Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial

Abstract

Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18-65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9-12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (-26.9% versus -20.5%; difference -6.4%; 95% confidence interval: -15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were -6.2 versus -7.0 (difference: 0.8; 95% confidence interval: -1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA.

Keywords: botulinum toxin A; chronic migraine; detoxification; medication overuse; withdrawal.

Figure 1

Trial profile. Primary analysis included all participants (intention-to-treat), using outcomes after 12 weeks. Of 90 participants receiving withdrawal and BTA during the double blind phase, 31 still had chronic migraine after 12 weeks, of whom 28 participants received one cycle open label BTA. Accordingly, of 89 participants receiving withdrawal and placebo during the double blind phase, 41 still had chronic migraine, of whom 32 received one cycle open label BTA. Long term analyses, comparing one or two cycles of BTA versus placebo after 12, 24, 36, and 48 weeks, included all participants providing at least one outcome measurement. The open-label results (i.e. outcomes after 24, 36, and 48 weeks) of placebo treated patients receiving open label BTA were set as missing (depicted in grey within dashed boxes). The boxes show the number of participants of whom data were available.

Figure 2

Percentage change in 4-weekly headache days from baseline to the last four weeks of double-blind treatment (Weeks 9–12). Depicted are unadjusted values and means.

Figure 3

Migraine status after 12 weeks. Proportion of participants who remained to have chronic migraine, or who transformed to episodic migraine. Episodic migraine was subcategorized in high frequent, moderate frequent and low frequent episodic migraine. Chronic migraine: ≥15 headache days of which ≥8 are migraine days; episodic migraine: = not fulfilling chronic migraine criteria; episodic migraine–high frequency: = >15 headache days, but <8 are migraine days; episodic migraine–moderate frequency: = 10–14 headache days; episodic migraine–low frequency: <10 headache days.

Figure 4

Change from baseline of the 4-weekly number of days with headache (A) and migraine (B) over 48 weeks. To compare the long-term effects of withdrawal plus BTA versus withdrawal plus placebo, the open label phase and follow-up phase were included in the analysis. As some placebo-treated participants received BTA in the open label phase, including the outcomes of these patients in the analysis of ‘placebo-treated participants’ would potentially influence the comparison. To avoid this, the open-label results (i.e. outcomes after 24, 36 and 48 weeks) of placebo-treated participants receiving open-label BTA were set to missing. In this way, participants treated only with placebo were compared to participants who had received one or two cycles of BTA. Depicted are adjusted means with 95% CI; headache and migraine days at baseline are derived from the model. A headache day is a day with a migraine or non-migraine headache of any duration; a migraine day is a day with headache fulfilling migraine criteria or treated with acute anti-migraine medication.