Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers

Abstract

Nalbuphine (Nubain®) is a mixed action mu-kappa agonist used clinically for the management of pain. Nalbuphine and other mu-kappa agonists decreased cocaine self-administration in preclinical models. Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effects of nalbuphine on the HPA axis are unknown. Analgesic doses (5 and 10 mg/70 kg) of IV nalbuphine were administered to healthy male cocaine abusers, and plasma levels of PRL, ACTH and cortisol were measured before and at 10, 17, 19, 23, 27, 31, 35, 40, 45, 60, 75, 105, 135 min after nalbuphine administration. Subjective effects were measured on a Visual Analog Scale (VAS). Prolactin (PRL) increased significantly within 17 min (P=.04) and reached peak levels of 22.1 ± 7.1 ng/ml and 54.1 ± 11.3 at 60 min after low and high dose nalbuphine administration, respectively. VAS reports of "Sick," "Bad" and "Dizzy" were significantly higher after 10 mg/70 kg than after 5 mg/70 kg nalbuphine (P=.05−.0001), and were significantly correlated with increases in PRL (P=.05−.0003). However, sedation and emesis were observed only after a 10 mg/70 kg dose of nalbuphine. Interestingly, ACTH and cortisol levels did not change significantly after administration of either dose of nalbuphine. Taken together, these data suggest that nalbuphine had both mu-and kappa-like effects on PRL (PRL increase) but did not increase ACTH and cortisol.

Opioid and cocaine combined effect on cocaine-induced changes in HPA and HPG axes hormones in men

“…In normal healthy volunteers, these doses of nalbuphine and morphine have been shown to produce similar subjective and physiological effects (Zacny et al, 1997). However, 10 mg/70 kg nalbuphine produced emesis and sedation as previously reported by our group (Goletiani et al, 2007), therefore, a lower dose of 5 mg/70 kg was used for all 7 subjects. Nalbuphine doses of 5 or 6 mg/70 kg have proven to be safe and to induce changes in positive subjective effects (e.g., High, Like Drug Effects, Feel Drug Effect) (Preston and Bigelow, 2000; Zacny et al, 1997).…”

Novel pharmacology: asimadoline, a κ‐opioid agonist, and visceral sensation

“…Table 1 summarizes the cumulative safety of asimadoline from several clinical trials involving somatic pain and visceral pain syndromes. It is worth noting that symptoms like polyuria with high dose asimadoline suggest aquaresis, an effect of κ‐opioid agonists that is associated with increased serum prolactin, 58,59 possibly mediated through inhibition of dopaminergic tuberoinfundibular dopaminergic neurons 60 which are outside the blood–brain barrier.…”

Evaluation of Therapies for Peripheral and Neuraxial Opioid-induced Pruritus based on Molecular and Cellular Discoveries

“…107 Nalbuphine is a mixed antagonist of the μ-opioid receptor and agonist of the κ-opioid receptor, and because of its partial antagonism of the μ-opioid receptor, reversal of analgesia remains a concern. 109 Another potential limitation of nalbuphine is its sedating side effect, 19,133 although this is only observed when a high dose (10 mg/70 kg) is used, 139 which is beyond the range used to manage pruritus clinically. 24 In contrast, butorphanol is a partial agonist of both the μ- and κ-opioid receptors.…”