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

Sex differences in clinical pain

Population-based research consistently demonstrates greater pain prevalence among women relative to men. For example, large-scale epidemiological studies across multiple geographic regions find that pain is reported more frequently by women than by men¹ (Fig. 1). Gerdle and colleagues⁹ found that for each of 10 different anatomical regions, a greater proportion of women than men reported pain in the past week, and women were significantly more likely to report chronic widespread pain. Moreover, the population prevalence of several common chronic pain conditions is greater for women than men, including fibromyalgia, migraine and chronic tension-type headache, irritable bowel syndrome, temporomandibular disorders, and interstitial cystitis.^1,4

In addition to these findings demonstrating that pain is reported more frequently by women compared with men, another relevant research question is whether the severity of pain differs by sex. This issue is surprisingly more difficult to address. For example, several investigators have examined sex differences in pain severity among samples of patients seeking care for their chronic pain. While some studies have reported greater pain severity among women than men,^10–13 other studies have found no sex differences in pain severity among treatment-seeking patients.^14–16 There is a potential for bias in these results as patients with less severe pain are under-represented in these studies. Sex differences in the delivery, effectiveness or both of pain treatments in these clinical samples could also influence the presence, magnitude and direction of sex differences in pain severity. Another approach to studying sex differences in pain severity has been to compare levels of post-procedural or post-surgical pain in women and men. Results from these studies have been inconsistent, with some reporting more severe pain among women,^17–19 others reporting more severe pain among men,²⁰ and others reporting no sex differences.²¹ On balance, the trend is towards greater acute post-procedural pain in women.¹ Interpretation of these studies is complicated by potential sex differences in responses to pain treatments because pharmacological interventions are always provided in these settings. A recent study exploited a large electronic medical record database to study sex differences in pain severity in >11 000 patients.²² Importantly, pain ratings were collected as part of standard care, but these patients were not necessarily seeking treatment for pain and procedural pain was excluded. The investigators reported consistently higher pain ratings for women compared with men across the vast majority of diagnostic groups.

Taken together, the findings from epidemiological and clinical studies demonstrate convincingly that women are at substantially higher risk for many common pain conditions. Regarding pain severity, the findings are less consistent and are likely influenced by multiple methodological factors, including selection biases in clinical studies and the potential for sex differences in the effects of pain treatments. In order to exert greater control over such sources of variability, investigators have exploited quantitative sensory testing in order to explore sex differences in pain in response to controlled noxious stimuli, and these findings are discussed next.

Sex differences in response to experimentally induced pain

Sex differences in responses to experimental pain have been investigated using a wide variety of stimulus modalities including mechanical (blunt pressure and punctate mechanical stimuli), electrical, thermal (heat and cold), ischaemic, and chemical stimuli (e.g. capsaicin, hypertonic saline). Increasingly in recent years, more sophisticated experimental pain models have been used to characterize dynamic pain modulatory processes, such as temporal summation of pain (pain facilitatory measure) and conditioned pain modulation (measure of pain inhibition). Pain responses have been assessed by a number of different outcome measures including behavioural indices of threshold (defined by time or intensity to the first sensation of pain) and tolerance, and self-report measures of pain intensity and unpleasantness. Previous qualitative and quantitative reviews have generally concluded that women display greater sensitivity to multiple pain modalities compared with men, and that women show greater temporal summation of pain while men display greater conditioned pain modulation.^1,4,8,23,24 In contrast, a recent systematic review concluded that ‘10 years of laboratory research have not been successful in producing a clear and consistent pattern of sex differences in human pain sensitivity’.⁵ A quantitative analysis of the studies that served as the foundation of their conclusion did however reveal a very consistent pattern of results in the direction of greater pain sensitivity in females.⁴ Figure 1 provides a graphical presentation of a dataset that reflects the typical pattern of findings across studies of sex differences in experimental pain responses, which helps explain the varying interpretations by some authors (for details regarding methodology see refs^25,26). The direction of sex differences in pain responses across multiple stimulus modalities and pain measures is highly consistent, with women showing greater sensitivity than men. However, the magnitude (and statistical significance) of the sex difference varies across measures, as it does across published studies. The potential mechanisms underlying these differences and the clinical implications of sex differences in pain sensitivity will be discussed further below.

Sex differences in response to pain intervention

Sex differences in response to pain treatment have also been described in the literature. In a review of 18 studies, Miaskowski and colleagues²⁷ observed lower opioid consumption postoperatively among women. This has not been a consistent finding and may depend on the type of surgical procedure²⁸ or result from increased prevalence of side-effects in women.²⁹ A recent meta-analysis⁷ reported mixed results for sex differences in opioid analgesia. While the authors found no sex-specific effects for mu-opioid analgesia across clinical studies of mu-opioids, greater ‘analgesic’ effects were observed for women when restricting analyses to patient-controlled analgesia (PCA) and were even more robust when considering only PCA morphine studies. It is important to note that these studies actually assessed opioid consumption rather than pain relief, which may be influenced by factors other than analgesia (e.g. side-effects). Despite this, results were similar for experimental studies that directly assessed analgesic responses, suggesting greater morphine analgesia for women. Interestingly, while no sex-dependent effects were found for mixed action opioids (e.g. butorphanol, nalbuphine, and pentazocine) across experimental studies, it was concluded that women exhibit greater analgesia than men in response to mixed action opioids in clinical studies.

Several investigators have also examined gender biases in pain treatment. In an often-cited study with multiple methodological shortcomings, women were given sedatives more often for pain after surgery, whereas men were more likely to receive analgesics.³⁰ This has led many to conclude that women are at risk for under-treatment of their pain. However, a recent review of this literature concluded that while women and men are often treated differently, this disparity sometimes favours women and sometimes favours men.³¹ Moreover, such gender biases are influenced by both patient and provider characteristics, which sometimes interact. For example, in a medical vignette study, physicians were more likely to prescribe opioid analgesics to patients of the same sex.³² More recent studies using virtual human technology have demonstrated that females are considered to have greater intensity and unpleasantness of pain than males and are more likely to be recommended for opioid treatment as evaluated by healthcare professionals and students.^33–35 These studies suggest that biases exist in healthcare, an effect which may lead to disparities in pain management.

Other research has investigated the impact of sex differences on non-pharmacological pain interventions. In a study by Keogh and Herdenfeldt,³⁶ men reported less pain when asked to focus on the sensory components of pain, while focusing on affective pain was not beneficial for women. There is also evidence that acceptance-based interventions for pain may be helpful towards reducing affective-related pain for women relative to men.³⁷ In another study, pain sensitivity was decreased after treadmill exercise in female athletes while these effects were only seen in male athletes after engaging in a video game competition.³⁸ In an interdisciplinary pain management programme, improvements in pain were found in both male and female patients after treatment; however, these effects disappeared 3 months later for women as they reported significantly more pain and catastrophizing than men.³⁹ More recently, results from a 5-week multimodal pain management programme found that women exhibited an improvement in pain-related disability as compared with men.⁴⁰ Hence, the literature seems to suggest that responses to non-pharmacologic treatments may differ for men and women, but the pattern of results is somewhat variable across studies.

Mechanisms underlying sex differences in pain

As the above summary indicates, it is well established that sex differences in pain exist; however, the specific underlying mechanisms contributing to this disparity are far from clear. It has been suggested that an interaction of biological, psychological, and sociocultural factors likely contribute to these differences. The following section will present a brief overview of the possible mechanisms implicated in sex-related differences in pain (see refs^1,6,41 for a more extensive review).

Conclusions

Sex differences in pain have been a topic of increased interest in recent years. Epidemiologic and clinical findings clearly demonstrate that women are at increased risk for chronic pain and some evidence suggests that women may experience more severe clinical pain. Studies of experimentally induced pain have produced a very consistent pattern of results, with women exhibiting greater pain sensitivity, enhanced pain facilitation and reduced pain inhibition compared with men, though the magnitude of these sex differences varies across studies. In addition, some evidence suggests sex differences in responses to pharmacological and non-pharmacological pain treatments, though the findings differ depending on the specific treatment and perhaps on characteristics of the pain. Also, gender biases in pain treatment appear to exist, which are influenced by characteristics of both the patient and the provider.

Multiple biopsychosocial mechanisms contribute to these sex differences in pain, including sex hormones, endogenous opioid function, genetic factors, pain coping and catastrophizing, and gender roles. At present, the available evidence does not support sex-specific tailoring of treatments; however, this is a conceivable outcome in the foreseeable future. Additional research to elucidate the mechanisms driving sex differences in pain responses is needed in order to foster future interventions to reduce these disparities in pain.

Authors' contributions

Both authors contributed to this work. E.J.B. generated the chief discussion points of the review article, wrote the abstract, and drafted the article. R.B.F. assisted in drafting the article and provided the statistical data. Both authors conducted the literature review, edited the manuscript, and approved the final version for publication.

Declaration of interest

E.J.B. declares no financial interests. R.B.F. is a consultant and equity stock holder in Algynomics, Inc., a company providing research services in personalized pain medication. Also, R.B.F. has received an honorarium from MedScape.

Funding

This work was supported by National Institutes of Health grants NS045551 and TR000064.