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

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

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

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

Reliability and Validity of the Psoriasis Symptom Inventory in Patients With Psoriatic Arthritis.

OBJECTIVE: To evaluate the measurement properties of the Psoriasis Symptom Inventory (PSI) in psoriatic arthritis (PsA). METHODS: The PSI is an 8-item, patient-reported outcome measure of the severity of psoriasis signs and symptoms. This was a secondary analysis of pooled data from a phase II study evaluating the efficacy of brodalumab in patients with PsA. Unidimensionality and item evaluation were assessed using factor and Rasch analyses. Reliability was assessed using Cronbach's alpha (internal consistency) and intraclass correlation coefficients (ICCs) for PSI scores in patients with stable disease (test-retest). Construct validity was evaluated by correlations between PSI scores and body surface area (BSA) affected by psoriasis and selected Short Form 36 (SF-36) health survey domains. Known-groups validity was evaluated based on BSA severity categories, and the ability to detect change was evaluated based on improvement in the subject's global assessment (SGA). RESULTS: The analysis sample (n = 154) was 93.5% white and 63.0% female. The mean ± SD baseline affected BSA was 10.4% ± 15.6%, and age was 52.2 ± 11.5 years. The PSI demonstrated unidimensionality, with good item fit and correctly ordered categories, excellent internal consistency (α = 0.95), good test-retest reliability (total score ICC 0.70; item ICCs range 0.67-0.81), convergent validity based on moderate correlations with BSA (r = 0.50), discriminant validity based on small baseline correlations (r <-0.3) with the SF-36 domains (role-physical, role-emotional, vitality), known groups validity based on significant differences between BSA groups, and responsiveness based on SGA improvements (P < 0.05). CONCLUSION: The PSI demonstrated excellent test-retest and internal consistency reliability and good construct validity in measuring psoriasis signs and symptoms severity in PsA.

Attitudes and Beliefs of Working and Work-Disabled People with Chronic Pain Prescribed Long-Term Opioids.

OBJECTIVE: This study was designed to gain insight into the apparent contradiction between the perspectives of researchers and policy makers, who have questioned the efficacy and safety of chronic opioid therapy for non-cancer pain patients, and the patients themselves, who often indicate that the therapy has value. SUBJECTS: A convenience sample of 54 patients on chronic opioid therapy was studied. METHODS: Participants completed a questionnaire specifically designed for the study, and also several standard instruments that addressed functional interference, emotional functioning, and possible misuse of opioids. Their treating physicians rated the participants on the severity of their disability and the success of their opioid therapy. RESULTS: Although participants reported significant ongoing pain, they gave positive global ratings to their opioid therapy, and reported little concern about addiction or side effects of opioids. They strongly endorsed the beliefs that opioids helped them control their pain and allowed them to participate in important activities such as work. They expressed the belief that their pain would be severe if they did not have access to opioids, and reported negative experiences with tapering or discontinuing opioids in the past. Work-disabled participants reported higher levels of affective distress, catastrophizing, and functional interference than working participants, and were judged by their physicians to be relatively less successful in managing their pain. CONCLUSION: The results of this study suggest several tentative hypotheses about why patients on chronic opioid therapy value opioids, and identified several areas for systematic investigation in the future.

Quality of pain intensity assessment reporting: ACTTION systematic review and recommendations.

UNLABELLED: Pain intensity assessments are used widely in human pain research, and their transparent reporting is crucial to interpreting study results. In this systematic review, we examined reporting of human pain intensity assessments and related elements (eg, administration frequency, time period assessed, type of pain) in all empirical pain studies with adult participants in 3 major pain journals (ie, European Journal of Pain, Journal of Pain, and Pain) between January 2011 and July 2012. Of the 262 articles identified, close to one-quarter (24%) ambiguously reported the pain intensity assessment. Elements related to the pain intensity assessment were frequently not reported: 31% did not identify the time period participants were asked to rate, 43% failed to report the type of pain intensity rated, and 58% did not report the specific location or pain condition rated. No differences were observed between randomized clinical trials and experimental (eg, studies involving experimental manipulation without random group assignment and blinding) and observational studies in reporting quality. The ability to understand study results, and to compare results between studies, is compromised when pain intensity assessments are not fully reported. Recommendations are presented regarding key details for investigators to consider when conducting and reporting pain intensity assessments in human adults. PERSPECTIVE: This systematic review demonstrates that publications of pain research often incompletely report pain intensity assessments and their details (eg, administration frequency, type of pain). Failure to fully report details of pain intensity assessments creates ambiguity in interpreting research results. Recommendations are proposed to increase transparent reporting.

Physicians' beliefs and likelihood of prescribing opioid tamper-resistant formulations for chronic noncancer pain patients.

BACKGROUND: Tamper-resistant opioid formulations (TRFs) have recently been the target of active development in an effort to deter opioid misuse and abuse. OBJECTIVE: To understand factors that are predictive of physicians' likelihoods of prescribing TRFs to patients with chronic noncancer pain (CNCP). DESIGN: A cross-sectional survey was conducted, utilizing a questionnaire of clinicians' attitudes and opinions about opioids for CNCP (Clinicians' Attitudes about Opioids Scale) to explore beliefs about and likelihood of prescribing TRFs. SUBJECTS: A nationally representative sample of 1,535 practicing physicians throughout the United States. METHODS: A stepwise hierarchical multiple linear regression analysis was conducted to estimate if physician characteristics, opinions, or geographic region categorized according to state rates of mortality by drug overdose and milligrams of opioids prescribed by state were predictive of the likelihood of prescribing TRFs. RESULTS: Board certification in Pain Medicine and prescribing opioids to a higher volume of CNCP patients were significantly predictive of a reported likelihood of prescribing TRFs, in addition to concerns about possible misuse and abuse of opioids, beliefs in the effectiveness of opioids for CNCP, and greater satisfaction with education and training in pain management this set of factors accounted for 21% of the model variance. Rates of mortality by drug overdose and opioid prescription volume by location were not predictive of TRF usage. CONCLUSIONS: Reducing physician concerns about potential misuse and abuse of opioids through additional education in pain management and dissemination of information about the potential benefits and availability of TRFs should influence physicians' attitudes about and the adoption of TRFs.

Reliability and validity of the psoriasis symptom inventory in patients with moderate-to-severe psoriasis.

OBJECTIVES: The psoriasis symptom inventory (PSI) is a patient-reported outcome measure for assessing symptom severity in patients with moderate-to-severe psoriasis. The primary objective of this study was to evaluate the measurement properties of the PSI. MATERIALS AND METHODS: Analyses of psychometric characteristics (reliability, convergent and known-groups validity,responsiveness, item performance, and dimensionality) were conducted using data from a Phase II trail to evaluate efficacy of brodalumab in subjects with moderate-to-severe psoriasis. RESULTS: The PSI had excellent internal consistency (α = 0.93-0.98) and good test-retest reliability (ICCs = 0.77-0.87). Convergent and discriminant validity was indicated by moderate-to-strong correlations between the PSI and Dermatology Life Quality Index scores, and small correlations between PSI total scores and ShortfFrm-36 Health Survey mental health, role emotional, and role physical scales. Known groups validity was shown as mean PSI total scores varied by Psoriasis Area and Severity Index (PASI) and Static Physician's Global Assessment (sPGA) defined groups (p < 0.001). PSI total scores were responsive to changes in clinical status as assessed by PASI (p < 0.001) and sPGA (p < 0.001). Unidimensionality of the PSI was supported. CONCLUSIONS: The PSI is a short and valid unidimensional measure of psoriasis symptom severity that is well suited for use in clinical trials.

Clinicians' attitudes and beliefs about opioids survey (CAOS): instrument development and results of a national physician survey.

UNLABELLED: Beliefs surrounding the use of opioids for chronic noncancer pain have vacillated over time. Concerns regarding long-term efficacy and adverse effects of opioids, along with increases in opioid prescribing, have contributed to many political, regulatory, and clinical responses. The present study was designed to (1) develop a reliable and valid measure (Clinicians' Attitudes about Opioids Scale [CAOS]) to assess current and evolving beliefs regarding opioids and opioid use in patients with chronic pain; and (2) survey these beliefs in a nationally representative sample of providers from multiple medical specialties throughout the United States. We developed the questionnaire in 3 phases: (1) focus groups and content development; (2) pilot testing and subsequent revisions; and (3) formal survey (N = 1,535) and assessment of stability (N = 251). The resulting 38-item measure assessed 5 domains: (1) Impediments and Concerns; (2) Perceived Effectiveness; (3) Schedule II versus III Opioids; (4) Medical Education; and (5) Tamper Resistant Formulations. No significant differences were identified among geographical regions; however, several differences were observed among medical specialties. Orthopedists were most troubled by impediments/concerns from long-term opioid use and had the least confidence in opioid efficacy, whereas Pain Medicine specialists and Physical Medicine and Rehabilitation specialists were the most confident in efficacy. PERSPECTIVE: This article presents the psychometric properties of a new measure of clinicians' beliefs surrounding opioid use for chronic pain. Using this measure, beliefs and behaviors of physicians across medical specialties and geographic regions using a nationally representative sample are presented, updating findings from a similar survey conducted 20 years ago.

Redesigning delivery of opioids to optimize pain management, improve outcomes, and contain costs.

INTRODUCTION: Chronic pain is a public health concern, and in the last decade, there has been a dramatic increase in the use and abuse of prescription opioids for chronic non-cancer pain. METHODS: We present an overview of a five-component model of pain management implemented at the University of Washington Division of Pain Medicine designed to facilitate recent state guidelines to reduce the risks associated with long-term use of prescription opioids. RESULTS: Central to the model described are guidelines for best clinical practice, a collaborative care approach, telehealth solutions, comprehensive prescription-monitoring, and measurement-based care. DISCUSSION: The model presented is a patient-centered, efficient, and cost-effective approach to the management of chronic pain.

The role of fear of movement in subacute whiplash-associated disorders grades I and II.

Fear and avoidance of activity may play a role in fostering disability in whiplash-associated disorders (WAD). This study examined the role of fear after WAD and assessed the effectiveness of 3 treatments targeting fear. People still symptomatic from WAD grade I-II injuries approximately 3months previously (n=191) completed questionnaires (eg, Neck Disability Index [NDI]) and were randomized to 1 of the treatments: (1) informational booklet (IB) describing WAD and the importance of resuming activities, (2) IB+didactic discussions (DD) with clinicians reinforcing the booklet, and (3) IB+imaginal and direct exposure desensitization (ET) to feared activities. DD and ET participants received three 2-hour treatment sessions. Absolute improvements in NDI were in predicted direction (ET=14.7, DD=11.9, IB=9.9). ETs reported significantly less posttreatment pain severity compared with the IB (Mean=1.5 vs 2.3, P<.001, d=0.6) and DD (M=1.5 vs 2.0, P=.039, d=0.6) groups. Reduction in fear was the most important predictor of improvement in NDI (ß=0.30, P<.001), followed by reductions in pain (ß=0.20, P=.003) and depression (ß=0.18, P=.004). The mediational analysis confirmed that fear reduction significantly mediated the effect of treatment group on outcome. Results highlight the importance of fear in individuals with subacute WAD and suggest the importance of addressing fear via exposure therapy and/or educational interventions to improve function.

Treatment of chronic non-cancer pain.

Chronic pain is a pervasive problem that affects the patient, their significant others, and society in many ways. The past decade has seen advances in our understanding of the mechanisms underlying pain and in the availability of technically advanced diagnostic procedures; however, the most notable therapeutic changes have not been the development of novel evidenced-based methods, but rather changing trends in applications and practices within the available clinical armamentarium. We provide a general overview of empirical evidence for the most commonly used interventions in the management of chronic non-cancer pain, including pharmacological, interventional, physical, psychological, rehabilitative, and alternative modalities. Overall, currently available treatments provide modest improvements in pain and minimum improvements in physical and emotional functioning. The quality of evidence is mediocre and has not improved substantially during the past decade. There is a crucial need for assessment of combination treatments, identification of indicators of treatment response, and assessment of the benefit of matching of treatments to patient characteristics.

Anesthesia awareness: narrative review of psychological sequelae, treatment, and incidence.

Awareness during general anesthesia occurs when patients recall events or sensations during their surgeries, although the patients should have been unconscious at the time. Anesthesiologists are cognizant of this phenomenon, but few discussions occur outside the discipline. This narrative review summarizes the patient recollections, psychological sequelae, treatment and follow-up of psychological consequences, as well as incidence and etiology of awareness during general anesthesia. Recalled memories include noises, conversations, images, mental processes, feelings of pain and/or paralysis. Psychological consequences include anxiety, flashbacks, and posttraumatic stress disorder diagnosis. Limited discussion for therapeutic treatment after an anesthesia awareness experience exists. The incidence of anesthesia awareness ranges from 0.1 to 0.2% (e.g., 1-2/1000 patients). Increased recognition of awareness during general anesthesia within the psychological/counseling community, with additional research focusing on optimal therapeutic treatment, will improve the care of these patients.

Determination of fibromyalgia syndrome after whiplash injuries: methodologic issues.

Problems in diagnosing fibromyalgia syndrome (FM) among motor vehicle collision (MVC) patients with whiplash (WL) include the following: the predominance of tender points (TPs) in the neck/shoulder girdle region; the 3-month duration of widespread pain criterion; and, the stability of diagnosis. The present study examined the prevalence of FM in a cohort (N = 326) patients with persistent neck pain 3 months after WL injury who were enrolled in a treatment program. Physical examinations were performed at baseline and at the end of treatment. Results indicated that WL patients had a greater proportion of neck/shoulder girdle TPs, relative to distal TPs. Compared with a matched cohort of treatment-seeking FM patients, WL patients indicated less distal TPs (mean = 7.3 TPs vs. mean = 5.6 TPs, P < .001), but were equivalent on neck/shoulder girdle TPs (mean = 9.0 TPs vs. 9.2 TPs, NS). Baseline prevalence of FM for the WL cohort based on ACR criteria was 14% (95% CI = 10%-18%), adjusted TP criterion discounting for neck/shoulder tenderness indicated a prevalence of FM of 8% (95% CI = 5%-11%). Finally, 63% of patients meeting American College of Rheumatology FM criteria at baseline did not meet this criterion at post-treatment (∼6-months after an MVC). In conclusion, present criteria used in determining FM may result in spuriously inflated rates of diagnosis among WL patients because of persistent localized tenderness after an MVC. Furthermore, the transient nature of FM "symptoms" among WL patients should be taken into account before making a final diagnosis. The present criteria used in determining fibromyalgia may result in spuriously inflated rates of diagnosis among whiplash patients because of persistent localized tenderness after motor vehicle collisions.

The lack of association between changes in functional outcomes and work retention in a chronic disabling occupational spinal disorder population: implications for the minimum clinical important difference.

STUDY DESIGN: A prospective study in a chronic pain/ disability population, relating changes in the Oswestry Disability Index (ODI), as well as the Mental Component Summary (MCS) and Physical Component Summary (PCS) of the Short Form-36 (SF-36), to work retention (WR) status at 1-year postrehabilitation. OBJECTIVE: To explore the relationship between WR status and change in ODI, and the MCS and PCS of the SF-36, and determine if an MCID can be identified using WR as an external criterion for the group of patients under consideration. SUMMARY OF BACKGROUND DATA: Clinically meaningful change may be defined through self-report, physician- based, or objective criteria of improvement, although most assessments have been based on self-report assessment of improvement. The disability occurring after work-related spinal disorders lends itself to anchoring self-report measures to objective work status outcomes 1-year post-treatment. Additional research is needed to evaluate the relationship between change and objective markers of improvement. METHODS: A consecutive cohort of patients (n = 2024) with chronic disabling occupational spinal disorders completed an interdisciplinary functional restoration program, and underwent a structured clinical interview for objective, socioeconomic outcomes at 1-year post-treatment. The average percent change in the ODI, as well as the MCS and PCS of the SF-36, were calculated for patients who successfully retained work and those who had not after completing a functional restoration program. Predictive ability of the percent change scores were evaluated through logistic regression analysis. RESULTS: No percent difference variables were strong predictors of WR status 1-year following treatment. CONCLUSION: The current analyses suggest that the ODI and SF-36 MCS and PCS measures are not responsive at the individual patient level when WR data are used as the external criterion using an anchor-based approach. This finding contrasts to reports of responsiveness based on distributional methods, or methods using self-report anchors of change.

Fear of pain as a prognostic factor in chronic pain: conceptual models, assessment, and treatment implications.

Chronic pain is a pervasive health care issue affecting over 50 million Americans and costing more than $100 billion dollars annually in lost productivity and health care costs. As a financially and emotionally taxing condition, the families and friends of people with chronic pain, as well as society at large, are affected. Current theory supports the role of biological, psychological, and environmental factors in the etiology, exacerbation, and maintenance of chronic pain. Recently, the specific role of pain-related fear in pain experience has received increasing attention. This article summarizes current understanding of the role of pain-related fear in the onset of acute pain incidents, the transition of acute pain to chronic, and the pain severity and disability of patients with ongoing chronic pain conditions. Treatments demonstrated to reduce pain-related fear are presented, evidence demonstrating their efficacy at reducing disability and pain severity are summarized, and recent criticisms of the fear-avoidance model and future directions are considered.

Heterogeneity within the fibromyalgia population: theoretical implications of variable tender point severity ratings.

OBJECTIVE: The American College of Rheumatology (ACR) tender point (TP) criterion is used in diagnosing fibromyalgia syndrome (FM). There has been little research investigating patterns of positive TP. We investigated response patterns of TP in a sample of patients with FM. METHODS: Manual TP survey data were available on 1433 patients with FM. Factor analysis was conducted on ACR TP and control (CON) points. Factor scores were cluster analyzed to identify subgroups based on TP scores. Subgroups were compared on demographic and psychosocial variables. RESULTS: Factor analysis resulted in 4 TP groupings: neck/shoulder girdle, gluteal/trochanteric, and upper extremity regions, and a set of CON TP. Cluster analysis revealed 3 clusters. Group 1 was high on all 3 TP regions and the CON set; Group 2 moderate on the 3 TP regions, low on the CON set; and Group 3 was relatively low on all 3 TP regions and the CON set. The group highest on the CON and TP regions reported the greatest pain (7.58 +/- 1.23; p < 0.001), sleep disturbance (7.05 +/- 1.61; p < 0.001), anxiety (10.14 +/- 4.57; p < 0.001), and depression (8.42 +/- 4.4; p < 0.001). CONCLUSION: TP severity ratings varied among cluster groups, suggesting patients with FM are not homogeneous. Variations in TP severity provide information regarding the degree to which FM affects patients' quality of life. Patients with elevated scores on the CON TP demonstrated a general pattern reflecting lower thresholds for symptom reporting and, perhaps, disease severity. Research is needed to elucidate mechanisms underlying heterogeneity among the FM population.

Toward the identification of symptom patterns in people with fibromyalgia.

OBJECTIVE: People with fibromyalgia (FM) report a number of physical, cognitive, and psychological symptoms. The purpose of the current study was to determine whether people with FM differed based on the type and severity of symptoms, and if so, whether subgroups differ with respect to health care utilization, functional ability, and work status. METHODS: Symptom, health care utilization, work, and physical data were available for 2,182 female responders to an Internet survey. Factor analysis was conducted on the physical and cognitive/psychological symptoms, and resulting factor scores were utilized in a cluster analysis to identify subgroups based on symptoms. Cluster groups were compared on a set of variables (e.g., health care utilization, coping). RESULTS: Factor analyses resulted in 3 symptom factor scores: musculoskeletal, non-musculoskeletal, and cognitive/psychological symptoms. The optimal cluster solution to the cluster analysis revealed 4 clusters. Group 1 was high on all 3 symptom domains, group 2 was moderate on the 2 physical symptom domains and high on cognitive/psychological symptoms, group 3 was moderate on the 2 physical symptom domains and low on cognitive/psychological symptoms, and group 4 was low on all symptom domains. The more symptomatic groups reported the greatest amount of health care utilization and difficulty in coping with symptoms. CONCLUSION: The FM population is heterogeneous with regard to symptom reporting. Additional research is needed to better understand differential symptom experience among people with FM. Clarification of these differences may increase understanding of the mechanisms involved in FM and provide guidance for treatment decisions.

Examining the role of the medial thalamus in modulating the affective dimension of pain.

The purpose of this project was to explore the role of the medial thalamus (MT), including the medial dorsal thalamus (MD) and associated midline nuclei in pain processing. Experiment 1 explored the role of electrolytic lesions to the MT in the formalin test. It was hypothesized that animals with electrolytic lesions to the MT would have attenuated paw licking behavior during the second phase of the formalin tests as compared to sham lesion controls. This hypothesis was based on evidence of projections from the MD to the ACC, and previous research demonstrating attenuation of paw licking behavior in the second phase of the formalin test in animals with ACC lesions. Experiment 2 tested the effects of electrolytic MT lesions on mechanical paw withdrawal thresholds in the L5 nerve ligation model. It was hypothesized that lesions of the MT would not alter mechanical paw withdrawal thresholds. Experiment 3 tested the effects of electrolytic MT lesions on escape/avoidance behavior in the place escape avoidance paradigm. For experiment 1, animals with MT lesions were found to have slightly elevated paw licking behavior, but only across two time points. No differences in mechanical paw withdrawal thresholds and in escape/avoidance behavior were detected as compared to the sham lesion group. These results indicate a limited role for the medial thalamic nuclei in coding for pain intensity and the affective dimension of pain. Additional research is needed to explore the role of individual medial nuclei in pain processing.