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Sex differences in pain: a brief review of clinicaland 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 painmodels 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 in-

creasing 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 sum-marize 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 isgreater for women than men, including fibromyalgia, mi-

graine 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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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 sever-

ity among treatment-seeking patients.14 16 There is a poten-

tial 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 treatmentsin 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 sever-

ity 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 recentstudy 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 treat-

ment for pain and procedural pain was excluded. The investi-

gators 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 condi-

tions. 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, inves-

tigators have exploited quantitative sensory testing in orderto explore sex differences in pain in response to controlled

noxious stimuli, and these findings are discussed next.

Sex differences in response toexperimentally induced pain

Sex differences in responses to experimental pain have been

investigated using a wide variety of stimulus modalities in-

cluding mechanical (blunt pressure and punctate mechanical

stimuli), electrical, thermal (heat and cold), ischaemic, and

chemical stimuli (e.g. capsaicin, hypertonic saline). Increas-

ingly in recent years, more sophisticated experimental pain

models have been used to characterize dynamic pain modu-latory 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 includ-

ing behavioural indices of threshold (defined by time or in-

tensity 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

0.5

0.4

0.3

0.2

0.1

0

0.1

0.2

0.3

0.4

0.5

Z-score

Pain Measure

Male (n=166) Female (n=167)

HPTH

HPTO

IPTH

IPTO

CPTH

CPTO

PPTT

rap

PPTM

ass

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 (Cohensd in parenthesesbelow), 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 tol-

erance (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

Sex differences in pain BJA

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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 la-

boratory 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 agraphical presentation of a dataset that reflects the typical

pattern of findings across studies of sex differences in experi-

mental pain responses, which helps explain the varying inter-

pretations 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 dis-

cussed further below.

Sex differences in response to painintervention

Sex differences in response to pain treatment have also been

described in the literature. In a review of 18 studies, Mias-

kowski and colleagues27 observed lower opioid consumption

postoperatively among women. This has not been a consist-

ent finding and may depend on the type of surgical proced-

ure28 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 authorsfound 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 im-

portant to note that these studies actually assessed opioid

consumption rather than pain relief, which may be influ-

enced 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 meth-

odological 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

while women and men are often treated differently, this dis-

parity 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 thanmales and are more likely to be recommended for opioid

treatment as evaluated by healthcare professionals and stu-

dents.33 35 These studies suggest that biases exist in health-

care, an effect which may lead to disparities in pain

management.

Other research has investigated the impact of sex differ-

ences 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 inter-

ventions 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 compe-

tition.38 In an interdisciplinary pain management pro-

gramme, 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 responsesto non-pharmacologic treatments may differ for men and

women, but the pattern of results is somewhat variable

across studies.

Mechanisms underlying sex differencesin 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, psy-

chological, and sociocultural factors likely contribute to these

differences. The following section will present a brief over-view 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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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 tes-

tosterone appears to be more anti-nociceptive and protective

in nature,42 especially given the association between

decreased androgen concentrations and chronic pain.45 Re-

search 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 re-search 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 pain 50 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 elec-

trocutaneous 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 dif-

ferences 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 influ-

ences on cerebral responses to pain.

Sex-related differences in pain may also reflect differencesin the endogenous opioid system. For instance, there are dis-

tinct differences between men and women in pain-related

activation of brain mu-opioid receptors.66 Smith and collea-

gues44 found that women in high oestradiol/low progester-

one states exhibit decreased pain sensitivity and increased

brain mu-opioid receptor binding than women in low oestra-

diol states, while decreased endogenous opioid neurotrans-

mission was associated with low oestradiol. Therefore,

these findings suggest that the interactive effects of the

opioidergic system with gonadal hormones may be an im-

portant determinant of sex-based differences in pain

sensitivity.

It is established that genotype may be a contributingfactor to sex differences in pain. Preclinical research consist-

ently shows that genotype and sex interact to influence noci-

ceptive 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 pentazo-

cine (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 alleleshowed 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, cogni-

tive 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 ru-

mination of pain-related information,73 while self-efficacy

refers to the belief that one can successfully perform a be-

haviour 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 factorssuch as personality disposition.6 A lower degree of self-

efficacy 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 social-

ly acceptable among women, an effect which may lead to

biased reporting of pain. In a study by Robinson and collea-

gues79, both men and women believed that men are less

willing to report pain than the typical woman and suchgender role expectations may contribute to sex differences

in experimental pain.80 Supporting the role of gender expect-

ancies 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 sensitiv-

ity and gender roles among Israelites and Americans found

that both Israelite men and women reported a more mascu-

line role in regards to views of pain sensitivity when com-

pared 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 sensitiv-

ity 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 inter-

est 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 experi-

ence 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 com-

pared with men, though the magnitude of these sex differ-

ences varies across studies. In addition, some evidencesuggests sex differences in responses to pharmacological

and non-pharmacological pain treatments, though the find-

ings 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 charac-

teristics 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 catastro-

phizing, 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 dispar-

ities in pain.

Authors contributions

Both authors contributed to this work. E.J.B. generated the

chief discussion points of the review article, wrote the ab-

stract, and drafted the article. R.B.F. assisted in drafting the

article and provided the statistical data. Both authors

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.

References1 Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B,

Riley JL III. Sex, gender, and pain: a review of recent clinical

and experimental findings. J Pain2009; 10: 44785

2 Bernardes SF, Keogh E, Lima ML. Bridging the gap between pain

and gender research: a selective literature review. Eur J Pain

2008; 12: 427403 Hurley RW, Adams MC. Sex, gender, and pain: an overview of a

complex field. Anesth Analg2008; 107: 30917

4 Mogil JS. Sex differences in pain and pain inhibition: multiple

explanations of a controversial phenomenon. Nat Rev Neurosci

2012; 13: 85966

5 Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G,

Choiniere M. A systematic literature review of 10 years of research

on sex/gender and experimental pain perceptionpart 1: are

there really differences between women and men? Pain 2012;

153: 60218

6 Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G,

Choiniere M. A systematic literature review of 10 years of research

on sex/gender and pain perceptionpart 2: do biopsychosocial

factors alter pain sensitivity differently in women and men?Pain 2012;153: 61935

7 Niesters M, Dahan A, Kest B, et al. Do sex differences exist in

opioid analgesia? A systematic review and meta-analysis of

human experimental and clinical studies. Pain2010; 151: 618

8 Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differ-

ences in pain perception and treatment. Pain Med 2009; 10:

28999

9 Gerdle B, Bjork J, Coster L, Henriksson K, Henriksson C,

Bengtsson A. Prevalence of widespread pain and associations

with work status: a population study. BMC Musculoskeletal Disor-

ders2008; 9: 102

10 Fillingim RB, Doleys DM, Edwards RR, Lowery D. Clinical character-

istics of chronic back pain as a function of gender and oral opioid

use.Spine2003; 28: 1435011 Keefe FJ, Lefebvre JC, Egert JR, Affleck G, Sullivan MJ, Caldwell DS.

The relationship of gender to pain, pain behavior, and disability in

osteoarthritis patients: the role of catastrophizing. Pain2000;87:

32534

12 Barnabe C, Bessette L, Flanagan C,et al. Sex differences in pain

scores and localization in inflammatory arthritis: A systematic

review and metaanalysis. J Rheumatol 2012; 39: 122130

13 Tang YR, Yang WW, Wang YL, Lin L. Sex differences in the symp-

toms and psychological factors that influence quality of life in

patients with irritable bowel syndrome. Eur J Gastroenterol

Hepatol2012; 24: 7027

BJA Bartley and Fillingim

56

7/26/2019 aet127

6/7

14 Edwards RR, Augustson E, Fillingim RB. Differential relationships

retween anxiety and treatment-associated pain reduction

among male and female chronic pain patients. Clin J Pain2003;

19: 20816

15 Robinson ME, Wise EA, Riley JLI. Sex differences in clinical pain: a

multi-sample study.J Clin Psychol Med Settings 1998;5: 41323

16 Turk DC, Okifuji A. Does sex make a difference in the prescription

of treatments and the adaptation to chronic pain by cancer and

non-cancer patients? Pain 1999; 82: 13948

17 Averbuch M, Katzper M. A search for sex differences in response

to analgesia.Arch Intern Med 2000; 160: 34248

18 Rosseland LA, Stubhaug A. Gender is a confounding factor in pain

trials: women report more pain than men after arthroscopic

surgery.Pain2004;112: 24853

19 Taenzer AH, Clark C, Curry CS. Gender affects report of pain and

function after arthroscopic anterior cruciate ligament reconstruc-

tion. Anesthesiology2000; 93: 6705

20 Chia YY, Chow LH, Hung CC, Liu K, Ger LP, Wang PN. Gender and

pain upon movement are associated with the requirements for

postoperative patient-controlled iv analgesia: a prospective

survey of 2,298 Chinese patients. Can J Anesth2002;49: 24955

21 Vetrhus M, Berhane T, Soreide O, Sondenaa K. Pain persists in

many patients five years after removal of the gallbladder: obser-

vations from two randomized controlled trials of symptomatic,

noncomplicated gallstone disease and acute cholecystitis.

J Gastrointestinal Surg 2005; 9: 82631

22 Ruau D, Liu LY, Clark JD, Angst MS, Butte AJ. Sex differences in

reported pain across 11,000 patients captured in electronic

medical records. J Pain 2012;13: 22834

23 Fillingim RB, Maixner W. Gender differences in the responses to

noxious stimuli. Pain Forum1995; 4: 20921

24 Popescu A, LeResche L, Truelove EL, Drangsholt MT. Gender differ-

ences in pain modulation by diffuse noxious inhibitory controls: a

systematic review.Pain 2010; 150: 30918

25 Hastie BA, Riley JL III, Kaplan L,et al.Ethnicity interacts with the

OPRM1 gene in experimental pain sensitivity. Pain 2012; 153:

161019

26 Rahim-Williams B, Riley JL III, Williams AK, Fillingim RB. A quan-

titative review of ethnic group differences in experimental pain

response: do biology, psychology, and culture matter? Pain Med

2012; 13: 52240

27 Miaskowski C, Gear RW, Levine JD. Sex-related differences in an-

algesic responses. In: Fillingim RB, ed. Sex, Gender, and Pain.

Seattle, WA: IASP Press, 2000; 20930

28 Chang K-Y, Tsou M-Y, Chan K-H, Sung C-S, Chang W-K. Factors

affecting patient-controlled analgesia requirements. J Formos

Med Assoc2006;105: 91825

29 Fillingim RB, Ness TJ, Glover TL,et al.Morphine responses and ex-

perimental pain: sex differences in side effects and cardiovascu-

lar responses but not analgesia. J Pain 2005;6: 11624

30 Calderone KL. The influence of gender on the frequency of painand sedative medication administered to postoperative patients.

Sex Roles1990; 23: 71325

31 Leresche L. Defining gender disparities in pain management.Clin

Orthop Relat Res 2011; 469: 18717

32 Weisse CS, Sorum PC, Sanders KN, Syat BL. Do gender and race

affect decisions about pain management? J General Inter Med

2001; 16: 211

33 Alqudah AF, Hirsh AT, Stutts LA, Scipio CD, Robinson ME. Sex and

race differences in rating others pain, pain-related negative

mood, pain coping, and recommending medical help. J Cyber

Ther Rehabil 2010; 3: 6370

34 Wandner LD, Stutts LA, Alqudah AF,et al.Virtual human technol-

ogy: patient demographics and healthcare training factors in

pain observation and treatment recommendations. J Pain Res

2010; 3: 2417

35 Hirsh AT, George SZ, Robinson ME. Pain assessment and treat-

ment disparities: a virtual human technology investigation. Pain

2009; 143: 10613

36 Keogh E, Herdenfeldt M. Gender, coping and the perception of

pain.Pain2002;97: 195

37 Keogh E, Bond FW, Hanmer R, Tilston J. Comparing acceptance-

and control-based coping instructions on the cold-pressor pain

experiences of healthy men and women. Eur J Pain 2005; 9:

5918

38 Sternberg WF, Bokat C, Kass L, Alboyadjian A, Gracely RH. Sex-

dependent components of the analgesia produced by athletic

competition.J Pain2001; 2: 6574

39 Keogh E, McCracken LM, Eccleston C. Do men and women differ in

their response to interdisciplinary chronic pain management?

Pain2005; 114: 3746

40 Pieh C, Altmeppen J, Neumeier S, Loew T, Angerer M, Lahmann C.

Gender differences in outcomes of a multimodal pain manage-

ment program. Pain 2012; 153: 197202

41 Greenspan JD, Craft RM, LeResche L, et al. Studying sex and

gender differences in pain and analgesia: a consensus report.

Pain2007; 132: S26S45

42 Craft RM. Modulation of pain by estrogens. Pain 2007; 132:

S3S12

43 Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and

analgesia: the role of gonadal hormones. Eur J Pain2004;8: 397

44 Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA,

Zubieta JK. Pronociceptive and antinociceptive effects of estradiol

through endogenous opioid neurotransmission in women.

J Neurosci2006; 26: 577785

45 Cairns BE, Gazerani P. Sex-related differences in pain. Maturitas

2009; 63: 2926

46 LeResche L, Mancl L, Sherman JJ, Gandara B, Dworkin SF. Changes

in temporomandibular pain and other symptoms across themenstrual cycle. Pain 2003; 106: 253

47 Ader DN, South-Paul J, Adera T, Deuster PA. Cyclical mastalgia:

prevalence and associated health and behavioral factors.

J Psychosom Obstet Gynaecol2001; 22: 716

48 Silberstein SD, Merriam GR. Sex hormones and headache.J Pain

Symptom Manag 1993; 8: 98

49 Huerta-Franco MR, Malacara JM. Association of physical and emo-

tional symptoms with the menstrual cycle and life-style.J Reprod

Med1993; 38: 44854

50 LeResche L, Saunders K, Von Korff MR, Barlow W. Use of exogen-

ous hormones and risk of temporomandibular disorder pain.Pain

1997; 69: 153

51 Tedford WH, Warren DE, Flynn WE. Alteration of shock aversion

thresholds during the menstrual cycle. Percept Psychophys1977; 21: 1936

52 Goolkasian P. Cyclic changes in pain perception: an ROC analysis.

Percept Psychophys1980; 27: 499

53 Dao TT, Knight K, Ton-That V. Modulation of myofascial pain by

the reproductive hormones: a preliminary report. The J Prosthet

Dent 1998; 79: 66370

54 Hapidou EG, Rollman GB. Menstrual cycle modulation of tender

points.Pain 1998; 77: 151

55 Sherman JJ, LeResche L, Mancl LA, Huggins K, Sage JC,

Dworkin SF. Cyclic effects on experimental pain response in

Sex differences in pain BJA

57

7/26/2019 aet127

7/7

women with temporomandibular disorders. J Orofac Pain 2005;

19: 13343

56 Riley JL III, Robinson ME, Wise EA, Price DD. A meta-analytic

review of pain perception across the menstrual cycle. Pain

1999; 81: 225

57 Sherman JJ, LeResche L. Does experimental pain response vary

across the menstrual cycle? A methodological review. Am J

Physiol 2006; 291: R245R56

58 Klatzkin RR, Mechlin B, Girdler SS. Menstrual cycle phase does not

influence gender differences in experimental pain sensitivity. Eur

J Pain2010; 14: 7782

59 Bartley EJ, Rhudy JL. Comparing pain sensitivity and the nocicep-

tive flexion reflex threshold across the mid-follicular and late-

luteal menstrual phases in healthy women. Clin J Pain 2013;

29: 15461

60 Berman SM, Naliboff BD, Suyenobu B, et al.Sex differences in re-

gional brain response to aversive pelvic visceral stimuli. Am J

Physiol 2006; 60: R268R76

61 Berman S, Munakata J, Naliboff BD, Chang L, Mandelkern M,

Silverman D. Gender differences in regional brain response to vis-

ceral pressure in IBS patients. Eur J Pain 2000; 4: 157

62 Moulton EA, Keaser ML, Guliapalli RP, Maitra R, Greenspan JD. Sex

differences in the cerebral BOLD signal response to painful heat

stimuli.Am J Physiol 2006; 60: R257R67

63 Kern MK, Jaradeh S, Arndorfer RC, Jesmanowicz A, Hyde J,

Shaker R. Gender differences in cortical representation of rectal

distension in healthy humans. Am J Physiol 2001; 281:

G1512G23

64 Derbyshire SWG, Nichols TE, Firestone L, Townsend DW, Jones AKP.

Gender differences in patterns of cerebral activation during equal

experience of painful laser stimulation. J Pain2002;3: 401

65 Vincent K, Warnaby C, Stagg CJ, Moore J, Kennedy S, Tracey I.

Brain imaging reveals that engagement of descending inhibitory

pain pathways in healthy women in a low endogenous estradiol

state varies with testosterone. Pain 2013; 154: 51524

66 Zubieta J-K, Smith YR, Bueller JA, et al. Mu-opioid receptor-

mediated antinociceptive responses differ in men and women.

J Neurosci2002; 22: 51007

67 Mogil JS. Interactions between sex and genotype in the medi-

ation and modulation of nociception in rodents. In: Fillingim RB,

ed.Sex, Gender, and Pain(Progress in pain research and manage-

ment, Vol. 17). Seattle, WA: IASP Press, 2000; 25 40

68 Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV,

Lariviere WR. The melanocortin-1 receptor gene mediates

female-specific mechanisms of analgesia in mice and humans.

Proc Natl Acad Sci USA 2003;100: 4867

69 Fillingim RB, Kaplan L, Staud R, et al.The A118G single nucleotide

polymorphism of the mu-opioid receptor gene (OPRM1) is asso-

ciated with pressure pain sensitivity in humans. J Pain 2005; 6:

15967

70 Olsen MB, Jacobsen LM, Schistad EI, et al. Pain intensity the first

year after lumbar disc herniation is associated with the A118G

polymorphism in the opioid receptor mu 1 gene: evidence of a

sex and genotype interaction. J Neurosci2012; 32: 98314

71 Unruh AM, Ritchie J, Merskey H. Does gender affect appraisal of

pain and pain coping strategies? Clin J Pain 1999; 15: 3140

72 Keogh E, Eccleston C. Sex differences in adolescent chronic pain

and pain-related coping. Pain 2006; 123: 27584

73 Sullivan MJ, Thorn B, Haythornthwaite JA, et al. Theoretical per-

spectives on the relation between catastrophizing and pain. Clin

J Pain2001; 17: 5264

74 Bandura A. Self-efficacy: toward a unifying theory of behavioral

change.Psychol Rev1977; 84: 191215

75 Keefe FJ, Brown GK, Wallston KA, Caldwell DS. Coping with

rheumatoid arthritis pain: catastrophizing as a maladaptive strat-

egy.Pain 1989; 37: 516

76 Forsythe LP, Thorn B, Day M, Shelby G. Race and sex differences in

primary appraisals, catastrophizing, and experimental pain out-

comes.J Pain2011; 12: 56372

77 Somers TJ, Kurakula PC, Criscione-Schreiber L, Keefe FJ,

Clowse MEB. Self-efficacy and pain catastrophizing in

systemic lupus erythematosus: relationship to pain, stiffness,

fatigue, and psychological distress. Arthritis Care Res 2012; 64:

133440

78 Jackson T, Iezzi T, Gunderson J, Nagasaka T, Fritch A. Gender dif-

ferences in pain perception: the mediating role of self-efficacy

beliefs.Sex Roles 2002; 47: 5618

79 Robinson ME, Riley JL III, Myers CD, et al. Gender role expecta-

tions of pain: relationship to sex differences in pain. J Pain

2001; 2: 2517

80 Wise EA, Price DD, Myers CD, Heft MW, Robinson ME. Gender role

expectations of pain: relationship to experimental pain percep-

tion.Pain 2002; 96: 335

81 Fillingim RB, Browning AD, Powell T, Wright RA. Sex

differences in perceptual and cardiovascular responses to pain:

the influence of a perceived ability manipulation. J Pain 2002;

3: 43945

82 Robinson ME, Gagnon CM, Riley JL 3rd, Price DD. Altering gender

role expectations: effects on pain tolerance, pain threshold, and

pain ratings. J Pain 2003; 4: 2848

83 Fowler SL, Rasinski HM, Geers AL, Helfer SG, France CR. Concept

priming and pain: an experimental approach to understanding

gender roles in sex-related pain differences. J Behav Med 2011;

34: 13947

84 Defrin R, Shramm L, Eli I. Gender role expectations of pain is asso-

ciated with pain tolerance limit but not with pain threshold. Pain

2009; 145: 2306

85 Walsh CA, Jamieson E, MacMillan H, Boyle M. Child abuse and

chronic pain in a community survey of women. J Interpers

Violence2007; 22: 153654

86 Fillingim RB, Edwards RR. Is self-reported childhood abuse history

associated with pain perception among healthy young women

and men? Clin J Pain2005; 21: 38797

87 Edwards PW, Zeichner A, Kuczmierczyk AR, Boczkowski J. Familial

pain models: the relationship between family history of pain and

current pain experience. Pain1985; 21: 379

88 Fillingim RB, Edwards RR, Powell T. Sex-dependent effects ofreported familial pain history on recent pain complaints and

experimental pain responses. Pain 2000;86: 8794

89 Koutantji M, Pearce SA, Oakley DA. The relationship between

gender and family history of pain with current pain experience

and awareness of pain in others. Pain 1998; 77: 25

Handling editors: L. Colvin and D. J. Rowbotham

BJA Bartley and Fillingim

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