Oxford University Press
Reply: OnabotulinumtoxinA should be considered in medication overuse withdrawal in patients with chronic migraine
DOI 10.1093/brain/awz368, Volume: 143, Issue: 1,

Table of Contents



Pijpers, Ferrari, and Terwindt: Reply: OnabotulinumtoxinA should be considered in medication overuse withdrawal in patients with chronic migraine


We thank Prof. Dressler for his interest in our study and his honesty to report that he is shareholder of Allergan, the manufacturer of the drug tested in our trial, and that he holds patents on botulinum toxin and botulinum toxin therapy (Dressler, 2019).

His letter offers us the opportunity to correct some misconceptions with respect to the perceived efficacy of botulinum toxin A (BTA) in chronic migraine with medication overuse (CM+MO). It also enables us to correct some apparent misunderstandings with respect to the study design and to present new additional evidence, further supporting the conclusion that BTA does not afford any additional clinical benefit over withdrawal in patients with CM+MO.

Professor Dressler suggests that BTA is an effective treatment for chronic migraine. We would like to put this claim into perspective. While statistically significant, the greater reduction in headache days with BTA versus placebo was clinically hardly relevant: 1.8 days from 19.9 days at baseline (<10%) (Aurora et al., 2010; Diener et al., 2010; Dodick et al., 2010; May and Schulte, 2016). Moreover, unblinding due to BTA-induced removal of facial wrinkling might well have biased outcome. Up to 90% of participants had correctly guessed their treatment in similar trials, mainly because of the cosmetic effect (Australian Government, 2011; Wollmer et al., 2012). In a recent Cochrane review, the efficacy of BTA was disputed because of the large and unexplained heterogeneity in the studies (Herd et al., 2018).

To avoid unblinding, we administered 17.5 units of BTA in the forehead of participants in the placebo group. This is very low compared to the 155 units used in the PREEMPT studies (Aurora et al., 2010; Diener et al., 2010). We are not aware of any published evidence that such low doses may afford clinically relevant improvement. In fact, 17.5 units is significantly lower than the lowest dose ever reported for headache (Jackson et al., 2012; Herd et al., 2018), psychiatric disorders (Wollmer et al., 2012), peripheral neuropathy (Attal et al., 2016), or regular cosmetic purposes (Durand et al., 2016). In animal studies, low doses were clearly less effective (Zhang et al., 2016) or not effective at all (Antonucci et al., 2008; Lawrence et al., 2012) on putative therapeutic modes of action. In conclusion, there is no evidence that seven injections with in total 17.5 units BTA in the forehead might have caused a clinically relevant reduction in headache days. Moreover, if such low doses were indeed effective, why then should we continue to treat patients with 31 injections totalling a 9-fold higher dose?

In his letter, Professor Dressler seems also mistaken with the study design and patient number. To clarify, all 179 participants were advised to stop all headache medication and were randomly allocated (1:1) to receive BTA (n = 90; 31 injections; in total 155 units) or placebo (n = 89; seven injections with a total of 17.5 units BTA in the forehead and 24 injections with saline elsewhere). Importantly, blinding was well kept. BTA did not afford any additional clinical benefit over withdrawal alone (Pijpers et al., 2019).

The effect of withdrawal in our study was similar to that in other studies, showing similar proportions of patients reverting from chronic to episodic headache (Rossi et al., 2006; Munksgaard et al., 2012) or with at least 50% reduction in headache days (Zeeberg et al., 2006; Rossi et al., 2011; Munksgaard et al., 2012). In a recent randomized, controlled, clinical trial, patients with mainly CM+MO had 6.7 fewer migraine days after withdrawal (Carlsen et al., 2018). In a recent review, it was recommended to implement withdrawal in the care of patients with CM+MO (Diener et al., 2019). In summary, withdrawal is now recognized as a highly cost-effective therapy (Jellestad et al., 2019) leading to substantial reduction of headache days in most patients (Munksgaard et al., 2012; Pijpers et al., 2016; Carlsen et al., 2018; Diener et al., 2019; Jellestad et al., 2019).

Data availability

The trial is registered at the Netherlands trial registry, #3440, The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Competing interests

All authors have completed the ICMJE uniform disclosure form at and declare: Support from the Netherlands Organisation for Scientific Research (NWO), VIDI 91711319 and the Dutch Brain Foundation for the submitted work. No author has financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years. No other relationships or activities that could appear to have influenced the submitted work.



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