Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n=15, effect size 0.22, 95% c.i. 0.02-0.42, P=0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n=11, effect size=0.36, 95% c.i. 0.17-0.56, P=0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n=11, effect size=0.35; 95% c.i. 0.01-0.69, P=0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n=7, effect size 0.84; 95% c.i. 0.25-1.43, P=0.005), but no sex-analgesia association was present in experimental studies (n=7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.

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Sex differences in the neurochemical mediation of swim stress-induced analgesia (SSIA) were examined in Swiss-Webster mice. Intact and gonadectomized adult mice of both sexes were tested for their analgesic response (hot-plate test) to 3 min of forced swimming in 15 degrees C and 20 degrees C water. SSIA resulting from 15 degrees C swim was previously shown to be naloxone-insensitive (i.e., non-opioid) whereas SSIA resulting from 20 degrees C swim produced an analgesia that was partially reversible by naloxone (i.e., mixed opioid/non-opioid). The non-opioid components of these SSIA paradigms were attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). We now report that in males, but not females, dizocilpine (0.075 mg/kg, i.p.) and naloxone (10 mg/kg, i.p.) antagonized the non-opioid and opioid components of SSIA, respectively. After ovariectomy, females displayed a pattern of antagonism similar to males such that dizocilpine attenuated non-opioid SSIA, although naloxone remained ineffective in antagonizing 20 degrees C SSIA. Thus, SSIA in intact females was neither opioid- nor NMDA-mediated, yet it was of similar magnitude to the SSIA displayed by intact males. In separate experiments, estrogen replacement (estrogen benzoate; 5.0 micrograms/day, i.p.) administered to ovariectomized mice over a 6-8 day period reinstated the dizocilpine-insensitivity of 15 degrees C SSIA characteristic of intact females. However, a similar estrogen regimen administered to both intact and castrated males did not compromise the sensitivity to dizocilpine previously noted in male mice.(ABSTRACT TRUNCATED AT 250 WORDS)

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It is widely reported that analgesic drugs acting at mu, kappa, and delta opioid-receptors display quantitative and qualitative differences in effect in males and females. These sex-related differences are not restricted to the analgesic/antinociceptive properties of opioids, but are also present in opioid-induced side effects, such as changes in respiration, locomotor activity, learning/memory, addiction, and changes in the cardiovascular system. An increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids show that, although sex may affect opioid analgesia, the direction and magnitude of sex differences depend on many interacting variables. These include those specific to the drug itself, such as dose, pharmacology, and route and time of administration, and those particular to the subject, such as species, type of pain, genetics, age, and gonadal/hormonal status. In the current review, we systematically present these animal and human studies and discuss the data in relation to the depending variables. Although the observed sex differences in opioid effect may be clinically relevant, lack of knowledge on other factors involved in the large variability in patient opioid analgesic sensitivity should compel practitioners to customize their dosing regimens based on individual requirements.

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