Sex Differences in Side Effects to Butorphanol and Morphine

Morphine is a prototypical mu-agonist and butorphanol is a mixed action opioid that acts as an agonist at kappa-opioid receptors. Both are potent analgesic drugs prescribed for moderate to severe pain, but they also produce significant side effects, including drowsiness, weakness, sweating, feelings of floating, euphoria, and nausea. We investigated the difference in side effects of morphine and butorphanol by gender in a single dose trial. Sixt-six healthy volunteers (36 female, 30 male) received intravenous butorphanol (.016 mg/kg) and morphine (.08 mg/kg) on two separate days in a randomized, double-blinded design. Responses to thermal, mechanical, and ischemic pain were assessed in all subjects, and all participants completed the Somatic Side Effects questionnaire (SSE) and the Cognitive/Affective Side Effects questionnaire (CASE). Also, current mood was assessed using the Visual Analog Mood Scale (VAMS) before and after drug administration. Statistical analyses indicated that overall the two drugs produced relatively equal analgesic effects for most pain stimuli. Regarding side effects, butorphanol produced significantly more side effects than morphine regardless of gender. While sex differences in somatic side effects to butorphanol and morphine were minimal, a few somatic effects such as “dry mouth,” “shortness of breath” and “unusual sensation in throat” were greater in women than men with butorphanol. In addition, with both morphine and butorphanol, men reported more pleasant cognitive-affective effects, such as euphoria and relaxation, than women. Also, butorphanol produced positive mood effects in men but not women. These data indicate that at relatively equianalgesic doses, butorphanol generally produces more side effects than morphine. Moreover, the pattern of sex differences in side effects was such that women reported slightly more somatic (unpleasant) side effects while men reported more pleasant cognitive-affective side effects. The implications of these findings for both medical and non-medical uses of opioids will be discussed.