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.

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

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

Short-acting and Long-acting Opioids Utilization among Women Diagnosed with Endometriosis in the United States: A Population-based Claims Study.

STUDY OBJECTIVE: To determine the prevalence and pattern of opioid use in endometriosis and the characteristics of patients prescribed an opioid using medical insurance claims data. DESIGN: We performed a retrospective cohort analysis of data from the Truven MarketScan Commercial database for the period of January 1, 2011 to December 31, 2016. SETTING: The Truven database includes inpatient, outpatient, and prescription claims covering more than 115 million unique individuals and over 36 million inpatient hospital discharges across multiple payer types and all 50 states. PATIENTS: Women with endometriosis were defined as those with 1 inpatient or 2 outpatient codes for endometriosis. INTERVENTIONS: No interventions were assigned. Women who filled an opioid prescription within 12 months of diagnosis were placed in the opioid cohort and women who did not fill an opioid prescription were placed in the nonopioid cohort. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were evaluated 12 months preindex (date of the first diagnosis) and opioid use was assessed for 12 months after the index date. The dataset included 58 472 women with endometriosis. Of these, 61.7% filled an opioid prescription during the study period. More than 95% filled prescriptions for short-acting opioids (SAOs) only, 4.1% filled prescriptions for both SAOs and extended-release/long-acting opioids (LAOs), and 0.6% filled prescriptions for LAOs only. Patients who filled an opioid prescription had higher baseline comorbidities (especially gynecologic and chronic pain comorbidities) and endometriosis-related medication use compared with patients who did not fill an opioid prescription during the study period. Patients who filled both LAO and SAO prescriptions had the highest total days' supply of opioids, the proportion of days covered by prescriptions, and morphine equivalent daily dose. These patients also had the highest proportions of opioid switching and dose augmentation. Statistical trends in data were not substantially altered when analyses excluded patients with chronic pain comorbidities or surgical opioid prescriptions. CONCLUSION: Although opioids are not a recommended treatment for endometriosis, more than half of our cohort filled an opioid prescription within 1 year after a first recorded diagnosis of endometriosis. Patients who filled an opioid prescription tended to use more endometriosis-related medications and have a higher comorbidity burden. Additional research is necessary to better understand the reasons and outcomes associated with opioid utilization in endometriosis and to determine if there is a more effective pain management treatment plan for patients taking opioids.

Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS® system (Misuse, Abuse, and Diversion Drug Event Reporting System).

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12 weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo. System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest.Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to "Withdrawal" and, primarily in SUMMIT-07, "Therapeutic Error" (unintentional overuse) or "Misuse" (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible "Abuse" events (three NKTR-181, two placebo) in SUMMIT-07 and four possible "Abuse" events (all NKTR-181) in SUMMIT-LTS.Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.

Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

BACKGROUND AND OBJECTIVES: Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. METHODS: The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. RESULTS: The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. DISCUSSION AND CONCLUSIONS: MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. SCIENTIFIC SIGNIFICANCE: Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651).

Assessment of pain and activity using an electronic pain diary and actigraphy device in a randomized, placebo-controlled crossover trial of celecoxib in osteoarthritis of the knee.

OBJECTIVE: The primary goal was to determine whether a composite measure of pain and activity is a more responsive assessment of analgesic effect than pain alone or activity alone in patients with osteoarthritis (OA) of the knee. DESIGN: We conducted a randomized, double-blind, placebo-controlled, 2-period, crossover study of celecoxib vs. placebo in subjects with chronic pain due to knee OA. Patients with knee OA and baseline pain intensity score ≥4 on a 0-10 numerical rating scale (NRS) before each period were randomized. Pain endpoints included in-clinic pain score (24-hour and 1-week recall), daily paper diary pain score, current pain on an electronic pain diary (each on NRS), and WOMAC pain subscale. Activity measures included WOMAC function subscale and actigraphy using a device. Three composite pain-activity measures were prespecified. RESULTS: Sixty-three patients were randomized and 47 completed the study. The WOMAC pain subscale was the most responsive of all five pain measures. Pain-activity composites resulted in a statistically significant difference between celecoxib and placebo but were not more responsive than pain measures alone. However, a composite responder defined as having 20% improvement in pain or 10% improvement in activity yielded much larger differences between celecoxib and placebo than with pain scores alone. Actigraphy was more responsive than the WOMAC function scale, possibly due to lower placebo responsiveness. CONCLUSION: We have identified composite pain-activity measures that are similarly or more responsive than pain-alone measures in patients with OA. Further research is warranted to determine the optimal method for computing these composites.

Prescription opioid abuse: challenges and opportunities for payers.

OBJECTIVES: Prescription opioid abuse and addiction are serious problems with growing societal and medical costs, resulting in billions of dollars of excess costs to private and governmental health insurers annually. Although difficult to accurately assess, prescription opioid abuse also leads to increased insurance costs in the form of property and liability claims, and costs to state and local governments for judicial, emergency, and social services. This manuscript's objective is to provide payers with strategies to control these costs, while supporting safe use of prescription opioid medications for patients with chronic pain. METHOD: A Tufts Health Care Institute Program on Opioid Risk Management meeting was convened in June 2010 with private and public payer representatives, public health and law enforcement officials, pain specialists, and other stakeholders to present research and develop recommendations on solutions that payers might implement to combat this problem. RESULTS: While protecting access to prescription opioids for patients with pain, private and public payers can implement strategies to mitigate financial risks associated with opioid abuse, using internal strategies such as formulary controls, claims data surveillance, and claims matching; and external policies and procedures that support and educate physicians on reducing opioid risks among patients with chronic pain. CONCLUSIONS: Reimbursement policies, incentives, and health technology systems that encourage physicians to use universal precautions, to consult prescription monitoring program (PMP) data, and to implement Screening, Brief Intervention, and Referral to Treatment protocols have a high potential to reduce insurer risks while addressing a serious public health problem.

Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations.

The development of valid and informative treatment risk-benefit profiles requires consistent and thorough information about adverse event (AE) assessment and participants' AEs during randomized controlled trials (RCTs). Despite a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement recommending the specific AE information that investigators should report, there is little evidence that analgesic RCTs adequately adhere to these recommendations. This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinically important AE information. Using this checklist, we coded AE assessment methods and reporting in all 80 double-blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain, Journal of Pain, and PAIN® from 2006 to 2011. Across all trials, reports of AEs were frequently incomplete, inconsistent across trials, and, in some cases, missing. For example, >40% of trials failed to report any information on serious adverse events. Trials of participants with acute or chronic pain conditions and industry-sponsored trials typically provided more and better-quality AE data than trials involving pain-free volunteers or trials that were not industry sponsored. The results of this review suggest that improved AE reporting is needed in analgesic RCTs. We developed an ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations.

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Prevention of prescription opioid abuse: the role of the dentist.

BACKGROUND: Opioids are analgesics that have potential for misuse, abuse or addiction. Up to an estimated 23 percent of prescribed doses are used nonmedically. As prescribers of 12 percent of immediate-release (IR) opioids in the United States, dentists can minimize the potential for misuse or abuse. METHODS: The authors participated in a two-day meeting in March 2010 cohosted by Tufts Health Care Institute Program on Opioid Risk Management, Boston, and Tufts University School of Dental Medicine, Boston. The purpose of the meeting was to synthesize available opioid abuse literature and data from a 2010 survey regarding West Virginia dentists' analgesic prescribing practices, identify dentists' roles in prescribing opioids that are used nonmedically, highlight practices that dentists can implement and identify research gaps. RESULTS: Dentists can play a role in minimizing opioid abuse through patient education, careful patient assessment and referral for substance abuse treatment when indicated, and using tools such as prescription monitoring programs. Research is needed to determine the optimal number of doses needed to treat dental-related pain. CONCLUSIONS: Dentists cannot assume that their prescribing of opioids does not affect the opioid abuse problem in the United States. The authors suggest that dentists, along with other prescribers, take steps to identify problems and minimize prescription opioid abuse through greater prescriber and patient education; use of peer-reviewed recommendations for analgesia; and, when indicated, the tailoring of the appropriate and legitimate prescribing of opioids to adequately treat pain. Practice Implications. The authors encourage dentists to incorporate practical safeguards when prescribing opioids, consistently educate patients about how to secure unused opioids properly, screen patients for substance use disorders and develop a referral network for the treatment of substance use disorders.

Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

Challenges in the development of prescription opioid abuse-deterrent formulations.

Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics--if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.

Foundations of opioid risk management.

Increased abuse and diversion of prescription opioids has been a consequence of the increased availability of opioids to address the widespread problem of undertreated pain. Opioid risk management refers to the effort to minimize harms associated with opioid therapy while maintaining appropriate access to therapy. Management of these linked public health issues requires a coordinated and balanced effort among a disparate group of stakeholders at the federal, state, industry, practitioner, and patient levels. This paper reviews the principles of opioid risk management by examining the epidemiology of prescription opioid abuse in the United States; identifying key stakeholders involved in opioid risk management and their responsibilities for managing or monitoring opioid abuse and diversion; and summarizing the mechanisms currently used to monitor and address prescription opioid abuse. Limitations of current approaches, and emerging directions in opioid risk management, are also presented.

Estimated costs of prescription opioid analgesic abuse in the United States in 2001: a societal perspective.

OBJECTIVES: This study estimates the costs to society of prescription opioid analgesic (RxO) abuse in the United States. METHODS: Costs associated with RxO abuse were grouped into healthcare, criminal justice, and workplace categories. Costs were estimated by either (1) a quantity method that multiplies the number of RxO abusers derived from various national surveys by the estimated per abuser cost, or (2) an apportionment method that starts with overall (ie, prescription and nonprescription) drug abuse costs for a cost component (eg, police protection) and apportions the share of costs based on the prevalence of RxO abuse relative to overall drug abuse. Medical costs in excess of those for otherwise similar nonabusers were based on an analysis of a large administrative claims database for an employed population using multivariate regression methods. RESULTS: A lower bound estimate of the costs of RxO abuse in the United States was 8.6 billion dollars in 2001 (or 9.5 billion dollars in 2005 dollars). Of this amount, 2.6 billion dollarswere healthcare costs, 1.4 billion dollars were criminal justice costs, and 4.6 billion dollars were workplace costs. CONCLUSIONS: The costs of RxO abuse represent a substantial economic burden. Rising trends of RxO abuse suggest an escalating economic and public health burden in coming years in the United States, and potentially, elsewhere.

Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP).

The Screener and Opioid Assessment for Patients with Pain (SOAPP) is a brief, self-administered screening instrument used to assess suitability of long-term opioid therapy for chronic pain patients. This study presents preliminary data to examine the reliability and validity of the SOAPP as a measure of risk of opioid abuse for patients on opioid medication. Patients taking opioids for noncancer pain (n=396) from two pain centers completed the SOAPP prior to being placed on opioids for pain. Demographic data, SOAPP scores, and results of urine toxicology screens from the patients' medical records were examined. Patients were divided into two groups of high and low risk of opioid abuse potential based on cutoff scores of 8 and higher on the SOAPP. Results showed that patients in the high-risk group were younger, more likely to be asked to give a urine screen, and had more abnormal urine screens compared with those in the low-risk group (P<0.05). A combined factor analysis of the SOAPP revealed five factors labeled 1) history of substance abuse, 2) legal problems, 3) craving medication, 4) heavy smoking, and 5) mood swings. Preliminary support was found for the internal reliability and predictive validity of the SOAPP. Current limitations of the SOAPP and future directions for change are discussed.

Monitoring outcomes during long-term opioid therapy for noncancer pain: results with the Pain Assessment and Documentation Tool.

The increasingly common practice of long-term opioid therapy for chronic noncancer pain must be guided by ongoing assessment of four types of outcomes: pain relief, function, side effects, and drug-related behaviors. Our objective was to gather initial pilot data on the clinical application of a specialized chart note, the Pain Assessment and Documentation Tool (PADT), which was developed and tested with 27 physicians. This pilot test provided the means to collect cross-sectional outcome data on a large sample of opioid-treated chronic pain patients. Each of the physician volunteers (located in a variety of settings across the United States) completed the PADT for a convenience sample of personally treated chronic pain patients who had received at least three months of opioid therapy. Completion of the PADT required a clinical interview, review of the medical chart, and direct clinical observation. Data from the PADTs were collated and analyzed. The results suggested that the majority of patients with chronic pain achieve relatively positive outcomes in the eyes of their prescribing physicians in all four relevant domains with opioid therapy. Analgesia was modest but meaningful, functionality was generally stabilized or improved, and side effects were tolerable. Potentially aberrant behaviors were common but viewed as an indicator of a problem (i.e., addiction or diversion) in only approximately 10 percent of cases. Using the PADT physician ratings can be developed in four domains. In this sample, outcomes suggested that opioid therapy provided meaningful analgesia.