Expectations for Improvement: A Neglected but Potentially Important Covariate or Moderator for Chronic Pain Clinical Trials.

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.

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.

Evaluating the stability of opioid efficacy over 12 months in patients with chronic noncancer pain who initially demonstrate benefit from extended release oxycodone or hydrocodone: harmonization of Food and Drug Administration patient-level drug safety study data.

ABSTRACT: 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.

Improved Treatment Effect of Triamcinolone Acetonide Extended-Release in Patients with Concordant Baseline Pain Scores on the Average Daily Pain and Western Ontario and McMaster Universities Osteoarthritis Index Pain Scales.

INTRODUCTION: A phase 3 randomized controlled study comparing triamcinolone acetonide extended-release (TA-ER) to conventional TA crystalline suspension (TAcs) reported variable efficacy results. Enrollment criteria may have contributed to this discrepancy, as moderate-to-severe average daily pain (ADP) was required at baseline, whereas no limitations were placed on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A) pain severity. We conducted a post hoc sensitivity analysis to compare treatment effects in patients reporting moderate-to-severe osteoarthritis (OA) pain on both scales. METHODS: Participants > 40 years old with symptomatic knee OA were randomly assigned to a single intra-articular injection of TA-ER 32 mg, TAcs 40 mg, or saline-placebo and followed for 24 weeks. Patient-reported ADP, WOMAC-A, rescue medication usage, and adverse events (AEs) were assessed. Participants who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥ 5 to ≤ 9, maximum 10 and WOMAC-A ≥ 2, maximum 4) were categorized as "concordant" pain reporters; patients with baseline moderate-to-severe OA on ADP only were termed "discordant" pain reporters. RESULTS: Two-hundred-ninety-two concordant pain reporters of 484 total subjects received TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or saline-placebo (n = 97). Baseline characteristics and AE profiles of the concordant and discordant pain responders were consistent with the full analysis population. Among concordant pain reporters, TA-ER significantly (p < 0.05) improved ADP scores vs. TAcs (weeks 5-19; area-under-the-effect [AUE]weeks1-12; AUEweeks1-24) and saline-placebo (weeks 1-20; AUEweeks1-12; AUEweeks1-24). At week 12, a higher proportion reported no knee pain (ADP = 0) with TA-ER (~ 28%) vs. TAcs (~ 8%). TA-ER significantly improved WOMAC-A vs. TAcs at weeks 4, 8, and 12, with significant reduction in rescue medication usage observed with TA-ER from weeks 2 to 20 vs. TAcs. CONCLUSIONS: In patients reporting moderate-to-severe knee OA pain at baseline based on concordant ADP and WOMAC-A scores, TA-ER provided statistically significant pain relief for ≥ 12 weeks compared with conventional TAcs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357459.

Osteoarthritis is a chronic condition that greatly impacts patients. Pain is the most common symptom of osteoarthritis. Clinical trials evaluating the effects of new drugs to treat osteoarthritis pain frequently use scales to rate overall pain following treatment. Patients may rate their pain using a number that best describes their pain, with the lowest number typically meaning "no pain," and the highest number typically meaning "pain as bad as you can imagine." Other rating scales may be used to rate pain in situations commonly associated with osteoarthritis.Results from a large clinical trial demonstrated that injection of an extended-release steroid significantly reduced pain compared with a conventional steroid injection on only one of the two pain-reporting scales used in the trial. A closer look found that some patients reported their pain differently on the two rating scales at the start of the trial, with some reporting moderate-to-severe pain using one questionnaire and mild pain using the other. Here, we focused on those patients who reported having moderate-to-severe osteoarthritis knee pain on both pain scales at the start and found that the pain relief benefit associated with the extended-release steroid injection was greatly improved compared with the conventional steroid injection with both measures. Patients receiving the extended-release steroid injection also decreased their use of rescue medication for pain relief.

What can be done to control the placebo response in clinical trials? A narrative review.

The desire to reduce high placebo response rates in clinical trials is a popular concept. However, few studies have rigorously examined the effectiveness of methods to control for placebo responses that are relevant to randomized controlled trials. The primary objective of this review was to evaluate the effect of experimental placebo manipulations in randomized controlled trials (RCTs). We critically reviewed studies designed to manipulate placebo responses including positive expectations regarding the effectiveness of the placebo treatment, manipulating the time spent with subjects, and training study staff and subjects to accurately report symptom severity. These efforts have generally resulted in reduced placebo response and improved discrimination between drug and placebo. Interventions that neutralize staff and subject expectations and improve the ability of subjects to accurately report symptom severity have shown the most promise. Reduction of the placebo response has the potential to accelerate the development of new therapeutics.

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.

Design and conduct of confirmatory chronic pain clinical trials.

The purpose of this article is to provide readers with a basis for understanding the emerging science of clinical trials and to provide a set of practical, evidence-based suggestions for designing and executing confirmatory clinical trials in a manner that minimizes measurement error. The most important step in creating a mindset of quality clinical research is to abandon the antiquated concept that clinical trials are a method for capturing data from clinical practice and shifting to a concept of the clinical trial as a measurement system, consisting of an interconnected set of processes, each of which must be in calibration for the trial to generate an accurate and reliable estimate of the efficacy (and safety) of a given treatment. The status quo of inaccurate, unreliable, and protracted clinical trials is unacceptable and unsustainable. This article gathers aspects of study design and conduct under a single broad umbrella of techniques available to improve the accuracy and reliability of confirmatory clinical trials across traditional domain boundaries.

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations.

ABSTRACT: Spinal cord stimulation (SCS) is an interventional nonpharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). Although randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, nonspecific effects of treatment variables (eg, paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. To address these challenges, 3 professional societies (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, Institute of Neuromodulation, and International Neuromodulation Society) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This article summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding noninferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and nonpharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.

A 3-way Cross-over Study of Pregabalin, Placebo, and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination With Pregabalin in Patients With Painful Diabetic Neuropathy and Good Pain-reporting Ability.

OBJECTIVES: In this study, patients with painful diabetic neuropathy were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments. METHODS: AZD5213, a novel histamine H3 receptor inverse agonist+pregabalin, pregabalin, and placebo were then tested in a 3-period cross-over. RESULTS: The study did not provide any evidence of clinical efficacy for AZD5213 when combined with pregabalin in the treatment of painful diabetic neuropathy. DISCUSSION: The training of study patients in pain reporting and subsequent enrichment with good pain reporters also did not enable the robust detection of the efficacy of pregabalin relative to placebo in a small sample size. Further work is required before recommending the use of "connoisseur" patients in future neuropathic pain studies.

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.

Systematic Review of Research Methods and Reporting Quality of Randomized Clinical Trials of Spinal Cord Stimulation for Pain.

This systematic review assessed design characteristics and reporting quality of published randomized clinical trials of spinal cord stimulation (SCS) for treatment of pain in adults and adolescents. The study protocol was registered with PROSPERO (CRD42018090412). Relevant articles were identified by searching the following databases through December 31, 2018: MEDLINE, Embase, WikiStim, The Cochrane Database of Systematic Reviews, and The Cochrane Central Register of Controlled Trials. Forty-six studies were included. Eighty-seven percent of articles identified a pain-related primary outcome. Secondary outcomes included physical functioning, health-related quality of life, and reductions in opioid use. Nineteen of the 46 studies prespecified adverse events as an outcome, with 4 assessing them as a primary outcome. Eleven studies stated that they blinded participants. Of these, only 5 were assessed as being adequately blinded. The number of participants enrolled was generally low (median 38) and study durations were short (median 12 weeks), particularly in studies of angina. Fifteen studies employed an intention-to-treat analysis, of which only seven specified a method to accommodate missing data. Review of these studies identified deficiencies in both reporting and methodology. The review's findings suggest areas for improving the design of future studies and increasing transparency of reporting. PERSPECTIVE: This article presents a systematic review of research methods and reporting quality of randomized clinical trials of SCS for the treatment of various pain complaints. The review identifies deficiencies in both methodology and reporting, which may inform the design of future studies and improve reporting standards.

The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments.

OBJECTIVE: To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine. METHODS: A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher's exact tests were performed on the level of placebo response and the success in meeting the study's primary endpoint. RESULTS: After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = -0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders (p = 0.03). CONCLUSION: Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.

Direct Costs of Opioid Abuse in an Insured Population in the United States.

OBJECTIVE: To (a) describe the demographics of opioid abusers; (b) compare the prevalence rates of selected comorbidities and the medical and drug utilization patterns of opioid abusers with patients from a control group, for the period from 1998 to 2002; and (c) calculate the mean annual per-patient total health care costs (e.g., inpatient, outpatient, emergency room, drug, other) from the perspective of a private payer. METHODS: An administrative database of medical and pharmacy claims from 1998 to 2002 of 16 self-insured employer health plans with approximately 2 million lives was used to identify "opioid abusers"-patients with claims associated with ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes for opioid abuse (304.0, 304.7, 305.5, and 965.0 [excluding 965.01]). A control group of nonabusers was selected using a matched sample (by age, gender, employment status, and census region) in a 3:1 ratio. Per-patient annual health care costs (mean total medical and drug costs) were measured in 2003 U.S. dollars. Multivariate regression techniques were also used to control for comorbidities and to compare costs with a benchmark of depressed patients. RESULTS: 740 patients were identified as opioid abusers, a prevalence of 8 in 10,000 persons aged 12 to 64 years continuously enrolled in health care plans for whom 12 months of data were available for calculating costs. Opioid abusers, compared with nonabusers, had significantly higher prevalence rates for a number of specific comorbidities, including nonopioid poisoning, hepatitis (A, B, or C), psychiatric illnesses, and pancreatitis, which were approximately 78, 36, 9, and 21 (P<0.01) times higher, respectively, compared with nonabusers. Opioid abusers also had higher levels of medical and prescription drug utilization. Almost 60% of opioid abusers had prescription drug claims for opioids compared with approximately 20% for nonabusers. Prevalence rates for hospital inpatient visits for opioid abusers were more than 12 times higher compared with nonabusers (P<0.01). Mean annual direct health care costs for opioid abusers were more than 8 times higher than for nonabusers ($15,884 versus $1,830, respectively, P < 0.01). Hospital inpatient and physician-outpatient costs accounted for 46% ($7,239) and 31% ($5,000) of opioid abusers' health care costs, compared with 17% ($310) and 50% ($906), respectively, for nonabusers. Mean drug costs for opioid abusers were more than 5 times higher than costs for nonabusers ($2,034 vs. $386, respectively, P<0.01), driven by higher drug utilization (including opioids) for opioid abusers. Even when controlling for comorbidities using a multivariate regression model of a matched control of depressed patients, the average health care costs of opioid abusers were 1.8 times higher than the average health care costs of depressed patients. CONCLUSION: The high costs of opioid abuse were driven primarily by high prevalence rates of costly comorbidites and high utilization rates of medical services and prescription drugs. DISCLOSURES: Funding for this research was provided by an unrestricted grant from Janssen Medical Affairs, L.L.C. and was obtained by authors Susan Vallow and Jeff Schein, who are employed by Janssen Medical Affairs, L.L.C. Nathaniel Katz is a consultant to Janssen and numerous other pharmaceutical companies that manufacture branded opioid products and nonopioid analgesics; authors Alan G. White, Howard G. Birnbaum, Milena N. Mareva, and Maham Daher disclose no potential bias or conflict of interest relating to this article. White served as principal author of the study. Study concept and design were contributed primarily by White, Vallow, Schein, and Katz. Analysis and interpretation of data were contributed by all authors. Drafting of the manuscript was primarily the work of White, and its critical revision was the work of White and Vallow. Statistical expertise was contributed by White, Birnbaum, and Daher, and administrative, technical, and/or material support was provided by Analysis Group, Inc., Boston, MA.

Placebo Response Reduction and Accurate Pain Reporting Training Reduces Placebo Responses in a Clinical Trial on Chronic Low Back Pain: Results From a Comparison to the Literature.

OBJECTIVE: A literature review was conducted to compare placebo responses in a recent trial-which implemented an accurate pain reporting (APR) and placebo response reduction (PRR) training program-with placebo responses in similar previous trials in chronic lower back pain (CLBP) that did not use such training. METHODS: A literature search was performed to find parallel design, randomized, controlled trials of pharmacological treatments administered orally or through intravenous injection for CLBP. Studies were assessed for the proportion of placebo responders, defined as the proportion of patients in the placebo group with ≥30% reduction in pain intensity. A χ analysis was performed on the proportion of responders from the SPRINT trial and from other similar studies. RESULTS: Of 844 studies identified in the initial screening process, 16 studies were included for comparison. The percentage of placebo responders was statistically significantly lower in the SPRINT study (19.1%) compared with other CLBP trials (38.0%) (P=0.003). Our results show that the placebo response was lower in the SPRINT trial than other comparable studies on CLBP. DISCUSSION: These findings are consistent with results from other studies showing that neutralizing subject and study staff expectations of therapeutic benefit can decrease the placebo response in clinical trials. The results of this study suggest training participants and staff to improve pain reporting accuracy, neutralize expectations, and decrease external cues that may bias participants' pain ratings in clinical trials may effectively decrease the placebo response leading to increased assay sensitivity.

A Real-World Study Using Claims Data to Evaluate Possible Failure of Opioid Treatment Regimens Among Patients with Hip and/or Knee Osteoarthritis in the US.

BACKGROUND: Although opioids may be used in the management of pain in patients with osteoarthritis (OA), there is a dearth of real-world data characterizing opioid regimen failure in these patients. OBJECTIVE: Using claims data, this study explored measures that may be potentially indicative of opioid treatment failure and the association of such potential failure with health care resource utilization (HRU) and costs. PATIENTS AND METHODS: Using a national employer-sponsored insurance claims database covering the years 2011-2016, this retrospective longitudinal study identified adults with hip/knee osteoarthritis who filled ≥1 opioid prescription (index event) and had continuous health plan enrollment 6 months pre- and ≥12 months post-index. Index opioid regimen intensity was defined in the 3-month post-index period by frequency, average daily dose, and duration of action. Possible index opioid regimen failure was defined as an increase in opioid regimen intensity, addition of a non-opioid pain medication, joint surgery, or opioid-abuse-related events. One-year follow-up HRU and costs were compared between those with possible treatment failure and those without. RESULTS: Among 271,512 OA patients (61.5% knee; 11.1% hip; 27.4% both), 34.9% met the definition of possible index opioid regimen failure within a year: increased regimen intensity (16.1%), joint surgery (14.0%), addition of non-opioid pain medication (11.4%), and opioid-abuse-related events (1.9%). Rates of possible failure generally increased with higher index regimen intensity. Compared with those who did not fail, those who potentially failed their index treatment regimen had significantly higher HRU (P<0.001), and all-cause ($36,699 vs $15,114) and osteoarthritis-related costs ($17,298 vs $1,967) (both P<0.0001). CONCLUSION: Among OA patients treated with opioids, approximately one-third may fail their index opioid regimen within a year and incur significantly higher HRU and costs than those without. Further research is needed to validate these findings with clinical outcomes.

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.

Measuring Opioid Withdrawal in a Phase 3 Study of a New Analgesic, NKTR-181 (Oxycodegol), in Patients with Moderate to Severe Chronic Low Back Pain.

OBJECTIVE: To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist. DESIGN: Phase 3, enriched-enrollment, double-blind, randomized-withdrawal study in patients with chronic low back pain (CLBP). SETTING: Conducted in the United States at multiple sites. METHODS: SUMMIT-07 was comprised of five periods: screening; NKTR-181 open-label titration (100 to 400 mg twice daily); 12-week randomized, double-blind study drug (NKTR-181 or placebo); one-week study drug taper; and two-week safety follow-up. Permitted rescue medication included hydrocodone 5 mg/acetaminophen 300 mg (two tablets daily) for two weeks after randomization, then acetaminophen 1.0 gm daily for the remainder of the trial. Signs and symptoms of drug withdrawal were evaluated using the Clinical Opiate Withdrawal Scale (COWS); Subjective Opiate Withdrawal Scale (SOWS); Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS); and withdrawal-related adverse events. RESULTS: Of 1,190 patients entering titration, one patient had moderate withdrawal (COWS score 13/48 maximum) three days after discontinuing NKTR-181. Of 610 patients randomized (N = 309, NKTR-181; N = 301, placebo), no COWS scores indicating withdrawal at a moderate level or greater (i.e., score ≥13) were observed at any time point. At day 8 after randomization, week 12, and the end of tapering, COWS scores indicating mild withdrawal (<13) were observed in seven (2.4%), one (0.4%), and one (0.5%) placebo patients, respectively, and three (1.0%), one (0.4%), and five (2.3%) NKTR-181 patients, respectively. Mean SOWS scores in both arms were ≤2.8 of 64 possible points at all time points. During the randomized period, of 35 events identified by MADDERS, adjudicators identified 20 possible "withdrawal" events (9 [2.9%] NKTR-181 and 11 [3.7%] placebo). CONCLUSIONS: NKTR-181 exhibited a low rate and severity of opioid withdrawal in SUMMIT-07 patients with CLBP.

Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS).

OBJECTIVE: To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP). DESIGN: Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181). SETTING: Multicenter, long-term clinical research study. METHODS: NKTR-181 administered at doses of 100-600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF). RESULTS: The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events. CONCLUSIONS: The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP.