Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioid use disorder.

Many patients with opioid use disorder do not have successful outcomes during treatment but the underlying reasons are not well understood. An OPRD1 variant (rs678849) was previously associated with methadone and buprenorphine efficacy in African-Americans with opioid use disorder. The objective of this study was to determine if the effect of rs678849 on opioid use disorder treatment outcome could be replicated in an independent population. Participants were recruited from African-American patients who had participated in previous studies of methadone or buprenorphine treatment at the outpatient treatment research clinic of the NIDA Intramural Research Program in Baltimore, MD, USA between 2000 and 2017. Rs678849 was genotyped retrospectively, and genotypes were compared with urine drug screen results from the previous studies for opioids other than the one prescribed for treatment. Genotypes were available for 24 methadone patients and 55 buprenorphine patients. After controlling for demographics, the effect of rs678849 genotype was significant in the buprenorphine treatment group (RR = 1.69, 95% confidence interval (CI) 1.59-1.79, p = 0.021). Buprenorphine patients with the C/C genotype were more likely to have opioid-positive drug screens than individuals with the C/T or T/T genotypes, replicating the original pharmacogenetic finding. The effect of genotype was not significant in the methadone group (p = 0.087). Thus, the genotype at rs678849 is associated with buprenorphine efficacy in African-Americans being treated for opioid use disorder. This replication suggests that rs678849 genotype may be a valuable pharmacogenetic marker for deciding which opioid use disorder medication to prescribe in this population.

Safe methadone induction and stabilization: report of an expert panel.

OBJECTIVES: Methadone is a well-studied, safe, and effective medication when dispensed and consumed properly. However, a number of studies have identified elevated rates of overdose and death in patients being treated with methadone for either addiction or chronic pain. Among patients being treated with methadone in federally certified opioid treatment programs, deaths most often occur during the induction and stabilization phases of treatment. To address this issue, the federal Substance Abuse and Mental Health Services Administration invited the American Society of Addiction Medicine to convene an expert panel to develop a consensus statement on methadone induction and stabilization, with recommendations to reduce the risk of patient overdose or death related to methadone maintenance treatment of addiction. METHODS: A comprehensive literature search of English-language publications (1979-2011) was conducted via MEDLINE and EMBASE. Methadone Action Group members evaluated the resulting information and collaborated in formulating the consensus statement presented here, which subsequently was reviewed by more than 100 experts in the field. RESULTS: Published data indicate that deaths during methadone induction occur because the initial dose is too high, the dose is increased too rapidly, or the prescribed methadone interacts with another drug. Therefore, the Methadone Action Group has developed recommendations to help methadone providers avoid or minimize these risks. CONCLUSIONS: Careful management of methadone induction and stabilization, coupled with patient education and increased clinical vigilance, can save lives in this vulnerable patient population.

Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol.

OBJECTIVE: Sublingual buprenorphine/naloxone (Bup/Nx) is approved for addiction treatment and may be useful for pain management, particularly in opioid-treated patients with pain with nonadherence behaviors. The transition of opioid-treated patients with pain to buprenorphine carries the risk of precipitated withdrawal and increased pain. This study convened pain and addiction specialists to develop and pilot a clinical protocol for safe transitioning to Bup/Nx. DESIGN: The protocol was revised three times based on outside expert review and pilot study observations. The pilot was conducted with a prospective cohort of 12 patients with moderate to severe chronic pain, who were receiving long-term opioid therapy with any full m-agonist drug, and had exhibited one or more aberrant drug-related behaviors. Patients were followed up for 3-6 months with the expectation that they would experience few adverse events (AEs) and report lower pain severity. RESULTS: The three patients on the highest baseline opioid dose (equivalent to 303-450 mg of oral morphine) and the three on the lowest doses (≤20 mg) had early AEs when switched to Bup/Nx and did not complete the trial. Of the remaining six, one withdrew due to AEs; one responded well, then withdrew; and four completed a 3-month trial. A mixed-effects model controlling for dropouts found that average and worst pain significantly decreased after the switch to Bup/Nx (both p < 0.01). CONCLUSION: Based on this experience, the protocol recommends Bup/Nx for pain only when baseline opioid doses are within bounds that reduce AEs at transition and incorporates dose flexibility to further reduce risks. This protocol warrants further testing.

Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication.

AIM: To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on methadone or buprenorphine. DESIGN: Participants were randomized to either methadone or buprenorphine maintenance. Blood chemistry tests, including liver transaminases and hepatitis C virus (HCV) status, were determined every 4 weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. SETTING: Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. PARTICIPANTS: A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. FINDINGS: ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transaminases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). CONCLUSIONS: Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women.

Outcomes of DATA 2000 certification trainings for the provision of buprenorphine treatment in the Veterans Health Administration.

Despite the high numbers of veterans with opioid dependence, few receive pharmacologic treatment for this disorder. The adoption of buprenorphine treatment within the Veterans Health Administration (VHA) has been slow. To expand capacity for buprenorphine treatment, the VHA sponsored two eight-hour credentialing courses for the Drug Addiction Treatment Act of 2000. We sought to describe the outcomes of such training. Following the training sessions, 29 participants (18 physicians) were highly satisfied with course content and affirmed their intention to prescribe buprenorphine; after nine-month follow-up, two physicians were prescribing. We conclude that providing credentialing courses, while popular, did not markedly promote the prescription of buprenorphine.

Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

CONTEXT: The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. OBJECTIVE: To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. DESIGN, SETTING, AND PATIENTS: Clinical 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). INTERVENTIONS: Patients 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 MEASURE: Opioid-positive urine test result at weeks 4, 8, and 12. RESULTS: The 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. CONCLUSIONS: Continuing 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 REGISTRATION: clinicaltrials.gov Identifier: NCT00078130.

Implementation of buprenorphine in the Veterans Health Administration: results of the first 3 years.

BACKGROUND: Compared to non-veterans, veterans are disproportionately diagnosed with opioid dependence. Sublingual buprenorphine provides greater access to opioid agonist therapy. To understand the diffusion of this innovative treatment within a large healthcare system, we describe the introduction of buprenorphine within the Veterans Health Administration (VHA) during the first 3 years of its approval as a VHA non-formulary medication. METHODS: Using VHA pharmacy databases, we examined the number of physicians who have prescribed buprenorphine and the number of veterans who have received office-based buprenorphine within VHA veterans integrated service networks (VISN) from fiscal years (FY) 2003 through FY 2005 (October 2002 through September 2005). RESULTS: From FY2003 through FY2005 the number of veterans with opioid dependence increased from 25,031 to 26,859 (>7.3%) and the number of veterans prescribed office-based buprenorphine increased from 53 to 739. During this interval, 16 of 21 VISNs had prescribed buprenorphine. In FY2005, two VISNs accounted for 31% of buprenorphine prescriptions. The number of buprenorphine prescriptions varied widely by VISN, but increased from 212 to 7076 from FY2003 through FY2005. During this interval, prescriptions per patient increased from 4.0 to 9.6 and physicians prescribing buprenorphine increased from 14 to 170. The ratio of patients prescribed buprenorphine to providers prescribing buprenorphine increased from 3.8 to 4.3 with an average increase of 15.1-41.6 of prescriptions per provider. CONCLUSIONS: VHA increased, but not uniformly, the non-formulary use of office-based buprenorphine during the first 3 years of availability.

Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.

BACKGROUND: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. RESULTS: The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. CONCLUSIONS: Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting.

Staff beliefs about drug abuse clinical trials.

Staff from 10 community-based addiction treatment organizations in the National Drug Abuse Clinical Trials Network participated in an educational session about addiction research practices and human subject protections. This 1.5-hour presentation addressed "informed consent," "confidentiality of research information," "inclusion and exclusion criteria," "random assignment," "patient protections," and "patient payments." Pre- and postsession surveys were administered to 115 staff members measuring their beliefs about clinical trials. At baseline, 52% of staff believed patients could transfer out of a study even if they were doing poorly, and 55% believed staff had this right; 44% agreed that patients could participate in a clinical trial without understanding what would take place in the study. After the educational session, staff beliefs about patient protections were significantly increased in five of the seven items. A fourth of staff continued to believe patient payments were harmful, and 37% did not believe participation in a clinical trial would increase a patient's chances at recovery.