The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain

Abstract

Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

“…42). Gear and colleagues (10)(11)(12)(13), in contrast, have reported that women are more sensitive to the inhibition of molar extraction pain by a number of nonselective -opioid analgesics including pentazocine. We observed a trend in the opposite direction presently: toward greater analgesia in nonredheaded men than women.…”

Formation of μ-/κ-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia

“…For example, there is little mechanistic understanding of why women are more likely than men to experience myriad chronic pain syndromes (1-3) as well as recurrent pain, more severe levels of pain, and pain of longer duration (10). Similarly, reports of more robust κ-opioid receptor (KOR) antinociception in females vs. males (11)(12)(13)(14) are not accompanied by compelling mechanistic rationales.In addition to proposed genetic contributions (15), the milieu of ovarian sex steroids is thought to contribute to sex-dependent nociception (5, 6) and opioid antinociception (5, 16). However, sex steroid molecular targets and their altered functionality that are relevant to sex-dependent nociception and opioid antinociception are not defined.…”

“…For example, there is little mechanistic understanding of why women are more likely than men to experience myriad chronic pain syndromes (1-3) as well as recurrent pain, more severe levels of pain, and pain of longer duration (10). Similarly, reports of more robust κ-opioid receptor (KOR) antinociception in females vs. males (11)(12)(13)(14) are not accompanied by compelling mechanistic rationales.…”

Molecular, Anatomical, Physiological, and Behavioral Studies of Rats Treated with Buprenorphine after Spinal Cord Injury

“…However, prolonged use of morphine may lead to tolerance and, subsequently, withdrawal symptoms (Fernández-Dueñ as et al, 2007;Ledeboer et al, 2007;Noble and Roques, 2007). In trauma, rat model compounds, such as butorphanol, nalbuphine, meperidine, pentazocine, and codeine, can be used to alleviate acute pain, but buprenorphine is the analgesic recommended by veterinarians due to its potency and long-lasting duration (Kaiko et al, 1983;Gear et al, 1999;Katzung, 2001;Roughan and Flecknell, 2002). Moreover, subcutaneously administration of 0.05 mg=kg reduces pain sensitivity after postoperative surgeries (Curtin et al, 2009).…”