Evaluating the balance of benefits and harms in chronic pain clinical trials: prioritizing individual participants over individual outcomes.

BACKGROUND: Randomized clinical trials (RCTs) generally assess efficacy and safety separately, with the conclusion of whether a treatment is beneficial based solely on the efficacy endpoint. However, assessing and combining efficacy and safety domains, using a single composite outcome measure, can provide a more comprehensive assessment of the overall effect of a treatment. Furthermore, composite outcomes can incorporate information regarding the relationship between the individual outcomes. In fact, such outcomes have been suggested in the clinical trials literature for at least 15 years. OBJECTIVES: To (1) identify whether recent primary publications of chronic pain RCTs from major pain journals included a composite outcome measure of benefits and harms and (2) discuss the potential benefits of such outcomes in various stages of treatment development, including as outcome measures in RCTs, and to support decisions of Data and Safety Monitoring Boards and ordering of treatments in the context of treatment guidelines. EVIDENCE REVIEW: RCTs published in 6 major pain journals published between 2016 and 2021 that investigated interventions for chronic pain were reviewed. FINDINGS: Of 73 RCTs identified, only 2 included a composite outcome measure of benefits and harms. Both of these articles compared 2 active treatments. CONCLUSIONS: Composite outcomes of benefits and harms are underutilized in chronic pain RCTs. The advantages and challenges of using such outcomes are discussed.

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.

Examining the Relationships Among Treatment, Pain, and Physical Function in Patients With Osteoarthritis: A Mediation-Modeling Approach.

OBJECTIVES: To better understand the relationships among treatment, pain, and physical function (PF). METHODS: Data were collected from 2 published randomized clinical trials of osteoarthritis patients who received tanezumab or a placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period. RESULTS: The cross-sectional and longitudinal mediation models showed a stable indirect effect of treatment through the pain on PF across time, indicating that a pseudo-steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in study 1 (NCT02697773) and 74.1% in study 2 (NCT02709486), both P <0.0001, whereas the direct effect was 22.2% for study 1 ( P = 0.0003) and 25.9% for study 2 ( P = 0.0019). DISCUSSION: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.

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.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Predicting Treatment Response with Sensory Phenotyping in Post-Traumatic Neuropathic Pain.

OBJECTIVE: Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. METHODS: Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. RESULTS: The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). CONCLUSIONS: These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

ABSTRACT: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Tanezumab for chronic low back pain: a long-term, randomized, celecoxib-controlled Japanese Phase III safety study.

Aim & methods: This trial investigated long-term (56-week treatment/24-week follow-up) use of subcutaneous tanezumab (5 or 10 mg every 8 weeks) or oral celecoxib (200 mg/day) in Japanese patients with chronic low back pain. Results & conclusion: Tanezumab safety was consistent with previous studies, except overall adverse events (tanezumab 5 mg = 63.0%, tanezumab 10 mg = 54.8%, celecoxib = 67.4%) and events of abnormal peripheral sensation (tanezumab 5 mg = 9.8%, tanezumab 10 mg = 4.3%, celecoxib = 4.3%) were more frequent with 5 mg than 10 mg tanezumab. Joint safety event rates were 1.1% for tanezumab 5 mg, 2.2% for tanezumab 10 mg and 0% for celecoxib. All treatments improved pain and function throughout the treatment period. Clinical trial registration number: NCT02725411.

In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Tanezumab for chronic low back pain: a randomized, double-blind, placebo- and active-controlled, phase 3 study of efficacy and safety.

ABSTRACT: This randomized, double-blind, phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5 or 10 mg every 8 weeks), or oral tramadol prolonged-release (100-300 mg/day). Primary endpoint was change in low back pain intensity (LBPI) at week 16 for tanezumab vs placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire at week 16, and change in LBPI at week 2 for tanezumab vs placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10 mg met the primary endpoint by significantly improving LBPI at week 16 vs placebo; least squares (LS) mean (95% CI) difference = -0.40 (-0.76 to -0.04; P = 0.0281). Tanezumab 10 mg significantly improved all key secondary endpoints. Tanezumab 5 mg did not meet the primary endpoint (LS mean [95% CI] treatment difference vs placebo = -0.30 [-0.66 to 0.07; P = 0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5 mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97 to 1.70; P = 0.0846]), and 46.3% in the tanezumab 10 mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09 to 1.91; P = 0.0101]). Prespecified joint safety events were more frequent with tanezumab 10 mg (2.6%) than tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10 mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10 mg significantly improved pain and function vs placebo in patients with difficult-to-treat chronic low back pain. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement.

AAPT Diagnostic Criteria for Chronic Low Back Pain.

Chronic low back pain (CLBP) conditions are highly prevalent and constitute the leading cause of disability worldwide. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS), have combined to create the ACTTION-APS Pain Taxonomy (AAPT). The AAPT initiative convened a working group to develop diagnostic criteria for CLBP. The working group identified 3 distinct low back pain conditions which result in a vast public health burden across the lifespan. This article focuses on: 1) the axial predominant syndrome of chronic musculoskeletal low back pain, 2) the lateralized, distally-radiating syndrome of chronic lumbosacral radicular pain 3) and neurogenic claudication associated with lumbar spinal stenosis. This classification of CLBP is organized according to the AAPT multidimensional framework, specifically 1) core diagnostic criteria; 2) common features; 3) common medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. PERSPECTIVE: An evidence-based classification of CLBP conditions was constructed for the AAPT initiative. This multidimensional diagnostic framework includes: 1) core diagnostic criteria; 2) common features; 3) medical and psychiatric comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Association Between Opioid Use and Patient-Reported Outcomes in a Randomized Trial Evaluating Basivertebral Nerve Ablation for the Relief of Chronic Low Back Pain.

BACKGROUND: Chronic low back pain (CLBP) is a primary indication for opioid therapy. OBJECTIVE: To evaluate the hypothesis that CLBP patients reporting reduced opioid use have superior functional outcomes following basivertebral nerve (BVN) radiofrequency ablation. METHODS: This post hoc analysis from a sham-controlled trial examined short-acting opioid use from baseline through 1 yr. Opioid use was stratified into 3 groups by two blinded external reviewers. Two-sample t-tests were used to compare Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) measurements between those patients who increased or decreased their opioid usage compared to baseline. RESULTS: Actively treated patients with decreased opioid use at 12 mo had a mean ODI improvement of 24.9 ± 16.0 (n = 27) compared to 7.3 ± 9.8 (n = 18) for patients reporting increased opioid use (P < .001). In the sham arm, the improvements in ODI were 17.4 ± 16.1 (n = 19) and 1.2 ± 14.3 (n = 5; P = .053) for the patients reporting decreased vs increased opioid usage, respectively. Actively treated patients reporting decreased opioid use had a mean improvement in VAS of 3.3 ± 2.5 (n = 27) compared to 0.6 ± 1.8 (n = 18) for patients reporting increased opioid use (P < .001). In the sham arm, the improvements in VAS were 2.5 ± 2.6 (n = 19) and 1.4 ± 1.9 (n = 5; P = .374) for patients reporting decreased vs increased opioid use, respectively. CONCLUSION: Subjects undergoing BVN ablation who decreased opioid use had greater improvement in ODI and VAS scores compared with those reporting increased opioid usage. There is an association between functional benefit from BVN ablation and reduced opioid use.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Characteristics of patients with neuropathic pain syndromes screened by the painDETECT questionnaire and diagnosed by physician exam.

BACKGROUND: The aim of this study was to identify the clinical characteristics, treatment usage, and health outcomes of US adults diagnosed with neuropathic pain (NeP) by experienced physicians. METHODS: Adults with scores exceeding the threshold for probable NeP (painDETECT ≥19) and diagnosed with NeP by a qualified physician completed a questionnaire that included comorbid conditions, pain symptoms and experiences, medication use, health status (3-level EuroQol 5 Dimensions (EQ-5D-3L]: health utilities index and visual analog scale), pain severity and interference with functioning (Brief Pain Inventory), and work and activity impairment (Work Productivity and Activity Impairment questionnaire). Descriptive analyses were performed for each NeP subtype. RESULTS: Participants (n=295) were predominantly female (64.4%), middle-aged (53.9%), and white (51.5%). Chronic low back pain was the most frequently diagnosed major NeP syndrome (n=166), followed by diabetic peripheral neuropathy (n=58), post-trauma neuropathy (n=47), post-surgical neuropathy (n=28), and central NeP (n=23). An additional 45 participants were diagnosed, but did not meet the criteria for the aforementioned subtypes. Participants could be diagnosed with multiple subtypes. Across each NeP subtype, patients reported high rates of comorbid disease, including arthritis (range: 39.1%-64.3%) and high blood pressure (range: 26.1%-69.0%), as well as symptomology that included numbness (range: 68.1%-91.4%) and changes in muscular strength (range: 24.1%-65.2%). The majority of patients reported back pain (range: 77.8%-95.7%) and arthritis/joint pain (range: 68.1%-78.6%). The most commonly reported types of NeP pain medication were non-steroidal anti-inflammatory drugs (range: 43.1%-70.2%), weak opioids (range: 22.2%-39.3%), and strong opioids (range: 8.7%-28.6%). All six NeP groups generally reported similar levels of dysfunction on all self-report measures. The most notable finding was that the EuroQol-5D-3L health utilities index scores for each of the six groups were lower than the US norms by a clinically important amount. CONCLUSION: These exploratory findings indicate that patients with NeP across different etiologies are medically complex and experience impaired function across multiple domains.

Demonstrating Heterogeneity of Treatment Effects Among Patients: An Overlooked but Important Step Toward Precision Medicine.

Although heterogeneity in the observed outcomes in clinical trials is often assumed to reflect a true heterogeneous response, it could actually be due to random variability. This retrospective analysis of four randomized, double-blind, placebo-controlled multiperiod (i.e., episode) crossover trials of fentanyl for breakthrough cancer pain illustrates the use of multiperiod crossover trials to examine heterogeneity of treatment response. A mixed-effects model, including fixed effects for treatment and episode and random effects for patient and treatment-by-patient interaction, was used to assess the heterogeneity in patients' responses to treatment during each episode. A significant treatment-by-patient interaction was found for three of four trials (P < 0.05), suggesting heterogeneity of the effect of fentanyl among different patients in each trial. Similar analyses in other therapeutic areas could identify conditions and therapies that should be investigated further for predictors of treatment response in efforts to maximize the efficiency of developing precision medicine strategies.