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Ian Kudel,1 Markay Hopps,2 Joseph C Cappelleri,3 Alesia Sadosky,2 Kristen King-Concialdi,1 Ryan Liebert,1 Bruce Parsons,2 Patrick Hlavacek,2 Andrea H Alexander,2 Marco D DiBonaventura,4 John D Markman,5 John T Farrar,6 Brett R Stacey7 1Health Outcomes Practice, Kantar Health, New York, NY, USA; 2Pfizer Inc, New York, NY, USA; 3Pfizer Inc, Groton, CT, USA; 4Pfizer Inc, New York, NY, USA; 5University of Rochester Medical Center School of Medicine and Dentistry, Rochester, NY, USA; 6Department of Biostatistics and Epidemiology University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 7UW Center for Pain Relief, University of Washington, Seattle, WA, USA 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. Keywords: activity impairment, functional status, health-related quality of life, neuropathic pain, pain medication use, physician diagnosis, work impairment

Marco D DiBonaventura,1 Alesia Sadosky,2 Kristen Concialdi,1 Markay Hopps,2 Ian Kudel,1 Bruce Parsons,2 Joseph C Cappelleri,3 Patrick Hlavacek,2 Andrea H Alexander,2 Brett R Stacey,4 John D Markman,5 John T Farrar6 1Health Outcomes Practice, Kantar Health, 2Pfizer Inc, New York, NY, 3Pfizer Inc, Groton, CT, 4University of Washington, Seattle, WA, 5University of Rochester School of Medicine and Dentistry, Rochester, NY, 6University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, US Background: The prevalence of neuropathic pain (NeP) has been estimated within specific health conditions; however, there are no published data on its broad prevalence in the US. The current exploratory study addresses this gap using the validated PainDetect questionnaire as a screener for probable NeP in a general-population health survey conducted with a multimodal recruitment strategy to maximize demographic representativeness. Materials and methods: Adult respondents were recruited from a combination of Internet panels, telephone lists, address lists, mall-based interviews, and store-receipt invitations using a random stratified-sampling framework, with strata defined by age, sex, and race/ethnicity. Older persons and minorities were oversampled to improve prevalence estimates. Results were weighted to match the total adult US population using US Census data. Demographic information was collected, and respondents who experienced physical pain in the past 12 months completed the PainDetect and provided additional pain history. A cutoff score of 19 or greater on the PainDetect was used to define probable NeP. Results: A total of 24,925 respondents (average response rate 2.5%) provided demographic data (52.2% female, mean age 51.5 years); 15,751 respondents reported pain (63.7%), of which 2,548 (15.7%, 95% confidence interval 14.9%–16.5%) had probable NeP based on the PainDetect, which was 10% (95% confidence interval 9.5%–10.5%) of all respondents. Among those reporting pain, the prevalence of probable NeP among Blacks and Hispanics was consistently higher than Whites in each age- and sex group. The highest prevalence among those with pain was among male Hispanics 35–44 years (32.4%) and 45–54 years (24.2%) old. The most commonly used medications reported by those with probable NeP were nonsteroidal anti-inflammatory drugs (44.2%), followed by weak opioids (31.7%), antiepileptics (10.9%), and strong opioids (10.9%). Conclusion: This is the first study to provide an estimate of the prevalence of probable NeP in the US, showing significant variation by age and ethnicity. Keywords: neuropathic pain, prevalence, pain types, epidemiology

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., Competing Interests: Competing interests: RHD has received in the past 5 years research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, Beckley, Biogen, Biohaven, Biosplice, Boston Scientific, Braeburn, Cardialen, Centrexion, Chiesi, Chromocell, Clexio, Collegium, CoimbiGene, Confo, Decibel, Editas, Eli Lilly, Endo, Ethismos (equity), Eupraxia, Exicure, GlaxoSmithKline, Glenmark, Gloriana, Hope, Kriya, Lotus, Mainstay, Merck, Mind Medicine (also equity), Neumentum, Neurana, NeuroBo, Novaremed, Novartis, OliPass, Orion, Oxford Cannabinoid Technologies, Pfizer, Q-State, Reckitt Benckiser, Regenacy (also equity), Rho, Sangamo, Sanifit, Scilex, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sollis, SPM Therapeutics SPRIM, Teva, Theranexus, Vertex, Vizuri, and WCG. JG, in the past 36 months, has received (unrelated to this work) grant support from the NIH and Neurometrix, consulting income from AlgoTX, GW pharmaceuticals, Eikonozo, and Saluda, and shares for consulting from Eisana Corp. DL, in the past 36 months, has received (unrelated to this work) support from the NIH and the US Food & Drug Administration. DT, in the last 36 months, have received (unrelated to this work) grant support from NIH and NIOSH, consulting fees from Eli Lilly, Pfizer, GSK/Novartis, and Omnicom Health Group, and is Editor-in-Chief of the Clinical Journal of Pain., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Inappropriate patient sexual behaviors (IPSBs) can negatively impact work performance, job satisfaction, and the psychological well-being of clinicians and staff. Although the Veterans Health Administration (VHA) is the largest integrated healthcare system in the United States, the rate of IPSBs in VHA hospitals is unknown. The unique demographic and cultural characteristics of military populations may be associated with IPSBs. To evaluate the extent and impact of IPSBs within a large VA healthcare system (VAHS), a survey was disseminated to all staff. Among the 32% of staff who responded (N = 1359), over half (n = 789; 58.1%) of participants reported at least one instance of IPSB during the past year; this included 67.9% (n = 644) of staff who identified as women and 33.4% (n = 126) of staff who identified as men. There was a significantly greater impact of IPSBs for women, as compared to men, on psychological well-being (X 2 1  = 60.4, p < .001, odds ratio [OR] = 4.55, 95% confidence interval [CI]: [3.08, 6.79]), work satisfaction (X 2 1  = 43.0, p < .001, OR = 3.51, 95% CI: [2.40, 5.18]), and workplace practices (X 2 1  = 48.9, p < .001, OR = 4.02, 95% CI: [2.69, 6.11]). The results of this project highlight the need for overcoming barriers to reducing the pervasiveness and impact of these experiences., (Published 2024. This article is a US Government work and is in the public domain in the USA.)

The U.S. Department of Veterans Affairs (VA) and Department of Defense clinical practice guideline on the treatment of veterans at risk for suicide recommends considering caring contacts interventions after a psychiatric hospitalization for suicidal ideation or suicide attempt. This quality improvement project examined the implementation of the recommendation at a large VA health care system. The project enrolled 29% of hospitalized veterans (N=135 of 462). Enrollment barriers included lack of staff availability and veteran ineligibility due to homelessness or housing instability. Opportunities to improve the reach of the intervention in future quality improvement processes are discussed, especially because acceptability of the intervention was high among veterans., Competing Interests: The contents of this column do not represent the views of the VA or the U.S. government.The authors report no financial relationships with commercial interests.

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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: The authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Caring Letters is recommended in multiple best practice guidelines; however, the Caring Letters intervention has not been widely implemented. The process of tracking, scheduling, and mailing letters for multiple patients over many months may represent a significant barrier for busy clinicians. This evaluation examined whether the use of centralized administrative support (Centralized Caring Letters; CCL) was associated with increased utilization of the intervention. These procedures were tested in the Department of Veterans Affairs (VA) Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program. In REACH VET, VA clinicians are routinely asked to consider Caring Letters as one option for veterans identified as at-risk. In this evaluation, clinicians at two VA facilities were offered assistance in the tracking, preparation, mailing, and documentation of Caring Letters for veterans they chose to enroll in CCL. The utilization of Caring Letters increased more than 14-fold after CCL was implemented. In the year that preceded CCL, 3% of REACH VET veterans were sent Caring Letters at the two sites; this increased to 43% of cases after the implementation of CCL (45% at Site 1 and 41% at Site 2). In qualitative interviews with providers, clinicians described Caring Letters as beneficial and stated that the centralized features of the program were helpful. Caring Letters were discontinued for 30% of enrolled veterans, often because of a bad address (9% of enrolled) or relocation (8% of enrolled). Although there are barriers for the use of Caring Letters, CCL was associated with a very large increase in the use of Caring Letters. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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., (© 2022. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2021 International Association for the Study of Pain.)

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.

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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

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., Competing Interests: The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies, and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting from the University of Rochester Office of Continuing Professional Education with funds from unrestricted grants to support the activities of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) provided by multiple pharmaceutical companies. Preparation of background literature reviews and draft manuscripts was supported by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US FDA, which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. No official endorsement by the FDA, US Department of Veterans Affairs, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of IMMPACT and ACTTION should be inferred.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

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.

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., (Copyright © 2020. Published by Elsevier Inc.)

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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

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., (Copyright © 2020. Published by Elsevier Inc.)

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., (© Congress of Neurological Surgeons 2019.)

Introduction: Mistreatment in medical school is an enduring problem in medical education. Little is known about the concept of 'public humiliation,' one of the most common forms of mistreatment as identified on the AAMC Graduation Questionnaire. The objective of this study was to further investigate 'public humiliation' and to understand the underpinnings and realities of 'public humiliation' in medical education., Method: Focus groups of medical students on clinical rotation at the University of Washington School of Medicine were conducted over one and a half years. Qualitative analysis of responses identified emergent themes., Results: Study results included responses from 28 third year and one fourth-year medical student obtained over five different focus groups. Participants defined the term 'public humiliation' as negatively, purposefully induced embarrassment. Risk factors for the experience of public humiliation in educational settings were found to include the perceived intent and tone of the teacher, as well as situations being 'public' to patients and taking place during a medical or surgical procedure. Socratic teaching or 'pimping' was not found to be a risk factor as long as learners were properly oriented to the teaching practice., Discussion: This study investigated and defined 'public humiliation' in the setting of medical student mistreatment. More subtle forms of mistreatment, like public humiliation, may be amenable to interventions focused on teaching educators about the importance of orientation and clear communication of intent during the teaching process.

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., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Persistent pain after lumbar surgery (failed back surgery syndrome [FBSS]) remains a leading indication for chronic analgesia. However, no analgesics have proven efficacious for this condition. Although trials have evaluated gabapentinoids for chronic low back pain, none of these trials focused solely on FBSS. This randomized, double-blind cross-over trial evaluated the efficacy of gabapentin (1800 mg/day) for FBSS. Eligible patients had a diagnosis of FBBS, an average daily pain score of at least 4 of 10, a neuropathic pain component (indicated by the PainDetect), and reported at least half of their pain radiating in their lower extremity. Participants were randomized to 2, 7-week study periods separated by a 10-day washout. The primary outcome measure was a 0 to 10 numeric rating scale (NRS) of average pain. Secondary measures included the McGill Pain Questionnaire and Patient Global Impression of Change. The treatment effect was analyzed using a mixed effect analysis of covariance with fixed effects for treatment, period, and baseline 7-day mean NRS pain score and a random effect for the participant. The outcome of the model was the mean 7-day NRS score for the last 7 days of each treatment period. Thirty-two participants were randomized and included in the primary analysis; 25 completed both study periods. No difference was detected between treatments on any outcome measure, including the primary (least square mean difference in NRS: -0.01 confidence interval: [-0.22 to 0.20]). Given the escalating rate of complex lumbar surgery, future research to develop novel therapies for this prevalent syndrome is needed.

Objective: To address a gap in the literature for concise recommendations on psychotropic medication monitoring geared to prescribers in primary care psychiatry., Data Sources: Large institutional guidelines from the United States, United Kingdom, Canada, and Australia/New Zealand combined with manual searches for psychiatric medication monitoring consensus and other recommendations up to January 31, 2018., Study Selection: Any available guidelines and consensus statements making psychotropic medication monitoring recommendations for treatment of adults and published in English., Data Extraction: Manual identification of all specific recommendations on psychotropic medication monitoring from the sources., Results: Psychotropic medication monitoring recommendations vary by source, but there is considerable agreement among English-language sources, which can be readily summarized for teaching and everyday use., Conclusions: For prescribers working in many disciplines, medication monitoring may be improved by having more ready access to recommendations., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.

This review examines the stark contrast between the successes and failures of the clinical development of analgesics for different types of chronic low back pain (CLBP) syndrome over the past three decades. Multiple drugs with differing mechanisms of action have been developed for nonspecific axial-predominant low back syndromes and yet not a single therapy is indicated for any neuropathic low back pain syndrome (e.g., sciatica). Clinician findings have informed the entry criteria for neuropathic low back pain clinical trials, whereas entry criteria of axial CLBP trials have prioritized only patient reports of pain. This key difference could account for the lack of success in developing therapies for neuropathic low back pain in an era marked by successful development of analgesics for other types of CLBP as well as many chronic pain syndromes associated with nerve injury, such as post-herpetic neuralgia (PHN)., (Copyright © 2018. Published by Elsevier Ltd.)

The authors report the case of a 52-year-old man who presented with rapid-onset lancinating facial pain consistent with trigeminal neuralgia. Magnetic resonance imaging revealed a nonenhancing small lesion on the right trigeminal nerve concerning for an atypical schwannoma or neuroma. The patient underwent resection of the mass via a right retrosigmoid approach. His facial pain completely resolved immediately postoperatively and had not recurred at 6 months after surgery. The mass was consistent with normal brain tissue (neurons and glial cells) without evidence of mitoses. A final histopathological diagnosis of ectopic brain tissue with neural tissue demonstrating focal, chronic T-cell inflammation was made. The partial rhizotomy during resection was curative for the facial pain. To the authors' knowledge, this is the first report of neuroglial ectopia causing trigeminal neuralgia.

Background: Percutaneous trigeminal rhizotomy or balloon compression for trigeminal neuralgia carries a potential risk for the brainstem, the carotid artery, and the basilar artery., Objective: To detail the relation of critical neural and vascular structures to expanded balloons used for percutaneous compression of the trigeminal ganglion., Method: A retrospective analysis of preprocedural magnetic resonance imaging (MRI) and procedural X-ray-based imaging for 9 patients detailed balloon proximity to the brainstem, carotid artery, and basilar artery., Results: Balloons extended 10.96 ± 5.54 mm (mean ± SD) posterior to the clival line. The average distance from the balloon to the brainstem was 6.89 mm, and that to the basilar artery was 12.12 mm (range: 0-18.2). The medial edge of the balloon was an average distance of 1.39 mm from the baseline position of the carotid lumen., Conclusion: Preprocedural MRI, merged with 3-D rotational angiography suite imaging, detailed the proximity of the balloon to critical neural and vascular structures. Our study found that the standard technique for percutaneous trigeminal compression, with balloon placement at an average depth of 10.96 mm posterior to the clival line, on average, provided an additional 6.89 mm of space before the brainstem would have been encountered, demonstrating safe positioning., (© 2018 S. Karger AG, Basel.)

Introduction: With changes in duty hours and supervision requirements, educators have raised concerns about erosion of patient care ownership by resident physicians. However, the definition of ownership is unclear. This qualitative study investigated definitions of ownership in medicine and psychiatry faculty and residents., Methods: The authors distributed an anonymous online survey regarding definitions of ownership to faculty and residents at the psychiatry and internal medicine residency programs at the University of Washington and the Harvard Longwood psychiatry residency and conducted a qualitative analysis of free-text responses to identify emergent themes., Results: 225 faculty (48.6%) and 131 residents (43.8%) across the three programs responded. Responses yielded themes in five domains: Physician Actions, Physician Attitudes, Physician Identity, Physician Qualities, and Quality of Patient Care. All groups identified themes of advocacy, communication and care coordination, decision-making, follow through, knowledge, leadership, attitudes of going 'above and beyond' and 'the buck stops here', responsibility, serving as primary provider, demonstrating initiative, and providing the best care as central to ownership. Residents and faculty had differing perspectives on 'shift work' and transitions of care and on resident decision-making as elements of ownership., Discussion: This study expanded and enriched the definition of patient care ownership. There were more similarities than differences across groups, a reassuring finding for those concerned about a decreasing understanding of ownership in trainees. Findings regarding shared values, shift work, and the decision-making role can inform educators in setting clear expectations and fostering ownership despite changing educational and care models.

Objectives: Interpretation of CIs in randomised clinical trials (RCTs) with treatment effects that are not statistically significant can distinguish between results that are 'negative' (the data are not consistent with a clinically meaningful treatment effect) or 'inconclusive' (the data remain consistent with the possibility of a clinically meaningful treatment effect). This interpretation is important to ensure that potentially beneficial treatments are not prematurely abandoned in future research or clinical practice based on invalid conclusions., Design: Systematic review of RCT reports published in 2014 in Annals of Internal Medicine , New England Journal of Medicine , JAMA , JAMA Internal Medicine and The Lancet (n=247)., Results: 85 of 99 articles with statistically non-significant results reported CIs for the treatment effect. Only 17 of those 99 articles interpreted the CI. Of the 22 articles in which CIs indicated an inconclusive result, only four acknowledged that the study could not rule out a clinically meaningful treatment effect., Conclusions: Interpretation of CIs is important but occurs infrequently in study reports of trials with treatment effects that are not statistically significant. Increased author interpretation of CIs could improve application of RCT results. Reporting recommendations are provided., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: This analysis compared the therapeutic response of pregabalin in patients with neuropathic pain (NeP) who had been previously treated with gabapentin to the therapeutic response in patients who had not received gabapentin previously., Methods: Data were pooled from 18 randomized, double-blind, placebo-controlled trials of pregabalin in patients with NeP. Pregabalin-mediated changes in pain and pain-related sleep interference scores, patient global impression of change scores at endpoint, and the occurrence of adverse events were compared between patients who had received gabapentin previously (+GBN) and patients who had not received gabapentin previously (-GBN)., Results: There were no significant differences between the -GBN and +GBN cohorts with regard to the extent of pain relief and relief of pain-related sleep interference for any dose of pregabalin (150, 300, 600, or 150 to 600 mg/day) at any time point (6, 8, or 12 weeks). Additionally, there was no significant difference in the distribution of patient global impression of change scores at study endpoint, or the occurrence of adverse events, between the -GBN and +GBN cohorts., Discussion: The findings presented here support the idea that pregabalin may be used successfully to treat patients with NeP who may be refractory, respond inadequately, or are intolerant to gabapentin. These findings highlight the importance of tailoring treatment of NeP based on individual patient response to different treatments, including the trial of multiple agents within the same mechanistic class., (© 2016 World Institute of Pain.)

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials., Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability., (Copyright © 2017 American Pain Society. All rights reserved.)

Introduction: Low back pain (LBP) is among the leading indications for the prescription of opioid analgesics in clinical practice. There is increasing evidence suggesting that these agents may have diminished efficacy in the treatment of LBP., Objectives: We evaluated the relationship between depression, the probability of receiving an opioid prescription, and the amount of morphine equivalent amounts prescribed per year among patients with LBP using nationwide data., Methods: A cross-sectional analysis was performed on existing data from the Medical Expenditure Panel Survey data set from the period 2004 to 2009. Demographic, medical condition, Patient Health Questionnaire-2 responses, and prescription drug information were obtained on 56,811,864 weighted person-years of data from individuals aged 18 to 65 with an ICD-9 code specific to LBP., Results: Increases in PHQ-2 score, as well a positive screen for depression, were associated with an increased probability of being prescribed opioid therapy and more morphine equivalents per year., Conclusion: Analysis of a nationwide sample of patients with LBP shows an association between depression and higher rates of opioid prescribing after controlling for several known cofounders. Clinicians prescribing opioids in LBP populations that rely on clinical trial results that exclude depressed patients may misjudge the risks and benefits of this class of therapy., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Barriers to clinical trial recruitment can delay study completion, potentially resulting in increased costs and an unrepresentative sample. In the current study of 150 participants with chronic pain, we used a computerized adaptive choice-based conjoint survey that included 8 characteristics that may affect enrollment in pharmacologic pain treatment trials (ie, treatment allocation, frequency of pain ratings, treatment administration method, current medications, number of study visits, availability of evening and weekend visits, invasiveness of laboratory procedures, payment). These data were analyzed using Sawtooth Software ver. 8.4.8 (Sawtooth Software, Inc, Orem, UT), which identifies the characteristics that dominate participants' decisions across multiple sets of potential trials. Three characteristics had the largest relative importance in participants' trial preferences: 1) invasiveness of required laboratory procedures (ie, 22%), with no procedures or blood tests preferred over ice-water sensory testing or skin biopsy; 2) ability to continue current pain medications (21%); and 3) payment for study participation (21%), with higher payment preferred. The fourth most important characteristic was number of study visits (13%), with participants preferring fewer in-person visits and more phone contacts. Understanding the preferences of potential participants is an important step toward enhancing enrollment in pain treatment trials., Perspective: This article presents the preferences of individuals with chronic pain conditions regarding modifiable pain treatment trial characteristics (eg, number of study visits, payment, treatment allocation). These findings may help to improve enrollment into analgesic clinical trials and in turn accelerate the development of new pain treatments., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Targeted interventional delivery of corticosteroids remains a mainstay of treatment for spinal pain syndromes because this approach has a wider therapeutic index than other approaches. The best evidence for analgesic efficacy is in subacute radicular syndromes associated with new-onset or recurrent lumbar radiculitis. Complications often relate to drug delivery technique as much as actions of the steroid itself and require careful consideration and vigilance by the administering physician. Considerable uncertainty persists concerning which patients with chronic pain are most likely to benefit from corticosteroid injections. Matching this treatment option with specific spinal pain syndromes remains a major challenge., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine whether patients with neurogenic claudication associated with lumbar spinal stenosis would prefer a treatment that makes it possible for them to walk farther or walk with less pain; to examine associations between this treatment preference and patient-reported and in-clinic treadmill testing measures of walking ability and walking-associated pain., Methods: In this cross-sectional study, 269 patients with neurogenic claudication were asked to report their pain intensity when walking, complete the Swiss Spinal Stenosis Questionnaire, rank their outcome preferences for treatment, and undergo standardized treadmill testing, including measures of final pain rating and time to first pain of moderate intensity (Tfirst). Descriptive statistics were used to characterize patient preferences for treatment outcome. Associations between self-report questionnaires and standardized treadmill testing outcomes were evaluated using Spearman correlations., Results: Seventy-nine percent of patients expressed a preference for treatment that allowed them to walk with less pain. Preference for reduced pain was associated with higher pain during daily walking, along with a shorter Tfirst and higher final pain severity on treadmill testing. In contrast, patient preference for treatment outcome was not associated with self-reported measures of daily walking capacity or walking distance on the treadmill., Conclusions: A majority of patients with neurogenic claudication prioritized walking with reduced pain over walking farther. Reduction in pain while walking may therefore constitute a sufficient patient-focused treatment outcome for the majority of these patients. These results have implications for clinical trial design and assessment of treatment efficacy in neurogenic claudication., (© 2015 American Academy of Neurology.)

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.

Objective: To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated., Design: Retrospective chart review., Subjects: Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits., Methods: Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients., Results: While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients., Conclusions: These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. © 2014 Wiley Periodicals, Inc., (Wiley Periodicals, Inc.)

Study Design: Randomized, double-blind, placebo-controlled, single-dose crossover study., Objective: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis., Summary of Background Data: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations., Methods: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire., Results: The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66])., Conclusion: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication., Level of Evidence: 2.

Objective: Neuropathic pain screening tools have shown promise in identifying common neuropathic pain characteristics that derive from diverse etiologies (e.g., diabetic peripheral neuropathy, postherpetic neuralgia). However, no prior studies have specifically assessed whether these tools are capable of discerning the underlying pain mechanisms in the vast, heterogeneous group of patients diagnosed with failed back surgery syndrome (FBSS)., Design: In this clinical observational study, two tests for neuropathic pain characteristics, the Douleur Neuropathique en 4 (DN4) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaires, were performed on 43 subjects with FBSS. Subjects underwent physical or neurosensory exam components of the DN4 and LANSS in the region of most severe pain (e.g., axial low back or lower extremities). DN4 and LANSS scores were correlated with clinical history and neurologic exam, pain-related quality of life questionnaires, and compared to an independent assessment of pain distribution., Results: The presence of neuropathic characteristics, determined by the DN4 (62% sensitivity, 44% specificity), LANSS (38% sensitivity, 75% specificity; cut-offs of 4 and 12, respectively), or their combination (20% sensitivity, 58% specificity) was associated with higher pain intensity as measured by the visual analog scale (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.042), modified Brief Pain Inventory-Short Form (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.082), and Neuropathic Pain Symptom Inventory (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.001), and greater pain-related functional impairment as measured by the Roland-Morris Disability Questionnaire (DN4 > 4, P = 0.006; LANSS ≥ 12, P = 0.018). The percentage of subjects characterized as neuropathic by the DN4 and LANSS lacked concordance (67.4 vs. 25.6), and the distribution of most severe symptoms (i.e., axial vs radicular) did not correlate with subjects determined to have neuropathic pain., Conclusions: Unlike other neuropathic syndromes, the neuropathic component of FBSS is less reliably identified by the LANSS and DN4., (Wiley Periodicals, Inc.)

Objectives: To test the effects of pregabalin on the induction of neurogenic claudication., Methods: This study was a randomized, double-blind, active placebo-controlled, 2-period, crossover trial. Twenty-nine subjects were randomized to receive pregabalin followed by active placebo (i.e., diphenhydramine) or active placebo followed by pregabalin. Each treatment period lasted 10 days, including a 2-step titration. Periods were separated by a 10-day washout period, including a 3-day taper phase after the first period. The primary outcome variable was the time to first moderate pain symptom (Numeric Rating Scale score ≥4) during a 15-minute treadmill test (Tfirst). Secondary outcome measures included pain intensity at rest, pain intensity at the end of the treadmill test, distance walked, and validated self-report measures of pain and functional limitation including the Roland-Morris Disability Questionnaire, modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire., Results: No significant difference was found between pregabalin and active placebo for the time to first moderate pain symptom (difference in median Tfirst = -1.08 [95% confidence interval -2.25 to 0.08], p = 0.61). In addition, none of the secondary outcome measures of pain or functional limitation were significantly improved by pregabalin compared with active placebo., Conclusions: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis., Classification of Evidence: This study provides Class I evidence that for patients with neurogenic claudication, compared with diphenhydramine, pregabalin does not increase the time to moderate pain during a treadmill test., (© 2014 American Academy of Neurology.)

Objective: In this study, the functional recoveries of Sprague-Dawley rats following repair of a complete sciatic nerve transection using allotransplanted dorsal root ganglion (DRG) neurons or Schwann cells were examined using a number of outcome measures., Methods: Four groups were compared: (1) repair with a nerve guide conduit seeded with allotransplanted Schwann cells harvested from Wistar rats, (2) repair with a nerve guide conduit seeded with DRG neurons, (3) repair with solely a nerve guide conduit, and (4) sham-surgery animals where the sciatic nerve was left intact. The results corroborated our previous reported histology findings and measures of immunogenicity., Results: The Wistar-DRG-treated group achieved the best recovery, significantly outperforming both the Wistar-Schwann group and the nerve guide conduit group in the Von Frey assay of touch response (P < 0.05). Additionally, Wistar-DRG and Wistar-Schwann seeded repairs showed lower frequency and severity in an autotomy measure of the self-mutilation of the injured leg because of neuralgia., Conclusion: These results suggest that in complete peripheral nerve transections, surgical repair using nerve guide conduits with allotransplanted DRG and Schwann cells may improve recovery, especially DRG neurons, which elicit less of an immune response.

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential., (Copyright © 2013 International Association for the Study of Pain. All rights reserved.)

Unlabelled: Acupuncture is a form of Eastern medicine that has been practiced for centuries. Despite its long history and worldwide application, the biological mechanisms of acupuncture in relieving pain have been poorly defined. Recent studies in mice, however, demonstrate that acupuncture triggers increases in interstitial adenosine, which reduces the severity of chronic pain through adenosine A1 receptors, suggesting that adenosine-mediated antinociception contributes to the clinical benefits of acupuncture. We asked here whether acupuncture in human subjects is also linked to a local increase in interstitial adenosine concentration. We collected microdialysis samples of interstitial fluid before, during, and after delivering 30 minutes of conventional acupuncture in the Zusanli point in human subjects. The interstitial adenosine concentration increased significantly during acupuncture and remained elevated for 30 minutes after the acupuncture. Acupuncture-mediated adenosine release was not observed if acupuncture was not delivered in the Zusanli point or if the acupuncture needle was inserted, but not rotated. This study strengthens the role of adenosine in acupuncture-mediated antinociception by directly providing such evidence in humans., Perspective: This article presents further evidence of the role of adenosine in acupuncture-mediated antinociception by demonstrating that local adenosine concentrations increase in the acupoint in human subjects receiving traditional acupuncture., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)