The Use of Botulinum Toxin in Migraines: A Review
Headache disorders are one of the most frequent pain complaints seen by primary care physicians. Half of the general population experience headaches during any given year, and more than 90% report a lifetime history of head pain. One of the most disabling headache disorders is migraine, which affects about 13% to 18% of women and 5% to 10% of men.1 In fact, migraines are the most common reason for patients to consult a neurologist, resulting in 20% of neurological consultations.2 The most severely disabled migraineurs, approximately 4% of the adult population, experience chronic migraines. The International Headache Society defines chronic migraines as headaches that occur 15 days or more per month for more than 3 months and last 4 hours or more per day (Table 1).3
Botulinum toxin (BoNT) has been used for more than two decades to treat spasticity, autonomic overactivity, and as a cosmetic procedure to reduce wrinkles. More recently, injections with BoNT have been shown to be effective for improving headache symptoms and preventing chronic migraines. According to the International Association for the Study of Pain, the best scientific evidence supports the use of topiramate or BoNT injections for the prevention of chronic migraine.1 In 2010, the FDA approved onabotulinumtoxinA (BoNTA, Botox) to prevent headaches in adults with chronic migraines. Most other treatment options, such as oral preventative medications, offer limited benefit. Thus, management presents a challenge. Many neurologists, pain specialists, and physiatrists now use botulinum neurotoxin to treat patients with refractory migraines. This article will review how BoNT works on migraines and the clinical trials that led to its approval.
How Does Botulinum Toxin Work?
BoNT is produced from the gram-positive bacterium, Clostridium botulinum. In 1895, during a botulism outbreak, this toxin was initially recognized and isolated by Émile van Ermengem.4 There are multiple forms of BoNT, classified from A to G. The most commonly used clinically are serotypes A and B. The mechanism causing muscle paralysis has been well described in the literature. The toxin inhibits the release of neurotransmitters located at the presynaptic junction via deactivation of membrane vesicular proteins. BoNTA uses its endopeptidase light chain to deactivate the synaptosomal protein known as SNAP 25. This protein is located on the cell membrane and its deactivation prevents the release of acetylcholine. This causes muscle paralysis for a prolonged period of time.5
The mechanism of action of BoNTA has been explained; however, there are still unanswered questions. How does this schematic decrease the symptomatology in migraine headaches? A recent study from the University of British Columbia and the Center for Sensory-Motor Interaction in Denmark observed the effects of BoNTA when injected into craniofacial muscles of rats.6 Previous studies have shown that the plasma levels of glutamate are increased during migraines. This study investigated how BoNTA affected the mechanical and chemical responsiveness of the nociceptors, as well as the glutamate concentration in the temporalis muscles. Glutamate concentrations in the temporalis muscles of rats were decreased by approximately 70% when injected with 5 units of BoNTA. In addition, nociceptors became desensitized in comparison to the control animals. Research suggests that glutamate has a large role in BoNTA effectiveness; however, other undiscovered substances may also play a role. The study conducted by researchers in Canada and Denmark supported the theory that superficial cutaneous muscle nociceptors trigger a response that progressively spreads to cause central sensitization and thereby creates migraine headaches.6
Recent Studies on BoNTA Efficacy
There has been much debate on the efficacy of BoNTA in treating headaches.7 This is secondary to inconsistencies found in previous smaller studies. More recent trials, however, started to prove the effectiveness of BoNTA in migraine prevention. 2,7-9 The largest trials were conducted by the pharmaceutical company Allergan, makers of Botox.8,9 The PREEMPT (The Phase III REsearch Evaluating Migraine Prophylaxis Therapy) study examined the efficacy and safety of using Botox for chronic migraine prophylaxis in a total of 1,384 patients.8 Each study was randomized, double-blinded, and placebo-controlled in nature.
Additionally, each study consisted of a 24-week double-blind phase with two injection cycles, followed by a 32-week open-label phase with three injection cycles. Botox or placebo was administered in fixed doses at 31 specific sites across head/neck muscle areas. The maximum dose a patient could receive was 195 units of BoNT. Doses injected in temporalis, occipitalis, and trapezius muscles could vary based on a patient's symptomatology.
Results were tracked using a telephone diary so patients could record their headache symptoms. At 24 weeks, a statistically significant change from baseline was recorded in frequency of headache days (P=.006) and episode intensity among the Botox group. Other variables included cumulative headache hours and acute medication use. As a result, both studies supported the benefits of Botox treatment by showing a significant decrease from baseline in the frequency of headache days.8
Allergan has relied upon the PREEMPT studies to disclose the most effective injection paradigm for migraines (Table 2). A total of 155 units to 195 units of Botox can be injected at each visit on a fixed site. There should be a period of 3 months between each injection for best results. In regards to the safety profile of each study, adverse events were similar within both trials. Within the double-blinded phase, 5% of participants experienced neck pain or muscular weakness. Most adverse events were mild or moderate in severity and resolved without sequelae. Discontinuation rates were low. These results provide some evidence to the possible effectiveness of Botox in the treatment of chronic migraine headache. Future studies will need to be conducted to evaluate long-term effectiveness and sequelae.8
Although it is still unclear what the exact mechanism of action is, BoNT appears to be helping many patients cope with migraine headaches. The aforementioned studies show that many migraine sufferers have benefitted from BoNTA. Other trials have shown poor outcomes when BoNTA is used in patients who don't meet the migraine headache criteria. Ultimately, physicians have to make a decision about which patient is the proper candidate for treatment.