“Equality consists in the same treatment of similar persons.” —Aristotle
By Kern A. Olson, PhD
Do men and women perceive and react to pain differently? Do men and women use different coping strategies when they experience recurrent or chronic pain? These questions are relevant to pain management providers when they assess and develop treatment plans for patients who experience pain on a daily basis.
Although once ignored in medical research, the idea that men andwomen experience pain differently is now accepted.1 In 1995, a major review of the research on gender and pain found that women experience more pain compared to men.2
The authors suggested that women have a lower pain threshold and tolerance to experimental pain including mechanical, thermal, and electrical stimuli. In other words, women experience painful stimuli as more intense than men.
However, the authors pointed out that there are a number of issues that contribute to the variability between the genders, including whether pain threshold or tolerance were being measured. In 2000, Dao and LeResche listed a number of factors that contribute to this variability, including dimensions of pain measured, type of stimulus, characteristics of the experimental environment, spatial and temporal aspects of the stimulus, and characteristics of the subject.3
I believe an additional factor must be controlled, and that is the sex of the observer. It is well understood that both men and women subjects react differently based on the gender of the experimenter.
Mechanisms Driving Differences
A well-designed study by Roger Fillingim et al showed that sex differences in pain response are well documented, but the mechanisms underlying these differences are not well understood.4 Fillingim proposed that gender roles and pain responses could be mediated by a subject’s perceived ability to tolerate pain. In other words, stereotypical sex roles are perceived to influence greater tolerance for pain among men than women. The results of this study showed that men had higher pain tolerance, but this triggered a higher blood pressure (BP) response. Fillingim et al pointed out that a body of evidence suggests that higher resting BP is associated with lower pain sensitivity.4 (see Interview with Roger B. Fillingim, PhD.)
One interesting explanation forwarded by the authors was that men tried harder to tolerate the pain, resulting in higher systolic BP. Also, keep in mind that systolic BP is related to sympathetic arousal. The authors concluded that perceived ability to tolerate pain may have influenced the relationship between cardiovascular variables and pain tolerance.2
Even though men appear to tolerate painful stimulus better, some data suggest that sustained low-level pain may be more disturbing to men than women. In a study by Frot et al, 10 men and 10 women received 2 applications of topical capsaicin for 30 minutes—first on the face and then the ankle. The subjects rated pain intensity, unpleasantness, and anxiety each minute during capsaicin application and for 30 minutes after its removal.
The investigators found that men showed a significant positive correlation between anxiety (sympathetic arousal) and pain intensity, whereas women did not.5 The results of the study support the general conclusion that although men perceive experimental pain less intensely than women do, they have more anxiety related to pain.
Evidence of the magnitude of gender differences in pain was revealed by a meta-analysis of research using experimentally induced pain.6 In this meta-analysis, Riley et al pointed out a number of assumptions relevant to gender differences, such as cultural and physiological influences, including the fact that males have been socialized to suppress outward signs of pain. They also mentioned the important influence of the menstrual cycle on pain perception. Females demonstrated more pain sensitivity following a mid-cycle surge during the luteal phase.7
An interesting study by Sarlani et al examined the concept oftemporal summation as it relates to gender and pain.8 Temporal summation of pain is the increase in pain intensity after repetitive noxious stimulation of constant intensity. Temporal summation is regarded as a psycho-physiological correlate of wind-up. Wind-up is the increase in the magnitude of second-order nociceptive neuron responses to the application of repetitive noxious stimuli of constant strength. The authors believe that wind-up and temporal summation of pain share common features and have a central basis. Current thinking suggests that temporal summation is upregulated more frequently in women than in men.
Sarlani et al applied a series of repetitive, mildly noxious, mechanical stimuli to the fingers of 25 women and 25 men.8 The subjects rated the pain intensity and unpleasantness caused by the first, fifth, and tenth stimulus in the series, as well as after-sensations 15 seconds and 1 minute after the end of stimulation.
The investigators found that temporal summation of pain intensity and unpleasantness ratings were more pronounced in women than men (P<0.0001).8 Moreover, women reported higher ratings for the intensity and the unpleasantness of after-sensations (P<0.0005) and more frequent painful after-sensations (P<0.05).
“Greater temporal summation of pain and after sensations in women suggests that their central processing of nociceptive input may be more easily upregulated into pathological hyperexcitability, possibly accounting for the higher prevalence of various chronic pain conditions among women,” noted the authors.8
Most recently, Sorge et al discovered that female mice do not require microglia activation to produce mechanical pain hypersensitivity. Rather, the researchers wrote that “female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.”9
Pain Medicine and Gender
The fact that men and women respond differently to pain medicine is an important issue in the practice of pain management. The most frequently prescribed pain medicines belong in the opioid class. Opioids work through specific opioid receptors that are well documented. Three types of opioid receptors have been identified: mu, delta, and kappa, with mu and kappa being the most frequently occurring receptors in humans.1
Research by Craft found that women use 40% less opioid-based medicine than men for postoperative pain.10 This finding was confirmed by Miaskowski et al in an analysis of 18 studies of postoperative opioid use. The researchers found an increase in opioid consumption among male patients in 10 studies (56%), but the remaining 8 studies (44%) showed no gender difference.11
Several studies of pain after oral surgery revealed that women get much greater pain relief from mixed-action opioid medications (eg, pentazocine, nalbuphine, butorphanol).12 More recently, a meta-analysis of this literature confirmed that women seem to experience greater pain relief with opioids; however, they also report more side effects.13
Several factors can explain the differential response to pain medicine between men and women. Sex hormones (estrogen) can modulate the density of opioid receptors.14 In addition, research on sex hormones indicates there is improved mu receptor binding in some brain regions in women after they receive estrogen, as measured by PET scans.15 Recent advances in genetics also have revealed greater opioid analgesia in women with specific receptor genes that mediate female responses.11
Finally, it is important to remember that psychological factors influence the response to opioid-based therapy. Anxiety and sympathetic reactivity [as seen more in male patients] imposes a major negative influence in pain perception and brain activity and may influence opioid analgesia among the sexes.16
Biological Factors Influence Perception of Pain
In 2000, Fillingim published a biopsychosocial model that has influenced the thinking about the differences between genders that is evident today.17 The factors he proposed as being responsible for the differences are:
- Biological factors, including sex hormones and endogenous pain control mechanisms
- Psychological factors, including anxiety and negative affect
- Sociocultural factors, including gender role expectations of pain
The model also shows that the perception of pain is influenced by the interaction of all these factors working together.2,17
Sex hormones, according to this model, are relevant to the evaluation and treatment of pain.18 When considering all of the biological factors, the role of sex hormones has received the most research attention. According to Marchand, sex hormones in the central nervous system (CNS) have been documented to influence the neurotransmitters that are involved in the perception of pain.1
The main sex hormones in women are estrogen and progesterone, which will vary according to the menstrual cycle. Testosterone also is present in women but at a level that is 10 to 15 times lower than the level present in men. In addition, girls and boys react to pain in a similar fashion before puberty but differently after puberty; these differences, however, decrease as levels of sex hormones decrease as people age.19
In a recent well-designed study, investigators demonstrated that changes in plasma levels of estrogen influenced changes in serotonin, acetylcholine, dopamine, and endorphine.20 Additional research has examined the role of progesterone and found similar influences on levels of dopamine and acetycholine.21
Estrogen receptors have been found in the dorsal horn, which suggests there may be mechanisms that could regulate pain sensitivity by influencing neurotransmitters such as substance P, gamma-amino butyric acid, dopamine, serotonin, and norepinephrine.22 One of the conclusions forwarded from this research is that a decrease in estrogen would increase sensitivity to pain. Conversely, an increase in estrogen would promote analgesic effect by stimulating a bolus of pain-inhibiting transmitters.22
It appears that testosterone plays a protective role in decreasing the perception of pain.23 An example of this protective role was suggested recently in a study investigating the protective effect testosterone plays in rheumatoid arthritis (RA), which affects 3 times as many women as men.24 Further evidence was demonstrated when men who experience RA reported fewer affected joints after taking testosterone.25
Fillingim’s model described the importance of psychosocial factors that contribute gender differences in pain responses. One question that is frequently raised is the weight given to each factor in Fillingim’s model—biological and psychosocial.17 In my opinion, Fillingim’s biopsychosocial model would answer that it is a reciprocal interaction between the 2 factors. To determine the amount of weight given to each factor is a difficult task because it is a dynamic model that will change depending on the internal and external forces in play at any given moment.
Anxiety at a clinical level includes both cognitive and physiological contributions that have a cumulative impact on the perception of pain and how a person copes with that perception. As an emotional state, anxiety can be described as hyper-vigilant tension that is usually associated with the unpleasant feeling of fear.26
The psycho-physiological component of anxiety is reflected in an elevated sympathetic nervous system reaction. It is well accepted that elevated levels of anxiety increase the perception of pain.27This finding is independent of the intensity of the painful stimulus.
Recent research has examined the influence of anxiety in relation to gender differences and the reaction to pain. Both clinical and experimental studies have found that anxiety was associated with increased pain sensitivity in men but not women.6,16,28,29
It is important to point out that, historically, the concept of anxiety was divided into 2 categories: State Anxiety and Trait Anxiety. State Anxiety implies a time-limited state, or “an anxious state,” as compared to Trait Anxiety, which is a longer-lasting feature of the personality. One study suggested that men feel more State Anxiety associated with pain or that the reaction (anxiety) in men is more time limited than it is in women.29Another study on the topic suggested that women may have a lower level of State Anxiety related to pain but a higher level of Trait Anxiety independent of pain.16
The anxiety differences between men and women have been examined in experimental pain research. In men, acute stress and State Anxiety are associated with increased opioid inhibitory response and higher levels of cortisol.30 This finding may help explain gender differences by suggesting that men, when they experience elevated levels of State Anxiety, also activate descending inhibitory mechanisms. The differences between men and women may be explained by dividing anxiety into the 2 separate factors. Pain perception is related to State Anxiety in men and Trait Anxiety in women.16
The role of depression and gender also has been examined extensively in recent years. The overall evidence suggests that depression is a significant predictor of the development of chronic pain.31 In addition, research supports the finding that as the number of depressive symptoms increase, pain will increase.32 The prevalence of depression in patients who experience chronic pain suggests a wide range, from a low of 30% to a high of 54%, in the total pain population.33 The question that must be answered is, does depression influence the role of pain between the genders?
Research suggests that an association exists between depressive symptoms and increased somatic focus only for women.34Somatic focus influences the reporting of pain, and the consensus of research suggests that depression is positively correlated with pain in women and not men.35,36 As mentioned earlier, Marchand pointed out that depression is related to reduced opioid analgesia. He proposed that this link could explain, in part, why women perceive more pain than men.1
It is well understood that negative emotions, such as anger, magnify the pain experience.37 We also now know that pain does not generate the same emotional response across both genders. Research suggests that women become more frustrated and men become more anxious when coping with persistent pain.38 In addition, anger has been associated with greater sensitivity to acute pain and to persistent pain.4 Conversely, it is interesting to note that positive emotions inhibit the pain response and facilitate coping.29
I remember reading Norman Cousins’ Anatomy of an Illness, which was published in 1979.39 When Cousins wrote the book, he was experiencing a serious collagen illness, a disease of the connective tissue. He talked about the work of Walter B. Cannon who introduced the concept of homeostatic responses, or natural processes that enable the individual to return to the “normal” state before it experienced the noxious influence.
He also referenced the work of William Osler, who felt that successful healing was due to the individual’s personality and behavior, independent of medicine. So, in cooperation with his doctors, Cousins developed a program to enhance positive affirmative emotions, with the goal of enhancing body chemistry. To achieve this goal, he used funny movies, such as Marx Brothers’ films, to generate genuine belly laughter. The program worked—his sedimentation rates improved, inflammation was reduced, and he experienced more pain-free sleep. I still recommend this book to patients, and the feedback usually is positive.39
Cognition and Pain
How we think about pain and the language we use to describe our pain are very important cognitive factors that influence how we react to and cope with persistent pain. Research suggests that women use more emotional and social strategies to cope with pain, whereas men use more active approaches to deal with pain.40
In my opinion, the explanation for this difference is based in how boys and girls are socialized. This opinion is based on a well-designed study by Mechanic conducted in the 1960s, during which he found that boys express pain less than girls.41 It has been suggested that masculine behavior is more narrowly defined and rigid compared to feminine behavior.41
A related recent study suggested that young girls express more emotional distress than boys when they experience pain. This same study indicated that girls are more adept at using social and emotional support from those around them compared to boys.42
The role of catastrophizing in recent years has become a major predictive factor in outcome studies involving pain treatment. Edwards et al designed a study examining catastrophizing as a mediator of gender differences in both recurrent daily pain and experimental pain.43
The results of this study suggested that sex differences in recurrent daily pain are due to levels of catastrophizing. However, the results did not support the higher threshold and tolerance levels to thermal and cold pain observed in men. The authors stated that catastrophizing appears to emerge relatively early in development and is more common among adolescent girls.
A well-designed study by Keefe et al examined the role of gender differences in pain coping and mood in individuals with osteoarthritic knee pain. What was unique about this study is the format of multiple pain ratings twice a day (afternoon and evening) for 30 days.44 Women exhibited an increase in pain over the course of the day, whereas men exhibited an increase in coping efficacy over the day. In addition, men experienced more negative mood in the morning after an evening of increased pain.
The uniqueness of this study pointed out the importance of obtaining multiple daily assessments when studying gender differences.44
Gender and Neurological Differences
Research examining neural differences between the genders to a painful stimulus has gained more attention in recent years. Improvements in brain imaging have provided additional information that helps us understand how men and women respond to pain.
A Canadian research group, using healthy, normal subjects, found a positive relationship in activation differences between men and women. Their findings suggested that women, not men, demonstrate a strong positive, linear relationship between perigenual anterior cingulated cortex and the report of pain.45
This finding is consistent with other research suggesting that women are more emotionally responsive and perceptive when presented with a negative emotional experience.42 Tremblay et al suggested that men deactivate prefrontal suppression when processing pain, which leads to the mobilization of threat control circuits when they experience pain.45
What evolutionary purpose could explain gender differences in relation to the pain experience? Tremblay et al speculated that men have occupied the role of hunter and defender against aggressive behavior, so they have learned to cope with pain to survive; in contrast, women have developed a strong sense of trust and sensitivity, which promotes strong social bonds that help them cope with pain and support the survival of the group.45
Pain medicine has evolved and matured since I started practicing some 30 years ago. During this time, the field has gained an understanding of the importance of gender in the pain experience. I hope all pain providers incorporate these findings to improve treatment plans to benefit all patients coping with persistent pain.
- Marchand S.The Phenomenon of Pain. Seattle, WA: IASP Press:2012.
- Fillingim RB, Maixner W. Gender differences in the responses to noxious stimuli.Pain Forum. 1995;4:209-221.
- Dao TT, LeResche L. Gender differences in pain.J Orofac Pain. 2000;14(3):169-184.
- 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(6):439-445.
- Frot M, Feine JS, Bushnell MC. Sex differences in pain perception and anxiety. A psychophysical study with topical capsaicin.Pain. 2004;108(3):230-236.
- Riley JL 3rd, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. 1998;74(2-3):181-187.
- Riley JL 3rd, Robinson ME, Wise EA, Price DD. A meta-analytic review of pain perception across the menstrual cycle.Pain. 1999;81(3):225-35.
- Sarlani E, Grace EG, Reynolds MA, Greenspan JD. Sex differences in temporal summation of pain and after sensations following repetitive noxious mechanical stimulation.Pain. 2004; 109(1-2):115-123.
- Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat Neurosci. 2015;18(8):1081-1083.
- Craft RM. Sex differences in opioid analgesia: “Fom mouse to man.”Clin J Pain. 2003;19(3):175-186.
- Miaskowski C. Sex related differences in analgesic responses. In: Fillingim RB, ed.Sex, Gender and Pain. Seattle, WA: IASP Press: 2000;209-230.
- Fillingim RB, Gear RW. Sex differences in opioid analgesia: clinical and experimental findings.Eur J Pain. 2004;8(5):413-425.
- 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. Pain. 2010;151(1):61-68.
- Haywood SA, Simonian SX, van der Beek EM, Bicknell RJ, Herbison AE. Fluctuating estrogen and progesterone receptor expression in brainstem norepinephrine neurons through the rat estrous cycle. 1999;140(7):355-363.
- Zubieta JK, Dannals RF, Frost JJ. Gender and age influences on human brain mu–opioid receptor binding measured by PET.Am J Psychiatry. 1999;156(6):842-848.
- Goffaux P, Michaud K, Gaudreau J, Chalaye P, Rainville P, Marchand S. Sex differences in perceived pain are affected by an anxious brain. 2011;52(9):2065-2073.
- Fillingim RB.Sex, Gender and Pain. Seattle, WA: ISAP Press: 2000.
- Kuba T, Quinones-Jenab V. The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: clinical versus preclinical studies.Brain Res Bull. 2005;66(3):179-188.
- Robinson JE, Short RV. Changes in breast sensitivity in puberty, during the menstrual cycle, and at parturition.Br Med J. 1977;1(6070):1188-1191.
- Aloisi AM, Pari G, Ceccarelli I, et. al. Gender-related effects of chronic non-malignant pain and opioid therapy on plasma levels of macrophage migration inhibitory factor (MIF). 2005;115(1-2):142-151.
- Meiri H. Is synaptic transmission modulated by progesterone?Brain Res. 1986;385(1):193-196.
- Aloisi AM, Monifazi M. Sex hormones, central nervous system and pain.Horm Behav. 2006;50(1):1-7.
- Gaumond I, Arsenault P, Marchand S. Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses.Brain Res. 2005;1052(1):105-111.
- Rovensky J, Kvetnansky R, Radikova Z, et al. Hormone concentrations in synovial fluid of patients with rheumatoid arthritis.Clin Exp Rheumatol. 2005;23(3):292-296.
- Cutolo M, Accardo S. Sex hormones, HLA and rheumatoid arthritis.Clin Exp Rheumatol.1991;9(6):641-646.
- Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds.2000;84(1):65-75.
- Tang J, Gibson SJ. A psychophysical evaluation of the relationship between trait anxiety, pain perception, and induced state anxiety.J Pain. 2005;6(9):612-619.
- Edwards RR, Augustson EM, Fillingim R. Sex-specific effects of pain related anxiety on adjustment to chronic pain.Clin J Pain. 2000;16(1):46-53.
- Rhudy JL, Williams AE. Gender differences in pain: do emotions play a role?Gend Med. 2005;2(4):208-226.
- Willer JC, Dehen H, Cambier J. Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes.Science. 1981;212(4495):689-691.
- Carroll LJ, Cassidy JD, Côté P. Depression as a risk factor for onset of an episode of troublesome neck and low back pain. 2004;107(1-2):134-139.
- Banks SM, Kerns RD. Explaining high rates of depression in chronic pain: a diathesis-stress framework.Psychol Bull. 1996;119:95-110.
- Anderson GB. Epidemiological features of chronic low-back pain.1999;354(9178):581-585.
- Bolton JE. Psychological distress and disability in back pain patients evidence of sex differences.J Psychosom Res. 1994;38(8):849-858.
- Haley WE, Turner JA, Romano JM. Depression in chronic pain patients relation to pain, activity, and sex differences. Pain.1985;23(4):337-343.
- Meana M. The meeting of pain and depression: comorbidity in women.Can J Psychiatry. 1998;43(9):893-899.
- Robinson ME, Riley JL. The role of emotion in pain. In: Gatchel RJ, Turk DC, ed.Psychosocial Factors in Pain. 1st ed. New York, NY: Guilford Press: 1999;74-88.
- Riley JL, Robinson ME, Wise EA, Myers CD, Price DD. Sex differences in negative emotional responses to chronic pain.J Pain. 2001;2(6):354-359.
- Cousins N.Anatomy of an Illness: As Perceived by the Patient. New York, NY: Norton & Co: 1979.
- Wallbott HG, Scherer KR. Stress specificities: differential effects of coping style, gender, and type of stressors on autonomic arousal, facial expression, and subjective feeling.J Pers Soc Psychol. 1991;61(1):147-156.
- Mechanic D. The influence of mothers on their children’s health attitudes and behavior.1964;33:444-453.
- Fearon I, McGrath PJ, Achat H. “Booboos”: the study of everyday pain among young children. 1996;68(1):55-62.
- Edwards RR, Haythornthwaite JA, Sullivan MJ, Fillingim RB. Catastrophizing as a mediator of sex differences pain: differential defects for daily pain versus laboratory induced pain. 2004;111(3):571-577.
- Keefe FJ, Affleck G, France Cr, et al. Gender differences in pain coping, mood, and individuals having osteoarthritic knee pain: a within-day analysis.2004;110(3):571-577.
- Girard-Tremblay L, Auclair V, Daigle K, Léonard G, Whittingstall K, Goffaux P. Sex differences in the neural representation of pain unpleasantness.J Pain. 2014;15(8):867-877.