Critical analysis of the use of onabotulinumtoxinA (botulinum toxin type A) in migraine

Figures & data

Table 1 Criteria for migraine without aura and chronic migraine (from the International Headache Society)^2,3

Migraine without aura: At least five attacks fulfilling the following criteria: Headaches lasting 4–72 hours (treated or untreated) At least two of the following characteristics: Unilateral location Pulsating or throbbing quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) During headache, at least one of the following: Nausea and/or vomiting Photophobia and phonophobia Not attributed to another disorder Chronic migraine (revised international Headache Society criteria): Headache (tension-type and/or migraine) on ≥15 days per month for at least 3 months Occurring in a patient who has had at least five attacks fulfilling criteria for migraine without aura On ≥8 days per month for at least 3 months headache has fulfilled criteria for pain and associated symptoms of migraine without aura (IA–ID above) and/or has treated and relieved their pain with a triptan before the expected development of the symptoms (listed in IA–ID) No medication overuse (use of ergotamine, triptans, opioids, or combination analgesics more than 9 days/month for more than 3 months) and not attributed to another causative disorder

Figure 1 Mechanism of botulinum neurotoxin type A (BoNT-A) at the neuromuscular junction. (A) Normal neurotransmitter release requires fusion of the vesicle membrane to the membrane of the presynaptic nerve terminal. This process is guided by the fusion of three proteins that make up the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex: the vesicle-associated membrane protein (VAMP or synaptobrevin) and the membrane-bound syntaxin and synaptosomeassociated protein of 25 kDa (SNAP-25). ACh is released from the vesicle, diffuses across the synaptic cleft, and binds to the acetylcholine (Ach) receptor, resulting in normal muscular contraction. (B) The heavy chain of BoNT-A binds to a ganglioside acceptor in the plasma membrane of the presynaptic nerve terminal. This leads to receptormediated endocytosis of the neurotoxin. The acidic environment of the synaptic vesicle or endosome leads to a conformational change in the toxin and eventual reduction of the linking disulfide bond, freeing the light chain. The light chain translocates to the cytosol and cleaves the C-terminal of the SNAP-25 protein. This inhibits SNARE complex formation and therefore inhibits neurotransmitter release.

Note: Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.

Table 2 Randomized, double-blind, placebo-controlled trials evaluating onabotulinumtoxinA efficacy in migraine prophylaxis

Study	Randomized subjects	Dropouts	Analgesic medication overuse included	Injection protocol	Injection sites	BT-A dose (U)	Other prophylactic medications allowed	Outcome
Episodic migraine
Silberstein et al^Citation47	123	1 (0.8%)	No	Fixed-site, fixed-dose	Head only	25, 75	Yes	Greater reduction in number of moderate-to-severe migraines in 25 U vs placebo at Month 2 (placebo, −0.37; 25 U BT-A, −1.57; P = 0.008) and Month 3 (placebo, −0.98; 25 U BT-A, −1.88; P = 0.042)
Evers et al^Citation48	60	0 (0%)	No	Fixed-site, fixed-dose	Head and neck	16, 100	Yes	Rate of patients with a ≥50% reduction of migraine frequency not different (P = 0.921) The 16 U group had fewer migraine-associated symptoms vs placebo in Month 3 (P = 0.048; post hoc test)
Elkind et al^Citation49	418	102 (24.4%)	No	Fixed-site, fixed-dose	Head only	7.5, 25, 50	Yes	Migraine frequency not different at any visit (assessed as change from baseline, all P > 0.201)
Anand et al^Citation51	32	0	Not specified	Fixed-site, fixed-dose	Head only	50	Yes	Primary efficacy parameter difficult to interpret 75% of BT-A patients improved in intensity compared with none of placebo (P < 0.05)
Aurora et al^Citation50	369	84 (22.7%)	Not specified	Follow-the-pain and fixed occipitalis dose	Head and neck	110–260	Yes	At Day 180, no significant change in frequency of migraine from baseline (P > 0.999) Possible benefit for those with higher baseline headache frequency
Relja et al^Citation54	495	94 (18.9%)	No	Fixed-site, fixed-dose	Exact sites not specified	75, 150, 225	No	At Day 180, all groups improved, with no significant differences (P = 0.817)
Saper et al^Citation55	232	7 (3.0%)	Not specified	Fixed-site, fixed-dose	Head only	6, 9, 10, 25	Yes	No significant decrease from baseline in frequency of migraine at 30, 60, or 90 days (all P ≥ 0.411)
Chronic migraine
Freitag et al^Citation53	41	5 (12.1%)	No	Fixed-site, fixed-dose	Head and neck	100	Yes	Decline in attack frequency from 13.8 to 10.1 per month in BT-A group (P = 0.001, correlation coefficient = 0.695) Rising frequency in placebo group 33% on BT-A had a ≥50% reduction in migraine episodes compared with 16.7% on placebo
Aurora et al^Citation56 (PREEMPT 1)	679	88 (12.9%)	Yes	Fixed-site fixed-dose ± follow-the-pain	Head and neck	155–195	No	No significant difference in mean change from baseline in headache episode frequency BT-A showed significant reduction in headache days (P = 0.006) and migraine days (P = 0.002) compared with placebo
Diener et al^Citation57 (PREEMPT 2)	705	60 (8.5%)	Yes	Fixed-site, fixed-dose ± follow-the-pain	Head and neck	155–195	No	BT-A showed significant reduction in headache days from baseline compared with placebo for the 28-day period ending with week 24 (−9.0 days with BT-A vs −6.7 placebo, P < 0.001)
Unspecified migraine subtype
Vo et al^Citation52	49	17 (34.6%)	Not specified	Fixed-site, fixed-dose	Head and neck	135, 205	Yes	High dropout rate led to small sample size Average frequency of headache days during 30-day blocks for 3 months not significantly different

Abbreviations: BT-A, botulinum toxin type A; PREEMPT, Phase II Research Evaluating Migraine Prophylaxis Therapy.

Figure 2 US Food and Drug Administration box warning included on package insert for onabotulinumtoxinA (BOTOX^®).

Figure 3 OnabotulinumtoxinA injection sites used by the authors (see Table 3 for dosing).

Note: Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.

Table 3 Standard fixed-site, fixed-dose 150 U protocol for onabotulinumtoxinA currently used by the authors at the time of this manuscript’s publication

5.0 U into each corrugator muscle and into the procerus muscle One injection site per muscle (15.0 U total) 5.0 U into the right and left superior frontalis muscle Two injection sites per muscle (10 U total) 12.5 U into each temporalis muscle Two injection sites per muscle (25 U total) 12.5 U into each splenius capitis muscle Two injection sites per muscle administered as two-thirds of 12.5 U (8.3 U) at superior injection site (near muscle insertion) and one third (4.2 U) at mid-belly of muscle to minimize neck weakness (25 U total) 12.5 U into each occipitalis muscle Two injection sites per muscle (25 U total) 25 U into each trapezius muscle Three injection sites per muscle (50 U total)

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