MIGRAINE Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks Slavenka Kam-Hansen, 1 Moshe Jakubowski, 2 John M. Kelley, 3,4,5 Irving Kirsch, 5,6 David C. Hoaglin, 7 Ted J. Kaptchuk, 5 * Rami Burstein 2 * † 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 compo- nents of care. INTRODUCTION It is generally thought that placebo and medication efficacies are in- fluenced by contextual factors such as the expectations embedded in the information clinicians provide (1). Much of the evidence for such beliefs is based on “balanced placebo design” experiments concerning mostly addictive or stimulant substances or their placebo controls that disentangle and reassemble placebo and medication effects by provid- ing subjects with various statements, including true and false informa- tion. These between-subjects studies have shown that information can significantly modulate the impact of such substances ( 2–6). To ascertain whether these findings apply in a clinical condition, we used a randomized 2 × 3 within-subjects expanded “balanced placebo design” to test the hypothesis that, in acute migraine, clinical outcomes with both placebo and medication treatment would increase progres- sively as information varied from negative (0% chance of receiving active medication) to uncertain (50% chance of medication) to positive (100% chance) (ClinicalTrials.gov identifier: NCT00719134). A seventh session provided a no-treatment baseline. As secondary questions, we planned to examine whether medication with negative information was different from placebo with positive information and whether open-label placebo was superior to no-treatment control. In an exploratory fashion, we also planned to examine whether the difference between medication and placebo changed under varying information conditions. We used migraine headache as a model because it is a naturally recurring neu- rological disorder of unilateral throbbing headache associated with variable incidence of aura, nausea, photophobia, allodynia, fatigue, and irritability (7). The recurring nature of migraine allowed us to compare for each subject the efficacies of treatment and placebo over con- secutive attacks using varying conditions of information. RESULTS Study design Participants were required to document one untreated attack at the beginning of the study and six subsequent attacks randomly as- signed for treatment with a pill of rizatriptan (10-mg Maxalt) or placebo, each labeled once as “Maxalt,” once as “placebo,” and once as “Maxalt or placebo” (Fig. 1 and Table 1). They were asked to record one pain score 30 min after the onset of headache (baseline), take the study pill at the same baseline time (but not in an untreated attack), and record a second pain score 2.5 hours after the onset of head- ache. Rescue medications were provided for each attack to be used as needed 2.5 hours after the onset of headache. Baseline pain scores were reported in 459 attacks, whereas the 2.5-hour pain scores were re- ported in 435 attacks. Using additional information available in the diaries, we were able to impute 18 of the missing pain scores at 2.5 hours, resulting in 453 analyzable attacks (Table 2 and table S1). Generalized linear mixed models were used to analyze the data as de- scribed in detail in Materials and Methods and Supplementary Methods. Participant enrollment and characteristics Of 98 persons prescreened for eligibility between December 2008 and March 2010, 19 were excluded for reasons listed in table S2, 1 Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 2 Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 3 Psychology Department, Endicott College, Beverly, MA 01915, USA. 4 Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. 5 Program in Placebo Studies and the Therapeutic Encounter, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 6 School of Psychology, Plymouth University, Plymouth PL4 8AA, UK. 7 Independent consultant, Sudbury, MA 01776, USA. *These authors contributed equally to this work. †Corresponding author. 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