Hormonal and Other Effects of Naltrexone in Normal Men

Volavka, Jan; Mallya, Ashok; Bauman, Joan E.; Pevnick, Jeffrey S.; Cho, D.; Reker, Dean M.; James, Bárbara; Dornbush, Rhea L.

doi:10.1007/978-1-4684-3503-0_17

Cited by 30 publications

(12 citation statements)

References 28 publications

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“…Naltrex- one, a primarily -receptor antagonist but also acting on ␦ and receptors, undergoes extensive first-pass metabolism and biotransformation and has not been studied as broadly as naloxone in terms of acute neuroendocrine and physiological mechanisms. Although the sample size in the present study was relatively modest, it exceeded the sample sizes in the two previous published studies of HPA response to naltrexone (Farren et al 1999;Volavka et al 1979b) and the results showed reliable and steady increases in ACTH and cortisol levels within two hours of administration. Following the acute peak increases in pituitary-and adrenal-derived ACTH and cortisol, respectively, there were slow declines over the next several hours, which is a likely result of the inherent negative feedback loops involved in normal regulation of the HPA axis.…”

Section: Discussioncontrasting

confidence: 55%

“…The first study (Volavka et al 1979b), conducted in ten normal male subjects, showed that oral naltrexone significantly increased cortisol levels two hours after administration and directionally (but nonsignificantly) increased ACTH levels one hour after administration. However, due to the small sample studied, the power may not have been sufficient to detect differences.…”

Section: We Examined Hpa Axis Response To 50 Mg Oral Naltrexone Compamentioning

confidence: 99%

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Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

King

Schluger

Gunduz

et al. 2002

Neuropsychopharmacology

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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 ϩ ) and half of whom who did not (FH Ϫ)The endogenous opioid system plays a role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis (Cushman and Kreek 1974;Johnson et al. 1992;Kreek 1972Kreek , 1973Kreek , 1978. Opioid antagonist administration blocks the tonic opioid inhibition of HPA axis activity, thereby resulting in release of POMC-derived hormones in the pituitary and cortisol from the adrenal gland. Indeed, numerous studies have demonstrated acute increases in adrenocorticotropin (ACTH) and cortisol levels in man after intravenous infusion of the opioid antagonists naloxone (Cohen et al. 1983;Conaglen et al. 1985;Delitala et al. 1994;Naber et al. 1981;Martin del Campo et al. 1994;Morley et al. 1980;Schluger et al. 1998;Volavka et al. 1979a) and nalmefene . However, few studies have examined acute neuroendocrine response to the opioid antagonist naltrexone, which, in contrast to naloxone and nalmefene, is not available for intravenous administration.The two published studies on the acute HPA axis effects of orally administered naltrexone have both been conducted with relatively small sample sizes (n р 10). NO . 6 Naltrexone, HPA Axis, and Biotransformation 779The first study (Volavka et al. 1979b), conducted in ten normal male subjects, showed that oral naltrexone significantly increased cortisol levels two hours after administration and directionally (but nonsignificantly) increased ACTH levels one hour after administration. However, due to the small sample studied, the power may not have been sufficient to detect differences. The results may also have been confounded by the co-occurrence of pain sensitivity testing (i.e., 2-min cold pressor task) during the protocol, which may have produced independent HPA axis responses. A more recent study in six abstinent alcoholic patients (Farren et al. 1999) showed significant increases in cortisol and ACTH to three doses of oral naltrexone (25, 50, and 100mg) with no dose-dependent effects (Farren et al. 1999). It has been hypothesized that alterations in HPA axis function may play a role in various stages of addiction, including initiation, maintenance, and relapse (Kreek 1992). Naltrexone (50 mg oral) has shown efficacy in the treatment of alcohol dependence (Volpicelli et al. 1992(Volpicelli et al. , 1997O'Malley et al. 1992;Anton et al. 1999), which led to its FDA-approval for adjunctive treatment of alcoholism. Studies examining HPA axis response after oral naltrexone administration might be of potential clinical relevance as neuroendocrine changes and sensitivity to naltrexone could relate to individual differences and treatment response. Hypothetically, the effects of an opioid antagonist, such as naltrexone, in modulating tonic inhibition of the opioid system at various receptors, including primarily , but also ␦ and , may relate to tr...

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Section: Discussioncontrasting

confidence: 55%

Section: We Examined Hpa Axis Response To 50 Mg Oral Naltrexone Compamentioning

confidence: 99%

Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

King

Schluger

Gunduz

et al. 2002

Neuropsychopharmacology

View full text Add to dashboard Cite

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“…For example, a number of studies have demonstrated that low doses of naloxone and naltrexone may be associated with hypoalgesia (Levine et al 1979;Woolf 1980;Dickenson et al 1981;Kayser and Guilbaud 1981;Ueda et al 1986;Vaccarino et al 1988;1989;Kolaric et al 1999), while still others have demonstrated hypoalgesic responding to more standard doses (Volavka et al 1979;Tassorelli et al 1995;Janssen and Arntz 1997;al'Absi et al 2004). For example, in a design that involved the repeated application of noxious electrocutaneous stimulation to the left ankle (i.e., similar to the pain stimulus applied in the present study), it was observed that a 4 mg dose of naloxone was associated with reduction in pain reports relative to a placebo condition (Janssen and Arntz 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have reported that naloxone has no effect on forearm ischemic pain (Grevert and Goldstein 1977;Grevert et al 1983a;Grevert et al 1983b;Posner and Burke 1985), cold pressor pain (Grevert and Goldstein 1978;McCubbin and Bruehl 1994), or electrocutaneous pain in response to stimulation applied to the finger (Bromm et al 1983), forearm (El-Sobky et al 1976), ear (Stacher et al 1988), or teeth (Ernst et al 1986). Finally, a few studies have suggested that, in some cases, opioid antagonists may actually inhibit pain (Volavka et al 1979;Tassorelli et al 1995;Janssen and Arntz 1997). More recent studies have also either failed to observe effects of opioid blockade on pain (McCubbin and Bruehl 1994;Mikkelsen et al 1999;Bruehl et al 2002;Edwards et al 2004), or have reported that the effects of opioid blockade varied as a function of subgroup membership (Schobel et al 1998;Bruehl and Chung 2006;McCubbin et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Nociceptive flexion reflex and pain rating responses during endogenous opiate blockade with naltrexone in healthy young adults

Al’Absi

Ring

Harju

et al. 2007

Biological Psychology

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The effect of opioid blockade on nociceptive flexion reflex (NFR) activity and subjective pain ratings was examined in 151 healthy young men and women. Using a within-subjects design, NFR threshold was assessed on two days after administration of either placebo or a 50 mg dose of naltrexone. Electrocutaneous pain threshold and tolerance levels were measured after NFR threshold assessment on each day. Results indicated that administration of naltrexone was consistently associated with hypoalgesic responding. Specifically, participants exhibited lower levels of NFR activity and reported lower pain ratings for electrocutaneous stimulation delivered at pain threshold and tolerance levels following administration of naltrexone as compared to placebo. These findings indicate that opiate blockade using the current standard dose may elicit hypoalgesia. A potential moderating effect of dose of opiate blockade medication and level of endogenous opioid activation should be carefully examined in future research.

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“…Another study found that nalmefene had no effect on serum prolactin in male rhesus monkeys (Mello et al, 2000), while another group found that nalmefene stimulated prolactin release in normal female rhesus monkeys but not in ovariectomized monkeys (VanVugt et al, 1989b). Naltrexone 50 mg stimulated prolactin release in normal male volunteers, early follicular phase female volunteers, and, following daily dosing for 1 week, in luteal phase female volunteers (Volavka et al, 1979;Mendelson et al, 1986;Gindoff et al, 1988), although, when studied in males, naltrexone 100 mg had no effect on prolactin (Volavka et al, 1979). In an all male study of oral nalmefene 10 mg, mean prolactin levels were not different compared to placebo-or naloxonetreated volunteers (Graves et al, 1993).…”

Section: Prolactin and Mu-and Kappa-opioidergic Drugsmentioning

confidence: 99%

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

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

123

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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 (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS 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 kappaopioid 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.

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Hormonal and Other Effects of Naltrexone in Normal Men

Cited by 30 publications

References 28 publications

Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

Nociceptive flexion reflex and pain rating responses during endogenous opiate blockade with naltrexone in healthy young adults

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

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