Roger B. Fillingim

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

UNLABELLED Sex-related influences on pain and analgesia have become a topic of tremendous scientific 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 suggestion 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. PERSPECTIVE This article reviews the recent literature regarding sex, gender, and pain. The growing body of evidence that has accumulated in the past 10 to 15 years continues to indicate substantial sex differences in clinical and experimental pain responses, and some evidence suggests that pain treatment responses may differ for women versus men.

Sex differences in the perception of noxious experimental stimuli: a meta-analysis

&NA; 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.

An interdisciplinary expert consensus statement on assessment of pain in older persons

This paper represents an expert-based consensus statement on pain assessment among older adults. It is intended to provide recommendations that will be useful for both researchers and clinicians. Contributors were identified based on literature prominence and with the aim of achieving a broad representation of disciplines. Recommendations are provided regarding the physical examination and the assessment of pain using self-report and observational methods (suitable for seniors with dementia). In addition, recommendations are provided regarding the assessment of the physical and emotional functioning of older adults experiencing pain. The literature underlying the consensus recommendations is reviewed. Multiple revisions led to final reviews of 2 complete drafts before consensus was reached.

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury–evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from κ-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates κ-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered κ-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the κ-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

Race, ethnicity and pain

The current paper provides a brief overview of research on the effects of race and ethnicity on pain. More specifically, the article reviews the utility of the concepts of race and ethnicity for pain research, suggests operational definitions of race and ethnicity, reviews the literature on the effects of race and ethnicity on laboratory and clinical pain, and provides suggestions for future research.

Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain

&NA; Temporomandibular disorders (TMD) represent a group of chronic painful conditions involving the muscles of mastication and the temporomandibular joint. We determined whether patients with painful TMD are more sensitive to noxious stimuli than age‐matched control subjects. Fifty‐two TMD patients (16 with muscle pain and 36 with combined muscle and joint pain) and 23 age‐matched and gender‐matched volunteers participated. Forearm thermal pain threshold and tolerance values were determined. A submaximal effort tourniquet procedure was used to evoke ischemic muscle pain. Relative to control subjects, TMD patients had significantly lower thermal pain threshold, ischemic pain threshold, and ischemic pain tolerance values; and thermal pain tolerance values also tended to be lower. Pain sensitivity did not differ between the two groups of TMD patients. Furthermore, the submaximal effort tourniquet procedure, which is capable of altering acute orofacial pain (Sigurdsson and Maixner, 1994) did not produce a consistent reduction in orofacial pain associated with TMD. We concluded that TMD patients are more sensitive to noxious stimuli than pain‐free controls. These findings provide additional evidence that TMD is a psychophysiological disorder of the central nervous system which modulates emotional, physiological and neuroendocrine responses to emotional and physical stressors.

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

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.

Idiopathic pain disorders--pathways of vulnerability.

Idiopathic pain disorders (IPDs) consist of such conditions as temporomandibular joint disorders (TMJD), fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), chronic headaches, interstitial cystitis, chronic pelvic pain, chronic tinnitus, whiplash-associated disorders, and vulvar vestibulitis (VVS). IPDs commonly aggregate as ‘‘comorbid’’ conditions that are characterized by a complaint of pain as well as a mosaic of abnormalities in motor function, autonomic balance, neuroendocrine function, and sleep. Although the mechanisms that underlie the majority of these conditions are poorly understood, IPDs have been associated with a state of pain amplification and psychological distress (McBeth et al., 2001; Bradley and McKendree-Smith, 2002; Verne and Price, 2002; Gracely et al., 2004).

Ethnic Differences in Pain Tolerance: Clinical Implications in a Chronic Pain Population

Objective Although numerous studies have independently examined ethnic differences in clinical and experimental pain, few have investigated differences in both sensitivity to controlled noxious stimuli and clinical pain reports in the same sample. The present experiment examined the effects of ethnicity (African American vs. white) on experimental pain tolerance and adjustment to chronic pain. Methods Three hundred thirty-seven (68 African American and 269 white) patients with chronic pain referred to a multidisciplinary treatment center participated in the study. In addition to completing a number of standardized questionnaires assessing adjustment to chronic pain, participants underwent a submaximal effort tourniquet procedure. This experimental pain procedure yields a measure of tolerance for a controlled noxious stimulus (ie, arm ischemia). Results African American subjects reported higher levels of clinical pain as well as greater pain-related disability than white participants. In addition, substantial group differences were observed for ischemic pain tolerance, with African Americans demonstrating less tolerance than whites. Correlational analyses revealed a small but significant inverse relationship between ischemic pain tolerance and the reported severity of chronic pain. Conclusions Collectively these findings support previous research revealing ethnic differences in responses to both clinical and experimental pain. Moreover, the present results suggest that enhanced sensitivity to noxious stimuli on the part of African Americans may be associated with ethnic differences in reported clinical pain, although the magnitude of ethnic differences was much greater for ischemic pain tolerance than for clinical pain measures.