Sex-based differences in pain perception and treatment.

OBJECTIVE This review highlights research on sex-based differences in pain perception and treatment. We sought to illuminate the complex factors contributing to differences in pain and analgesic responses between males and females, ranging from psychosocial to biological processes. DESIGN We reviewed published studies of pain induction by chemical, electric, heat, surgical, or psychological means, and opioid and nonopioid analgesia comparing responses in men and women. RESULTS A substantial body of research indicates that women experience greater clinical pain, suffer greater pain-related distress, and show heightened sensitivity to experimentally induced pain compared with men. Research on sex-based differences in the pain experience and treatment is beginning to uncover patterns that may enable tailoring of pain treatment to individual characteristics. The factors underpinning sex differences in the experience of pain are multifactorial and complex; for example, psychosocial factors such as pain-related catastrophizing may explain sex-based differences in reporting certain types of pain, as women tend to use catastrophizing to a greater degree. Gonadal hormone levels in cycling women also have a substantial impact on pain perception and analgesic response. Women perceive more pain during the luteal phase, and estrogen antagonists provide long-term pain relief in certain situations. CONCLUSIONS Collectively, greater understanding of the factors that commonly and differentially affect the disparity in pain perception, as well as analgesic response, are beginning to illuminate research targets and promising areas of therapeutic intervention for improved pain management.

[1]  R. de Leeuw,et al.  Influence of estrogen on brain activation during stimulation with painful heat. , 2006, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[2]  W. Maixner,et al.  Catastrophizing predicts changes in thermal pain responses after resolution of acute dental pain. , 2004, The journal of pain : official journal of the American Pain Society.

[3]  S. Weiss,et al.  Pain: Its Mediators and Associated Morbidity in Critically I11 Cardiovascular Surgical Patients , 1994, Nursing research.

[4]  Elissa J. Chesler,et al.  The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Fillingim,et al.  The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. , 2005, The journal of pain : official journal of the American Pain Society.

[6]  R. Cogan,et al.  Effects of laughter and relaxation on discomfort thresholds , 1987, Journal of Behavioral Medicine.

[7]  L. Arendt-Nielsen,et al.  Studying sex and gender differences in pain and analgesia: A consensus report , 2007, PAIN.

[8]  P. Micevych,et al.  Estrogen-Induced Alteration of μ-Opioid Receptor Immunoreactivity in the Medial Preoptic Nucleus and Medial Amygdala , 1998, The Journal of Neuroscience.

[9]  P. Leino,et al.  Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10-year follow-up of metal industry employees , 1993, Pain.

[10]  N. Çakır,et al.  The variation in chronic widespread pain and other symptoms in fibromyalgia patients. The effects of menses and menopause. , 2005, Clinical and experimental rheumatology.

[11]  Serge Marchand,et al.  Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms , 2002, Pain.

[12]  R. Fillingim Sex, gender, and pain: Women and men really are different , 2000, Current review of pain.

[13]  D. Price,et al.  Sex differences in common pain events: expectations and anchors. , 2003, The journal of pain : official journal of the American Pain Society.

[14]  R. Fillingim,et al.  Sex differences in the perception of noxious experimental stimuli: a meta-analysis , 1998, Pain.

[15]  J. Cantrill,et al.  Use of medication , 2007 .

[16]  Robert R. Edwards,et al.  Quantitative assessment of experimental pain perception: multiple domains of clinical relevance , 2005, Pain.

[17]  R. Goldberg,et al.  Relationship between traumatic events in childhood and chronic pain. , 1999, Disability and rehabilitation.

[18]  S. Dworkin,et al.  Changes in temporomandibular pain and other symptoms across the menstrual cycle , 2003, Pain.

[19]  D. Isacson,et al.  Epidemiology of analgesic use: a gender perspective , 2002, European journal of anaesthesiology. Supplement.

[20]  R. Craft,et al.  Sex differences in opioid antinociception: κ and ‘mixed action’ agonists , 2001 .

[21]  A. Dahan,et al.  Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop. , 2000, Anesthesiology.

[22]  W. Katon,et al.  Adult health status of women with histories of childhood abuse and neglect. , 1999, The American journal of medicine.

[23]  J. Riley,et al.  Altering gender role expectations: effects on pain tolerance, pain threshold, and pain ratings. , 2003, The journal of pain : official journal of the American Pain Society.

[24]  R. Steeds,et al.  Chronic Stable Angina : A Randomized , Double-Blind , Placebo-Controlled Study Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With , 2000 .

[25]  N. Mello,et al.  Opioid antinociception in ovariectomized monkeys: comparison with antinociception in males and effects of estradiol replacement. , 1999, The Journal of pharmacology and experimental therapeutics.

[26]  H. Evrard,et al.  Testosterone reduces responsiveness to nociceptive stimuli in a wild bird , 2004, Hormones and Behavior.

[27]  M. Averbuch,et al.  A search for sex differences in response to analgesia. , 2000, Archives of internal medicine.

[28]  A. Aloisi,et al.  Cross-sex hormone administration changes pain in transsexual women and men , 2007, PAIN.

[29]  Ranjan Maitra,et al.  Sex differences in the cerebral BOLD signal response to painful heat stimuli. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  N. Mello,et al.  Sex differences in opioid antinociception in rhesus monkeys: antagonism of fentanyl and U50,488 by quadazocine. , 2002, The journal of pain : official journal of the American Pain Society.

[31]  Kathleen B. Egan,et al.  The association between pain and disability , 2004, Pain.

[32]  C. France,et al.  A comparison of diffuse noxious inhibitory controls in men and women , 1999, Pain.

[33]  R. Fillingim,et al.  Sex differences in heat pain thresholds as a function of assessment method and rate of rise. , 1999, Somatosensory & motor research.

[34]  R. Craft,et al.  Sex differences in opioid antinociception: kappa and 'mixed action' agonists. , 2001, Drug and alcohol dependence.

[35]  P. Salmon,et al.  Childhood trauma and diurnal cortisol disruption in fibromyalgia syndrome , 2006, Psychoneuroendocrinology.

[36]  A. Ratka,et al.  Sex-specific differences in levels of morphine, morphine-3-glucuronide, and morphine antinociception in rats , 2002, Pain.

[37]  Serge Marchand,et al.  Odors modulate pain perception A gender-specific effect , 2002, Physiology & Behavior.

[38]  A. Dahan,et al.  Sex Differences in Morphine Analgesia: An Experimental Study in Healthy Volunteers , 2000, Anesthesiology.

[39]  D. Redelmeier,et al.  Medical illness and the risk of suicide in the elderly. , 2004, Archives of internal medicine.

[40]  D. Yarnitsky,et al.  Can personality traits and gender predict the response to morphine? An experimental cold pain study , 2006, European journal of pain.

[41]  D. Pfaff,et al.  Estrogen regulation of mu-opioid receptor mRNA in the forebrain of female rats. , 1997, Brain research. Molecular brain research.

[42]  Jean Stains,et al.  Sex differences in regional brain response to aversive pelvic visceral stimuli. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[43]  S. Sereika,et al.  Quality of Life in Prostate Cancer Patients Taking Androgen Deprivation Therapy , 2006, Journal of the American Geriatrics Society.

[44]  Robert A Koeppe,et al.  mu-opioid receptor-mediated antinociceptive responses differ in men and women. , 2002, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  J. Levine,et al.  Kappa–opioids produce significantly greater analgesia in women than in men , 1996, Nature Medicine.

[46]  Joshua A. Bueller,et al.  μ-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women , 2002, The Journal of Neuroscience.

[47]  E. Keogh,et al.  Gender, coping and the perception of pain , 2002, Pain.

[48]  J. Mogil,et al.  Sex differences in opioid analgesia , 1999 .

[49]  J. C. Bedran-de-Castro,et al.  Sex-related differences in the analgesic response to the rat tail immersion test. , 1994, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[50]  J. Levine,et al.  Gender difference in analgesic response to the kappa-opioid pentazocine , 1996, Neuroscience Letters.

[51]  A. Unruh Gender variations in clinical pain experience , 1996, Pain.

[52]  R. Przewłocki,et al.  Opioids in chronic pain. , 2001, European journal of pharmacology.

[53]  Thomas E. Nichols,et al.  Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women , 2006, The Journal of Neuroscience.

[54]  J. Levine,et al.  Enhancement of morphine analgesia by the GABAB agonist baclofen , 1995, Neuroscience.

[55]  D. Cooney,et al.  Increased Cutaneous Nerve Fibers in Female Specimens , 2005, Plastic and reconstructive surgery.

[56]  J. Bensing,et al.  Prevalence of chronic benign pain disorder among adults: a review of the literature , 1998, Pain.

[57]  D. Turk,et al.  Biopsychosocial perspective on chronic pain. , 1996 .

[58]  L. Leresche,et al.  Does experimental pain response vary across the menstrual cycle? A methodological review. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[59]  K. Kyvik,et al.  Sex differences in heritability of neck pain. , 2006, Twin research and human genetics : the official journal of the International Society for Twin Studies.

[60]  R. Fillingim,et al.  Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia. , 2005, The journal of pain : official journal of the American Pain Society.

[61]  J. Carmody,et al.  Experimental Pain in Healthy Human Subjects: Gender Differences in Nociception and in Response to Ibuprofen , 1998, Anesthesia and analgesia.

[62]  William J. Roberts Sex differences in pain: And now for something completely different , 1997, Behavioral and Brain Sciences.

[63]  W. Maixner,et al.  Cigarette smoking, stress-induced analgesia and pain perception in men and women , 2005, Pain.

[64]  R. Fillingim,et al.  Is Self-Reported Childhood Abuse History Associated With Pain Perception Among Healthy Young Women and Men? , 2005, The Clinical journal of pain.

[65]  A. Gintzler,et al.  Gestational and ovarian sex steroid antinociception: synergy between spinal κ and δ opioid systems , 1998, Brain Research.

[66]  F. Wolfe,et al.  Aspects of fibromyalgia in the general population: sex, pain threshold, and fibromyalgia symptoms. , 1995, The Journal of rheumatology.

[67]  J. Hyde,et al.  Gender differences in cortical representation of rectal distension in healthy humans. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[68]  L. Arendt-Nielsen,et al.  Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain , 2004, Pain.

[69]  J. García-Sevilla,et al.  Increased density of μ-opioid receptors in the postmortem brain of suicide victims , 1995, Brain Research.

[70]  M. Tarnopolsky,et al.  No effect of short-term 17beta-estradiol supplementation in healthy men on systemic inflammatory responses to exercise. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[71]  J. van Buyten,et al.  Endocrine consequences of long-term intrathecal administration of opioids. , 2000, The Journal of clinical endocrinology and metabolism.

[72]  E. Keogh,et al.  Sex differences in adolescent chronic pain and pain-related coping , 2006, PAIN.

[73]  J. Riley,et al.  A meta-analytic review of pain perception across the menstrual cycle , 1999, Pain.

[74]  I. Navrozoglou,et al.  Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. , 1997, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[75]  M. Picker,et al.  Sex and rat strain determine sensitivity to κ opioid-induced antinociception , 2002, Psychopharmacology.

[76]  J. Prochaska,et al.  Understanding the adoption of arthritis self-management: stages of change profiles among arthritis patients , 2000, Pain.

[77]  S. Dworkin,et al.  Use of exogenous hormones and risk of temporomandibular disorder pain , 1997, Pain.

[78]  A. Stubhaug,et al.  Gender is a confounding factor in pain trials: women report more pain than men after arthroscopic surgery , 2004, Pain.

[79]  Sex differences in pain anchors revisited: further investigation of “most intense” and common pain events ⋆ , 2004, European journal of pain.

[80]  P. Sullivan,et al.  Importance of genetic influences on chronic widespread pain. , 2006, Arthritis and rheumatism.

[81]  E. Carstens,et al.  Rat tail flick reflex: magnitude measurement of stimulus-response function, suppression by morphine and habituation. , 1993, Journal of neurophysiology.

[82]  C. Vierck,et al.  Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients , 2003, Pain.

[83]  J. Levine,et al.  The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain , 1999, PAIN.

[84]  P. Sorum,et al.  Do gender and race affect decisions about pain management? , 2001, Journal of General Internal Medicine.

[85]  F. Pierelli,et al.  Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans , 2004, Pain.

[86]  A. Aloisi,et al.  Sex differences in pain and analgesia: the role of gonadal hormones , 2004, European journal of pain.

[87]  John N. Wood,et al.  Pain Genes , 2008, PLoS genetics.

[88]  G. Coukos,et al.  Efficacy of hormone replacement therapy in postmenopausal women with oral discomfort. , 1992, Oral surgery, oral medicine, and oral pathology.

[89]  E. Johansson,et al.  Gender bias in physicians' management of neck pain: a study of the answers in a Swedish national examination. , 2002, Journal of women's health & gender-based medicine.

[90]  M. Picker,et al.  Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor , 2000, Psychopharmacology.

[91]  J. Zubieta,et al.  Gender and age influences on human brain mu-opioid receptor binding measured by PET. , 1999, The American journal of psychiatry.

[92]  A. Field,et al.  A Systematic Review of Psychological Factors as Predictors of Chronicity/Disability in Prospective Cohorts of Low Back Pain , 2002, Spine.

[93]  A. Basbaum,et al.  Pain genes?: natural variation and transgenic mutants. , 2000, Annual review of neuroscience.

[94]  P. Cahusac,et al.  Decreased sensitivity to self-inflicted pain , 2006, Pain.

[95]  D Finkelhor,et al.  Sexual abuse in a national survey of adult men and women: prevalence, characteristics, and risk factors. , 1990, Child abuse & neglect.

[96]  Wolfgang Ellermeier,et al.  Gender differences in pain ratings and pupil reactions to painful pressure stimuli , 1995, Pain.

[97]  A. Dahan,et al.  Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop , 1999 .

[98]  Janet Kaye Heins,et al.  Disparities in analgesia and opioid prescribing practices for patients with musculoskeletal pain in the emergency department. , 2006, Journal of emergency nursing: JEN : official publication of the Emergency Department Nurses Association.

[99]  M. Picker,et al.  Sex and rat strain determine sensitivity to kappa opioid-induced antinociception. , 2002, Psychopharmacology.

[100]  Lin Chang,et al.  Sex-related differences in IBS patients: central processing of visceral stimuli. , 2003, Gastroenterology.

[101]  O. Vassend,et al.  Individual differences in pain sensitivity: Genetic and environmental contributions , 2008, PAIN.

[102]  R. Craft Sex Differences in Opioid Analgesia: “From Mouse to Man” , 2003, The Clinical journal of pain.

[103]  Tzipora Kuba,et al.  The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: Clinical versus preclinical studies , 2005, Brain Research Bulletin.

[104]  R. Edwards,et al.  Pain-related Catastrophizing in Healthy Women Is Associated With Greater Temporal Summation of and Reduced Habituation to Thermal Pain , 2006, The Clinical journal of pain.

[105]  L. Arendt-Nielsen,et al.  Antenatal women with or without pelvic pain can be characterized by generalized or segmental hypoalgesia in late pregnancy. , 2002, The journal of pain : official journal of the American Pain Society.