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      A systematic review of sex differences in the placebo and the nocebo effect

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          The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect.


          A literature search was conducted in multiple electronic databases. Studies were included if the study compared a group or condition where a placebo was administered to a natural history group or similar cohort.


          Eighteen studies were identified – 12 on placebo effects and 6 on nocebo effects. Chi-square tests revealed that 1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment, and 2) males responded with larger placebo effects induced by verbal information, and females responded with larger nocebo effects induced by conditioning procedures.


          This review indicates that there are sex differences in the placebo and nocebo effects, probably caused by sex differences in stress, anxiety, and the endogenous opioid system.

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          Most cited references 42

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          Sex differences in the perception of noxious experimental stimuli: a meta-analysis.

          Fillingim and Maixner (Fillingim, R.B. and Maixner, W., Pain Forum, 4(4) (1995) 209-221) recently reviewed the body of literature examining possible sex differences in responses to experimentally induced noxious stimulation. Using a 'box score' methodology, they concluded the literature supports sex differences in response to noxious stimuli, with females displaying greater sensitivity. However, Berkley (Berkley, K.J., Pain Forum, 4(4) (1995) 225-227) suggested the failure of a number of studies to reach statistical significance suggests the effect may be small and of little practical significance. This study used meta-analytic methodology to provide quantitative evidence to address the question of the magnitude of these sex differences in response to experimentally induced pain. We found the effect size to range from large to moderate, depending on whether threshold or tolerance were measured and which method of stimulus administration was used. The values for pressure pain and electrical stimulation, for both threshold and tolerance measures, were the largest. For studies employing a threshold measure, the effect for thermal pain was smaller and more variable. The failures to reject the null hypothesis in a number of these studies appear to have been a function of lack of power from an insufficient number of subjects. Given the estimated effect size of 0.55 threshold or 0.57 for tolerance, 41 subjects per group are necessary to provide adequate power (0.70) to test for this difference. Of the 34 studies reviewed by Fillingim and Maixner, only seven were conducted with groups of this magnitude. The results of this study compels to caution authors to obtain adequate sample sizes and hope that this meta-analytic review can aid in the determination of sample size for future studies.
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            Stress-induced analgesia.

            For over 30 years, scientists have been investigating the phenomenon of pain suppression upon exposure to unconditioned or conditioned stressful stimuli, commonly known as stress-induced analgesia. These studies have revealed that individual sensitivity to stress-induced analgesia can vary greatly and that this sensitivity is coupled to many different phenotypes including the degree of opioid sensitivity and startle response. Furthermore, stress-induced analgesia is influenced by age, gender, and prior experience to stressful, painful, or other environmental stimuli. Stress-induced analgesia is mediated by activation of the descending inhibitory pain pathway. Pharmacological and neurochemical studies have demonstrated involvement of a large number of neurotransmitters and neuropeptides. In particular, there are key roles for the endogenous opioid, monoamine, cannabinoid, gamma-aminobutyric acid and glutamate systems. The study of stress-induced analgesia has enhanced our understanding of the fundamental physiology of pain and stress and can be a useful approach for uncovering new therapeutic targets for the treatment of pain and stress-related disorders.
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              Sex differences in musculoskeletal pain.

              Epidemiologic, clinical, and experimental evidence points to sex differences in musculoskeletal pain. Adult women more often have musculoskeletal problems than do men. Discrepant findings regarding the presence of such differences during childhood and adolescence continue. Biologic and psychosocial factors might account for these differences. The authors review evidence showing that mechanically induced pressure is more likely to show sex differences than other noxious stimuli and to discriminate between individuals suffering from musculoskeletal pain and matched controls. The authors suggest that a state of increased pain sensitivity, with a peripheral or central origin, predisposes individuals to chronic muscle pain conditions, and that there are sex differences in the operation of these mechanisms; women are vulnerable to the development and maintenance of musculoskeletal pain conditions.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                31 July 2017
                : 10
                : 1831-1839
                [1 ]Department of Psychology, UiT, The Arctic University of Norway, Tromsø
                [2 ]Department of Psychology, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
                Author notes
                Correspondence: Sara M Vambheim, Department of Psychology, UiT, The Arctic University of Norway, N-9037 Tromsø, Norway, Tel +47 975 69 020, Email sara.m.vambheim@ 123456uit.no
                © 2017 Vambheim and Flaten. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.



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