Page 140 - The clinical aspects and management of chronic migraine Judith Anne Pijpers

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Chapter 7
Chapter 4 shows that Botulinum toxin A (BTA) does not afford any benefit over withdrawal therapy alone. BTA did not improve any of the primary or secondary outcomes after the double-blind placebo-controlled phase (12 weeks), open label phase (24 weeks) or long term follow-up (48 weeks). Hence, in case of medication overuse, withdrawal therapy should be advised first to chronic migraine patients. After this study, the question remains whether BTA is indicated for chronic migraine patients without medication overuse. The lack of any additional benefit of BTA at all in our clinical trial described in chapter 4 cautiously suggests against the use of BTA in chronic migraine in general, but was not formerly studied. A common response to our trial by physicians in favour of implementation of BTA in chronic migraine treatment, is that we didn’t find any effect because the placebo-dose of 17.5 units is already biologically effective, resulting in significant improvement. This explanation seems unlikely, as 17.5 units is significantly lower than the lowest doses reported for headache57,58 or other applications, such as psychiatric disorders, peripheral neuropathy or even regular cosmetic purposes.59–61 Furthermore, animal studies on putative mechanisms of effect show that low doses are clearly less effective62 or not effective at all.63,64 Hence, there is no evidence that a low dose of 17.5 units would cause a clinically relevant effect. More importantly, if such a low dose is indeed effective, why should we treat patients with a nine fold higher dose? A meta-analysis published before our trial proves that BTA is not effective in episodic migraine and in (chronic) tension-type headache.57 BTA did have a modest effect in chronic migraine,11,57 which was mainly based on the PREEMPT trials. 65,66 The main remarks on these trials are i) a modest effect with a therapeutic gain of only 9% compared to placebo, ii) potential bias by unblinding, iii) potential selection bias due to a selection of less severe chronic migraine patients without depression and without daily headache. Since the registration trials, many observational cohort studies have been published. The longest open label observational study with repeated BTA cycles during 108 weeks implies a long-term effect, but the interpretation of these results is hampered due to bias because of a high rate of loss to follow-up (50%).67 The one-cycle open label administration of BTA in patients who still suffer from chronic migraine after withdrawal, described in chapter 4, is shorter compared to other observational studies, but led to a limited reduction in headache days only. Comparing BTA to other preventatives used in chronic migraine, the limited available data suggests that BTA is not superior to topiramate or valproate.57