Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08 mg/kg) or pentazocine (0.5 mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic, and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model analyses of variance. NOC women showed slightly greater heat pain sensitivity in the follicular vs luteal phase, while the reverse pattern emerged for OC women (P = 0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (P < 0.05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs the luteal phase (P = 0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (P = 0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude.     

Psychophysically determined thresholds for thermal perception and pain perception in healthy women across the menstrual cycle

OBJECTIVES: Several studies have indicated changes in sensation and/or pain sensitivity among women across the menstrual cycle, but the pattern of the changes varies considerably. One reason for the reported discrepancies could reside in lack of biochemical definition of menstrual cycle phase. The aim was to quantify temperature and temperature pain thresholds at biochemically defined stages of the menstrual cycle. METHODS: Nineteen healthy women were included in the study. Temperature and temperature pain thresholds were evaluated by quantitative sensory testing, performed at 3 occasions during the menstrual cycle (early follicular phase, late follicular phase, and mid-luteal phase). At each test session, serum concentrations of estradiol and progesterone were assessed. RESULTS: Thermal cold perception threshold at the mammilla was significantly lower in the late follicular and mid-luteal phases, compared with the early follicular phase (P<0.05, respectively). For the remaining test sites, no cycle related differences in thermal perception or thermal thresholds could be documented. CONCLUSIONS: The present study has indicated no major changes in thermal pain thresholds related to phase of the menstrual cycle for the tested locations, although thermal cold perception threshold at the mammilla was a significantly lower in the late follicular and mid-luteal phases, compared with the early follicular phase. The findings of the present study further underlines the need for strict criteria for menstrual cycle phase when studying pain sensitivity in relation to hormonal events in women.     

Cardiovascular functioning during the menstrual cycle

Variations in cardiovascular functioning during the ‘normal’ menstrual cycle have been little researched. Resting‐blood pressures, resting‐heart rate, rate‐pressure product (RPP) and a derived index of fitness (Schneider Index) were monitored throughout natural, hormonally defined menstrual cycles. Volunteers were 26 women (20–48 years) who had regular (25–35 days) cycles. Their blood pressures and heart rate (at rest and according to Schneider’s protocol) were measured at the same time daily (Monday–Friday) for 5 weeks. Daily, early morning‐urine samples were assayed for sex hormones enabling accurate definition of cycle phase for each woman. Resting systolic‐blood pressure was significantly higher in the ovulatory phase (P<0·05) than in the follicular or luteal phases, but resting‐diastolic pressures did not differ significantly between phases. Resting‐heart rate was significantly higher in both ovulatory (P<0·01) and luteal (P<0·01) phases than in the menstrual and follicular phases. The Schneider Index was higher during the follicular phase than during the ovulatory (P<0·005) or luteal (P<0·01) phases, the RPP was higher during the ovulatory phase than during the bleeding (P<0·05) and follicular (P<0·005) phases. These findings provide a pattern of menstrual cycle‐related variation in cardiovascular functioning that can be related to established actions of the ovarian steroids.     

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.     

Sensitivity to cold pressor pain in dysmenorrheic and non-dysmenorrheic women as a function of menstrual cycle phase

Pain responses (threshold, tolerance, and visual analog ratings) to the cold pressor task were studied in 46 normally menstruating dysmenorrheic and non-dysmenorrheic women during 2 phases of the menstrual cycle. Twenty-six women provided measurements during the follicular (days 8-14) and 20 during the luteal (days 15-21) phases of the menstrual cycle. A significantly lower pain threshold was obtained during the luteal as compared to the follicular phase. Pain tolerance showed a similar but non-significant trend. Visual analog ratings were significantly lower in dysmenorrheic women during the follicular than the luteal phase. Also, these ratings were lower than those of non-dysmenorrheic women in the follicular phase. This finding may support an adaptation-levels model, in that dysmenorrheic women report less pain than do non-dysmenorrheic women because they compare cold pressor pain with internal menstrual pain.     

Excitatory and inhibitory pain mechanisms during the menstrual cycle in healthy women

Sex differences in pain perception have been clearly documented in the literature during the last decades and it has been shown that women perceived more pain than men. Sex hormones (SHs) are thought to be one of the main mechanisms which explain sex differences in pain. Pain is a dynamic phenomenon involving both excitatory and inhibitory mechanisms. Previous studies have verified the effect of SH on excitatory mechanisms but not on endogenous pain inhibitory mechanisms. The main objective of this study was to establish if pain perception and diffuse noxious inhibitory control (DNIC) vary across the menstrual cycle (MC). Thirty-two healthy women with a regular MC were tested three times across their MC (days 1–3, days 12–14 and days 19–23). Experimental pain consisted of two tonic heat pain stimulations (thermode) separated by a 2-min cold pressor test (CPT) (conditioning stimulus activating DNIC). Pain ratings were measured with a visual analogue scale. Heat pain threshold, pain tolerance and mean pain intensity during both the 2-min thermode test and CPT did not vary throughout the MC. However, we found significantly more pain inhibition (DNIC effectiveness) during the ovulatory phase compared to the menstrual and luteal phases (p = 0.05). The main finding of this study is the observation that only inhibitory mechanisms (DNIC analgesia) and not excitatory pain mechanisms vary throughout the MC, where women have greater DNIC in the ovulatory phase. The higher occurrence of pain and lower pain threshold previously reported during the MC could be related to a reduction in endogenous pain control mechanisms.     

Cigarette smoking, stress-induced analgesia and pain perception in men and women

This study examined gender differences in smoking-related analgesia and stress-induced analgesia (SIA), as a function of pain modality. Forty men (20 smokers, 20 nonsmokers) and 37 women (17 smokers) were tested twice for pain sensitivity to tourniquet ischemia, thermal heat, and cold pressor tests; once following mental stress and once following rest control, counterbalancing order. Cardiovascular and neuroendocrine responses to mental stress were also examined. While expected gender differences in pain sensitivity were observed, women smokers had greater threshold and tolerance times to ischemic pain than women nonsmokers (P<0.05) when pain testing followed rest. Male smokers had greater threshold and tolerance to cold pressor pain than male nonsmokers (P<0.05) after both rest and stress. Only women showed evidence for SIA, since women nonsmokers demonstrated greater ischemic pain threshold and tolerance following mental stress versus rest (P<0.05), and all women reported lower thermal heat pain unpleasantness after stress versus rest (P=0.05). Only nonsmokers showed expected inverse relationships between sympathetic and hypothalamic-pituitary-adrenal (HPA) axis reactivity measures and sensitivity to pain. Smokers showed evidence for blunted HPA-axis function at rest and stress. These results indicate that analgesia related to both being a smoker and stress is influenced by gender and pain modality. The reduced pain perception in smokers and absence of relationships between endogenous pain regulatory mechanisms and pain sensitivity may reflect a maladaptive response to chronic smoking.     

Central pain in multiple sclerosis – Sensory abnormalities

Many patients with multiple sclerosis (MS) develop central neuropathic pain (CP). In the present study somatosensory abnormalities have been analysed in detail in 62 patients with MS and CP (42 women, 20 men; mean age 52 years) and in a control group of 10 women and 6 men (mean age 47 years) with MS and sensory symptoms, but without pain. Assessment included clinical testing and quantitative methods (QST) for the measurement of perception thresholds for touch, vibration, and temperatures. All CP patients except two (97%) had abnormal thresholds for innoxious and/or noxious temperatures, compared to 81% in the control group (p < 0.05). There was a tendency towards the opposite regarding sensibility to touch, which was decreased in 66% vs. 87% (n.s.), vibration (55% vs. 81%; n.s.) and to joint movement (32% vs. 62%; p < 0.04). Comparisons between painful and non‐painful regions showed both the absolute threshold values and the index values to be significantly more abnormal, in the CP regions, for warmth (p < 0.001), cold (p < 0.05), difference limen (innoxious warmth and cold, p < 0.01), cold pain (p < 0.01) and heat pain/cold pain combined (p < 0.001). Also the comparisons between regions with central pain and regions with sensory symptoms in the controls showed significantly more abnormal thresholds in the CP patients for warmth (p < 0.05), cold (p < 0.01), difference limen (innoxious warmth and cold, p < 0.01) and heat pain/cold pain combined (p < 0.001). The results support the general hypothesis that only patients who have lesions affecting the spinothalamo‐cortical pathways run the risk of developing central pain.     

Sex hormones and pain in regularly menstruating women with fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is more prevalent in women than in men. The skewed sex distribution in the prevalence has prompted questions of if and how sex hormones may be involved in the pathophysiology of FMS. In this study, we evaluated the levels of sex hormones and pain sensitivity at different phases of a menstrual cycle in regularly menstruating women with FMS relative to age-matched healthy women. Participants (n = 74 in each group) underwent a 9-day urine test to identify the date of ovulation. Three laboratory visits were scheduled to ascertain the varying levels of estrogen (E) and progesterone (P): Late-follicular phase (high E, low P); mid-luteal phase (high E, high P); and perimenstrual phase (low E, low P). At each visit, blood was drawn and ischemic pain testing was performed. The groups did not differ in the fluctuation of luteal hormone, follicular-stimulating hormone, E, and testosterone across a menstrual cycle. FMS patients showed slightly elevated P levels during the mid-luteal phase relative to healthy women but levels were within the normal range. Women with FMS showed consistently lower pain thresholds and tolerance relative to healthy women throughout the menstrual cycle. Pain threshold at the late follicular phase was modestly related to the P level. The results suggest that the disproportionate prevalence of females with FMS is not likely to be attributable to hormonal factors. Furthermore, the role of sex hormones in pain sensitivity for both FMS and healthy women seems to be limited. PERSPECTIVE: Normally menstruating women with FMS and healthy women do not seem to show fluctuating threshold and tolerance to the ischemic pain test. The role of sex hormones in the hyperalgesia of FMS appears limited.     

Sex Differences and Hormonal Influences on Response to Mechanical Pressure Pain in Humans

Previous studies have demonstrated that sex differences in pain responsivity can be detected using various models of experimentally induced pain. The present study employed the mechanical pressure test in order to examine potential differences in pain report among men, normally menstruating women (NMW), and women taking monophasic oral contraceptives (OCW). Testing occurred during 5 phases of the menstrual cycle (menstrual, follicular, ovulatory, luteal, and late luteal) and all participants completed 10 sessions (2 sessions per phase). Menstrual-cycle phase was estimated for OCW based on their first day of menses. Men were tested at time points that roughly corresponded to the intervals during which the different phases occurred in NMW. During the mechanical pressure test, 4 different weights were placed on the fingers, one at a time, and ratings of pain were recorded for 30 seconds. The statistical decision-making model and a forced-choice procedure were used to analyze the response data. Two variables, based on signal detection theory, were thus generated: P(A), a measure of sensory pain, and B, a measure of response bias. P(A) is believed to be a measure of pain sensitivity while B measures stoicism. NMW tended to report lower P(A) values, indicating reduced ability to discriminate among different stimulus intensities, during the menstrual and late luteal phases compared to the luteal phase. OCW reported lower B values, indicating less stoicism, during the menstrual compared to the follicular and ovulatory phases. Men tended to have significantly lower B values than OCW, but not NMW. These results demonstrate subtle menstrual-cycle effects in NMW and OCW. Sex differences were few, with more group differences and trends emerging between OCW and men, as opposed to men and NMW.PerspectiveThe lack of consistent differences between men and NMW underscores the subtle impact of sex and hormonal changes in pain report. In addition, the data obtained in NMW support the notion that changes in hormone levels during the menstrual cycle can lead to changes in pain responsivity as NMW had trends for better discrimination in menstrual phases when estradiol levels were highest.     

Effects of cocaine on luteinizing hormone in women during the follicular and luteal phases of the menstrual cycle and in men

Cocaine stimulates luteinizing hormone (LH) release in rhesus monkeys and in men, but its effects on LH in women are unknown. Cocaine (0.2 and 0.4 mg/kg i.v.) was administered to groups of follicular and luteal phase women (N = 22) and to men (N = 12) to examine the influence of gender and menstrual cycle phase on cocaine and LH interactions. All subjects met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for cocaine abuse, and menstrual cycle phase was verified by estradiol and progesterone measures. Baseline LH levels were equivalent between groups. Peak cocaine levels did not differ significantly between men and women and averaged between 87 +/- 21 and 124 +/- 18 ng/ml after 0.2 mg/kg cocaine and between 227 +/- 22 and 287 +/- 21 ng/ml after 0.4 mg/kg cocaine. The lower dose of cocaine (0.2 mg/kg) significantly increased LH levels in men (P < 0.001) but not in women at either phase of the menstrual cycle. The higher dose of cocaine (0.4 mg/kg) stimulated significant increases in LH in men (P < 0.001) and in women at both phases of the menstrual cycle (P < 0.004-0.001). Although cocaine's effects on LH in women were dose-dependent, there were no significant differences as a function of menstrual cycle phase. LH remained significantly elevated longer in men (32 min) than in women (8 and 12 min). This gender difference in cocaine's potency in stimulating LH was unexpected.     

Sex differences and hormonal influences on response to cold pressor pain in humans.

Although most studies show that women have higher subjective pain ratings in response to painful stimuli, there is less consistency across studies with regard to the influence of gonadal hormones on pain responsivity. The present study evaluated sex differences in response to cold pressor pain in normally menstruating women (NMW), women maintained on oral contraceptives (OCW), and men. Testing occurred during 5 phases of the menstrual cycle. All participants completed 10 sessions (2 sessions per phase). During the cold pressor test, participants immersed the forearm into water maintained at 4 degrees C, and pain threshold and tolerance were measured. Subjective ratings of pain, physiologic indices, and plasma levels of estradiol and progesterone were also assessed. Both estradiol and progesterone levels varied as a function of menstrual cycle phase in NMW and were significantly higher in NMW compared with OCW and men. There were no significant differences in pain threshold or tolerance for any of the groups as a function of menstrual cycle phase. There were no significant differences in pain tolerance between groups. However, pain threshold was higher in NMW compared with OCW and men. When the data were reanalyzed across consecutive sessions, a significant sex-by-day interaction was observed for both threshold and tolerance. Specifically, pain threshold and tolerance were similar for NMW, OCW, and men, but these latencies changed at different rates across session days. Pain threshold remained relatively constant for both OCW and men, but it increased across days for NMW. Pain tolerance remained stable across sessions in OCW, a slow consistent increase was observed for men, whereas a sharper increase, followed by an asymptote, was observed for NMW. These results suggest that circulating gonadal hormones might mediate adaptation to cold pressor pain. PERSPECTIVE: The present study supports the notion that differences in pain perception between the sexes and among menstrual cycle phases are subtle. However, normally menstruating women exhibited an increase in pain tolerance and threshold over repeated stimulation, whereas men exhibited a shallow increase in pain threshold only, suggesting a sex difference in the adaptation to painful stimuli in men and women.     

Diclofenac Potassium Attenuates Dysmenorrhea and Restores Exercise Performance in Women With Primary Dysmenorrhea

We assessed the efficacy of diclofenac potassium, a nonsteroidal anti-inflammatory drug, in alleviating menstrual pain and restoring exercise performance to that measured in the late-follicular phase of the menstrual cycle. Twelve healthy young women with a history of primary dysmenorrhea completed, in a random order, laboratory exercise-testing sessions when they were in the late-follicular (no menstruation, no pain) phase of the menstrual cycle and when they were experiencing dysmenorrhea and receiving, in a double-blinded fashion, either 100 mg of diclofenac potassium or placebo. We assessed the women's leg strength (1-repetition maximum test), aerobic capacity (treadmill walking test), and ability to perform a functional test (task-specific test). Compared with placebo, diclofenac potassium significantly decreased dysmenorrhea on the day of administration (Visual Analog Scale, P < .001 at all times). When receiving placebo for menstrual pain, the women's performance in the tests was decreased significantly, compared with when they were receiving diclofenac potassium for menstrual pain (P < .05) and compared with when they were in the late-follicular phase of the menstrual cycle (P < .05 for treadmill test, P < .01 for task-specific test and 1-repetition maximum test). Administration of diclofenac potassium for menstrual pain restored exercise performance to a level not different from that achieved in the late-follicular phase of the cycle.PerspectiveIn women with primary dysmenorrhea, menstrual pain, if untreated, decreases laboratory-assessed exercise performance. A recommended daily dose of a readily available nonsteroidal anti-inflammatory drug, diclofenac potassium, is effective in relieving menstrual pain and restoring physical performance to levels achieved when the women were in the late-follicular (no menstruation, no pain) phase of the menstrual cycle.     

The influence of menstrual phases on pain modulation in healthy women

This study investigated if conditioned pain modulation (CPM) varies across the menstrual cycle in healthy, normally menstruating women and investigated correlations between sex hormone levels and CPM across the menstrual cycle. Thirty-six normally menstruating women were tested during 3 phases of the menstrual cycle: early follicular, ovulatory, and midluteal, confirmed by hormone determinations. Mechanical pressure (test stimulus) was applied to the masseter muscle and the induced pain assessed before, during, and after immersion of the hand into ice water (conditioning stimulus) to activate CPM or tepid water (control). Conditioning pain, ie, pain in the hand during CPM/control experiment, and tolerance time were also measured. Test pain intensity was suppressed during CPM in all phases (P < .001), but with more effective suppression during the ovulatry than during the early follicular phase (P < .05). There were no changes in test pain intensity during the control experiment and no significant differences in conditioning pain, or tolerance time between phases. In conclusion, our results showed more effective pain modulation in the ovulatory phase of the menstrual cycle, when estradiol levels are high and progesterone levels are low, than in the early follicular phase when both these hormones are low. PERSPECTIVE: Deficient pain modulation is believed to be an important pathogenic factor in many chronic pain conditions that affect women. This article shows that sex hormones modulate conditioned pain modulation, because pain inhibition was more effective in the ovulatory phase of the menstrual cycle than in the early follicular phase.     

Influence of menstrual cycle and gender on alprazolam pharmacokinetics

The effects of menstrual cycle phases and gender on alprazolam pharmacokinetics were evaluated in normal volunteers. Alprazolam (1 mg) was administered to seven women during the late follicular and luteal phases of the menstrual cycle and to eight men on one occasion. No difference in alprazolam pharmacokinetic parameters was observed during the menstrual cycle phases. Mean alprazolam clearance (+/- SD) was 0.0037 +/- 0.0009 ml/hr during the follicular phase and 0.0036 +/- 0.001 ml/hr during the luteal phase (p greater than 0.05, difference not significant). With use of weight as a covariant, there was no difference in alprazolam pharmacokinetic parameters between women and men. Mean alprazolam clearance (+/- SD) was 0.0036 +/- 0.0009 ml/hr in women compared with 0.0041 +/- 0.0006 ml/hr in men (p greater than 0.05, difference not significant). Although alprazolam metabolism was similar on the 2 days tested, alterations may occur at other times during the menstrual cycle. Further investigation is needed to understand the effects of menstrual cycle phases and gender on drug metabolism.     

Mechanical Pain Sensitivity and the Severity of Chronic Neck Pain and Disability Are Not Modulated Across the Menstrual Cycle

Despite the high prevalence of neck pain among women, menstrual effects on regional pain outcomes have not been investigated in this clinical population. This study evaluated menstrual effects on mechanical pain sensitivity (pressure pain threshold [PPT]), neck pain intensity (numeric pain rating scale [NPRS]), and neck-related disability (Neck Disability Index [NDI]) in 22 normally menstruating (NM) and 17 hormonal contraceptive users with chronic neck pain. Sex hormones, PPT, and NDI were measured during the early follicular (F1), late follicular (F2), and luteal (L) menstrual phases. Daily NPRS scores were recorded in an online symptom diary and averaged within each phase. Estradiol and progesterone increased only for NM women in F2 and L, respectively. Phase effects on PPT (η² = .003), NDI (η² = .003), and NPRS (η² = .016) for NM women were small and did not differ from those for the hormonal contraceptive users (P ≥ .386). Averaged across the menstrual cycle, PPT scores explained 29% of the variance in NPRS scores for NM women but were not associated with NDI scores in either group. Results indicate that the magnitude of menstrual effects on mechanical pain sensitivity and the severity of neck pain and disability do not exceed thresholds of clinically detectable change in women with chronic neck pain.     

The relationship of allopregnanolone immunoreactivity and HPA-axis measures to experimental pain sensitivity: Evidence for ethnic differences

In animal models, allopregnanolone (ALLO) negatively modulates the hypothalamic-pituitary-adrenal (HPA) axis and has been shown to exert analgesic effects. The purpose of this study was to assess the relationship between plasma ALLO immunoreactivity (ALLO-ir), HPA-axis measures, and pain sensitivity in humans. Forty-five African Americans (21 men, 24 women) and 39 non-Hispanic Whites (20 men, 19 women) were tested for pain sensitivity to tourniquet ischemia, thermal heat, and cold pressor tests. Plasma ALLO-ir, cortisol, and beta-endorphin concentrations were taken following an extended rest period. Lower concentrations of ALLO-ir were associated with increased pain tolerance to all three pain tests and increased pain threshold to the thermal heat pain task in the non-Hispanic Whites only (rs=-.35 to -.49, ps<.05). Also, only in the non-Hispanic Whites was cortisol associated with thermal heat tolerance (r=+.39, p<.05) and threshold (r=+.50, p<.01) and cold pressor tolerance (r=+.32, p<.05), and were beta-endorphin concentrations associated with cold pressor tolerance (r=+.33, p<.05). Mediational analyses revealed that higher cortisol levels mediated the relationship between lower ALLO-ir and increased thermal heat pain threshold in the non-Hispanic Whites only. These results suggest that lower ALLO-ir concentrations are associated with decreased pain sensitivity in humans, especially in non-Hispanic Whites, and that this relationship may be mediated by HPA-axis function.     

Sex differences in the long-term stability of forehead cold pressor pain.

The purpose of this study was to examine sex differences in the stability of experimental pain responding across time. Stability was assessed by using 2 forehead cold pressor applications separated by 9 months. Twenty-eight men and 20 women completed both Session 1 and Session 2. Repeated measures analysis of variance showed a main effect for Session on maximum pain level. Women reported significantly more pain at Session 2, whereas men showed no difference between sessions. There were no differences on pain report between men and women at Session 1. A significant Session by Sex interaction was associated with perceived chronic stress and trait anxiety levels. At Session 2 but not Session 1, women endorsed a significantly greater expectation than men to experience unpleasant aftereffects from the cold pressor task. Additional analysis showed that chronic stress and trait anxiety were significantly associated with sex-specific pain responding. We propose that the influence of a prior painful incident on an identical repeated painful experience differs between men and women. We speculate that this influence is related to sex differences in psychological mechanisms used to interpret painful stimuli within the context of remembered experiences. To our knowledge, this is the first report of sex differences in the long-term stability of an experimental laboratory pain stimulus, controlling for follicular phase of the female menstrual cycle. PERSPECTIVE: This study examines sex differences in the stability of experimental pain responding across a 9-month period. We speculate that psychological mechanisms influence one's interpretation of a prior painful incident and that this interpretation facilitates increased pain reporting in response to an identical repeated exposure, as was observed for women.     

Women With Dysmenorrhea Are Hypersensitive to Experimental Deep Muscle Pain Across the Menstrual Cycle

Primary dysmenorrhea is a common painful condition in women that recurs every month across the reproductive years. The recurrent nociceptive input into the central nervous system that occurs during menstruation each month in women with dysmenorrhea is hypothesized to lead to increased sensitivity to painful stimuli. We investigated whether women with primary dysmenorrhea are hyperalgesic to deep muscle pain induced by a cleanly nociceptive method of hypertonic saline injection. Pain stimulation was applied both within an area of referred menstrual pain (lower back) and at a remote site outside of referred menstrual pain (forearm) in 12 healthy women with severe dysmenorrhea and 9 healthy women without dysmenorrhea, at 3 phases of the menstrual cycle: menstruation and follicular and luteal phases. Women rated their pain severity on a 100-mm visual analog scale every 30 seconds after injection until the pain subsided. In both groups of women, menstrual cycle phase had no effect on the reported intensity and duration of muscle pain. However, women with dysmenorrhea had increased sensitivity to experimental muscle pain both at the site of referred pain and at a remote nonpainful site, as assessed by peak pain severity visual analog scale rating, area under the visual analog scale curve, and pain duration, compared to women without dysmenorrhea. These data show that women with severe primary dysmenorrhea, who experience monthly menstrual pain, are hyperalgesic to deep muscle pain compared to women without dysmenorrhea.     

Gender role expectations of pain mediate sex differences in cold pain responses in healthy Libyans

Previous studies found a relationship between response to experimentally‐induced pain and scores for the gender role expectations of pain (GREP) questionnaire. Findings were similar in individuals from America, Portugal and Israel suggesting that gender role expectations may be universal. The aim of this study was to translate and validate Arabic GREP using Factor Analysis and to investigate if sex differences to cold‐pressor pain in healthy Libyan men and women are mediated through stereotypical social constructs of gender role expectations and/or pain‐related anxiety. One hundred fourteen university students (58 women) underwent two cycles of cold pressor pain test to measure pain threshold, tolerance, intensity, and unpleasantness. Participants also completed the Arabic GREP questionnaire and the Pain Anxiety Symptom Scale‐Short form (PASS‐20). It was found that Libyan men had higher pain thresholds and tolerances than women (mean difference, 95% CI: threshold = 4.69 (s), ?0.72 to 10.1, p = 0.005; tolerance = 13.46 (s), 0.5–26.4, p = 0.018). There were significant differences between sexes in 6 out of 12 GREP items (p < 0.004 after Bonferonni adjustment). The results of mediational analysis showed that GREP factors were the mediators of the effects of sex on pain threshold (z = ?2.452, p = 0.014 for Self Sensitivity); (z = ?2.563, p = 0.01, for Self Endurance) and on pain tolerance (z = ?2.538, p = 0.01 for Self Endurance). In conclusion, sex differences in response to pain were mediated by gender role expectations of pain but not pain‐related anxiety.