Blinding of patients to their assigned treatment (active or placebo) is a standard procedure in clinical trials to assess the “true” efficacy of the active drug. But what happens when patients are certain whether they are receiving active treatment or placebo? How does this information affect treatment outcomes? This topic was recently explored by Slavenka Kam-Hansen, MD, PhD, Instructor in Neurology, Beth Israel Deaconess Medical Center, Boston, and colleagues, in patients with acute migraine headaches (Kam-Hansen S, et al. Sci Transl Med. 2014;6:218ra5).
The study included 66 patients with episodic migraine who reported approximately 1 untreated migraine attack at the beginning of the study, followed by 6 migraine attacks that were randomly assigned to 1 of the following open-labeled treatment options: placebo, rizatriptan (Maxalt) 10 mg, or rizatriptan or placebo. As noted, 2 of the treatments were mislabeled.
“When we gave Maxalt and told them it’s placebo, we were trying to take away the placebo effect; we wanted to see what the pure pharmacology of Maxalt would do without the patients thinking there was drug there, and the placebo labeled as drug we thought was a good way of giving a placebo with high expectations,” explained Ted J. Kaptchuk, Professor of Medicine, Harvard Medical School, and Director, Program in Placebo Studies and the Therapeutic Encounter, Beth Israel Deaconess Medical Center, Boston.
The primary end point was the difference among treatment groups in pain score 30 minutes after the start of the headache and 2 hours after the start of the headache. The secondary end point was the proportion of patients who were pain-free 2.5 hours after the start of the headache.Unexpected Findings
The results showed that openly labeling pills and treatment with the pills significantly affected pain scores in terms of difference between pain scores at baseline versus 2 hours after the start of a headache. Several unexpected outcomes were uncovered.
First, the investigators presumed that there would be a greater decrease in pain scores with a drug labeled “Maxalt” than with a drug labeled “Maxalt or placebo,” because patients would be more certain that they were receiving the active treatment.
Nevertheless, the decrease in pain score was 40.1% in patients receiving a drug labeled “Maxalt or placebo” and 39.5% in those receiving a drug labeled “Maxalt.” Overall, the decrease in pain scores was 47.6% with the active treatment and 20.7% with placebo.
“What that suggests is that, in fact, knowing you’re taking a drug or being in a randomized controlled trial where you’re told you’re either taking a drug or placebo doesn’t make a difference in the outcome of the drug. Most people would have said that this is not possible; they assume that there’s a better expectation in the labeled ‘Maxalt’ than there is in ‘either or,’ and I would say that this suggests that we don’t know something about how expectations operate with the drug,” Mr Kaptchuk added.
Another interesting finding was that even when patients knew they were receiving the placebo (and the placebo was correctly labeled), and therefore would not typically expect their symptoms to improve, pain scores still decreased by 14.5%. Conversely, pain scores increased by 15.4% in patients with the untreated attack.
Judging by these results, the investigators concluded that the placebo effect in this study was particularly strong––more than half as large as the effect of rizatriptan.
Mr Kaptchuk offered a hypothesis for these unexpected results, saying, “There is some way that this underscores the possibility that nonconscious processes are involved in the placebo effect besides conscious processes.”
One of the more surprising findings was the lack of significant difference in the efficacy of rizatriptan that was mislabeled “placebo” compared with the efficacy of placebo that was mislabeled “Maxalt”––pain scores decreased by 36.1% with rizatriptan mislabeled as “placebo” and 24.6% with placebo mislabeled as “Maxalt” (P = .127).
“The fact that there were basically no statistical differences suggests that in this study, the placebo with high expectations can be as good as a pharmacological agent without expectations, and it’s confirmed, because when we gave Maxalt and labeled it as ‘Maxalt,’ the Maxalt’s effect was 50% greater than the effect of Maxalt labeled as placebo,” Mr Kaptchuk said. “For us, this was a very important finding.”
The secondary end point revealed several areas where primary and secondary end points diverged and converged. Results from the secondary end point showed that treatment had a significant effect on outcomes, whereas labeling did not. Overall, 25.5% of patients were pain-free with rizatriptan, and 6.6% of patients were pain-free with placebo. Furthermore, 16.6% of patients were pain-free with “Maxalt”-labeled pills, 15.5% were pain-free with “Maxalt or placebo”–labeled pills, and 9.2% were pain-free with “placebo”-labeled pills.
Another area of difference between the primary and secondary end points emerged when the proportion of patients who were pain-free after taking the open-labeled placebo (5.7%) was not significantly different from the proportion of patients who were pain-free after not receiving any treatment (0.7%).
Overall, the investigators concluded that treatment and information about the treatment may be equally important for pain relief. Furthermore, the mere act of taking medication (regardless of whether it is active or placebo), as opposed to no treatment, proved to be an important factor in pain outcomes.