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Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U. Effect of Oxytocin on Placebo Analgesia: A Randomized Study. JAMA. 2013;310(16):1733–1735. doi:10.1001/jama.2013.277446
Placebo responses have been shown to contribute to clinical treatment outcomes.1 The pharmacological enhancement of placebo responses therefore has the potential to increase treatment benefits. The neuropeptide oxytocin may mediate processes such as empathy, trust, and social learning.2 These are key elements of the patient-physician relationship, which is an important mediator of placebo responses.3 We tested whether oxytocin enhances the placebo response in an experimental placebo analgesia model.
In January to September 2012, we recruited 80 healthy male volunteers at the University of Hamburg, Germany. Based on previous data, we expected this sample size to provide 80% power to detect an effect size of 0.35 with a 2-sided α of .05. Participants were randomly assigned to the double-blind administration of 40 IU of oxytocin or saline intranasally using a simple algorithm. After 45 minutes, placebo analgesia was assessed using an established paradigm. Two identical inert ointments were applied to 2 sites on each participant’s forearm, with the sites randomized across participants. The ointments were introduced by a male study physician using a script, described as an anesthetic that reduces pain (placebo) and an inert control cream (control). During the 15 minutes in which the anesthetic was believed to take effect, a calibration procedure was performed to identify the individual stimulation intensity at which a 20-second painful heat stimulus (Medoc-TSA-II; NeuroSensory Analyser) was perceived as a 60 on a visual analogue scale (VAS) (ranging from 0, no pain, to 100, unbearable pain). During the subsequent test phase, a series of 10 stimuli of the calibrated intensity was applied to each of the 2 sites in pseudorandomized order. Each stimulus lasted for 20 seconds, followed by a rating procedure and 40-second rest.
The primary outcome was the placebo analgesic response, defined as the reduction of perceived pain intensity on the placebo site compared with the control site in the oxytocin and saline groups. We also assessed the temperatures needed to induce a sensation of VAS score 60, physical and psychological adverse effects (using the multidimensional mood scale4 and an open response format), and participants’ treatment guess, to control for an effect of oxytocin on general pain sensitivity and blinding. Measures were analyzed using repeated-measures analysis of variance, 2-tailed 2-sample t tests, or χ2 test. Statistical threshold was set at P < .05. Statistical analyses were performed using PASW Statistics version 18.0 (IBM SPSS). The study was approved by the local ethics committee, and all participants provided written informed consent.
Data for 5 participants were excluded because of technical failure, leaving 75 participants (age, 20-38 years; oxytocin group, n = 37). Groups did not differ significantly with regard to age, weight, anxiety, or depression scores (Table 1). Despite identical thermal stimulation on both sites, pain ratings for the placebo site were significantly lower compared with the control site across both treatment groups (Table 2). The placebo analgesic response was significantly higher in the oxytocin group compared with the saline group (oxytocin group difference, 12.84 [95% CI, 8.67-17.01]; saline group difference, 7.08 [95% CI, 3.84-10.31]) (Table 2). Temperature levels needed to induce a sensation of VAS score 60, pain ratings on the control site, adverse effects, and post hoc treatment guesses did not differ significantly between groups (Table 2), consistent with oxytocin having no analgesic effect. The dose of oxytocin induced no significant adverse effects.
To our knowledge, our study provides the first experimental evidence that placebo responses can be pharmacologically enhanced by the application of intranasal oxytocin. This effect was not explained by a general effect of oxytocin on pain sensitivity. Such enhancement could be used to support—not replace—active treatments through placebo mechanisms. Based on its effects on trust and empathy, we hypothesize that oxytocin might have increased the believability of the instructions by the study physician. Furthermore, the potential of oxytocin to reduce stress and anxiety might have increased responsiveness to the placebo manipulation. Further studies are needed to replicate our findings in larger clinical populations, identify the underlying mechanisms, and explore moderating variables such as sex or aspects of patient-physician communication.
Corresponding Author: Ulrike Bingel, MD, Department of Neurology, University Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany (firstname.lastname@example.org).
Author Contributions: Dr Bingel had full access to all of the data obtained in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mr Kessner and Dr Sprenger contributed equally to this work.
Study concept and design: Sprenger, Wiech, Bingel.
Acquisition of data: Kessner, Sprenger.
Analysis and interpretation of data: Kessner, Sprenger, Wrobel, Wiech, Bingel.
Drafting of the manuscript: Kessner, Wiech, Bingel.
Critical revision of the manuscript for important intellectual content: Sprenger, Wrobel, Wiech, Bingel.
Statistical analysis: Kessner, Wrobel.
Obtained funding: Bingel.
Administrative, technical, or material support: Kessner, Sprenger.
Study supervision: Wiech, Bingel.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Wiech reported having received payment from various congresses for reimbursement of travel expenses. Dr Bingel reported having received payments for lectures about pain and placebo responses from Grunenthal and Bayer and having had a consultant contract about placebo and pain with the company Bionorica. No other disclosures were reported.
Funding/Support: This work (NCT01886014) was supported by grants from the German Research Foundation (FO-1328, BI 789/2-1) and the Federal Ministry of Education and Research (01GQ0808). Dr Wiech is Senior Research Fellow at the University of Bath and is funded by a University of Bath Prize Fellowship to the Centre for Pain Research.
Trial Registration: clinicaltrials.gov Identifier: NCT01886014
Additional Contributions: We thank Matthias Gamer, PhD, at the Department for Systems Neuroscience, Hamburg, for advice with the oxytocin intervention. He was not compensated for his contribution.
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