Review: Prophylactic botulinum toxin Areduces frequency of chronic migraineheadaches in adults

Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A forprophylactic treatment of migraine and tension headaches in adults: ameta-analysis. JAMA. 2012;307:1736-45.

ConclusionIn adults, prophylactic botulinum toxin A reduces frequency ofchronic migraine headaches and chronic daily headaches butincreases adverse events.

*Number needed to harm calculated using relative risk and control event ratein article.

Source of funding: No external funding.

For correspondence: Dr. J.L. Jackson, Medical College of Wisconsin,Milwaukee, WI, USA. E-mail jjackson@mcw.edu. ■

CommentaryJackson and colleagues conclude that botulinum toxin may helpchronic migraine and chronic daily headaches. They suggest thatthe latter group benefited because patients with chronic migraineswere included; we address the claim of benefit for chronic migraine.

Jackson and colleagues note that trials included in their reviewwere mostly small, short, and industry-sponsored. They acknowl-edge that botulinum toxin may be less beneficial than other pro-phylactic medications. However, we believe that their conclusionsare still optimistic. We closely examined the 2 PREEMPT trials,which contributed 92% of patients (1384/1508) to the meta-analysisof chronic migraine. First, we strongly agree with concerns expressedby Olesen and Tfelt-Hansen about the inability to blind patientsowing to the paralytic effects of the drug (1). Second, about twothirds of patients had medication overuse (1). In 2010, the PRE-EMPT Chronic Migraine Study Group promised a separateanalysis of this subgroup; however, we have been unable to find areport of such an analysis. Finally, the PREEMPT 2 trial changedits primary outcome after the trial started based on the results ofthe PREEMPT 1 trial.

Although the meta-analysis suggests benefits with botulinum, itdoes not address whether these benefits are clinically important.When a patient has ≥ 15 headaches per month, having 2 to 3fewer seems less than robust, especially at a cost of $1000 to $2000per treatment (2). In addition, long-term safety is uncertain.Botulinum toxin is probably safe in long-term treatment of dystonias(3); however, because it incompletely prevents migraines, patientsmay request more frequent dosing, which may lead to toxicity.

We remain skeptical about botulinum toxin A for preventingchronic migraine.

Robert Badgett, MDAndrew Massey, MD

Kansas University School of MedicineWichita, Kansas, USA

References

1. Olesen J, Tfelt-Hansen P. Licence for Botox in so-called chronicmigraine [Letter]. Lancet. 2010;376:1825-6.

2. Singer N. Botox shots approved for migraine. New York Times. 2010 Oct15. www.nytimes.com/2010/10/16/health/16drug.html (accessed 14 Jun2012).

3. Colosimo C, Tiple D, Berardelli A. Efficacy and safety of long-term botu-linum toxin treatment in craniocervical dystonia: a systematic review.Neurotox Res. 2012;Feb 23 [Epub ahead of print].

Clinical impact ratings: F★★★★★✩✩ N★★★★★★✩

Therapeutics

JC4-10 21 August 2012 | ACP Journal Club | Volume 157 • Number 4© 2012 American College of Physicians

QuestionDoes prophylactic botulinum toxin A reduce frequency of migraineor tension headaches, or chronic daily headaches in adults?

Review scopeIncluded studies compared botulinum toxin A, alone or combinedwith other prophylactic or analgesic treatments, with placebo orother treatments in adults who had headaches; were ≥ 4 weeks induration; and reported headache frequency or severity. Exclusioncriteria were headaches associated with other disorders (e.g., cervical dystonia) or secondary headaches (e.g., postlumbar punc-ture headaches). Outcomes were patient-reported headache fre-quency or severity, indices that included patient-reportedheadache frequency and severity, and adverse events.

Review methodsMEDLINE, EMBASE/Excerpta Medica, Cochrane Library,and reference lists were searched to March 2012 for randomizedcontrolled trials (RCTs). 31 RCTs met inclusion criteria: 27 usedplacebo controls (n = 5423, mean age 42 y, 76% women) and 4used active controls (n = 210, mean age range 30 to 42 y, 89%women), including topiramate, amitriptyline, methylpred-nisolone, and valproate. 10 placebo-controlled trials evaluatedtreatment for episodic migraine headaches (< 15 headaches/mo),8 for chronic tension-type headaches (≥ 15 headaches/mo), 5 forchronic migraine headaches, 3 for chronic daily migraine or ten-sion-type headaches, and 1 for a mixed population; 2 active-con-trolled trials evaluated treatment for chronic migraine headachesand 2 for a mixed population. 17 placebo-controlled RCTs and 1active-controlled RCT scored ≥ 6 out of 8 on the Jadad scale formethodological quality.

Main resultsBotulinum toxin A reduced frequency of chronic migraine andchronic daily headaches more than placebo; groups did not differfor reducing frequency of episodic migraine or chronic tension-type headaches (Table). In single RCTs, botulinum toxin Areduced the severity of chronic tension-type headaches more thanmethylprednisolone; botulinum toxin A did not differ from topi-ramate, valproate, or amitriptyline for reducing headache frequency.Botulinum toxin A increased adverse events more than placebo(25 RCTs; 57% vs 46%; relative risk increase 25%, 95% CI 14 to36; number needed to harm 9, CI 7 to 16*).

Prophylactic botulinum toxin A vs placebo in adults withheadaches†Outcome Headache type‡ Number of Weighted mean

trials (n) difference (95% CI)§Headaches/mo Episodic migraine 9 (1838) 0.05 (−0.26 to 0.36)

Chronic migraine 5 (1508) −2.30 (−3.66 to −0.94)

Chronic tension-type 7 (675) −1.43 (−3.13 to 0.27)

Chronic daily 3 (1115) −2.06 (−3.56 to −0.56)

†CI defined in Glossary.

‡Episodic headache, < 15 headaches/mo; chronic headache, ≥ 15 headaches/mo.

§Negative values favor treatment.

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