Variable dose naltrexone-induced hypothalamic-pituitary-adrenal stimulation in abstinent alcoholics: a preliminary study.
Opiate antagonists have been found to stimulate the hypothalamic-pituitary-adrenal axis. However, despite established usefulness in the management of alcoholism, systematic, oral dose-titrated natrexone-induced hypothalamic-pituitary-adrenal stimulation has never been studied in alcoholics. Six patients (5 males, 1 female) with DSM-IV alcohol dependence, who were at least 4 weeks abstinent from any alcohol [mean 55 days (+/-SE 7.5)], were given four challenges of oral naltrexone (0, 25, 50, and 100 mg) in a randomized order at least 3 days apart, after an overnight fast. Naltrexone was administered at 9 AM; serum ACTH, cortisol, and prolactin were measured at time 0 and at 9 time points over the next 4 hr. Subjects also filled out a side effect questionnaire and an alcohol urge questionnaire. Physiological measurements of blood pressure and pulse rate were taken at the same time points. Repeated-measures ANOVA of the changes in serum ACTHs over time revealed a significant effect of drug (placebo vs. any dose of naltrexone) (p < 0.05). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), the 50 mg dose (p < 0.01), but no significance between the placebo and the 100 mg dose (p = 0.1). A repeated-measures ANOVA of the changes in serum cortisols over time revealed a significant effect of drug (p < 0.01). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), between placebo and the 50 mg dose (p < 0.05), and placebo and the 100 mg dose (p < 0.01). There was a significant between dose difference in pulse rate changes over baseline (p < 0.01), and post-hoc analysis revealed a significant diminution in pulse rate at the 100 mg dose relative to placebo (p < 0.001), and to the other doses. There were no significant differences in reported side effects, alcohol urge questionnaire scores, or in other physiological measurements between doses. These data suggest a significant rise in ACTH and cortisol in response to naltrexone in alcoholics compared with placebo, with no differences between 25 mg, 50 mg, and 100 mg doses, and a significant diminution in pulse rate responses at the 100 mg dose.
Farren
C K
CK
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA. conor.farren@yale.edu
O'Malley
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Grebski
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Maniar
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Porter
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Kreek
M J
MJ
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000437:Alcoholism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000503:physiopathology; D011388:Prolactin / Q000097:blood; D011863:Radioimmunoassay; D013268:Stimulation, Chemical; D011795:Surveys and Questionnaires; D013695:Temperance
D009292:Narcotic Antagonists; D009271:Naltrexone; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D006854:Hydrocortisone