Individual Differences in Pain: The Roles of Gender, Ethnicity, and Genetics

Roger B. Fillingim

The experience of pain is characterized by tremendous interindividual variability.¹ Indeed, similar injuries, disease states, or noxious stimuli are often accompanied by pain responses that differ dramatically across people. Although it is inarguable that such individual differences in pain responses exist, their contributing factors and clinical importance remain important topics of study. This chapter aims to review the nature of individual differences in responses to pain and its treatment. After briefly highlighting several examples of individual differences, several individual difference factors are reviewed, emphasizing demographic variables (e.g., sex/gender and race/ethnicity) and genetic contributions to individual differences in pain. This chapter concludes by considering the interactions among different individual difference variables and discusses the clinical relevance of individual differences, including implications for treatment tailoring.

In the clinical setting, providers are well acquainted with individual differences in pain, as patients with the same pain condition often vary markedly in their self-reported pain and related symptoms. This variability is often attributed to differences in disease severity, based on the misguided assumption that the noxious stimulus itself is the primary determinant of the pain experience, despite considerable evidence suggesting otherwise. For example, the majority of individuals who show radiographic evidence of osteoarthritis (OA) are asymptomatic,² and even in symptomatic patients, radiographic measures of disease severity in OA account for a limited proportion of the interindividual variability in pain and disability.³^,⁴ Likewise, physical and diagnostic findings have limited value in predicting the occurrence or severity of low back pain.⁵^,⁶ Moreover, in the acute pain setting, patients undergoing similar surgical procedures report widely varying amounts of pain.⁷^,⁸^,⁹^,¹⁰^,¹¹ Thus, for many forms of clinical pain, the nature or magnitude of the noxious clinical stimulus appears to be a poor predictor of the degree of pain experienced.

Studying individual differences in the clinical setting is challenging because it is often difficult to quantify with any accuracy the noxious stimulus thought to be responsible for the patient’s pain. Moreover, clinical pain reports are commonly influenced by previous or current therapies, creating additional sources of interindividual variability. In order to circumvent some of these issues, investigators have turned to the application of quantifiable and controllable painful stimuli in the laboratory setting. Interestingly, responses to experimentally induced pain are also marked by robust individual differences. For example, in a previous study of healthy adults undergoing an identical cold water stimulus, pain intensity ratings ranged from 0 to 100.¹² In subsequent analyses, the authors found that that the intensity of the noxious stimulus accounted for only 40% of the variance in pain ratings, with the remaining 60% accounted for by true individual differences. More recently, findings from 321 healthy young adults revealed that pain ratings in response to a 48° C heat stimulus ranged from 4 to 100.¹ Similarly, a prior study assessed 16 different experimental pain measures using identical methods in more than 200 healthy young females.¹³ They subsequently combined these measures into overall index scores by summing standardized (z scores) scores for each of the individual pain tests. This yielded a normal distribution of summary scores with a mean of 0, where positive and negative values indicated higher and lower pain sensitivity, respectively. They observed a range of summary scores from -20 to greater than 30 across the sample. These findings clearly demonstrate that even under experimental conditions in which stimulus intensity is carefully controlled, pain responses are marked by robust individual differences.

It is important to recognize that in addition to interindividual variability in pain responses, pain treatment outcomes are characterized by substantial individual differences. For example, a study of more than 3,000 patients undergoing different surgical procedures revealed that the number of morphine boluses required to produce adequate postoperative pain relief (Visual Analog Scale rating <30) ranged from 1 to 20.⁷ A clinical trial of opioid therapy for chronic neuropathic pain showed that following treatment, patients reported changes in pain ranging from a 100% decrease to a nearly 70% increase in pain.¹⁴ Likewise, even in laboratory pain studies, analgesic responses to opioids differ considerably across individuals.¹⁵^,¹⁶^,¹⁷ In addition to variability in responses to medications, responses to nonpharmacologic pain treatments also vary widely from person to person. For example, a long-term (8 to 10 years) follow-up study of outcomes from surgical and nonsurgical management of spinal stenosis showed that approximately half of the patients in both treatment groups reported improvement in their symptoms over the follow-up period, whereas 20% to 25% reported no change and 20% to 25% reported that their symptoms had worsened.¹⁸ Several other nonpharmacologic treatments have also been shown to confer widely varying amounts of pain relief across individuals, including acupuncture¹⁹ and psychological interventions for pain.²⁰^,²¹

This brief overview of individual differences demonstrates that responses to pain and its treatment vary substantially from person to person. Although the study of this variability in pain responses has a long history,²²^,²³ recent years have witnessed substantially increased interest in individual differences, motivated in large part by the contemporaneous explosion of research on genetic determinants of health and disease. Although genetic factors contribute importantly to pain and analgesia, it is critical to remember that responses to pain and its treatment result from complex and dynamic interactions among numerous biologic, psychological, and social factors.¹ Thus, before discussing findings regarding the contribution of various demographic, genetic, and psychosocial factors to individual differences in pain, I provide a brief overview of the biopsychosocial model (Fig. 8.1), which represents the optimal model for conceptualizing individual differences in pain.

The biopsychosocial model emerged as an alternative to the unsatisfactory medical model, which reductionistically viewed health and symptoms as products of biologic disease.²⁴ In its application to pain, the model posits that the experience of and response to pain are determined by multiple biologic,
psychological, and social factors.²⁵ In addition to their individual contributions, an important tenet of the biopsychosocial model is that these factors interact dynamically to drive the pain experience. Of particular relevance to individual differences, this mosaic of pain-related biopsychosocial influences varies considerably from person to person. Hence, for each individual at a given point in time, a unique combination of biologic and psychosocial factors operates to sculpt the experience of pain.

FIGURE 8.1 Biopsychosocial model of pain. The figure shows that pain experiences are influenced by the combined effects of biologic, psychological, and social factors. Although variables from each of the three domains can impact pain individually (as shown by small bidirectional arrows), biologic, psychological, and social factors also interact to produce complex and important influences on pain, as illustrated by the large three-way arrows. These interactions across numerous biopsychosocial factors produce myriad possible pain-modulating combinations of variables, resulting in tremendous interindividual variability of pain experiences. (Modified with permission from Fillingim RB. Individual differences in pain: understanding the mosaic that makes pain personal. Pain 2017;158[suppl 1]:S11-S18.)

Next, I discuss sex/gender and race/ethnicity as potentially important individual difference variables. I emphasize these demographic variables for several reasons. First, sex and ethnic differences in pain have tremendous public health implications, as they may contribute to differences in pain prevalence or severity that impact large population groups. Second, such demographic variables represent important proxies for a variety of other biopsychosocial factors that can influence pain, and the observation of group differences in pain is often the impetus for further exploration of these other pain-related factors. Finally, these demographic variables may be important moderators of the influence of other individual difference factors on pain, as discussed in the following text.

Sex and Gender Differences in Pain

CLINICAL PAIN

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 women⁶⁰^,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 some⁶⁴^,⁶⁵ but not other studies.⁶⁶ Women have also been found to report higher pain levels following orthopedic⁶⁷^,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.

EXPERIMENTAL PAIN

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.

RESPONSES TO PAIN TREATMENT

In addition to sex differences in clinical and experimental pain responses, whether women and men respond differently to pain treatment represents a topic of substantial interest. Before reviewing sex differences in treatment efficacy, it is important to consider whether there are differences in the provision of treatment to male and female patients. A gender bias in pain treatment has been previously described,¹⁰⁹ although the patterns of gender differences in pain treatment are complex. Indeed, a systematic review noted that although different pain treatments are often provided to women and men, the evidence does not demonstrate a consistent bias in pain treatment against women or men.¹¹⁰ A study of veterans typifies this pattern, as the authors found that compared to males, females received pain care that was more consistent with clinical practice guidelines; however, sedatives were prescribed more often for females than males, which is not supported by guidelines.¹¹¹ When biases in pain treatment do occur, they emerge from a complex mosaic of factors, including characteristics of both the patient and the provider. In a recent study, after viewing a patient video, specialist physicians and medical students concluded that female patients had less pain and were more likely to exaggerate their pain,¹¹² and providers were less likely to prescribe analgesics and more likely to recommend psychological treatment for female patients. Using computerized avatars to depict patients with chronic low back pain, Hirsh and colleagues¹¹³ reported that female but not male health care providers and trainees were more likely to prescribe antidepressants and mental health treatments for female versus male patients. Thus, there appear to be some gender-related biases in pain treatment, but these biases are influenced by interactions among multiple contextual factors, including but not limited to the gender of both the patient and the provider.

Another important issue regarding pain treatment is whether the effectiveness of treatments differs for women versus men. The treatment that has been most extensively studied in this regard is opioid therapy. In their meta-analysis, Niesters and colleagues¹¹⁴ examined whether responses to opioids differed across sex for both acute clinical pain and for experimental pain. Postoperatively, females consumed lower amounts of µ-opioid agonists than males, particularly for morphine administered via patient-controlled analgesia (PCA). The authors speculated that this pattern of results may have emerged because PCA studies often assess opioid use for a longer duration, which may increase detection of sex differences because morphine has a longer duration of action for women. Interestingly, a recent study reported sex differences in the daily rhythmicity of postoperative morphine consumption, with men using more morphine during the night.¹¹⁵ It should be mentioned that because these findings are based on opioid consumption rather than analgesic efficacy, it is possible that other factors may have contributed to lower consumption in women. Indeed, increased side effects, including nausea and vomiting, and unpleasant cognitive-affective effects have been reported for females.¹¹⁶ However, in experimental studies that directly measure analgesic responses, females showed greater analgesia in response to µ-opioids, with moderate effect sizes, which were larger than those observed for acute clinical pain. The authors also reviewed studies of mixed action opioids (e.g., pentazocine, nalbuphine, butorphanol), and in acute clinical pain, these agents produced considerably more robust analgesia in women. In contrast, studies of these medications tested against experimental pain models showed a striking absence of sex differences in analgesia. The most obvious explanation for these conflicting results lies in the characteristics of the pain models. Specifically, greater analgesic responses in women were observed for acute postoperative pain, which includes a strong inflammatory component, whereas the experimental pain models were decidedly noninflammatory. Taken together, the existing evidence suggests that women exhibit greater analgesic responses to µ-opioid agonists analgesia, whereas mixed-action opioid medications produce greater analgesia in females for postoperative but not experimental pain.

In the last 20 years, prescriptions of opioids for chronic pain have increased dramatically, resulting in a major public health crisis of opioid misuse and overdose in the United States.¹¹⁷^,¹¹⁸^,¹¹⁹ Very little research has addressed whether males and females with chronic pain respond differently to opioid therapy; however, there is evidence that the opioid crisis is differentially impacting women versus men. Opioids are prescribed more often for women than men, in part due to the excess female prevalence of chronic pain.¹²⁰^,¹²¹ Although even among individuals with chronic pain, women are more likely than men to use prescription opioids.¹²²^,¹²³^,¹²⁴ Also, among people with chronic pain using long-term opioids, women showed poorer overall chronic pain status.⁹⁴ However, nonmedical use of opioids is higher for males,¹²⁵ as are risks for dose escalation and opioid-related death.¹²⁶^,¹²⁷^,¹²⁸ Thus, despite more frequent opioid use in women with chronic pain, adverse outcomes are more common among males.

Scant research has addressed sex differences in responses to nonopioid therapies, and the inconsistent results of these studies defies general conclusions. For example, males exhibited greater analgesic responses to ibuprofen tested against experimental¹²⁹ but not postoperative pain.⁶⁴ Analgesic responses tested with electrical pain were more robust for males who expected to receive ibuprofen regardless of whether they received ibuprofen or placebo.¹³⁰ These findings suggesting that expectations induce greater analgesia in males are paralleled by other laboratory pain studies in which placebo analgesia has been found to be higher among males than females.¹³¹^,¹³² In contrast, women displayed greater placebo responses in another study,¹³³ and consistent findings were observed in a pediatric study that demonstrated increased placebo analgesia in girls compared to boys.¹³⁴ Additional research elucidating sex differences in placebo analgesia is warranted not only because such information influences clinical trial design and interpretation but also because sex differences in placebo analgesia could reflect sex differences in the engagement of endogenous analgesic mechanisms.

Research investigating sex differences in outcomes from nonpharmacologic pain treatments is even more limited, with variable results. As described in our previous review,⁹⁸ some evidence suggests more positive treatment effects in men, others show greater improvements among women; yet, others show similar outcomes across sex. A recent meta-analysis of sex differences in responses to psychological pain therapies in children and adolescents reported that boys and girls generally showed similar treatment responses.¹³⁵ Clearly, more research is needed to determine the extent to which nonpharmacologic pain treatments impact males and females differently and whether the mechanisms underlying treatment response differ by sex.

BIOPSYCHOSOCIAL MECHANISMS

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 studies¹⁴¹^,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.

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