British Journal of Anaesthesia 111 (1): 528 (2013)

doi:10.1093/bja/aet127

Sex differences in pain: a brief review of clinical

and experimental findings
E. J. Bartley* and R. B. Fillingim
Pain Research and Intervention Center of Excellence, University of Florida, 1395 Center Drive, Room D2-148, PO Box 100404, Gainesville,
FL 32610, USA
* Corresponding author. E-mail: ebartley@dental.ufl.edu

Editors key points

There is increasing
evidence for sex
differences in pain
sensitivity and analgesic
response.
Clinical pain, both acute
and chronic, and
experimental pain
models all show sex
differences.
While chronic pain is
commoner in women the
evidence on pain severity
is less clear.
Further study is needed of
underlying mechanisms,
including the contribution
of hormonal and genetic
factors.

Summary. Recent years have witnessed substantially increased research regarding sex
differences in pain. The expansive body of literature in this area clearly suggests that
men and women differ in their responses to pain, with increased pain sensitivity and risk
for clinical pain commonly being observed among women. Also, differences in
responsivity to pharmacological and non-pharmacological pain interventions have been
observed; however, these effects are not always consistent and appear dependent on
treatment type and characteristics of both the pain and the provider. Although the
specific aetiological basis underlying these sex differences is unknown, it seems
inevitable that multiple biological and psychosocial processes are contributing factors.
For instance, emerging evidence suggests that genotype and endogenous opioid
functioning play a causal role in these disparities, and considerable literature implicates
sex hormones as factors influencing pain sensitivity. However, the specific modulatory
effect of sex hormones on pain among men and women requires further exploration.
Psychosocial processes such as pain coping and early-life exposure to stress may also
explain sex differences in pain, in addition to stereotypical gender roles that may
contribute to differences in pain expression. Therefore, this review will provide a brief
overview of the extant literature examining sex-related differences in clinical and
experimental pain, and highlights several biopsychosocial mechanisms implicated in
these malefemale differences. The future directions of this field of research are
discussed with an emphasis aimed towards further elucidation of mechanisms which
may inform future efforts to develop sex-specific treatments.
Keywords: gender differences; opioid analgesics; pain; pain perception; sex differences

Research regarding sex, gender, and pain has proliferated in

recent decades.1 This expanding literature covers a broad
range of topics, including preclinical studies of mechanisms
contributing to sex differences in pain, human laboratory
research exploring sex differences in pain perception and
endogenous pain modulation, clinical and epidemiological
investigations of sex differences in pain prevalence and an increasing number of studies examining sex differences in
responses to pain treatments. Recent publications provide
thorough examinations of various areas of this literature,1 8
and in this brief review article we intend to highlight and summarize important findings regarding sex, gender, and pain.
Specifically, we will discuss findings regarding sex differences
in clinical pain prevalence and severity, followed by a brief
review of sex differences in experimental measures of pain
perception. Next, we will review existing research exploring
sex differences in responses to pain treatment followed by a
brief discussion of biopsychosocial mechanisms underlying
sex differences in responses to pain and its treatment. We
will conclude with a brief commentary on clinical implications
and future directions.

Sex differences in clinical pain

Population-based research consistently demonstrates
greater pain prevalence among women relative to men. For
example, large-scale epidemiological studies across multiple
geographic regions find that pain is reported more frequently
by women than by men1 (Fig. 1). Gerdle and colleagues9
found that for each of 10 different anatomical regions, a
greater proportion of women than men reported pain in
the past week, and women were significantly more likely to
report chronic widespread pain. Moreover, the population
prevalence of several common chronic pain conditions is
greater for women than men, including fibromyalgia, migraine and chronic tension-type headache, irritable bowel
syndrome, temporomandibular disorders, and interstitial
cystitis.1 4
In addition to these findings demonstrating that pain is
reported more frequently by women compared with men,
another relevant research question is whether the severity
of pain differs by sex. This issue is surprisingly more difficult
to address. For example, several investigators have examined
sex differences in pain severity among samples of patients

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Sex differences in pain

Male (n =166)

Female (n =167)

0.5
0.4
0.3

Z-score

0.2
0.1
0
0.1
0.2
0.3
0.4
s
as
PP
TM

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TT
ra
p

PT
O
C

PT
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TH

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0.5

Pain Measure
Fig 1 Z-scores for multiple pain measures in a sample of healthy young adults (166 female, 167 male). Z-scores were computed such that the
mean for the entire sample is 0. Higher Z-scores reflect lower pain sensitivity and lower Z-scores reflect higher pain sensitivity. Sex differences
were statistically significant for all pain measures (P ,0.05); however, the effect sizes ranged from small to large (Cohens d in parentheses
below), with a mean effect size in the moderate range (d0.62). HPTHheat pain threshold (d0.48), HPTOheat pain tolerance (d0.98),
IPTHischaemic pain threshold (d0.24), IPTOischaemic pain tolerance (d0.52), CPTHcold pain threshold (d0.41), CPTOcold pain tolerance (d0.55), PPTTrappressure pain threshold at the trapezius muscle (d0.90), PPTMasspressure pain threshold at the masseter
muscle (d0.89). Details regarding pain testing methods have been reported previously.25 26

seeking care for their chronic pain. While some studies have
reported greater pain severity among women than men,10 13
other studies have found no sex differences in pain severity among treatment-seeking patients.14 16 There is a potential for bias in these results as patients with less severe
pain are under-represented in these studies. Sex differences
in the delivery, effectiveness or both of pain treatments
in these clinical samples could also influence the presence,
magnitude and direction of sex differences in pain severity.
Another approach to studying sex differences in pain severity has been to compare levels of post-procedural or
post-surgical pain in women and men. Results from
these studies have been inconsistent, with some reporting
more severe pain among women,17 19 others reporting
more severe pain among men,20 and others reporting no
sex differences.21 On balance, the trend is towards greater
acute post-procedural pain in women.1 Interpretation of
these studies is complicated by potential sex differences in
responses to pain treatments because pharmacological
interventions are always provided in these settings. A recent
study exploited a large electronic medical record database
to study sex differences in pain severity in .11 000 patients.22
Importantly, pain ratings were collected as part of standard
care, but these patients were not necessarily seeking treatment for pain and procedural pain was excluded. The investigators reported consistently higher pain ratings for women
compared with men across the vast majority of diagnostic
groups.
Taken together, the findings from epidemiological and
clinical studies demonstrate convincingly that women are

at substantially higher risk for many common pain conditions. Regarding pain severity, the findings are less consistent
and are likely influenced by multiple methodological factors,
including selection biases in clinical studies and the potential
for sex differences in the effects of pain treatments. In order
to exert greater control over such sources of variability, investigators have exploited quantitative sensory testing in order
to explore sex differences in pain in response to controlled
noxious stimuli, and these findings are discussed next.

Sex differences in response to

experimentally induced pain
Sex differences in responses to experimental pain have been
investigated using a wide variety of stimulus modalities including mechanical (blunt pressure and punctate mechanical
stimuli), electrical, thermal (heat and cold), ischaemic, and
chemical stimuli (e.g. capsaicin, hypertonic saline). Increasingly in recent years, more sophisticated experimental pain
models have been used to characterize dynamic pain modulatory processes, such as temporal summation of pain (pain
facilitatory measure) and conditioned pain modulation
(measure of pain inhibition). Pain responses have been
assessed by a number of different outcome measures including behavioural indices of threshold (defined by time or intensity to the first sensation of pain) and tolerance, and
self-report measures of pain intensity and unpleasantness.
Previous qualitative and quantitative reviews have generally
concluded that women display greater sensitivity to multiple
pain modalities compared with men, and that women show

53

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greater temporal summation of pain while men display
greater conditioned pain modulation.1 4 8 23 24 In contrast,
a recent systematic review concluded that 10 years of laboratory research have not been successful in producing a
clear and consistent pattern of sex differences in human
pain sensitivity.5 A quantitative analysis of the studies that
served as the foundation of their conclusion did however
reveal a very consistent pattern of results in the direction
of greater pain sensitivity in females.4 Figure 1 provides a
graphical presentation of a dataset that reflects the typical
pattern of findings across studies of sex differences in experimental pain responses, which helps explain the varying interpretations by some authors (for details regarding
methodology see refs25 26). The direction of sex differences
in pain responses across multiple stimulus modalities and
pain measures is highly consistent, with women showing
greater sensitivity than men. However, the magnitude (and
statistical significance) of the sex difference varies across
measures, as it does across published studies. The potential
mechanisms underlying these differences and the clinical
implications of sex differences in pain sensitivity will be discussed further below.

Sex differences in response to pain

intervention
Sex differences in response to pain treatment have also been
described in the literature. In a review of 18 studies, Miaskowski and colleagues27 observed lower opioid consumption
postoperatively among women. This has not been a consistent finding and may depend on the type of surgical procedure28 or result from increased prevalence of side-effects in
women.29 A recent meta-analysis7 reported mixed results
for sex differences in opioid analgesia. While the authors
found no sex-specific effects for mu-opioid analgesia
across clinical studies of mu-opioids, greater analgesic
effects were observed for women when restricting analyses
to patient-controlled analgesia (PCA) and were even more
robust when considering only PCA morphine studies. It is important to note that these studies actually assessed opioid
consumption rather than pain relief, which may be influenced by factors other than analgesia (e.g. side-effects).
Despite this, results were similar for experimental studies
that directly assessed analgesic responses, suggesting
greater morphine analgesia for women. Interestingly, while
no sex-dependent effects were found for mixed action
opioids (e.g. butorphanol, nalbuphine, and pentazocine)
across experimental studies, it was concluded that women
exhibit greater analgesia than men in response to mixed
action opioids in clinical studies.
Several investigators have also examined gender biases in
pain treatment. In an often-cited study with multiple methodological shortcomings, women were given sedatives more
often for pain after surgery, whereas men were more likely to
receive analgesics.30 This has led many to conclude that
women are at risk for under-treatment of their pain.
However, a recent review of this literature concluded that

54

Bartley and Fillingim

while women and men are often treated differently, this disparity sometimes favours women and sometimes favours
men.31 Moreover, such gender biases are influenced by
both patient and provider characteristics, which sometimes
interact. For example, in a medical vignette study, physicians
were more likely to prescribe opioid analgesics to patients of
the same sex.32 More recent studies using virtual human
technology have demonstrated that females are considered
to have greater intensity and unpleasantness of pain than
males and are more likely to be recommended for opioid
treatment as evaluated by healthcare professionals and students.33 35 These studies suggest that biases exist in healthcare, an effect which may lead to disparities in pain
management.
Other research has investigated the impact of sex differences on non-pharmacological pain interventions. In a
study by Keogh and Herdenfeldt,36 men reported less pain
when asked to focus on the sensory components of pain,
while focusing on affective pain was not beneficial for
women. There is also evidence that acceptance-based interventions for pain may be helpful towards reducing
affective-related pain for women relative to men.37 In
another study, pain sensitivity was decreased after treadmill
exercise in female athletes while these effects were only
seen in male athletes after engaging in a video game competition.38 In an interdisciplinary pain management programme, improvements in pain were found in both male
and female patients after treatment; however, these
effects disappeared 3 months later for women as they
reported significantly more pain and catastrophizing than
men.39 More recently, results from a 5-week multimodal
pain management programme found that women exhibited
an improvement in pain-related disability as compared with
men.40 Hence, the literature seems to suggest that responses
to non-pharmacologic treatments may differ for men and
women, but the pattern of results is somewhat variable
across studies.

Mechanisms underlying sex differences

in pain
As the above summary indicates, it is well established that
sex differences in pain exist; however, the specific underlying
mechanisms contributing to this disparity are far from clear.
It has been suggested that an interaction of biological, psychological, and sociocultural factors likely contribute to these
differences. The following section will present a brief overview of the possible mechanisms implicated in sex-related
differences in pain (see refs1 6 41 for a more extensive
review).

Biological mechanisms
The influence of sex hormones represents a significant source
of pain-related variability that likely impacts men and women
differently. This is not surprising given the distribution of sex
hormones and their receptors in areas of the peripheral and
central nervous systems associated with nociceptive

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Sex differences in pain

transmission.42 43Although oestradiol and progesterones

effects on pain sensitivity are relatively complex (both exert
pro-nociceptive and anti-nociceptive effects on pain),42 44 testosterone appears to be more anti-nociceptive and protective
in nature,42 especially given the association between
decreased androgen concentrations and chronic pain.45 Research on progesterone and testosterones effects on pain is
still very limited, thus reflecting the need for further research
assessing their specific modulatory effects. Most of the research to support sex hormone effects on pain stems from
studies demonstrating exacerbation of clinical pain across
the menstrual cycle.46 49 Furthermore, exogenous hormone
use increases risk for some types of clinical pain50 and also
reduces menstrual cycle effects on experimental pain
sensitivity.51 55 It is also suggested that experimental pain
sensitivity changes across the menstrual cycle, with increased
sensitivity to most pain modalities (with the exception of electrocutaneous stimuli) during the luteal phase relative to the
follicular phase.56 Unfortunately, much of the research in
this area suffers from methodological limitations and more
recent research suggests that these effects are absent or
small at best.57 59
There is also evidence suggesting sex-related cortical differences during the processing of pain-related stimuli,60 64
thus potentially implicating the influence of sex hormones
on differential brain activation. A recent brain imaging
study revealed that women using oral contraceptives who
had low levels of testosterone showed reduced pain-related
activation in pain inhibitory brain regions (e.g. the rostral
ventromedial medulla).65 However, given the limited degree
of studies in this area, further research is needed before
firm conclusions can be drawn regarding hormonal influences on cerebral responses to pain.
Sex-related differences in pain may also reflect differences
in the endogenous opioid system. For instance, there are distinct differences between men and women in pain-related
activation of brain mu-opioid receptors.66 Smith and colleagues44 found that women in high oestradiol/low progesterone states exhibit decreased pain sensitivity and increased
brain mu-opioid receptor binding than women in low oestradiol states, while decreased endogenous opioid neurotransmission was associated with low oestradiol. Therefore,
these findings suggest that the interactive effects of the
opioidergic system with gonadal hormones may be an important determinant of sex-based differences in pain
sensitivity.
It is established that genotype may be a contributing
factor to sex differences in pain. Preclinical research consistently shows that genotype and sex interact to influence nociceptive sensitivity,67 and these findings have been extended
to humans in recent years. For example, the melanocortin-1
receptor (MC1R) gene, associated with red hair and fair skin,
has been found to moderate analgesia in a sex-dependent
manner. Specifically, women with two variant alleles of the
gene demonstrate greater analgesic responses to pentazocine (kappa opioid) relative to men and women who do not
have the variant alleles.68 In another study suggesting a sex-

dependent genetic association, the A118G single nucleotide

polymorphism of the mu-opioid receptor gene (OPRM1) was
found to be associated with pressure pain sensitivity in
men but not women. Furthermore, differential effects on
thermal pain sensitivity were observed between the sexes
in that women with a rare allele exhibited increased pain
sensitivity while the opposite was observed for men with
the rare allele.69 These findings were recently extended to
a clinical population, in that women with the rare allele
showed poorer recovery from lumbar disc herniation, while
the rare allele predicted enhanced recovery among men.70

Psychosocial mechanisms
Various psychosocial mechanisms may play a fundamental
role in sex-related differences in pain. For instance, pain
coping strategies have been found to differ between men
and women. While men tend to use behavioural distraction
and problem-focused tactics to manage pain, women tend
to use a range of coping techniques including social support,
positive self-statements, emotion-focused techniques, cognitive reinterpretation, and attentional focus.1 6 71 72
Two constructs proven to be integral to pain responsivity
are catastrophizing and self-efficacy. Catastrophizing is a
method of pain coping referring to the magnification and rumination of pain-related information,73 while self-efficacy
refers to the belief that one can successfully perform a behaviour to achieve a desirable goal.74 Research has shown
that catastrophizing is associated with pain and pain-related
disability75 and women engage in catastrophizing more
often than men. Furthermore, catastrophizing appears to
mediate sex differences in pain responsivity;76 however, it
has been suggested that the effect of catastrophizing on
sex differences in pain may be modulated by other factors
such as personality disposition.6 A lower degree of selfefficacy has been found to be associated with higher levels
of pain and physical symptomatology.77 Other evidence has
indicated that men demonstrate greater self-efficacy which
was subsequently related to lower cold pressor pain
sensitivity.78
Sociocultural beliefs about femininity and masculinity also
appear to be an important determinant of pain responses
among the sexes as pain expression is generally more socially acceptable among women, an effect which may lead to
biased reporting of pain. In a study by Robinson and colleagues79, both men and women believed that men are less
willing to report pain than the typical woman and such
gender role expectations may contribute to sex differences
in experimental pain.80 Supporting the role of gender expectancies on pain are studies finding that sex differences in pain
sensitivity may be influenced by sex-related expectations
regarding performance on the pain task, suggesting that
gender-related motivation may influence pain expression.81 82
A study by Fowler and colleagues83 found that social
priming may impact sex differences in pain. When primed
with a feminine gender role, men reported increased cold
pressor pain. The authors highlighted that feminine role

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cues may alter pain report more so than masculine role cues.
Culture-related variability in stereotypical beliefs about pain
may also play a role in noted differences between men and
women. For instance, a recent study assessing pain sensitivity and gender roles among Israelites and Americans found
that both Israelite men and women reported a more masculine role in regards to views of pain sensitivity when compared with Americans,84 thus implying the importance of
cultural differences in pain-related beliefs.
Early exposure to environmental stress, such as prior pain
and history of abuse, may also contribute to variability in
pain report between men and women. Childhood abuse
has been linked to adult chronic pain with individuals
having pain complaints later in life reporting a history of
early-life abuse.85 With respect to sex differences, Fillingim
and colleagues86 observed that a history of childhood
abuse was associated with decreased pain sensitivity;
however, this effect was only observed in women. It has
also been reported that a family history of pain is associated
with greater pain symptoms87 88 and increased pain sensitivity among females relative to men;88 although this has not
been a consistent finding.89

Conclusions
Sex differences in pain have been a topic of increased interest in recent years. Epidemiologic and clinical findings clearly
demonstrate that women are at increased risk for chronic
pain and some evidence suggests that women may experience more severe clinical pain. Studies of experimentally
induced pain have produced a very consistent pattern of
results, with women exhibiting greater pain sensitivity,
enhanced pain facilitation and reduced pain inhibition compared with men, though the magnitude of these sex differences varies across studies. In addition, some evidence
suggests sex differences in responses to pharmacological
and non-pharmacological pain treatments, though the findings differ depending on the specific treatment and perhaps
on characteristics of the pain. Also, gender biases in pain
treatment appear to exist, which are influenced by characteristics of both the patient and the provider.
Multiple biopsychosocial mechanisms contribute to these
sex differences in pain, including sex hormones, endogenous
opioid function, genetic factors, pain coping and catastrophizing, and gender roles. At present, the available evidence
does not support sex-specific tailoring of treatments;
however, this is a conceivable outcome in the foreseeable
future. Additional research to elucidate the mechanisms
driving sex differences in pain responses is needed in
order to foster future interventions to reduce these disparities in pain.

Authors contributions
Both authors contributed to this work. E.J.B. generated the
chief discussion points of the review article, wrote the abstract, and drafted the article. R.B.F. assisted in drafting the
article and provided the statistical data. Both authors

56

Bartley and Fillingim

conducted the literature review, edited the manuscript, and

approved the final version for publication.

Declaration of interest
E.J.B. declares no financial interests. R.B.F. is a consultant and
equity stock holder in Algynomics, Inc., a company providing
research services in personalized pain medication. Also, R.B.F.
has received an honorarium from MedScape.

Funding
This work was supported by National Institutes of Health
grants NS045551 and TR000064.

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