Lisa Borg

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

In humans, mu- and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu- and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (p<0.002 for nalmefene 3 mg and p<0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefenes affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [35S]GTPγS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappa-opioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism.

We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of whom who did not (FH−). Mood response and naltrexone biotransformation were also examined at various intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly increased after naltrexone compared with placebo (p < .05). Secondary analyses showed the FH+ subgroup had a different pattern of response over time compared with the FH− subgroup, with heightened ACTH and cortisol, and decreased vigor ratings, during naltrexone (p < .05). The results demonstrate that orally administered naltrexone acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction, by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous opioid system. 166 words.

Altered HPA Axis Responsivity to Metyrapone Testing in Methadone Maintained Former Heroin Addicts with Ongoing Cocaine Addiction

Metyrapone testing, a provocation of hypothalamic-pituitary-adrenocortical (HPA) axis function, was performed in 39 in-patient subjects: 10 stable methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM), eight methadone- maintained former heroin addicts without ongoing drug or alcohol abuse or dependence other than ongoing cocaine dependence (C-MM), and 21 normal volunteers (NV). Plasma adrenocorticotrophic hormone (ACTH) levels were determined in samples drawn at 9 A.M., just before administration of 2.25 g metyrapone orally and 4 and 8 hours afterward. Following metyrapone, C-MM had levels of ACTH that were significantly higher than both MM (p < .05) and NV (p < .01); whereas, MM and NV had levels that were comparable. Area under the plasma ACTH curves yielded similar results. This study documents hyper-responsivity to removal of glucocorticoid negative feedback associated with cocaine addiction, even in the setting of methadone maintenance for heroin addiction, which here and previously has been shown to be associated with normalization of HPA axis function.

Pharmacotherapy in the Treatment of Addiction: Methadone

ABSTRACT Methadone maintenance treatment (MMT) is the most widely available pharmacotherapy for opioid addiction and has been shown to be an effective and safe treatment over a period of 40 years. Although women comprise approximately 40% of clients currently being treated in MMT programs, comparatively little research geared specifically toward this group has been published. This article begins with an overview of neurobiological studies on opioid addiction, including a discussion of gender differences, followed by a review of the pharmacology of methadone. The authors then examine the particular needs and differences of women being treated in MMTs, including co-dependence with other substances, womens health issues, and psychosocial needs unique to this population. Research shows that women have different substance abuse treatment needs in comparison to their male counterparts. One New York City MMT program that has attempted to address these differences is highlighted.

Former Heroin Addicts with or without a History of Cocaine Dependence are more Impulsive than Controls

BACKGROUND Personality traits such as impulsivity and sensation seeking may contribute to the initiation and maintenance of illicit drug use. Since studies have reported higher impulsivity and sensation seeking traits in cocaine dependent subjects, we were interested in determining whether former heroin addicts in methadone pharmacotherapy with comorbid cocaine addiction have greater impulsivity than those without. METHODS Instruments to assess impulsivity (Barratt Impulsiveness Scale version 11) and sensation seeking (Sensation Seeking Scale version V) were administered to former severe heroin addicts meeting Federal criteria for methadone maintenance pharmacotherapy with (n = 71) or without cocaine dependence (n = 31) and to 145 normal healthy (non-methadone-maintained) volunteers. RESULTS The methadone-maintained without cocaine dependence and the methadone-maintained with cocaine dependence groups, both scored higher than did the normal volunteer group on the Barratt Impulsiveness Scale total score (p<0.001). On the Barratt Impulsiveness Scale Attentional, Nonplanning, and Motor subscales, the methadone-maintained and methadone-maintained with cocaine dependence groups scored higher than did normal volunteers with no history of drug abuse or dependence (p<0.001). There was no difference among groups on total score or any subscale of the Sensation Seeking Scale. However, males in all groups overall scored higher than did females on Disinhibition and Thrill and Adventure seeking subscales of the Sensation Seeking Scale version V (p<0.001). CONCLUSIONS This study demonstrates higher impulsivity in former severe heroin addicts meeting criteria for or currently in stable methadone maintenance pharmacotherapy, irrespective of a positive or negative history of cocaine dependence.

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic–pituitary–adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

Hepatitis C Virus and Human Immunodeficiency Virus-1 Co-Infection in Former Heroin Addicts in Methadone Maintenance Treatment

ABSTRACT 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.

Sex, drugs, and infections among youth: Parenterally and sexually transmitted diseases in a high-risk neighborhood

Background and Objectives: To determine the extent to which youth who reside in households in a neighborhood with large numbers of drug injectors 1) are infected with parenterally or sexually transmitted agents, and 2) engage in high‐risk behaviors. Study Design: A multistage probability household sample survey was conducted in Bushwick, Brooklyn from 1994 to 1995. All households in 12 randomly selected primary sampling units were screened for age‐eligible youth. One hundred eleven English‐speaking 18‐ to 21‐year‐olds were interviewed. One hundred three sera were tested for human immunodeficiency virus type 1 (HIV‐1), hepatitis B virus, hepatitus C virus (HCV), human T‐cell lymphotrophic virus types I and II (HTLV‐I/II), herpes simplex virus type 2 (HSV‐2), or syphilis. Urines were tested for chlamydial infection, and for opiate and cocaine metabolites. Results: Eighty‐nine percent had sex in the past year, 45% with two or more partners. Only 19% of the sexually active always used condoms. Two (of 95) had had sex with a crack smoker. Thirty percent of women reported being coerced the first time they had sex, and 23% of women and 3% of men reported having been sexually abused. Only 3% reported ever using heroin, and 9% cocaine. Only one reported ever having injected drugs or smoked crack. Some underreporting of stigmatized behaviors occurred: two “nonreporters” had opiatepositive urines and two had cocaine‐positive urines. Marijuana use was common, with 48% using it in the past year. No subjects tested positive for HIV‐1, HTLV‐II, or syphilis; 2% tested positive for HTLV‐I and 3% for hepatitis C; 3% had hepatitis B markers, 12% had chlamydial infection, and 50% serologic HSV‐2 markers. Conclusions: Population‐representative samples of high‐risk communities can provide important knowledge. Although heroin and cocaine use, drug injection, and rates of infection with parenterally transmitted infectious agents appear to be lower among these youth, sexual risk behaviors and chlamydial and HSV‐2 infection are widespread. Sexually transmitted disease screening and outreach strategies are needed both to prevent sexually transmitted disease sequelae (including potential increased susceptibility to HIV infection) and to prevent transmission to partners.

Glucocorticoid negative feedback in methadone-maintained former heroin addicts with ongoing cocaine dependence: dose-response to dexamethasone suppression.

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.

Acute subjective effects of dynorphin A(1-13) infusion in normal healthy subjects

Twelve healthy subjects with no history of substance abuse participated in a placebo-controlled single-blinded study of subjective response to acute i.v. administration of placebo and two doses of the natural shortened peptide sequence of the kappa-opioid agonist, dynorphin A(1-13) (low dose 120 micrograms/kg, high dose 500 micrograms/kg). Visual analog scales showed small but significant negative mood and positive drug effect 10 min post infusion in the high dose dynorphin compared to placebo infusion. The differences were no longer apparent at 30 min. These results show that dynorphin A(1-13), shown previously to have both neuroendocrine and modest analgesic effects, was well tolerated and produced modest transient subjective responses.