STOWE, VERMONT—Manipulating the information provided to patients with migraine can reduce, but not increase, the difference in efficacy between drug and placebo, according to research presented at the Headache Cooperative of New England’s 24th Annual Headache Symposium. Patients who take an active drug that is labeled as a placebo have less pain relief than patients who take a correctly labeled active drug, said Rami Burstein, PhD. The efficacy of an active drug labeled as a placebo may be no better than that of a placebo mislabeled as an active drug.
Physicians tend to set expectations for treatment outcome according to the patient’s personality, even if they do not intend to do so, said Dr. Burstein, John Hedley-Whyte Professor of Anesthesia and Neuroscience at Beth Israel Deaconess Medical Center in Boston. They may set low expectations if the patient may react poorly to treatment failure, or raise expectations if the patient may take treatment failure in stride. The study results suggest that “raising the anticipation of pain relief is essential for successful triptan therapy for migraine,” said Dr. Burstein.
Patients Received Incorrectly Labeled Treatments
The goal of the investigation was to test whether clinicians can increase a medicine’s therapeutic gain: the difference between the effectiveness of the drug and that of placebo. Dr. Burstein’s theory was that eliminating the placebo effect would increase therapeutic gain. He chose to use rizatriptan in the investigation.
Dr. Burstein and his colleagues enrolled 76 patients who had had episodic migraine attacks for the previous three years to participate in the study. Individuals with chronic daily headache, tension-type headache, chronic pain, opioid use, uncontrolled hypertension, and cardiovascular disorders were excluded from the study. Of the 76 participants enrolled, 66 continued with the study as planned.
The investigators told patients that they would follow seven of their migraine attacks, the first of which would be untreated. For two of the attacks, participants would receive rizatriptan or placebo but be blinded to their treatment, said the investigators. Participants would receive open treatment, either rizatriptan or placebo, for the remaining four attacks.
In reality, the information provided to the participants was unreliable. For each attack, patients received an envelope labeled “placebo,” “rizatriptan,” or “uncertain.” But each patient received one envelope labeled “placebo” that actually contained rizatriptan and one envelope labeled “rizatriptan” that actually contained placebo. The other envelopes were labeled correctly.
Although the trial design involved deceiving the participants, Dr. Burstein’s group argued that it entailed minimal additional risk and did not adversely affect participants’ rights and welfare. The importance of the question at issue justified the study design, they added. An ethics committee at the NIH reviewed the study design, and the institutional review board ultimately granted permission.
Patients waited 30 minutes after the beginning of each attack, recorded their pain scores, and took their treatments. Patients recorded pain scores again two hours after treatment. The study’s primary outcome was pain relief, and the secondary outcome was pain freedom. The investigators analyzed the data according to the FDA’s guidelines for phase III clinical trials.
Labeling Affected Rates of Pain Relief and Pain Freedom
Patients’ pain scores increased by approximately 15% from 30 minutes to 2.5 hours after the onset of the untreated attack. Overall, pain relief was greater with rizatriptan than with placebo. Pain scores decreased by an average of 20.9% after treatment with placebo, compared with 46.4% after treatment with rizatriptan. Average pain relief was 26.9% for treatments labeled as placebo, 37.2% for treatments labeled as rizatriptan or placebo, and 39.9% for treatments labeled as rizatriptan.
Approximately 5% of patients were pain-free at two hours after taking correctly labeled placebo, compared with approximately 10% of patients who took placebo labeled as rizatriptan. Approximately 12% of patients were pain-free at two hours after taking rizatriptan labeled as placebo, compared with approximately 36% of patients who took correctly labeled rizatriptan.
“The efficacy of 10 mg of rizatriptan that was mislabeled as placebo was surprisingly similar to the efficacy of placebo treatment that was mislabeled as [rizatriptan],” said Dr. Burstein. Average pain relief was 36.5% for rizatriptan labeled as placebo, compared with 25.7% for placebo labeled as rizatriptan. When placebo was labeled correctly, pain scores decreased by an average of 15.7%. The therapeutic gain was 6.0% for rizatriptan labeled as placebo, 24.8% for rizatriptan labeled as rizatriptan or placebo, and 25.5% for correctly labeled rizatriptan.
Study Raises Scientific and Ethical Questions
The study results indicate that open-label placebo treatment is superior to lack of treatment for migraine. “These findings challenge the notion that intentional ignorance is an essential constituent of the placebo effect,” said Dr. Burstein. “The planted idea of receiving a drug could render the placebo effect sufficient to ameliorate the headache, and … planting the idea of receiving placebo could reduce the benefits of the drug,” he added.