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The mu-opioid receptor is the site of action of opiates and opioids. We examined whether there are differences in cytosine:guanine (CpG) dinucleotide methylation in the OPRM1 promoter between former heroin addicts and controls. We analyzed methylation at 16 CpG dinucleotides in DNA obtained from lymphocytes of 194 Caucasian former severe heroin addicts stabilized in methadone maintenance treatment and 135 Caucasian control subjects. Direct sequencing of bisulfite-treated DNA showed that the percent methylation at two CpG sites was significantly associated with heroin addiction. The level of methylation at the -18 CpG site was 25.4% in the stabilized methadone-maintained former heroin addicts and 21.4% in controls (p=0.0035, generalized estimating equations (GEE); p=0.0077, t-test; false discovery rate (FDR)=0.048), and the level of methylation at the +84 CpG dinucleotide site was 7.4% in cases and 5.6% in controls (p=0.0095, GEE; p=0.0067, t-test; FDR=0.080). Both the -18 and the +84 CpG sites are located in potential Sp1 transcription factor-binding sites. Methylation of these CpG sites may lead to reduced OPRM1 expression in the lymphocytes of these former heroin addicts.

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.

This study examined the impact of methadone maintenance treatment on an inclusive group of adolescent and young adult opiate-dependent patients, ages 15-23, admitted over a 6-year period, during their first year in the program. Retention in treatment was the primary outcome variable, and at 12 months, 48% were still in treatment. The findings were: (a) a stepwise discriminant function analysis revealed that patients who consistently used heroin were at a greater risk of leaving treatment within the first 12 months; (b) the use of cocaine was an indicator of higher levels of heroin use in those who reached the one-year mark; (c) among patients who stayed in treatment for one year, there was a significant reduction in heroin use, a trend toward a reduction in cocaine use, and no significant impact on benzodiazepine use; and (d) the group that stayed in treatment was slightly younger than the group that left before the first year ended. There were no gender or ethnic differences between the two groups. Suggestions for interventions that might improve treatment outcome are presented.

Dynorphin A1-13, a shortened sequence of the natural peptide dynorphin A1-17, is a primarily kappa-opioid receptor-preferring peptide. Previously, we showed that dynorphin A1-13 administered to normal volunteers causes a prompt dose-dependent elevation in serum prolactin that may reflect a reduction in tuberoinfundibular dopaminergic tone. This study was conducted to determine whether tuberoinfundibular dopaminergic tone is reduced in methadone-maintained patients. Eight former heroin addicts on stable-dose methadone maintenance with no ongoing drug or alcohol abuse or dependence and 15 normal volunteer controls with no history of drug or alcohol dependence received dynorphin A1-13 intravenously at doses of 120 microg/kg and 500 microg/kg. Studies began one hour before methadone dosing to avoid the expected increase in prolactin that coincides with peak plasma levels of methadone. After intravenous dynorphin A1-13, a dose-response increase in serum prolactin, which peaked within 20 min, was observed in both groups. There was no difference in prolactin between the two groups at baseline or following a placebo. The prolactin response to each dose of dynorphin A1-13 was significantly lower in the methadone-maintained volunteers compared with the controls. These results suggest that tuberoinfundibular dopaminergic tone is altered in methadone-maintained subjects. It is unknown whether altered dopaminergic tone existed before opiate addiction, is a result of heroin addiction, or is reflective of methadone maintenance. Whether methadone-maintained subjects also have decreased dopaminergic response to dynorphin and other kappa-opioid receptor ligands in mesolimbic-mesocortical and nigrostriatal dopaminergic systems cannot be determined from this study.

Opiate addiction is associated with abnormal function of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. In general, addiction and withdrawal are associated with abnormal HPA responsivity as demonstrated by baseline, dexamethasone, and metyrapone testing. Following stabilization in methadone maintenance treatment, normalization of HPA axis responsivity is observed. To further investigate HPA axis function associated with heroin addiction and its treatment, saline placebo and human corticotropin-releasing factor (hCRF) were administered intravenously in two doses, one dose lower (0.5 microg/kg) and one dose higher (2.0 microg/kg) than the dose used in standard clinical diagnostics (100 microg), to 16 normal male volunteer controls (NV) and eight male stable-dose methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM). Plasma adrenocorticotrophic hormone (ACTH) and cortisol levels were determined at serial time points. There was no difference in hormonal measurements between the two groups following placebo. NV as well as MM displayed a dose-response effect in plasma ACTH and cortisol levels. MM displayed a significantly greater increase in plasma ACTH levels than the NV following high-dose but not low-dose hCRF (p <0.05). There was no significant difference in plasma cortisol levels between the two groups following high-dose hCRF. Thus, despite earlier documented normalization of behavioral function and of several measures of neuroendocrine function during long-term methadone maintenance, some abnormalities in HPA axis responsivity that may be a consequence of heroin exposure, or that may have existed prior to the addiction, can persist during stable methadone treatment.

An analysis of the relationship among the Personality Assessment Inventory (PAI; Morey, 1991, 1996) Drug Problems (DRG) scale scores, the Addiction Severity Index (ASI; McLellan et al., 1992) scores, and urine toxicology reports revealed that the PAI Drug Problem scale scores of 100 substance-using and substance-abusing men and women were distributed in a manner that was in agreement with the guidelines suggested by Morey (1991, 1996) in the PAI manual. There were significant correlations among the PAI DRG scale and the ASI scales related to frequency of use, negative consequences of use, and need and desire for treatment. Overall, higher scores did reflect both more serious involvements with drug use and more serious problems as a consequence of their involvement.

Levo-alpha-acetylmethadol (LAAM) pharmacotherapy was offered to twelve patients who continued illicit opioid abuse after > or = eleven months in methadone maintenance treatment. After 6-8 weeks on LAAM, plasma concentrations of the norLAAM metabolite varied significantly by LAAM dosing day, plasma adrenocorticotropin (ACTH) concentrations were significantly increased compared to methadone, and two of the seven subjects remaining in LAAM treatment were free of illicit opioids and nonprescribed methadone. After one year, one of five remaining subjects was using illicit opioids, and three were using non-prescribed methadone. While subject acceptance of LAAM was high, subjects were not in a "steady-state," with evidence of ongoing illicit opioid abuse.

Objectives: To investigate hepatitis C (HCV) and human immunodeficiency virus (HIV-1) prevalence in former opiate or heroin addicts currently in methadone maintenance treatment (MMT).Methods: Retrospective chart review for patients (n = 342) currently attending two MMT clinics affiliated with New York Presbyterian Hospital (Adolescent Development Program, ADP: n = 106, median age 30 years; Adult Clinic, AC: n = 236, median age 45 years), as of May 2000. Results: Overall seroprevalence of those tested was 67% for HCV (ADP, 44%; AC, 80%), and 29% for HIV-1 (ADP, 13%, AC, 39%). Co-infection was present in 26% of patients (ADP, 13%; AC, 35%). Prevalence of HCV reached 92% in the 45-49 year old group (n = 53). The greatest HIV-1 prevalence (45%) was in the 35-39 year old group (n = 33). There was a linear relationship between infection seroprevalence and age at admission into MMT. Conclusions: The high prevalence of HCV and HIV-1 infections in MMT patients varies both by current age and by age at admission to MMT. This population needs risk reduction education and treatment for HCV and HIV-1. [ABSTRACT FROM PUBLISHER]

A comprehensive study of an urban methadone clinic with supervised urine analyses for illicit drugs was conducted over an 18 month period for a 133 patient cohort as they entered or remained in methadone maintenance for narcotic addiction. Overall retention during the study was 85%, with significantly (p < .05) higher daily methadone doses (mean 67.1 mg ± 2.1) in those patients still in treatment at the end of the study. Predictably, illicit opioid use was dramatically reduced, to 10% as measured by urine toxicology in the last month of treatment. Moreover, significantly more patients stopped regular cocaine abuse (69%) than started using cocaine (10%, Fisher's exact test, p = .02). Thus, with effective methadone maintenance using adequate dosages, the majority of patients remain in treatment and reduce cocaine abuse as well as illicit opioid use, with implications for public health by reducing the spread of infectious diseases including hepatitis B, C, D and human immunodeficiency virus (HIV-1). [ABSTRACT FROM AUTHOR]