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.

Fillingim and Maixner (Fillingim, R.B. and Maixner, W., Pain Forum, 4(4) (1995) 209-221) recently reviewed the body of literature examining possible sex differences in responses to experimentally induced noxious stimulation. Using a 'box score' methodology, they concluded the literature supports sex differences in response to noxious stimuli, with females displaying greater sensitivity. However, Berkley (Berkley, K.J., Pain Forum, 4(4) (1995) 225-227) suggested the failure of a number of studies to reach statistical significance suggests the effect may be small and of little practical significance. This study used meta-analytic methodology to provide quantitative evidence to address the question of the magnitude of these sex differences in response to experimentally induced pain. We found the effect size to range from large to moderate, depending on whether threshold or tolerance were measured and which method of stimulus administration was used. The values for pressure pain and electrical stimulation, for both threshold and tolerance measures, were the largest. For studies employing a threshold measure, the effect for thermal pain was smaller and more variable. The failures to reject the null hypothesis in a number of these studies appear to have been a function of lack of power from an insufficient number of subjects. Given the estimated effect size of 0.55 threshold or 0.57 for tolerance, 41 subjects per group are necessary to provide adequate power (0.70) to test for this difference. Of the 34 studies reviewed by Fillingim and Maixner, only seven were conducted with groups of this magnitude. The results of this study compels to caution authors to obtain adequate sample sizes and hope that this meta-analytic review can aid in the determination of sample size for future studies.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a “symptom iceberg” when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA’s separate case-control study. The puzzle was resolved in OPPERA’s nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD’s onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.