Sex and Gender in Adverse Drug Events, Addiction, and Placebo

  • Flavia Franconi
  • Ilaria Campesi
  • Stefano Occhioni
  • Paola Antonini
  • Michael F. Murphy
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 214)


Sex–gender-based differences in response to pharmaceutical treatments are still under evaluation but evidence already exists regarding the impact of sex–gender-related differences on drug safety profile, drug abuse/addiction, and placebo effects. For a number of drugs it is well recognized that a sex–gender dimorphic profile in terms of drug adverse effects exists and appears to be more frequent and severe in women than in men. However, it is not well known whether this is due to pharmacodynamic or pharmacokinetic differences. Indeed the optimization of therapy requires that attention is paid to single sex–gender. Numerous pharmacokinetic, pharmacodynamic, and sociocultural differences between women and men in drug abuse have been described. Here we focus on sex–gender differences in alcoholism and nicotine addiction. The relevance of sex and gender differences in addiction appear to be relevant. Specific programs aimed to address addicted women’s specific needs (child care, pregnancy, housing, and violence and others) are recommended. Finally, this article discusses the possible effect of sex–gender on placebo response in the light of the more significant recent literature evidencing that studies are urgently required in order to better understand the role of sex–gender on placebo mechanism and its impact on randomized clinical trials outcomes.


Adverse reactions Aging Sociocultural Addiction Stress Pregnancy Placebo Pain 



Sex–gender differences


Adverse drug events


Randomized controlled trials


Alcohol dehydrogenase


Oral contraceptives


Hormone replacement therapy



Supported by grants “La Medicina di Genere come Obiettivo Strategico per la Sanità Pubblica: l‘Appropriatezza della Cura per la Tutela della Salute della Donna from Ricerca Finalizzata Ministero della Salute” 2007 and by a grant of Legge Regionale 7 agosto 2007, no. 7: “Promozione della ricerca scientifica e dell’innovazione tecnologica in Sardegna.”


  1. Addis A, Moretti ME, Ahmed Syed F, Einarson TR, Koren G (2001) Fetal effects of cocaine: an updated meta-analysis. Reprod Toxicol 15:341–369CrossRefPubMedGoogle Scholar
  2. Ader R (1989) Conditioning effects in pharmacotherapy and the incompleteness of the double-blind, crossover design. Integr Psychiatry 69:165–170Google Scholar
  3. Ader R, Cohen N (1982) Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215:1534–1536CrossRefPubMedGoogle Scholar
  4. Ader R, Mercurio MG, Walton J, James D, Davis M, Ojha V, Kimball AB, Fiorentino D (2010) Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med 72:192–197CrossRefPubMedGoogle Scholar
  5. Alvestad S, Lydersen S, Brodtkorb E (2007) Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia 48:1360–1365CrossRefPubMedGoogle Scholar
  6. Anthony M, Berg MJ (2002a) Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I. J Womens Health Gend Based Med 11:601–615CrossRefPubMedGoogle Scholar
  7. Anthony M, Berg MJ (2002b) Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part II. J Womens Health Gend Based Med 11:617–629CrossRefPubMedGoogle Scholar
  8. Aslaksen PM, Flaten MA (2008) The roles of physiological and subjective stress in the effectiveness of a placebo on experimentally induced pain. Psychosom Med 70:811–818CrossRefPubMedGoogle Scholar
  9. Aslaksen PM, Bystad M, Vambheim SM, Flaten MA (2011) Gender differences in placebo analgesia: event-related potentials and emotional modulation. Psychosom Med 73:193–199CrossRefPubMedGoogle Scholar
  10. Averbuch M, Katzper M (2001) Gender and the placebo analgesic effect in acute pain. Clin Pharmacol Ther 70:287–291CrossRefPubMedGoogle Scholar
  11. Barsky AJ, Peekna HM, Borus JF (2001) Somatic symptom reporting in women and men. J Gen Intern Med 16:266–275CrossRefPubMedGoogle Scholar
  12. Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287:622–627CrossRefPubMedGoogle Scholar
  13. Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM (2007) Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med 120:880–885CrossRefPubMedGoogle Scholar
  14. Batterman RC (1965) Methodology of analgesic evaluation: experience with orphenadrine citrate compound. Curr Ther Res Clin Exp 7:639–647PubMedGoogle Scholar
  15. Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47CrossRefPubMedGoogle Scholar
  16. Beecher HK (1955) The powerful placebo. J Am Med Assoc 159:1602–1606CrossRefPubMedGoogle Scholar
  17. Benedetti F (2009) Placebo effects: understanding the mechanisms in health and disease. Oxford University Press, OxfordGoogle Scholar
  18. Benedetti F, Lanotte M, Lopiano L, Colloca L (2007) When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147:260–271CrossRefPubMedGoogle Scholar
  19. Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303CrossRefPubMedGoogle Scholar
  20. Berkley KJ, Zalcman SS, Simon VR (2006) Sex and gender differences in pain and inflammation: a rapidly maturing field. Am J Physiol Regul Integr Comp Physiol 291:R241–R244CrossRefPubMedGoogle Scholar
  21. Borchers AT, Keen CL, Gershwin ME (2007) Drug-induced lupus. Ann N Y Acad Sci 1108:166–182CrossRefPubMedGoogle Scholar
  22. Broome MV, Hurley RA, Taber KH (2010) Substance use disorders: do males and females have differential vulnerability? J Neuropsychiatry Clin Neurosci 22:4CrossRefGoogle Scholar
  23. Caamano F, Pedone C, Zuccala G, Carbonin P (2005) Socio-demographic factors related to the prevalence of adverse drug reaction at hospital admission in an elderly population. Arch Gerontol Geriatr 40:45–52CrossRefPubMedGoogle Scholar
  24. Ceylan-Isik AF, McBride SM, Ren J (2010) Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication? Life Sci 87:133–138CrossRefPubMedGoogle Scholar
  25. Chansky K, Benedetti J, Macdonald JS (2005) Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 103:1165–1171CrossRefPubMedGoogle Scholar
  26. Charron J, Rainville P, Marchand S (2006) Direct comparison of placebo effects on clinical and experimental pain. Clin J Pain 22:204–211CrossRefPubMedGoogle Scholar
  27. Cheng YC, Vyas A, Hymen E, Perlmuter LC (2011) Gender differences in orthostatic hypotension. Am J Med Sci 342:221–225CrossRefPubMedGoogle Scholar
  28. Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, Bradley JD, Bingham CO III, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ (2006) Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354:795–808CrossRefPubMedGoogle Scholar
  29. Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6:545–552CrossRefPubMedGoogle Scholar
  30. Curran GM, Stoltenberg SF, Hill EM, Mudd SA, Blow FC, Zucker RA (1999) Gender differences in the relationships among SES, family history of alcohol disorders and alcohol dependence. J Stud Alcohol 60:825–832PubMedGoogle Scholar
  31. Donovan MD (2005) Sex and racial differences in pharmacological response: effect of route of administration and drug delivery system on pharmacokinetics. J Womens Health (Larchmt) 14:30–37CrossRefGoogle Scholar
  32. Drici MD, Clement N (2001) Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 24:575–585CrossRefPubMedGoogle Scholar
  33. National Institute on Drug Abuse (1998) Nicotine addiction. In: 98-4342 Np (ed) Research report series. NIDA, Rockville, MDGoogle Scholar
  34. El-Khatib F, Rauchenzauner M, Lechleitner M, Hoppichler F, Naser A, Waldmann M, Trinka E, Unterberger I, Bauer G, Luef GJ (2007) Valproate, weight gain and carbohydrate craving: a gender study. Seizure 16:226–232CrossRefPubMedGoogle Scholar
  35. Ernst E (2007) Placebo: new insights into an old enigma. Drug Discov Today 12:413–418CrossRefPubMedGoogle Scholar
  36. Essebag V, Reynolds MR, Hadjis T, Lemery R, Olshansky B, Buxton AE, Josephson ME, Zimetbaum P (2007) Sex differences in the relationship between amiodarone use and the need for permanent pacing in patients with atrial fibrillation. Arch Intern Med 167:1648–1653CrossRefPubMedGoogle Scholar
  37. Evans SM, Foltin RW (2010) Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates? Horm Behav 58:13–21CrossRefPubMedGoogle Scholar
  38. Exton MS, von Horsten S, Schult M, Voge J, Strubel T, Donath S, Steinmuller C, Seeliger H, Nagel E, Westermann J, Schedlowski M (1998) Behaviorally conditioned immunosuppression using cyclosporine A: central nervous system reduces IL-2 production via splenic innervation. J Neuroimmunol 88:182–191CrossRefPubMedGoogle Scholar
  39. Fattore L, Altea S, Fratta W (2008) Sex differences in drug addiction: a review of animal and human studies. Womens Health (Lond Engl) 4:51–65CrossRefGoogle Scholar
  40. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd (2009) Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 10:447–485PubMedGoogle Scholar
  41. Flaten MA, Aslaksen PM, Finset A, Simonsen T, Johansen O (2006) Cognitive and emotional factors in placebo analgesia. J Psychosom Res 61:81–89CrossRefPubMedGoogle Scholar
  42. Fox HC, Sinha R (2009) Sex differences in drug-related stress-system changes: implications for treatment in substance-abusing women. Harv Rev Psychiatry 17:103–119CrossRefPubMedGoogle Scholar
  43. Franconi F, Brunelleschi S, Steardo L, Cuomo V (2007) Gender differences in drug responses. Pharmacol Res 55:81–95CrossRefPubMedGoogle Scholar
  44. Franconi F, Carru C, Malorni W, Vella S, Mercuro G (2011a) The effect of sex/gender on cardiovascular pharmacology. Curr Pharm Des 17:1095–1107PubMedGoogle Scholar
  45. Franconi F, Carru C, Spoletini I, Malorni W, Vella S, Mercuro G, Deidda M, Rosano G (2011) A GENS-based approach to cardiovascular pharmacology: impact on metabolism, pharmacokinetics and pharmacodynamics. Ther Deliv 2:1437–1453Google Scholar
  46. Frank E, Thase ME, Spanier CA, Reynolds CF III, Kupfer DJ (1999) Gender-specific response to depression treatment. J Gend Specif Med 2:40–44PubMedGoogle Scholar
  47. Frot M, Feine JS, Bushnell MC (2004) Sex differences in pain perception and anxiety. A psychophysical study with topical capsaicin. Pain 108:230–236CrossRefPubMedGoogle Scholar
  48. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523CrossRefPubMedGoogle Scholar
  49. Giang DW, Goodman AD, Schiffer RB, Mattson DH, Petrie M, Cohen N, Ader R (1996) Conditioning of cyclophosphamide-induced leukopenia in humans. J Neuropsychiatry Clin Neurosci 8:194–201PubMedGoogle Scholar
  50. Glaser R, Sheridan J, Malarkey WB, MacCallum RC, Kiecolt-Glaser JK (2000) Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med 62:804–807PubMedGoogle Scholar
  51. Gochfeld M (2007) Framework for gender differences in human and animal toxicology. Environ Res 104:4–21CrossRefPubMedGoogle Scholar
  52. Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowski M (2002) Behavioral conditioning of immunosuppression is possible in humans. FASEB J 16:1869–1873CrossRefPubMedGoogle Scholar
  53. Goffaux P, Léonard G, Marchand S, Rainville P (2010) Placebo analgesia, in: pharmacology of pain. IASP Press, Seattle, WAGoogle Scholar
  54. Gorczynski RM (1990) Conditioned enhancement of skin allografts in mice. Brain Behav Immun 4:85–92CrossRefPubMedGoogle Scholar
  55. Greenberg LM, Roth S (1966) Differential effects of abrupt versus gradual withdrawal of chlorpromazine in hospitalized chronic schizophrenic patients. Am J Psychiatry 123:221–226PubMedGoogle Scholar
  56. Greenfield SF, Back SE, Lawson K, Brady KT (2010) Substance abuse in women. Psychiatr Clin North Am 33:339–355CrossRefPubMedGoogle Scholar
  57. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ (2007) Studying sex and gender differences in pain and analgesia: a consensus report. Pain 132(Suppl 1):S26–S45CrossRefPubMedGoogle Scholar
  58. Grella CE (2008) From generic to gender-responsive treatment: changes in social policies, treatment services, and outcomes of women in substance abuse treatment. J Psychoactive Drugs Suppl 5: 327–343Google Scholar
  59. Gurwitz JH (2005) The age/gender interface in geriatric pharmacotherapy. J Womens Health (Larchmt) 14:68–72CrossRefGoogle Scholar
  60. Haltia LT, Rinne JO, Merisaari H, Maguire RP, Savontaus E, Helin S, Nagren K, Kaasinen V (2007) Effects of intravenous glucose on dopaminergic function in the human brain in vivo. Synapse 61:748–756CrossRefPubMedGoogle Scholar
  61. Haltia LT, Rinne JO, Helin S, Parkkola R, Nagren K, Kaasinen V (2008) Effects of intravenous placebo with glucose expectation on human basal ganglia dopaminergic function. Synapse 62:682–688CrossRefPubMedGoogle Scholar
  62. Han S, Fan Y, Mao L (2008) Gender difference in empathy for pain: an electrophysiological investigation. Brain Res 1196:85–93CrossRefPubMedGoogle Scholar
  63. Hauser W, Bartram-Wunn E, Bartram C, Reinecke H, Tolle T (2011) Systematic review: placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain 152:1709–1717CrossRefPubMedGoogle Scholar
  64. Howland RH (2008) Understanding the placebo effect. Part 1: placebo use in clinical trials. J Psychosoc Nurs Ment Heal Serv 46(5):17–20CrossRefGoogle Scholar
  65. Hudson A, Stamp JA (2011) Ovarian hormones and propensity to drug relapse: a review. Neurosci Biobehav Rev 35:427–436CrossRefPubMedGoogle Scholar
  66. Jaeger GT, Larsen S, Moe L (2005) Stratification, blinding and placebo effect in a randomized, double blind placebo-controlled clinical trial of gold bead implantation in dogs with hip dysplasia. Acta Vet Scand 46:57–68CrossRefPubMedGoogle Scholar
  67. Jensen MP, Karoly P (1991) Motivation and expectancy factors in symptom perception: a laboratory study of the placebo effect. Psychosom Med 53:144–152PubMedGoogle Scholar
  68. Jones RE, Moes N, Zwickey H, Cunningham CL, Gregory WL, Oken B (2008) Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning. Brain Behav Immun 22:538–543CrossRefPubMedGoogle Scholar
  69. Kallai I, Barke A, Voss U (2004) The effects of experimenter characteristics on pain reports in women and men. Pain 112:142–147CrossRefPubMedGoogle Scholar
  70. Kandel DB, Wu P, Davies M (1994) Maternal smoking during pregnancy and smoking by adolescent daughters. Am J Public Health 84:1407–1413CrossRefPubMedGoogle Scholar
  71. Kaptchuk TJ (1998) Powerful placebo: the dark side of the randomised controlled trial. Lancet 351:1722–1725CrossRefPubMedGoogle Scholar
  72. Kaptchuk TJ, Stason WB, Davis RB, Legedza AR, Schnyer RN, Kerr CE, Stone DA, Nam BH, Kirsch I, Goldman RH (2006) Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ 332:391–397CrossRefPubMedGoogle Scholar
  73. Kashuba AD, Nafziger AN (1998) Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 34:203–218CrossRefPubMedGoogle Scholar
  74. Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan J (1996) Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci U S A 93:3043–3047CrossRefPubMedGoogle Scholar
  75. Kim JS, Nafziger AN (2000) Is it sex or is it gender? Clin Pharmacol Ther 68:1–3CrossRefPubMedGoogle Scholar
  76. Kirsch I (2004) Conditioning, expectancy, and the placebo effect: comment on Stewart-Williams and Podd (2004). Psychol Bull 130:341–343, discussion 344–345CrossRefPubMedGoogle Scholar
  77. Klosterhalfen S, Enck P (2008) Neurophysiology and psychobiology of the placebo response. Curr Opin Psychiatry 21:189–195CrossRefPubMedGoogle Scholar
  78. Klosterhalfen W, Klosterhalfen S (1983) Pavlovian conditioning of immunosuppression modifies adjuvant arthritis in rats. Behav Neurosci 97:663–666CrossRefPubMedGoogle Scholar
  79. Komukai K, Mochizuki S, Yoshimura M (2010) Gender and the renin-angiotensin-aldosterone system. Fundam Clin Pharmacol 24:687–698CrossRefPubMedGoogle Scholar
  80. Koshi EB, Short CA (2007) Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract 7:4–20CrossRefPubMedGoogle Scholar
  81. Krahenbuhl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, Krahenbuhl S (2007) Drug-related problems in hospitals: a review of the recent literature. Drug Saf 30:379–407CrossRefPubMedGoogle Scholar
  82. Kurokawa J, Suzuki T, Furukawa T (2009) New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles: acute effects of female hormones on cardiac ion channels and cardiac repolarization. J Pharmacol Sci 109:334–340CrossRefPubMedGoogle Scholar
  83. Lajtha A, Sershen H (2010) Heterogeneity of reward mechanisms. Neurochem Res 35:851–867CrossRefPubMedGoogle Scholar
  84. Levine FM, De Simone LL (1991) The effects of experimenter gender on pain report in male and female subjects. Pain 44:69–72CrossRefPubMedGoogle Scholar
  85. Levy G (1998) What are narrow therapeutic index drugs? Clin Pharmacol Ther 63:501–505CrossRefPubMedGoogle Scholar
  86. Liamis G, Milionis H, Elisaf M (2008) A review of drug-induced hyponatremia. Am J Kidney Dis 52:144–153CrossRefPubMedGoogle Scholar
  87. Lynch WJ, Sofuoglu M (2010) Role of progesterone in nicotine addiction: evidence from initiation to relapse. Exp Clin Psychopharmacol 18:451–461CrossRefPubMedGoogle Scholar
  88. Malanga CJ, Kosofsky BE (2003) Does drug abuse beget drug abuse? Behavioral analysis of addiction liability in animal models of prenatal drug exposure. Brain Res Dev Brain Res 147:47–57CrossRefPubMedGoogle Scholar
  89. Mancini S, Amorotti E, Vecchio S, Ponz de Leon M, Roncucci L (2010) Infliximab-related hepatitis: discussion of a case and review of the literature. Intern Emerg Med 5:193–200CrossRefPubMedGoogle Scholar
  90. Mazziotti G, Canalis E, Giustina A (2010) Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 123:877–884CrossRefPubMedGoogle Scholar
  91. Substance Abuse and Mental Health Services Administration (2005)
  92. Miller FG, Colloca L, Kaptchuk TJ (2009) The placebo effect: illness and interpersonal healing. Perspect Biol Med 52:518–539CrossRefPubMedGoogle Scholar
  93. Moertel CG, Taylor WF, Roth A, Tyce FA (1976) Who responds to sugar pills? Mayo Clin Proc 51:96–100PubMedGoogle Scholar
  94. Niesters M, Dahan A, Kest B, Zacny J, Stijnen T, Aarts L, Sarton E (2010) Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain 151:61–68CrossRefPubMedGoogle Scholar
  95. Office of Strategic Planning Health Care Financing Administration (1998) The profile of Medicare chart book. U.S. Department of Health and Human ServicesGoogle Scholar
  96. Okuno J, Yanagi H, Tomura S (2001) Is cognitive impairment a risk factor for poor compliance among Japanese elderly in the community? Eur J Clin Pharmacol 57:589–594CrossRefPubMedGoogle Scholar
  97. Olness K, Ader R (1992) Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr 13:124–125CrossRefPubMedGoogle Scholar
  98. Olofsen E, Romberg R, Bijl H, Mooren R, Engbers F, Kest B, Dahan A (2005) Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain. Anesthesiology 103:130–139CrossRefPubMedGoogle Scholar
  99. Onder G, Landi F, Della Vedova C, Atkinson H, Pedone C, Cesari M, Bernabei R, Gambassi G (2002) Moderate alcohol consumption and adverse drug reactions among older adults. Pharmacoepidemiol Drug Saf 11:385–392CrossRefPubMedGoogle Scholar
  100. Onder G, Penninx BW, Landi F, Atkinson H, Cesari M, Bernabei R, Pahor M (2003) Depression and adverse drug reactions among hospitalized older adults. Arch Intern Med 163:301–305CrossRefPubMedGoogle Scholar
  101. Paller CJ, Campbell CM, Edwards RR, Dobs AS (2009) Sex-based differences in pain perception and treatment. Pain Med 10:289–299CrossRefPubMedGoogle Scholar
  102. Patel H, Bell D, Molokhia M, Srishanmuganathan J, Patel M, Car J, Majeed A (2007) Trends in hospital admissions for adverse drug reactions in England: analysis of national hospital episode statistics 1998-2005. BMC Clin Pharmacol 7:9CrossRefPubMedGoogle Scholar
  103. Paulson PE, Minoshima S, Morrow TJ, Casey KL (1998) Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 76:223–229CrossRefPubMedGoogle Scholar
  104. Pinnow E, Sharma P, Parekh A, Gevorkian N, Uhl K (2009) Increasing participation of women in early phase clinical trials approved by the FDA. Womens Health Issues 19:89–93CrossRefPubMedGoogle Scholar
  105. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329:15–19CrossRefPubMedGoogle Scholar
  106. Price DD, Finniss DG, Benedetti F (2008) A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59:565–590CrossRefPubMedGoogle Scholar
  107. Quinones-Jenab V, Jenab S (2010) Progesterone attenuates cocaine-induced responses. Horm Behav 58:22–32CrossRefPubMedGoogle Scholar
  108. Rademaker M (2001) Do women have more adverse drug reactions? Am J Clin Dermatol 2:349–351CrossRefPubMedGoogle Scholar
  109. Regitz-Zagrosek V (2006) Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 5:425–438CrossRefPubMedGoogle Scholar
  110. Rivero A, Curtis AB (2009) Sex differences in arrhythmias. Curr Opin Cardiol 25:8–15CrossRefGoogle Scholar
  111. Robinson ME, Riley JL III, Brown FF, Gremillion H (1998) Sex differences in response to cutaneous anesthesia: a double blind randomized study. Pain 77:143–149CrossRefPubMedGoogle Scholar
  112. Rodenburg EM, Stricker BH, Visser LE (2011) Sex-related differences in hospital admissions attributed to adverse drug reactions in the Netherlands. Br J Clin Pharmacol 71:95–104CrossRefPubMedGoogle Scholar
  113. Sanford SD, Kersh BC, Thorn BE, Rich MA, Ward LC (2002) Psychosocial mediators of sex differences in pain responsivity. J Pain 3:58–64CrossRefPubMedGoogle Scholar
  114. Sauro MD, Greenberg RP (2005) Endogenous opiates and the placebo effect: a meta-analytic review. J Psychosom Res 58:115–120CrossRefPubMedGoogle Scholar
  115. Saxon L, Hiltunen AJ, Hjemdahl P, Borg S (2001) Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study. Psychopharmacology (Berl) 153:231–237CrossRefGoogle Scholar
  116. Schwartz JB (2007) The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther 82:87–96CrossRefPubMedGoogle Scholar
  117. Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC (2009) The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J Neurosci 29:4882–4887CrossRefPubMedGoogle Scholar
  118. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2007) Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55:325–336CrossRefPubMedGoogle Scholar
  119. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008) Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65:220–231CrossRefPubMedGoogle Scholar
  120. Sikdar KC, Alaghehbandan R, MacDonald D, Barrett B, Collins KD, Donnan J, Gadag V (2010) Adverse drug events in adult patients leading to emergency department visits. Ann Pharmacother 44:641–649CrossRefPubMedGoogle Scholar
  121. Smith WB, Weisner C (2000) Women and alcohol problems: a critical analysis of the literature and unanswered questions. Alcohol Clin Exp Res 24:1320–1321CrossRefPubMedGoogle Scholar
  122. Soldin OP, Mattison DR (2009) Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48:143–157CrossRefPubMedGoogle Scholar
  123. Soldin OP, Chung SH, Mattison DR (2011) Sex differences in drug disposition. J Biomed Biotechnol 2011:187103CrossRefPubMedGoogle Scholar
  124. Stewart-Williams S, Podd J (2004) The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull 130:324–340CrossRefPubMedGoogle Scholar
  125. Stockhorst U, Mahl N, Krueger M, Huenig A, Schottenfeld-Naor Y, Huebinger A, Berresheim HW, Steingrueber HJ, Scherbaum WA (2004) Classical conditioning and conditionability of insulin and glucose effects in healthy humans. Physiol Behav 81:375–388CrossRefPubMedGoogle Scholar
  126. Suchman AL, Ader R (1992) Classic conditioning and placebo effects in crossover studies. Clin Pharmacol Ther 52:372–377CrossRefPubMedGoogle Scholar
  127. Sunshine A, Laska E, Meisner M, Morgan S (1964) Analgesic studies of indomethacin as analyzed by computer techniques. Clin Pharmacol Ther 5:699–707PubMedGoogle Scholar
  128. American Academy of pediatrics (2000) Committee on Substance Abuse and the Committee on Children with Disabilities. Fetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Pediatrics 106:358–361Google Scholar
  129. Toner JM, Ramsay LE (1984) Thiazide-induced hypokalaemia; prevalence higher in women. Br J Clin Pharmacol 18:449–452CrossRefPubMedGoogle Scholar
  130. Tricot L, Lebbe C, Pillebout E, Martinez F, Legendre C, Thervet E (2005) Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation 80:1546–1549CrossRefPubMedGoogle Scholar
  131. Unger A, Jung E, Winklbaur B, Fischer G (2010) Gender issues in the pharmacotherapy of opioid-addicted women: buprenorphine. J Addict Dis 29:217–230CrossRefPubMedGoogle Scholar
  132. van Leeuwen JH, Castro R, Busse M, Bemelmans BL (2006) The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol 50:440–452, discussion 453CrossRefPubMedGoogle Scholar
  133. Varvarigou AA, Asimakopoulou A, Beratis NG (2009) Impact of maternal smoking on birth size: effect of parity and sex dimorphism. Neonatology 95:61–67CrossRefPubMedGoogle Scholar
  134. Vedhara K, Cox NK, Wilcock GK, Perks P, Hunt M, Anderson S, Lightman SL, Shanks NM (1999) Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 353:627–631CrossRefPubMedGoogle Scholar
  135. Wager TD, Atlas LY, Leotti LA, Rilling JK (2011) Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci 31:439–452CrossRefPubMedGoogle Scholar
  136. White P, Lewith G, Hopwood V, Prescott P (2003) The placebo needle, is it a valid and convincing placebo for use in acupuncture trials? A randomised, single-blind, cross-over pilot trial. Pain 106:401–409CrossRefPubMedGoogle Scholar
  137. World Health Organization (2002) World health report-reducing risks, promoting healthy life. World Health Organization, GenevaGoogle Scholar
  138. Yang Y, Carlin AS, Faustino PJ, Motta MI, Hamad ML, He R, Watanuki Y, Pinnow EE, Khan MA (2009) Participation of women in clinical trials for new drugs approved by the food and drug administration in 2000-2002. J Womens Health (Larchmt) 18:303–310CrossRefGoogle Scholar
  139. Zender R, Olshansky E (2009) Women’s mental health: depression and anxiety. Nurs Clin North Am 44:355–364CrossRefPubMedGoogle Scholar
  140. Zopf Y, Rabe C, Neubert A, Gassmann KG, Rascher W, Hahn EG, Brune K, Dormann H (2008) Women encounter ADRs more often than do men. Eur J Clin Pharmacol 64:999–1004CrossRefPubMedGoogle Scholar
  141. Zubieta JK, Yau WY, Scott DJ, Stohler CS (2006) Belief or need? Accounting for individual variations in the neurochemistry of the placebo effect. Brain Behav Immun 20:15–26CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Flavia Franconi
    • 1
    • 2
  • Ilaria Campesi
    • 1
    • 2
  • Stefano Occhioni
    • 1
    • 2
  • Paola Antonini
    • 3
  • Michael F. Murphy
    • 3
  1. 1.Department of Biomedical SciencesUniversity of SassariSassariItaly
  2. 2.National Laboratory of Sex-Gender Medicine of the National Institute of Biostructures and BiosystemsOsiloItaly
  3. 3.Worldwide Clinical TrialsKing of PrussiaUSA

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