Botulinum Neurotoxin for the Treatment of Migraine and Other Primary Headache Disorders: From Bench to Bedside

Botulinum toxin type A, a neurotoxin, is effective for treating a variety of disorders of involuntary muscle contraction including cervical dystonia, blepharospasm, and hemifacial spasm. It inhibits neuromuscular signaling by blocking the release of acetylcholine at the neuromuscular junction. The biological effects of the toxin are transient, with normal neuronal signaling returning within approximately 3 to 6 months postinjection.
Recent clinical findings suggest that botulinum toxin type A may inhibit pain associated with migraine and other types of headache. However, the mechanism by which this toxin inhibits pain is not fully understood and is under investigation. Research findings suggest that botulinum toxin type A inhibits the release of neurotransmitters from nociceptive nerve terminals and, in this way, may possess an analgesic effect. A number of retrospective open-label chart reviews and 3 double-blind, placebo-controlled trials have demonstrated that localized injections of botulinum toxin type A significantly reduce the frequency, severity, and disability associated with migraine headaches. Although the majority of patients in these studies experienced no botulinum toxin type A-mediated side effects, a small percentage of patients did report transient minor side effects including blepharoptosis, diplopia, and injection-site weakness. Currently, 4 randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A as a novel treatment for migraine and other types of headache. These studies may provide further evidence that botulinum toxin type A is an effective option for the preventive treatment of migraine.     

Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain Management

The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems. ¹
The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c- fos , expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin.
These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine.     

The prophylactic treatment of chronic daily headache

Chronic daily headache (CDH), a heterogeneous group of headache disorders occurring on at least 15 days per month, affects up to 4% to 5% of the general population. CDH disorders include transformed (or chronic) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Patients with CDH have greater disability and lower quality of life than episodic migraine patients and often overuse headache pain medications. To date, only topiramate, gabapentin, tizanidine, fluoxetine, amitriptyline, and botulinum toxin type A (BoNTA) have been evaluated as prophylactic treatment of CDH in randomized, double-blind, placebo-controlled, or active comparator-controlled trials. The evidence supporting the use of BoNTA as prophylaxis of CDH is composed of larger and longer trials, as over 1000 patients were evaluated for up to 11 months duration. Compared with placebo BoNTA has significantly reduced the frequency of headache episodes, a recommended efficacy measure for headache trials and has been demonstrated to be safe and very well tolerated with few discontinuations due to adverse events. Side effects are generally transient, mild to moderate, and nonsystemic. The results of clinical trials using traditional oral pharmacotherapy, while supportive of their use as prophylactic treatment of CDH, are limited by several factors, including small numbers of patients, the choice of efficacy measures, and short treatment periods. The use of oral agents was associated with systemic side effects, which may limit their effectiveness as prophylactic treatment of CDH.     

Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders

OBJECTIVE: To measure the effect of botulinum toxin type A (Botox, Allergan, Inc, Irvine, CA) treatment in 271 patients diagnosed with headache in accordance with International Headache Society (IHS) criteria. BACKGROUND: Botulinum toxin type A has shown promise for the treatment of headache in several clinical trials, but uncertainty remains as to how botulinum toxin type A optimally should be used for treating headache and which patients are best suited for this treatment. METHODS: This was a retrospective chart review of all patients who received botulinum toxin type A for the treatment of headache from January 1999 to February 2002. Patients were injected with an average dose of 63.2 U (SD, 14.5) of botulinum toxin type A on 2 or more visits, with treatments involving a "fixed-site" or a "follow-the-pain" (or a combination of both) approach. In the fixed-site approach, botulinum toxin type A was injected into the procerus, corrugator, frontalis, and temporalis muscles. In the follow-the-pain approach, botulinum toxin type A was injected into a combination of the procerus, corrugator, frontalis, temporalis, occipitalis, trapezius, and/or semispinalis capitis muscles. The primary outcomes for the trial were the reduction in headache days per month or headache intensity (0 to 3 scale) (or both) from baseline. Patients were diagnosed according to IHS criteria and subsequently classified into the following categories: chronic daily headache (more than 15 headache days per month), episodic tension-type headache, episodic migraine, and "mixed" HA (less than 15 headache days per month, combination of migraine and tension-type headache). RESULTS: Treatment period was an average of 8.6 months (SD, 6.4); patients received an average of 3.4 doses (SD, 1.6) 3 months apart. Of the 271 patients, 29 (10.7%) had episodic migraine, 17 (6.3%) had episodic tension-type headache, 71 (26.2%) had mixed headache, and 154 (56.8%) had chronic daily headache. Two-hundred fifty-six patients had data for the number of headache days per month, 117 had data for headache intensity, and all 271 had data for headache days or headache intensity. Botulinum toxin type A treatment significantly reduced the number of headache days per month from 18.9 (SD, 10.3) to 8.3 (SD, 8.9) (n=256, P<.001)--a 56% reduction. Headache intensity decreased from 2.4 points (SD, 0.6) to 1.8 points (SD, 0.8) (n=117, P<.001)--a 25% reduction. Of 263 patients surveyed, 225 (85.6%) reported improvement in headache frequency and intensity. There was no correlation of effect/lack of effect with reason for treatment, duration/number of treatments, injection technique, mean/total dose, age, gender, or comorbidity. Approximately 95% of patients did not experience medication side effects. CONCLUSION: These results suggest that botulinum toxin type A may be an effective and safe prophylactic treatment for a variety of moderate to severe chronic headache types.     

Prophylaxe der chronischen Migr?ne mit Botulinumtoxin Typ A

Since the second edition of the International classification of headache disorders (ICDH-II 2004), chronic migraine has been listed amongst migraine complications. Compared to episodic migraine the prevalence of chronic migraine is low, its impact, however, significant. Until recently no prophylactic drug had been approved for chronic migraine prophylaxis. After case reports had stated an effect of botulinum toxin type?A on migraine, several randomized placebo-controlled studies were conducted in episodic headache; the results, however, were disappointing. Only when botulinum toxin type?A was used in chronic migraine in the PREEMPT (phase 3 research evaluating migraine prophylaxis therapy) trials, its superiority compared to placebo was established. Thus, for the first time a prophylactic drug against chronic migraine is available which is both effective and well tolerated. Botox? has been licensed in England for the prophylaxis of headaches in adults with chronic migraine in 2010. Approval for its use in Germany has been applied for.     

Botulinum toxin type A in the prophylactic treatment of chronic migraine

Since the second edition of the International classification of headache disorders (ICDH-II 2004), chronic migraine has been listed amongst migraine complications. Compared to episodic migraine the prevalence of chronic migraine is low, its impact, however, significant. Until recently no prophylactic drug had been approved for chronic migraine prophylaxis. After case reports had stated an effect of botulinum toxin type A on migraine, several randomized placebo-controlled studies were conducted in episodic headache; the results, however, were disappointing. Only when botulinum toxin type A was used in chronic migraine in the PREEMPT (phase 3 research evaluating migraine prophylaxis therapy) trials, its superiority compared to placebo was established. Thus, for the first time a prophylactic drug against chronic migraine is available which is both effective and well tolerated. Botox? has been licensed in England for the prophylaxis of headaches in adults with chronic migraine in 2010. Approval for its use in Germany has been applied for.     

Treatment of Chronic Migraine

Chronic migraine is defined in different ways. The most commonly used definition is headache on more than 15 days per month in patients with migraine. Chronic migraine is difficult to treat and requires a multidisciplinary approach. Only two pharmacological treatments have been shown to be effective in placebo-controlled randomized trials: topiramate and local injection of botulinum toxin. Both therapies are effective in patients with chronic migraine with and without medication overuse. Many other substances have been investigated in chronic daily headache. All trials were underpowered and, therefore, recommendations concerning possible efficacy are not possible.     

Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy

OBJECTIVES: To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. BACKGROUND: The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. RESULTS: A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. CONCLUSIONS: These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.     

Single-site botulinum toxin type a injection for elimination of migraine trigger points

BACKGROUND: Botulinum toxin may be effective in suppressing migraine. Most injection regimens utilized have involved multiple sites. PURPOSE: To evaluate prospectively the effect of botulinum toxin type A injections into the corrugator supercilii muscles alone on the frequency and severity of migraine. METHODS: Twenty-nine patients (24 women, 5 men) with migraine were enrolled in the study. Average age was 45 years (range, 24 to 63). The frequency (number of migraines per month) and intensity (recorded on an analog scale of 1 to 10, 10 being most severe) of headache were recorded before and after treatment. Twenty-five units of botulinum toxin type A was injected into each corrugator supercilii muscle, for a total of 50 units. RESULTS: At 2 months, 24 (83%) of 29 patients reported a positive response to the injection of botulinum toxin type A (P <.001). Sixteen patients (55%) reported complete elimination of headache (P <.001), 8 (28%) experienced significant improvement (at least 50% reduction in frequency or intensity) (P <.04), and 5 (17%) did not notice a change in headache. The duration of efficacy of the botulinum toxin type A injections ranged from 6 to 12 weeks, with an average of 8 weeks. In patients who had improvement in migraine but not complete elimination, the headache frequency decreased from 6.4 to 2.1 per month on average (P <.04), and the intensity decreased from 8.6 to 6.1 (P <.04). CONCLUSION: These results support the hypothesis that focal injection of botulinum toxin type A may be an effective therapy for migraine.     

Botulinum toxin type A in prophylactic treatment of migraine headaches: a preliminary study

Abstract The purpose of this study was to determine the safety and efficacy of botulinum toxin type A (BOTOX; Allergan, Irvine, USA) in migraine prophylaxis. We performed a double-blind, randomized, 90-day placebo-controlled study that enrolled 30 adult migraineurs. Patients received 50 units botulinum toxin type A (n=15) or placebo (n=15). Outcome measures were monthly frequency and duration of migraine attacks and the number of severe attacks. Botulinum toxin type A produced significantly greater reductions in the frequency of migraine attacks of any severity at Day 90 (-3.14 vs. -0.53; p<0.05) and in the frequency of severe migraine attacks at Days 60 (-1.4 vs. -0.54; p<0.05) and 90 (-1.8 vs. -0.20; p<0.02). One patient in the botulinum toxin type A group experienced mild, transient frontalis muscle weakness lasting approximately 30 days. Botulinum toxin type A injections were well tolerated and provided effective migraine prophylaxis in these patients.     

Botulinum toxin type A in the management of headache: a review of the literature and personal experience

Abstract Botulinum toxin type A (BoNT-A) shows significant promise in the management of a variety of headache types including migraine, chronic daily headache, tension-type headache, and other head and neck pains. Confirmation of efficacy still awaits the report of well-controlled double-blind placebo-controlled trials; however, a mounting body of evidence suggests that BoNT-A is effective, well-tolerated and safe for the management of many headache disorders. In this paper, I review recent evidence on the efficacy of BoNT-A, and also report my personal experience with the treatment in over 600 headache patients.     

Mechanism of action of botulinum toxin type A in migraine prevention: a pilot study

OBJECTIVE: The main objective of this study is to determine whether change in migraine frequency is correlated with a denervation pattern of the corrugator muscle after local botulinum toxin type A injections. BACKGROUND: Recent studies suggest botulinum toxin type A is effective in preventing migraine. Relaxation of the corrugator muscle may be one of multiple targets of botulinum toxin type A in relieving migraine pain. METHODS: The pretreatment amplitude of the compound muscle action potential (CMAP) was obtained in 10 patients with a migraine frequency of two to six attacks per month following stimulation of the temporal branch of the facial nerve. Patients were subsequently injected with 20 units of botulinum toxin type A at predefined sites in the procerus and corrugator muscles. CMAP was obtained on days 7, 30, 60, and 90 after injection. Migraine frequency, as reported in headache diaries, was compared with the amplitudes obtained. RESULTS: A 50% decrease in CMAP was demonstrated in the total group by day 7. Maximal decline of CMAP was observed by day 30, and was sustained at day 60. Migraine frequency declined by 50% or more in 7 of 10 patients by day 60. Migraine response to botulinum toxin type A treatment did not correlate with the denervation pattern. CONCLUSION: Relaxation of the corrugator muscles is not solely responsible for the pain relief in migraine patients treated with botulinum toxin type A.     

Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study

A beneficial effect of botulinum toxin on tension-type headache was reported in open-label studies but scientifically rigorous clinical studies are lacking. Therefore we conducted a prospective, multicenter, randomized, double-blind, placebo-controlled trial. Multiple pericranial muscles of 112 patients with chronic tension-type headache were treated either with 500 mouse units of botulinum toxin (Dysport) or with placebo. The diagnoses were made strictly following the International Headache Society criteria. Co-existence of migraine was an exclusion criterion. Injections were made following a fixed scheme and not adjusted to the patient's symptoms. Patients kept a headache diary that was used to calculate the area under the headache curve of 6 weeks before and 12 weeks after the treatment as the main effect measure. Secondary effect measures were the number of days with headache, the number of days with intake of analgesics, the duration of the nocturnal sleep, and the Beck Depression Inventory score. There were no significant differences between the verum group and the placebo group in any of these variables. Seven patients of the verum group had transient weakness of the eyelids, the neck, or both, indicating that a higher dose than used in this study does not seem sensible for the treatment of headache. The statistical power of the study was high enough to warrant the conclusion that there is no clinically significant effect of botulinum toxin A on chronic tension-type headache.     

The use of botulinum toxin in the treatment of headaches

The use of botulinum toxin for movement disorders and cosmesis led to an accidental discovery of its beneficial effect on headaches. Extensive anecdotal evidence and several controlled trials suggest that intermittent and chronic migraines and chronic tension headaches may respond to this treatment. The effect of a single treatment, which is simple to administer, can last for 3 months. Botulinum toxin does not cause systemic or any other serious side effects. Prophylactic pharmacotherapy of migraine headaches is limited in its efficacy and has a potential for systemic side effects. This makes botulinum toxin a preferred treatment for many patients. The large controlled trials that are underway may lead to a wider acceptance of this treatment by neurologists and pain specialists.     

Botulinum toxin for the treatment of musculoskeletal pain and spasm

The impressive pain relief experienced by sufferers of dystonia and spasticity from intramuscular injections of botulinum toxin suggested that patients with other chronic, musculoskeletal pain conditions also may benefit. However, there have been relatively few placebo-controlled studies of botulinum toxin in such non-neurologic conditions as myofascial pain syndrome, chronic neck and low back pain, and fibromyalgia; the results of these studies have not been impressive. One explanation for the lack of positive findings may be the lack of clinically evident muscle spasms (overactivity), despite the presence of muscle tenderness, tightness, or trigger points. Clinical observations of pain relief from injections of botulinum toxin for dystonia and spasticity and its apparent efficacy in treating migraine suggest an anti-nociceptive action independent of its neuromuscular junction-blocking action. Evidence from animal experiments supports this notion, and other data provide plausible physiologic mechanisms in the periphery and central nervous systems. These involve modulation of the activity of the neurotransmitters glutamate, substance P, calcitonin gene-related peptide, enkephalins, and others. However, even if botulinum toxin is firmly established as an analgesic, there is insufficient clinical evidence of its efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.     

Botulinum toxin injections for the treatment of frontal tension headache

Abstract We performed a randomized, double-blind, placebo-controlled trial to determine the efficacy of botulinum toxin type A (BOTOX; Allergan) in treating frontal tension-type headache (TTH). A total of 40 patients attending a headache treatment center were randomized to receive 50 U botulinum toxin type A or saline, injected at 10 sites of the forehead. Frequency and severity of headaches before and after injection were compared. The intensity of headaches in the botulinum toxin type A group, but not the placebo group, fell significantly from an average score of 5.19 to 4.65 (p<0.0001). Botulinum toxin type A patients and placebo patients experienced an average reduction in the number of headaches per month, but these reductions were not significantly different between groups. Botulinum toxin type A was well tolerated, with no significant adverse events. Botulinum toxin type A injections in the management of frontal TTH has been shown by this study to be both effective and well tolerated. It should be noted that the effect of botulinum toxin on intensity of headache, although statistically significant, was relatively small.     

Application of botulinum toxin to clinical therapy: advances and cautions

The therapeutic use of botulinum toxin Type A has followed a novel and unanticipated pathway of applications, from its initial application by Scott to paralyze the extraocular muscles of the eyes to correct strabismus. In the late 1970s, Scott formed a company, called Oculinum Inc, to make botulinum toxin Type A available for this ophthalmic application. From this modest and limited beginning, it has found use for treatment of a plethora of cosmetic, neuromuscular, and skeletal disabilities, including cervical dystonia, blepharospasm, and temporary improvement in the appearance of moderate to severe glabellar lines. Botulinum toxin Type A is now being used as therapy in voiding disorders, migraine and tension-type headache, writer's cramp, and laryngeal muscle hyperactivity syndromes. It has reduced the spasm and pain associated with perianal fissures. It has found application in the reduction of glandular function in severe primary axillary hyperhidrosis and sialorrhea. Additional applications are being studied in the area of pain management based on its apparent ability to inhibit neuropeptide release from nociceptors.     

Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group

OBJECTIVE: To assess the safety and efficacy of botulinum toxin type A (BOTOX; Allergan, Inc) in the prevention of migraine. BACKGROUND: Current migraine preventive therapies are often unsatisfactory because of their limited efficacy, adverse effects, and drug interactions. Botulinum toxin type A injections often reduce the pain associated with conditions such as cervical dystonia, achalasia, rectal fissures, and myofascial pain syndrome. An open-label, noncontrolled study of botulinum toxin type A suggested benefits for patients with migraine. DESIGN AND METHODS: This was a double-blind, vehicle-controlled study of 123 subjects with a history of two to eight moderate-to-severe migraine attacks per month, with or without aura. Participants were randomized to receive single administrations of vehicle or botulinum toxin type A, 25 U or 75 U, injected into multiple sites of pericranial muscles at the same visit. During a 1-month baseline period and for 3 months following injection, subjects kept daily diaries in which they recorded migraine frequency, migraine severity, and the occurrence of migraine-associated symptoms. RESULTS: Compared with vehicle treatment, subjects in the 25-U botulinum toxin type A treatment group showed significantly fewer migraine attacks per month, a reduced maximum severity of migraines, a reduced number of days using acute migraine medications, and reduced incidence of migraine-associated vomiting. Both the 25-U and 75-U botulinum toxin type A groups were significantly better than the vehicle group on subject global assessment. Botulinum toxin A treatment was well tolerated, with only the 75-U treatment group exhibiting a significantly higher rate of treatment-related adverse events than vehicle. CONCLUSIONS: Pericranial injection of botulinum toxin type A, 25 U, was found to be a safe treatment that significantly reduced migraine frequency, migraine severity, acute medication usage, and associated vomiting.     

Hourglass deformity after botulinum toxin type A injection

BACKGROUND: Complications, such as eyelid ptosis, have been attributed to botulinum toxin type A. An "hourglass" deformity, which is the consequence of temporalis muscle atrophy, has not been reported previously. OBJECTIVE: To report a transient muscle deformity of the temporalis muscle caused by botulinum toxin type A. METHODS: Patients who underwent injection of 25 units of botulinum toxin type A into the temporal muscle, in a fan-shaped fashion, during an ongoing study for treatment of migraine were noted to develop temporary depression of the temples. Preinjection and postinjection photographs were taken. Patients were also sent questionnaires to verify the observed information. RESULTS: Only 26 of 92 patients who underwent injection of botulinum toxin type A into the temporalis muscle subsequently reported depression of the muscle. When examined, all 92 patients exhibited this deformity ranging from minimal to significant. Patients who seemed to have less deformity were those who had excessive soft tissue overlying the muscle due to excess weight. CONCLUSION: A newly recognized deformity is reported subsequent to the injection of botulinum toxin type A into the temporalis muscle. Informing patients of this transient deformity may minimize concern following treatment.