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Abstract: Introduction: Prescription opioid dose reductions can raise the risk of adverse events for patients on long-term opioid therapy for non-cancer pain. Evidence on whether risks differ by age or sex is needed to support tailored clinical decision-making. Methods: In 2024, a secondary analysis of an observational cohort study (NIDA-CTN-0084) was conducted across 8 U.S. healthcare systems analyzing electronic health record and claims data from a prescription opioid registry (excluding buprenorphine prescriptions) between 1/1/2012 and 12/31/2018, including adults with stable prescription opioid use and a subsequent =2-month dose reduction period (n=60,040), yielding 600,234 dose reduction periods as the analytic sample. Differences in the association between dose reduction level (1-<15%, 15-<30%, 30-<100%, 100% from baseline) and potential adverse events (emergency department visits, opioid overdose, all-cause mortality, benzodiazepine prescription fills) in the month after dose reduction by sex and age group were examined by including interaction terms in logistic regression models. Results: Of the 600,234 dose reduction periods, 346,733 were among women, with a mean age of 57.5 [SD=13.2] years for women and 56.7 [SD=12.1] years for men. Associations between dose reduction levels and potential adverse events did not differ significantly by sex, but differed by age for emergency department visits: patients 40-64 and =65 years with dose reductions of 30-<100% had lower odds compared to those aged 19-39 (adjusted ratio of odds ratios [aROR]=0.87, CI 0.80, 0.96; aROR=0.82, CI 0.74, 0.91; respectively). Conclusions: Patients under 40 may benefit from closer monitoring in the month after dose reduction, given their higher odds of an emergency department visit. Related protocols: CTN-0084

Abstract:

Side effects of medications for opioid use disorder (MOUD) such as weight gain contribute to their stigma. Substantial evidence suggests that women have a more severe side effect profile to MOUD than men, and concerns about weight gain during treatment are prevalent. However, the few studies reporting sex differences in weight gain during treatment show conflicting results and are restricted to methadone. In addition, little is known about possible sex differences in weight gain to buprenorphine, which is the most commonly prescribed MOUD in the United States.

To address these issues, the authors performed a systematic review and meta-analysis on the few studies reporting longitudinal data on sex differences in body mass index (BMI) gain during methadone treatment (Study 1). In a separate study, they also re-analyzed data from trial CTN-0030 of the National Institute on Drug Abuse Clinical Trial Network (NIDA CTN), which involved a 12-week buprenorphine treatment regimen (Study 2; n = 360; 209 Male, 151 Female).

For Study 1, across all papers reporting longitudinal data (k = 4, n = 362 OUD patients), there were BMI increases that ranged from 2.2 to 5.4 BMI after at least one year of methadone treatment, but there were no significant sex differences in BMI increases (Standardized Mean Difference, Female > Male = 0.352, SE =0.270; 95 % CI = [-0.18 0.88]; p = .193). Study 2 showed no significant differences in weight before and after 12 weeks of buprenorphine treatment nor did it show sex differences in weight change with treatment (ß = 2.34, p = .511).

Conclusions: These analyses corroborate evidence of weight gain with methadone treatment but did not observe a sex-based disparity in weight gain with methadone or buprenorphine treatment for OUD.

Related protocols: CTN-0030

Abstract:

Extended-release naltrexone (XR-NTX), an opioid antagonist, and buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct opioid relapse prevention interventions. This study aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. This NIDA Clinical Trials Network protocol, CTN-0051, was initiated at 8 community-based inpatient programs, and followed participants as outpatients for 24 weeks. The primary outcome was opioid relapse-free survival (where relapse was defined as 4 consecutive weeks of non-study opioid use by urine toxicology or self-report, or 7 consecutive days by self-report).

Results found that, as expected, XR-NTX had a substantial induction hurdle — fewer initiated XR-NTX (72%) than BUP-NX (94%). Among the intention-to-treat (ITT) population (n=570), 24-week relapse events were greater for XR-NTX (65%) than for BUP-NX (57%). Most of this difference is accounted for by early relapse in nearly all (89%) XR-NTX induction failures. Among participants successfully inducted (n=474), 24-week relapse events were similar across arms. Opioid-negative urines and opioid-abstinent days favored BUP-NX among the ITT population, but were similar across arms among the per-protocol population. Opioid craving was initially less with XR-NTX than with BUP-NX, converging by week 24. Except for XR-NTX injection site reactions, treatment-emergent adverse events did not differ between treatment groups. Five fatal overdoses occurred (2 in the XR-NTX group, 3 in the BUP-NX group).

Conclusions: In these settings, it was more difficult for participants to initiate XR-NTX, and nearly all of those who failed induction quickly relapsed. Better overall opioid outcomes for the BUP-NX group in the intention-to-treat population were directly related to differential induction failure. No differences were found between the two groups for adverse events, serious adverse events, overdoses, and fatal overdoses. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention on both medications.

Abstract:

While several pharmacotherapies have been developed for substance use disorders (SUD) in adults, relatively few have been studied in adolescents, and complex design and execution issues must be addressed to optimize the potential impact of current and future research in this important area. This one-hour presentation discussed method, design, and key strategies for the optimization of conduct/execution, overall treatment adherence, participant enrollment and retention, documentation, and management of adverse events for adolescent SUD pharmacotherapy trials. With adequate understanding of challenges and opportunities in the design and conduct of these trials, attendees were equipped to incorporate this information into their research practices.

Additional Resources:

• Download slides (pdf)
• Download handout (pdf)

Abstract:

Induction is a crucial period of opioid addiction treatment. This study aimed to identify buprenorphine/naloxone (BUP) induction patterns and examine their association with outcomes (opioid use, retention, and related adverse events [AEs]). Using data from the NIDA Clinical Trials Network study Starting Treatment with Agonist Replacement Therapies (START) (CTN-0027), this study involved 740 participants inducted on BUP with flexible dosing, receiving treatment in 8 treatment settings. Latent class analysis models detected six distinctive induction trajectories: bup1-started and remained on law; bup2-started low, shifted slowly to moderate; bup4-started high, shifted to low; bup5-started and remained on moderate; and bup6-started moderate, shifted to high dose. Baseline characteristics, including Clinical Opioid Withdrawal Scale (COWS), were important predictors of retention. When controlled for the baseline characteristics, bup6 participants were three times less likely to drop out the first 7 days than bup1 participants. Opioid use and AEs were similar across trajectories. Participants on greater-than-or-equal-to 16mg BUP compared to those on less than 16mg at Day 28 were less likely to drop out and less likely to experience AEs during the first 28 days.

Conclusions: BUP induction dosing was guided by an objective measure of opioid withdrawal. Participants with higher baseline COWS whose BUP doses were raised more quickly were less likely to drop out in the first 7 days than those whose doses were raised more slowly. This study supports the use of an objective measure of opioid withdrawal (COWS) during BUP induction to improve retention early in treatment.

Related protocols: CTN-0027

Abstract:

This study aimed to evaluate buprenorphine-naloxone’s effects on the QTc in youth with opioid dependence (the QTc, or “corrected QT interval,” is a measure of the duration of electrical activation and recovery of the ventricular muscle). Prolongation of the QTc increases the risk for torsades de pointes (TdP), an uncommon variant of polymorphic ventricular tachycardia, that can result in syncope, ventricular fibrillation, and sudden death. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, and may also reduce the risk of TdP, but it is less studied in youth. This study involved a secondary analysis of the electrocardiogram data from 95 individuals who participated in a multi-site trial for youth with opioid dependence (CTN-0010). The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc.

Results found that mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (p=0.045), and women had longer mean QTc intervals than men (p<0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds — the level at which risk for TdP becomes more significant. The few QTc prolongations that occurred were among participants who were receiving psychotropic medications that are known to prolong the QTc, and indicate a need for further evaluation of potential interactions between buprenorphine-naloxone and SSRIs, or other commonly used psychotropic medications.

Conclusions: In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP. These results add to the known safety data on buprenorphine-naloxone among adults, and could add to the literature that buprenorphine-naloxone is a safe and effective treatment for opioid-dependent young adults with clinically significant QTc prolongations, or who are at risk for developing it.

Related protocols: CTN-0010

Abstract:

This article reports on a study examining predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of CTN-0029, a randomized, double-blind, placebo-controlled smoking cessation trial, non-hypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (+/-5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression.

Conclusions: This study suggests two findings: (1) adult ADHD participants with baseline normal blood pressure are more susceptible to the BP-raising effects of OROS-MPH than those with baseline prehypertensive BP, and (2) normotensive adults with ADHD have significantly greater odds of developing prehypertension when treated with OROS-MPH compared with placebo. Since previous studies have shown adverse cardiovascular outcomes associated with prehypertension, further studies are needed to clarify the long-term consequences, especially given the growing consensus of ADHD as a treatable lifelong illness.

Related protocols: CTN-0029

Abstract:

Reporting all adverse events (AEs) and serious adverse events (SAEs) in substance use disorder (SUD) clinical trials has yielded limited relevant safety information and has been burdensome to research sites. This article describes a new strategy utilizing standard data elements for AE and SAEs that defines a threshold to reduce unnecessary safety reporting burden in SUD clinical trials and describes retrospective review and prospective preliminary data on the strategy’s safety reporting impact. To develop the new strategy, protocols and safety data from 17 National Drug Abuse Treatment Clinical Trials Network (CTN) protocols were reviewed. Retrospective analysis of five of these studies and prospective application to new studies is described. Results found that, across the 17 previously completed trials, a total of 11,220 AEs and 1330 SAEs were reported in the 6737 participants. Wide variability in AE and SAE reporting rates were noted based on trial type and inconsistent reporting strategies. Application of the new, tailored safety strategy retrospectively and prospectively reduces reporting burden of irrelevant safety events.

Conclusions: Comparison of the previous reporting strategies used in SUD trials to the new strategy demonstrates a more consistent safety system with a reduction in safety reporting burden while maintaining appropriate safety monitoring. Safety assessments should be tailored to the participant risks based on the trial intervention. The current strategies could be applied to safety assessments across all clinical trials in SUDs (both behavioral or pharmacological), reducing burden, improving quality and relevance of safety data collected, and promoting comparability of safety data gathered across similar types of trials.

Abstract:

This presentation, which was also given at the National Drug Abuse Treatment Clinical Trials Network (CTN) 10th Anniversary Symposium in April 2010, highlights ten “take home lessons” from the CTN, describing one by one their impact on both research and treatment in the alcohol, tobacco, and other drugs field. The top ten accomplishments include the discovery of: multiple successes in establishing a partnership and building a research infrastructure; the safety of behavioral treatments (adverse event monitoring, e.g.); the power of incentives; the broad utility of the Stage Model; the fact that empirically validated treatments (EVTs) stand up in real world settings; the specific effects of behavioral treatments; the effectiveness of treatment-as-usual; effort, support and commitment as essential components of adopting and sustaining EVTs; the challenges of retention and broadening our scope; and the fact we still have a long way to go.

The presentation ends with a “tentative top ten to tackle in the next ten,” providing some examples of future directions for research in the CTN, including the development of a common outcome measure, ways to better keep clinicians engaged, how to sustain the effects of treatment and training, and more. [Note: Michael Levy, PhD, presented Dr. Carroll’s slides at the NIATx Summit and SAAS National Conference in her absence.]

Abstract:

Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non–substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD. Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (CTN-0028) with at least one non-nicotine SUD and one with 255 adult smokers (CTN-0029), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults.

Conclusions: With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence.

Related protocols: CTN-0028, CTN-0029

Abstract:

This one-hour webinar, produced by the National Drug Abuse Treatment Clinical Trials Network (CTN) Clinical Coordinating Center for CTN members and the public, provides guidelines on methods that have improved adverse event and serious adverse event identification and reporting in behavioral trials. The webinar includes discussion of the clinical and regulatory importance of monitoring safety in research studies; process recommendations for identifying, reviewing, reporting, and resolving safety events; and information about who is resonsible for what, and what resources are available to facilitate the process.

The target audience includes novice and experienced CTN or other research staff working in community treatment programs in the substance abuse field.

Presented by Blake Apple (University of Texas Southwestern Medical Center, TX Node), Maria Campanella, RN, BSN (EMMES Corporation), and Robert Lindblad, MD (EMMES Corporation).

Additional Resources:

• Download slides (ppt)

Abstract:

Behavioral intervention research has lagged behind biomedical research in developing principles for defining, categorizing, identifying, reporting, and monitoring adverse events and unanticipated problems. In this article, a set of principles for defining adverse events are presented, along with how they were applied in the National Drug Abuse Treatment Clinical Trials Network multi-site family therapy study for substance-using adolescents, protocol CTN-0014, the Brief Strategic Family Therapy (BSFT) for Adolescent Drug Abusers study. This study tested how BSFT compares to treatment as usual (TAU) for the treatment of drug-abusing adolescents. During protocol development, experts in the BSFT intervention, medical safety officers, ethicists, and senior investigators defined the procedures for identifying, tracking, and reporting adverse events for drug using adolescents as well as their family members. During this process, the team identified five key guiding principles: that the adverse events should be validated and plausible and that monitoring systems should assess relatedness, be systematic, and be a shared responsibility. Non-serious adverse events included arrest, school suspension and drop-out, runaway, kicked out of home, and violence. Serious adverse events included physical or sexual abuse, suicidal behavior, homicidal behavior, hospitalization (drug-related or psychiatric only), and death. More than 50% of the adolescent population experienced an adverse event during the trial. Family members experienced fewer (4.5%). The most common event for the adolescent group was arrest, followed by school suspension/drop-out. For the family member group, the most common event was violence, followed by arrest. There was a significant difference in the presence of adverse events in family members that were randomized to BSFT (6.1%) when compared to TAU (2.8%). One probable explanation for this is that there were more opportunities to identify adverse events for family members assigned to BSFT because family members attended therapy sessions.

The safety plan of the BSFT study has important implications for future studies with drug using adolescents and family-based interventions, though as these principles were developed specific to the issues and challenges faced in this single protocol, the application of the principles in designing procedures for defining and tracking adverse events in research on other behavioral interventions or clinical populations may be limited. Safety data in the BSFT trial support the principles that founded the BSFT safety plan, and illustrate the importance of safety monitoring in behavioral intervention research.

Related protocols: CTN-0014

Abstract:

Safety reporting in psychosocial trials is controversial. Reporting of all adverse events yields limited relevant safety information and is burdensome to clinical sites. Since 1999, the National Institute of Drug Abuse’s National Drug Abuse Treatment Clinical Trial Network (CTN) has conducted 24 randomized clinical trials in the field of drug abuse. Safety reporting was variable reflecting the numerous investigator’s and data center’s variety of prior experience and study type. In 2004 the CTN created a centralized safety office. Several distinct entities with a vested interest in safety reporting including the sponsor, the Institutional Review Board, a Data Safety Monitoring Board and the Food and Drug Administration, impact safety reporting strategies. We describe strategies to standardize safety data collection, reduce site reporting burden, problems encountered and maintain appropriate safety monitoring.

Protocols and safety data from the 17 completed trials available from the CTN public data share web site were reviewed. A total of 11,302 AEs and 1,330 SAEs were reported across approximately 6,700 participants enrolled in three investigational pharmaceutical intervention, one combination investigational pharmaceutical / psychosocial intervention, one combination marketed pharmaceutical / psychosocial intervention and twelve psychosocial intervention alone. Safety reporting variability resulted in problematic across-study comparisons. Since 2004 the safety office has instituted systematic processes to standardize safety reporting including consistent definitions and characterizations of adverse events and serious adverse events and clearly defining in the protocol which identified events require reporting in the central data base. Driven by lessons learned, the current strategies were developed to standardize adverse event reporting, support cross study comparisons, reduce reporting burden for clinical sites and preserve appropriate safety monitoring of clinical trial participants.

Abstract:

This two-hour webinar, produced by the National Drug Abuse Treatment Clinical Trials Network (CTN) Clinical Coordinating Center for CTN members and the public, is intended to assist CTN affiliated research staff in the identification, assessment, differentiation and reporting of adverse events and serious adverse events in behavioral research trials.

The target audience includes CTN members and interested members of the public.

Additional Resources:

• Download slides (pdf)

Abstract:

Human subjects protection policies developed for pharmaceutical trials are now being widely applied to psychosocial intervention studies. This study examined occurrences of serious adverse events (SAEs) reported in multicenter psychosocial trials of the National Institute on Drug Abuse Clinical Trials Network (protocols CTN-0004, -0005, -0006, and -0007). Substance-abusing participants (N=1,687) were randomized to standard care or standard care plus either contingency management or motivational enhancement. Twelve percent of participants experienced 1 or more SAEs during the 27,198 person-weeks of follow-up. Of the 260 SAEs recorded, none were judged by the data safety monitoring board to be study related, and there were no significant differences between experimental and control conditions in SAE incidence rates.

These data underscore the need to reconsider the rationale behind, and appropriate methods for, monitoring safety during psychosocial therapy trials.

Related protocols: CTN-0004, CTN-0005, CTN-0006, CTN-0007