A number of studies have shown differences between males and females in the pain-attenuating or analgesic effects of opioid drugs. In most of the animal studies, males achieved greater opioid-induced analgesia than did females. Of the three studies systematically examining gender and opioid analgesia in humans, there appears to be a gender difference except that it is in the opposite direction to that in animals: females achieve greater analgesia from opioids than do males. The effect appears to be specific to those opioids that have significant agonist activity at the kappa receptor, in that morphine, a full mu agonist, resulted in equivalent degrees of analgesia in males and females. These human studies are an excellent start for addressing an issue of clear clinical importance: the role of gender in opioid analgesia. It may be the case that females in pain would receive better analgesia from some opioids as opposed to others. However, such a notion is premature at this point, since the three studies used only single doses of drug, studied only one full mu agonist, and examined only one type of pain. In this grant application the investigators propose to conduct a behavioral analysis of opioid pharmacodynamics in order to characterize the potential modulating role of gender in opioid effects. The primary endpoint will be analgesia, but other variables will be tested as well, including mood and psychomotor performance. In two studies, healthy volunteers will be exposed to either full mu agonist (Study 1) or mixed agonist-antagonist (Study 2) opioids. A cumulative dosing procedure will be used so that multiple doses of each opioid will be tested, and two pain assays will be employed to induce cold and pressure pain. From the results of these two studies, the following questions (specific aims) can be addressed: a) Is there a gender difference in humans in opioid- induced analgesia? b) Is the gender difference as likely to occur with full mu agonists as with mixed agonist-antagonists? c) Within the class of full mu agonists and within the class of mixed agonist-antagonist drugs that have substantial kappa agonist activity are there uniform gender differences or do gender differences depend on the particular drug, and/or dose of drug within a class being tested? d) If there is a gender difference is it modulated by the type of pain being administered? e) If there is a gender difference, is it manifested in magnitude (peak) of drug effect or in duration of drug effect, or both? and f) If there is a gender effect, is it specific to the behavioral endpoint of analgesia or is it a generalized phenomenon that cuts across other variables such as mood and psychomotor/cognitive performance?

R01DA012330

1998-09-30

2001-08-31