Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Treatment outcomes in opioid dependent patients with different buprenorphine/naloxone induction dosing patterns and trajectories.

BACKGROUND AND OBJECTIVES: 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]). METHODS: The secondary analysis of a study of opioid-dependent adults seeking treatment in eight treatment settings included 740 participants inducted on BUP with flexible dosing. RESULTS: Latent class analysis models detected six distinctive induction trajectories: bup1-started and remained on low; bup2-started low, shifted slowly to moderate; bup3-started low, shifted quickly to moderate; bup4-started high, shifted to low; bup5-started and remained on moderate; bup6-started moderate, shifted to high dose (Fig. 1). 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 (adjusted hazard ratio (aHR) = .28, p = .03). Opioid use and AEs were similar across trajectories. Participants on ≥16 mg BUP compared to those on <16 mg at Day 28 were less likely to drop out (aHR = .013, p = .001) and less likely to have AEs during the first 28 days (aOR = .57, p = .03). DISCUSSION AND 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 slower. SCIENTIFIC SIGNIFICANCE: This study supports the use of an objective measure of opioid withdrawal (COWS) during BUP induction to improve retention early in treatment.

The relationship between primary prescription opioid and buprenorphine-naloxone induction outcomes in a prescription opioid dependent sample.

BACKGROUND AND OBJECTIVES: This analysis aims to: (1) compare induction experiences among participants who self-reported using one of the four most commonly reported POs, and (2) examine factors associated with difficult bup-nx induction. Our hypothesis, based on previous research and current guidelines, is that those on longer-acting opioids will have experienced more difficult inductions. METHODS: The Prescription Opioid Addiction Treatment Study (POATS) was a multi-site, randomized clinical trial, using a two-phase adaptive treatment research design. This analysis examines bup-nx induction of participants who self-reported primary PO use of methadone, ER-oxycodone, IR-oxycodone, and hydrocodone (n = 69). Analyses examined characteristics associated with difficult induction, defined as increased withdrawal symptoms measured by the Clinical Opiate Withdrawal Scale (COWS) after the first bup-nx dose with higher scores denoting greater withdrawal symptoms/severity. RESULTS: Contrary to our hypothesis, difficult induction experiences did not differ by primary PO type. Those who experienced a post-induction increase in COWS score had lower pre-dose COWS scores compared to those who did not experience a post-induction increase in COWS score (10.09 vs. 12.77, t(624) = -13.56, p < .001). Demographics characteristics, depression, and pain history did not predict a difficult induction. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Difficult bup-nx inductions were not associated with participants' primary PO. Severity of withdrawal, measured with the COWS, was an important variable, reminding clinicians that bup-nx should not be commenced prior to evidence of moderate opioid withdrawal. These findings add to the evidence that with careful procedures, bup-nx can used with few difficulties in PO-dependent patients. (Am J Addict 2014;23:343-348).

Does Posttraumatic Stress Disorder (PTSD) Affect Post-Treatment Methamphetamine Use?

OBJECTIVE: Although trauma is a well-established risk factor for substance use disorders, little is known about the association between posttraumatic stress disorder (PTSD) and treatment outcomes among methamphetamine users. In the present study, we examine the relationship between PTSD and post-treatment methamphetamine use outcomes, hospitalizations, and overall psychiatric impairment. METHODS: Using data from 526 adults in the largest psychosocial clinical trial of methamphetamine users conducted to date, this study examined: (1) treatment outcomes of methamphetamine users with concomitant PTSD three years after psychosocial treatment for methamphetamine dependence; and (2) PTSD symptom clusters as risk factors for post-treatment relapse to methamphetamine use. RESULTS: PTSD was associated with poorer methamphetamine use outcomes; methamphetamine use frequency throughout the 3-year follow-up was significantly greater among individuals with a PTSD diagnosis, and those with PTSD had more than five times the odds of reporting methamphetamine use in the 30 days prior to the follow-up interview, OR= 5.2, 95% CI [2.0-13.3]. Additionally, higher levels of other Axis I psychopathology were observed among methamphetamine users with PTSD. Avoidance and arousal symptoms predicted post-treatment methamphetamine use. CONCLUSIONS: Addressing these high risk PTSD symptoms and syndromes in methamphetamine users may be helpful as a means of improving treatment outcomes in this population.

Participant characteristics and buprenorphine dose.

BACKGROUND: Clinical parameters for determining buprenorphine dose have not been adequately examined in treatment outcome research. OBJECTIVES: This study is a secondary analysis of data collected in a recently completed comparison of buprenorphine taper schedules conducted as part of the National Institute on Drug Abuse's Clinical Trials Network to assess whether participant baseline characteristics are associated with buprenorphine dose. METHODS: After 3 weeks of flexible dosing, 516 participants were categorized by dose provided in the final dosing week (9.3% received a final week dose of 8 mg buprenorphine, 27.3% received 16 mg, and 63.4% received 24 mg). RESULTS: 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). Additional analyses address withdrawal symptoms and craving. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Final week dose groups 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.

Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial.

BACKGROUND: Accumulating evidence indicates important gender differences in substance use disorders. Little is known, however, about gender differences and opioid use disorders. OBJECTIVES: To compare demographic characteristics, substance use severity, and other associated areas of functioning (as measured by the Addiction Severity Index-Lite (ASI-Lite)) among opioid-dependent men and women participating in a multisite effectiveness trial. METHODS: Participants were 892 adults screened for the National Institute on Drug Abuse Clinical Trials Network investigation of the effectiveness of two buprenorphine tapering schedules. RESULTS: The majority of men and women tested positive for oxycodone (68% and 65%, respectively) and morphine (89% each). More women than men tested positive for amphetamines (4% vs. 1%, p < .01), methamphetamine (11% vs. 4%, p < .01), and phencyclidine (8% vs. 4%, p = .02). More men than women tested positive for methadone (11% vs. 6%, p = .05) and marijuana (22% vs. 15%, p = .03). Craving for opioids was significantly higher among women (p < .01). Men evidenced higher alcohol (p < .01) and legal (p = .04) ASI composite scores, whereas women had higher drug (p < .01), employment (p < .01), family (p < .01), medical (p < .01), and psychiatric (p < .01) ASI composite scores. Women endorsed significantly more current and past medical problems. CONCLUSIONS: Important gender differences in the clinical profiles of opioid-dependent individuals were observed with regard to substance use severity, craving, medical conditions, and impairment in associated areas of functioning. The findings enhance understanding of the characteristics of treatment-seeking men and women with opioid dependence, and may be useful in improving identification, prevention, and treatment efforts for this challenging and growing population.

Bulimia nervosa among methamphetamine dependent adults: association with outcomes three years after treatment.

Although weight loss is among the most commonly cited reasons for using methamphetamine (MA), little is known about the association between eating disorders and treatment outcomes in this population. This study examined psychiatric, substance use, and functional outcomes of MA users (N = 526) with bulimia nervosa 3 years after treatment for MA dependence. Bulimia nervosa was observed among 2.4% (N = 13) of the participants and was associated with poorer MA use outcomes, increased health service utilization, and higher levels of functional impairment. Addressing MA use among adults with eating disorders may be helpful as a means of improving treatment outcomes.

Anxiety disorders among methamphetamine dependent adults: association with post-treatment functioning.

Although anxiety is one of the most prominent psychiatric complaints of methamphetamine (MA) users, little is known about the association between anxiety disorders and treatment outcomes in this population. Using data from 526 adults in the largest psychosocial clinical trial of MA users conducted to date, this study examined psychiatric, substance use, and functional outcomes of MA users with concomitant anxiety disorders 3 years after treatment. Anxiety disorders were associated with poorer alcohol and drug use outcomes, increased health service utilization, and higher levels of psychiatric symptomatology, including suicidality. Addressing anxiety symptoms and syndromes in MA users may be helpful as a means of optimizing treatment outcomes.

Association of race and ethnicity with withdrawal symptoms, attrition, opioid use, and side-effects during buprenorphine therapy.

Some studies report differences in opioid withdrawal between racial/ethnic groups. However, it is not known if these differences are reflected in differential treatment response. Data from National Institute on Drug Abuse (NIDA) Clinical Trials Network-003 were used to examine racial/ethnic differences before and during stabilization with buprenorphine. At induction, non-Hispanic Caucasians had higher objective and subjective withdrawal scores and greater opioid craving than minority participants. No significant between-group differences were observed on these scales following buprenorphine. Non-Hispanic Caucasians and Hispanics reported more adverse events than African Americans. Although ethnic and racial differences were observed prior to buprenorphine treatment, scores following buprenorphine treatment were similar between groups.

Depression among methamphetamine users: association with outcomes from the Methamphetamine Treatment Project at 3-year follow-up.

Although depression is highly comorbid with substance use disorders, little is known about the clinical course and outcomes of methamphetamine (MA) users with depressive symptoms and syndromes. In this study of MA-dependent individuals entering psychosocial treatment, we predicted that (1) depressive symptoms would decline during treatment, an effect that would vary as a function of MA use and (2) depression diagnoses post-treatment would be associated with poorer outcomes. Participants (N = 526) were assessed for depression, substance use, and psychosocial outcomes at baseline, treatment discharge, and 3-year follow-up. Depressive symptoms declined significantly during treatment, an effect that was greatest among those who abstained from MA. Major depression at follow-up was associated with poorer MA use outcomes and impairment across multiple domains of functioning. The findings highlight the relationship of depressive symptoms and diagnoses to treatment outcomes, and suggest a need for further studies of depression in populations using MA.

Medication Adherence Monitoring Using Smartphone Video Dosing in an Open-label Pilot Study of Monthly Naltrexone Plus Once-daily Bupropion for Methamphetamine Use Disorder: Feasibility and Acceptability.

OBJECTIVES: This article describes how smartphones were used to monitor and encourage medication adherence in a pilot study evaluating the potential efficacy of a combination pharmacotherapy for methamphetamine use disorder. We examine the feasibility, utility, and acceptability of using smartphones to capture dosing videos from the perspectives of participants and staff. METHODS: The study was an 8-week, open-label evaluation of extended-release injectable naltrexone combined with once-daily oral extended-release bupropion (BRP, Welbutrin XL, 450 mg/day). Participants attended visits twice-weekly for observed BRP dosing, assessments, and medical management. BRP was dispensed once weekly for dosing on nonclinic days. Medication adherence was assessed objectively (by observation in the clinic and smartphone videos for dosing at home) and subjectively (self-reports of dosing). Surveys assessing the smartphone component were completed by participants and study staff. RESULTS: Participants (N = 49) reported taking 93.6% of the dispensed BRP doses while 86.6% of dispensed doses were confirmed via dosing video and in-person observations. Most participants who completed the survey agreed that the smartphone was easy to use (92.6%) and that taking the dosing videos helped to remember to take the study medication (80.5%). Staff agreed that the smartphone helped collect accurate dosing data for most (77.5%) participants. CONCLUSIONS: The use of smartphones for video-based oral medication dosing in this study provided a feasible and acceptable mechanism to encourage, monitor, and confirm medication adherence. Video-confirmed dosing adherence provides an objective numerical indicator of the lowest medication adherence rate participants achieve, allowing investigators to more confidently interpret results.

Identifying methamphetamine users at risk for major depressive disorder: findings from the methamphetamine treatment project at three-year follow-up.

Little is known about risk factors for depression in methamphetamine users. Using data from 526 adults in the largest psychosocial clinical trial of methamphetamine users conducted to date, this study examined clinical, demographic, and substance use characteristics that predict the presence of a diagnosis of major depressive disorder (MDD) three years after treatment for methamphetamine dependence. The results indicate that two risk factors predict a diagnosis of MDD: a Beck Depression Inventory total score greater than 20, and one or more prior suicide attempts. These risk factors identify methamphetamine users who may benefit from early interventions for psychiatric symptoms.

Drug court treatment for methamphetamine dependence: treatment response and posttreatment outcomes.

Relatively little is known about the impact of drug court treatment programs for methamphetamine (MA) dependence. This article examines treatment performance among a subsample of 287 MA-dependent adults who participated in the Methamphetamine Treatment Project from 1999 to 2001. To gain a preliminary indication of MA users' response to drug court intervention, we compared a group of 57 MA-dependent participants treated in outpatient treatment within the context of a drug court to a group of comparable MA-dependent individuals treated in outpatient treatment but not supervised by a drug court (n = 230). Analyses reveal that drug court participation was associated with better rates of engagement, retention, completion, and abstinence, compared to outpatient treatment without drug court supervision. Six- and 12-month outcome analyses indicated that participants who were enrolled in drug court intervention used MA significantly less frequently. These findings suggest that drug court supervision coupled with treatment may improve the outcomes of MA-dependent offenders beyond that seen from treatment alone.

Childhood adverse events and methamphetamine use among men and women.

Women report extensive histories of childhood abuse, often leading to addiction. Studies assessing the same effects for men are lacking. This study describes childhood adverse events (CAEs) among methamphetamine (MA)-dependent men and women and assesses the relationship of CAEs to the onset and severity of dependence. Baseline and three-year interview data were collected for 236 men and 351 women. Dependent variables included onset of MA and severity of dependence. Women reported greater occurrence of all types of CAEs than men (28% vs. 13%,p < .01). Familial substance abuse was most predictive of onset for men and of dependence severity for women. The collective impact of CAEs was related to both age of onset and severity. This demonstrates the intergenerational cycle of addiction, and indicates the need for early intervention, which could prevent the onset of MA use and reduce the course of addiction.

Predicting in-treatment performance and post-treatment outcomes in methamphetamine users.

AIMS: This study examines the utility of individual drug use and treatment characteristics for predicting in-treatment performance and post-treatment outcomes over a 1-year period. DESIGN, SETTING AND PARTICIPANTS: Data were collected from 420 adults who participated in the Methamphetamine Treatment Project (MTP), a multi-site study of randomly assigned treatment for methamphetamine dependence. Interviews were conducted at baseline, during treatment and during three follow-up time-points: treatment discharge and at 6 and 12 months following admission. MEASUREMENTS: The Addiction Severity Index (ASI); the Craving, Frequency, Intensity and Duration Estimate (CFIDE); and laboratory urinalysis results were used in the current study. FINDINGS: Analyses addressed both in-treatment performance and post-treatment outcomes. The most consistent finding is that pre-treatment methamphetamine use predicts in-treatment performance and post-treatment outcomes. No one variable predicted all in-treatment performance measures; however, gender, route of administration and pre-treatment methamphetamine use were significant predictors. Similarly, post-treatment outcomes were predicted by a range of variables, although pre-treatment methamphetamine use was significantly associated with each post-treatment outcome. CONCLUSIONS: These findings provide useful empirical information about treatment outcomes for methamphetamine abusers, and highlight the utility of assessing individual and in-treatment characteristics in the development of appropriate treatment plans.

Buprenorphine 101: treating opioid dependence with buprenorphine in an office-based setting.

This clinical observation provides a first look at differences between two patient subgroups, prescription opiate (PO) abusers and heroin abusers, presenting for office-based buprenorphine treatment. Medical and drug use histories, medication dose, treatment outcome, and demographic information were collected from the first 101 opiate-dependent adults entering treatment. The results indicate that PO abusers (n = 42) and heroin abusers (n = 59) differed in several demographic characteristics, drug use history, and treatment outcome. Physicians may benefit from this information by using it to tailor comprehensive treatment and medical care plans for opioid-dependent patients taking buprenorphine.

Injectable pharmacotherapy for opioid use disorders (IPOD).

BACKGROUND: Despite the growing prevalence of opioid use among offenders, pharmacotherapy remains an underused treatment approach in correctional settings. The aim of this 4-year trial is to assess the clinical utility, effectiveness, and cost implications of extended-release naltrexone (XR-NTX, Vivitrol®; Alkermes Inc.) alone and in conjunction with patient navigation for jail inmates with opioid use disorder (OUD). METHODS: Opioid-dependent inmates will be randomly assigned to one of three treatment conditions before being released to the community to include: 1) XR-NTX only; 2) XR-NTX plus patient navigation (PN), and 3) enhanced treatment-as-usual (ETAU) with drug education and a community treatment referral. Before release from jail, participants in the XR-NTX and XR-NTX plus PN conditions will receive their first XR-NTX injection. Those in the XR-NTX plus PN condition also will meet with a patient navigator. Participants in both XR-NTX conditions will be scheduled for medical management sessions twice monthly for months 1-3, monthly medical management sessions for months 4-6, with monthly injections for 5months post-release (which, given the pre-release injection, results in a 6-month medication phase). Follow-up data collection will occur at 1, 3, 6, and 12months post release. RESULTS: We discuss the study's rationale, aims, methods, and anticipated findings. The primary outcome is the presence of a DSM 5 OUD diagnosis 1year after randomization (6months after the end of the active treatment phase). DISCUSSION: We hypothesize that providing XR-NTX prior to release from jail will be particularly beneficial for this extremely high-risk population by reducing opioid use, associated criminal behavior, and injection-related disease risk. ClinicalTrials.Gov: NCT02110264.

Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder.

OBJECTIVES: This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. METHODS: The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9. RESULTS: Analyses evaluated effects of XR-NTX + BRP to determine the number of "responders" according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield ≥3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2). CONCLUSIONS: Under the statistical analysis plan, study "success" required ≥9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study.

Dose, Plasma Level, and Treatment Outcome Among Methadone Patients in Shanghai, China.

The purpose of this study was to investigate the blood levels of methadone in participants receiving methadone for the treatment of opioid dependence. After stabilization on methadone for four weeks, blood samples from 95 participants were collected between treatment weeks 4 and 12, before and after receiving doses of methadone, and its blood levels were measured. A multiple linear regression model was used to examine the association between methadone blood levels and the outcomes of methadone maintenance treatment (MMT). Outcome differences between participants who had high (≥2) or low (<2) peak-to-trough ratios were also compared using an independent sample t-test. The blood level of methadone was not correlated with the clinical outcome of MMT with the moderate range of doses given. However, the retention of patients who had a free peak-to-trough ratio >2 was significantly poorer than those whose ratio was <2. Thus, monitoring plasma methadone levels is unlikely to be effective for guiding dosing decisions in situations where compliance with MMT is already very high or when the methadone dose is no longer the dominant factor in determining the clinical outcome. However, monitoring plasma methadone levels is still helpful for guiding the dosage for patients with a rapid metabolism.

The SOMATICS collaborative: Introduction to a National Institute on Drug Abuse cooperative study of pharmacotherapy for opioid treatment in criminal justice settings.

BACKGROUND: Among the nearly 750,000 inmates in U.S. jails, 12% report using opioids regularly, 8% report use in the month prior to their offense, and 4% report use at the time of their offense. Although ample evidence exists that medications effectively treat Opiate Use Disorder (OUD) in the community, strong evidence is lacking in jail settings. The general lack of medications for OUD in jail settings may place persons suffering from OUD at high risk for relapse to drug use and overdose following release from jail. METHODS: The three study sites in this collaborative are pooling data for secondary analyses from three open-label randomized effectiveness trials comparing: (1) the initiation of extended-release naltrexone [XR-NTX] in Sites 1 and 2 and interim methadone in Site 3 with enhanced treatment-as usual (ETAU); (2) the additional benefit of patient navigation plus medications at Sites 2 and 3 vs. medication alone vs. ETAU. Participants are adults with OUD incarcerated in jail and transitioning to the community. RESULTS: We describe the rationale, specific aims, and designs of three separate studies harmonized to enhance their scientific yield to investigate how to best prevent jail inmates from relapsing to opioid use and associated problems as they transition back to the community. CONCLUSIONS: Conducting drug abuse research during incarceration is challenging and study designs with data harmonization across different sites can increase the potential value of research to develop effective treatments for individuals in jail with OUD.