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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:

Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD.

The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine.

Conclusions: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue.

Related protocols: CTN-0100

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:

Buprenorphine-naloxone (BUP-NLX) can be used to manage prescription opioid addiction among persons with chronic pain, but post-treatment relapse is common and difficult to predict. This study, a secondary analysis of data from the CTN’s Prescription Opioid Addiction Treatment Study (POATS), estimated whether changes in pain over time and pain volatility during BUP-NLX maintenance would predict opioid use during the BUP-NLX taper. Study participants, from community clinics affiliated with POATS in 10 U.S. cities, were subjects with chronic pain who entered the BUP-NLX taper phase (N=125), with enrollment occurring from June 2006 to July 2009 (52% male, 88% Caucasian, 31% married). Outcomes were weekly biologically-verified and self-reported opiate use from the 4-week taper phase. Predictors were estimates of baseline severity, rate of change, and volatility in pain from weekly self-reports during the 12-week maintenance phase.

Controlling for baseline pain and treatment condition, increased pain and greater pain volatility predicted greater odds of positive opioid urine screen during BUP-NLX taper. Increased pain and greater pain volatility also predicted greater frequency of self-reported opioid use.

Conclusions: Adults with chronic pain receiving outpatient treatment with buprenorphine-naloxone (BUP-NLX) for prescription opioid addiction have elevated risk for opioid use when tapering off maintenance treatment. Those with relative persistence in pain over time and greater volatility in pain during treatment are less likely to sustain abstinence during BUP-NLX taper. These findings suggest that stabilizing and/or reducing subjective pain prior to discontinuation of BUP-NLX maintenance may be a means to improve treatment outcomes in this population.

Related protocols: CTN-0030

Abstract:

The Clinical Opiate Withdrawal Scale (COWS) is used to assess withdrawal in clinical trials and practice. The aims of this study were to examine the inter-item correlations and factor structure of the COWS in opioid-dependent men and women. This is a secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network study CTN-0003, a randomized clinical trial that compared buprenorphine/naloxone tapering strategies. The trial included 11 sites in 10 US cities. Participants were opioid-dependent individuals (n=516) that had data on the COWS. The COWS at study baseline was analyzed in the study. Inter-item correlations showed weak to moderate relationships between the items. A 1-factor model did not fit the data for men, where resting pulse rate was not related to withdrawal for men, and yawning and gooseflesh skin was not related to withdrawal for women. A reduced model comprised of only the 8 items that were significantly related to the construct of withdrawal in both men and women, and an exploratory 2-factor model, were also assessed but not retained due to inconsistencies across gender.

Conclusions: This study failed to find a single model where all items were related to the construct of withdrawal (i.e., statistically significant meaningful factor loadings) for men and women in mild withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples, particularly in samples with greater variation in COWS scores and for those in moderate opioid withdrawal, is needed. The COWS was developed to rate severity within each item because that corresponds with clinical severity within the individual on each item; that may not be necessarily the case across items. The composite score simply acknowledges that some individual will show more, or less, withdrawal symptoms within certain physiological systems and may therefore not assess a single construct of withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples is needed.

Related protocols: CTN-0003

Abstract:

This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0003 (“Suboxone (Buprenorphine/Naloxone) Taper: A Comparison of Taper Schedules”) compared three missing data strategies: 1) Latent growth model that assumes the data are missing at random (MAR), 2) Diggle-Kenward missing not at random (MNAR) model where dropout is a function of previous/concurrent urinalysis (UA) submissions, and 3) Wu-Carroll MNAR model where dropout is a function of the growth factors. CTN-0003 examined a 7-day versus 28-day taper for buprenorphine/naloxone to see which taper schedule reduced the likelihood of submitting an opioid-positive UA during treatment.

The MAR model showed a significant effect (B=-0.45, p <0.05) of trial arm on the opioid-positive UA slope (i.e., 28-day taper participants were less likely to submit a positive UA over time) with a small effect size (d=0.20). The MNAR Diggle-Kenward model demonstrated a significant (B=-0.64, p<0.01) effect of trial arm on the slope with a large effect size (d=0.82). The MNAR Wu-Carroll model evidenced a significant (B=-0.41, p<0.05) effect of trial arm on the UA slope that was relatively small (d=0.31).

Conclusions: This performance comparison of three missing data strategies (latent growth model, Diggle-Kenward selection model, Wu-Carrol selection model) on sample data indicates a need for increased use of sensitivity analyses in clinical trial research. Given the potential sensitivity of the trial arm effect to missing data assumptions, it is critical for researchers to consider whether the assumptions associated with each model are defensible.

Abstract:

Most patients relapse to opioids within one month of opioid agonist detoxification, making the antecedents and parallel processes of first use critical for investigation. Craving and withdrawal are often studied in relationship to opioid outcomes, and a novel analytic strategy applied to these two phenomena may indicate targeted intervention strategies. Specifically, this secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study (POATS, CTN-0030) used a discrete-time mixture analysis with time-to-first opioid use (survival) simultaneously predicted by craving and withdrawal growth trajectories. This analysis characterized heterogeneity among prescription opioid-dependent individuals (N=653) into latent classes (i.e., latent class analysis [LCA]) during and after buprenorphine/naloxone stabilization and taper. A 4-latent class solution was selected for overall model fit and clinical parsimony. In order of shortest to longest time-to-first use, the 4 classes were characterized as 1) high craving and withdrawal; 2) intermediate craving and withdrawal; 3) high initial craving with low craving and withdrawal trajectories; and 4) a low initial craving with low craving and withdrawal trajectories. Odds ratio calculations showed statistically significant differences in time-to-first use across classes.

Conclusions: Generally, participants with lower baseline levels and greater decreases in craving and withdrawal during stabilization combined with slower craving and withdrawal rebound during buprenorphine taper remained opioid-free longer. This exploratory work expanded on the importance of monitoring craving and withdrawal during buprenorphine induction, stabilization, and taper. Future research may allow individually tailored and timely interventions to be developed to extent time-to-first opioid use.

Related protocols: CTN-0030

Abstract:

Despite the high prevalence of prescription opioid dependence in the U.S., little is known about the course of this disorder and the long-term response to treatment. This study examined 18-month post-randomization outcomes of participants in the National Drug Abuse Treatment Clinical Trials Network (CTN) Prescription Opioid Addiction Treatment Study (POATS), a multi-site, randomized controlled trial examining varying durations of buprenorphine-naloxone treatment and different intensities of counseling for prescription opioid dependence. Participants from the treatment trial (N=252/653) completed an 18-month follow-up telephone assessment. Multivariable analyses examined associations between participant characteristics and key indicators of month-18 status: opioid abstinence, DSM-IV opioid dependence, and opioid agonist treatment.

Overall, participants showed improvement from baseline to month 18: 49.6% were abstinent in the previous 30 days, with only 16.3% opioid-dependent. Some participants, however, had initiated past-year heroin use (n=9) or opioid injection (n=17). Most participants (65.9%) engaged in substance use disorder treatment during the past year, most commonly opioid agonist therapy (48.8%). Of particular interest in this population, multivariable analysis showed that greater pain severity at baseline was associated with opioid dependence at 18 months.

Conclusions: This follow-up study provides a unique contribution to the field by reporting longer-term outcomes of a well-characterized population of treatment-seeking prescription opioid dependent patients. Although opioid use outcomes during the treatment trial were poor immediately following a buprenorphine-naloxone taper compared to those during 12 weeks of buprenorphine-naloxone stabilization, opioid use outcomes at 18-month follow-up showed substantial improvement over baseline and were comparable to the rate of successful outcomes during buprenorphine-naloxone stabilization in the treatment trial.

Related protocols: CTN-0030, CTN-0030-A-3

Abstract:

The prevalence of hepatitis-C-virus (HCV) infections is high among opioid-dependent individuals. Prior research on the simultaneous treatment of both conditions has primarily assessed success as it pertains to HCV. However, it has been noted that favorable substance use therapy outcomes may improve the likelihood of HCV-treatment initiation and success. Therefore, current guidelines for the treatment of HCV among illicit drug users suggest that treatment for addiction be given the highest priority. This study aimed to determine whether opioid-dependent participants in a clinical trial of buprenorphine-treatment tapering regimens, who tested positive for the HCV antibody, experienced significantly different levels of opioid abstinence than those not infected. Data came from the National Drug Abuse Treatment Clinical Trials Network study CTN-0003, which compared two taper schedules for buprenorphine-naloxone (one rapid and one gradual, n=516). Participants with the HCV antibody were significantly less likely to submit opioid-negative urine analyses during and/or immediately following active treatment, indicating a higher rate of opioid use among this group.

Conclusions: Individualized opioid-dependence treatment strategies may be required for opioid-dependent individuals who test positive for the HCV antibody in order to ensure resources for both opioid-dependence and HCV therapies are used efficiently.

Abstract:

Using data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0003, “Suboxone Taper: A Comparison of Taper Schedules,” this study examined predictors of opiate abstinence status 3 months after the end of buprenorphine/naloxone treatment for opioid-dependent participants. Participants (n=516, age > 15 years), received buprenorphine/naloxone treatment for 4 weeks and then were randomly assigned to undergo dose tapering over either 7 or 28 days. Bivariate analysis was performed to identify possible predictors of successful opiate abstinence outcome (p-value < 0.10). Logistic regression analysis with backward stepwise selection was then performed to produce final model containing independent predictors at p-value < 0.05. Bivariate analysis identified several possible predictors, including: opioid and drug urine tests result at the end of taper; employment status, family problems, and alcohol use domains of the Addiction Severity Index (ASI) score; and the Clinical Opiate Withdrawal Scale (COWS) at the end of stabilization. The final predictor list identified by logistic regression included: ASI domains for family and alcohol problems, COWS at the end of stabilization, and opiate urine test at the end of taper.

Conclusions: In this analysis, participants presenting with a negative urine test for opiates at the end of the taper period, more severe alcohol or family problems (contrary to previous studies), or fewer symptoms of opiate withdrawal at the end of stabilization were more likely to have successful opiate abstinence.

Related protocols: CTN-0003

Abstract:

Dependence on prescription opioids (PO) is a growing problem. Although most research with buprenorphine has focused on heroin-dependent populations, the authors hypothesize that individuals dependent on PO display characteristics that may predict different outcomes in treatment, particularly in short-term taper procedures in which comorbidities such as pain conditions may complicate taper. This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0003 (Suboxone Taper: A Comparison of Taper Schedules) examined differences in outcomes between PO users (n=90) and heroin users (n=426) after a buprenorphine taper. After a 4-week buprenorphine induction/stabilization phase, 516 opioid-dependent individuals were randomized into 1 of 2 taper lengths (7 vs 28 days) to assess the association between taper length and outcome. The primary outcome was measured by urine drug test for opioids at the end of the taper period. Craving, withdrawal, and buprenorphine dose were also examined. After controlling for baseline demographic and drug use differences between the opioid use groups, results indicate that a higher percentage of the PO group (49%) provided an opioid-free urine drug specimen at the end of taper compared with the heroin group (36%; [chi]21 = 6.592, P < 0.010).

Conclusions: Although buprenorphine taper is not recommended as a stand-alone treatment, there are clinical scenarios where it may be required to taper a patient off buprenorphine, making the findings of this study an important addition to the evidence base in the management of PO dependence with buprenorphine. Results of this secondary analysis additionally confirm the main study’s findings that there seems to be no benefit in prolonging the taper period for PO users beyond 7 days. Should a taper be indicated for a medical reason (for example, for opioid rotation for pain management, or to commence and extended-release naltrexone injection), a 7-day taper seems to be an appropriate schedule. Further studies are required to examine longer-term treatment outcomes.

Related protocols: CTN-0003

Abstract:

Using buprenorphine as a medication to treat opioid dependence is becoming more prevalent as illicit opiate use increases. Identifying the characteristics of opiate dependent individuals best suited to benefit from buprenorphine would improve guidelines for its administration. This ancillary investigation of data from National Drug Abuse Treatment Clinical Trials Network (CTN) protocol CTN-0003 (“Suboxone (Buprenorphine/Naloxone) Taper : A Comparison of Taper Schedules”) evaluates baseline and treatment participation variables for predicting positive response to short-term stabilization with buprenorphine. Data include demographic, drug use, and other variables collected from participants undergoing stabilization over a 4-week period before being tapered off buprenorphine in a short-term detoxification process as part of CTN-0003. Outcome variables include opioid use and retention. Several characteristics were associated with opioid use at the end of the stabilization period, including age, criminal history, and previous opioid use. In particular, criminal activity and opioid use in the last 30 days were significantly associated with shorter treatment stays.

Conclusions: The findings from this study have important clinical applications for treatment providers, specifically providing information for those who offer buprenorphine treatment to opiate-dependent patients. Treatment providers and private practice clinicians may find it useful to know that positive outcomes may be likely when using buprenorphine for short-term treatment in some patients. For example, these findings show that those with more severe withdrawal symptoms at baseline do not experience higher levels of drop out or continued opiate use. Conversely, these findings have identified those for whom this short-term treatment with buprenorphine may not be successful such as those who use opioids more often, have a previous treatment experience, and have a criminal justice history. These findings support previous study results demonstrating that those with more severe drug use and less social stability are less likely to have positive treatment outcomes.

Related protocols: CTN-0003

Abstract:

This presentation begins with an overall examination of the prevalence of prescription opioid dependence and its societal/public health consequences. In 2010, 5.1 million people over 12 years of age used prescription opioids non-medically within the previous month (1.7% of the population). Almost half of those people were new users, the second largest number of past year initiates of any drug (second only to marijuana by about 400,000 people). The presentation then goes on to describe the design, methodology, and outcomes of the National Drug Abuse Treatment Clinical Trials Network (CTN) protocol CTN-0030, “Prescription Opioid Addiction Treatment Study (POATS).” This study’s main objective was to determine whether the addition of individual drug counseling to the prescription of buprenorphine/naloxone and standard medical management (SMM) improves outcome. After the study’s completion, researchers found that prescription opioid-dependent patients are most likely to reduce opioid use during buprenorphine/naloxone treatment. However, tapering from buprenorphine/naloxone, whether initially or after a period of substantial improvement, led to nearly universal relapse, even in patients receiving counseling in addition to standard medical management. Implications for social workers are presented, along with suggested resources for more information.

Related protocols: CTN-0030

Abstract:

Two common procedures for the treatment of missing information, listwise deletion and positive urine analysis (UA) imputation (e.g., if the participant fails to provide urine for analysis, then score the UA positive), may result in significant biases during the interpretation of treatment effects. To compare these approaches and to offer a possible alternative, these two procedures were compared to the multiple imputation (MI) procedure with publicly available data from a recent clinical trial (National Drug Abuse Treatment Clinical Trials Network protocol CTN-0003, Ling et al, 2009). Listwise deletion, single imputation (i.e., positive UA imputation), and MI missing data procedures were used to comparatively examine the effect of the protocol’s two different buprenorphine/naloxone tapering schedules (7- or 28-days) for opioid addiction on the likelihood of a positive UA. The listwise deletion of missing data resulted in a nonsignificant effect for the taper while the positive UA imputation procedure resulted in a significant effects, replicating the original findings by Ling et al (2009). Although the MI procedure also resulted in a significant effect, the effect size was meaningfully smaller and the standard errors meaningfully larger when compared to the positive UA procedure. This study demonstrates that the researcher can obtain markedly different results depending on how the missing data are handled. Missing data theory suggests that listwise deletion and single imputation procedures should not be used to account for missing information, and that MI has advantages with respect to internal and external validity when the assumption of missing at random can be reasonably supported. Consistent with previous investigation of missing data in substance abuse treatment, the authors encourage researchers to understand and report the missing data mechanism as well as use newer procedures for the treatment of missing information (i.e., MI or direct maximum likelihood procedures) that are based on a research-specified “best estimate” of the missing values.

Related protocols: CTN-0003

Abstract:

Clinical parameters for determining buprenorphine dose have not been adequately examined in treatment outcome research. This study is a secondary analysis of data collected from National Drug Abuse Treatment Clinical Trials Network (CTN) protocol CTN-0003, a recently completed comparison of buprenorphine taper schedules designed to assess whether participant baseline characteristics are associated with buprenorphine dose. For this ancillary investigation, 516 participants were categorized by dose provided in the final dosing week after 3 weeks of flexible dosing (9.3% received a final week dose of 8 mg buprenorphine, 27.3% received 16 mg, and 63.4% received 24 mg). Findings show that final week dose groups differed in baseline demographic and drug use characteristics including education, heroin use, route of drug administration, withdrawal symptoms, and craving. These groups also differed in opioid use during the four dosing weeks, with the lowest use in the 8 mg group and highest use in the 24 mg group (p < .0001). A significant association was also found between final week dose group and withdrawal and craving. Participants with greater withdrawal symptoms and craving scores had larger final week doses.

Conclusions: Final week dose groups in this investigation differed in demographic and drug use characteristics, and the group receiving the largest final week dose had the highest rate of continued opioid use. These findings may contribute to the development of clinical guidelines regarding buprenorphine dose in the treatment of opioid dependence; however, further investigations that include random assignment to dose by baseline characteristics are needed. Methods for determining optimal buprenorphine dose will be extremely helpful in clinical settings in which physicians currently have no formal tools for determining appropriate dosages.

Related protocols: CTN-0003