Corticotropin-Releasing Factor Testing Reveals a Dose-Dependent Difference in Methadone Maintained Vs Control Subjects

Abstract

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 mg/kg) and one dose higher (2.0 mg/kg) than the dose used in standard clinical diagnostics (100 mg), 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 (po0.05). 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.

Chronic Morphine Sensitizes the Brain Norepinephrine System to Corticotropin-Releasing Factor and Stress

“…Previous studies provided evidence for dysregulation of the hypothalamic-pituitary-adrenal axis by chronic opiates (Kreek and Koob, 1998;Houshyar et al, 2001;Schluger et al, 2003). Given the role of the LC-NE system in stress and its regulation by opioids, this system presents an additional potential target through which chronic opiates could act to dysregulate the stress response.…”

“…One consequence that may contribute to drug-seeking behavior is dysregulation of the stress response (Kreek and Koob, 1998;Houshyar et al, 2001;Schluger et al, 2003). Dysregulation of the stress response may additionally predispose chronic opiate users to stress-related diseases.…”

The Impact of Diacetylmorphine on Hypothalamic-Pituitary-Adrenal Axis Activity and Heroin Craving in Heroin Dependence

“…Drug-related cues, stress or negative mood are associated with craving [2,3,4,5]. Several previous studies have shown the relevance of stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction in substance use disorders [6,7,8,9,10,11]. …”

The Stress Respond, Related To the Opioid Abstinence And Detoxification: literature review

“…Opioidinė priklausomybė yra susijusi ir su sutrikusia stresinio atsako funkcija pagumburio-hipofizės-antinksčių ašyje (toliau -PHA) [12]. Atliktoje klinikinėje studijoje, kurioje nuo opioidų priklausomiems, bet ilgą laiką nevartojusiems asmenims dirbtiniu būdu (naudojant metyraponą -medžiagą, laikinai blokuojančią kortizolio sintezę organizme) buvo sukelta farmakologinė gliukokortikoidų sintezės blokada, pasireiškė toks pat subjektyvus opioidų pavartojimo efektas kaip po tikros heroino dozės.…”