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

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.PerspectiveThis 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.     

Gender Differences in Acute and Chronic Pain in the Emergency Department: Results of the 2014 Academic Emergency Medicine Consensus Conference Pain Section

Pain is a leading public health problem in the United States, with an annual economic burden of more than $630 billion, and is one of the most common reasons that individuals seek emergency department (ED) care. There is a paucity of data regarding sex differences in the assessment and treatment of acute and chronic pain conditions in the ED. The Academic Emergency Medicine consensus conference convened in Dallas, Texas, in May 2014 to develop a research agenda to address this issue among others related to sex differences in the ED. Prior to the conference, experts and stakeholders from emergency medicine and the pain research field reviewed the current literature and identified eight candidate priority areas. At the conference, these eight areas were reviewed and all eight were ratified using a nominal group technique to build consensus. These priority areas were: 1) gender differences in the pharmacological and nonpharmacological interventions for pain, including differences in opioid tolerance, side effects, or misuse; 2) gender differences in pain severity perceptions, clinically meaningful differences in acute pain, and pain treatment preferences; 3) gender differences in pain outcomes of ED patients across the life span; 4) gender differences in the relationship between acute pain and acute psychological responses; 5) the influence of physician–patient gender differences and characteristics on the assessment and treatment of pain; 6) gender differences in the influence of acute stress and chronic stress on acute pain responses; 7) gender differences in biological mechanisms and molecular pathways mediating acute pain in ED populations; and 8) gender differences in biological mechanisms and molecular pathways mediating chronic pain development after trauma, stress, or acute illness exposure. These areas represent priority areas for future scientific inquiry, and gaining understanding in these will be essential to improving our understanding of sex and gender differences in the assessment and treatment of pain conditions in emergency care settings.     

Sex differences in pain and analgesia: the role of gonadal hormones.

There is now strong evidence for sex differences in pain and analgesia. These differences imply that gonadal steroid hormones such as estradiol and testosterone modulate sensitivity to pain and analgesia. The goal of this review is to present an overview of gonadal steroid modulation of pain and analgesia in animals and humans, and to describe mechanisms by which males' and females' biology may differentially predispose them to pain and to analgesic effects of drugs and stress. Evidence is presented to demonstrate that sex differences in pain and analgesia may be both quantitative and qualitative in nature. Current research suggests that sex-specific management of clinical pain will be a reality in the not-so-distant future.     

Women and the Experience of Pain and Opioid Use Disorder: A Literature-based Commentary

It is generally understood that pain experience and opioid abuse have relied on male-dominated models. However, sex and gender play a role in both pain experience and opioid use disorder.Using the previously validated Texas Tech University Health Sciences Center Sex and Gender Specific Health PubMed Advanced Search Tool, the authors used pertinent literature to develop this literature-based commentary on sex and gender differences in pain experience and opioid use disorder. Women report their experience of pain more frequently, have increased rates of diagnoses related to pain, have increased pain sensitivity, and have a variable response to pain and analgesia. This variable response is due to anatomic, physiologic, hormonal, psychological, and social factors that differ by sex and gender. Women have been found to be at greater risk for opioid abuse in all age groups. This may be due to the differences in pain experience, as well as sex and gender differences in prescribing patterns, cultural norms, and the increased likelihood to experience dependency and withdrawal. Approaches to the treatment of opioid use disorder are also subject to sex and gender differences—an area in need of further investigation.     

Racial Differences in Receiving Morphine among Prehospital Patients with Blunt Trauma

Background

Pain management is an important part of prehospital care, yet few studies have addressed the effects of age, sex, race, or pain severity on prehospital pain management.

Objectives

To examine the association of sex, age, race, and pain severity with analgesia administration for blunt trauma in the prehospital setting.

Methods

In this retrospective cohort study, we used the automated registry of a large urban Emergency Medical Services agency to identify records of all patients transported for blunt trauma injuries between February 1 and November 1, 2009. We used bivariable and multivariable analyses with logistic regression models to determine the relationship between analgesia administration and patient sex, race, age, pain score on a pain scale, and time under prehospital care.

Results

We identified 6398 blunt trauma cases. There were 516 patients (8%) who received analgesia overall; among patients for whom a pain scale was recorded, 25% received analgesia. By multivariable analysis, adjusting for race, sex, age, time with patient, and pain score, African-American and Hispanic patients were less likely than Caucasian patients to receive analgesia. Pain score and prehospital time were both significant predictors of analgesia administration, with higher pain score and longer prehospital time associated with increased administration of pain medication. Neither sex nor age was a significant predictor of analgesia administration in the regression analysis.

Conclusion

This study suggests that Caucasians are more likely than African-Americans or Hispanics to receive prehospital analgesia for blunt trauma injuries. In addition, patients with whom paramedics spend more time and for whom a pain score is recorded are more likely to receive analgesia.     

Depression in chronic pain patients: relation to pain, activity, and sex differences

Depression is commonly reported among chronic pain patients and receiving increased attention from clinicians and researchers. There is, however, little empirical evidence concerning variables that differentiate depressed from non-depressed chronic pain patients, and whether depression is related to factors such as gender, pain report, and activity. As part of a study to address these questions, 63 chronic pain patients completed daily diaries of activity, pain levels, and medication intake, and completed questionnaires and interviews assessing depression, medical history, and demographic variables. Male and female depressed and non-depressed chronic pain patients did not differ on demographic and medical history data, but sex differences were found in patterns of the relationships of depression, activity, and pain. For women, depression was closely related to pain report, whereas for men depression was more strongly related to impairment of activity. Pain report was related only minimally to activity for male and female patients. Implications of the results of behavioral research on depression in chronic pain patients are discussed. Researchers are urged to carefully consider sex differences in future research with chronic pain patients.     

Sex,gender, coping,and self‐efficacy: Mediation of sex differences in pain perception in children and adolescents

Sex differences in pain perception have been reported in an expanding literature based on adult samples in epidemiological as well as laboratory studies. Especially with respect to the latter, studies with children and adolescents do not consistently show that females report higher pain ratings and display lower pain tolerance than males. The first aim of the presented studies is to comparably examine sex differences in children and adolescents based on experimental and questionnaire approach indices of pain perception. The second aim is to examine the contribution of three prominent psychosocial factors (gender‐role expectations, coping with pain, and pain self‐efficacy) to these sex differences. In Study 1, a total of 118 children and adolescents from grades 5 to 9 were tested with the Cold Pressor Task (CPT) and a Pain Perception Questionnaire. In Study 2, 148 participants additionally reported on their gender‐role expectations, coping with pain, and pain self‐efficacy. Although the results reveal only medium‐sized correlations between the CPT and the questionnaire measures, both measures indicate substantial sex differences in pain perception in both studies. In Study 2, sex differences are also present for masculinity, femininity, catastrophizing as well as pain self‐efficacy. However, while the relation between sex and the CPT rating is partially mediated by pain self‐efficacy, catastrophizing partially mediates the relation between sex and the questionnaire based pain ratings. The results of both studies are discussed with respect to the difference between experimental assessments of pain perception and assessments by questionnaire in children and adolescents.     

A comparison of health locus of control beliefs in low-back patients from the U.S. and New Zealand

In order to study differences in health control attitudes between chronic low-back patients from the U.S. and New Zealand, the Health Locus of Control (HLC) was administered to 284 consecutive admissions to pain clinics in those countries: 96 patients seen at the Auckland (New Zealand) Pain Clinic and 188 seen at the University of Virginia (U.S.) Pain Clinic. The HLC is an 11-item instrument [23] that assesses general control over health matters. Principal component factor analyses indicated 3 distinct subscales for the low back patients: (a) personal health control, (b) external health control, and (c) control by powerful others (physicians). HLC responses were analyzed with univariate analyses of variance using subscale scores as dependent measures and country and sex as independent variables. New Zealanders rated themselves as less dependent on physicians' orders (F (1,280)=3.92, P less than 0.05), and women were seen as having less personal control over their pain conditions than men (F (1,280)=6.29, P less than 0.02). The differences related to sex and country are discussed within a social learning framework. Suggestions are made for future cross-cultural research, especially related to issues of dependency on others for health control and outcomes in the treatment of chronic pain.     

A survey of postoperative pain management in fourteen hospitals in the UK

The effectiveness of acute pain services in 14 hospitals in one English region was audited. We collected data on analgesia used, its efficacy and patient satisfaction for 522 patients after four commonly performed procedures: abdominal hysterectomy, total knee replacement, mastectomy and major abdominal surgery.Pain scores were measured on a verbal numeric rating scale in the recovery room and both pain scores and patient satisfaction were assessed at 24 h and 7 days postoperatively.Pain was managed well in recovery rooms but less well on the wards. Epidural analgesia gave significantly better pain scores than other therapies. Better pain relief was obtained if opioids were combined with NSAIDs than when given alone. There were marked differences between hospitals in the delivery of postoperative analgesia. Pain scores in most hospitals left room for improvement, particularly following abdominal hysterectomy, but patient satisfaction was good. The better efficacy of multimodal analgesia was confirmed. Evidence from this data for the effectiveness of multidisciplinary acute pain services was equivocal.     

Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain

An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0°C or .4°C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0°C or .4°C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0–100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle-aged adults showed reduced offset analgesia compared with younger adults in the 1.0°C and .4°C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults.

Sex differences in opioid analgesia: "from mouse to man"

BACKGROUND: Numerous experimental studies, conducted primarily over the past 10 years, show that there are sex differences in opioid analgesia. This review summarizes the published literature on sex differences in analgesia produced by acute administration of drugs acting at mu-, kappa-, and delta-opioid receptors, in animals and humans. Additionally, methodological issues in research into opioid sex differences are discussed. CONCLUSIONS: Procedural variables that may influence the outcome of studies examining sex differences in opioid analgesia include modality and intensity of the noxious stimulus used in the pain test, opioid type (efficacy and selectivity), and experimental design and data analytic techniques. Subject variables that may be important to consider include subject genotype and gonadal steroid hormone state of the subject at the time of analgesia testing. Evidence is provided for multiple mechanisms underlying sex differences in opioid analgesia, including both pharmacokinetic and pharmacodynamic factors. Future research directions are suggested, such as examining sex differences in opioid tolerance development, sex differences in opioid analgesia using models of acute inflammatory pain and chronic pain, and sex differences in effects of opioids other than analgesia, which may limit their therapeutic use.     

The perception of pain in others: how gender, race, and age influence pain expectations

Sex, race/ethnic, and age differences in pain have been reported in clinical and experimental research. Gender role expectations have partly explained the variability in sex differences in pain, and the Gender Role Expectations of Pain questionnaire (GREP) was developed to measure sex-related stereotypic attributions about pain. It is hypothesized that similar expectations exist for age- and race-related pain decisions. This study investigated new measures of race/ethnic- and age-related stereotypic attributions of pain sensitivity and willingness to report pain, and examined the psychometric properties of a modified GREP. Participants completed the Race/Ethnicity Expectations of Pain questionnaire, Age Expectations of Pain questionnaire, and modified GREP. Results revealed a 3-factor solution to the race/ethnicity questionnaire and a 2-factor solution to the age questionnaire, consistent with theoretical construction of the items. Results revealed a 4-factor solution to the modified GREP that differed from the original GREP and theoretical construction of the items. Participants' pain-related stereotypic attributions differed across racial/ethnic, age, and gender groups. These findings provide psychometric support for the measures examined herein and suggest that stereotypic attributions of pain in others differ across demographic categories. Future work can refine the measures and examine whether select demographic variables influence pain perception, assessment, and/or treatment. PERSPECTIVE: The findings suggest that one's expectations of the pain experience of another person are influenced by the stereotypes one has about different genders, races, and ages. The 3 pain expectation measures investigated in the current study could be used in future work examining biases in pain assessment and treatment.     

Effect of hypnotic suggestion on fibromyalgic pain: comparison between hypnosis and relaxation.

The main aims of this experimental study are: (1) to compare the relative effects of analgesia suggestions and relaxation suggestions on clinical pain, and (2) to compare the relative effect of relaxation suggestions when they are presented as "hypnosis" and as "relaxation training". Forty-five patients with fibromyalgia were randomly assigned to one of the following experimental conditions: (a) hypnosis with relaxation suggestions; (b) hypnosis with analgesia suggestions; (c) relaxation. Before and after the experimental session, the pain intensity was measured using a visual analogue scale (VAS) and the sensory and affective dimensions were measured with the McGill Pain Questionnaire. The results showed: (1) that hypnosis followed by analgesia suggestions has a greater effect on the intensity of pain and on the sensory dimension of pain than hypnosis followed by relaxation suggestions; (2) that the effect of hypnosis followed by relaxation suggestions is not greater than relaxation. We discuss the implications of the study on our understanding of the importance of suggestions used in hypnosis and of the differences and similarities between hypnotic relaxation and relaxation training.     

Categorising the severity of neck pain: establishment of cut-points for use in clinical and epidemiological research

Grading pain intensity scales into simple categories provides useful information for both clinicians and epidemiologists and methods to classify pain severity for numerical rating scales have been recommended. However, the establishment of cut-points is still in its infancy and little is known as to whether cut-points are affected by age or gender. The objectives of this paper were to establish optimal cut-points in pain severity in individuals with neck pain (NP) and to investigate if the cut-points were influenced by gender, age, and NP duration. Data from the population-based ;Funen Neck and Chest Pain Study' was used. Univariate and multivariate analyses of variance were performed to calculate optimal single and double cut-points for three different pain intensity scores within the past 2 weeks relative to two neck disability scales (;global assessment of NP' and the ;Copenhagen Neck Functional Disability Scale'). The two disability scales showed small differences in optimal cut-points. Furthermore, cut-points changed for each of the three pain intensity scales. Only small gender differences in cut-points were seen and no specific trend was noted in either single or double cut-points in different age groups. The cut-points were almost identical for acute, subacute, and chronic NP. This paper has implications for understanding the impact of using different pain intensity scales and provides reference cut-points in NP for use in future clinical and epidemiological research.     

Sex and Race Differences in Pain Sensitization among Patients with Chronic Low Back Pain

Growing evidence suggests that chronic low back pain (CLBP) is associated with pain sensitization, and that there are sex and race disparities in CLBP. Given the sex and race differences in pain sensitization, this has been hypothesized as a mechanism contributing to the sex and race disparities in CLBP. This study examined sex and race differences in pain sensitization among patients with CLBP, as well as the role of catastrophizing as a potential mediator of those differences. The study found that compared with men, women required less pressure to produce deep muscle pain and rated mechanical punctate pain as more painful. Compared with non-Hispanic white patients, black patients demonstrated greater pain sensitivity for measures of deep muscle hyperalgesia and mechanical punctate pain. Furthermore, catastrophizing partially mediated the race differences in deep muscle pain such that black participants endorsed greater pain catastrophizing, which partially accounted for their increased sensitivity to, and temporal summation of, deep muscle pain. Taken together, these results support the need to further examine the role of catastrophizing and pain sensitization in the context of sex and race disparities in the experience of CLBP.

Cluster analysis of multiple experimental pain modalities

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.     

Pain,Please: An Investigation of Sampling Bias in Pain Research

Experimental pain research frequently relies on the recruitment of volunteers. However, because experimental pain research often involves unpleasant and painful sensations, it may be especially susceptible to sampling bias. That is, volunteers in experimental pain research might differ from nonvolunteers on several relevant variables that could affect the generalizability and external validity of the research. We conducted 2 studies to investigate potential sampling bias in experimental pain research. In study 1 we assessed participants' (N?=?275; age = 17–30 years) perceived likelihood of participating in pain research. Pain catastrophizing, fear of pain, illness and injury sensitivity, depression, anxiety, sensation-seeking, gender identity, body appreciation, and social desirability were also assessed as potential predictors of the likelihood to participate. In study 2, participants (N?=?87; Age = 18–31 years) could sign up for 2 nearly identical studies, with only one involving painful sensations. Thirty-six participants signed up for the pain study and 51 participants signed up for the no-pain study. Study 1 showed that lower levels of fear of pain, higher levels of sensation-seeking, and older age predicted the perceived likelihood of participating in pain research. Study 2 showed significantly higher levels of sensation-seeking in participants who signed up for the pain study compared with those who signed up for the no-pain study. The implications of these findings for future research, as well as the clinical conclusions on the basis of experimental pain research, are discussed.

Influences of gender role and anxiety on sex differences in temporal summation of pain.

Previous research has consistently shown moderate to large differences between pain reports of men and women undergoing experimental pain testing. These differences have been shown for a variety of types of stimulation. However, only recently have sex differences been demonstrated for temporal summation of second pain. This study examined sex differences in response to temporal summation of second pain elicited by thermal stimulation of the skin. The relative influences of state anxiety and gender role expectations on temporal summation were investigated. Asymptomatic undergraduates (37 women and 30 men) underwent thermal testing of the thenar surface of the hand in a temporal summation protocol. Our results replicated those of Fillingim et al indicating that women showed increased temporal summation compared to men. We extended those findings to demonstrate that temporal summation is influenced by anxiety and gender role stereotypes about pain responding. When anxiety and gender role stereotypes are taken into account, sex is no longer a significant predictor of temporal summation. These findings highlight the contribution of social learning factors in the differences between sexes' pain perception. PERSPECTIVE: Results of this study demonstrate that psychosocial variables influence pain mechanisms. Temporal summation was related to gender role expectations of pain and anxiety. These variables explain a significant portion of the differences between men and women's pain processing, and may be related to differences in clinical presentation.     

Women suffer more short and long-term pain than men after major thoracotomy

OBJECTIVES: Prolonged activation of pain centers is a proposed cause of chronic pain syndromes. Women are at particular risk for chronic pain as they tend to more readily detect pain and to attenuate it less than men. We set out to determine whether sex affected pain and recovery after major surgery by analyzing data originally collected to determine the effect of the timing of epidural analgesia on long-term outcome after thoracotomy. METHODS: Patients presenting for lobectomy, segmentectomy, or bilobectomy, but not pneumonectomy or chest wall resection, were enrolled. Pain, physical activity, and the extent that pain interfered with activities after surgery were prospectively assessed with standard questionnaires (Brief Pain Inventory and physical component score of SF-36) on postoperative days 1 to 5, and at postoperative weeks 4, 8, 12, 24, 36, and 48 by a blinded research assistant. Perioperative care was standardized and included patient-controlled thoracic epidural analgesia until thoracostomy tube removal. RESULTS: Fifty eight men and 62 women were enrolled. Women reported more pain than men throughout the entire study period, and they had a higher rate of nonsteroidal anti-inflammatory drug use, but not opioid use. This increased pain was not explained by incision type, surgeon, tumor type, or tumor stage. Older patients reported less pain after discharge than younger patients. Postoperative physical activity levels were significantly less than those reported preoperatively, but did not differ by sex. DISCUSSION: Women have a distinctly different pain experience than men after thoracic surgery and probably require novel and/or multimodal analgesic regimens to improve their comfort.