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Abstract: While polysubstance use has consistently been associated with higher rates of relapse, few studies have examined subgroups with specific combinations and time course of polysubstance use (i.e., polysubstance use patterns). This study aimed to classify and compare polysubstance use patterns and their associations with relapse to opioid use in 2637 participants in three large opioid use disorder (OUD) treatment trials in the NIDA Clinical Trials Network (CTN-0027, CTN-0030, and CTN-0051). Researchers explored the daily patterns of self-reported substance use in the 28 days prior to treatment entry. Market basket analysis (MBA) and repeated measure latent class analysis (RMLCA) were used to examine the subgroups of polysubstance use patterns, and multiple logistic regression was used to examine associations between identified classes and relapse. MBA and RMLCA identified 34 “associations rules” and 6 classes, respectively. Specific combinations of polysubstance use and time course (high baseline use and rapid decrease of use prior to initiation) predicts a worse relapse outcome. MBA showed individuals who co-used cocaine, heroin, prescription opioids, and cannabis had a higher risk for relapse (OR=2.82, 95%CI=1.13, 7.03). In RMLCA, higher risk of relapse was observed in individuals who presented with high baseline prescription opioid (OR = 1.9, 95% CI = 1.3, 2.76) or heroin use (OR = 3.54, 95%CI = 1.86, 6.72), although use decreased in both cases prior to treatment initiation. Conclusions: Our analyses identified subgroups with distinct patterns of polysubstance use. Different patterns of polysubstance use differentially predict relapse outcomes. Interventions tailored to these individuals with specific polysubstance use patterns prior to treatment initiation may increase the effectiveness of relapse prevention. Related protocols: CTN-0027, CTN-0030, CTN-0051

Abstract:

Emergency clinicians are on the front lines of responding to the opioid epidemic and are leading innovations to reduce opioid overdose deaths through safer prescribing, harm reduction, and improved linkage to outpatient treatment. Currently, there are no nationally recognized quality measures or best practices to guide emergency department quality improvement efforts, implementation science researchers, or policymakers seeking to reduce opioid-associated morbidity and mortality. To address this gap, in May 2017, the National Institute on Drug Abuse’s Center for the Clinical Trials Network convened experts in quality measurement from the American College of Emergency Physicians’ (ACEP’s) Clinical Emergency Data Registry, researchers in emergency and addiction medicine, and representatives from federal agencies, including the National Institute on Drug Abuse and the Centers for Medicare & Medicaid Services. Drawing from discussions at this meeting and with experts in opioid use disorder treatment and quality measure development, we developed a multistakeholder quality improvement framework with specific structural, process, and outcome measures to guide an emergency medicine agenda for opioid use disorder policy, research, and clinical quality improvement.

Abstract:

Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for medical conditions, their addiction, withdrawal symptoms, or complications from injection drug use, such as soft tissue infections. ED-initiated buprenorphine has been shown to be effective in increasing patient engagement in treatment compared with brief intervention with a facilitated referral or referral alone. However, adoption into practice has lagged behind need. To address this implementation change, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice.

This article describes a study that is being conducted through the NIDA Clinical Trials Network (CTN-0099). A hybrid type III effectiveness-implementation study design is being used to evaluate the effectiveness of a standard educational dissemination strategy versus IF on implementation (primary) and effectiveness (secondary) outcomes in four urban, academic EDs. Sites start with a standard 60-minute “Grand Rounds” educational intervention describing the prevalence of ED patients with OUD, the evidence for opioid agonist treatment and for innovative interventions with ED-initiated buprenorphine, followed by a 1-year baseline evaluation period.

Using a modified stepped wedge design, sites are randomly assigned to the IF intervention, which is guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework to assess evidence, context, and facilitation-related factors impacting the adoption of ED-initiated buprenorphine.

During the 6 months of IF through the 1-year IF evaluation period, external facilitators will work with local stakeholders to tailor and refine a bundle of activities to meet the site’s needs. The primary analyses will compare the baseline evaluation period to the IF evaluation period (n=120 patients with untreated OUD enrolled during each period) on (1) rates of provision of ED-initiated buprenorphine by ED providers with referral for ongoing medication (implementation outcome) and (2) rates of patient engagement in addiction treatment on the 30th day after the ED visit (effectiveness outcome). Finally, researchers will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs.

Conclusions: The ED is rapidly being identified as a “24/7/365” site to combat the opioid crisis by offering access to medications for opioid use disorder treatment. Sustainable, evidence-based practice implementation is a complex and challenging process. This study has the potential to identify an implementation strategy that can be translated to other EDs, thereby increasing the adoption of ED-initiated buprenorphine into practice, narrowing the gap between OUD identification and treatment.

Related protocols: CTN-0099

Abstract:

Dysregulation of the stress response is implicated in drug addiction; therefore, polymorphisms in stress-related genes may be involved in this disease. Using samples from CTN-0051 (X:BOT), an analysis was performed to identify associations between variants in 11 stress-related genes, selected a priori, and heroin addiction. Two discovery samples of American subjects of European descent (EA, n = 601) and of African Americans (AA, n = 400) were analyzed separately. Ancestry was verified by principal component analysis. Final sets of 414 (EA) and 562 (AA) variants were analyzed after filtering of 846 high-quality variants. The main result was an association of a non-coding SNP rs255105 in the CRH (CRF) receptor 2 gene (CRHR2), in the discovery EA sample (Pnominal = .00006; OR = 2.1; 95% CI 1.4–3.1). The association signal remained significant after permutation-based multiple testing correction. The result was corroborated by an independent EA case sample (n = 364). Bioinformatics analysis revealed that SNP rs255105 is associated with the expression of a downstream long intergenic non-coding RNA (lincRNA) gene AC005154.6. AC005154.6 is highly expressed in the pituitary but its functions are unknown. LincRNAs have been previously associated with adaptive behavior, PTSD, and alcohol addiction.

Conclusions: Hypothesis-driven study of variants in stress-related genes and heroin addiction identified an association with non-coding SNP in the CRHR2 gene. A downstream lincRNA gene is a ciseQTL of this SNP and additional SNPs in the region. This result is intriguing since lincRNAs play a role in adaptive behavior and neurological diseases and are potential drug targets for stress-related disorders. Further studies are warranted to corroborate the association results and to assess the potential relevance of this lincRNA to addiction and other stress-related disorders.

Related protocols: CTN-0051, CTN-0051-A-1

Abstract:

Opioid use disorder (OUD) is a chronic, relapsing condition with severe negative health consequences. Previous studies have reported that 5-year abstinence is a good predictor of reduced likelihoods of relapse, but factors that shape long-term opioid abstinence are poorly understood.

The present study is based on data from a prospective study of 699 adults with OUD who had been randomized to either methadone or buprenorphine/naloxone and who were followed for at least 5 years (CTN-0050, Long Term Follow-Up of START Patients). During the 5 years prior to the participants’ last follow-up interview, 232 (33.2%) had achieved 5-year abstinence from heroin. Of those 232, 145 (20.7% of the total) had remained abstinent from both heroin and other opioids (e.g., hydrocodone, oxycodone, other opioid analgesics, excluding methadone or buprenorphine). Compared to non-abstinent individuals, those in both categories of opioid abstinence had lower problem severity in health and social functioning at the final follow-up. Logistic regression results indicated that cocaine users and injection drug users were less likely to achieve 5-year heroin abstinence, whereas Hispanics (vs. whites) and those treated in clinics on the West Coast (vs. East) were less likely to achieve 5-year abstinence from heroin and other opioids. For both abstinence category groups, abstinence was positively associated with older age at first opioid use, lower impulsivity, longer duration of treatment for OUD, and greater social support.

Conclusions: Given the current opioid crisis, this study contributes valuable information by identifying correlates of long-term opioid abstinence that are important for efforts to facilitate stable recovery. Reducing cocaine use and injection drug use and increasing social support and retention in treatment may help maintain long-term abstinence from opioids among individuals treated with agonist pharmacotherapy.

Related protocols: CTN-0050

Abstract:

Addressing multiple substance use disorders (SUDs) in primary care-based screening and intervention may improve SUD treatment access, engagement, and outcomes. To inform such efforts, research is needed on the prevalence and patterns of multiple SUDs among primary care patients. Data were analyzed from a sample of 2,000 adult (aged 18 or older) primary care patients recruited from a multisite NIDA Clinical Trials Network (CTN) study (CTN-0059). Past-year DSM-5 SUDs (tobacco, alcohol, and drug) were assessed by the modified Composite International Diagnostic Interview. Prevalence and correlates of multiple versus single SUDs were examined. Latent class analysis (LCA) was used to explore patterns of multiple SUDs.

Analysis revealed multiple SUDs among the majority of patients with SUD for alcohol, cannabis, prescription opioids, cocaine, and heroin. Participants who were male, ages 26-34, less educated, and unemployed had increased odds of multiple SUDs compared to one SUD. Having multiple SUDs was associated with greater severity of tobacco or alcohol use disorder. LCA of the sample identified three classes: class 1 (83.7%) exhibited low prevalence of all SUDs; class 2 (12%) had high-moderate prevalence of SUDs for tobacco, alcohol, and cannabis; class 3 (4.3%) showed high prevalence of SUD for tobacco, opioids, and cocaine. LCA-defined classes were distinguished by sex, age, race, education, and employment status.

Conclusions: Findings suggest that multiple SUDs are the norm rather than the exception among primary care patients with SUD. Primary care physicians should be aware of multiple SUDs when planning treatment, especially among adults who are male, younger, less educated, or unemployed. However, it should be noted that the treatment and management of multiple SUDs and other associated comorbidities may be out of the scope of expertise for many primary care physicians. This argues for the need of additional approaches to address SUD in primary care, such as the development of coordinated care models and linkage services to improve access to specialty care and follow-up of clinical outcomes.

Related protocols: CTN-0059

Abstract:

This study is a secondary descriptive analysis that explores and compares the cognitive profiles of adults entering treatment at geographically diverse community-based substance use disorder treatment facilities. Performance on cognitive measures at baseline was compared across 5 primary substance subgroups of individuals (alcohol=104; cocaine=102; stimulants=69; opioids=108; marijuana=114) enrolled in a web-based psychosocial treatment study conducted within the NIDA Clinical Trials Network (protocol CTN-0044, “Web Delivery of Evidence-Based, Psychosocial Treatment for Substance Use Disorders”). Microcog subtests were used to assess cognitive domains of attention and mental control, reasoning and cognitive flexibility, and spatial processing.

The average age of onset for a substance use disorder was early to mid-20s, with marijuana users reporting the earliest age of onset (mean 19.9, SD 7.5) and stimulant users reporting the latest (mean 25.2, SD 9.9). Among the total sample, half (49.7%) demonstrated impairment in cognitive flexibility and reasoning, and over one-third (37.3%) had impairment in verbal learning and memory. Stimulant (37.68%) and cocaine (34.31%) users showed significantly greater clinical impairment in attention and mental control compared with alcohol users (17.31%) and opioid (21.3%) users (stimulant subgroup only). Cocaine users showed the greatest overall impairment across total and proficiency subtest scores, although these were not statistically different from other subgroups.

Conclusions: These findings confirmed previous studies, indicating a high prevalence of significant cognitive dysfunction across all substance use categories among treatment-seeking adults, and found that cocaine use appears to be associated with the most impairment. Increasing knowledge of similarities and differences between primary substance subgroups can help guide substance use disorder treatment planning.

Related protocols: CTN-0044

Abstract:

This is the primary outcomes article for CTN-0051.

Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. This study in the NIDA Clinical Trials Network (CTN-0051) aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.

This 24-week, open-label, randomized controlled, comparative effectiveness trial was initiated at eight U.S. community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had opioid use disorder as defined by the DSM-5, and had used non-prescribed opioids in the past 30 days. Participants were stratified by treatment site and opioid use severity and a web-based permuted block design was used with random equally weighted block sizes of 4 and 6 for randomization (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcomes was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.

Between January 30, 2014 and May 25, 2016, 570 participants were randomly assigned to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was January 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283; p<0.0001) than BUP-NX (270 [94%] of 287). Among all participants who were randomly assigned (intention-to-treat population, n=570), 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10–1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.

Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0.44). Opioid-negative urine samples (p<0.0001) and opioid-abstinent days (p<0.0001) favored BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0.0012), then converged by week 24 (p=0.20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (2 in the XR-NTX group and 3 in the BUP-NX group).

Conclusions: In this population, it is more difficult to initiate patients to XR-NTX than to BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.

Related protocols: CTN-0051

Abstract:

The multi-site Prescription Opioid Addiction Treatment Study (POATS), conducted by the NIDA Clinical Trials Network, was the largest clinical trial yet conducted with patients dependent on prescription opioids (N=653). In addition to main trial results, the study yielded numerous secondary analyses, and included a 3.5-year follow-up study, the first of its kind with this population. This paper summarizes the POATS design, main outcomes, predictors of outcome, subgroup analyses, the predictive power of early treatment response, and the long-term follow-up study.

POATS examined combinations of buprenorphine-naloxone of varying duration and counseling of varying intensity. The primary outcome analysis showed no overall benefit to adding drug counseling to buprenorphine-naloxone and weekly medical management. Only 7% of patients achieved a successful outcome (abstinence or near-abstinence from opioids) during a 4-week taper and 8-week follow-up; by comparison, 49% of patients achieved success while subsequently stabilized on buprenorphine-naloxone.

Long-term follow-up results were more encouraging, with higher abstinence rates than in the main trial. Patients receiving opioid agonist treatment at the time of follow-up were more likely to have better outcomes, though a sizeable number of patients succeeded without agonist treatment. Some patients initiated risky use patterns, including heroin use and drug injection. A limitation of the long-term follow-up study was the low follow-up rate.

Conclusions: POATS was the first large-scale study of the treatment of prescription opioid dependence; its findings can influence both treatment guidelines and future. In particular, the results of POATS suggest support for an individualized approach to behavioral interventions in the context of buprenorphine-naloxone treatment of prescription opioid use disorders. The fact that some patients benefited from counseling (heroin users who attended sessions regularly, for example) suggests that some patients would do well with just medical management and others should receive additional counseling.

Related protocols: CTN-0030

Abstract:

There are limited data about the extent of DSM-5 substance use disorders (SUDs) among primary care patients. This study analyzed data from a multisite validation study of a substance use screening instrument conducted in a diverse sample of 2,000 adults aged 18 or older recruited from five primary care practices in four states, NIDA Clinical Trials Network protocol CTN-0059, the TAPS Tool study. Prevalence and correlates of 12-month DSM-5 SUDs were examined. Results found that overall, 75.5% of the sample used any substance, including alcohol (62%), tobacco (44.1%), or illicit drugs/nonmedical medications (27.9%) in the past 12 months (marijuana 20.8%, cocaine 7.3%, opioids 4.8%, sedatives 4.1%, heroin 3.9%). The prevalence of any 12-month SUD was 36% (mild disorder 14.2%, moderate/severe disorder 21.8%): tobacco 25.3% (mild 11.5%, moderate/severe 13.8%); alcohol 13.9% (mild 6.9%, moderate/severe 7%); and any illicit/nonmedical drug 14% (mild 4%, moderate/severe 10%). Among past 12-month users, a high proportion of tobacco and drug users met criteria for a disorder: tobacco use disorder 57.4% (26.1% mild, 31.3% moderate/severe) and any drug use disorder 50.2% (14.3% mild, 35.8% moderate/severe); a lower proportion of alcohol users (22.4%) met criteria for alcohol use disorder (11.1% mild, 11.3% moderate/severe). Over 80% of adults with opioid/heroin use disorder met criteria for a moderate/severe disorder. Younger ages, male sex, and low education were associated with increased odds of having SUD.

Conclusions: Given the national movement toward the integration of primary care and SUD treatment, these findings have implications for clinical practice. Twelve-month SUDs were prevalent among primary care patients in this sample, which highlights a need to improve primary care providers’ training and willingness to provide screening and treatment for SUD. To improve that integration, research is needed to inform primary care physicians’ willingness to use validated tools for screening substance misuse, identify effective approaches for addressing SUDs in medical settings, and engage patients into SUD treatment.

Related protocols: CTN-0059

Abstract:

This is the Results Article for CTN-0066-Ot.

Elevated mortality has been observed among individuals with opioid use disorder (OUD) treated in addiction specialty clinics or programs. Information about OUD patients in general healthcare settings is needed in light of the current effort to integrate addiction services into primary healthcare systems. This study examined mortality rates, causes of death, and associated risk factors among patients with OUD in a large general healthcare system. Mortality data were linked with the electronic health records of 1,683 OUD patients cared for in a large university health system from 2006-2014 (UCLA of the former CTN Pacific Region Node).

There were 465 deaths confirmed (27.6% of the study participants), corresponding to a crude mortality rate of 68.7 per 1000 person-years and SMR of 15.9 (95% CI, 14.5-17.4). Drug overdose and disorder (19.4%), cardiovascular diseases (16.9%), cancer (16.3%), and infectious diseases (14.5%, including 12% hepatitis C virus [HCV]) were the leading causes of death. HCV (HR: 2.08, 95% CI, 1.68-2.59) and cannabis use disorder (HR: 1.63, 95% CI, 1.28-2.07) were two clinically important indicators of overall mortality risk. Chronic pain (AHR: 1.92, 95% CI, 1.16-3.19) and tobacco use disorder (AHR: 2.88; 95% CI, 1.80-4.63) were associated with increased risk of cardiovascular death, HCV infection with cancer mortality risk (AHR: 2.51, 95% CI, 1.47-4.28), and alcohol use disorder with liver-related mortality risk (AHR: 5.06, 95% CI, 2.72-9.42).

Conclusions: Patients with OUD in a general healthcare system demonstrated alarmingly high morbidity and mortality, which challenges health care systems to find innovative ways to identify and treat patients with substance use disorder. Given the chronic, relapsing nature of OUD, and high medical and psychiatric comorbidity, continued care encompassing screening, early intervention, support, and monitoring is essential.

Related protocols: CTN-0066-Ot

Abstract:

This study compared the cause-specific standardized mortality ratios (SMRs) and expected years of life lost (EYLL) among opioid-dependent individuals in the United States and Taiwan. Survival data came from two cohorts followed until 2014: The U.S. data were based on a randomized trial of 1267 opioid-dependent participants enrolled between 2006 and 2009, the CTN START study (CTN-0027); the Taiwan data were from a study of 983 individuals that began in 2006, when opioid agonist treatment (OAT) was implemented in Taiwan. SMRs were calculated for each national cohort and compared. Kaplan-Meier estimation was performed on the survival data, then lifespans were extrapolated to 70 years (840 months) to estimate life expectancy using a semi-parametric method. EYLLs for both cohorts were estimated by subtracting their life expectancies from the age- and gender-matched referents within the general population of their respective country.

Compared with age- and gender-matched references, the SMRs were 3.2 for the U.S. sample and 7.8 for the Taiwan sample; the EYLLs were 7.7 and 16.4 years, respectively. Half of decedents died of unnatural causes in both cohorts; overdose deaths predominated in the U.S. and suicide in Taiwan (with suicide mortality among the Taiwan OAT group 20 times greater than that of the U.S. START group).

Conclusions: Despite different contexts in two vastly different countries, the current estimates of EYLL highlight that opioid dependence and its associated comorbidities and risk factors still contribute severe health burdens across regions. This comparison of cause-specific SMRs could inform stakeholders as they make health policy modifications relevant to their region. Given the prominent role of overdose in the U.S. START cohort, improving access to medication-assisted treatment to prevent overdoses or naloxone to treat them will help address the problem. Suicide is preventable; intervention strategies, including regular screening of ideation and depressive symptoms and providing treatment and support among opioid users in OAT treatment, are urgently needed in Taiwan.

Related protocols: CTN-0027

Abstract:

Uncovering heterogeneities in longitudinal patterns (trajectories) of opioid use among individuals with opioid use disorder can increase our understanding of disease progression and treatment responses to improve care. The present study aims to identify distinctive opioid use trajectories and factors associated with those patterns among participants randomized to treatment with methadone (MET) or buprenorphine + naloxone (BUP). Growth mixture modeling was applied to identify distinctive opioid use trajectories among 795 opioid users after their enrollment in CTN-0027 (CTN START trial), a multisite trial during 2006 to 2009, with follow-up interviews conducted during 2011 to 2014 (CTN-0050 START Follow-up trial).

Four distinctive trajectories were identified based on opioid use over the follow-up period: low use (42%), high use (22.3%), increasing use (17.1%), and decreasing use (18.6%). Greater odds of being in the high use group (relative to low use) was associated with Hispanics (relative to African American, odds ratio [OR] 3.21), injection drug use (OR 2.12), higher mental health functioning at baseline (OR 1.23), location on the West Coast (vs. East Coast, OR 2.15), and randomization to BUP (relative to MET, OR 1.53). High use and increasing use groups had greater severity in problems related to drug, employment, legal, and social/family relationships, and worsened mental health functioning at follow-up. Participation in treatment significantly accounted for both within and between-group differences in opioid use.

A very promising finding is that the largest group (more than 40% of the sample) demonstrated a consistently low level of use after entering the medication trial. In contrast, approximately 17% of the participants gradually increased their opioid use after they initially reduced use, and another 19% did not respond well initially, but gradually decreased use over time.

Conclusions: The study findings underscore the importance of keeping opioid-dependent individuals in treatment and making treatment more widely available and accessible. Identifying factors that may account for distinctive opioid use trajectory patterns can further information policy decisions and clinic practice in targeting those at greatest need for opioid treatment.

Related protocols: CTN-0027, CTN-0050

Abstract:

This article discusses ethical challenges encountered in the design of an effectiveness trial (CTN-0051, X:BOT), comparing sublingual buprenorphine-naloxone (BUP-NX), an established treatment for opioid dependence, to the newer extended-release injectable naltrexone (XR-NTX). Ethical issues surrounded:

1) Known poor effectiveness of one possible, commonly used Treatment as Usual control condition — detoxification followed by counseling without medication;

2) The role of patients’ preferences for treatments, given that treatments were clinically approved and available to the population;

3) Differences between the optimal “usual treatment” clinical settings for different treatments making it challenging to design a fair comparison;

4) Vested interest groups favoring different treatments exerting potential influence on the design process;

5) Potentially vulnerable populations of substance users and prisoners;

6) Potential therapeutic misconception in the implementation of safety procedures; and

7) High cost of a large trial limited questions that could be addressed.

The authors examine how the design features underlying these ethical issues are characteristic of effectiveness trials, which are often large trials that compare treatments with varying degrees of existing effectiveness data and familiarity to patients and clinicians, in community-based treatment settings, with minimal exclusion criteria that could involve vulnerable populations. Hence, investigators designing effectiveness trials may wish to remain alert to the possibility of similar ethical issues.

Related protocols: CTN-0051

Abstract:

The use of blinding in trials is an established element of study design, intended to minimize bias and expectation effects and strengthen the internal validity of the results. The goal of the current analysis was to assess participants’ perceptions of their blinded treatment assignment and examine whether these perceptions were associated with the primary outcome results of the trial. Perceived treatment assignment was evaluated in the NIDA Clinical Trials Network (CTN) trial “Cocaine Use Reduction with Buprenorphine (CURB)” at the the end of active medication. Participants were randomly assigned to 1 of 3 conditions: 16mg buprenorphine+naloxone (BUP16), 4mg (BUP4), placebo (PLB), plus cognitive behavioral therapy and extended-release naloxone (XR-NTX). Data was available for 281/302 participants (93%). 57% of participants had an opinion regarding their assignment and 43% were unsure. Of those who had an opinion, 46% guessed correctly. There was no association with actual treatment group. In the BUP16 arm, 55% guessed correctly, 44% in the BUP4 arm, and 39% in the PLB arm. Perceived treatment assignment was not related to the primary outcome (self-reported cocaine use combined with urine drug screens during last 30 days of medication) or the number of cocaine-negative UDS collected during that period. The fewest average number of days of cocaine use was 6.4 for participants who believed they got BUP16; the greatest was for PLB at 8.0 days. These differences were not significant. There was no difference in the number of cocaine-negative UDS across perceived treatment.

Conclusions: This secondary analysis showed that the blind was maintained in CURB. Participants who speculated about their arm were no more likely to be correct than by chance. This finding increases the confidence in the validity of trial results. Further examination revealed no association with cocaine abstinence.

Related protocols: CTN-0048