S. Palit

Emotional modulation of pain and spinal nociception in fibromyalgia

&NA; Fibromyalgia is associated with disrupted emotional processing and emotional modulation of pain, but intact descending emotional modulation of spinal nociception. &NA; Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well‐validated affective picture‐viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain‐free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological‐emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain‐to‐spinal cord circuitry that modulates spinal nociceptive processes.

Natural variation in testosterone is associated with hypoalgesia in healthy women.

Objective:Sex differences in pain are well established, with women reporting greater incidence of clinical pain and heightened responsivity to experimental pain stimuli relative to men. Sex hormones (ie, estrogens, progestins, androgens) could contribute to extant differences in pain sensitivity between men and women. Despite this, there has been limited experimental research assessing the relationship between pain and sex hormones. The purpose of this study was to extend previous research and examine the association between sex hormones and nociceptive processing in healthy women. Materials and Methods:A total of 40 healthy women were tested during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (testing order counterbalanced). Salivary estradiol, progesterone, and testosterone were collected at each testing session and pain was examined from electrocutaneous threshold/tolerance, ischemia threshold/tolerance, and McGill Pain Questionnaire-Short Form ratings of noxious stimuli. Nociceptive flexion reflex threshold was assessed as a measure of spinal nociception. Results:Overall, there were no significant menstrual phase-related differences in pain outcomes. Nonetheless, variability in testosterone (and to a lesser degree estradiol) was associated with pain; testosterone was antinociceptive, whereas estradiol was pronociceptive. No hormone was associated with nociceptive flexion reflex threshold. Discussion:Although future research is needed to replicate and extend these findings to clinical populations (ie, chronic pain, premenstrual dysphoric disorder), results from the present study indicate that menstrual phase-related changes in sex hormones have minimal influence on experimental pain. However, individual differences in testosterone may play a protective role against pain in healthy women.

Do sex hormones influence emotional modulation of pain and nociception in healthy women

Sex hormones may contribute to inter- and intra-individual differences in pain by influencing emotional modulation of pain and nociception. To study this, a well-validated picture-viewing paradigm was used to assess emotional modulation of pain and the nociceptive flexion reflex (NFR; physiologic measure of nociception) during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle in healthy normally cycling women (n=40). Salivary estradiol, progesterone, and testosterone were assessed at each testing session. Emotional modulation of pain/NFR did not differ across menstrual phases, but low estradiol was associated with weaker emotional modulation of NFR (during all phases) and emotional modulation of pain (ovulatory and late-luteal phases). Given evidence that a failure to emotionally modulate pain might be a risk factor for chronic pain, low estradiol may promote chronic pain via this mechanism. However, future research is needed to extend these findings to women with disturbances of pain, emotion, and/or sex hormones.

Serotonin transporter gene (5-HTTLPR) polymorphisms are associated with emotional modulation of pain but not emotional modulation of spinal nociception.

The short allele of the serotonin transporter gene (5-HTTLPR) is associated with greater negative emotionality. Given that emotion modulates pain, short allele carriers (s-carriers) may also demonstrate altered pain modulation. The present study used a well-validated emotional picture-viewing paradigm to modulate pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception) in 144 healthy genotyped participants. As expected, pain/NFR responses were largest during unpleasant pictures and smallest during pleasant pictures. However, relative to l/l-carriers, s-carriers demonstrated greater pain inhibition during pleasant pictures and greater pain facilitation during unpleasant pictures. Neither emotional modulation of NFR nor NFR threshold was associated with 5-HTTLPR polymorphisms. Results also indicated that men who were s-carriers had a higher pain threshold and tolerance than other participants. Taken together, our results indicate 5-HTTLPR polymorphisms may influence pain modulation at the supraspinal (not spinal) level; however, the influence on pain sensitivity may be sex-specific.

Exploring pain processing differences in Native Americans.

OBJECTIVE Several chronic pain conditions are more prevalent in Native Americans than in any other group in the United States; however, little has been done to identify factors contributing to this disparity. The study presented here was designed to examine whether there were pain processing differences in Native Americans relative to non-Hispanic White controls. METHODS Participants were healthy, pain-free Native Americans (n = 22, 8 females) and non-Hispanic Whites (n = 20, 7 females). Pain processing was assessed from electric pain threshold/tolerance, ischemia pain threshold/tolerance, nociceptive flexion reflex threshold (NFR; an electrophysiological measure of spinal nociception), pain ratings of suprathreshold electric stimuli, and temporal summation of pain and NFR (an electrophysiological measure of spinal cord sensitization). The institutional review board approved all procedures. RESULTS Compared to non-Hispanic Whites, Native Americans had dampened pain perception (higher ischemia pain tolerance, higher electric pain threshold, lower ratings of electric stimuli). Additionally, temporal summation of NFR was reduced in Native Americans, suggesting sensitization was reduced at the spinal level. CONCLUSIONS Findings suggest Native Americans have dampened pain and pain signaling, perhaps due to overactivation of descending pain inhibition mechanisms. Given research indicating that other ethnic groups at risk for chronic pain (e.g., African Americans) show enhanced pain and enhanced central sensitization on experimental pain measures, chronic pain risk could be different for Native Americans, thus emphasizing the need for different treatment interventions.

Respiration-Induced Hypoalgesia: Exploration of Potential Mechanisms

UNLABELLED Slow breathing is used as a means to reduce pain, yet the mechanisms responsible for respiration-induced hypoalgesia are poorly understood. The present study asked 30 healthy participants (M(age) = 21 years, M(education) = 15 years, 80% white non-Hispanic) to breathe at normal, slow (50% normal), and fast (125% normal) rates while constant-intensity, suprathreshold electric stimulations were delivered to the sural nerve to elicit pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception). Stimulations were equally balanced across inhalations and exhalations to determine whether parasympathetic activation during exhalations contributes to hypoalgesia. Respiration rate, heart rate variability (HRV, a measure of parasympathetic activity), heart rate, and subjective arousal were assessed as manipulation checks. Slow breathing reduced pain relative to normal breathing and fast breathing, but NFR was not influenced by breathing. Further, pain and NFR did not differ between exhalations and inhalations, and changes in HRV did not correlate with changes in pain or NFR. Together, these findings suggest that respiration-induced hypoalgesia does not require gating of spinal nociception or changes in parasympathetic activity. PERSPECTIVE Slow breathing reduced pain relative to normal and fast breathing. This respiration-induced hypoalgesia does not appear to be due to gating of spinal nociception or changes in parasympathetic activity.

Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR)

TOC summary Within‐subject changes in emotions do not promote central sensitization via amplification of temporal summation processes. ABSTRACT Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive‐emotional processes can facilitate wind‐up‐like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within‐subject changes in emotion influence temporal summation of pain (TS‐pain) and the nociceptive flexion reflex (TS‐NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS‐pain and TS‐NFR. Participants (n = 46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2‐Hz stimulation series, the magnitude of pain summation (TS‐pain) and NFR summation (TS‐NFR) was not modulated by picture‐viewing. These results imply that, at least in healthy humans, within‐subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain).

Affective disturbance associated with premenstrual dysphoric disorder does not disrupt emotional modulation of pain and spinal nociception.

&NA; Unlike persons with insomnia, major depression, and fibromyalgia, women with premenstrual dysphoric disorder do not have disrupted emotional modulation of pain. &NA; In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late‐luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture‐viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid‐follicular, ovulatory, and late‐luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD‐related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia.

Nociceptive processing in women with premenstrual dysphoric disorder (PMDD): the role of menstrual phase and sex hormones.

Objective:Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature. Materials and Methods:Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception). Results:Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid-follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group. Discussion:Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia.

Gender and Pain

Purpose of ReviewSex differences in pain have become a topic of significant interest over the past two decades. This brief review addresses the epidemiological literature on sex-related influences on pain, with an emphasis on the mechanisms that may account for the greater incidence of chronic pain in women.Recent FindingsAlthough the magnitude of effects varies, overwhelming evidence suggests that women are at greater risk for clinical pain and have heightened sensitivity to experimental pain stimuli. There are also notable differences between men and women in their response to pharmacologic and non-pharmacologic pain treatments; however, findings across studies have been mixed.SummaryGiven the evidence of pain disparities, a number of biological and psychosocial mechanisms accounting for the variation in pain among men and women have been proposed. Continued investigation of the factors driving sex differences in pain may facilitate advances in pain management for both sexes.