Joseph L. Riley

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.

A meta-analytic review of pain perception across the menstrual cycle

The purpose of this article is to review the sixteen published studies that examine associations between the perception of experimentally induced pain across menstrual cycle phases of healthy females. We also performed a meta-analysis to quantitatively analyze the data and attempt to draw conclusions. The results suggest that there are relatively consistent patterns in the sensitivity to painful stimulation. These patterns are similar across stimulus modality with the exception of electrical stimulation. The magnitude of the effect was approximately 0.40 across all stimulation. For pressure stimulation, cold pressor pain, thermal heat stimulation, and ischemic muscle pain, a clear pattern emerges with the follicular phase demonstrating higher thresholds than later phases. When the effect size was pooled across studies (excluding electrical) comparisons involving the follicular phase were small to moderate (periovulatory phase, d(thr) = 0.34; luteal phase, d(thr) = 0.37; premenstrual phase, d(thr) = 0.48). The pattern of effects was similar for tolerance measures. Electrical stimulation was different than the other stimulus modalities, showing the highest thresholds for the luteal phase. When the effect size was pooled across studies for electrical stimulation, effect sizes were small to moderate (menstrual (d(thr) = -0.37), follicular d(thr) = -0.30) periovulatory d(thr) = -0.61), and premenstrual d(thr) = 0.35) phases. This paper raises several important questions, which are yet to be answered. How much and in what way does this menstrual cycle effect bias studies of female subjects participating in clinical trials? Furthermore, how should studies of clinical pain samples control for menstrual related differences in pain ratings and do they exist in clinical pain syndromes? What this paper does suggest is that the menstrual cycle effect on human pain perception is too large to ignore.

A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia

&NA; A previous meta‐analysis of clinical analgesic trial studies showed generally low magnitudes of placebo analgesia (N. Engl. J. Med. 344 (2001) 1594). However, as studies included in their analysis used only placebo as a control condition, we conducted two meta‐analyses, one in which 23 studies used only placebo as a control condition, and one in which 14 studies investigated placebo analgesic mechanisms. Magnitudes of placebo analgesic effects were much higher in the latter (mean effect size=0.95) as compared to the former (mean effect size=0.15) and were significantly different (P=0.003). This difference as well as differences in effect sizes within studies of placebo mechanisms may be parsimoniously explained by differences in expected pain levels produced by placebo suggestions and by conditioning. Furthermore, some of the studies of placebo analgesic mechanisms indicate that the magnitude of placebo analgesia is higher when the placebo analgesic effect is induced via suggestion combined with conditioning than via suggestion alone or conditioning alone. Based on these findings, we suggest that placebo analgesic effects are most optimally conceptualized in terms of perception of the placebo agent, and therefore a new definition of placebo response is proposed.

Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder

ABSTRACT Females with Irritable Bowel Syndrome (IBS) and Temporomandibular Disorder (TMD) are characterized by enhanced sensitivity to experimental pain. One possible explanation for this observation is deficiencies in pain modulation systems such as Diffuse Noxious Inhibitory Control (DNIC). In a few studies that used brief stimuli, chronic pain patients demonstrate reduced DNIC. The purpose of this study was to compare sensitivity to prolonged heat pain and the efficacy of DNIC in controls to IBS and TMD patients. Heat pain (experimental stimulus; 44.0–49.0 °C), which was applied to left palm, was continuously rated during three 30‐s trials across three separate testing sessions under the following conditions: without a conditioning stimulus; during concurrent immersion of the right foot in a 23.0 °C (control); and during noxious cold immersion in a (DNIC; 8.0–16.0 °C) water bath. Compared to controls, IBS and TMD patients reported an increased sensitivity to heat pain and failed to demonstrate pain inhibition due to DNIC. Controls showed a significant reduction in pain during the DNIC session. These findings support the idea that chronic pain patients are not only more pain sensitive but also demonstrate reduced pain inhibition by pain, possibly because of dysfunction of endogenous pain inhibition systems.

Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics.

Abstract The aim of this study was to examine experimental pain sensitivity in three ethnic groups, African Americans, Hispanic Americans and non‐Hispanic White Americans, and to determine whether ethnic identity is differentially associated with pain sensitivity across ethnic groups. Participants included sixty‐three African American, sixty‐one Hispanic and eighty‐two non‐Hispanic white participants who were assessed using three experimental pain measures: thermal, cold‐pressor and ischemic. Participants’ ethnic identity was assessed using the Multi‐group Ethnic Identity Measure (MEIM). Ethnic group differences in pain responses were observed, with African American and Hispanic subjects showing lower cold and heat pain tolerances than non‐Hispanic White Americans. In addition, pain range (i.e. tolerance‐threshold) was computed for heat, cold and ischemic pain, and the two minority groups again had lower values compared to non‐Hispanic White Americans. Ethnic identity was associated with pain range only for African American and Hispanic groups. Statistically controlling for ethnic identity rendered some of the group differences in pain range non‐significant. These findings indicate that ethnic identity is associated with pain sensitivity in ethnic minority groups, and may partially mediate group differences in pain perception. The results of the present investigation provide evidence of ethnic group differences in responses to experimental pain across multiple noxious stimuli, with both minority groups exhibiting greater sensitivity to laboratory evoked pain compared to non‐Hispanic White Americans.

The Coping Strategies questionnaire : A large sample, item level factor analysis

OBJECTIVE The Coping Strategies Questionnaire (CSQ), a measure of coping in chronic pain patients, was subjected to item-level exploratory factor analysis. SUBJECTS A sample of 965 chronic pain patients were used in the analysis. RESULTS Principal components analysis using a varimax rotation procedure identified nine factors that accounted for 54.5% of the variance. Of these nine factors, the first five represent subscales of the original CSQ subscales. The catastrophizing subscale replicated with significant loadings for all six original items, and ignoring sensations replicated with five of six items. Factors representing reinterpreting pain sensations, coping self-statements, and diverting attention subscales also appeared. The items from the praying and hoping subscale split into separate praying and hoping factors (factors 6 and 8). When reliability coefficients were calculated, factors 7 through 9 had unacceptably low internal consistency and thus were not considered stable factors. Correlations between factors 1 through 6 and other measures of psychological and physical functioning were calculated in the construct validation portion of this study. Previously found relationships were replicated in that the correlations between CSQ factor scores and measures of pain, depression, and disability were in the same direction in this data set as those previously reported.

Racial/ethnic differences in the experience of chronic pain.

&NA; The purpose of this study was to examine racial/ethnic‐related differences in a four‐stage model of the processing of chronic pain. The subjects were 1557 chronic pain patients (White=1084, African American=473) evaluated at a pain management clinic at a large southeastern university medical center. Using an analysis of covariance controlling for pain duration and education, African American patients reported significantly higher levels of pain unpleasantness, emotional response to pain, and pain behavior, but not pain intensity than Whites. Differences were largest for the unpleasantness and emotion measures, particularly depression and fear. The groups differed by approximately 1.0 visual analogue scale unit, a magnitude that may be clinically significant. Racial/ethnic differences in the linear relationship between stages were also tested using structural equation modeling and LISREL‐8. The results indicate differences in linear associations between pain measures with African Americans showing a stronger link between emotions and pain behavior than Whites.

A Meta-Analytic Review of the Hypoalgesic Effects of Exercise

UNLABELLED The purpose of this article was to examine the effects of acute exercise on pain perception in healthy adults and adults with chronic pain using meta-analytic techniques. Specifically, studies using a repeated measures design to examine the effect of acute isometric, aerobic, or dynamic resistance exercise on pain threshold and pain intensity measures were included in this meta-analysis. The results suggest that all 3 types of exercise reduce perception of experimentally induced pain in healthy participants, with effects ranging from small to large depending on pain induction method and exercise protocol. In healthy participants, the mean effect size for aerobic exercise was moderate (d(thr) = .41, d(int) = .59), while the mean effect sizes for isometric exercise (d(thr) = 1.02, d(int) = .72) and dynamic resistance exercise (d(thr) = .83, d(int) = .75) were large. In chronic pain populations, the magnitude and direction of the effect sizes were highly variable for aerobic and isometric exercise and appeared to depend on the chronic pain condition being studied as well as the intensity of the exercise. While trends could be identified, the optimal dose of exercise that is needed to produce hypoalgesia could not be systematically determined with the amount of data available. PERSPECTIVE This article presents a quantitative review of the exercise-induced hypoalgesia literature. This review raises several important questions that need to be addressed while also demonstrating that acute exercise has a hypoalgesic effect on experimentally induced pain in healthy adults, and both a hypoalgesic and hyperalgesic effect in adults with chronic pain.

Cluster analysis of multiple experimental pain modalities.

&NA; Identifying individual differences in pain is an important topic; however, little is known regarding patterns of responses across various experimental pain modalities. This study evaluated subgroups emerging from multiple experimental pain measures. One hundred and eighty‐eight individuals (59.0% female) completed several psychological instruments and underwent ischemic, pressure, and thermal pain assessments. Thirteen separate pain measures were obtained by using three experimental pain modalities with several parameters tested within each modality. The pain ratings and scores were submitted to factor analysis that identified four pain factors from which Pain Sensitivity Index (PSI) scores were computed: heat pain (HP), pressure pain (PP), ischemic pain (IP), and temporal summation of heat pain (TS). Cluster analyses of PSI scores revealed four distinct clusters. The first cluster demonstrated high overall pain sensitivity, the second cluster revealed high TS, the third cluster showed particular insensitivity to IP and low sensitivity across pain modalities except PP, and the fourth cluster demonstrated low sensitivity to PP. Significant correlations were found between psychological measures and Index scores and those differed by sex. Cluster membership was associated with demographic variables of ethnicity and sex as well as specific psychosocial variables, although cluster differences were only partially explained by such factors. These analyses revealed that groups respond differently across varied pain stimuli, and this was not related solely to demographic or psychosocial factors. These findings highlight the need for future investigation to identify patterns of responses across different pain modalities in order to more accurately characterize individual differences in responses to experimental pain.