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Try out PMC Labs and tell us what you think. Learn More. 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 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.

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.

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Research regarding sex and gender, differences in pain has increased substantially in recent years. As Fig 1 depicts, publications regarding sex, gender, and pain have increased at a much greater rate over the past 25 to 30 years relative to the pain field in general.

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In particular, a dramatic increase in publications began in the mids, which may be attributable to several influential review articles along with other events occurring in the s that drew considerable attention to the topic. Inan important publication by Karen Berkley 32 highlighted the importance of sex-related issues in neuroscience research. Subsequently, a review article appeared in Pain Forumthe predecessor of this journal, which discussed the literature regarding sex differences in responses to experimentally induced pain and offered a heuristic model outlining multiple mechanisms underlying these sex differences.

Thus, the early to mids was a period of increased scholarly activity regarding sex differences in pain. Average annual percentage increase in publications over each 2-year period afterwhich served as the reference year. These percentages were computed by conducting literature searches using PubMed for every year since Forthe first 6 months was collected and doubled to obtain an annualized estimate. The burgeoning interest in sex, gender, and pain embodied in this series of prominent publications culminated in two NIH initiatives, which ensured the continued growth of research on the topic.

This generated substantial interest from the scientific community and launched multiple new research programs related to sex differences in pain. Thus, a combination of events has prompted the recent and dramatic increase in research on issues regarding sex, gender, and pain. In addition to those alluded to above, several subsequent reviews of this rapidly expanding literature have been provided, often focusing on particular segments of research regarding sex, gender, and pain.

More than 10 years ago, a quantitative review of the literature regarding sex differences in experimental pain responses concluded that females show greater sensitivity than males to several modalities of experimental pain. We will conclude with a synopsis of the current state of the literature followed by a discussion of important issues to be addressed in future research.

The goal of this section is to examine whether more recent studies corroborate these findings. The organization of studies for this review has been challenging as publications have focused on differing dimensions or characteristics of clinical pain. Pain studies can be organized by chronicity chronic, acutesite low-back, abdominalof sites regional, widespreadtissue type musculoskeletal, neuropathicor etiology iatrogenic, trauma, insidious. A complete review of sex differences in pain prevalence across all possible pain conditions, sites or etiologies is not feasible given the constraints of this broad review of sex differences in pain.

Consequently, we will consider recent findings regarding the following pain conditions: cancer pain, neuropathic pain, musculoskeletal pain, oral pain, headache, abdominal pain, headache, pain in children and adolescents, and postprocedural pain.

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The general goal of all sampling methods is to obtain a sample that is representative of the target population. The most accurate inferences about sex differences in pain would derive from studies based on a randomly selected representative national or regional sample. However, sex differences in pain have been investigated in samples collected in a variety of ways. Studies that report on clinical samples, often from pain treatment centers, can suffer from the bias associated with health care seeking.

Caution must be exercised when interpreting these data because women utilize health care services to a greater extent than men, 48consequently a clinical sample does not reflect the general population. Where possible, we will rely on studies drawn from general population-based samples. As epidemiological studies of pain typically rely on self-report via surveys or telephone interviews, one potential problem can be nonparticipation bias; that is, differences in the outcome of interest between persons willing to participate and those that decline to do so.

Some studies report participation rates, and fewer test for differences between participants and nonparticipants as often little information is available from nonparticipants. In complex sampling des, weighting adjustments can for some bias, but whether this has occurred is seldom described in the papers we have reviewed. Another issue concerns geographic or cultural characteristics of the reference population.

It cannot be assumed that sex differences are consistent across the world. Because of strong interests in public health, most epidemiological data on pain conditions come from Europe and particularly the Scandinavian countries. However, we have attempted to select studies from a range of geographic regions and cultures. Epidemiologic studies of pain typically report point prevalence currently in painperiod prevalence ie, experiencing pain during the past month or yearor lifetime prevalence. Some of the studies reviewed have measured pain intensity or severity ratings and depression, a common impact of chronic pain, and when sex differences were tested, we will report the findings.

One issue worth mentioning is over interpretation of positive findings for sex differences in pain due to publication biases. It seems plausible that in some cases sex differences were tested, found to be nonificant, and then not reported in a manuscript. Several studies drawn from multiple geographic locations report prevalence of pain by sex across a of anatomic sites. Gerdle et al found the 7-day prevalence for females was higher than males for all 10 anatomic regions assessed, but no sex difference was found for pain intensity ratings.

Several papers from a Dutch population-based study of musculoskeletal complaints have reported higher pain prevalence among females at nearly all body sites. An estimate of pain prevalence is also available for rural India.

Chopra and colleagues 69 found higher 7-day point prevalence across all 24 body sites for females compared with males. Small sex differences in pain prevalence emerged for most sites in a representative sample of the US noninstitutionalized population. A retrospective study of cancer patients referred for pain treatment found no sex differences in pain intensity or disability. Two studies, one of patients 2 to 3 weeks after their last hospitalization and another of oncology outpatients with bone metastasis, did not find sex was related to cancer pain.

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Another study that followed patients with inoperable lung cancer reported that women were more depressed at baseline than men but no differences were found in pain ratings. Schmidt et al found that women reported greater pain in the abdomen before rectal cancer surgery, at discharge, and at 3 months after surgery; however, there were no sex differences in pain at later time periods.

Valeberg et al reported that among outpatients at a large cancer hospital in Norway, females were more likely to have comorbid cancer pain and noncancer pain than males, and these authors also found that women were at increased risk for more severe pain. We have identified two studies that used population-level sampling.

Reyes-Gibby et al reported that among adults ages 50 and older with cancer from the United States, females were more likely to have the symptom cluster of pain, depression, and fatigue than males by a factor of 1. A study from the Netherlands found that sex was not associated with prevalence or severity of cancer pain. Neuropathic pain is a complex pain state in which the nerve fibers may be damaged, dysfunctional, or injured.

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Recently, questionnaires have been developed based on the analysis of the characteristics of pain ie, pain descriptors that discriminate pain due to a definite neurological lesion. Torrance et al estimated the prevalence of pain of predominantly neuropathic origin using a random sample of adults from family practices in three United Kingdom cities using a 5-item neuropathic pain scale developed by Bennett.

Neither study reported sex differences in the effects of age, pain intensity, or depression. Consequently, it appears that women are at greater risk for neuropathic pain than men. Many studies have investigated the prevalence of musculoskeletal pain in men and women, with some assessing chronic musculoskeletal pain irrespective of the site, whereas others have been site specific.

In a review, Rollman and Lautenbacher concluded that women have greater frequency of musculoskeletal pain than men. A of recent studies have tested for sex differences in chronic musculoskeletal pain at any site. In one study, women reported ificantly higher ratings of worst and current pain intensity but there were no differences on the rating for least pain.

Bolded s reflect ificant sex differences in prevalence. Several investigators have examined sex differences in back pain prevalence and severity, including a of studies in European samples. Females had a higher prevalence of low back pain than males for both areas across all time periods with the exception that males living in the Norwegian region had a higher lifetime prevalence of low back pain.

Interestingly, female sex was no longer a ificant predictor following adjustment in multivariate models that included age, body mass index, and several socioeconomic variables.

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No sex differences were found for pain intensity. Data are available from other regions as well. In a sample of nearly 14, adults from a rural region of China, the 1-year prevalence of low back pain was higher among females than in males across all age groups below 60 years of age. ificant sex differences were not found on pain intensity.

Two studies addressed sex differences in the chronicity of back pain. Thomas and colleagues followed patients for 12 months after consultation with acute back pain. Other factors associated with persistent back pain included employment dissatisfaction and history of widespread pain.

The predictors of poor outcome were the same for men and women. In a population-based cohort of over participants in a back pain survey, women with chronic back pain at baseline were more likely than men to still have chronic back pain 4 years later. Women without back pain at baseline were no more likely to have developed chronic back pain than pain-free men. Thus, on balance, the recent evidence suggests higher prevalence of back pain in women, but there is limited evidence that females are at greater risk for chronicity.

Sex differences in the prevalence of widespread musculoskeletal pain have also been documented. These studies typically include a pain drawing to identity the painful sites. The most common definition is pain present in both the left and right side of the body as well as above and below the waist.

Multiple studies from various geographic regions indicate higher prevalence rates across all age groups in women compared to men see Table 2. In a 3-year follow-up of a study, 30 women without chronic pain or women with regional chronic pain did not develop persistence of chronic widespread pain more often than men. Other studies have specifically screened for fibromyalgia syndrome FMS.

FMS is a common, chronically painful, soft tissue pain condition. Affected individuals exhibit persistent, widespread pain and tenderness to palpation at anatomically defined tender points located in soft tissue musculoskeletal structures. A recent meta-analysis on sex differences in osteoarthritis using clinical markers as the case definition not pain indicated that females are at ificantly increased risk for osteoarthritis OA in the knee and hand compared with males.

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Two papers have reported sex differences in the prevalence of OA related pain pain on most days for the past 6 weeks based on representative samples of adults 60 years and older from the United States. Jinks et al followed a prospective cohort of persons without knee symptoms at baseline for 3 years. At follow-up, sex was not a risk factor to develop mild or severe knee pain. However, in a second analysis, females were more likely than males to have developed severe knee pain at 3-year follow-up. Data from an Italian community based cohort also using the WOMAC found females had ificantly greater hip and knee pain than males.

Several studies have examined sex differences in depression among persons with OA. Data from a large sample of German primary care patients indicated that sex was not a predictor of the depression among patients with OA of the hip or knee as diagnosed by a general practitioner. Taken together, these findings from studies of musculoskeletal pain indicate that regardless of site or time frame, females consistently are more likely to report musculoskeletal pain than males, though these differences may be less consistent for low back pain.

There is limited evidence for increased pain intensity among women with the possible exception of OA, where greater pain severity among women is more common. There is limited evidence that women with musculoskeletal pain are more likely to be depressed than men.

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