. Older individuals and those using meditation were more likely to report early positive perceptions. Mean number of therapy sessions over the 6-month study was 11 (range 1 to 168). Early positive perceptions had a small effect on overall use, increasing mean sessions by 2.5 (1.3 to 3.6). Other factors such as recent physical therapy use and distance to primary care explained more variation in total utilization. Pragmatic pain trials should examine factors associated with engagement across assigned treatment protocols, especially if any of the treatment protocols being tested are sensitive to long-term engagement.

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

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).

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.

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.

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.