Sex Differences In Pain Research Articles

Sex and Gender Differences in Central Nervous System-Related Disorders.

There are important sex differences in the brain that seem to arise from biology as well as psychosocial influences. Sex differences in several aspects of human behavior and cognition have been reported. Gonadal sex steroids or genes found on sex chromosomes influence sex differences in neuroanatomy, neurochemistry and neuronal structure, and connectivity. There has been some resistance to accept that sex differences in the human brain exist and have biological relevance; however, a few years ago, it has been recommended by the USA National Institute of Mental Health to incorporate sex as a variable in experimental and clinical neurological and psychiatric studies. We here review the clinical literature on sex differences in pain and neurological and psychiatric diseases, with the aim to further stimulate interest in sexual dimorphisms in the brain and brain diseases, possibly encouraging more research in the field of the implications of sex differences for treating these conditions.

(103) Sex differences in pain and functioning among Total Knee Arthroplasty patients

(103) Sex differences in pain and functioning among Total Knee Arthroplasty patients

Sex differences in pain: a tale of two immune cells.

Substantial evidence has implicated microglia in neuropathic pain. After peripheral nerve injury, microglia in the spinal cord proliferate and increase cell-surface expression of the purinergic receptor P2X4. Activation of P2X4 receptors results in release of brain-derived neurotrophic factor, which acts on neurons to produce disinhibition of dorsal horn neurons which transmit nociceptive information to the brain. Disinhibition of these neurons produces pain hypersensitivity, a hallmark symptom of neuropathic pain. However, elucidating this microglia-neuronal signalling pathway was based on studies using only male rodents. Recent evidence has shown that the role of microglia in pain is sexually dimorphic. Despite similar microglia proliferation in the dorsal horn in both sexes, females do not upregulate P2X4Rs and use a microglia-independent pathway to mediate pain hypersensitivity. Instead, adaptive immune cells, possibly T cells, may mediate pain hypersensitivity in female mice. This profound sex difference highlights the importance of including subjects of both sexes in preclinical pain research.

Natural variation in testosterone is associated with hypoalgesia in healthy women.

Sex differences in pain are well established, with women reporting greater incidence of clinical pain and heightened responsivity to experimental pain stimuli relative to men. Sex hormones (ie, estrogens, progestins, androgens) could contribute to extant differences in pain sensitivity between men and women. Despite this, there has been limited experimental research assessing the relationship between pain and sex hormones. The purpose of this study was to extend previous research and examine the association between sex hormones and nociceptive processing in healthy women. A total of 40 healthy women were tested during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (testing order counterbalanced). Salivary estradiol, progesterone, and testosterone were collected at each testing session and pain was examined from electrocutaneous threshold/tolerance, ischemia threshold/tolerance, and McGill Pain Questionnaire-Short Form ratings of noxious stimuli. Nociceptive flexion reflex threshold was assessed as a measure of spinal nociception. Overall, there were no significant menstrual phase-related differences in pain outcomes. Nonetheless, variability in testosterone (and to a lesser degree estradiol) was associated with pain; testosterone was antinociceptive, whereas estradiol was pronociceptive. No hormone was associated with nociceptive flexion reflex threshold. Although future research is needed to replicate and extend these findings to clinical populations (ie, chronic pain, premenstrual dysphoric disorder), results from the present study indicate that menstrual phase-related changes in sex hormones have minimal influence on experimental pain. However, individual differences in testosterone may play a protective role against pain in healthy women.

Biopsychosocial contributions to sex differences in pain.

Women are at greater risk for pelvic and abdominal pain, compared with men, as discussed in the commentary by Curran. Indeed, women are at greater risk for most common forms of chronic pain, which has prompted abundant research to elucidate potential sex differences in pain processing. The optimal theoretical model for conceptualising sex differences in pain is the biopsychosocial model. This model posits that the experience of pain is sculpted by complex bidirectional interactions among biological, psychological and social factors, and sex differences in pain provide an excellent example of the biopsychosocial model in action. Specifically, biological processes, including sex hormones, endogenous opioid function, and genetic contributions influence pain in a sex-dependent manner (Fillingim et al. J Pain 2009;10:447–85). Also, recent studies suggest that sex differences in brain structure and function between females and males may contribute to differences in the experience of pain, including visceral pain (e.g. Hong et al. J Neurosci 2014;34:14252–9). In addition, psychological processes, including mood/affect and coping, as well as social influences such as gender stereotypes are also known to contribute to sex differences in pain. These three sets of factors interact to impact pain in ways that remain poorly understood. Thus, it is important to recognise that sex differences in pain are real and driven by a complex web of causation. Understanding the nature and mechanisms underlying sex differences in pain has important implications for pain prevention and treatment. An important yet often overlooked aspect of sex differences in pain is qualitative sex differences. That is, notwithstanding whether men and women have different amounts of pain, the mechanisms driving the pain can be fundamentally different between sexes. For example, a recent translational study demonstrated that vasopressin activates endogenous analgesic mechanisms, except when they have already been activated by stress, as in males with high functioning of the AVPR1A receptor (Mogil et al. Nat Neurosci 2011;14:1569–73). This genotype by sex by stress interaction is an example of a qualitative sex difference, as the vasopressin by stress interaction only emerged in males. These findings also typify the complexity of biopsychosocial influences on pain. Another important issue to consider regarding sex differences in pain relates to pain treatment. Curran notes the potential for bias in the provision of treatment, with women at greater risk for undertreatment of pain. Such findings do exist and providers do well to acknowledge their potential biases and misconceptions and mitigate their intrusion into clinical care. However, on balance the literature does not suggest widespread gender bias in pain treatment. Another treatment consideration is whether some therapies are more effective for women than for men (or vice versa). Opioids may be more effective for women than men, particularly in the acute pain setting (Niesters, Pain 2010;151:61–8), and sex differences in response to other kinds of treatment remain understudied. Nonetheless, it seems plausible that sex-specific treatments for certain types of pain could emerge in the future. For now, an understanding of the biopsychosocial underpinnings of sex differences in pain will allow providers to approach pain in women from a more informed perspective. I have no conflicts of interest related to this mini-commentary.

Examining sex differences in knee pain: the Multicenter Osteoarthritis Study

To determine whether women experience greater knee pain severity than men at equivalent levels of radiographic knee osteoarthritis (OA). A cross-sectional analysis of 2712 individuals (60% women) without knee replacement or a recent steroid injection. Sex differences in pain severity at each Kellgren-Lawrence (KL) grade were assessed by knee using visual analog scale (VAS) scale and Western Ontario and McMaster Universities Arthritis Index (WOMAC) with and without adjustment for age, analgesic use, Body mass index (BMI), clinic site, comorbid conditions, depression score, education, race, and widespread pain (WSP) using generalized estimating equations. Effect sizes (Cohen's d) were also calculated. Analyses were repeated in those with and without patellofemoral OA (PFOA). Women reported higher VAS pain at all KL grades in unadjusted analyses (d=0.21-0.31, P<0.0001-0.0038) and in analyses adjusted for all covariates except WSP (d=0.16-0.22, P<0.0001-0.0472). Pain severity differences further decreased with adjustment for WSP (d=0.10-0.18) and were significant for KL grade ≤2 (P=0.0015) and 2 (P=0.0200). Presence compared with absence of WSP was associated with significantly greater knee pain at all KL grades (d=0.32-0.52, P<0.0001-0.0008). In knees with PFOA, VAS pain severity sex differences were greater at each KL grade (d=0.45-0.62, P=0.0006-0.0030) and remained significant for all KL grades in adjusted analyses (d=0.31-0.57, P=0.0013-0.0361). Results using WOMAC were similar. Women reported greater knee pain than men regardless of KL grade, though effect sizes were generally small. These differences increased in the presence of PFOA. The strong contribution of WSP to sex differences in knee pain suggests that central sensitivity plays a role in these differences.

Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat

Though sex differences in pain and analgesia are known, underlying mechanisms remain elusive. This study addresses the selective contribution of membrane estrogen receptors (mERs) and mER-initiated non-genomic signaling mechanisms in our previously reported estrogen-induced attenuation of α2-adrenoceptor-mediated antinociception. By selectively targeting spinal mERs in ovariectomized female rats using β-estradiol 6-(O-carboxy-methyl)oxime bovine serum albumin (E2BSA) (membrane impermeant estradiol analog), and ERα selective agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), ERβ selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), G-protein-coupled estrogen receptor 30 (GPR30) agonist G1 and Gq-coupled mER (Gq-mER) agonist STX, we provide strong evidence that Gq-mER activation may solely contribute to suppressing clonidine (an α2-adrenoceptor agonist)-induced antinociception, using the nociceptive tail-flick test. Increased tail-flick latencies (TFLs) by intrathecal (i.t.) clonidine were not significantly altered by i.t. PPT, DPN, or G1. In contrast, E2BSA or STX rapidly and dose-dependently attenuated clonidine-induced increase in TFL. ICI 182,780, the ER antagonist, blocked this effect. Consistent with findings with the lack of effect of ERα and ERβ agonists that modulate receptor-regulated transcription, inhibition of de novo protein synthesis using anisomycin also failed to alter the effect of E2BSA or STX, arguing against a contribution of genomic mechanisms. Immunoblotting of spinal tissue revealed that mER activation increased levels of phosphorylated extracellular signal-regulated kinase (ERK) but not of protein kinase A (PKA) or C (PKC). In vivo inhibition of ERK with U0126 blocked the effect of STX and restored clonidine antinociception. Although estrogen-induced delayed genomic mechanisms may still exist, data presented here indicate that Gq-mER may solely mediate estradiol-induced attenuation of clonidine antinociception via a rapid, reversible, and ERK-dependent, non-genomic mechanism, suggesting that Gq-mER blockade might provide improved analgesia in females.

Sex differences in experimental pain among healthy children: A systematic review and meta-analysis

Sex differences in response to experimental pain are commonly reported in systematic reviews in the adult literature. The objective of the present research was to conduct a systematic review and meta-analysis of sex differences in healthy children’s responses to experimental pain (eg, cold pressor, heat pain, pressure pain) and, where possible, to conduct analyses separately for children and adolescents. A search was conducted of electronic databases for published papers in English of empirical research using experimental pain tasks to examine pain-related outcomes in healthy boys and girls between 0 and 18years of age. Eighty articles were eligible for inclusion and were coded to extract information relevant to sex differences. The systematic review indicated that, across different experimental pain tasks, the majority of studies reported no significant differences between boys and girls on pain-related outcomes. However, the meta-analysis of available combined data found that girls reported significantly higher cold pressor pain intensity compared to boys in studies where the mean age of participants was greater than 12years. Additionally, a meta-analysis of heat pain found that boys had significantly higher tolerance than girls overall, and boys had significantly higher heat pain threshold than girls in studies where the mean age of participants was 12years or younger. These findings suggest that developmental stage may be relevant for understanding sex differences in pain.

Towards understanding sex differences in visceral pain: Enhanced reactivation of classically-conditioned fear in healthy women

Sex differences in learned fear regarding aversive gastrointestinal stimuli could play a role in the female preponderance of chronic abdominal pain. In a fear conditioning model with rectal pain as unconditioned stimulus (US), we compared healthy males and females with respect to neural responses during aversive visceral learning, extinction and re-activation of fear memory (i.e., reinstatement). To do so, conditioned visual stimuli (CS+) were consistently paired with painful rectal distensions as US, while different visual stimuli (CS−) were presented without US. During extinction, both CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, sexes were compared with respect to conditioned anticipatory neural activation (CS+>CS−). The results revealed that in late acquisition, CS+ presentation induced significantly greater anticipatory activation of the insula in women. During extinction, women demonstrated reduced activation of the posterior cingulate cortex. During reinstatement, the CS+ led to greater activation of the hippocampus, thalamus and cerebellum in women. These group effects in neural activation during learning and memory processes were not accounted for by sex differences in pain thresholds, pain ratings, or stress parameters. In conclusion, this is the first study to support sex differences in neural processes mediating aversive visceral learning. Our finding of enhanced neural responses during reinstatement in key brain areas relevant for memory suggests enhanced reactivation of old fear memory trace in women. Sex differences in “gut memories” could play a role in the female preponderance of chronic abdominal pain.

Sex differences in pain: a brief review of clinical and experimental findings

Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male-female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments.

Sex differences in formalin‐evoked primary afferent release of substance P

Sex differences in pain have been well documented; however, the mechanisms involved remain to be elucidated. The present study examined whether sex differences exist in the functioning of primary afferent fibres by assessing formalin-evoked release of substance P by way of neurokinin 1 receptor (NK1r) internalization. The study also investigated whether the observed effects would be oestradiol-sensitive. Intact and gonadectomized male and female rats were given intraplantar formalin and then euthanized either 5 or 30 min later, representing phase 1 or 2 of the formalin response, respectively. In a subsequent experiment, ovariectomized females received oestradiol prior to formalin administration. Lastly, formalin-evoked NK1r internalization was assessed across the female oestrous cycle. Intraplantar formalin evoked significant NK1r internalization, during phase 1 and 2, in both males and females. During phase 1, no differences in NK1r internalization were detected between males or females, regardless of the gonadal status. In contrast, during phase 2, intact females exhibited greater NK1r internalization than intact males. Moreover, ovariectomy reduced NK1r internalization as compared to intact females, whereas castration had no effect as compared to intact males. Oestradiol supplementation in ovariectomized females increased NK1r internalization to levels observed in intact females. Formalin-evoked NK1r internalization did not differ across the oestrous cycle. These findings suggest that oestradiol mediates sex differences in formalin-evoked substance P release, which may contribute to a differential development of central sensitization and pain behaviours in males and females.

Sex-related differences in acute and chronic pain: a bench to bedside perspective

Chronic pain affects the daily lives of millions. It has been estimated that nearly one-quarter of the world’s population suffers from chronic pain, making it the most common human health problem. The most recent estimates of the prevalence of chronic pain in Canada indicate that approximately 29% of the population experiences chronic pain, with nearly 80% of these people reporting their pain as moderate to severe. Interestingly, there is increased pain sensitivity and a higher prevalence of chronic pain conditions in females than in males. To date, however, there has been little basic research examining these sex differences from a mechanistic standpoint, with researchers either doubting or simply ignoring the evidence. Nevertheless, numerous studies and a recent review of the literature provide convincing evidence that there are indeed sex differences relating to chronic and acute pain. Sex differences have been examined in many areas of biological research, particularly in the field of molecular neuroscience. Numerous studies have shown somatic and hormonal sex differences at a molecular level, and these molecular differences between sexes are often reflected by differences in the outcome and progression of disease. This can been seen in Alzheimer’s disease, depression, Huntington’s disease, and cerebral ischemia, as well as in models of cognitive ability. Despite the well-described sex differences in pain and in other disease models, basic pain research has been slow to adopt systematic study of these differences. Common barriers to the study of sex differences in the basic mechanisms of pain include doubt for the need to study sex differences (an impact by conflicting studies devaluing the importance of sex studies), possible complications from different hormonal influences on behaviour, and the complexity of trying to determine the interacting roles of sex, pain, and the secondary factors associated with pain (e.g., depression). Dr. Jeffery Mogil of McGill University addressed these concerns in a recent review of both clinical and basic studies examining sex differences. Dr. Mogil presents strong evidence that there is indeed a prevalence of bias in pain towards females. Although not all studies found a statistically significant difference between the sexes, when examining the overall trends present in the data, the results overwhelmingly indicate that females suffer more than men from chronic pain disorders (e.g., back pain, migraine, osteoarthritis, widespread pain, and musculoskeletal, oral, and neuropathic pain). Also, trends in basic pain sensitivity in healthy human subjects have shown that females experience increased sensitivity to electrical stimulation, ischemic pain, cold and heat pain, pressure pain, and muscle pain. These findings are in contrast with a review of 122 studies examining sex differences in laboratory pain sensitivity where the results showed no overall sex differences . Dr. Mogil points out, however, that, upon closer examination of the review, it can be argued that rather stringent inclusion criteria were used to indicate a K. A. Mifflin, BSc B. J. Kerr, PhD Centre for Neuroscience, University of Alberta, Edmonton, AB, Canada

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

A clear majority of patients with chronic pain are women; however, it has been surprisingly difficult to determine whether this sex bias corresponds to actual sex differences in pain sensitivity. A survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming. Various explanations for this phenomenon have been given, ranging from experiential and sociocultural differences in pain experience between men and women to hormonally and genetically driven sex differences in brain neurochemistry.

Sex differences in pain

A 28-year-old female university student complained to her dentist about recurrent pain in her face. The pain “comes and goes, is more intense in the presence of stress and fatigue, in particular around school examination periods.” Her dentist told her that she had no identifiable signs of disease. The dentist also told her that the type of pain she was experiencing is common among women, especially in the presence of stress, and therefore “could be psychosomatic.” The patient wondered whether her pain really was a “woman's condition” and wanted to know if her condition was of “psychological” origin.

Insomnia, sleep quality, pain, and somatic symptoms: Sex differences and shared genetic components

This study investigated the sex differences, and the shared genetic and environmental factors underlying the associations of sleep disturbances (insomnia and sleep quality) with pain and somatic symptoms in both adolescents and middle-aged adults. We recruited 259 adolescents (69 with current insomnia) and their parents (256 middle-aged adults, 78 with current insomnia). Insomnia severity and sleep quality were measured by the Insomnia Severity Inventory (ISI) and Pittsburgh Sleep Quality Index (PSQI), respectively. Pain and somatic symptoms were measured by the Somatic Symptom Inventory and Visual Analogue Scale for overall pain. Subjects with insomnia scored higher on all measures of pain and somatic symptoms than non-insomnia patients, in both adolescents and adults (P<.001). Both pain and somatic measures were associated with ISI and PSQI scores after controlling for age, sex, depressive and anxiety symptoms. There was an interaction effect between insomnia and female sex on pain and somatic symptoms (P<.05), especially in adults. Pain and somatic symptoms ran in family with moderate heritability (range h2=0.15–0.42). The phenotypic associations of ISI and PSQI with pain and somatic measures were both contributed by genetic (range pG=0.41–0.96) and environmental (range pE=0.27–0.40) factors with a major genetic contribution. In summary, insomnia and poor sleep quality are closely associated with pain and somatic symptoms. Insomnia seems to modulate the sex differences in pain and somatic symptoms, especially in the adult population. A shared genetic predisposition might underlie the associations of insomnia and sleep quality with pain and somatic symptoms.

The Perception of Pain in Others: How Gender, Race, and Age Influence Pain Expectations

Sex, race/ethnic, and age differences in pain have been reported in clinical and experimental research. Gender role expectations have partly explained the variability in sex differences in pain, and the Gender Role Expectations of Pain questionnaire (GREP) was developed to measure sex-related stereotypic attributions about pain. It is hypothesized that similar expectations exist for age- and race-related pain decisions. This study investigated new measures of race/ethnic- and age-related stereotypic attributions of pain sensitivity and willingness to report pain, and examined the psychometric properties of a modified GREP. Participants completed the Race/Ethnicity Expectations of Pain questionnaire, Age Expectations of Pain questionnaire, and modified GREP. Results revealed a 3-factor solution to the race/ethnicity questionnaire and a 2-factor solution to the age questionnaire, consistent with theoretical construction of the items. Results revealed a 4-factor solution to the modified GREP that differed from the original GREP and theoretical construction of the items. Participants’ pain-related stereotypic attributions differed across racial/ethnic, age, and gender groups. These findings provide psychometric support for the measures examined herein and suggest that stereotypic attributions of pain in others differ across demographic categories. Future work can refine the measures and examine whether select demographic variables influence pain perception, assessment, and/or treatment. PerspectiveThe findings suggest that one’s expectations of the pain experience of another person are influenced by the stereotypes one has about different genders, races, and ages. The 3 pain expectation measures investigated in the current study could be used in future work examining biases in pain assessment and treatment.

S287 GENDER ROLE EXPECTATIONS OF PAIN PREDICT RESPONSE TO EXPERIMENTALLY-INDUCED ISCHAEMIC AND MECHANICAL PAIN IN HEALTHY WHITE BRITISH PARTICIPANTS

References Sex and gender differences in experimental pain are well documented with women display greater sensitivity to multiple pain modalities compared with men . One of the psycho-social factors contributing to sex differences in pain is gender role. A Gender Role Expectancy of Pain Questionnaire (GREP, Robinson et al., 2001) is composed of twelve 10-cm visual analogue scales (VAS) categorised into three dimensions; Sensitivity, Endurance, and Willingness to Report Pain. For each dimension, participants were required to estimate their individual perception of pain response when compared with a typical woman and typical man, as well as stereotypical perceptions of typical men and typical woman to each other. GREP have been found to predict sex differences in response to heat (Wise et al.2002; Defrin et al., 2009) and cold (Alabas et al., 2011) pain.

Sex differences in perceived pain are affected by an anxious brain

Decades of research confirm that women have greater pain sensitivity than men. Women also show greater overall anxiety sensitivity than men. Given these differences, we hypothesized that sex differences in anxiety would explain sex differences in experienced pain and physiological responses to pain (at both spinal and cortical levels). By measuring subjective pain, state/trait anxiety, nociceptive flexion reflexes, and somatosensory evoked potentials (SEPs), it was possible to test the effects of anxiety on the processing of painful drives at different levels of the neuraxis while also documenting the role played by anxiety on sex differences in experienced pain. Results confirm that women are indeed more sensitive to pain than men. Importantly, this difference was accompanied by a significant sex difference in cortical activity (SEP amplitude) but not spinal nociceptive activity, suggesting that much of the sex difference in experienced pain is attributable to variations in thalamocortical processing and to ensuing changes in the appraisal of and/or emotional response to noxious insult. In support of this claim, we found that sex differences in cortical activity and subjective pain disappeared when trait anxiety was controlled for. This means that stable predispositions to respond with heightened apprehension contribute to baseline pain sensitivity differences between the sexes. These results indicate that the modulatory effect of affect on pain-related brain processes may explain why men and women experience painful shocks so differently. In our study, the mediating role of anxiety on sex differences in pain was tested and confirmed using path analysis.

Race and Sex Differences in Primary Appraisals, Catastrophizing, and Experimental Pain Outcomes

The aims of this study were: 1) to examine race and sex differences in primary pain appraisals and catastrophizing; 2) to test the unique ability of race, sex, primary pain appraisals, and catastrophizing to predict experimental pain outcomes; and 3) to conduct mediational analyses testing pain appraisals and catastrophizing as explanatory mechanisms for race and sex differences in pain. One hundred and fifty-five college students at The University of Alabama completed a cold pressor experimental pain task and a questionnaire battery. Statistical methods included multivariable regression models and nonparametric bootstrapping methods for tests of mediation. African-Americans reported higher catastrophizing and had lower pain tolerance than white Americans. Males demonstrated higher challenge appraisals, lower pain intensity, and longer pain tolerance. Challenge appraisals were positively related to pain tolerance, threat/harm appraisals were inversely related to pain tolerance, and pain catastrophizing was positively related to both pain intensity and pain unpleasantness. Pain catastrophizing partially mediated race differences in pain tolerance and mediated sex differences in intensity, whereas primary pain appraisals did not significantly mediate race or sex differences in pain variables. Primary appraisals and catastrophizing appear to be separable constructs related to different aspects of the pain experience. PerspectiveThis study found that important race and sex differences exist in relation to pain appraisals and catastrophizing, and that these cognitive variables play unique roles in different aspects of the pain experience. Cognitive-behavioral therapies for pain may be enhanced by including a focus on both pain appraisals and pain catastrophizing.

Current States of Opinion and Future Directions on the Epidemiology of Sex Differences in Human Pain

One of the most commonly neglected findings in the human pain literature is the observation of sex differences in the mechanisms that support the phenotypic expression of pain. The present commentary describes an assessment of the prevalence of observed sex differences in various pain processes, and of how expert pain researchers interpret the epidemiology and, hence, the proximate and ultimate causes of such differences. Forty-two pain investigators completed an anonymous survey on the epidemiology of sex differences in the human pain experience. Investigator responses indicated that sex differences are pervasive across various areas of pain research, that sex differences are particularly pronounced in the area of situational influences on pain behaviors, and that contemporary pain researchers largely disagree on the epidemiology of, and hence, proximate and ultimate causes of the differences. The relevance of social situational factors on sex differences in pain behaviours is discussed in the context of evolutionary, developmental, social psychology and pain sensory systems that may function, in part, for regulating interpersonal intimacy.