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Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.

ABSTRACT: Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX.We compared rates of alanine aminotransferase (ALT) elevation?grade 3 (ALT?5.1 times the upper limit of normal) and graded bilirubin elevations in HIV-negative opioid injectors randomized to long-term (52 weeks) or short-term (18 days) medication assisted treatment (LT-MAT and ST-MAT, respectively) with BUP/NX in a multisite trial conducted in China and Thailand. ALT and bilirubin were measured at baseline, 12, 26, 40 and 52 weeks, times temporally remote from BUP/NX exposure in the ST-MAT participants.Among1036 subjects with at least one laboratory follow-up measurement, 76 (7%) participants experienced ALT elevation?grade 3. In an intent-to-treat analysis, the risk of ALT events was similar in participants randomized to LT-MAT compared with ST-MAT (adjusted hazard ratio 1.25, 95% confidence interval 0.79 to 1.98). This finding was supported by an as-treated analysis, in which actual exposure to BUP/NX was considered. Hepatitis C seroconversion during follow-up was strongly associated with ALT events. Bilirubin elevations?grade 2 occurred in 2% of subjects, with no significant difference between arms.Over 52-week follow-up, the risk of hepatotoxicity was similar in opioid injectors receiving brief and prolonged treatment with BUP/NX. These data suggest that most hepatotoxic events observed during treatment with BUP/NX are due to other factors.

SUBMITTER: Lucas GM

PROVIDER: S-EPMC4127183 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.

Lucas Gregory M GM Young Alicia A Donnell Deborah D Richardson Paul P Aramrattana Apinun A Shao Yiming Y Ruan Yuhua Y Liu Wei W Fu Liping L Ma Jun J Celentano David D DD Metzger David D Jackson J Brooks JB Burns David D

Drug and alcohol dependence 20140619

<h4>Background</h4>Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX.<h4>Methods</h4>We compared rates of alanine aminotransferase (ALT) elevation≥grade 3 (ALT≥5.1 times the upper limit of normal) and graded bilirubin elevations in HIV-negative opioid injectors randomized to long-te ...[more]

PMID: 24999060

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Project description:Initial medication response has been shown to predict treatment outcome across a variety of substance use disorders, but no studies have examined the predictive power of initial response to buprenorphine-naloxone in the treatment of prescription opioid dependence. We therefore conducted a secondary analysis of data from the Prescription Opioid Addiction Treatment Study to determine whether initial response to buprenorphine-naloxone predicted 12-week treatment outcome in a prescription opioid-dependent population.Using data from a multisite, randomized controlled trial of buprenorphine-naloxone plus counseling for DSM-IV prescription opioid dependence (June 2006-July 2009), we conducted a secondary analysis to investigate the relationship between initial medication response and 12-week treatment outcome to establish how soon the efficacy of buprenorphine-naloxone could be predicted (N = 360). Outcomes were determined from the Substance Use Report, a self-report measure of substance use, and confirmatory urinalysis. Predictive values were calculated to determine the importance of abstinence versus use at various time points within the first month of treatment (week 1, weeks 1-2, 1-3, or 1-4) in predicting successful versus unsuccessful treatment outcome (based on abstinence or near-abstinence from opioids) in the last 4 weeks of buprenorphine-naloxone treatment (weeks 9-12).Outcome was best predicted by medication response after 2 weeks of treatment. Two weeks of initial abstinence was moderately predictive of treatment success (positive predictive value = 71%), while opioid use in both of the first 2 weeks was strongly predictive of unsuccessful treatment outcome (negative predictive value [NPV] = 84%), especially when successful outcome was defined as total abstinence from opioids in weeks 9-12 (NPV = 94%).Evaluating prescription opioid-dependent patients after 2 weeks of buprenorphine-naloxone treatment may help determine the likelihood of successful outcome at completion of the current treatment regimen.ClinicalTrials.gov identifier: NCT00316277.

Project description:ContextThe usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful.ObjectiveTo evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth.Design, setting, and patientsClinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox).InterventionsPatients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling.Main outcome measureOpioid-positive urine test result at weeks 4, 8, and 12.ResultsThe number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (chi(2)(2) = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; chi(2)(1) = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (chi(2)(1) = 18.45, P < .001), less injecting (chi(2)(1) = 6.00, P = .01), and less nonstudy addiction treatment (chi(2)(1) = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested negative for hepatitis C at baseline were positive for hepatitis C at week 12.ConclusionsContinuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification. Further research is necessary to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence.Trial registrationclinicaltrials.gov Identifier: NCT00078130.

Project description:IMPORTANCE:Opioid-dependent patients often use the emergency department (ED) for medical care. OBJECTIVE:To test the efficacy of 3 interventions for opioid dependence: (1) screening and referral to treatment (referral); (2) screening, brief intervention, and facilitated referral to community-based treatment services (brief intervention); and (3) screening, brief intervention, ED-initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine). DESIGN, SETTING, AND PARTICIPANTS:A randomized clinical trial involving 329 opioid-dependent patients who were treated at an urban teaching hospital ED from April 7, 2009, through June 25, 2013. INTERVENTIONS:After screening, 104 patients were randomized to the referral group, 111 to the brief intervention group, and 114 to the buprenorphine treatment group. MAIN OUTCOMES AND MEASURES:Enrollment in and receiving addiction treatment 30 days after randomization was the primary outcome. Self-reported days of illicit opioid use, urine testing for illicit opioids, human immunodeficiency virus (HIV) risk, and use of addiction treatment services were the secondary outcomes. RESULTS:Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%-85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%-47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%-54%]) were engaged in addiction treatment on the 30th day after randomization (P?<?.001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1-5.7) to 0.9 days (95% CI, 0.5-1.3) vs a reduction from 5.4 days (95% CI, 5.1-5.7) to 2.3 days (95% CI, 1.7-3.0) in the referral group and from 5.6 days (95% CI, 5.3-5.9) to 2.4 days (95% CI, 1.8-3.0) in the brief intervention group (P?<?.001 for both time and intervention effects; P?=?.02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31%-55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P?=?.17). There were no statistically significant differences in HIV risk across groups (P?=?.66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P?<?.001). CONCLUSIONS AND RELEVANCE:Among opioid-dependent patients, ED-initiated buprenorphine treatment vs brief intervention and referral significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk. These findings require replication in other centers before widespread adoption. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00913770.

Dataset Information

Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.

Publications

Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.

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