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The Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) was developed to identify prescription opioid misuse and abuse among patients with chronic pain. A clinical scoring algorithm was developed and refined to align with the patient experience. This study utilized data from the POMAQ validation study (3033-4, NCT02660606) conducted on a sample of patients with chronic pain living in the United States. The study was carried out in two phases. Two purposefully enriched patient samples, one for each phase, were created based on patient responses to select POMAQ items and the availability of urine and hair samples. Two clinical experts (SHS, SFB) reviewed patient data to classify prescription opioid use behavior. Classification differences were adjudicated by a third clinical expert (JTF). Comparisons were made between the final clinical classification determined by the experts and the proposed classification based on the POMAQ algorithm. Sixty patients were included in Phase I (only POMAQ data) and 52 in Phase II (including POMAQ and ancillary sources [e.g. electronic medical records, urine toxicity screen]). Refinements were made to the POMAQ scoring algorithm following discussions with clinical experts to ensure it was clinically relevant. For both phases, classifications were reviewed and discussed to achieve maximal concordance of classifications across experts. The proposed scoring algorithm was then modified to maximize agreement with the expert interpretation of clinically relevant patient experiences. The clinical scoring algorithm for the POMAQ was developed and refined to reflect clinically relevant patient behaviors identified by expert review. Future testing is needed to determine the sensitivity and specificity of this measure.

To identify patient risk factors associated with prescription opioid misuse and abuse as well as groupings of misuse and abuse behaviors as measured by the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ). Adults with chronic pain requiring long-term treatment with opioids completed the POMAQ and other study questionnaires. Latent class analysis (LCA) was used to examine underlying subgroups exhibiting particular risk profiles. Patient demographic and clinical characteristics were examined as covariates and the concordance between the identified latent classes at-risk classifications and the POMAQ clinical scoring algorithm was assessed. Analysis of data from 809 patients revealed four classes: “chronic pain, low risk” (n = 473, low to no prevalence of POMAQ behaviors), “chronic pain, comorbid condition” (n = 152, high prevalence of anti-anxiety, sleeping pill, and antihistamine use), “at risk” (n = 154, taking more opioids than prescribed and drinking alcohol with opioids more frequently than other groups), and “high risk” (n = 30, highest prevalence of each behavior). The “high risk” group was associated with being younger, less educated, and unemployed compared to other groups. When examining the LCA classes by groups defined by the original POMAQ clinical scoring algorithm, the “high risk” class had the highest proportion of participants identified with abuse behaviors (46.7%), compared to just 4.7% in the “chronic pain, low risk” group. Findings suggest there are four distinct subgroups of patients defined by chronic opioid misuse and abuse behaviors and support the use of the POMAQ to identify risk factors associated with prescription opioid misuse and abuse.

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.

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.

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants' expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and nonpharmacological pain treatments. We highlight the potential benefit of adjusting for participants' expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PERSPECTIVE: This focus article provides an overview of the relationship between participants' baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity.

Supplemental Digital Content is Available in the Text., Opioids relieve acute pain, but there is little evidence to support the stability of the benefit over long-term treatment of chronic noncancer pain. Previous systematic reviews consider only group level published data which did not provide adequate detail. Our goal was to use patient-level data to explore the stability of pain, opioid dose, and either physical function or pain interference in patients treated for 12 months with abuse deterrent formulations of oxycodone and hydrocodone. All available studies in the Food and Drug Administration Document Archiving, Reporting, and Regulatory Tracking System were included. Patient-level demographics, baseline data, exposure, and outcomes were harmonized. Individual patient slopes were calculated from a linear model of pain, physical function, and pain interference to determine response over time. Opioid dose was summarized by change between baseline and the final month of observation. Patients with stable or less pain, stable or lower opioid dose, and stable or better physical function (where available) met our prespecified criteria for maintaining long-term benefit from chronic opioids. Of the complete data set of 3192 patients, 1422 (44.5%) maintained their pain level and opioid dose. In a secondary analysis of 985 patients with a measured physical function, 338 (34.3%) maintained their physical function in addition to pain and opioid dose. Of 2040 patients with pain interference measured, 788 (38.6%) met criteria in addition. In a carefully controlled environment, about one-third of patients successfully titrated on opioids to treat chronic noncancer pain demonstrated continued benefit for up to 12 months.

Background and ObjectiveCurrent studies of end-of-life care in Parkinson disease (PD) do not focus on diverse patient samples or provide national views of end-of-life resource utilization. We determined sociodemographic and geographic differences in end-of-life inpatient care intensity among persons with PD in the United States (US).MethodsThis retrospective cohort study included Medicare Part A and Part B beneficiaries 65 years and older with a qualifying PD diagnosis who died between January 1, 2017, and December 31, 2017. Medicare Advantage beneficiaries and those with atypical or secondary parkinsonism were excluded. Primary outcomes included rates of hospitalization, intensive care unit (ICU) admission, in-hospital death, and hospice discharge in the last 6 months of life. Descriptive analyses and multivariable logistic regression models compared differences in end-of-life resource utilization and treatment intensity. Adjusted models included demographic and geographic variables, Charlson Comorbidity Index score, and Social Deprivation Index score. The national distribution of primary outcomes was mapped and compared by hospital referral region using Moran I.ResultsOf 400,791 Medicare beneficiaries with PD in 2017, 53,279 (13.3%) died. Of decedents, 33,107 (62.1%) were hospitalized in the last 6 months of life. In covariate-adjusted regression models using White male decedents as the reference category, odds of hospitalization was greater for Asian (AOR 1.38; CI 1.11–1.71) and Black (AOR 1.23; CI 1.08–1.39) male decedents and lower for White female decedents (AOR 0.80; CI 0.76–0.83). ICU admissions were less likely in female decedents and more likely in Asian, Black, and Hispanic decedents. Odds of in-hospital death was greater among Asian (AOR 2.49, CI 2.10–2.96), Black (AOR 1.11, CI 1.00–1.24), Hispanic (AOR 1.59; CI 1.33–1.91), and Native American (AOR 1.49; CI 1.05–2.10) decedents. Asian and Hispanic male decedents were less likely to be discharged to hospice. In geographical analyses, rural-dwelling decedents had lower odds of ICU admission (AOR 0.77; CI 0.73–0.81) and hospice discharge (AOR 0.69; CI 0.65–0.73) than urban-dwelling decedents. Nonrandom clusters of primary outcomes were observed across the US, with highest rates of hospitalization in the South and Midwest (Moran I = 0.134;p< 0.001).DiscussionMost persons with PD in the US are hospitalized in the last 6 months of life, and treatment intensity varies by sex, race, ethnicity, and geographic location. These group differences emphasize the importance of exploring end-of-life care preferences, service availability, and care quality among diverse populations with PD and may inform new approaches to advance care planning.

A chronic pain patient sample living in the United States who participated in a cross-sectional study to evaluate the validity and reproducibility of the Prescription Opioid Misuse and Abuse Questionnaire is characterized.Patients with chronic pain identified through electronic medical records as refilling at least one opioid prescription within the prior 3 months were recruited from five United States Department of Defense Military Health System clinics. Patients completed the Prescription Opioid Misuse and Abuse Questionnaire, Brief Pain Inventory-Short Form, Medical Outcomes Study: 36-item Short Form, and sociodemographic questions online. Clinical characteristics and electronic medical records for 1 year prior to consent were collected.809 (86.2%) participants completed the Prescription Opioid Misuse and Abuse Questionnaire. Mean (± standard deviation) age was 55.4 ± 12.7 years; the majority female (55.5%) and white (74.8%). Mean duration of chronic pain was 14.7 ± 10.5 years; the most common pain conditions were lower back pain (76.6%), neck or shoulder pain (60.3%), and osteoarthritis (38.7%). The most commonly prescribed opioids were oxycodone (35.7%), tramadol (34.5%), and hydrocodone (26.9%); 54.8% took one opioid, 44.9% took 2 or more opioids.Participants' health status was poor; pain severity and interference were moderate. Electronic medical record data revealed high healthcare resource utilization. This chronic pain population was severely impacted by their pain condition(s).

The Prescription Opioid Misuse and Abuse Questionnaire was developed to identify prescription opioid abuse and misuse among patients with chronic pain, however evidence of construct validity and reproducibility is needed. Chronic pain patients were recruited from five Department of Defense Military Health System clinics across the United States. Construct validity was examined using subjective clinician-reported and patient-reported measures as well as objective information (e.g., hair/urine drug screens and electronic medical records). Test-retest reliability was assessed across 2-time points among a subgroup of patients with stable chronic pain. Of 3,263 screened patients, 938 (28.7%) met eligibility and were enrolled; 809 (86.2%) completed the Prescription Opioid Misuse and Abuse Questionnaire. Construct validity was supported by comparison to other validated questionnaires and hair and urine screens which yielded high agreements with patient reports on the Prescription Opioid Misuse and Abuse Questionnaire. Electronic medical record data supported patients’ Prescription Opioid Misuse and Abuse Questionnaire responses regarding physician and emergency room visits and opioid refills. The Prescription Opioid Misuse and Abuse Questionnaire had excellent test-retest reliability; the percentage agreement between the two Prescription Opioid Misuse and Abuse Questionnaire administrations was high (>90%) for most questions. Results suggest that the Prescription Opioid Misuse and Abuse Questionnaire is a valid and reproducible tool that can be used to assess the presence of prescription opioid misuse and abuse among patients with chronic pain.

Purpose To assess the association of severity of ocular discomfort with measures of quality of life among patients with moderate to severe dry eye disease (DED). Methods This is a prospective, observational, cohort study within a randomized clinical trial. Patients (N = 535) in the Dry Eye Assessment and Management study with moderate to severe DED completed the Ocular Surface Disease Index on DED symptoms, the SF-36 on quality of life, and the Brief Ocular Discomfort Inventory questionnaire and had a comprehensive ophthalmic assessment by a study-certified clinician. The ocular discomfort on average over the past week was scored on an 11-point scale (0 for no discomfort and 10 for discomfort as bad as you can imagine). Results The average ocular discomfort scores for patients ranged from 0 to 10, with a mean of 4.28. Discomfort scores did not vary with demographic characteristics, signs of DED, self-reported depression, or self-reported nonocular pain conditions. Ocular discomfort scores did correlate moderately to strongly with total Ocular Surface Disease Index scores (Spearman correlation coefficient, rs, 0.47-0.67) and with measures of interference with activities of daily living [general activity level, mood, walking ability, ability for normal work, relations with other people, sleep, and enjoyment of life (rs = 0.39-0.65)]. Conclusions Among patients in the Dry Eye Assessment and Management study, worse ocular discomfort was associated with worse overall DED symptoms and interfered to a greater degree with activities of daily living. Ocular discomfort is an important part of the assessment of patients with DED.

BACKGROUND: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. AIMS: We determined the CID of 6-minute walking distance (6MWD) and physical function component (PF10) of Medical Outcomes Study Short Form-36 in mobility-limited older men using the Testosterone Trials (TTrials) data. METHODS: TTrials participants (n=429) with mobility limitation and gait speed

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.

Summary Objective Knee osteoarthritis (OA) is predominantly characterized by pain with weight-bearing activities. Pain at rest also occurs but the mechanisms for this are not clear. We evaluated the relations of nociceptive signal alterations to weight-bearing and non-weight-bearing pain in knee OA. Design We used data from a NIH–funded longitudinal cohort of older adults with or at risk of knee OA. We evaluated quantitative sensory testing (QST) measures (pressure pain threshold (PPT) at patellae and the wrist; mechanical temporal summation (TS); conditioned pain modulation (CPM)). Each WOMAC pain question was dichotomized as having at least moderate pain, and we further categorized them as weight-bearing pain and non-weight-bearing pain. We evaluated the relation of QST measures to each pain outcome using logistic regression, adjusting for potential confounders. Results 2749 participants (5479 knees) were included (mean age 64±11, 57% female). Each SD unit decrease in patellar PPT was associated with greater odds of both weight-bearing pain (OR 1.51 (95% CI 1.27, 1.79)) and non-weight-bearing pain (OR 1.46 (1.20-1.77)), while wrist PPT was associated with greater odds of weight-bearing pain (OR 1.27 (1.15, 1.39)) but only with pain during sitting/lying (OR 1.20 (1.01, 1.43)). TS was significantly associated with greater odds of pain with walking and stairs (OR 1.11 (1.01, 1.23), 1.11 (1.03, 1.20), respectively). CPM was not associated with any pain outcomes. Conclusions Our findings challenge the hypothesis that non-weight-bearing pain may reflect greater pain sensitization and/or inefficient CPM than weight-bearing pain in knee OA, suggesting other mechanisms are likely responsible.

Background Revised diagnostic criteria for pseudotumor cerebri syndrome require three of four neuroimaging findings in the absence of papilledema. We examined the sensitivity and specificity of three or more of four of these magnetic resonance imaging (MRI) findings for pseudotumor cerebri syndrome in children. Methods As part of clinical care, patients in whom there was suspicion for pseudotumor cerebri syndrome underwent neurological and fundoscopic examinations, lumbar puncture, MRI, or magnetic resonance venogram. For this retrospective study, we used this information to classify 119 subjects into definite (n = 66) or probable pseudotumor cerebri syndrome (n = 12), elevated opening pressure without papilledema (n = 23), or controls who had normal opening pressure without papilledema (n = 24). A neuroradiologist, unaware of the clinical findings or original MRI report, reviewed MRIs for pituitary gland flattening, flattening of the posterior sclera, optic nerve sheath distention, and transverse venous sinus stenosis. Results The presence of three or more MRI findings has a sensitivity of 62% (95% confidence interval: 47% to 75%) and a specificity of 95% (95% confidence interval: 77% to 100%), compared with controls. Two of three (transverse venous sinus stenosis, pituitary gland flattening, flattening of the posterior sclera) had a similar sensitivity and specificity. Transverse venous sinus stenosis alone had a slightly higher sensitivity (74%, 95% confidence interval: 60% to 85%) and specificity (100%, 95% confidence interval: 80% to 100%). Conclusions In children, three of four of the proposed neuroimaging criteria and transverse venous sinus stenosis alone have a moderate sensitivity and robust specificity for pseudotumor cerebri syndrome. MRIs should be reviewed for these criteria, and their presence should raise suspicion for pseudotumor cerebri syndrome in children, particularly if the presence of papilledema is uncertain.

Objective This study evaluated the association between pain outcomes and post-traumatic stress disorder (PTSD) symptom trajectories after combat-related injury, while adjusting for receipt of regional anesthesia (RA) soon after injury. Methods The PTSD symptom trajectories of N = 288 combat-injured service members were examined from within a month of injury up to two-years after. Linear mixed-effects models evaluated the association between PTSD symptom trajectories and average pain and pain interference outcomes while adjusting for receipt of RA during combat casualty care. Results Four PTSD trajectories were characterized: resilient, recovering, worsening, and chronic. Differential pain presentations were associated with PTSD symptom trajectories, even after adjusting for receipt of RA. Compared to those with a resilient PTSD symptom trajectory, individuals presenting with chronic PTSD trajectories were estimated to experience average pain scores 2.61 points higher (95% CI: 1.71, 3.14). Participants presenting with worsening (β = 1.42; 95% CI: 0.77, 1.78) and recovering PTSD trajectories (β = 0.65; 95% CI: 0.09, 1.08) were estimated to experience higher average pain scores than participants with resilient PTSD trajectories. Significant differences in pain interference scores were observed across PTSD trajectories. Receiving RA was associated with improved pain up to two years after injury (β = -0.31; 95% CI: -0.90, -0.04), however no statistically significant association was detected between RA and PTSD trajectories. Conclusions Chronic and worsening PTSD trajectories were associated with greater pain intensity and interference following combat injury even when accounting for receipt of early RA for pain management. These findings underscore the need to jointly assess pain and PTSD symptoms across the trauma care continuum.

Objective Absent adequate randomized control trials to inform appropriate treatment for concussion in pediatric patients, guidelines have been developed based on expert opinion and observational data that may not apply to all groups. This study examines differences in the previous clinical care between concussed patients who present in pediatric practice and specialty clinics. Differences found might influence treatment recommendations for each setting. Study design Prospective data collected from a pediatric practice in 2011 to 2013 were compared to chart review data from two specialty clinics between 2015 and 2017. In all three groups patients 11–19 years of age with an ICD9 billing code for concussion were included if they met the 4th International Consensus definition of concussion. Patients were excluded if hospitalized or had abnormal CNS imaging. Results The time between injury and presentation was substantially longer in specialty clinic patients versus those seen in the primary pediatric care office. (median 10 vs. 2 days-p Conclusion Several differences in previous clinical care between the groups were found. These included the time of presentation from injury, rates of cognitive rest both immediate and non-immediate, and emergency department visits. These differences may have implications for management recommendations. Accordingly, the appropriate treatment for patients seen by the primary pediatric care physicians may be different from those referred to specialty care. Given these findings randomized controlled trails should be conducted independently in both groups of patients.

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.

Supplemental Digital Content is Available in the Text., 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.

Copyright © 2020 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.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

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

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities on drug development for pancreatitis. This conference was held on July 25, 2018, and structured into 3 working groups (WG): acute pancreatitis (AP) WG, recurrent AP WG, and chronic pancreatitis WG. This article reports the outcome of the work accomplished by the AP WG to provide the natural history, epidemiology, and current management of AP; inform about the role of preclinical models in therapy selection; and discuss clinical trial designs with clinical and patient-reported outcomes to test new therapies.

The lack of effective therapeutic agents specifically tailored for chronic pancreatitis has hampered clinical care and negatively impacted patients’ lives. New mechanistic insights now point to novel therapies, which involve both recently developed and/or repurposed agents. This working group focused on two main outcomes for chronic pancreatitis: pain and progression of disease. The goal is to frame the essential aspects of trial design including patient-centered outcomes, proposed methods to measure the outcomes of pain and progression, and study design considerations for future trials to facilitate rapid drug development for patients with chronic pancreatitis.

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.

OBJECTIVE To describe development and initial psychometric testing of an owner-reported questionnaire designed to standardize measurement of general quality of life (QOL) in dogs with cancer. DESIGN Key-informant interviews, questionnaire development, and field trial. SAMPLE Owners of 25 dogs with cancer for item development and pretesting and owners of 90 dogs with cancer for reliability and validity testing. PROCEDURES Standard methods for development and testing of questionnaire instruments intended to measure subjective states were used. Items were generated, selected, scaled, and pretested for content, meaning, and readability. Response items were evaluated with exploratory factor analysis and by assessing internal consistency (Cronbach α) and convergence with global QOL as determined with a visual analog scale. Preliminary tests of stability and responsiveness were performed. RESULTS The final questionnaire—which was named the Canine Owner-Reported Quality of Life (CORQ) questionnaire—contained 17 items related to observable behaviors commonly used by owners to evaluate QOL in their dogs. Several items pertaining to physical symptoms performed poorly and were omitted. The 17 items were assigned to 4 factors—vitality, companionship, pain, and mobility—on the basis of the items they contained. The CORQ questionnaire and its factors had high internal consistency (Cronbach α = 0.68 to 0.90) and moderate to strong correlations (r = 0.49 to 0.71) with global QOL as measured on a visual analog scale. Preliminary testing indicated good test-retest reliability and responsiveness to improvements in overall QOL. CONCLUSIONS AND CLINICAL RELEVANCE The CORQ questionnaire was a valid, reliable owner-reported questionnaire that measured general QOL in dogs with cancer and showed promise as a clinical trial outcome measure for quantifying changes in individual dog QOL occurring in response to cancer treatment and progression.

PURPOSE: Breast cancer treatments may lead to chronic pain. For some breast cancer survivors (BCS), this experience can develop into the perception of living with chronic pain. The majority of BCS are postmenopausal and have hormone receptor-positive (HR+) breast cancer requiring aromatase inhibitors (Als). Neither the prevalence nor risk factors associated with the perception of living with chronic pain among this population are well defined. METHODS: We conducted a cross-sectional survey among postmenopausal, HR+ BCS who previously took or were currently taking Als. The primary outcome was patients’ perception of living with chronic pain over the past 6 months. We measured pain and demographic and clinical variables. Multivariable logistic regression analysis was performed to evaluate risk factors associated with the perception of chronic pain. RESULTS: Among 1280 participants, 167 (13%) reported having the perception of living with chronic pain before their breast cancer diagnosis; 426 (34%) reported this perception after completion of non-hormonal cancer treatment. Seventy-eight percent of BCSs reported experiencing at least one type of treatment-related pain within the past 7 days, with 23% experiencing at least three types. The most common types of pain were Al-induced musculoskeletal pain (49%) and pain at the surgery or radiation site (31%). Younger age (< 56), BMI > 25, and the perception of living with chronic pain before diagnosis were risk factors associated with the perception of living with chronic pain. CONCLUSIONS: One in three postmenopausal, HR+ BCS considered themselves to be living with chronic pain. Effective interventions to reduce chronic pain are needed.

OBJECTIVE To describe development and initial psychometric testing of the Canine Symptom Assessment Scale (CSAS), a multidimensional owner-reported questionnaire instrument, in a population of dogs with solid tumors enrolled in clinical trials. DESIGN Questionnaire development and validation study. ANIMALS 238 client-owned dogs with solid tumors. PROCEDURES A 14-symptom questionnaire was developed. Symptoms were defined as subjective physical disturbances dogs experienced during the course of daily living as assessed through proxy reports of pet owners. For each symptom, owners reported frequency and severity of the symptom and extent of distress caused by the symptom for the dog and the owner. Questionnaire content, symptom prevalence and dimensionality, internal consistency, and factor structure were examined. Construct and criterion validity were examined via comparison with the Canine Brief Pain Inventory (CBPI). RESULTS Symptom prevalence was high, with pain and lack of energy reported in most dogs. Severity, versus frequency, was most highly correlated with both dog and owner distress. Two symptoms were removed from consideration because of poor performance. Analysis of the remaining 12 symptoms revealed that they could be grouped into 3 factors: malaise, anxiety, and digestive upset. The CSAS factor and total scores demonstrated predictable relationships with quality of life and pain scores as measured by the CBPI, including a significant association between increasing symptom burden and decreasing quality of life. The Cronbach α for the CSAS was 0.77. CONCLUSIONS AND CLINICAL RELEVANCE The 12-item CSAS was a psychometrically sound owner-reported instrument for assessment of symptom frequency and characteristics in client-owned dogs with solid tumors. Potential applications include clinical research and practice settings.

We characterized the location and spatial distribution of whole body pain in patients with urological chronic pelvic pain syndrome using a body map. We also compared the severity of urinary symptoms, pelvic pain, nonpelvic pain and psychosocial health among patients with different pain patterns.A total of 233 women and 191 men with urological chronic pelvic pain syndrome enrolled in a multicenter, 1-year observational study completed a battery of baseline measures, including a body map describing the location of pain during the last week. Participants were categorized with pelvic pain if they reported pain in the abdomen and pelvis only. Participants who reported pain beyond the pelvis were further divided into 2 subgroups based on the number of broader body regions affected by pain, including an intermediate group with 1 or 2 additional regions outside the pelvis and a widespread pain group with 3 to 7 additional regions.Of the 424 enrolled patients 25% reported pelvic pain only and 75% reported pain beyond the pelvis, of whom 38% reported widespread pain. Participants with a greater number of pain locations had greater nonpelvic pain severity (p0.0001), sleep disturbance (p = 0.035), depression (p = 0.005), anxiety (p = 0.011), psychological stress (p = 0.005) and negative affect scores (p = 0.0004), and worse quality of life (p ≤0.021). No difference in pelvic pain and urinary symptom severity was observed according to increasing pain distribution.Three-quarters of the men and women with urological chronic pelvic pain syndrome reported pain outside the pelvis. Widespread pain was associated with greater severity of nonpelvic pain symptoms, poorer psychosocial health and worse quality of life but not with worse pelvic pain or urinary symptoms.

Postsurgical dental pain is mainly driven by inflammation, particularly through the generation of prostaglandins via the cyclooxygenase system. Thus, it is no surprise that numerous randomized placebo-controlled trials studying acute pain following the surgical extraction of impacted third molars have demonstrated the remarkable efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen sodium, etodolac, diclofenac, and ketorolac in this prototypic condition of acute inflammatory pain. Combining an optimal dose of an NSAID with an appropriate dose of acetaminophen appears to further enhance analgesic efficacy and potentially reduce the need for opioids. In addition to being on average inferior to NSAIDs as analgesics in postsurgical dental pain, opioids produce a higher incidence of side effects in dental outpatients, including dizziness, drowsiness, psychomotor impairment, nausea/vomiting, and constipation. Unused opioids are also subject to misuse and diversion, and they may cause addiction. Despite these risks, some dental surgical outpatients may benefit from a 1- or 2-d course of opioids added to their NSAID regimen. NSAID use may carry significant risks in certain patient populations, in which a short course of an acetaminophen/opioid combination may provide a more favorable benefit versus risk ratio than an NSAID regimen.

BackgroundNo studies have examined the long-term benefits of regional anesthesia (RA) for pain management after combat-related injury. The objective of this prospective cohort study was to examine the relationship between RA administration and patient-reported pain-related outcomes among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) service members sustaining a combat-related extremity injury.MethodsBetween 2007 and 2013, n=358 American military personnel injured in OEF/OIF were enrolled at two military treatment facilities. Individuals were followed for up to 2 years after injury. Cohorts were defined based on whether participants were administered RA within 7 days after sustaining a combat-related injury, or not. Linear mixed effects models examined the association between RA and average pain intensity. Secondary outcomes included pain relief, pain interference, neuropathic pain symptoms, treatment outcomes related to pain management, and mental health symptoms.ResultsReceiving early RA was associated with improved average pain over the first 6 months after injury (β=−0.57; p=0.012) adjusting for injury severity and length of stay at the primary treatment facility. This difference was observed up to 24 months after injury (β=−0.36; p=0.046). Individuals receiving early RA reported greater pain relief, improved neuropathic pain intensity, and higher satisfaction with pain outcomes; however, by 24 months, mean scores did not significantly differ between cohorts.ConclusionFindings indicate that when administered soon after traumatic injury, RA is a valuable pain management intervention. Future longitudinal studies investigating the timely delivery of RA for optimal pain management in civilian trauma settings are needed.Trial registration numberNCT00431847

Chronic pain continues to be a significant global burden despite the availability of a variety of nonpharmacologic and pharmacologic treatment options. Thus, there is a need for new analgesics with novel mechanisms of action. In this regard, antibodies directed against nerve growth factor (NGF-Abs) are a new class of agents in development for the treatment of chronic pain conditions such as osteoarthritis and chronic low-back pain. This comprehensive narrative review summarizes evidence supporting pronociceptive functions for NGF that include contributing to peripheral and central sensitization through tropomyosin receptor kinase A activation and stimulation of local neuronal sprouting. The potential role of NGF in osteoarthritis and chronic low-back pain signaling is also examined to provide a mechanistic basis for the observed efficacy of NGF-Abs in clinical trials of these particular pain states. Finally, the safety profile of NGF-Abs in terms of common adverse events, joint safety, and nerve structure/function is discussed.

This cohort study examines whether the specific word and phrase frequency used in physician trainee narrative evaluations of medical faculty and qualified by automated text mining is associated with the gender of the faculty member evaluated., Key Points Question Are there gender-based linguistic differences in narrative evaluations of medical faculty written by physician trainees? Findings In this cohort study of 7326 narrative evaluations for 521 medical faculty members, the words art, trials, master, and humor were significantly associated with evaluations of male faculty, whereas the words empathetic, delight, and warm were significantly associated with evaluations of female faculty. Two-word phrase associations included run rounds, big picture, and master clinician in male faculty evaluations and model physician and attention (to) detail in female faculty evaluations. Meaning The findings suggest that quantitative linguistic differences between free-text comments about male and female medical faculty may occur in physician trainee evaluations., Importance Women are underrepresented at higher ranks in academic medicine. However, the factors contributing to this disparity have not been fully elucidated. Implicit bias and unconscious mental attitudes toward a person or group may be factors. Although academic medical centers use physician trainee evaluations of faculty to inform promotion decisions, little is known about gender bias in these evaluations. To date, no studies have examined narrative evaluations of medical faculty by physician trainees for differences based on gender. Objective To characterize gender-associated linguistic differences in narrative evaluations of medical faculty written by physician trainees. Design, Setting, and Participants This retrospective cohort study included all faculty teaching evaluations completed for the department of medicine faculty by medical students, residents, and fellows at a large academic center in Pennsylvania from July 1, 2015, through June 30, 2016. Data analysis was performed from June 1, 2018, through July 31, 2018. Main Outcomes and Measures Word use in faculty evaluations was quantified using automated text mining by converting free-text comments into unique 1- and 2-word phrases. Mixed-effects logistic regression analysis was performed to assess associations of faculty gender with frequencies of specific words and phrases present in a physician trainee evaluation. Results A total of 7326 unique evaluations were collected for 521 faculty (325 men [62.4%] and 196 women [37.6%]). The individual words art (odds ratio [OR], 7.78; 95% CI, 1.01-59.89), trials (OR, 4.43; 95% CI, 1.34-14.69), master (OR, 4.24; 95% CI, 1.69-10.63), and humor (OR, 2.32; 95% CI, 1.44-3.73) were significantly associated with evaluations of male faculty, whereas the words empathetic (OR, 4.34; 95% CI, 1.56-12.07), delight (OR, 4.26; 95% CI, 1.35-13.40), and warm (OR, 3.45; 95% CI, 1.83-6.49) were significantly associated with evaluations of female faculty. Two-word phrases associated with male faculty evaluations included run rounds (OR, 7.78; 95% CI, 1.01-59.84), big picture (OR, 7.15; 95% CI, 1.68-30.42), and master clinician (OR, 4.02; 95% CI, 1.21-13.36), whereas evaluations of female faculty were more likely to be associated with model physician (OR, 7.75; 95% CI, 1.70-35.39), just right (OR, 6.97; 95% CI, 1.51-32.30), and attention (to) detail (OR, 4.26; 95% CI, 1.36-13.40). Conclusions and Relevance The data showed quantifiable linguistic differences between free-text comments about male and female faculty in physician trainee evaluations. Further evaluation of these differences, particularly in association with ongoing gender disparities in faculty promotion and retention, may be warranted.

To evaluate feasibility and impact of evidence-based medicine (EBM) educational prescriptions (EPs) in medical student clerkships.Students answered clinical questions during clerkships using EPs, which guide learners through the "four As" of EBM. Epidemiology fellows graded EPs using a rubric. Feasibility was assessed using descriptive statistics and student and fellow end-of-study questionnaires, which also measured impact. In addition, for each EP, students reported patient impact. Impact on EBM skills was assessed by change in EP scores over time and scores on an EBM objective structured clinical exam (OSCE) that were compared to controls from the prior year.117 students completed 402 EPs evaluated by 24 fellows. Average score was 7.34/9.00 (SD 1.58). 69 students (59%) and 21 fellows (88%) completed questionnaires. Most students thought EPs improved "Acquiring" and "Appraising". Almost half thought EPs improved "Asking" and "Applying". Fellows did not value grading EPs. For 18% of EPs, students reported a "change" or "potential change" in treatment. 56% "confirmed" treatment. EP scores increased by 1.27 (95% CI: 0.81-1.72). There were no differences in OSCE scores between cohorts.Integrating EPs into clerkships is feasible and has impact, yet OSCEs were unchanged, and research fellows had limitations as evaluators.

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.

The analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized to be limited by substantial interindividual variability in pain relief, but the underlying mechanisms are not well understood. We performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars, in order to characterize factors associated with heterogeneity in response to ibuprofen.Subjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design. Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in regional cerebral blood flow in brain regions associated with pain processing, and inhibition of ex vivo cyclooxygenase activity and urinary prostaglandin metabolite excretion as indices of biochemical drug action (p2 metabolite, serum TNFα and IL-8 were higher in patients who did not require rescue medication compared those who did (p < 0.05). RNAseq gene expression analysis in PBMCs collected after surgery and ibuprofen administration showed enrichment of inflammation related pathways among genes differentially expressed (q < 0.2) between complete and partial respondersThese findings suggest that patients who receive substantial pain relief from ibuprofen have a more pronounced activation of the prostanoid biosynthetic pathway and regulation of the inflammatory pain phenotype differs from those patients who are insufficiently treated with ibuprofen alone and may require an opioid or other therapeutic intervention.

Purpose Many neonates undergo electroencephalogram (EEG) monitoring to identify and manage acute symptomatic seizures. Information about brain function contained in the EEG background data may also help predict neurobehavioral outcomes. For EEG background features to be useful as prognostic indicators, the interpretation of these features must be standardized across electroencephalographers. We aimed at determining the interrater and intrarater agreement among electroencephalographers interpreting neonatal EEG background patterns. Methods Five neonatal electroencephalographers reviewed 5-to-7.5-minute epochs of EEG from full-term neonates who underwent continuous conventional EEG monitoring. The EEG assessment tool used to classify background patterns was based on the American Clinical Neurophysiology Society's guideline for neonatal EEG terminology. Interrater and intrarater agreement were measured using Kappa coefficients. Results Interrater agreement was consistently highest for voltage (binary: substantial, kappa = 0.783; categorical: moderate, kappa = 0.562), seizure presence (fair-substantial; kappa = 0.375-0.697), continuity (moderate; kappa = 0.481), burst voltage (moderate; kappa = 0.574), suppressed background presence (moderate-substantial; kappa = 0.493-0.643), delta activity presence (fair-moderate; kappa = 0.369-0.432), theta activity presence (fair-moderate; kappa = 0.347-0.600), presence of graphoelements (fair; kappa = 0.381), and overall impression (binary: moderate, kappa = 0.495; categorical: fair-moderate, kappa = 0.347, 0.465). Agreement was poor or inconsistent for all other patterns. Intrarater agreement was variable, with highest average agreement for voltage (binary: substantial, kappa = 0.75; categorical: substantial, kappa = 0.714) and highest consistent agreement for continuity (moderate-substantial; kappa = 0.43-0.67) and overall impression (moderate-substantial; kappa = 0.42-0.68). Conclusions This study demonstrates substantial variability in neonatal EEG background interpretation across electroencephalographers, indicating a need for educational and technological strategies aimed at improving performance.

Summary Background The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. Methods The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov , number NCT00799617 . Findings The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2–15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5–6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5–21·9; p=0·0004) and PF10 (4·9, 2·2–7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0–14·1; p=0·0237) and PF10 (3·6, 1·3–5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35–3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61–5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall). Interpretation Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations. Funding US National Institute on Aging and AbbVie.

© 2015, Springer International Publishing Switzerland.Purpose: Patient-reported outcome (PRO) measures are essential for assessing subjective patient experiences. Interactive voice response (IVR) data collection provides advantages for clinical trial design by standardizing and centralizing the assessment. Prior to adoption of IVR as a mode of PRO administration in the Testosterone Trials (TTrials), we compared IVR to paper versions of the instruments to be used. Methods: IVR versions of the FACIT-Fatigue scale and Psychosexual Daily Questionnaire, Question 4, were developed. In one pilot study, IVR versions of these scales were compared to paper versions in 25 men ≥ 65 years at each of two clinical sites. In another study, IVR versions of the SF-36 Vitality Scale (SF-36), Positive and Negative Affect Scale, and Patient Health Questionnaire were evaluated in comparison with previously validated paper versions in 25 men at two clinical sites. Both paper and IVR versions of each instrument were administered in counterbalanced order, and test–retest reliability was evaluated by repeated administration of the test. Bland–Altman plots were used to assess the degree of agreement. Test–retest correlations for each measure were also determined. Results: Satisfactory agreement was observed between IVR and paper versions of each study measure. Specifically, linear and highly positive associations were observed consistently across the study for IVR and paper versions of all study measures. These ranged from r = 0.91–0.99. Test–retest reliability for all measures was acceptable or better (r = 0.70–0.90). Conclusions: The IVR versions of TTrials endpoints in these two studies performed consistently well in comparison with paper versions.

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 (T first ). 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 T first 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.

Pain intensity ratings have been the basis of pain diagnosis and a fundamental tool in pain research, but are not always used. Frequent comments by physicians that pain ratings, sometimes called pain scores, are not useful in clinical practice and comments by basic scientists that pain ratings may measure the wrong thing, have been in significant part supported by a short survey conducted among members of American Pain Society (APS). Though limited by small number of respondents, the findings of this survey and additional comments by members of APS raise critical questions about why pain ratings do not serve the clinical communities. These findings send an urgent call to the pain community to reassess the status of currently used pain ratings and to find solutions to this fundamental issue.

Purpose Hot flashes are a common and debilitating symptom negatively affecting the quality of life of breast cancer survivors. We sought to compare the short and long term effects of electro-acupuncture (EA) vs. gabapentin for hot flashes among breast cancer survivors. Patients and Methods We conducted a randomized controlled trial of EA vs. gabapentin vs. placebos (sham acupuncture [SA] or placebo medication) in women with breast cancer who had completed primary cancer treatments and experienced bothersome hot flashes twice daily or greater. Acupuncturists performed ten EA/SA treatments over eight weeks using a manualized protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. Gabapentin (900 mg daily) or placebo medication were continued for eight weeks and then weaned off. The primary endpoint was the hot flash composite score measured by the daily diary at the end of the intervention (Week 8). A secondary endpoint, durability of response, was evaluated at Week 24 from randomization. Longitudinal mixed effects models were used to evaluate change in outcomes over time and group differences. Results Of 120 randomly assigned patients, the mean age was 52.3, 75% were White, 12.5% were peri-menopausal, and 20%/25%/37.5% had natural/surgically/chemically induced menopause, respectively. By Week 8, significant group differences were observed. Mean reduction in hot flash composite scores was greatest in the EA group, followed by SA and gabapentin, with placebo medication having the lowest reduction in hot flashes (-7.4 vs. –5.9 vs. –5.2 vs. –3.4, p=0.0003). By Week 24 and off treatment, reduction in hot flashes in the EA group persisted whereas the hot flashes in the gabapentin group retuned to baseline. The reduction in hot flashes was greatest in the EA group, followed by SA, placebo medication, and gabapentin (-8.5 vs. –6.1 vs. –4.6 vs. –2.8, p=0.0024). No serious adverse events were reported in any groups. The gabapentin group had the highest percentage of participants reporting treatment- related adverse events followed by placebo medication, EA, and SA (48.4% vs. 29.0% vs. 19.3% vs. 3.2%, p=0.004). Conclusion: Electro-acupuncture was more effective than gabapentin, sham acupuncture, or placebo medication in reducing hot flashes for breast cancer survivors both short term and long term with few side effects. Gabapentin produced significant short term reduction in hot flashes that did not persist off medication and was associated with more side effects. Clinical Trial Registration: NCT01005108. Citation Format: Jun J Mao, Sharon X Xie, Marjorie A Bowman, Deborah Bruner, Susan Q Li, Angela DeMichele, John T Farrar. A randomized placebo-controlled trial of acupuncture and gabapentin for hot flashes among breast cancer survivors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD4-7.

Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are multisystem diseases of the small blood vessels. Patients experience irreversible damage and psychological effects from AAV and its treatment. An international collaboration was created to investigate the impact of AAV on health-related quality of life (HRQoL), and develop a disease-specific patient-reported outcome measure to assess outcomes of importance to patients. Methods: Patients with AAV from the UK, USA, and Canada were interviewed to identify salient aspects of HRQoL affected by AAV. The study was overseen by a steering committee including four patient research partners. Purposive sampling of interviewees ensured representation of a range of disease manifestations and demographics. Inductive analysis was used to identify themes of importance to patients; these were further confirmed by a free-listing exercise in the US. Individual themes were recast into candidate items, which were scrutinized by patients, piloted through cognitive interviews and received a linguistic and translatability evaluation. Results: Fifty interviews, conducted to saturation, with patients from the UK, USA, and Canada, identified 55 individual themes of interest within seven broad domains: general health perceptions, impact on function, psychological perceptions, social perceptions, social contact, social role, and symptoms. Individual themes were constructed into >100 candidate questionnaire items, which were then reduced and refined to 35 candidate items. Conclusion: This is the largest international qualitative analysis of HRQoL in AAV to date, and the results have underpinned the development of 35 candidate items for a disease-specific, patient-reported outcome questionnaire., Sponsored by the University of Oxford, the Vasculitis Clinical Research Consortium and the University of Ottawa. With support from the Medical Research Fund, Oxford, the Oxfordshire Health Services Research Committee (Ref 1098), the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research. Oxford University Innovation funded the translatability exercise. Additional support received by a Patient-Centred Outcomes Research Institute Pilot Project Grant.