Intranasal Oxytocin Enhances Placebo Response

Pauline Anderson

October 24, 2013

Researchers have provided experimental evidence that intranasal administration of the neuropeptide oxytocin can enhance placebo responses.

The results add important insights into mechanisms explaining placebo responses related to pain, according to study author Ulrike Bingel, consultant of neurology and head of a research group on pain and cognition, University Medical Center, Hamburg-Eppendorf, Germany, who is now professor, Clinic for Neurology at the Medical Faculty, University of Duisburg-Essen, Germany.

The research is published in the October 23 issue of JAMA.

No Analgesic Effect

The study included healthy male volunteers randomly assigned to the double-blind intranasal administration of 40 IU of oxytocin or saline. The groups didn't differ significantly with respect to weight, age, or scores for anxiety and depression.

Researchers then applied 2 identical inert ointments to 2 sites on each participant's forearm, with the sites randomized across participants. Using a script, a male study physician described the ointment as a painkiller (placebo) and an inert control cream (control).

Next, investigators performed a calibration procedure to identify the intensity at which a heat stimulus was perceived by each participant as a 60 on a visual analogue scale (VAS) that ranges from 0 (no pain) to 100 (unbearable pain). They applied a series of 10 stimuli of the calibrated intensity to each of the 2 sites in a pseudo-randomized order, with each stimulus lasting 20 seconds, followed by a rating procedure and a 40-second rest.

The analysis, which included 75 participants, showed that despite identical thermal stimulation on both sites, pain ratings for the placebo site were significantly lower than those for the control site across both treatment groups (oxytocin and saline).

The placebo analgesic response was significantly higher in the oxytocin group compared with the saline group. The oxytocin group difference (control-placebo) was12.84 (95% confidence interval [CI], 8.67 - 17.01) whereas the saline group difference was 7.08 (95% CI, 3.84 - 10.31).

Temperature levels needed to induce a sensation of VAS score of 60, pain ratings on the control site, physical and psychological adverse effects, and post hoc guesses from participants as to whether they were in the oxytocin or saline group did not differ significantly between groups. This, said Dr. Bingel, is consistent with oxytocin having no analgesic effect.

Potential Mechanism

Because oxytocin may mediate empathy, trust, and social learning, the authors hypothesize that it might have increased the believability of the instruction given by the study physician.

The results seem to indicate that oxytocin increases the odds that a patient will believe a doctor's claim that an ointment is an analgesic, added Dr. Bingel.

In addition to information provided by a physician, the nature of the physician-patient relationship may also affect a patient's treatment expectations. A patient's medical history might be another factor moderating the placebo response, said Dr. Bingel.

The potential of oxytocin to reduce stress and anxiety might also increase responsiveness to the placebo manipulation, said the authors.

Additional studies are needed to replicate the findings and to identify the underlying mechanisms, said the authors. However, in a previous article (Nature Rev Drug Discov. 2013;12:191-204), Dr. Bingel and colleagues suggest that underlying mechanisms of placebo responses related to pain may include activation of endogenous opioids and dopamine, activation of cannabinoid receptors, and genetic variants of catechol-O-methyltransferase, an enzyme that metabolizes other neurotransmitters such as dopamine and indirectly affects opioids.

According to that article, placebo analgesia is mediated by changes in the neural activity in the dorsolateral prefrontal cortex, the anterior cingulate cortex, the amygdala, and the periaqueductal grey.

Maximizing and personalizing the placebo response may help identify and develop better drugs, choose the best dosage of a therapy, find the best targeted treatment for a specific clinical condition, and optimize adherence.

Fascinating Study

Commenting for Medscape Medical News, Lynn R. Webster, MD, president, American Academy of Pain Medicine, and medical director, CRI Lifetree, Salt Lake City, Utah, described the study as "fascinating."

"The paper supports what is well known in the field — that affect influences pain perception," said Dr. Webster.

"The most important quality of a physician is to have compassion and empathy for their patients. This is particularly true for people in pain which is a biopsychosocial disease."

The study also illustrates why the placebo response is so pronounced in people with pain, most of whom are desperately seeking physiologic and psychological relief, added Dr. Webster. "A clinical trial is perceived as hope for people in chronic pain. Naturally this would yield a placebo response."

Dr. Bingel has received payments for lectures about pain and placebo responses from Grunenthal and Bayer and has had a consultant contract about placebo and pain with Bionorica.

JAMA. 2013;310:1733-1735. Abstract

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