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In Migraine, Why the Placebo Effect Can Be a ‘Good’ Thing

Talan, Jamie

doi: 10.1097/01.NT.0000444719.85878.9d
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By manipulating the information provided to patients, investigators were able to show that the magnitude of headache relief induced by Maxalt (10-mg rizatriptan), as well as that of placebo, was lowest when pills were labeled as placebo, and higher when pills had uncertain labeling or were labeled as active medication.

The findings of a new study by a team of Harvard scientists support the idea that a positive spin on a migraine therapy could enhance its effectiveness.

Studies on the placebo effect have suggested that a patient's expectation might play an important role in the response to treatment.

In the latest study, published in the Jan. 8 issue of Science Translational Medicine, researchers showed that how an agent is labeled — whether it is placebo or the real treatment — has a strong effect on a patient's response to the therapy.

By manipulating the information provided to patients, their analysis showed that the magnitude of headache relief induced by 10-mg rizatriptan (Maxalt), as well as that of placebo, was lowest when pills were labeled as placebo, and higher when pills had uncertain labeling or were labeled as active medication.

This was a surprise to lead researcher Rami Burstein, PhD, vice chairman of research and director of pain research in the department of anesthesia and critical care at Beth Israel Deaconess Medical Center and professor of anesthesia at Harvard Medical School. His latest study was triggered by his team's work with migraine patients who have said that their response to the same dose of medication is so variable that they experience complete symptom relief in some, but not all migraine attacks. They wanted to determine whether there was a way to improve the effectiveness of migraine medicines.

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The researchers enrolled 66 patients with episodic migraine who had at least four attacks a month. Their initial attack following enrollment in the study was not treated, and served as a baseline to compare the response to randomized placebo and drug labeling changes. The primary goal of the study was to test whether there was a change in clinical outcome if the patient thought that they were on active medicine, placebo, or unsure of what they were taking. During every subsequent migraine attack, patients would open a specific package containing a pill. The envelope would be labeled placebo, Maxalt (rizatriptan), or an unspecified label that read Maxalt or placebo.

The package label seemed to have a significant effect on a patient's pain scores. Among their findings, they found that placebo treatment mislabeled as 10-mg rizatripan reduced headache severity as effectively as did the triptan mislabeled as placebo, and open-label placebo treatment was superior to no treatment. The patients rated their pain on a scale of one (pain-free) to 10 (severe pain) within 30 minutes of the onset of the attack (pre-treatment baseline) and two hours later (post-treatment). Information was collected over a total of six treated migraine attacks.

The average decrease in pain score was 26.1 percent with placebo labeling; 40.1 percent with rizatriptan or placebo labeling; and 47.6 percent with rizatriptan labeling.

When the investigators analyzed the effect of accurate or inaccurate labeling, they found that there was a 14.5 percent reduction in pain scores in those who thought they were taking a placebo dose and those who actually were. (By comparison, the untreated attack showed pain scores rising by 15.4 percent.) Based on the pain ratings, the effectiveness of 10-mg rizatriptan labeled as placebo was not statistically different from the effectiveness of the placebo dose that was mislabeled as Maxalt (36.1 percent versus 24.6 percent, with a p value of 0.127).

There were also differences in patient reports of being pain-free from the treatment. According to the study findings, an average of 25.5 percent of those taking rizatriptan reported feeling pain-free at the two-hour mark compared with an average of 6.6 percent of the people on placebo. But then when they analyzed the percentage of pain-free patients based on mislabeling they found something different.

“The typical percentage of participants who were pain-free was 16.6 percent for Maxalt labeling versus 9.2 percent for placebo labeling (p=0.082). The typical percentage of participants who were pain-free for Maxalt or placebo labeling was 15.5 percent.”

So what does it mean? “People have learned from an early age to associate taking a pill with wanting to get better,” said Dr. Burstein. “The act of taking a pill may make us feel better. But we have also shown that changing the information we give patients — positive, negative, or neutral — can impact how drugs work for them,” said Dr. Burstein. “This tells us that a positive message can improve the therapeutic gain. What we told them (on the label of their medicine) was almost as effective as giving them the actual drug.”

In those patients who were given the negative information — that they were swallowing a placebo pill when they were actually taking the real medicine — the benefit was lower than when they received — and were told they were taking — rizatriptan. “This means that the effect of the medication was significantly reduced by negative information,” said Dr. Burstein.

The study authors concluded that “positive information about active medication contributes to successful treatment of episodic migraine. Medication and information (which presumably influences expectancies) may be equally critical for pain relief. The benefits of placebo persist even if placebo treatment is honestly described. Whether treatment involves medication or placebo, our study clearly shows that the information provided to patients and the predictable ritual of pill taking are important components of care.”

“We need to figure out how we want to take advantage of our findings. Perhaps medical ethicists need to weigh in on this,” Dr. Burstein said. “This study should open a debate about what we should do to enhance the effectiveness of the drugs we prescribe.”

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“I think the study reinforces the utility of placebo effects in practice and the necessity for their use in studies,” said Peter Goadsby, MD, PhD, director of the Headache Center at University of California, San Francisco (UCSF). “This study shows that placebo adds to the active medication to produce a better response.”

That said, he added that it is a “small study and adverse event rates are not documented, which would have been helpful.”

Elizabeth W. Loder, MD, MPH, an associate neurologist at Brigham and Women's Hospital and associate professor of neurology at Harvard Medical School, agreed. “The research design was really useful in disentangling placebo from the effects of the actual drug. It helps us understand belief in the absence of the real drug.”

“It also shows us how the ritual of taking a pill has a powerful and measured benefit,” said Dr. Loder, president of the American Headache Society. “There may be other behavioral factors that could enhance the treatment effect.”

She added: “It would be the wrong message to think that placebo is all a patient needs to get better. That was not the case at all. The power of expectation and belief is very real and it should be used to enhance the benefit of medications.”

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•. Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med 2014; 6(218): 218ra5.
    •. Neurology Today archive on placebo effect:
      •. Neurology Today archive on migraine:
        © 2014 American Academy of Neurology