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.
University of Rochester Medical Center1, University of Washington2, Stony Brook University3, Queen's University4, Food and Drug Administration5, Johns Hopkins University6, University of California, San Francisco7, University of Pennsylvania8, Indiana University9, Brigham and Women's Hospital10, Wake Forest University11, Southern Illinois University Edwardsville12, GW Pharmaceuticals13, Biogen Idec14, University at Buffalo15, McGill University16, MCPHS University17, United States Department of Veterans Affairs18, Pfizer19, University of Pittsburgh20
TL;DR: In this paper, the authors present the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials based on the following definition: any intervention that prevents the initiation of treatment with opioid analgesics, decreases the duration of such treatment, reduces the total dosages of opioids that are prescribed for or used by patients, or reduces opioidrelated adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain.
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.
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TL;DR: A recent systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements as mentioned in this paper , found that the median effective dose (ED 50 ) administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED 50 of morphine alone.
18 citations
TL;DR: In this paper , a systematic review and meta-analysis was conducted to estimate the extent to which opioid prescribing after discharge affects self-reported pain intensity and adverse events in comparison with an opioid-free analgesic regimen.
16 citations
TL;DR: Evidence on the reduction of long term opioid treatment for chronic pain continues to be constrained by poor study methodology, and the lack of evidence relating to possible harms is of particular concern.
Abstract: Abstract Objective To review interventions to reduce long term opioid treatment in people with chronic non-cancer pain, considering efficacy on dose reduction and discontinuation, pain, function, quality of life, withdrawal symptoms, substance use, and adverse events. Design Systematic review and meta-analysis of randomised controlled trials and non-randomised studies of interventions. Data sources Medline, Embase, PsycINFO, CINAHL, and the Cochrane Library searched from inception to July 2021. Reference lists and previous reviews were also searched and experts were contacted. Eligibility criteria for study selection Original research in English. Case reports and cross sectional studies were excluded. Data extraction and synthesis Two authors independently selected studies, extracted data, and used the Cochrane risk-of-bias tools for randomised and non-randomised studies (RoB 2 and ROBINS-I). Authors grouped interventions into five categories (pain self-management, complementary and alternative medicine, pharmacological and biomedical devices and interventions, opioid replacement treatment, and deprescription methods), estimated pooled effects using random effects meta-analytical models, and appraised the certainty of evidence using GRADE (grading of recommendations, assessment, development, and evaluation). Results Of 166 studies meeting inclusion criteria, 130 (78%) were considered at critical risk of bias and were excluded from the evidence synthesis. Of the 36 included studies, few had comparable treatment arms and sample sizes were generally small. Consequently, the certainty of the evidence was low or very low for more than 90% (41/44) of GRADE outcomes, including for all non-opioid patient outcomes. Despite these limitations, evidence of moderate certainty indicated that interventions to support prescribers’ adherence to guidelines increased the likelihood of patients discontinuing opioid treatment (adjusted odds ratio 1.5, 95% confidence interval 1.0 to 2.1), and that these prescriber interventions as well as pain self-management programmes reduced opioid dose more than controls (intervention v control, mean difference –6.8 mg (standard error 1.6) daily oral morphine equivalent, P<0.001; pain programme v control, −14.31 mg daily oral morphine equivalent, 95% confidence interval −21.57 to −7.05). Conclusions Evidence on the reduction of long term opioid treatment for chronic pain continues to be constrained by poor study methodology. Of particular concern is the lack of evidence relating to possible harms. Agreed standards for designing and reporting studies on the reduction of opioid treatment are urgently needed. Review registration PROSPERO CRD42020140943.
14 citations
TL;DR: Interscalene brachial plexus blocks performed with bupvacaine alone did not demonstrate non-inferiority compared to a mixture of liposomal bupivacaine plus bupavacaine with regards to 72-hour cumulative opioid consumption following total shoulder arthroplasty, and the difference between groups did not appear to be clinically meaningful.
5 citations
TL;DR: While most studies showed effects immediately or up to one month post treatment, RCTs are needed to further evaluate VR/AR/MR, establish long-term benefits, and assess accessibility, especially among individuals who experience pain management disparities.
Abstract: Aim: Characterize use and efficacy/effectiveness of virtual, augmented, or mixed reality (VR/AR/MR) technology as non-pharmacological therapy for chronic pain. Methods: Systematic search of 12 databases to identify empirical studies, of individuals who experience chronic pain or illness involving chronic pain, published between 1990 and 2021. JBI Critical Appraisal Checklists assessed study bias and a narrative synthesis was provided. Results: 46 studies, investigating a total of 1456 participants and including 19 randomized controlled trials (RCT), were reviewed. VR/AR/MR was associated with improved pain-related outcomes in 78% of the RCTs. Conclusion: While most studies showed effects immediately or up to one month post treatment, RCTs are needed to further evaluate VR/AR/MR, establish long-term benefits, and assess accessibility, especially among individuals who experience pain management disparities.
5 citations
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TL;DR: This guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.
Abstract: Importance Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose. Objective To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care. Process The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category. Evidence Synthesis Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects. Recommendations There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone. Conclusions and Relevance The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.
3,935 citations
American College of Rheumatology1, Boston University2, University of Toronto3, Virginia Mason Medical Center4, McMaster University5, Food and Drug Administration6, University of Kentucky7, University of California, Los Angeles8, Stanford University9, Brigham and Women's Hospital10, University of Utah11
TL;DR: The results suggest that the definition of improvement presented is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved, which the authors hope will be used widely in RA trials.
Abstract: Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
2,593 citations
TL;DR: In this paper, the Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at the time of overdose, and 51 opioid-related overdoses were identified, including 6 deaths.
Abstract: Background Long-term opioid therapy for chronic noncancer pain is becoming increasingly common in community practice. Concomitant with this change in practice, rates of fatal opioid overdose have increased. The extent to which overdose risks are elevated among patients receiving medically prescribed long-term opioid therapy is unknown. Objective To estimate rates of opioid overdose and their association with an average prescribed daily opioid dose among patients receiving medically prescribed, long-term opioid therapy. Design Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at the time of overdose. Setting HMO. Patients 9940 persons who received 3 or more opioid prescriptions within 90 days for chronic noncancer pain between 1997 and 2005. Measurements Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes--nonfatal and fatal overdoses--were identified through diagnostic codes from inpatient and outpatient care and death certificates and were confirmed by medical record review. Results 51 opioid-related overdoses were identified, including 6 deaths. Compared with patients receiving 1 to 20 mg/d of opioids (0.2% annual overdose rate), patients receiving 50 to 99 mg/d had a 3.7-fold increase in overdose risk (95% CI, 1.5 to 9.5) and a 0.7% annual overdose rate. Patients receiving 100 mg/d or more had an 8.9-fold increase in overdose risk (CI, 4.0 to 19.7) and a 1.8% annual overdose rate. Limitations Increased overdose risk among patients receiving higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation. Conclusion Patients receiving higher doses of prescribed opioids are at increased risk for overdose, which underscores the need for close supervision of these patients. Primary funding source National Institute of Drug Abuse.
1,080 citations
TL;DR: Five procedures are considered for the comparison of two or more multivariate samples, including a newly proposed nonparametric rank-sum test and a generalized least squares test, which may be useful with normally distributed data in moderate or large samples.
Abstract: SUMMARY Five procedures are considered for the comparison of two or more multivariate samples. These procedures include a newly proposed nonparametric rank-sum test and a generalized least squares test. Also considered are the following tests: ordinary least squares, Hotelling's P, and a Bonferroni per-experiment error-rate approach. Applications are envisaged in which each variable represents a qualitatively different measure of response to treatment. The null hypothesis of no treatment difference is tested with power directed towards alternatives in which at least one treatment is uniformly better than the others. In all simulations the nonparametric procedure provided relatively good power and accurate control over the size of the test, and is recommended for general use. Alternatively, the generalized least squares procedure may also be useful with normally distributed data in moderate or large samples. A convenient expression for this procedure is obtained and its asymptotic relative efficiency with respect to the ordinary least squares test is evaluated. Clinical trials are often conducted for the purpose of evaluating the relative efficacy of two or more modes of therapy. When the therapies are administered to independent groups and efficacy is measured on the basis of a single response variable, appropriate parametric and nonparametric one-way analysis-of-variance (ANOVA) procedures and their properties are well-known. Often, however, efficacy is measured by more than one variable. Although univariate methods for assessing each characteristic individually are useful in this setting, there is often the additional need for a single, overall, objective probability statement that addresses the question of whether or not the experimental therapy is efficacious. This need is particularly acute when the medical question is controversial and the sample size is small. Although a large literature exists on the comparison of multivariate samples, the procedures tend to be infrequently used in practice. As pointed out by Meier (1975, p. 523), the standard analysis for the comparison of two multivariate samples, which is based on Hotelling's T2 statistic, addresses somewhat the wrong question and consequently has very poor power for the alternatives of primary interest. Specifically, the T2 procedure addresses the question 'Are one or more of the treatments different?', making no distinction between variables that change favorably and variables that change unfavorably. A second approach would be to assign per-experiment error rates to each of the univariate tests by using Bonferroni's inequality (i.e. by multiplying each univariate P-value by the number of variables studied). The desired overall probability statement is then given by the minimum of the per-experiment univariate P-values. Although this approach may be useful in some settings, it may lack power for alternatives in which most or all measures of efficacy are improved. This will be of particular concern when the number, K, of endpoints studied is large relative to sample size. In fact, statistical significance will not be possible in some instances. This problem will be exacerbated when the measures of efficacy are highly
1,079 citations
TL;DR: Although significant variability remains in this literature, this review provides guidance regarding possible average rates of opioid misuse and addiction and also highlights areas in need of further clarification.
Abstract: Opioid use in chronic pain treatment is complex, as patients may derive both benefit and harm. Identification of individuals currently using opioids in a problematic way is important given the substantial recent increases in prescription rates and consequent increases in morbidity and mortality. The present review provides updated and expanded information regarding rates of problematic opioid use in chronic pain. Because previous reviews have indicated substantial variability in this literature, several steps were taken to enhance precision and utility. First, problematic use was coded using explicitly defined terms, referring to different patterns of use (ie, misuse, abuse, and addiction). Second, average prevalence rates were calculated and weighted by sample size and study quality. Third, the influence of differences in study methodology was examined. In total, data from 38 studies were included. Rates of problematic use were quite broad, ranging from <1% to 81% across studies. Across most calculations, rates of misuse averaged between 21% and 29% (range, 95% confidence interval [CI]: 13%-38%). Rates of addiction averaged between 8% and 12% (range, 95% CI: 3%-17%). Abuse was reported in only a single study. Only 1 difference emerged when study methods were examined, where rates of addiction were lower in studies that identified prevalence assessment as a primary, rather than secondary, objective. Although significant variability remains in this literature, this review provides guidance regarding possible average rates of opioid misuse and addiction and also highlights areas in need of further clarification.
852 citations