Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos

We carried out a metaanalysis of 22 trials to determine the comparative pla cebo effect of (a) subcutaneous vs, oral and (b) in-hospital vs, at-home ad ministration in the treatment of migraine. The headache relief rates were c ombined from the placebo arms of these randomised clinical trials assessing the value of sumatriptan in acute treatment of migraine. The main outcome measure was the proportion of patients reclassified from severe or moderate headache severity to no or mild headache severity 2 h after the beginning of treatment. In the oral regimen 222 of 865 patients (25.7%) reported no o r mild headache severity after 2 h, compared to 279 of 862 patients (32.4%) of those :receiving subcutaneous placebo (6.7% difference; 95% CI 2.4-11.0 %). Adjusting for treatment setting and severity of headache at baseline di d not change the observed difference. After placebo treatment at home 285 o f 1054 patients (27.0%) reported no or mild headache severity after 2 h, co mpared to 216 of 673 patients (32.1%) among those receiving placebo in hosp ital (5.1% difference; 95% CI 0.6-9.5%). When adjusted for route of adminis tration and severity of headache at baseline, the difference in relief rate s between home and hospital setting disappeared. These findings indicate th at subcutaneous administration enhances the placebo effect of acute treatme nt of migraine. Future trials of antimigraine drugs assessing the relative efficacy of various routes of administration should use a double-dummy tech nique. The interpreting of placebo-controlled trial results must therefore consider that the effect in the drug arm of the trial depends in part on th e route of administration.