Altered placebo and drug labeling changes the outcome of episodic migraine attacks

Abstract

Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing "positive" information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care.

Figure 1. CONSORT flow diagram

^aNine subjects submitted no diary (2 relocated, 3 withdrew from the study, 4 gave no specific reason). ^bOne withdrew after submitting a diary for the untreated attack.

Figure 2. Labeling of the ‘study drug’ and optional ‘rescue medications’ envelopes

The study drug envelope was labeled ‘placebo’ (2 attacks), ‘Maxalt or placebo’ (2 attacks) or ‘Maxalt’ (2 attacks), in order to provide negative, neutral or positive information, respectively. Subjects were instructed to open the envelope and swallow the pill 30 min after onset of headache. They were asked to refrain from taking rescue medications during the first 2.5 h of each attack, including untreated attack (control).

Figure 3. Changes in headache intensity as a percentage of the 30-min pain score (estimate with 95% confidence intervals

The within-subjects design of this study allowed each subject to serve as his or her own control, which substantially increased statistical power. Consequently, 95% confidence intervals could not be interpreted in the same manner as in a typical between-subjects study. Thus, two groups can differ significantly even when the mean for one group falls within the 95% confidence interval for the other group. NT = no treatment, P = ‘placebo’ labeling, U = unspecified (‘Maxalt or placebo’) labeling, M = ‘Maxalt’ labeling.

Figure 4. Percentage of subjects who reported being pain free 2.5 h after onset of headache (estimate with 95% confidence intervals

NT = no treatment, P = ‘placebo’ labeling, U = unspecified (‘Maxalt or placebo’) labeling, M = ‘Maxalt’ labeling.