Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial

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

Upon arrival of screened participants, a baseline saliva sample was collected for cortisol determination. Then pain sensitivity was assessed to define the intensity (in mA) of electrical shocks to induce moderate pain. Afterwards, participants were instructed to self-administer intranasal oxytocin, vasopressin or placebo. A no-treatment group (nor drugs neither saline) was included to control for effects related to the mere administration of drugs. Forty minutes after the acute administration of one of the three agents or watchful waiting, the individual level of intensity necessary to induce moderate pain was re-tested. Then the placebo manipulation took place. A sham electrode was pasted on the middle finger of the non-dominant hand and participants were informed about the pain-relief procedure. During the testing phase, red and green lights were displayed for 5–7 seconds and followed by the electric shock (0.3 second delay) set at the current (mA) inducing moderate pain and scored as 6 on a Visual Analogue Scale (VAS) ranging from 0 (no pain) to 10 (most tolerable pain). The inter-trial interval (ITI) was 12.5 seconds. A total of 12 shocks (6 red+ 6 green) were delivered. t0= Baseline pain assessment. t1: Intranasal administration of vasopressin, oxytocin, saline or watchful waiting. t40: Post-drug pain sensitivity assessment. t42: Placebo manipulation. t45: Testing of placebo analgesia. t65: End of the placebo analgesia testing and saliva collection.

Figure 2. Impact of vasopressin on placebo effects

Arginine vasopressin increased placebo analgesia significantly relative to saline (p

Figure 3. Relation between vasopressin-induced effects and stress responses

Baseline levels of cortisol were not different in women and men (t(1,28)=−.0547, p=0.558). After vasopressin administration, cortisol levels decreased significantly in women (t(1,14)=2.646; p<0.019), but not in men (t(1,14)=1.279; p=0.222) (a). Lower cortisol levels correlated inversely with placebo analgesic effects (r=−0.500; p