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New Guidelines for Treatment of Migraine with Botox

April 25, 2016
The American Academy of Neurology recently published updated guidelines for the treatment of migraine and related conditions using FDA-approved preparations of Botulinum neurotoxin

Interview with Mark Hallett, MD

In 2010, the Food and Drug Administration (FDA) approved the use of onabotulinumtoxinA (Botox) for the treatment of chronic migraine in patients. However, the use of Botulinum neurotoxin (BoNT) for chronic migraine has lacked professional consensus—until now.

Injections of botulintoxinA may help reduce the number of migraine attacks in a month.

New guidelines published by the American Academy of Neurology (AAN) have updated their position, officially recommending that onabotulinumtoxinA should be offered as a treatment option to patients suffering from chronic migraines in order to increase the number of headache-free days, although the clinical benefit may be small.1

The AAN’s new guidelines, presented at the 2016 annual meeting held in Vancouver, British Columbia, Canada, cover 4 specific indications for BoNT, including blepharospasm, cervical dystonia (CD), adult spasticity, and headache.2 These indications have taken into consideration new research that has been published since the last version of the guidelines were published in 2008.3

Treatment of Chronic Migraines

The 2008 guidelines stated there was insufficient evidence to support or refute the use of BoNT for the treatment of chronic migraine,3 which is defined as a patient experiencing migraine attacks occurring 15 days or more monthly for at least 3 months, with attacks typically lasting 4 hours or more.4

Since 2008, new studies addressing the possible benefits of commercially available BoNT pharmacology have come to light, including 2 PREEMPT trials that investigated the use of BoNT for chronic migraine.5,6 The first of the studies found onabotulinumtoxinA was ineffective at changing total headache episodes but did provide a noticeable change in the frequency of headache days/28 days, with a mean intergroup difference of -1.4 days (95% CI 22.4 to 20.40).5

The second study found comparable results, where onabotulinumtoxinA effectively reduced total headache days from baseline up to weeks 21 through 24 after treatment. Patients enjoyed 9 fewer headache days, compared to 6.7 in the placebo group (P<0.001).6 Later pooled analyses also found onabotulinumtoxinA decreased headache impact and improved patients’ health-related quality of life (QOL), following 24 weeks of double-blind treatment.7

The guidelines noted that the placebo response was high in both studies, a recurring problem in pain trials. “If the placebo response is high, then it becomes difficult to identify a therapeutic response on top of it,” Mark Hallett, MD, a coauthor of the guidelines, told Practical Pain Management. While this is something to keep in mind, it doesn’t limit the results of the study, said Dr. Hallett, it just makes it more difficult to find a significant benefit.

AAN guidelines now support the use of OnabotulinumtoxinA as a treatment option to increase headache-free days (level A) and reduce headache impact on health-related QOL (Level B). However, the clinical benefit may be relatively meager. “Although the reduction of headache days with onabotulinumtoxinA was statistically superior to placebo in 2 Class I studies, the magnitude of the difference is small (1.7 and 2.3),” the authors noted. Adverse effects associated with onabotulinumtoxinA include neck pain and muscle weakness.

Topiramate and Other Drugs for Chronic Migraine

Research has explored the possibility that similar benefits can be achieved with oral topiramate, an anticonvulsant agent approved by the FDA for treatment of migraines. Indeed, in a side-by-side comparison trial, topiramate and OnabotulinumtoxinA both achieved statistically significant results treating chronic migraine, although no notable difference in efficacy was found between the two agents.8

However, the AAN panel refrained from endorsing the use of topiramate for chronic migraine, stating “there is insufficient evidence to compare the effectiveness of BoNT with that of oral prophylactic topiramate.” Since no other studies investigating other formulations of BoNT or oral preventive medications met guideline inclusion criteria, the update provides no other pharmacological recommendations for chronic migraine.

The lack of recommendation for topiramate and other therapies may come as a surprise, given the popularity of oral topiramate as an effective preventive treatment of migraine. Topiramate may not be as clinically effective as Botox, though it does seem to work for “at least 33% to 40%” of patients. Topiramate does not cause weight gain or bad side effects, something hard to find in other preventive treatments. Also, OnabotulinumtoxinA injections can be expensive, while topiramate is not.

Guidelines like these have limited utility, and only a small minority of physicians base their treatment of migraine on AAN guidelines. There are other preventive drugs commonly used for migraine—the majority of them lacking recommendation from the AAN—including anticonvulsants like valproic acid (Depakote; AbbVie Inc.), tricyclic antidepressants, and beta blockers, which are still relevant for clinical use.

Practitioners should have “many tools in their toolbox” when it comes to treating chronic migraine in adult patients, and while the new AAN guidelines do not explicitly mention those other drugs, that shouldn’t mean those treatment options are now irrelevant. Just because we do not have Class A evidence for something does not mean we should not use it.

Botox Not for Episodic Migraine or Tension-type Headache

Unlike chronic migraine, AAN guideline recommendations for episodic migraine and tension-type headache have not changed since 2008. A batch of Class I and Class II level studies previously concluded that Botox injections probably were ineffective for the treatment of episodic migraine (defined as lesser frequency than chronic migraine). Since 2008, however, there has been one Class I study assessing OnabotulinumtoxinA at doses of 75 U, 150 U, and 225 U compared to placebo, with 3 treatment cycles set 3 months apart. Up to day 180, all three doses of OnabotulinumtoxinA were found to be ineffective for reducing migraine frequency from baseline.9

The 2008 guideline recommendation also concluded BoNT injection is probably ineffective for treating chronic tension-type headaches, according to two Class I studies.3 Since that time, no new studies have been published to challenge the AAN’s position, today.

Guidelines May Clash with Regulatory Indications

The AAN’s updated recommendations may serve as a valuable guidepost to practitioners considering BoNT for various clinical contexts, given AAN consensus does not always coalesce with other resources. In fact, regulatory-approved indications do not necessarily correspond with the AAN guidelines, the authors noted.

Indeed, oral topiramate has been officially indicated by the FDA “for prophylaxis of migraine headache” in adults and adolescents 12 years of age and older,10  with a recommendation that patients be titrated weekly from 25 mg/day to a 100 mg/day in 2 divided doses. However, the AAN guidelines make no endorsement of this medication for chronic migraine, or other related conditions.

While 28 headache articles did meet the guideline’s inclusion criteria, some articles presumably were excluded from the panel’s systematic review, especially given that only randomized, masked trials (RMT) were considered. Nonrandomized trials were used, however, to assess long term outcomes, including the safety profiles of the various BoNT formulations.

BoNT currently is available in two serotypes – A and B – of which there are 4 FDA-approved preparations:

  • onabotulinumtoxinA (Botox)
  • abobotulinumtoxinA (Dysport)
  • incobotulinumtoxinA (Xeomin)
  • rimabotulinumtoxinB (Myobloc)

However, only Botox is approved for the treatment of chronic migraine.

Of note, the previous 2008 guidelines evaluated BoNT injections as a single class. However, given the fact these BoNT preparations do differ in pharmacological characteristics, such as potency and duration of action, the 2016 guidelines assess each formulation individually for each indication. “As a result, the level of support for efficacy in the conclusions and recommendations may be lower for the individual BoNT formulations than it would be had BoNT been considered as a class. Efficacy of BoNT is for symptomatic control, as there is no evidence for disease modification,” the authors noted. More information on the development of the AAN guidelines can be found in the 2004 AAN guideline process manual.11


Last updated on: April 26, 2016
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