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From the *Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Psychology, The City University of New York, New York.
Address correspondence and reprint requests to Prof. Dr. Albert Dahan, Department of Anesthesiology, Leiden University Medical Center, P5-Q, 2300 RC Leiden, The Netherlands. Address e-mail to a.dahan{at}lumc.nl.
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Abstract |
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 Top Abstract IntroductionCONCLUSIONSREFERENCES |
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, and 
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. |
Introduction |
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TopAbstractIntroductionCONCLUSIONSREFERENCES |
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-, and -opioid receptors. Recently, a fourth opioid-receptor was identified, the opioid receptor-like type 1 (ORL1) receptor. The opioid system is involved in responses to pain, stress, reward, and emotion, and has a modulatory influence on physiological functions, such as control of breathing, thermoregulation, nociception, appetite, and the immune response.1 The opioid system displays marked differences among individuals in its pharmacological and physiological effects. Evidently, this is the cause of the large response variability in the effects of exogenous opioids in the delivery of adequate analgesia in patients with acute and chronic pain. Animal studies, particularly those using inbred strains of mice and rats, show that the variability in the antinociceptive responses to opiates is related, in part, to genetic differences in pain sensitivity (a phenomenon which is dependent on the applied nociceptive assay), genetic differences in the sensitivity to exogenously administered opioids, and to the variable response of the endogenous opioid system to pain and stress.2–4 There are also numerous studies reporting that the variability in responses to opioids is attributable to subject/patient sex. The current state of this literature and the possible underlying causes for any putative sex differences are the subject of this review. Sex differences are not restricted to the analgesic properties of opioids, but are also present in other opioid-mediated responses, such as those involving locomotor activity, the respiratory system, learning and memory, addiction, and the cardiovascular system. In the current review, we will address the issue of sex-differences in opioid-mediated responses in humans with a special focus on antinociception/analgesia and opioid side effects. We will review the increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids. Studies included for review were identified by two initial online searches of PubMed (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed;U.S.NationalLibraryofMedicine), the first using the keywords "sex differences" and "opioids" and the second using "sex differences" and "analgesia." Relevant articles referenced in these initial reports were also included for review, and these were in turn also used to identify additional reports. Every effort has been made to provide as compressive a review as possible at the time of manuscript submission. Finally, it is important to note from the outset that there are equally as many preclinical and clinical studies reporting sex differences in pain perception/nociception per se, as well as in the expression and tolerance of pain.5,6 These studies also indicate that such differences are attributable to biological determinants. It is thus possible that these sex differences manifest as unequal opioid analgesia even where opioids are equally effective in each sex. Some of the studies described in the present review have indeed implemented experimental designs or analysis to account for this possibility. At a minimum, however, one should appreciate (and be mindful) that sex differences in pain-related processes might confound the perceived magnitude and direction of sex differences in opioid analgesia.
Animal Studies
Ligands acting at µ, , , and ORL1 opioid receptors (OR) cause uneven effects on nociception. These are discussed in turn immediately below and summarized in Table 1.
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Despite the apparently greater sensitivity of males to the prototypic µ-OR agonists morphine and DAMGO, it is not possible to generalize about sex differences in µ-OR. For example, there are no analgesic differences between male and female rats on either the hotplate or tail-withdrawal assay after systemic administration of fentanyl.34 Instead, the presence and magnitude of sex differences on the tail-withdrawal assay may be related to the relative efficacy and potency of the opioid tested. Indeed, such a hypothesis was suggested by Cook et al. who compared males and females after systemic administration of dezocine, morphine, etorphine, and levorphanol, µ opioids varying in potency and analgesic effectiveness.20 Furthermore, although male rats display significantly greater DAMGO analgesic magnitude on the tail-flick test relative to female rats after ICV injections, there were no sex differences in ED50 values derived from the DAMGO dose–response curve, nor were there sex differences in either magnitude or ED50 values on the jump test.28
The magnitude and direction of analgesic sex differences for morphine and other µ opioids also appear to interact with other factors unrelated to the opioid or nociceptive modality tested. For example, the magnitude of sex differences after systemic µ opioid administration differed between Fisher 344 and Lewis rats20 and between Sprague-Dawley and Wistar-Furth rats.17 Nonetheless, a pattern of greater analgesia in males was a consistent finding for all strains. In mice, the presence, magnitude, and direction of sex differences in morphine analgesia after ICV administration differed among 11 genetically distinct inbred strains.30 The influence of genotype on sex differences is not limited to morphine analgesia. In a study examining central DAMGO analgesia in mice selected from Swiss-Webster stock for high and low stress-induced analgesia, high stress-induced analgesia male mice, but not low stress-induced analgesia male mice, displayed greater analgesic potency than their female counterparts.29 Age has also been shown to interact with sex in the modulation of morphine analgesia. Whereas there is an age-related increase of peak and total (area under the curve) morphine analgesia in male rats, female rats display an age-related decrease, although at a low dose females may actually show an enhanced response.8 Finally, sex differences fluctuate throughout the day in mice and are maximal during the dark period, during which opioid sensitivity is greater in males.11 Collectively, these data indicate that µ-OR analgesia may depend on the specific opioid tested, the route of administration and nociceptive assay used, the method used to quantify analgesia, and intrinsic factors such as genotype and age.
- and - Opioid Receptor Agonists
Sex differences in the analgesic effects of opioids acting at the - and -OR types have also been reported (Table 1). Similar to µ-OR analgesia, sex differences in rats may be dependent on several variables, including the opioid, dose, and assay used as well as the interval between opioid administration and nociceptive testing. For example, there were sex differences in latency to peak analgesia on the tail-withdrawal test (females, 5–15 min; males, 30 min) but not the hotplate test after injecting the -OR agonist U69,593.34 In the same study, the -OR agonist bremazocine produced more analgesia in females compared with males at some dose and time points on both assays. As with µ opioids, there is evidence that sex differences in opioid analgesia in rats is strain-dependent. For example, male F344 and SD rats were consistently more sensitive to the effects of bremazocine, enadoline, and nalorphine than their female counterparts.36 However, these opioids caused equipotent analgesia in male and female Lewis rats. As with µ opioids, it has been suggested that the magnitude of sex differences in opioid analgesia is related to opioid efficacy. This supposition is based on the finding that sex differences are more robust when testing bremazocine, enadoline, and nalorphine, opioids with low efficacy, than those observed with the relatively more effective opioids, spiradoline, and U50,488.36
Sex differences in the magnitude of -OR analgesia are also observed in mice, with males displaying greater analgesia than females on the hotplate after the -OR selective agonist U-50,488H.11 There were no sex differences in analgesia in response to -OR of [D-Ser2, Leu5]enkephalin-Thr6 (DSLET),27 an enkephalin-containing ligand, on the tail-flick or hotplate test. Subsequent studies have resolved the -OR into distinct subtypes, termed 1 and 2.39 Their respective selective agonists, [d-Pen2, d-Pen5]enkephalin (DPDPE) and deltorphin, caused analgesia in rats that displayed sex differences at some doses on the hotplate test but not the tail-flick test, with significantly less analgesia in females than in males.34 Additionally, the time to peak DPDPE analgesia also differed between males (15–30 min postinjection) and females (5 min postinjection).
ORL1 Receptor Agonists
There are few studies assessing sex differences caused by ORL1 receptor agonists on nociception. It has been reported that there are no sex differences in either the supraspinal antianalgesic effects40 or the spinal analgesic effects41 of the endogenous ORL1 receptor ligand orphanin FQ (OFQ/nociceptin). In contrast, it has also been reported that intrathecal microinjection of OFQ produced a significant increase in the tail-flick latency in male, ovariectomized female, and diestrous female rats.42 OFQ in that study, however, failed to produce antinociception in proestrous females and in gonadectomized males. The authors of this study suggest that estrogen attenuates OFQ antinociception in females, cooperatively working with the normal cycling of estrogen levels, whereas testosterone is necessary for the expression of antinociception in males. Administering OFQ via the ICV route has also been shown to reduce N-methyl-d-aspartate (NMDA)-induced scatching behavior by 92% in the male and 96% in ovariectomized female rats, but enhanced this behavior by 210% in proestrous females.43
Buprenorphine has also been identified as a full ORL1 agonist through the use of a receptor gene assay.44 Systemic administration of buprenorphine produced more analgesia in male compared with female rats on the tail-withdrawal test.20,22,23 In contrast, Bartok and Craft found no analgesic differences between male and female rats on either the hotplate or tail-withdrawal assay after subcutaneous administration of buprenorphine.34 To fully investigate the agonistic effects of buprenorphine on sex differences, more behavioral studies with different routes of administration, noxious modality assays, doses of buprenorphine, and rodent strains must be conducted.
Mechanisms of Sex Differences in Opioid Analgesia
The mechanism(s) underlying sex differences in opioid analgesia remains elusive. The larger concentration of morphine in the brain of male mice relative to female mice after systemic injections suggests simple sex differences in drug disposition.10 However, in rats, there are no differences in morphine serum levels between sexes at times corresponding to the drug’s peak analgesic effect.7 Additionally, the larger magnitude of analgesia observed in male mice29,30 and rats20,22,27,28,32,33,36 relative to female counterparts after the administration of opioids directly into the CNS makes sex differences in opioid pharmacokinetics an unlikely explanation of sex differences in opioid analgesia. Sex differences in opioid analgesia are also not likely related to differences in supraspinal OR density, because there are no differences between male and female rats in brain µ- or -OR populations.27 In mice, studies of sex-related differences in brain OR populations yield conflicting results; one study reported increased levels in males45 whereas another reported no differences between sexes.10 The relation between OR density and sex differences in analgesia is further rendered tenuous by the report that male mice display increased sensitivity to morphine analgesia relative to females after chronic opioid antagonist treatment, despite no effect of sex on the degree of OR upregulation.10 Nonetheless, Loyd and Murphy46 report on a sexual dimorphism of the anatomical and functional organization of the periaqueductal gray-RVM (PAG-RVM) pathway, supraspinal regions critical in opioid analgesia, and descending pain inhibition. Using retrograde tracing combined with Fos immunocytochemisty, they found that morphine causes significantly greater suppression of complete Freund’s adjuvant-induced Fos in PAG neurons in males than in females. Retrograde labeling also indicated that females have significantly more PAG-RVM output neurons in comparison with males. They suggest that activation of this circuit could account for sex differences in morphine analgesia.46
Sex differences in opioid analgesia may also result from sex differences of the endogenous neurochemical systems that participate in the analgesic response. For example, the endogenous opioid peptides leu- and met-enkephalin can also affect morphine potency,47 and sex differences in their density has been shown in the rat.48,49 In this regard, it is worth noting that the activity of endogenous opioid peptides are terminated by several proteolytic enzymes,50 and that the antinociceptive effects of enkephalinase inhibition are larger in males.51 Sex differences in the antiopioid effects of the endogenous peptides Tyr-MIF-1, neuropeptide FF,12,13 and nociceptin-orphanin FQ41,42 on morphine analgesia in mice have also been reported. Finally, selective blockade of NMDA-sensitive excitatory amino acid receptors significantly decreases µ-OR (morphine) and -OR (U69,593) analgesia in male mice only,18,24,52 suggesting that different neural substrates underlie even equipotent opioid analgesia in males and females.
Sex Hormones and Opioid Analgesia
Given the ubiquitous actions and sex differences of sex steroids in the CNS, it is not surprising that many investigators have attempted to relate sex differences in opioid analgesia to gonadal hormone levels. A summary of these studies is presented in Table 2. Indeed, estrous phase modulates the expression of morphine analgesia. Whereas intact rats are more sensitive to the analgesic effects of morphine on the mornings of diestrous,53,54 and proestrous53–55 after systemic administration, the magnitude of morphine analgesia is larger during proestrous and estrous after its administration directly into the CNS.28 However, in mice, opioid sensitivity does not vary throughout the estrous cycle.56
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Ovariectomized subjects have been used repeatedly in the literature.19,22,54 Ovariectomized females compared with sham-operated controls show increases in systemic morphine analgesia on the hotplate test16 and on the tail-withdrawal test.22 However, no significant effect is observed in a visceral nociceptive assay.9 Because ovariectomy also increased supraspinal morphine analgesic sensitivity against electric shock and thermal nociception (i.e., tail-flick test),32 it might be argued that gonadal hormones have different effects on different nociceptive modalities. Although adult ovariectomy has been reported to reduce the magnitude but not potency of morphine analgesia on the tail-flick test in rats after central27 and systemic53 administration, morphine analgesia after systemic administration has also been reported to be increased17 or not changed.7 Therefore, conflicting results are also observed using the same nociceptive assay. Exposure to estradiol or progesterone replacement therapy in ovariectomized rats decreased morphine analgesia on the hotplate and tail-withdrawal tests,22 although the effect of the lower progesterone dose varied with time of treatment.57 In intact rats, however, simulating pregnancy concentrations of estradiol 17 and progesterone in nonpregnant rats increased responsiveness to the -OR agonist U-50,488H after spinal administration.58
The effect of gonadectomy on morphine analgesia in male rats and mice is similarly inconsistent. There are reports of reduced,22,59 increased,22 and unaltered7,17 systemic morphine analgesia on the tail-flick test in castrated rats. Castration also reduces analgesia on the paw-withdrawal test in response to variety of systemically administered µ opioids.60 Thus, the effects of castration may be nociceptive modality-specific. Similar to results in female rats, ICV morphine injections in castrated male rats also produces analgesia on the tail-flick and jump tests that is reduced in efficacy but not potency.27 This effect may be CNS region-dependent because morphine potency after microinjection into the ventrolateral PAG in castrated male rats is slightly increased.32 Generalizations cannot be made from morphine to other µ-OR agonists because gonadectomy failed to consistently affect analgesia produced by ICV injections of DAMGO.28 Gonadectomy was similarly without effect on the -OR analgesia of DSLET.28
In castrated male mice, morphine analgesia is increased on the hotplate test and against abdominal writhing induced by acetic acid16 but decreased on the tail-flick,10,22 and paw-withdrawal tests.61 Testosterone reversed the attenuated morphine sensitivity of the castrated rat.22,59 In fact, whereas estradiol 17-β and progesterone had no significant effect on morphine potency in intact male rats, testosterone produced biphasic effects, first enhancing (30 min) then attenuating (4 h) systemic morphine analgesia.59 Testosterone, but not estradiol 17-β or progesterone alone or in combination, also restored morphine potency in ovariectomized and postpartum rats, in which normal ovarian activity is halted.19,21,53 These findings suggest that testosterone regulates morphine sensitivity in female rats. However, the progesterone metabolite 17-
-hydroxyprogesterone had no effect on morphine analgesia per se but antagonized the effect of testosterone in restoring morphine sensitivity in ovariectomized rats,53 suggesting an interaction between ovarian steroids in modulating morphine potency. Ovariectomy also eliminates the age-related attenuation (see section µ-Opioid Receptor Agonists above) in the potency and magnitude of morphine analgesia relative to intact females, but castration had only marginal effects on the increased morphine analgesia observed in aged males.8 Finally, the role of gonadal hormones in the adaptive changes after chronic morphine may differ between the sexes because ovariectomized rats developed somewhat less morphine tolerance than estradiol-treated females,17 but castration and testosterone supplementation does not affect morphine tolerance in males.60
The effect of gonadal/hormonal manipulation on morphine analgesia has not been restricted to adults. Systemic morphine analgesia after neonatal gonadectomy in male rats is decreased on the hotplate test.19 In the same study, neonatal testosterone treatment in females increased analgesia on the hotplate test. Similar results were obtained when analgesia was elicited by the direct microinjection of morphine into the ventrolateral PAG.21 That is, neonatally gonadectomized males tested in adulthood displayed severe reductions in morphine analgesia on the tail-flick and jump tests compared with sham-operated controls, and resembled vehicle-treated females. Furthermore, females androgenized neonatally displayed substantial increases in morphine analgesia on the tail-flick and jump tests compared with vehicle-treated females when tested in adulthood, and resembled the sham-operated males.21 Collectively, these results demonstrate the important contribution of sex steroids in the developing rat brain to morphine analgesia in adulthood.
It should be noted that sex steroids exert widespread short- and long-term effects on cellular physiology and organization and, as can be appreciated by a review of Table 2, there is significant variability among studies with regard to the age of the animals at the time of, and the latencies between, ovariectomy, hormone replacement therapy, and nociceptive testing. This lack of uniform methodology may contribute to the discrepancies in the literature.
Mechanisms of Sex Hormone Action on Opioid Analgesia
Apparent inconsistencies notwithstanding the mechanism by which gonadal hormonal milieu may modulate opioid analgesia remains unknown. For example, there are conflicting reports regarding the effect of castration on ORs. Whereas increased OR density has been reported for rats,62 other investigators report no changes in OR density or affinity in rats and mice.10,63,64 In female rats, ovarian steroid treatment and ovariectomy alters brain opioid binding sites.65–67 This regulation may occur at the level of the gene as progesterone increases levels of µ-OR mRNA in hypothalamic regions of ovariectomized, estradiol-treated rats.65 However, as noted previously, it is unlikely that sex differences in OR binding in intact mice or rats is a viable explanation for sex differences in analgesia. Kepler et al.27 suggest that the colocalization of opioid and gonadal steroid receptors in the mesencephalic central gray and amygdala may allow gonadal hormones to modulate opioid analgesia.48,49,68 They also suggest that gonadal hormones interact with transmitters relevant to opioid analgesia (e.g., serotonin and the opioid peptides leu- and met-enkephalin), whose concentrations differ in males and females in these regions. Indeed, estradiol has been shown to control opioid peptide synthesis in the hypothalamus at rates that differ between the sexes and throughout the estrous cycle in females,69,70 and ovariectomy alters levels of the opioid peptides leu- and met-enkephalin and dynorphin A and B.48,71,72 In this context, Krzanowska and Bodnar32 suggested that their observation of sex differences in morphine analgesia after microinjections into the ventrolateral PAG may result from this region’s interaction with estradiol-containing hypothalamic nuclei, and ultimately, its opioid peptide content. The relevance of these interactions in the analgesic effects of morphine and other opioids, however, has not been shown.
Opioid Tolerance
One consequence of repeated opioid exposure is a decrease in its analgesic potency (i.e., tolerance), which, like opioid analgesia, may be influenced by sex. To our knowledge, all preclinical studies have focused exclusively on morphine. In one study, for example, there was a significant reduction of morphine analgesia on the hotplate and jump tests in male rats treated with morphine for 14 days.37 Females, in contrast, displayed no tolerance on the jump test and less tolerance on the hotplate test. Male rats were similarly more tolerant than females to morphine analgesia on the hotplate test after twice-daily or once-weekly morphine injections and, intriguingly, recovered their morphine analgesic potency more rapidly after the discontinuation of chronic morphine treatment.38 In addition to sex difference in magnitude, males also develop tolerance more rapidly.17,38,73 That castrated male rats also develop morphine tolerance more slowly than testosterone-pretreated females indicates that testosterone contributes to the sex difference in the rate of tolerance onset, possibly by regulating morphine clearance.73 Greater morphine tolerance in males is also reported when analgesia is measured after a variety of morphine dosing schedules and a range of temperatures on tail-withdrawal test.17,38,74 However, others report similar rates of tolerance induction between the sexes on the tail-withdrawal test75 or that the demonstrated sex difference is nullified when the initial sex difference in acute morphine analgesia is considered.23 Also, whereas only female Long-Evans rats exposed to continuous morphine infusion (20–22 mg/kg/24 h) for 7 days were tolerant on the hotplate test, only males were tolerant on the tail-withdrawal test.76 Some of these discrepancies may have resulted from testing females at different stages of the estrous cycle. As evidence, it has been reported that only male and proestrous female rats develop acute morphine tolerance on the tail-withdrawal test.77,78 Ovariectomized females, and those in all other estrous phases, were refractory to tolerance. Gonadectomy also abolished tolerance sex differences on the tail-flick test in rats.74 Other methodological differences, such as the strains,26 morphine dosing, and nociceptive testing variables used, may also have confounded data from one study to the next. Within a single study of morphine analgesic tolerance using mice, for example, 3 and 7 days of systemic morphine injections produced significant, but unequal, rightward shifts in the morphine dose–response curve with greater ED50 value increases (i.e., greater tolerance) in females relative to males.79 However, when analgesic data from other mice in the same study were analyzed using the common indices of % maximum possible effect or area under the curve, there were no sex differences in tolerance. It should be noted that, although morphine tolerance is exhibited on the tail-flick test in neonatal rats, the magnitude of analgesic loss is not affected by sex.80 Thus, the ontological development of any sex difference in morphine tolerance in rodents remains to be determined. However, maternal separation can differentially impact male and female susceptibility to morphine tolerance in later adulthood.76
Several approaches have been used to describe the basis for putative sex differences in tolerance. To asses the relevant CNS loci in mice, one study assessed systemic morphine analgesia after chronic intrathecal morphine injections. Although this spinal opioid pretreatment increased ED50 values in both males and females, significantly larger increases were detected in females.81 Since these authors also reported that chronic ICV morphine injections induced tolerance of equal magnitude in male and female mice,82 the data collectively suggest that sexually diergic spinal opioid analgesic mechanisms contribute to greater analgesic tolerance in female relative to male mice after chronic systemic morphine exposure.79 Other studies assessed possible sex differences in receptor function, such as opioid receptors coupled to excitatory second messengers. These receptors, which have been proposed to contribute to morphine tolerance, were blocked using ultra-low doses of the wide-spectrum opioid receptor antagonist naltrexone. Whereas naltrexone enhanced morphine analgesia per se, it did not eliminate sex differences in the ensuing tolerance.26 In contrast to excitatory opioid receptors, there is evidence that the NMDA receptor system may contribute to sex differences in tolerance. Cerebrospinal fluid dialysates collected from the n. accumbens show that glutamate concentrations are decreased 30% in male rats but increased 200% in females subsequent to chronic morphine.74 We already noted above that ovariectomized females are refractory to tolerance77,78 and, in this study, gonadectomy decreased glutamate levels in females but not in males, implicating an estrogen-sensitive mechanism.74 However, this contribution may be limited to the species, strain, and or/drug tested as NMDA receptor blockade with MK-801 or CPP produced the opposite results, disrupting the development of morphine tolerance in male, but not female, C57BL/6J mice.83 The inability of NMDA receptor antagonists to inhibit tolerance did not appear to be regulated by sex hormones as ovariectomized mice were similarly insensitive to MK-801. The authors of that study concluded that the mechanisms underlying female insensitivity to NMDA receptor antagonists are likely to be different from those mediating the sex difference in NMDA receptor modulation of acute morphine analgesia previously reported. Finally, the ability of flumazenil to attenuate the development of morphine tolerance in female rats while having negligible effect on males25 suggests a contribution of 
-aminobutyric acid receptors to sex differences in morphine tolerance.
Human Studies
In initial studies that compared the analgesic effects of opioids in men and women, sex comparisons were not the primary focus of investigation, resulting in inadequate controls for confounding variables, such as underlying disease, age, and opioid plasma concentrations. In 1999, Miaskowski and Levine reviewed all available studies (n = 18, studies published from 1966 to 1998) on µ-opioid patient-controlled analgesia (PCA) for postoperative pain that listed data from men and women.84 In 10 studies, opioid consumption was higher in men than in women, whereas in the remainder, no differences were found between the sexes. In more recent prospective studies comparing PCA opioid consumption during the first days postoperatively higher opioid use in men was a consistent finding.85,86 A major problem with these PCA studies in this context that they study opioid consumption rather than analgesia. Opioid consumption may be affected by other factors than just postoperative pain, such as baseline pain sensitivity, expectation, fear (e.g., of addiction), and the occurrence of nausea/vomiting. For example, the higher occurrence of nausea/vomiting in women may cause less opioid consumption in this group. Furthermore, since onset times of opioids may differ between men and women,86 studies that assessed pain scores and opioid efficacy during the first hours postoperatively would yield different results from studies that used an extended study period (>4 h postoperatively, see also below).87,88 Also, none of the studies on PCA morphine corrected for body weight differences between the sexes. Finally, for all clinical pain reports, it is important to know that sex differences in opioid use and efficacy may reflect sex differences in reporting pain and seeking pain relief and by unwarranted psychogenic attributions made by health care providers regarding pain in one sex but not the other.89–93
We will discuss prospective experimental human and clinical studies that were designed a priori to examine sex differences in opioid effect. Where possible we will address confounding issues.
-Opioid Receptor Agonists
In three studies Gear et al. showed that -opioid analgesics (nalbuphine, butorphanol, and pentazocine) but not morphine produced more intense and prolonged pain relief in women than in men after dental surgery (molar extraction).94–97 In contrast to these data, Mogil et al.98 and Fillingim et al.,99 using three experimental pain models (heat pain, pressure pain, and ischemic pain), showed that pentazocine (0.5 mg/kg) produced significant analgesia of similar magnitude in men and women. None of these studies provided information on the opioid plasma concentrations, a highly relevant variable, since sex differences in pentazocine pharmacokinetics have been described (t
elimination is greater in women than in men).100 The discrepancy between studies is best explained by the differences in pain models.99 During and after dental surgery, other drugs (e.g., benzodiazepines, nitrous oxide) may have contributed to the observation of sex differences. However, most importantly, dental pain has a strong inflammatory component that is absent in acute pain models. Finally, the dental surgical pain model addresses the analgesic properties of opioids, whereas in the experimental studies, antinociception was studied.
Mogil et al. were the first to relate sex-differences in -opioid analgesia with one specific gene, the melanocortin-1 receptor (MC1r) gene.98 First, they showed linkage of distal mouse chromosome 8 to -opioid analgesia in female but not in male mice. Using a candidate gene strategy, they demonstrated that it is the MC1r gene that mediates -opioid analgesia in female mice only. In agreement with their animal data, Mogil et al. observed that women (but not men) with two or more variant alleles of the MC1r gene (all with red hair) displayed significantly greater antinociception from pentazocine than women without variants (or with just one variant) of the MC1r gene. In humans, variants of the MC1r gene are associated with red hair, fair skin, freckles, and high chance of melanoma (60% of red heads have at least two variant alleles of the MC1r gene).101 The MC1r gene had not been related to noninflammatory acute pain before, but MC1 receptors are present in brain areas involved in modulation of nociception. The authors argue that MC1r activation by endogenous neuromodulators (-MSH but possibly also dynorphin) produces antiopioid actions in females only. Interestingly, the MC1r gene is also associated with µ-opioid analgesia, but in a non–sex-specific manner.101 The µ-opioid morphine-6-glucuronide produced significantly greater antinociception in males and in females with at least two variant alleles of the MC1r gene and in e/e mice (mice with a dysfunctional MC1r gene). This indicates that the MC1r gene is an anti µ-opioid gene in both sexes.
µ-Opioid Receptor Agonists
We were the first to compare the analgesic effects of morphine in men and women and link these effects to plasma concentrations using a pharmacokinetic–pharmacodynamic modeling design.102 We studied healthy volunteers using an experimental electrical pain model and came to three important conclusions: (i) morphine is more potent in women than in men (as expressed by the C50 values); (ii) the onset/offset of morphine is slower in women than in men; and (iii) plasma concentrations of morphine and its two major metabolites, morphine 6- and 3-glucuronide, were identical in the two sexes. These conclusions are important, as they may explain why studies on PCA morphine for postoperative pain relief show that women require more morphine in the first hours after surgery before adequate analgesia sets in.87,88,103 For example, various authors observed that women required up to 20%–30% larger morphine titration doses, compared with men.87,88 The two to three times slower onset of action of morphine in women (possibly due to a slower passage of morphine across the blood–brain barrier) and the need for rapid analgesia is the cause for the larger opioid dose requirement in women, as was elegantly shown in a simulation study by Sarton et al.102 Interestingly, Aubrun et al.88 showed that this sex effect disappears in elderly patients, suggesting a hormonal effect on the passage of morphine across the blood–brain barrier.
Some studies on the effect of morphine on analgesia observed the absence of sex dependency97,99 or observed that gender effects were reliant on the specific pain model used.104 For example, Zacny104 found sex differences in morphine analgesia in the cold pressure test but not for pressure pain; Fillingim et al.99 observed similar analgesic responses in men and women after 0.08 mg/kg morphine in heat, pressure, and ischemic pain models. Furthermore, µ-opioids other than morphine, such as alfentanil and morphine’s active metabolite, morphine-6-glucuronide, cause analgesic responses of similar magnitude in the two sexes in an electrical pain model.105,106 Finding the causes for these differences in study results on µ-opioids is not simple. Various factors may contribute: the very low opioid doses tested in some studies (as a consequence the study is performed at the initial flat part of the dose–response curve, an area where sex differences do not present themselves)99,104; differences in pain models; the absence of reporting on plasma drug concentrations; the timing of the pain assessments (see above); differences in specific end-points; and, finally, differences in the opioids used (different opioids may activate different opioid receptor splice variants or recruit different intracellular G-proteins).
µ-Opioid Receptor-Related Side Effects
Opioids have multiple side effects which range from not harmful (such as itch, nausea/vomiting, constipation, hallucinations) to potentially life-threatening (sedation and respiratory depression). However, the side effects considered minor in the eyes of the physician cause severe discomfort to the patient (e.g., itch and nausea/vomiting). Several studies addressed the interaction of sex and opioid side effect and it is safe to state that, in general, women experience more side effects and with greater intensity.
Nausea and Vomiting
In a retrospective study of 8855 patients, Cepeda et al.107 observed 50% less nausea in men than women (odds ratio = 0.5) after short-term administration of an opioid (meperidine, morphine, or fentanyl) for pain treatment after minor surgery. Similar observations have been by others.108,109 Fillingim et al.99 observed even larger sex differences in a prospective study on morphine-related side effects in healthy volunteers (nausea in women 35% versus in men 3%). These findings are in agreement with the general notion that women experience more postoperative nausea and vomiting which, at least partly, is due to the administration of opioids for acute pain relief.
Respiratory Depression
Graff et al.110 examined retrospectively the influence of conscious sedation with the combination fentanyl/midazolam on respiratory events in a pediatric patient population (1–8 yr). They observed respiratory events in 11% of patients with an increased risk in female patients (odds ratio = 2.4). This observation was not replicated in an adult population.107 The most compelling evidence of the existence of sex difference in opioid-induced respiratory depression comes from two prospective placebo-controlled studies from our laboratory on the effect of morphine on the control of breathing.111,112 We observed both qualitative and quantitative differences between sexes with greater morphine-induced respiratory depression in females. These findings are in-line with the greater morphine analgesic potency in women, compared with men,102 and suggest a common underlying mechanism.
Cardiovascular Effects
Fillingim et al.99 observed that the cardiovascular response to morphine differed between men and women with the development of hypertension in men but not in women after 0.08 mg/kg IV morphine. However, morphine was associated with lower heart rate values in women. But, more importantly, the cardiovascular response to ischemic pain was attenuated in men only. The observed differences were small, however, and only one low morphine dose was tested. We therefore suggest that these preliminary results are followed by more elaborate gender studies on opioid-induced cardiovascular changes.
Subjective Effects
In a retrospective analysis of six studies, Zacny113 examined the subjective and psychomotor side effects of morphine as a function of sex. He observed distinct differences in subjective side effects but none in motor function. Women experienced more frequently and more intensely the feeling of being "high" (spaced out), a heavy feeling and a dry mouth.
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Despite evidence of sex-related differences, variability inpatient opioid analgesic sensitivity should compel practitioners to customize their dosing regimens based on individual requirements. The studies presently reviewed suggest that patient gender may contribute to this variability. We also note that sex differences in analgesia are not limited to opioid drugs. Differences in analgesic sensitivity between males and females are observed after administration of diverse classes of non-opioid compounds, such as ibuprofen, nicotine, cocaine, and cholinergic and noradrenergic agonists.115–117 Furthermore, activation of endogenous pain inhibitory mechanisms in response to stress also produces magnitudes of analgesia that differ between the sexes, irrespective of whether analgesia is mediated by endogenous opioid peptides.118 These data would suggest that sex differences in analgesia arise from seemingly fundamental and ubiquitous differences in endogenous pain inhibitory circuitry. Further studies are needed to clarify the conditions in which patient gender considerations will afford the most effective use of opioids for the control of pain.
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opioid-induced antinociception. Psychopharmacology 2002;160:170–181[Medline]This article has been cited by other articles:
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  K. Gelb and A. W. Gelb Sex and Gender in the Perioperative Period: Wake Up to Reality Anesth. Analg., July 1, 2008; 107(1): 1 - 3. [Full Text] [PDF]
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