Although research addressing sex and gender differences in pain has a long history, interest in this topic has increased dramatically in the last two decades. Several recent reviews have addressed the topic from different perspectives and in varying levels of detail.^26,27,28,29 The importance of the topic is dictated by the abundance of epidemiologic and clinical research demonstrating that, compared to men, women are at greater risk for pain, tend to have higher levels of pain, and are more likely to seek treatment for pain. Findings from myriad population-based studies demonstrate greater prevalence of chronic pain among females versus males. In a Canadian household survey, women reported higher rates of both temporary and persistent pain,³⁰ and a mail survey of more than 3600 adults in Scotland found that women were significantly more likely than men to report chronic pain.³¹ Two Scandinavian studies found that multisite body pain was more common among women than men.^32,33 Similarly, in a survey of health maintenance organization enrollees in Seattle, Von Korff and colleagues³⁴ found that women were significantly more likely than men to report at least three of the following five pain conditions: headache, back pain, chest pain, abdominal pain, and facial pain. In our 2009 review article,²⁶ we summarized the findings of 10 population-based studies of general pain prevalence that were conducted in different geographical regions. These studies reported widely varying prevalences of pain for both women (11% to 59%) and men (10% to 49%). Every study reported higher pain prevalence among women, although the magnitude of the excess female prevalence varied considerably across studies, ranging from 1% to 14%. Subsequently, findings from the National Health Interview Survey (NHIS) revealed significantly higher frequency of persistent pain (i.e., pain on most days or every day for the past 3 months) among women (21.6%) than men (16.2%).^35,36 A recent meta-analytic review of epidemiologic studies reported an overall female-to-male prevalence ratio of 1.27, indicating that 27% more females than males reported chronic pain.³⁷ Overall, these findings from numerous population-based studies conducted in varied geographic regions across the world reveal a consistent pattern of higher prevalence of general chronic pain among women than men, although the magnitude of the sex difference varies across studies.

In addition to these data on general pain symptoms, considerable research suggests that specific pain conditions show sex differences in their prevalence. More than 30 years ago, the NUPRIN Pain Report, based on a telephone survey of 1,254 US adults, found that women were more likely to report headaches, stomach pain, joint pain, and back pain than men.³⁸ An abundance of epidemiologic evidence shows that several common chronic pain conditions are more common among women, including fibromyalgia (FM),³⁹ chronic widespread pain (CWP),⁴⁰ migraine headache,⁴¹ temporomandibular disorder (TMD),^42,43 irritable bowel syndrome,⁴⁴ and low back pain.^45,46,47 Sex differences in the prevalence of specific pain conditions were recently summarized by examining findings from 47 studies that reported on sex differences in pain prevalence across the following pain conditions: back pain, migraine, musculoskeletal pain, neuropathic pain, oral pain, OA pain, and widespread pain.²⁷ For each comparison, the excess female prevalence was computed by subtracting the prevalence in men from that in women. Prevalence in females was greater than in males in 45 of 47 comparisons, and the average excess female prevalence across all of the pain conditions was 5.5%. Sex differences in back pain prevalence were examined in a more recent study of adults aged 50 years and older from six low- and middle-income countries conducted by the World Health Organization. These authors reported that back pain during the past month was significantly more frequent for women (34.9%) than men (24.2%), and women also had more severe pain.⁴⁸ Also, in a Canadian study, both knee and hip OA were more prevalent among women versus men.⁴⁹ A recent meta-analysis of 14 studies that reported sex-specific prevalence of CWP found that prevalence was approximately twice as great in women as men.⁴⁰ Also, Jones and colleagues³⁹ compared the prevalence of FM in females and males using three different diagnostic criteria. Prevalence was substantially higher in women, but the magnitude of the sex difference varied dramatically across diagnostic criteria. It is worth noting
that these epidemiologic findings reflect the frequency of pain in the general population. The disproportionate impact of pain among women is even greater in the clinical setting due to their increased health care use for pain.^50,51,52,53 Taken together, these findings demonstrate that the frequency of pain is higher for women than men, particularly for pain conditions that are both common and associated with substantial societal costs.

These findings of greater pain prevalence among adults are somewhat mirrored by studies of children and adolescents. For example, a systematic review found that pain prevalence for most pain types was higher for girls than for boys, including headaches, abdominal pain, musculoskeletal pain, combined pain types, and general chronic pain.⁵⁴ Also, a recent study of children and adolescents (aged 10 to 17 years) found that females were more likely than males to transition from acute to persistent musculoskeletal pain.⁵⁵ However, several studies of acute pain report no sex differences in children, and age appears to be an important moderating factor, as sex differences generally become more pronounced as children age.^56,57,58 For example, LeResche and colleagues⁵⁹ reported increasing excess female prevalence of pain conditions as children progressed through pubertal development, implicating potential hormonal contributions.

The aforementioned findings speak to the frequency of pain but not to its impact or severity, which has been addressed in a number of clinical studies. Regarding acute pain, sex differences in postoperative pain have been inconsistent. In cohorts of patients undergoing mixed surgical procedures, results have shown greater pain among women^60,61,62 as well as greater pain among men.⁶³ Other studies have evaluated sex differences in pain after specific types of surgery. More severe pain has been observed for women after dental surgery in some^64,65 but not other studies.⁶⁶ Women have also been found to report higher pain levels following orthopedic^{67,68,69,70,71} and cardiothoracic surgery⁷² and after laparoscopic cholecystectomy.⁷³ A recent review of this literature concluded that women generally experience more severe postoperative pain, but the observed sex differences are often small and of limited clinical significance.⁷⁴ It should also be noted that persistent pain after surgery represents an important clinical concern, and several studies have shown that females are at greater risk for pain persistence than males.^72,75,76

In addition to these findings addressing acute pain, sex differences in the severity of chronic pain have also been investigated. Women with arthritis have been found to report higher levels of pain and disability than their male counterparts.^77,78,79 In addition, in a cohort of people with mixed chronic pain conditions seeking treatment in a multidisciplinary pain clinic, women reported higher pain severity than men.⁸⁰ In a sample of patients with chronic musculoskeletal pain, pain ratings did not differ by sex; however, women’s pain drawings showed a greater area of pain compared to men.⁸¹ In contrast to these findings of sex differences in chronic pain severity and impact, many other studies have found little evidence for sex differences in the severity of chronic pain.^{82,83,84,85,86} Moreover, in a treatment-seeking sample of patients composed largely of individuals with myofascial pain conditions, men reported more frequent and severe pain and greater disability compared to women.⁸⁷ Thus, the available evidence regarding sex differences in chronic pain severity is inconsistent and precludes firm conclusions. Perhaps, this should not be surprising because most of the evidence regarding chronic pain derives from patients whose pain was severe enough to motivate treatment seeking, thereby increasing the likelihood of sampling bias. A handful of studies have examined sex differences in chronic pain severity in community-based samples, providing a less biased approach to the issue. A population-based study in Australia reported that among people reporting chronic pain, a greater proportion of females than males characterized their pain as moderate to severe.⁸⁸ Among people reporting activity-limiting pain, pain frequency, pain-related negative affect, and disability were all greater for women compared to men.⁸⁹ In a community-based study of knee OA, Glass and colleagues⁹⁰ found that women reported higher pain levels that men across all grades of radiographic knee OA severity, but these differences were small in magnitude, and some became nonsignificant after controlling for confounders. Similarly, we recently reported no differences in clinical pain severity in women and men with knee OA; however, women reported pain in more body sites than did men.⁹¹ A Scandinavian study revealed higher pain levels among women with musculoskeletal conditions compared to their male counterparts.⁹² In a study of individuals with painful TMD, multiple comorbid pain conditions (e.g., headache/migraine, neck pain, low back pain, joint pain) were significantly more prevalent among women than men.⁹³ Recently, findings from a telephone survey showed that compared to men, women using chronic opioid therapy reported poorer pain-related adjustment.⁹⁴ Thus, when considering these findings from community-based studies of individuals with existing chronic pain, women appear to have higher impact pain than men.

Although sex differences in clinical pain prevalence and severity are inevitably driven by multiple factors, one possible contributor could be sex differences in the functioning of pain processing systems. Indeed, altered nociceptive processing characterizes many of the female-predominant pain disorders, which adds further credibility to this argument.^1,26,95 Several reviews have examined the literature regarding sex differences in experimental pain sensitivity.^26,27,28,29 Overall, the findings reveal lower pain thresholds (i.e., the minimum stimulus intensity required to produce pain) and tolerances (i.e., the maximum stimulus intensity that the individual is willing to tolerate) among women relative to men, across multiple stimulus modalities. The direction of the findings has been highly consistent across studies; however, the magnitude of the sex difference has been quite variable. Some 20 years ago, our meta-analysis reported that the average effect size was moderate.⁹⁶

Over the past two decades, multiple review articles have summarized existing findings related to sex differences in responses to laboratory pain stimuli. For example, in a 2009 review paper⁹⁷, we concluded that “current human findings regarding sex differences in experimental pain indicate greater pain sensitivity among females compared with males for most pain modalities, including more recently implemented clinically relevant pain models such as temporal summation of pain and intramuscular injection of algesic substances.”⁹⁸ Shortly thereafter, based on examination of largely the same literature, Racine and colleagues⁹⁹ came to the contrasting conclusion that “10 years of laboratory research have not been successful in producing a clear and consistent pattern of sex differences in human pain sensitivity, even with the use of deep, tonic, long-lasting stimuli, which are known to better mimic clinical pain.” In an effort to reconcile these discrepant conclusions, Mogil²⁷ conducted a careful analysis of the studies reviewed by Racine and colleagues, and his findings provided strong evidence of higher pain sensitivity among females. In another recent review article, the authors state that existing findings from laboratory pain studies of sex differences “represent trends, but, in most cases, the findings are more nuanced than the conclusions.” So what is one to conclude from these widely varying views of the same literature?

The answer is both simple and complex. Regarding the former, the existing literature shows that sex differences in responses experimental pain stimuli are undeniably consistent in their direction in that females are consistently found to be
more pain-sensitive than men. This pattern has been observed for multiple stimulus modalities, numerous body regions, and across all common pain sensitivity measures (i.e., pain threshold, pain tolerance, and suprathreshold pain ratings). In addition, more sophisticated measures of pain modulatory processes have demonstrated greater temporal summation of pain among women versus men, in response to different stimuli, including heat,¹⁰⁰ cutaneous mechanical,¹⁰¹ and pressure stimuli.¹⁰² Laboratory measures of pain inhibitory function seem to vary somewhat across assessment methods, with men showing greater conditioned pain modulation (CPM),¹⁰³ but sex differences have been less consistent using other assays of pain inhibition.⁹⁸ Findings from studies of children and adolescents reveal a pattern of results that is similar those observed in adults, but the differences in children are generally of lesser magnitude, and sex differences in pain responses are influenced by age, likely reflecting the influence of developmental stage.¹⁰⁴ Thus, the simple answer regarding sex differences in experimental pain sensitivity is that women are consistently more sensitive than men.⁹⁹ However, the complexity of the issue is reflected in the highly variable magnitude of the sex difference, which suggests important influences of methodologic and contextual factors. For example, brief, repeated thermal stimuli evoke greater temporal summation of pain among females than males, whereas, in response to sustained heat stimuli, females show greater attenuation of pain over time.¹⁰⁵ The study sample can also impact sex differences in pain sensitivity because in addition to sex, multiple individual difference factors are known to influence pain responses,¹⁰⁶ including other demographic factors. For example, race/ethnicity and age are known to affect experimental pain responses; therefore, the age and ethnic diversity of the study sample could influence the magnitude of the sex differences observed. Moreover, a variety of other biopsychosocial variables can impact pain responses, sometimes in a sex-dependent manner, which could modulate the magnitude of observed sex differences in pain sensitivity. Regarding contextual factors, some evidence suggests that experimenter sex/gender may affect pain responses in the laboratory setting,^107,108 and this could certainly contribute to the inconsistent magnitude of sex differences that have been reported.

Thus, studies of experimental pain reveal a consistent pattern of sex differences, with women showing more robust perceptual responses to painful stimuli than men. However, the magnitude of these differences varies considerably across studies, and the underlying mechanisms remain poorly understood.

The mechanisms responsible for sex differences in pain are complex and incompletely understood. Multiple biologic and psychosocial factors contribute to sex differences in pain, as previously reviewed by multiple authors.^{26,27,28,29,136} Considerable evidence suggests that sex hormones may importantly influence pain responses and the effects of pain medications.^{26,36,137,138} For example, both clinical pain severity and experimental pain sensitivity have been found to fluctuate across the female menstrual cycle.^139,140 Moreover, use of exogenous hormones, particularly estrogen replacement in postmenopausal women, is associated with greater risk for clinical pain in some studies^141,142,143 but not others.^144,145 However, the association of gonadal hormones with pain appears complex and bidirectional. In contrast to the earlier findings suggesting pain promoting effects of estrogen, other findings imply an antinociceptive role for estrogen. For example, pain-evoked brain responses were attenuated during menstrual phases characterized by high estrogen levels, particularly in brain regions subserving the affective dimension of pain.¹⁴⁶ Moreover, in healthy women, administration of exogenous estrogen reduced muscle pain sensitivity and increased pain-related brain µ-opioid receptor binding.¹⁴⁷ Thus, sex hormones clearly can influence pain responses; yet, the pattern and direction of hormonal effects on pain are complex and remain poorly understood.