Sharing information about the nature of a treatment boosted the beneficial effects of both active treatment and placebo in a prospective study of episodic migraine patients who received treatments with a pill that was truthfully, equivocally, or untruthfully labeled across a series of migraine episodes.
The ritual of pill taking also appeared to be an important component of care, Dr. Slavenka Kam-Hansen of the department of neurology at Beth Israel Deaconess Medical Center, Boston, and her colleagues reported Jan. 8 in Science Translational Medicine.
The investigators determined that open-label placebo treatment may have important therapeutic benefits because it induced pain relief when compared with the worsening of pain during the untreated migraine attacks. Similar findings were reported from a recent study of patients with irritable bowel syndrome and from another study in patients with depression. The findings also are supported by a prior between-subjects study in thoracotomy patients in which active and placebo treatments were labeled truthfully, equivocally, or untruthfully, suggesting that medication and information may be equally critical for pain relief, they said.
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The placebo effect may have unheralded benefits in the treatment of episodic migraine patients.
To test the hypothesis that placebo and medication treatment-related outcomes would improve progressively as the information provided to subjects varied from negative (indicating 0% chance of receiving active medication) to uncertain (indicating a 50% chance of receiving active medication) to positive (indicating 100% chance of receiving active medication), the investigators randomly assigned 66 adult subjects aged 18 years and older who had experienced episodic migraine in the past 3 years to receive placebo or active treatment with 10 mg of rizatriptan (Maxalt-MLT) during six migraine attacks.
Each subject received placebo three times and Maxalt three times, each labeled once as "placebo," once as "Maxalt," and once as "Maxalt or placebo." An untreated seventh baseline migraine served as a control condition.
Both treatment type and labeling information had statistically significant effects on the primary endpoint of the study, which was the percentage change in self-reported headache pain score on a 0-10 scale (no pain to maximal pain) from 30 minutes after onset to 2 hours later. The types of treatment and labeling did not show any significant interaction, the investigators reported (Sci. Transl. Med. 2014;6:218ra5).
Across labels, they found that "placebo" labeling resulted in a typical decrease in pain score of 26.1%, "Maxalt or placebo" labeling gave a 40.1% decline, and "Maxalt" labeling yielded a 39.5% decrease. Across treatments, "the typical decrease in pain score was 47.6% for Maxalt treatment versus 20.7% for placebo treatment," Dr. Kam-Hansen and her associates wrote.
A secondary analysis showed that, even when placebo was identified as such, pain scores typically decreased by 14.5%. "This contrasted significantly with the untreated attacks, during which pain scores typically rose by 15.4%," they noted.
Furthermore, "relative to the no-treatment condition, the effect of placebo under ‘placebo’ labeling was 60.0% as large as the corresponding effect of Maxalt treatment. Similarly, the placebo effect was 59.8% as large as the Maxalt effect under ‘Maxalt’ labeling and 55.3% as large under ‘Maxalt or placebo’ labeling," they explained.
Additionally, the efficacy of Maxalt mislabeled as placebo was similar to that of placebo mislabeled as Maxalt (pain score decreases of 36.1% and 24.6%, respectively).
Dr. Kam-Hansen and her associates not only concluded that open-label placebo treatment may have important therapeutic benefits but also suggested that expectancy can modulate placebo and medication effects. Because the actual expectancies were not assessed, however, they cannot be certain that the manipulation "worked through changes in conscious or nonconscious expectations due to the information provided."
Also, because the study involved deception, its applicability to routine clinical care is limited and the findings thus serve as proof of concept. "It would be important to expand our findings with experimental manipulation of expectancy considered ethical in clinical practice," they said, adding that further research regarding the application of these findings to clinical practice and research design is warranted.
This study was funded by Merck, which manufacturers Maxalt-MLT. Dr. Kam-Hansen reported having no disclosures. Coauthor Dr. Rami Burstein disclosed ties with Allergan and Merck and grant support from the National Institutes of Health.