Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients. Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01). Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.
Background/Aim: Heroin dependence is a chronic relapsing disorder characterized by the compulsion to seek and use heroin. Stress and craving are seen as key factors for heroin use. Moreover, altered hypothalamic-pituitary-adrenal (HPA) axis function has been frequently reported. However, the acute effects of diacetylmorphine (DAM) on HPA axis activity and craving have not been investigated in a controlled study. The present randomized controlled study examined whether DAM administration differs from placebo (saline) administration with regard to HPA axis response and heroin craving. Methods: In a crossover experiment, 28 DAM-maintained heroin-dependent patients were first injected with DAM and then saline, or the converse. Plasma adrenocorticotropic hormone (ACTH) and cortisol in saliva and serum were measured at baseline and 20 and 60 min after both injections. Heroin craving was measured at baseline and 60 min after both injections, by means of the Heroin Craving Questionnaire. Results: Compared to saline, DAM administration induced a significant decrease in plasma ACTH (p < 0.01), serum cortisol (p < 0.0001) and saliva cortisol (p < 0.01), as well as in craving (p < 0.0001), over time. Conclusion: Since acute DAM administration suppresses the stress response, DAM-assisted treatment may be an effective alternative to methadone maintenance in stress-sensitive heroin-dependent patients.
This study suggests a positive association between extensive CYP2D6 metabolism and outcome in early-stage ER-positive BC patients using tamoxifen and in particular, when a sufficient number ERs are represented on the primary tumor.
Background: The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. Methods: The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. Results: From 151 patients predicted based on their genotype data for the ‘traditional’ CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. Conclusions: The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity.
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