Publications
APS Bulletin • Volume 10, Number 1, January/February 2000
Research Update
Richard H. Gracely, PhD, Department Editor
Sex-Related Differences in the Experience of Pain
Roger B. Fillingim, PhD
Considerable evidence suggests that females and males experience pain differently, and sex-related influences on pain responses recently have received a great deal of scientific and clinical attention. Indeed, clinical research indicates that compared with males, females are overrepresented in a variety of chronic pain disorders (Unruh, 1996), including temporomandibular disorders (TMDs), fibromyalgia, migraine headache, and irritable bowel syndrome. Likewise, epidemiologic and survey research typically have demonstrated greater frequencies of pain-related symptoms among females than males in the general population (Andersson, Ejlertsson, Leden, & Rosenberg, 1993, Rajala, Keinanen-Kiukaanniemi, Uusimaki, & Kivela, 1995; Skovron, Szpalski, Nordin, Melot, & Cukier, 1994). In addition, laboratory studies of pain-free individuals indicate that when females were exposed to a variety of stimulus modalities and assessment methods, they exhibited greater sensitivity to the experimentally induced pain than males (Berkley, 1997; Fillingim & Maixner, 1995; Riley, Robinson, Wise, Myers, & Fillingim, 1998).
This article addresses three important questions regarding sex-related differences in the experience of pain: (a) What are the mechanisms underlying sex differences in the experience of pain?, (b) What is the relationship between sex differences in clinical versus experimental pain responses?, and (c) What is the practical significance of sex-related differences in pain?
Mechanisms underlying sex-related differences in the experience of pain
Various systems could influence pain responses in a sex-dependent manner, including, but not limited to, gonadal hormone activity, endogenous pain modulatory pathways (both inhibitory and excitatory), and psychosocial factors.
Hormonal Factors. Gonadal hormones can alter the processing of nociceptive information in both the central nervous system (CNS) and the peripheral nervous system. In the peripheral nervous system, “silent” afferents, which arise from the uterus, appear to be affected by the estrous cycle, and estrogen alters the receptive field properties of primary afferents (Berkley, Robbins, & Sato, 1988; Robbins, Berkley, & Sato, 1992; Robbins, Sato, Hotta, & Berkley, 1990; Smith et al., 1998). Moreover, pregnancy and progesterone influence nerve conduction and the susceptibility of the somatic and visceral peripheral nerves to the effects of local anesthetics (Butterworth, Walker, & Lysak, 1990; Datta, Migliozzi, Flanagan, & Krieger, 1989; Kaneko, Saito, Kirihara, & Kosaka, 1994). In the CNS, gonadal hormones influence endogenous opioid systems (Berglund, Derendorf, & Simpkins, 1988; Smith et al., 1998), as well as the activity of other neuromodulators involved in nociceptive processing, including substance P (Duval, Lenoir, Moussaoui, Garret, & Kerdelhue, 1996), amino acids (e.g., gamma-aminobutyric acid, glutamate), and other neurotransmitters (e.g., dopamine, serotonin, norepinephrine) (Smith, 1994).
Endogenous pain modulation. Sex differences in several endogenous analgesic responses have been reported. In response to a variety of stressors, female rats displayed fewer opioid- and nonopioid-mediated, stress-induced analgesia (SIA) than male rats; these differences appeared to be mediated by gonadal hormones (Bodnar, Romero, & Kramer, 1988; Kavaliers & Colwell, 1991). Another investigation reported that the analgesia displayed by females with intact ovaries was neurochemically different from the analgesia displayed by males and ovariectomized females (Mogil, Sternberg, Kest, Marek, & Leibeskind, 1993). In addition to SIA, two other hormonally mediated endogenous analgesic processes, pregnancy-induced analgesia (Dawson-Basoa & Gintzler, 1998) and vaginocervical stimulation-produced analgesia, are unique to females. Thus, quantitative and qualitative sex differences, as well as hormonal effects, have been shown to produce numerous endogenous analgesic responses.
Psychosocial and sex-role factors. Psychosocial factors, such as coping and affective distress, can alter pain responses and could contribute to sex-related differences in the experience of pain. Psychological symptoms such as depression and anxiety are more prevalent among females than among males and are associated with increased pain and other physical symptoms (Kroenke & Spitzer, 1998; Moldin et al., 1993; Rajala, Keinanen-Kiukaanniemi, Uusimaki, & Kivela, 1995). Moreover, affective distress has been associated with experimental pain responses (Cornwall & Donderi, 1988; Zelman, Howland, Nichols, & Cleeland, 1991), and Fillingim, Keefe, Light, Booker, and Maixner (1996) demonstrated that individuals’ expectations about efficacy, control, and anxiety are associated with experimental pain responses in a sex-based manner. Patients’ endorsements of stereotypical sex roles also have been associated with pain responses, such that a high degree of masculinity was associated with higher pain thresholds for males but not for females (Otto & Dougher, 1985). However, even after controlling for sex-role masculinity factors, the sex difference in pain responses remained significant. Thus, several psychological variables are linked with pain sensitivity in a sex-based manner, but the extent to which these factors account for sex differences in pain responses remains unknown.
Sex differences in clinical versus experimental pain
The findings regarding sex-related differences in clinical pain and experimentally induced pain derive from independent bodies of research, and the relationship between the two types of pain remains unclear. Several factors could contribute to sex differences in clinical pain, including sex-related influences on disease-specific pathophysiology and gender differences in psychosocial responses (e.g., coping, affective distress, cognitive appraisal), and these factors may not be associated with the observed sex differences in experimentally evoked pain responses. Another possibility, however, is that there are sex differences in nociceptive processing that are associated with enhanced sensitivity to experimentally induced pain and with an increased risk of the development of certain chronic pain disorders among females. At present, however, only indirect support for this hypothesis is available. Several chronic pain disorders experienced predominantly by females are characterized by enhanced sensitivity to experimentally induced pain. These syndromes include TMD (Maixner, Fillingim, Booker, & Sigurdsson, 1995; Maixner, Fillingim, Sigurdsson, Kincaid, & Silva, 1998), fibromyalgia (Lautenbacher, Rollman, & McCain, 1994; Mountz et al., 1995), tension-type headache (Langemark, Jensen, Jensen, & Olesen, 1989), and irritable bowel syndrome (Costantini et al., 1993; Jorgensen et al., 1993). Also, some studies have demonstrated that in certain patient populations, enhanced laboratory-based pain responses are associated with increased clinical pain (Fillingim, Maixner, Kincaid, Sigurdsson, & Harris, 1996; Langemark, Jensen, Jensen, & Olesen, 1989; Lautenbacher, Rollman, & McCain, 1994). Fillingim, Edwards, and Powell (1999) found that generally healthy young females who reported a greater number of recent pain episodes also exhibited greater thermal pain sensitivity in laboratory tests. This finding, however, was not observed in males. These studies suggest that under certain circumstances, clinical and experimental pain responses are related; however, large-scale prospective studies are needed to determine whether laboratory-assessed pain sensitivity predicts the development of certain pain disorders.
The practical significance of sex differences in pain
Sex and gender represent only one set of biopsychosocial variables that can alter pain responses, and the magnitude of sex-related influences on pain relative to other factors (e.g., age, race, coping skills) has not been determined. However, further investigation of sex differences in pain responses could reveal at least three areas of significant practical importance. First, investigating sex differences may enhance our understanding of the pathophysiology of certain pain conditions. For example, investigating symptomatology in pain disorders predominantly experienced by females throughout the menstrual cycle can reveal the influence of gonadal hormones on specific and nonspecific pathophysiological processes. Second, sex differences in the experience of pain can have implications for tailoring patients’ pain treatment. Recent research has suggested sex differences in patients’ responses to opioid analgesics (Miaskowski & Levine, 1999), a finding that has obvious implications for managing both acute and chronic clinical pain. In addition, sex-dependent relationships between psychosocial variables (e.g., coping, mood) and pain responses may suggest that optimal cognitive-behavioral treatments for pain differ for females and males. Third, research of this type could lead to new treatments for pain, especially in the area of hormonal manipulations. For example, antiestrogenic agents (e.g., tamoxifen) appear to be effective in the treatment of cyclical mastalgia in women (Kontostolis, Stefanidis, Navrozoglou, & Lolis, 1997; Messinis & Lolis, 1988) and gynecomastia in men (McDermott, Hofeldt, & Kidd, 1990). It seems plausible that antiestrogen therapies would be effective for the treatment of other chronic pain conditions that are hormonally influenced (e.g., rheumatoid arthritis, TMD, fibromyalgia). Also, if such treatments potentiate the effects of other analgesic agents, a more optimal therapeutic profile could emerge. The effectiveness of various sex steroid treatments for the amelioration of chronic pain remains an important yet unexplored area of research. Additional research is needed to facilitate the clinical application of findings regarding sex- and gender-related differences in the experience of pain.
The future of sex, gender, and pain research
Given the increased interest in this area of research, we can expect more rapid advances in our understanding of sex-related influences on pain responses in the near future. One promising area involves investigating the influence of sex-dependent genetic factors on pain sensitivity (Mogil, Richards, O’Toole, Helms, Mitchell, & Belknap, 1997; Mogil, Richards, O’Toole, Helms, Mitchell, Kest et al., 1997). We can also anticipate that scientific findings regarding sex and pain will make their way into clinical practice. For example, recent findings of sex differences in analgesic responses to opioid (Miaskowski & Levine, 1999) and nonopioid agents (Eisenach & Hood, 1998; Robinson, Riley, Brown, & Gremillion, 1998) may lead to sex-specific tailoring of analgesic regimens. Thus, although presently there are more questions than answers regarding how sex and gender relate to pain, the future looks promising for this important area of inquiry.
References
Andersson, H.I., Ejlertsson, G., Leden, I., & Rosenberg, C. (1993). Chronic pain in a geographically defined general population: Studies of differences in age, gender, social class, and pain localization. Clinical Journal of Pain, 9, 174-182.
Berglund, L.A., Derendorf, H., & Simpkins, J.W. (1988). Desensitization of brain opiate receptor mechanisms by gonadal steroid treatments that stimulate luteinizing hormone secretion. Endocrinology, 122, 2718-2726.
Berkley, K.J. (1997). Sex differences in pain. (1988). Behavioral and Brain Sciences, 20, 371-380.
Berkley, K.J., Robbins, A., & Sato, Y. (1988). Afferent fibres supplying the uterus in the rat. Journal of Neurophysiology, 59, 142-163.
Bodnar, R.J., Romero, M.T., & Kramer, E. (1988). Organismic variables and pain inhibition: Roles of gender and aging. Brain Research Bulletin, 21, 947-953.
Butterworth, J.F., Walker, F.O., & Lysak, S.C. (1990). Pregnancy increases median nerve susceptibility to lidocaine. Anesthesiology, 72, 962-965.
Cornwall, A., & Donderi, D.C. (1988). The effect of experimentally induced anxiety on the experience of pressure pain. Pain, 35, 105-113.
Costantini, M., Sturniolo, G.C., Zaninotto, G., D’Inca, R., Polo, R., Naccarato, R., & Ancona, E. (1993). Altered esophageal pain threshold in irritable bowel syndrome. Digestive Diseases and Sciences, 38, 206-212.
Datta, S., Migliozzi, R.P., Flanagan, H.L., & Krieger, N.R. (1989). Chronically administered progesterone decreases halothane requirements in rabbits. Anesthesia and Analgesia, 68, 46-50.
Dawson-Basoa, M., & Gintzler, A.R. (1998). Gestational and ovarian sex steroid antinociception: Synergy between spinal kappa and delta opioid systems. Brain Research, 794, 61-67.
Duval, P., Lenoir, V., Moussaoui, S., Garret, C., & Kerdelhue, B. (1996). Substance P and neurokinin A variations throughout the rat estrous cycle; comparison with ovariectomized and male rats: II. Trigeminal nucleus and cervical spinal cord. Journal of Neuroscience Research, 45, 610-616.
Eisenach, J.C., & Hood, D.D. (1998). Sex differences in analgesia from intrathecal neostigmine in humans. Anesthesiology, 89, A1106.
Fillingim, R.B., Edwards, R.R., & Powell, T. (1999). The relationship of sex and clinical pain to experimental pain responses. Pain, 83, 419-425.
Fillingim, R.B., Keefe, F.J., Light, K.C., Booker, D.K., & Maixner, W. (1996). The influence of gender and psychological factors on pain perception, Journal of Gender Culture and Health, 1, 21-36.
Fillingim, R.B., & Maixner, W. (1995). Gender differences in the responses to noxious stimuli. Pain Forum, 4, 209-221.
Fillingim, R.B., Maixner, W., Kincaid, S., Sigurdsson, A., & Harris, M.B. (1996). Pain sensitivity in patients with temporomandibular disorders: Relationship to clinical and psychosocial factors. Clinical Journal of Pain, 12, 260-269.
Jorgensen, L.S., Bach, F.W., Christiansen, P., Raundahl, U., Ostgaard, S., & Ekman, R. (1993). Decreased cerebrospinal fluid beta-endorphin and increased pain sensitivity in patients with functional abdominal pain. Scandinavian Journal of Gastroenterology, 28, 763-766.
Kaneko, M., Saito, Y., Kirihara, Y., & Kosaka, Y. (1994). Pregnancy enhances the antinociceptive effects of extradural lignocaine in the rat. British Journal of Anaesthesia, 72, 657-661.
Kavaliers, M., & Colwell, D.D. (1991). Sex differences in opioid and non-opioid mediated predator-induced analgesia in mice. Brain Research, 568, 173-177.
Kontostolis, E., Stefanidis, K., Navrozoglou, I., & Lolis, D. (1997). Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecological Endocrinology, 11, 393-397.
Kroenke, K., & Spitzer, R.L. (1998). Gender differences in the reporting of physical and somatoform symptoms. Psychosomatic Medicine, 60, 150-155.
Langemark, M., Jensen, K., Jensen, T.S., & Olesen, J. (1989). Pressure pain thresholds and thermal nociceptive thresholds in chronic tension-type headache. Pain, 38, 203-210.
Lautenbacher, S., Rollman, G.B., & McCain, G.A. (1994). Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain, 59, 45-53.
Maixner, W, Fillingim, R., Booker, D., & Sigurdsson, A. (1995). Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain. Pain, 63, 341-351.
Maixner, W., Fillingim, R., Sigurdsson, A., Kincaid, S., & Silva, S. (1998). Sensitivity of patients with temporomandibular disorders to experimentally evoked pain: Evidence for altered temporal summation of pain. Pain, 76, 71-81.
McDermott, M.T., Hofeldt, F.D., & Kidd, G.S. (1990). Tamoxifen therapy for painful idiopathic gynecomastia. Southern Medical Journal, 83, 1283-1285.
Messinis, I.E., & Lolis, D. (1988). Treatment of premenstrual mastalgia with tamoxifen. Acta Obstetricia et Gynecologica Scandinavica, 67, 307-309.
Miaskowski, C., & Levine, J.D. (1999). Does opioid analgesia show a gender preference for females? Pain Forum, 8, 34-44.
Mogil, J.S., Richards, S.P., O’Toole, L.A., Helms, M.L., Mitchell, S.R., & Belknap, J.K. (1997). Genetic sensitivity to hot-plate nociception in DBA/2J and C57BL/6J inbred mouse strains: Possible sex-specific mediation by delta2-opioid receptors. Pain, 70(2-3), 267-277.
Mogil, J.S., Richards, S.P., O’Toole, L.A., Helms, M.L., Mitchell, S.R., Kest, B., & Belknap, J.K. (1997). Identification of a sex-specific quantitative trait locus mediating nonopioid stress-induced analgesia in female mice. Journal of Neuroscience, 17, 7995-8022.
Mogil, J.S., Sternberg, W.F., Kest, B., Marek, P., & Liebeskind, J.C. (1993). Sex differences in the antagonism of stress-induced analgesia: Effects of gonadectomy and estrogen replacement. Pain, 53, 17-25.
Moldin, S.O., Scheftner, W.A., Rice, J.P., Nelson, E., Knesevich, M.A., & Akiskal, H. (1993). Association between major depressive disorder and physical illness. Psychological Medicine, 23, 755-761.
Mountz, J.M., Bradley, L.A., Modell, J.G., Alexander, R.W., Triana-Alexander, M., Aaron, L.A., Stewart, K.E., Alarcon, G.S., & Mountz, J.D. (1995). Fibromyalgia in women: Abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis and Rheumatism, 38, 926-938.
Otto, M.W., & Dougher, M.J. (1985). Sex differences and personality factors in responsivity to pain. Perceptual and Motor Skills, 61, 383-390.
Rajala, U., Keinanen-Kiukaanniemi, S., Uusimaki, A., & Kivela, S.L. (1995). Musculoskeletal pains and depression in a middle-aged Finnish population. Pain, 61, 451-457.
Riley, J.L., Robinson, M.E., Wise, E.A., Myers, C.D., & Fillingim, R.B. (1998). Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain, 74, 181-187.
Robbins, A., Berkley, K.J., & Sato, Y. (1992). Estrous cycle variation of afferent fibers supplying reproductive organs in the female rat. Brain Research, 596, 353-356.
Robbins, A., Sato, Y., Hotta, H., & Berkley, K.J. (1990). Responses of hypogastric nerve afferent fibers to uterine distension in estrous or metestrous rats. Neuroscience Letters, 110, 82-85.
Robinson, M.E., Riley, J.L., Brown, F.F., & Gremillion, H. (1998). Sex differences in response to cutaneous anesthesia: A double blind randomized study. Pain, 77, 143-149.
Skovron, M.L., Szpalski, M., Nordin, M., Melot, C., & Cukier, D. (1994). Sociocultural factors and back pain: A population-based study in Belgian adults. Spine, 19, 129-137.
Smith, S.S. (1994). Female sex steroid hormones: From receptors to networks to performance-actions on the sensorimotor system. Progress in Neurobiology, 44, 55-86.
Smith, Y.R., Zubieta, J.K., del Carmen, M.G., Dannals, R.F., Ravert, H.T., Zacur, H.A., & Frost, J.J. (1998). Brain opioid receptor measurements by positron emission tomography in normal cycling women: Relationship to luteinizing hormone pulsatility and gonadal steroid hormones. Journal of Clinical Endocrinology and Metabolism, 83, 4498-4505.
Unruh, A.M. (1996). Gender variations in clinical pain experience. Pain, 65, 123-167.
Zelman, D.C., Howland, E.W., Nichols, S.N., & Cleeland, C.S. (1991). The effects of induced mood on laboratory pain. Pain, 46, 105-111.
Roger B. Fillingim is an assistant professor of psychology and orthodontics at the University of Alabama at Birmingham.