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From the Department of Anesthesiology and Critical Care Medicine, Division of Pain Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
Address correspondence and reprint requests to Robert W. Hurley, MD, PhD, Anesthesiology and Critical Care Medicine, 600 N. Wolfe St., Osler 292, Baltimore, MD 21287. Address e-mail to rwhurley{at}hotmail.com.
Abstract
Traditionally, biomedical research in the field of pain has been conducted with male animals and subjects. Over the past 20–30 yr, it has been increasingly recognized that this narrow approach has missed an important variable: sex. An ever-increasing number of studies have established sex differences in response to pain and analgesics. These studies have demonstrated that the differences between the sexes appear to have a biological and psychological basis. We will provide brief review of the epidemiology, rodent, and human experimental findings. The controversies and widespread disagreement in the literature highlight the need for a progressive approach to the questions involving collaborative efforts between those trained in the basic and clinical biomedical sciences and those in the epidemiological and social sciences. In order for patients suffering from acute and/or chronic pain to benefit from this work, the approach has to involve the use or development of clinically relevant models of nociception or pain to answer the basic, but complex, question. The present state of the literature allows no translation of the work to our clinical decision-making.
The terms "sex" and "gender" are not synonymous. According to the Institute of Medicine definition, sex is "the classifications of living things, generally as male or female according to their reproductive organs and function assigned by the chromosomal complement." Gender is "a person's self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual's gender presentation."1 The lack of semantic precision in the literature can and has led to confusion and faulty conclusions.
A large body of data has been collected in the past 20 years concerning differences between the sexes in response to pain, including pain thresholds, and in the tolerance and response to pain treatment. However, the exact differences, as well as their relevance, are far from clear. According to the International Association for the Study of Pain, "pain is an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage." This definition does not differentiate between "pain" as a woman experiences it from "pain" as a man experiences it, and thus fundamental questions still remain. If there are differences, are they the result of nature or nurture or a combination of both? Or are the differences noted in the literature a result of a known or unknown testing bias? If there are differences, do they matter for our clinical management of acute and chronic pain?
This brief review is intended as an introduction to the history of the field of sex differences in pain medicine and as a discussion of the state of the literature. Our intent is to highlight some of the ambiguities that have developed in the field. It is hoped that this summary will spur future research into sex differences and pain but will also make clinical investigators aware that there are differences and they should be considered in the design of future studies.
The National Library of Medicine's PubMed database, EMBASE, PsychInfo, OVID/Medline were searched for the time period from the databases inception to September 1, 2007. Terms for the primary search were ("gender" OR "sex") AND ("pain" OR "analgesia" OR "antinociception"). "AND" and "OR" represent Boolean search terms. The search was furthered narrowed by limiting it to humans or animals in the English or translated literature where relevant. Attempts were made to restrict the manuscripts to those addressing "sex" or "gender" as a primary goal of the study not a secondary finding.2 The search was further narrowed to examine specific medications including drugs from the following classes: local anesthetics, N-methyl-d-aspartate modulators, opioids, 
-adrenergics, anticonvulsants, and antidepressants (Table 1). These medications were queried by adding the generic or trade name of specific medications to the primary search; for example ("Neurontin" OR "gabapentin") AND ("gender" OR "sex") AND ("pain" OR "analgesia" OR "antinociception").
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EPIDEMIOLOGY OF SEX DIFFERENCES IN PAIN MEDICINE
Females report more severe pain, more frequent bouts of pain, more anatomically diffuse and longer-lasting pain than males with similar disease processes, even when male and female specific disorders, including male urologic and female gynecologic pain, are excluded from the analysis. Females have a more frequent prevalence of pain related to musculoskeletal or to visceral origin, as well as pain related to autoimmune disease (Table 2).3 Substantial amounts of the accumulated data are from animal models, which rely heavily upon the objective but indirect signs of the pain or, more precisely, the nociceptive experience.4 However, human research models are highly influenced by sociocultural variables that have little to do with a biological difference of pain threshold or sensation between women and men. These sociocultural variables influence the social interaction between the human subjects and their experimenters, which can confound their reporting of the pain experience, resulting in biased or confounded data. There is an inherent reporting bias in the epidemiological research related to the incidence of pain in the sexes. Females are more likely to visit a physician and are more likely to report pain as a symptom than males5,6 [reviewed in Ref. 7], which can therefore lead to an over-estimation of the differences between the sexes. Furthermore, the incidence of specific pain syndromes or pain related to certain disease states is not absolute; it changes as people age8 and as their diseases progress.9 In an effort to reduce these biases, there has been substantial research in rodents, in which it is assumed many of these variables can be controlled and therefore removed from consideration.
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ANIMAL MODELS
Baseline Differences
Differences in pain thresholds between male and female rodents have been explicitly studied during the last 20–30 yr, but it has only been over the past 15 yr that this issue has gained the prominence and the attention it deserves.10 It has become "well accepted" that female rodents have a lower pain threshold in experimental models of hot thermal,11–15 chemical,16–18 inflammatory,19–21 and mechanical nociception.22,23 Mixed results among the animal models are most likely due to study design variation, but potentially also to the rodent population being tested. Studies with divergent results when examining thermal and inflammatory nociception considered additional variables in their study design, such as rodent population genotype.24
The nature of the animal injury either transient or persistent also has an impact on the sex differences in pain testing.25 In animal models of persistent nociception, such as neuropathic or inflammatory injuries, the results are mixed. In neuropathic pain models, some investigators have not found a difference between males and females,23 whereas others have found differences dependent on rat strain, with females having a more robust response to injury. Still other researchers have reported inconsistent findings.26–28 Furthermore, the developmental rate of self-injurious behavior or autotomy after sciatic nerve destruction was lower in female rats.29 Others have found the response amplitude to neuropathic injury to be the same, but the resultant duration of hyperalgesia to be longer, in female rats.26,30 Female rodents appear to have a longer lasting response to inflammatory injuries in some experimental models20 but not in others.25,31 Interestingly, using the Brennan et al. model of postincisional pain,32 there were no sex differences in tests of mechanical allodynia or hyperalgesia.33,34 This model of nociception could be considered one of the more clinically applicable or valid pain models. It involves an incision to the hindpaw of a rodent under brief anesthesia and produces a mixed inflammatory/neuropathic and nociceptive "injury" similar to that in humans after minor surgical procedures.
In order for conclusions to be drawn regarding sex differences in experimental models of nociception, a large trial assessing all variables known to affect pain thresholds and tolerance including, but not limited to, strain, age, bedding, food, acute versus persistent nociception, and modality of noxious stimulus needs to be conducted. Until such a trial is conducted, the most clinically relevant animal models for extrapolation to humans, including the Brennan et al. postincisional model and the various models of complex regional pain syndrome type II (or causalgia) such as the sciatic nerve injury model, show either no difference or modest differences between male and female animals.
Nondrug Induced Antinociception
In addition to baseline differences in nociceptive threshold or in response to transient injury, female rodents respond differently than male rodents to nondrug induced antinociception. Stress-induced antinociception (SIA) is the most common category of environmentally induced antinociception. Male rodents appear to have greater SIA resulting from numerous techniques, including forced cold water swim,35–37 mild electroshocks,38 restraint39,40 and predator exposure.41 The results with exercise-induced analgesia (EIA), which is considered a form of SIA, are somewhat different. EIA stimulates decreased sensitivity to morphine-induced analgesia in male and female rats, potentially due to the increased endogenous B-endorphin levels.42
Drug-Induced Antinociception
Opioids
Since 2000, more than 70 papers (excluding reviews) have been published on the topic of sex differences in the response to opioid antinociception in animals. Forty-three directly tested the hypothesis that male and female rodents respond differently to opioid-induced antinociception. Male rodents had a more robust response to opioids in 70% of these studies. However, 19% of these studies found that males and females had an equal response, and 11% showed that females had a greater antinociceptive response. Although most studies adjusted dosage for weight, plasma concentrations of opioids were not measured throughout the main body of the literature. This leaves the question of pharmacokinetic effects on sex differences unresolved.
Opioid analgesia is unlikely to be a uniform phenomenon because there are a minimum of three separate endogenous opioid receptors: µ, 
, and 
. These receptors are differentially located throughout the neuraxis and periphery and have disparate functions, depending on location as well as receptor subtype.43–46 In more than 90% of the papers showing a male predominance of antinociception, a µ opioid receptor agonist was used. Interestingly, in five studies in which females had a greater antinociceptive response to opioid receptor agonists, four used a opioid receptor agonist.17,47–49 The remaining study examined the effect of morphine antinociception after early maternal separation in rat pups, which alters endogenous steroid production and postnatal development.50 Opioid receptor agonists, similar to µ opioid receptor agonists, produce antinociception in some animal models of pain. The dissimilar response between males and females to these subtype agonists lends further credence to the notion that opioid-induced analgesia is not a uniform "opioid class" effect. However, this should not be interpreted to mean that µ opioid receptor agonists are antinociceptive in males and opioid receptor agonists are antinociceptive in females. Two recent studies51,52 examined receptor agonists in rats and mice and found that males had a greater response than females. This response contradicts earlier work17,47–49 and is similar to the antinociceptive response of rodents to µ receptor agonists. Although the behavioral results are conflicting, genetic studies appear to support a biological basis for the µ/ dichotomy between the male and female response to opioid agonists. Indeed, Mogil et al.52 discovered the gene for melanocortin-1 receptor (MC1r) mediated opioid agonist antinociception in female but not in male mice. In the absence of this gene, female mice had an enhanced antinociceptive response to opioids. This gene mutation has no known effect on µ opioid receptor-induced antinociception. Although most literature demonstrates a more robust response of male rodents, this may be the result of multifarious variables including receptor subtypes. Future studies should control potentially important baseline variables, such as rodent strain, and to explore the opioid receptor subtypes.
Other Drugs
Unlike the relative abundance of literature around the question of sex differences in the response to opioid administration in animals, there is a paucity of research regarding the use of any of the more common analgesic medications (Table 1). The most commonly investigated class of non-opioid agonists is the indirect and the direct-acting cholinergic agonists.53 These drugs show male predominant antinociception in most studies,53 but not all studies.34 This will not be further discussed here as cholinergic agonists are not currently in common use for analgesia in pain medicine.
The next most commonly studied class of drugs is the -adrenergic medications. Systemically administered clonidine has consistently been found to be more effective in producing antinociception in male rodents in models of acute thermal nociception.54–59 However, Kroin et al.,34 using the clinically applicable Brennan et al. model of postincisional nociception, reported the absence of a sex difference after intrathecal administration of clonidine. The other non-opioid drugs unfortunately have little supporting data and have each only been examined by a single laboratory. Baclofen was found to have similar results to µ opioid receptor agonists and clonidine, demonstrating male predominance of antinociception.54 Gabapentin,34 paroxetine,60 cannabinoids,58,59 and ketamine54 were found to have no sex difference. The newly developed anticonvulsant, lacosamide, produced a greater amount of antihyperalgesia in females in the clinically relevant spinal cord injury model of nociception.61 The dearth of information makes it difficult to infer whether sex determines efficacy of non-opioid analgesics.
Unfortunately, the testing of clinically applicable analgesics on animals of either sex has not provided any greater clarity. The greatest amount of data supports the current belief that, among the opioid compounds, µ opioid agonists produce significantly greater antinociception in males and agonists produce greater antinociception in females than in males. Unfortunately, recently performed, methodologically rigorous studies have brought the previously accepted notions into doubt.34
HUMAN MODELS
In 1994, the United States National Institutes of Health mandated that all human clinical trials supported by National Institutes of Health funds have a representative sample of females. This decision was based on the accepted and assumed biological differences between females and males, including the differences in pain thresholds and analgesic response to pain medications.
Superficially, the determination of pain thresholds in human subjects appears to be a simpler experimental paradigm. Humans, unlike rodents, can verbally express the sensory and affective components of a painful stimulus. The investigator is therefore not forced to use indirect reflexive responses to determine the point at which the stimulus crosses the threshold from innocuous to noxious. Experimentation with humans has obvious external validity that is lacking in animal research. However, human research presents manifold challenges. The straightforward challenge is that the human experimentation is expensive, and that subjecting people to painful stimuli for research can be difficult to defend to the Institutional Research Review Board. More importantly, the painful stimuli that can be used are transient (e.g., thermal—cold or heat, chemical—capsaicin, and mechanical—algometry) and may represent only a subset of clinical pain, thus reducing its validity. Although some of the testing regimens simulate acute pain, there are not sufficient data to extrapolate to persistent and/or neuropathic pain states. The intricate challenges to objective data collection in humans include the fact that human response to pain is influenced by numerous social, cultural, and psychological variables that are not uniform to one sex or the other.
In a meta-analysis of studies examining sex differences in pain response in healthy subjects <60-yr-old, the authors found that women report higher pain severity at lower thresholds and have less tolerance to noxious stimulation than males.62 The greatest sex differences were noted in tests examining mechanical pain via a pressure algometer or calibrated calipers. The second largest effect size was in electrical noxious stimulation, followed by thermal and ischemic stimuli. Interestingly, the most common stimuli used to test sex differences in animals has traditionally been thermal stimulation vide supra. In a large multicenter trial, Rolke et al.63 used quantitative sensory testing to determine sensory detection thresholds and pain thresholds for thermal and mechanical noxious stimuli. The results demonstrated a similar trend: females had lower pain thresholds, but the modalities were not in the same rank order. The greatest disparities for sex differences were found for heat pain threshold, followed by cold pain and pain to blunt pressure.
Many other physiological, sociocultural, and psychological variables have been identified as contributing to the differences between the two sexes with regard to pain. One set of factors includes the reproductive status and menstrual cycle of female subjects.64 A number of pain states, such as temporomandibular joint disorder, are more commonly diagnosed in women but only after puberty.65 Furthermore, pain thresholds have been found to be lower in females during their menses.66 Stening et al.67 found that women in low progesterone and high estradiol states had pain thresholds that were not different from men. During the low estradiol phase of the menstrual cycle, females were found to have higher pain scores to persistent noxious stimulation.68 This has been attributed to a reduction in endogenous opioid receptor activation in brain regions associated with analgesia when compared with the high estradiol state. The age of the subject also modifies the pain threshold. Advancing age is positively associated with pain threshold.63,69 Pickering et al.70 found that the difference in score between males and females decreased with advancing age. The significant sex difference seen in thermal and mechanical threshold and in tolerance in younger volunteers became nonsignificant in volunteers older than 40-yr-old.
Another influential factor includes the "pain" end-point being examined, such as pain threshold versus pain tolerance.62,70,71 Pool et al.72 showed that pain tolerance is highly malleable and strongly influenced by the subject's "gender" norms. Males who are highly identified with the "male" role tolerate higher levels of noxious stimuli, but those males who do not have this belief tolerate noxious stimuli at the same level as females. Stereotypical social gender roles also influence pain threshold differences. In two very revealing studies, the investigators showed that the gender of the experimenter influences the response and pain threshold of the subjects. Male subjects reported less pain and had higher thresholds when tested by a female examiner.73 This effect was accentuated when the examiner of the opposite sex was attractive. Male subjects, again, had lower reports of pain and higher thresholds with the attractive female examiner; interestingly, females reported more pain and had lower thresholds with attractive male examiners.74 Therefore, the examiner introduces a substantial testing bias and entirely different results are produced if a male subject is tested by a male examiner (no sex difference) versus a female examiner (large sex difference).
Subject coping strategies can also be important in pain threshold modulation. Maladaptive pain coping strategies, such as catastrophizing, have been associated with poorer adjustment to clinical pain and higher sensitivity to experimental pain.75–78 Importantly, higher catastrophizing among women than men has been reported, and can account for the sex difference.79–81 Edwards et al.82 further examined this issue and found that controlling for negative affect and catastrophizing did not fully explain the sex differences in threshold or tolerance but these factors have large effect sizes on their own.
As discussed above, the sex difference in humans is neither a universal nor a large effect. Furthermore, no difference between sexes is found in at least one-third of the published studies, and effect sizes are often in the small to moderate range.62 Other investigators have sought objective measures of pain as a result of the numerous factors that have been shown to influence, and in some cases abolish the pain threshold and tolerance differences between the sexes. Paulson et al.71 used positron emission tomography (PET) to investigate regional brain activation after a painful somatic thermal stimulus in healthy normal volunteer male and female subjects. They reported that females had significantly greater activation of the contralateral prefrontal cortex, the contralateral insula and the thalamus compared with males, suggesting sexual dimorphism in response to pain. Unfortunately, the investigators used a standardized thermal stimulus at 40°C or 50°C and therefore did not match the thermal stimulus subjective pain intensity between males and females. Thus, this study reflected a difference in brain activation that was more likely the result of different perceived pain intensities rather than a true sex difference. In a later study, also using PET technology, the pain intensity was matched between the sexes and the results were the opposite of the earlier study, males had greater activation than females.83 Finally, a study using matched pain intensity and functional magnetic resonance imaging (fMRI) showed no sex-based difference in brain activation.84 Other PET studies have described sex differences in responses to visceral pain from rectal balloon distension, although principally with chronic visceral pain patients.85,86 However, the differences reported were predominantly in the direction of greater activation in men. These studies were replicated using fMRI with similar results of a male predominance of neuronal activation in pain-related areas of the brain.85
In summary, pain thresholds in humans vary by internal factors such as sex, gender, age, female menstrual phase, and psychological variables, including catastrophizing, anxiety, and depression. External factors also affect the outcome including testing environment, sex, and gender of the examiner, and the modality of the noxious stimuli. In the largest study assessing the role of sex on pain thresholds using multiple modalities, it was found that females had lower pain thresholds in thermal and mechanical pain testing.63 Unfortunately, this subjective difference has not been consistently supported by other confirmatory techniques including PET or fMRI brain imaging. Awareness of the possible differences between males and females in response to pain is the only clinical application of the present data with no guidance for particular situations.
Nondrug Induced Analgesia
SIA has very different effects on humans than on rodents. For instance, stress produces a pain threshold increase in male rodents, whereas stress in humans results in either no difference between the sexes or female predominance.87–89 EIA in humans produces similarly disparate findings. In two studies in which the participants were required to do isometric exercises90 or run on a treadmill,89 females had the greatest increase in pain thresholds and tolerance.
Drug-Induced Analgesia
Unlike the abundance of literature addressing the question of drug-induced sex differences in experimental pain in rodents, the human literature is not as voluminous. Most literature addresses the response to µ opioid receptor agonists and the remainder addresses opioid receptor agonists. As far as we know, there has not been testing of other clinically available medications on humans in models of experimental pain. With respect to µ opioid receptor agonists, primarily morphine, human females have a very different response than their rodent counterparts. In multiple studies, either no difference91–93 was noted between sexes or females had a significantly greater response to the medication.94–96 Although initial studies attributed the difference to a pharmacokinetic difference,97 the metabolism of morphine to morphine-6-glucuronide, more recent work by Romberg et al.92 demonstrates that there is no sex difference in morphine-6-glucuronide concentrations. To further exclude pharmacokinetic explanations for the sex differences, the same investigative group subsequently published findings using the potent synthetic µ opioid receptor agonist alfentanil. The subjects’ responses to alfentanil did not differ based on their sex.98
The human response to opioid receptor agonists is not fully elucidated. In a postsurgical model of pain, females had a greater analgesic response to agonist-antagonist medications, including pentazocine, nalbuphine, and butorphanol.99–101 However, in experimental models of pain either no difference between males and females was noted102 or males had an increased sensitivity to the medications.52 Currently, there is no cohesive theory that would explain these conflicting results. Mogil et al.52 suggest that the increased responsiveness of males to opioid receptors agonists may be related to the absence of the MC1r gene. In an elegant study, this group studied women with fair skin and red hair who often have a functional reduction in MC1r. The women with a genetically proven loss of function polymorphisms experienced an accentuated analgesic response to pentazocine similar to the mice without the MC1r gene. Their analgesic response was indistinguishable from the male subjects in the study.52 This finding has led to the proposal that the MC1r gene product acts as an anti-opioid and, therefore, when removed, unmasks the full opioid analgesic effect. Thus females with a subpopulation of MC1r deficient members would have an enhanced "population" effect in comparison to males with a full MC1r complement. However, this does not explain the lack of difference or the greater analgesic response of females to µ opioids in clinical and experimental models. Unfortunately, the data with regard to opioid analgesics garnered from human trials are not sufficient to guide clinical practice. The studies do not justify the conclusion that males or females have a greater responsiveness to µ or opioid receptor agonists and therefore they should continue to receive similar pain management until more definitive studies are conducted.
CONCLUSION
Although this review is, by necessity, an overview of an enormous, active and growing field, it is intended to provide the history of the field from, and the rationale for, the basic science work in rodents progressing to the clinical experimental work in humans and the mandatory inclusion of females in all clinical trials of medications that are intend for either sex. Both the animal and human literature are rife with disagreement and conflicting findings within each species and, importantly, between each species. This supports the thesis that more work needs to be done to elucidate the common/basic biological and psychological factors that produce the differences that are described. These are important questions not just for the satisfaction of simple intellectual curiosity, but also to allow the pain practitioner to offer more focused or empirically guided therapy to his or her patients.
Footnotes
Accepted for publication January 22, 2008.
Supported by NIH grant MH075884.
REFERENCES
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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M. L. Chin and R. Rosenquist Sex, Gender, and Pain: "Men Are from Mars, Women Are from Venus ..." Anesth. Analg., July 1, 2008; 107(1): 4 - 5. [Full Text] [PDF]
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