Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings

Fillingim RB1, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd.

Sex-related influences on pain and analgesia have become a topic of tremendous scien- tific and clinical interest, especially in the last 10 to 15 years. Members of our research group published reviews of this literature more than a decade ago, and the intervening time period has witnessed robust growth in research regarding sex, gender, and pain. Therefore, it seems timely to revisit this literature. Abundant evidence from recent epidemiologic studies clearly demonstrates that women are at substantially greater risk for many clinical pain conditions, and there is some sug- gestion that postoperative and procedural pain may be more severe among women than men. Consistent with our previous reviews, 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. The evidence regarding sex differences in laboratory measures of endogenous pain modulation is mixed, as are findings from studies using functional brain imaging to ascertain sex differences in pain-related cerebral activation. Also inconsistent are findings regarding sex differences in responses to pharmacologic and non-pharmacologic pain treatments. The article concludes with a discussion of potential biopsychosocial mechanisms that may underlie sex differences in pain, and considerations for future research are discussed. 

Given that the clinical pain conditions to which preclinical research is intended to apply are female-pre- dominant, one could argue that preclinical research that excludes females is incomplete at best and invalid at worst. Moreover, clinical studies, which typically include participants of both sexes, should consistently analyze for sex differences and report the findings, whether positive or negative. This would help overcome publication biases, which could overestimate sex differences based on the reduced likelihood of reporting negative findings. Another important conceptual and analytical concern is the distinction between qualitative and quantitative sex differences. Most of the studies reviewed above address quantitative differences, which refers to whether females and males dis- play different amounts of pain or analgesia. In contrast, qualitative sex differences are present when a given variable influences pain or analgesia differently in women versus men. Because qualitative differences may indicate sex-specific pain mechanisms they represent the most 

compelling rationale for the development of sex-specific pain treatments. Thus, even in the absence of quantitative sex differences, researchers should conduct analyses to un- cover potential qualitative sex differences, which simply in- volves including sex as a moderator in the statistical model.

In this era of translational science, an important goal for future research in this area is to generate information that will enhance pain treatment for both sexes. Despite the challenges of translational research, several opportunities that could be exploited to enhance translation have previously been suggested. For example, human laboratory pain models and genetic research could both serve as translational bridges between laboratory findings from nonhuman animals and clinical populations. For example, Mogil and colleagues successfully translated a novel sex-related genetic association (ie, the melanocortin-1-receptor gene, MC1R) with analgesic responses across species using experimental pain models in both mice and humans. To complete the translational continuum, it is important to determine whether sex-related genetic associations such as these discovered in the laboratory setting will extend to clinical populations. Human brain imaging represents another methodology that holds promise for facilitating mechanistic and translational advancements, and increased application of imaging to enhance understanding of sex differences in pain and analgesia is strongly recommended. We would like to echo the important issues demanding future investigation as delineated in the recent consensus report from the IASP Special Interest Group on Sex, Gender, and Pain, including identifying hormonal versus chromosomal contributions to sex differences in pain/analgesia; understanding the contribution of local (versus gonadal release) hormonal effects; elucidating the role of psychological factors; understanding whether pain chronicity contributes to sex differences; distinguishing the roles of sexual dimorphism in ascending versus descending modulatory pathways; determining the cellular and molecular bases of sex differences in pain/ analgesia; understanding sex differences across the lifespan; and considering whether diagnostic criteria for some pain disorders should be sex-specific. Empirical attention to these issues will further advance knowledge regarding sex, gender, and pain and could lead to sex- specific enhancements in clinical pain management in the not too distant future.