Improving maintenance treatment of heroin addiction : The role of buprenorphine

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Clinical Neuroscience

Sammanfattning: Background: Heroin addiction is a condition with high morbidity and mortality. The discovery of Methadone Maintenance Treatment (MMT) by Dole and co-workers 1964 represented the first major advance in the treatment of this condition. Through the work of Gunne et al in Uppsala, MMT was implemented in Sweden already in 1966. The use of this treatment has, however, been limited in Sweden. Some of the concerns have been related to safety issues. Methadone, a full opiate agonist, can lead to overdose and death due to respiratory depression. Buprenorphine, a partial opiate agonist, has a greater safety margin to overdosing, and therefore offers a safer alternative. Here, we studied efficacy of buprenorphine maintenance treatment (BMT) in the context of a comprehensive treatment package, and its place in a rational treatment strategy vs. methadone. We also examined the effects of buprenorphine on neuroendocrine hyperactivity in heroin addiction. Finally, we compared pregnancy outcomes in MMT and BMT pregnancies. Aims: The following research questions were addressed: the efficacy of buprenorphine combined with psychosocial interventions; a comparison between gold standard MMT and a novel stepped treatment strategy using buprenorphine as first-line treatment; whether BMT leads to a normalization of the hyperactive HPA axis, and the possible link to negative affect; a comparison of fetal growth and neonatal outcomes in two consecutive case series consisting of BMT and MMT exposed pregnancies. Methods: In two RCTs, with 40 subjects in study I and 96 subjects in study II, we measured retention in treatment, performed ASI interviews, and monitored illicit drug use by urine screens. In an experimental study, we used the metyrapone challenge (a chemically induced indirect stress provocation that measures HPA axis responsiveness), the Profile of Mood States self-report instrument and genotyping. The observational pregnancy study measured intrauterine growth, birth outcome, malformations, neonatal adaptation, neonatal abstinence syndrome (NAS) and infant mortality. Results: Study I: 1-year retention was 75% and 0% in the buprenorphine and placebo groups, respectively (p= 0.0001). Urine screens were about 75% negative for illicit drugs in the patients remaining in treatment (subjects in buprenorphine group). Study II: Overall, 6-month retention was 78%. Stepped treatment and enhanced MMT outcomes were virtually identical. Among completers of stepped treatment, 46% remained on buprenorphine-naloxone. Proportion of urine samples free of illicit opiates increased over time and reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. Study III: Although BMT appeared to normalize HPA axis response to metyrapone in heroin addicts, negative affect remained elevated in this group compared to healthy controls. Study IV: In the buprenorphine-exposed pregnancies NAS occurred in 19 cases (40.4%), only 7 (14.9%) needing withdrawal treatment, compared to 77.8% and 52.8% after intrauterine methadone exposure, respectively. Conclusions: The combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious. A stepped treatment of heroin addiction appears equally efficacious compared to optimally delivered MMT. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered. Response to metyrapone was dampened in heroin addicts maintained on buprenorphine. Despite the normalized HPA axis function, increased measures of negative affect were seen in the buprenorphine maintained group, implying a dissociation of HPA axis responsiveness and affect in heroin addiction. Finally, our preliminary data suggest that buprenorphine may offer advantages during pregnancies complicated by heroin addiction.

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