Page 84 - The clinical aspects and management of chronic migraine Judith Anne Pijpers

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Chapter 4
power seems an unlikely explanation. The 95% CIs for the treatment differences versus placebo are for nearly all endpoints very narrow. The interval for the primary endpoint (-2.5 to 15.2 percentage point change) does not include our predefined clinically meaningful treatment effect of 20-percentage points (corresponding with 4 headache days). Of note, our study was powered for detecting even smaller differences than the 30-percentage point treatment effect generally considered the smallest meaningful effect in chronic pain and migraine studies.34,46
Compared to previous studies suggesting efficacy of BTA in chronic migraine,20–24 our study shows three important methodological differences which potentially might explain the disparate outcome. First, while in earlier studies participants received two BTA treatment cycles three months apart,21–24 in our study participants received only one. We therefore cannot exclude that some participants might have benefitted from a second BTA treatment at 12 weeks. However, considering the only marginal improvement in the 28 BTA non-responders who received open label BTA at 12 weeks (0.9 days; 95% CI -0.9 to 2.7), we doubt that omission of a second treatment of BTA has materially affected the results.
Second, in our study, unblinding was successfully prevented. This was most likely due to the injection of low masking doses of BTA in the forehead of placebo- treated participants. As a result, removal of forehead wrinkling was similar in both the placebo and BTA-treated group. Some might argue that doses even as low as 17.5 units BTA might have been effective, thereby nullifying a potential treatment difference from placebo. There is however no documented, double- blind, placebo-controlled, evidence for any effect of BTA at doses considerably lower than 155 units, and certainly not with a total dose of as little as 17.5 units.47 This dose is even lower than doses used for cosmetic purposes. The therapeutic gain of 155 units BTA versus placebo in the PREEMPT studies was only modest at best (reduction of 1.9 headache days from a baseline of 19 days, i.e. only a mere 10% better improvement with BTA than with placebo).47 It therefore seems extremely unlikely that a dose of only 17.5 units would have produced any clinically relevant effect. Moreover, the effect of only 7 injections of only 2.5 units of BTA each in the forehead (17.5 units) was not inferior compared to currently recommended treatment protocols using 31 injections of 5 units of BTA