Recent years have witnessed a dramatic increase in research regarding sex-related influences on the experience of pain . Several lines of evidence indicate that women are at greater risk for experiencing clinical pain. For example, many common chronic pain disorders are more prevalent in women than men, and population-based studies have demonstrated more frequent pain-related symptoms among women relative to men [2-7]. In addition to these epidemiologic findings, sex differences in the severity of clinical pain have been examined. Women reported greater pain than men following colonoscopy , and after oral surgery, women have reported greater pain intensity than men in some [9-11] but not other [12,13] studies. In addition, women reported greater pain severity following orthopaedic surgery [14,15]. Among children, girls reported more pain from venepuncture than boys in some studies [16,17] but others have shown no sex differences in pain among children undergoing medical procedures [18,19]. Studies of persons with chronic pain provide less consistent evidence of sex differences, as some investigators have reported greater pain and disability among women [20-23], while others have reported minimal sex differences in pain severity in chronic pain populations [24,25].
While a variety of biopsychosocial factors could account for these sex differences in clinical pain, growing evidence suggests that nociceptive processing differs as a function of sex. Two lines of evidence are particularly relevant here. First, women and men differ in their responses to experimentally induced pain, and second, more recent research suggests that certain pharmacological agents produce different levels of analgesia in women and men. This paper will focus primarily on sex differences in analgesic responses. First, methodological issues regarding the use of laboratory pain models in studying analgesia will be reviewed. Then, the literature on sex differences in responses to experimental pain will be summarized, followed by an overview of sex differences in analgesic responses. Finally, several potential mechanisms underlying sex differences in analgesia will be discussed.
Experimental pain methodology
In assessing analgesic responses in the laboratory, the choice of pain induction and assessment procedures is paramount. Multiple experimental pain methods are available, including mechanical, thermal, electrical, ischaemic and chemical stimuli (for detailed reviews see [26,27]). These stimuli differ along several important dimensions, including temporal characteristics, depth of tissue stimulated, selectivity of afferent fibers stimulated, and the clinical relevance of the pain experienced (Table 1). In addition, the same stimulus class can be delivered to different tissues. For example, both electrical and mechanical stimuli can be applied to skin, muscle and visceral structures. These factors are particularly relevant when investigating sex differences in analgesia for two reasons. First, the magnitude of sex differences in pain perception varies across stimuli. A recent meta-analysis found the largest sex differences emerged for pressure and electrical pain, and the smallest effects were evident using thermal stimuli . Second, analgesic responses vary across pain induction methods. In this regard, a recent study reported that cold pressor, pressure, and electrical pain stimuli were sensitive to alfentanil, while ischaemic and heat pain were not . In addition, even within a pain induction method, the depth of tissue stimulated can influence results. Another study reported that remifentanil produced greater analgesia for electrical pain applied to muscle compared to skin, suggesting that different depths of tissue stimulation are differentially susceptible to opioid analgesia . Clearly, no single pain induction method is ideal for all analgesic applications, and the choice of methodologies will depend on the specific aims of the research. In general, using multiple pain stimulation techniques is optimal, and the stimuli should be chosen to vary along important dimensions, such as temporal characteristics and the depth of tissue stimulated.
The primary criticism of experimentally-induced pain has been its inability to effectively mimic clinical pain. However, several experimental procedures produce pain that is thought to be highly clinically relevant. For example, temporal summation of thermal pain can be evoked using repetitive, brief, suprathreshold heat pulses, and the neurochemical mechanisms supporting temporal summation are thought to be involved in the central sensitization observed in many clinical pain conditions . Similarly, application of capsaicin, a selective C-fibre stimulant, produces spontaneous pain, central sensitization and hyperalgesia similar to symptoms observed in neuropathic pain . Because musculoskeletal pain is a common and disabling form of clinical pain, experimental models that elicit muscle pain are important. The submaximal effort tourniquet procedure produces ischaemic muscle pain, which is both clinically relevant and opioid sensitive [33,34]. Infusing hypertonic saline into a muscle can induce another form of muscle pain, and when maintained for a prolonged period of time, this pain produces perceptual qualities that match chronic clinical muscle pain . Thus, several laboratory methods are capable of producing clinically relevant pain.
The method used to assess pain assessment is another important issue. Unidimensional measures, such as pain threshold and tolerance, are frequently used, and have the advantages of being both quantitative and relatively easy to assess. However, they are overly simplistic and fail to reflect the multidimensional nature of the pain experience. Assessing both sensory and affective dimensions of pain is recommended, as previous research has indicated that some analgesic interventions and certain experimental manipulations may selectively influence affective versus sensory pain responses [36-39]. This has been accomplished using numerical scales, verbal descriptor scales, visual analogue scales, and combined verbal-numerical scales. Numerical scales provide the best ease of use but may not represent true ratio scales. Visual analogue scales have ratio scale properties ; however, they can be difficult to use in some settings and with certain populations. Verbal descriptor scales require some transformation to convert them to quantitative values, but there is evidence that these scales may discriminate sensory and affective dimensions of pain more effectively than visual analogue scales . Combined numerical-verbal descriptor scales retain the advantages of verbal descriptors while providing quantitative values, and these scales have been used successfully to distinguish affective and sensory pain dimensions . In addition to these perceptual measures, neurophysiological and autonomic indices can be employed, including muscle reflexes [43,44], pupil dilation , cardiovascular responses , and functional brain imaging [47,48]. As with pain induction, the ideal pain assessment methodology will depend on the question, and investigators are encouraged to include multiple measures of pain, including both perceptual and physiological responses.
Sex differences in experimental pain responses
Laboratory-based research suggests greater sensitivity to experimentally-induced pain among women relative to men across a variety of stimulus modalities and assessment methods [28,49,50]. Some of these findings are based on subjective responses, such that women have lower pain thresholds and tolerances and generally describe noxious stimuli as more painful. However, sex differences have been reported for less subjective measures as well. For example, women showed greater temporal summation of thermal pain, which is thought to reflect increasing responses to repeated pain due to sensitization in central neurons . Also, the nociceptive flexion reflex, which is a spinal pain-related muscle response, occurs in women at a lower stimulus intensity than in men , and women exhibited greater pupil dilation in response to painful pressure than men . It has also been demonstrated that some brain regions show greater activation during painful stimulation among women than men . However, another group of investigators reported more robust cerebral activation among males in responses to nonpainful rectal stimulation .
Thus, the bulk of the experimental evidence suggests enhanced pain sensitivity among females; however, the magnitude and consistency of these differences have been questioned . Recent research from our laboratory addresses this issue. We have examined sex differences in experimental pain responses using multiple modalities over the past several years, including heat pain, pressure pain, ischaemic pain, and cold pressor pain. The sample sizes are as follows: heat pain (92 F, 75 M), ischaemic pain (90 F, 70 M), pressure pain (36 F, 19 M), and cold pressor pain (36 F, 36 M). In order to examine the consistency of sex differences across pain procedures, we determined effect sizes for sex differences in pain threshold and tolerance as well as temporal summation of heat pain. The findings are presented in Figure 1. These data indicate moderate to large effect sizes across most stimulus modalities, with the exception of ischaemic pain, where effect sizes were small, indicating that sex differences are of at least moderate magnitude and emerge across multiple stimulation modalities.
Sex differences in analgesic responses
Non-human animal research
Considerable non-human animal research has examined sex differences in analgesic responses to a variety of pharmacological agents. In a recent review, Kest and colleagues  examined 50 opioid analgesic assays from studies conducted in rodents. These authors found that males exhibited greater analgesic responses than females in 28 (56%) assays, females showed greater analgesia in 2 (4%) assays, and no sex differences emerged in 20 (40%) assays, suggesting greater opioid analgesia among males. Even more recently, Craft  reviewed the data and concluded that both μ- and κ-agonists generally produced greater analgesia in males than females. Sex differences in the analgesia produced by non-opioid agents have also been reported. For example, cocaine produced analgesia in male but not female rats . In contrast, nicotinic agonists [56-58] and cannabinoids  produce greater analgesic responses in female than male rats.
Much information regarding sex differences in analgesic responses among human beings has derived from clinical research. In reviewing the literature on patient controlled analgesia for postsurgical pain, Miaskowski and Levine  found that women demanded less postoperative opioid medication; however, because pain relief was not assessed in many of the studies, sex differences in analgesic responses could not be directly determined. These investigators have also conducted a series of studies examining opioid analgesic responses among women and men using the third molar extraction postoperative pain model (for review see ). The first study reported greater analgesic responses among females compared to males for pentazocine but not morphine , and a follow-up study replicated this finding . Subsequently, these researchers found that females experienced more prolonged analgesia than males with the κ-opioid agonists nalbuphine and butorphanol . More recently, they have demonstrated that low dose nalbuphine (5 mg) produced hyperalgesia in men but no effect in women, while higher doses (10 and 20 mg) produced analgesia of longer duration in women than men . Using the same clinical model, no sex differences were reported in analgesic responses to ibuprofen .
While investigating analgesic responses in clinical settings has the advantage of direct clinical relevance, laboratory studies offer other advantages. For example, in clinical populations there is minimal experimental control over the painful stimulus, which can contribute to increased variability in patient responses. Laboratory pain induction methods offer tremendous stimulus control and even allow the experimenter to deliver multiple stimulus intensities. Also, using experimental pain, it is possible to deliver multiple pain stimuli that differ along important dimensions, such as temporal characteristics, sensory qualities, and depth of tissue stimulated. Moreover, experimental pain can be studied in healthy subjects in the absence of any pathophysiological process or potentially interacting medications, which represent more optimal conditions for answering basic scientific questions regarding analgesic responses.
In recent years, investigators have begun to examine sex differences in analgesia using experimentally-induced pain. Similar to their work in rodents, Eisenach and colleagues found that analgesic responses to spinally administered neostigmine were greater for women than men using a cold pressor pain stimulus . In contrast, the anti-inflammatory ibuprofen produced greater analgesia for electrical pain among men than women . Robinson and colleagues  used a mechanical pain stimulus and found that lidocaine produced greater cutaneous anaesthesia in men than women. With respect to opioid analgesia, Sarton and colleagues reported greater morphine analgesia among women than men using an electrical pain stimulus, and they also found that analgesia occurred earlier in men but lasted longer in women [66,67]. Zacny  has also recently examined sex differences in analgesic responses to three μ-agonists, morphine, meperidine, and hydromorphone, using two analgesic assays, mechanical pressure pain and cold pressor pain. The findings indicated that all three drugs produced equipotent analgesia in females and males for pressure pain; however, for cold pressor pain, analgesic responses were greater among females across all three drugs.
In an ongoing study in our laboratory we are examining sex differences in responses to morphine and pentazocine, using three different experimental pain induction procedures: cutaneous heat pain, mechanical pressure pain and ischaemic arm pain. Some preliminary findings from that project are presented below. This protocol involves double blind intravenous administration of pentazocine (0.5 mg kg−1) and placebo (saline) in counterbalanced order over two experimental sessions. In each experimental session, the three pain assessment procedures are conducted at baseline, and after a rest period drug is administered, and the pain assessment procedures are repeated post-drug. The pain measures include: pressure pain threshold assessed at the trapezius, heat pain threshold and tolerance assessed on the ventral forearm, temporal summation of heat pain assessed on the dorsal forearm, and ischaemic pain tolerance assessed using the submaximal effort tourniquet procedure. Methodological details of these procedures can be found elsewhere [51,69]. At this point, data for nine females, tested during the follicular phase of the menstrual cycle, and 11 males are available and are presented above.
For heat pain threshold, no significant effect of drug emerged (data not shown); however, for heat pain tolerance and pressure pain threshold, pentazocine produced a significant analgesic effect that was similar for females and males (Figs 2 and 3). Likewise, for temporal summation of thermal pain, similar reductions in pain were evident for females and males following pentazocine administration (data not shown). For the ischaemic pain procedure, pain tolerance was significantly increased by pentazocine among women but not men, and this sex × drug interaction was significant (P < 0.05, Fig. 4). These data suggest that pentazocine produced equipotent analgesia for women and men on the thermal and mechanical pain assays; however, sex differences in analgesia emerged for the ischaemic pain procedure. These data are based on a small sample and are preliminary in nature; however, along with the recent data by Zacny  they illustrate the importance of including multiple analgesic assays when investigating sex differences.
Thus, pharmacological interventions for pain often produce different effects in women and men; however, the pattern of results is not consistent across drugs and test conditions. Two recent reviews have noted that in contrast to the non-human animal literature, research in humans generally suggests greater opioid analgesia among women [54,55]. More limited data are available regarding sex differences in analgesic responses to non-opioid compounds. In addition, for opioids, it may be the case that sex differences in analgesia are more robust for tonic, deep pain stimuli (e.g. cold pressor, ischemic pain) than for phasic, superficial pains (e.g. thermal, pressure pain). Obviously more work is needed before firm conclusions can be drawn.
Mechanisms underlying sex differences in responses to analgesics
Addressing the mechanisms underlying sex differences in analgesia is complicated by several factors. First, the opposite direction of the sex differences in non-human animal versus human research makes it difficult to generalize mechanistic findings derived from non-human animal research to humans. Second, as Craft  has noted, several methodological (e.g. pain assay, efficacy of the opioid) and other (e.g. hormonal status, genotype) variables may influence findings regarding sex differences in analgesia. Third, multiple mechanisms inevitably interact to produce sex differences in analgesia, and these mechanisms likely differ across species, analgesic agent and pain assay.
Several possible mechanisms have been suggested to explain sex differences in opioid analgesia [54,55,70], and these may apply to other analgesic agents. For example, sex differences in drug metabolism or disposition could contribute to sex differences in analgesia. Indeed, differences in metabolism of morphine have been reported in rodents (see ), but a recent study found no differences among humans . Another possibility is that the sensitivity or density of receptors for a given drug may differ across sex. Conflicting findings exist regarding sex differences in opioid receptor density among rodents , but human research suggests greater μ-opioid receptor binding among women than men in certain brain regions , and μ-opioid receptor binding in the amygdala and hypothalamus was inversely correlated with circulating oestrogen among women in the follicular phase . The relevance of these findings to opioid analgesic responses remains to be determined.
Another potential mechanism explaining sex differences in analgesia is the influence of gonadal steroids. In a recent review, we  noted that 'hormonal conditions characterized by elevated oestrogen either alone or accompanied by increased progesterone levels are associated with increased responses to painful stimuli and diminished analgesic responses to stress and opioid pharmacotherapy (p 490).' For example, Banerjee et al. reported decreased analgesic responses to morphine in female rats in late pro oestrus. In addition, gonadectomy was reported to produce increased analgesia in females and decreased analgesia in males to clonidine and pilocarpine . Following ovariectomy, oestrogen and progesterone replacement, either alone or in combination, reduced morphine analgesia in female rats . Interestingly, long-term oestrogen replacement in ovariectomized rhesus monkeys enhanced κ-opioid analgesia but did not alter analgesic responses to μ-agonists . These findings indicate hormonal effects on analgesia; however, it is important to recognize that these results derive exclusively from non-human animal research, and their generalizability to humans is not known.
It is also important to consider psychosocial factors that may contribute sex differences in analgesic responses among humans. For example, both placebo analgesia and nocebo anti-analgesia have been well-documented, and these are based on expectancies of decreased pain and increased pain, respectively [77-80]. Sex differences in placebo/nocebo responses have not been investigated; however, it is possible that women and men possess dissimilar pain-related expectancies, which may differentially influence pain and analgesia. In addition, other psychosocial factors, including mood and pain coping, differ in women and men , which may impact analgesic responses. For example, women report higher levels of anxiety , which has been associated with both increased reporting of physical symptoms  and greater sensitivity to experimental pain [84-86]. Moreover, preoperative anxiety predicts postoperative pain and analgesic consumption [87-90]; therefore, it seems feasible that anxiety could affect analgesic responses. The contribution of such psychosocial factors to sex differences in analgesia has received minimal empirical attention, and future research in this area is needed.
Conclusions and future directions
The findings reviewed herein suggest several conclusions. First, experimental pain models can provide important and unique information regarding sex differences in analgesic responses. Second, non-human animal research suggests larger opioid analgesic responses among males, while human studies indicate that women experience greater opioid analgesia. Whether this is a species effect or is related to other aspects of the methodologies used remains to be determined. Several potential mechanisms underlying sex differences in analgesia have been suggested, including gonadal steroids, genotype, differences in central opioid receptor density or sensitivity, and psychosocial factors. At this point, sex differences in analgesia are well documented, but the nature and practical implications of these effects have not been fully delineated.
Previous authors have suggested important avenues for future research, including using more clinically relevant experimental pain models to test analgesic responses, examining sex differences in non-analgesic effects of opioids (e.g. side effects, physiological responses), further investigation of hormonal influences on analgesia, and analysis of data by sex in analgesic clinical trials [55,70]. In addition, most research on sex differences in analgesia has examined opioids, and investigation of responses to other analgesic compounds is needed. Also, whether long-term administration of opioids or other centrally acting analgesics differentially affects females and males should be determined, since most studies have involved only acute drug administration. Finally, the clinical relevance of sex differences in analgesic responses needs to be established. Are the effects of sufficient magnitude to warrant different dosing schedules in women and men? Should the choice of analgesic agent be based on the sex of the patient? The answers to these questions are not yet available; however, continued research using both clinical and experimental pain models will yield such answers and lead to enhanced pain management for patients of both sexes.
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VA Medical Center, Gainesville, FL. This work was supported by NIH/NINDS grant NS41670.
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