Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial
Luana Colloca, Daniel S Pine, Monique Ernst, Franklin G Miller, Christian Grillon, Luana Colloca, Daniel S Pine, Monique Ernst, Franklin G Miller, Christian Grillon
Abstract
Background: Social cues and interpersonal interactions strongly contribute to evoke placebo effects that are pervasive in medicine and depend upon the activation of endogenous modulatory systems. Here, we explore the possibility to boost placebo effects by targeting pharmacologically the vasopressin system, characterized by a sexually dimorphic response and involved in the regulation of human and nonhuman social behaviors.
Methods: We enrolled 109 healthy participants and studied the effects of intranasal administration of an arginine vasopressin 1A and 1B receptor agonist against 1) no treatment, 2) oxytocin, and 3) saline in a randomized, placebo-controlled, double-blind, parallel design trial using a well-established model of placebo analgesia while controlling for sex differences.
Results: Vasopressin agonists boosted placebo effects in women but had no effect in men. The effects of vasopressin on expectancy-induced analgesia were significantly larger than those observed in the no-treatment (p < .004), oxytocin (p < .001), and saline (p < .015) groups. Moreover, women with lower dispositional anxiety and cortisol levels showed the largest vasopressin-induced modulation of placebo effects, suggesting a moderating interplay between pre-existing psychological factors and treatment cortisol changes.
Conclusions: This is the first study that demonstrates that arginine vasopressin boosts placebo effects and that the effect of vasopressin depends upon a significant sex by treatment interaction. These findings are novel and might open up new avenues for clinically relevant research due to the therapeutic potentials of vasopressin as well as the possibility to systematically control for influences of placebo responses in clinical trials.
Keywords: Anxiety; Expectancy; Pain; Sexual dimorphism; Stress; Verbal suggestions.
Conflict of interest statement
Conflict of Interest Disclosures
All other authors reported no biomedical financial interests or potential conflicts of interest.
Copyright © 2016 Society of Biological Psychiatry. All rights reserved.
Figures
![Figure 1. Study outline](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4740270/bin/nihms713176f1.jpg)
![Figure 2. Impact of vasopressin on placebo…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4740270/bin/nihms713176f2.jpg)
Figure 3. Relation between vasopressin-induced effects and…
Figure 3. Relation between vasopressin-induced effects and stress responses
Baseline levels of cortisol were not…
- Sex, Drugs, and the Neurobiology of the Placebo Effect.Rubinow DR. Rubinow DR. Biol Psychiatry. 2016 May 15;79(10):788-789. doi: 10.1016/j.biopsych.2016.03.1051. Biol Psychiatry. 2016. PMID: 27130850 No abstract available.
- Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction.Rilling JK, DeMarco AC, Hackett PD, Chen X, Gautam P, Stair S, Haroon E, Thompson R, Ditzen B, Patel R, Pagnoni G. Rilling JK, et al. Psychoneuroendocrinology. 2014 Jan;39:237-248. doi: 10.1016/j.psyneuen.2013.09.022. Epub 2013 Sep 27. Psychoneuroendocrinology. 2014. PMID: 24157401 Free PMC article. Clinical Trial.
- Sex-specific effects of intranasal oxytocin on thermal pain perception: A randomised, double-blind, placebo-controlled cross-over study.Tracy LM, Labuschagne I, Georgiou-Karistianis N, Gibson SJ, Giummarra MJ. Tracy LM, et al. Psychoneuroendocrinology. 2017 Sep;83:101-110. doi: 10.1016/j.psyneuen.2017.05.028. Epub 2017 Jun 3. Psychoneuroendocrinology. 2017. PMID: 28601750 Clinical Trial.
- Effect of oxytocin on placebo analgesia: a randomized study.Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U. Kessner S, et al. JAMA. 2013 Oct 23;310(16):1733-5. doi: 10.1001/jama.2013.277446. JAMA. 2013. PMID: 24150470 Clinical Trial. No abstract available.
- Consequences of early experiences and exposure to oxytocin and vasopressin are sexually dimorphic.Carter CS, Boone EM, Pournajafi-Nazarloo H, Bales KL. Carter CS, et al. Dev Neurosci. 2009;31(4):332-41. doi: 10.1159/000216544. Epub 2009 Jun 17. Dev Neurosci. 2009. PMID: 19546570 Free PMC article. Review.
- A meta-analytic review of the impact of intranasal oxytocin administration on cortisol concentrations during laboratory tasks: moderation by method and mental health.Cardoso C, Kingdon D, Ellenbogen MA. Cardoso C, et al. Psychoneuroendocrinology. 2014 Nov;49:161-70. doi: 10.1016/j.psyneuen.2014.07.014. Epub 2014 Jul 22. Psychoneuroendocrinology. 2014. PMID: 25086828 Review.
- Placebo and nocebo effects: from observation to harnessing and clinical application.Tu Y, Zhang L, Kong J. Tu Y, et al. Transl Psychiatry. 2022 Dec 24;12(1):524. doi: 10.1038/s41398-022-02293-2. Transl Psychiatry. 2022. PMID: 36564374 Free PMC article. Review.
- Positive, but not negative, treatment outcome expectancies mediate the relation between depressive symptoms and treatment-related pain reduction.Paré C, Thibault P, Carriere JS, Sullivan MJL. Paré C, et al. J Behav Med. 2022 Nov 28. doi: 10.1007/s10865-022-00380-9. Online ahead of print. J Behav Med. 2022. PMID: 36441487
- The Heart as a Target of Vasopressin and Other Cardiovascular Peptides in Health and Cardiovascular Diseases.Szczepanska-Sadowska E. Szczepanska-Sadowska E. Int J Mol Sci. 2022 Nov 20;23(22):14414. doi: 10.3390/ijms232214414. Int J Mol Sci. 2022. PMID: 36430892 Free PMC article. Review.
- Placebo, nocebo: Believing in the field of medicine.Meissner K. Meissner K. Front Pain Res (Lausanne). 2022 Jul 29;3:972169. doi: 10.3389/fpain.2022.972169. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 35965595 Free PMC article. No abstract available.
- Placebo administration for dry eye disease: a level I evidence based systematic review and meta-analysis.Prinz J, Maffulli N, Fuest M, Walter P, Hildebrand F, Migliorini F. Prinz J, et al. Int J Clin Pharm. 2022 Oct;44(5):1087-1101. doi: 10.1007/s11096-022-01439-y. Epub 2022 Aug 8. Int J Clin Pharm. 2022. PMID: 35939178 Free PMC article. Review.
- Randomized Controlled Trial
- Administration, Intranasal
- Adult
- Analgesics, Non-Narcotic / administration & dosage*
- Anxiety / metabolism
- Arginine Vasopressin / administration & dosage*
- Double-Blind Method
- Female
- Humans
- Hydrocortisone / metabolism
- Male
- Middle Aged
- Oxytocin / administration & dosage*
- Pain / drug therapy*
- Pain / metabolism
- Pain / psychology*
- Pain Perception / drug effects*
- Pain Perception / physiology
- Placebo Effect
- Receptors, Vasopressin / agonists*
- Receptors, Vasopressin / metabolism
- Sex Characteristics
- Young Adult
- Analgesics, Non-Narcotic
- Receptors, Vasopressin
- Arginine Vasopressin
- Oxytocin
- Hydrocortisone
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3. Relation between vasopressin-induced effects and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4740270/bin/nihms713176f3.jpg)
Source: PubMed