Dermatol Clin 22 (2004) 167 – 175 Botulinum neurotoxin for the treatment of migraine and other primary headache disordersAndrew M. Blumenfeld, MDa,*, David W. Dodick, MD, FRCP(C), FACPb,c, Stephen D. Silberstein, MD, FACPd a Department of Neurology, Kaiser Permanente, 4405 Vandever Avenue, San Diego, CA 92120, USA b Department of Neurology, Mayo Medical School, USA c Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA d Jefferson Headache Center, Thomas Jefferson University Hospital, 111 South 11th Street, Suite 8130, Philadelphia, PA 19107, USA Migraine is a chronic neurovascular disorder that . There is a significant need to develop moreafflicts 2% to 15% of the world’s population. In the effective therapies for migraine prevention becauseUnited States there are an estimated 28 million mi- 35% of migraineurs suffer from two to three severegraine sufferers, with women being affected three attacks per month, whereas 25% suffer from more thantimes as often as men . It is characterized by severe four attacks per month . Furthermore, more than 4%headaches and is often associated with nausea, vomit- of the United States population suffers from chronicing, and heightened sensitivity to sound and light at the daily headache .peak of the attack. Migraine is considered to cause Patients with frequent, disabling, or refractorymore disability than epilepsy, and severe migraine has migraine should be considered for prophylactic treat-been judged by the World Health Organization to be as ment. Current United States guidelines recommenddisabling as quadriplegia, psychosis, and dementia . preventive therapy in one or more of the following Most sufferers are in their most socially active and situations: (1) frequent headaches; (2) recurring mi-productive years (25 to 55) . Not only is migraine graines that significantly interfere with daily routine;painful and disabling for the sufferer, but it exerts (3) failure of, a contraindication to, overuse of, or ad-a significant economic burden on society. It causes verse events (AEs) with acute migraine therapies;112 million bedridden days each year and costs (4) cost of acute and preventive therapies; (5) patient$14 billion in reduced productivity and missed work- preference; and (6) the presence of uncommon mi-days . The economic burden of migraine is com- graine conditions, including hemiplegic migraine,parable with that of diabetes  and higher than that basilar migraine, migraine with prolonged aura, orof asthma . migrainous infraction . Although numerous thera- Even among migraineurs who consult a physician, pies are currently available for the prevention andmany are not satisfied with their therapy and report that treatment of migraine, most of these agents have sig-prescribed medications are not always optimal. Triptan nificant side effects.medications, the most effective therapy for acute Commonly used agents for migraine prophy-migraine attacks, are only effective in improving the laxis include b-adrenergic blockers, calcium channelpain and associated migraine symptoms, such as blockers, tricyclic antidepressants, and anticonvul-photophobia and nausea, in up to two thirds of patients sants (Table 1). Moderate to severe AEs are not un- common with all available prophylactic medications. b-Blockers are known to produce a wide array of * Corresponding author. AEs, including drowsiness, fatigue, lethargy, sleep E-mail address: Andrew.m.Blumenfeld@kp.org disorders, and depression. AEs typically associated(A.M. Blumenfeld). with the calcium channel blockers include constipa-0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.doi:10.1016/S0733-8635(03)00105-0
168 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175Table 1 the treatment of glabellar lines . Although notPreventive therapeutics commonly prescribed for migraine currently indicated, it has also been safely used for Quality of Scientific Clinical spasticity; hyperkinetic disorders, such as tremor; Evidencea Effectb Impressionc autonomic disorders, such as hyperhidrosis; and cos-Anticonvulsants metically troublesome hyperfunctional facial lines Divalproex sodium A +++ +++ (crow’s feet, forehead lines) [12,13]. Topiramate A +++ +++ The analgesic effect of BoNT-A has long been Gabapentin B ++ ++ observed in the treatment of dystonia and spasticityAntidepressants [14,15]. This led to further investigation of the efficacy Amitriptyline A +++ +++ of BoNT-A for other painful conditions, including Fluoxetine B + + migraine and tension-type headaches. Because mostb-blockers clinical experience with the use of BoNT for the Propranolol A ++ +++ treatment of headache has been with BoNT-A, this Metoprolol B ++ +++ Timolol A +++ ++ article describes the potential antinociceptive mecha- Atenolol B ++ ++ nism of action of BoNT-A, summarizes the clinicalCalcium channel blockers evidence to date for BoNT-A as effective migraine Verapamil B + + prophylactic therapy, and reviews the injection tech- Nimodipine B + + nique and strategies used in treating headache and a A, Multiple well-designed randomized clinical trials, cervical myofascial pain.directly relevant to the recommendation, yielded a consistentpattern of findings; B, some evidence from randomized cli-nical trials supported the recommendation, but scientific sup- Mechanism of actionport was not optimal. b +, Effect of medication is either statistically or not Botulinum toxins are exotoxins of the anaerobicclinically significant; ++, effect of medication is statistically bacterium Clostridium botulinum. This bacterium hassignificant and exceeds the minimally clinically significant eight serotypes: A, B, C-alpha, C-beta, D, E, F, and G.benefit; +++, effect is statistically significant and far exceedsthe minimally clinically significant benefit. Seven serologically separate exotoxins are produced. c +, Somewhat effective: few people get clinically sig- The intracellular targets of each of these toxins vary;nificant improvement; ++, effective: some people get cli- however, their biologic activity at the neuromuscularnically significant improvement; +++, very effective: most junction is similar .people get clinically significant improvement. Injection of BoNT-A directly affects neuromuscu-Adapted from Silberstein SD, Goadsby PJ. Migraine: lar signaling processes. On injection, the toxin entersPreventive treatment. Cephalalgia 2002;22:491 – 512. the nerve terminals by endocytosis; interacts with intracellular proteins (snare proteins); and inhibits the vesicular release of the acetylcholine neurotrans-tion, peripheral edema, and weight gain , whereas mitter at the neuromuscular junction. Inhibition ofthe tricyclic antidepressants commonly are associated acetylcholine produces chemical denervation andwith a variety of AEs, including sedation, weight paralysis of the striated muscles. Paralysis usuallygain, dry mouth, constipation, dizziness, mental con- peaks 2 weeks postinjection. Because of molecularfusion, palpitations, blurred vision, and urinary reten- turnover within the neuromuscular junction and neu-tion. The AEs associated with antiepileptic drugs are ronal sprouting, neuronal activity begins to return atunique to each medication, but the most common AEs 3 months, with complete function at approximatelyinclude nausea, vomiting, and gastrointestinal distress 6 months .. Because of the AE profile and limited efficacy of Although neuromuscular activity inhibition maycurrently available preventive therapies, there is a alleviate a portion of the pain associated with headacheneed for novel and improved prophylactic therapies. disorders, it does not fully explain the pain relief Recently, the potent neurotoxin botulinum toxin mechanisms mediated by BoNT-A. Intensive researchtype-A (BoNT-A) has been under intensive clinical on BoNT-A has begun to suggest that this toxin mayinvestigation for the treatment of migraine and other interact with several other neuronal signaling path-types of headache. Over the last 20 years, BoNT-A has ways, although the exact mechanisms remain elusive.been used to treat a variety of disorders characterized Current data suggest that BoNT-A modifies the sen-by inappropriate and involuntary muscle contraction sory feedback loop to the central nervous system by. BNT-A is currently approved for blepharospasm, blocking intrafusal fibers, resulting in decreased acti-strabismus, cervical dystonia, and, more recently, for vation of muscle spindles. This effectively alters the
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 169sensory afferent system by reducing the traffic along Iaspindle afferent fibers . This toxin also seems toinhibit the release of glutamate from primary afferentnociceptive fibers, reduce the firing of wide dynamicrange neurons within the dorsal horn of the spinal cord,and reduce the activity of central nociceptive neuronsas measured by a reduction in the expression ofimmediate early genes (c-Fos) after nociceptor stimu-lation . A reduction in afferent sensory activitycoming from pericranial and cervical muscles, andinhibition of peripheral and central trigeminal sensi-tization, may represent the potential mechanisms bywhich BoNT-A exerts its therapeutic effect in mi-graine, tension-type headache, and other primaryheadache disorders .Clinical efficacy: retrospective reviews and open-label trial Historically, while conducting the initial clinicaltrials of BoNT-A for the treatment of hyperfunctional Fig. 2. Injection site: temporalis and masseter muscles.facial lines, Binder et al  noted a correlationbetween pericranial BoNT-A injections and alleviationof migraine headache symptoms. Based on these initialfindings, the authors conducted a combined, multicen-ter, open-label trial that evaluated the efficacy of Fig. 3. Injection site: occipital, suboccipital, and trapezius Fig. 1. Injection sites: glabellar and frontal regions. muscles.
170Table 2Retrospective/open-label and placebo-controlled trials of botulinum toxin A treatment for migraineStudy Design (N) and Patient Typea Dose Injection site Primary result reportedRetrospective Reviews/Prospective Open-label TrialsBinder et al (2000) Retrospective chart Mean dose 31 units Fixed injection sites 51% of migraine patients reported A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 review (N=77) (range 5 – 110 units) Glabellar complete response Frontal TemporalMauskop and Basedo (2000) Retrospective chart 25 – 100 units Fixed injection sites 85% (23 of 27) of patients reported significant review (N=27) (frontalis, glabellar, reduction in frequency and intensity and temporalis) Some patients received a combination of fixed injections and ‘‘follow-the-pain’’ injectionsMauskop (2002) Retrospective chart review (N=78) Varying dose from ‘‘Follow-the-pain’’ protocol Most patients reported partial to complete Episodic migraine, N=32 25 – 200 units response (no percentage improvement given Chronic migraine, N=46 in this study)Miller and Denny (2002) Retrospective chart review (N=48) Varying dose from Fixed injection site 86% of patients treated with BTX-A reported All patients were chronic headache 50 – 300 units (frontalis, corrugator, nominal benefit with 35% reporting good and patients who had failed temporalis, splenius captis) 27% very good benefits previous therapy with ‘‘follow-the-pain’’ as neededBlumenfeld (2002) Retrospective chart Average dose 63.2 units Injection sites were 25% reduction in headache intensity ( P < .001) review (N=271) either ‘‘fixed’’ or 56% reduction in headache days per month Headache types includeb ‘‘follow-the-pain’’ ( P < .0001) Chronic daily 85.6% of patients reported symptomatic improvement Episodic-tension Episodic-migraine MixedMathew et al (2002) Retrospective chart 50 – 100 units Combination of fixed Three months after third injection a significant review (N=112) injection sites (frontal/ decrease in the number of headache days All patients diagnosed with glabellar/ temporal/ ( P < .05) and a decrease in mean MIDAS scores chronic migraine occipital/ suboccipital) ( P < .01) were observed and ‘‘follow-the-pain’’
Smuts and Barnard (2000) Prospective, open-label 100 units Variable sites 68% (13 of 19) of migraine patients reported (N=19) (no specific protocol positive response mentioned in abstract)Eross and Dodick (2002) Prospective, open-label 25 units Fixed injection sites Of patients who responded > 50% reported an (N=73) If required based on Frontalis improvement in disability Episodic migraine, N=12 pain, 25 – 75 additional Temporalis 61% of responders reported decrease in headache Chronic migraine, N=36 units injected into Procerus frequency and 27% reported decrease in cervical paraspinals Corrugator headache severityPlacebo-Controlled TrialsBarrientos and Chana (2002) Placebo-controlled (N=30) 50 units Fixed injection sites Significant reduction in frequency (P < .001), Glabellar severity (P < .02), and adjunct medications A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 Frontal (P < .001) compared with placebo Temporal Procerus Trapezius Splenium capitisSilberstein et al (2000) Placebo-controlled/ 25 units (low dose) Fixed injection sites 45% of patients in low-dose group (25 units) double-blind (N=123) 75 units (high dose) Glabellar reported a >50% decrease in frequency Frontal TemporalBrin et al (2000) Placebo-controlled/ Dose not given Fixed injection sites BTX-A was superior than placebo in reducing double-blind (N=56) in study Frontal severity (P=.04) TemporalOndo et al (2002) Placebo-controlled/ 200 units Individual injection 10% of patients reported a ‘‘dramatic’’ improvement double-blind (N=60) choice using ‘‘follow- and 24% a ‘‘marked’’ improvement. Chronic migraine, N=19 the-pain’’ protocol Significant reduction in the number of headache Chronic tension headache, days (weeks 8 – 12) compared with placebo N=22 (P < .05) Features of both types of headache, N=19 a Unless specified, patient population consists of migraine headache. b Number of patients in each headache not specified. 171
172 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175BoNT-A for migraine management. Efficacy was poralis muscle. At the end of the 3-month follow-upcategorized as either complete response with total period postinjection, the low-dose BoNT-A groupsymptom elimination, partial response with greater experienced a mean decrease of 1.88 moderate-to-than 50% reduction in headache severity and fre- severe migraines compared with the placebo groupquency, or no beneficial response. In this study, 51% (P = .042). Furthermore, patients in the low-doseof patients treated with BoNT-A as migraine pro- group had a significant reduction in the incidence ofphylaxis reported a complete response to localized migraine-associated vomiting compared with placebohead and neck BoNT-A injections with a mean dura- (P = .012). The high-dose BoNT-A group, however,tion of 4.1 months. An additional 38% reported par- did not have a significant effect on migraine pain andtial improvement with a mean response period of associated symptoms. In fact, at the higher dose, there2.7 months . was an increase in AEs. The authors suggest that the Since then, many researchers have reported their lack of BoNT-A activity at this higher concentrationexperience with BoNT-A. Mauskop and Basedo  may actually be caused by a lower number of migrainereviewed chart records of 27 patients treated with headaches at baseline compared with the low-doseBoNT-A for migraine prophylaxis by injections in BoNT-A group . In this trial, BoNT-A was wellthe pericranium. A decrease in headache frequency tolerated with no AEs observed in the low-dose groupand severity was reported in 85% (N = 23) of patients. compared with placebo.Rather than focusing solely on the end point of severity Barrientos and Chana  also conducted a ran-and frequency of headache, Eross and Dodick  domized, placebo-controlled trial (no indication ofevaluated the effect of BoNT-A (25 to 100 units) on being double-blinded) that evaluated the efficacy andreducing disability in 47 patients with either episodic tolerability of BoNT-A as prophylaxis for episodicor chronic migraine. Using a well-validated tool to migraine. Thirty patients with a history of two toassess migraine-related disability (the MIDAS ques- eight migraine attacks per month were enrolled andtionnaire), 58% of all patients reported a decrease in randomized to receive placebo or 50 units of BoNT-Amigraine-associated disability. Episodic migraine injected in 15 pericranial muscle sites. During thepatients (N = 12) seemed to show the most benefit, 3-month study, when compared with baseline, patientswith 75% reporting a decrease in migraine frequency treated with BoNT-A experienced fewer attacks atcompared with 53% of chronic migraine patients . day 30 (3.7 versus 5.8, P < .02); day 60 (3.2 versus Other retrospective reviews [24 – 28] further sup- 5.8, P < .2); and day 90 (2.5 versus 5.8, P < .01). Inport the beneficial role of BoNT-A for the preventive comparison, no significant reduction from baselinetreatment of episodic migraine, chronic tension-type was observed in the placebo group. Severity andheadache, and treatment-refractory chronic migraine duration of migraine attacks also were significantlyheadaches. Aside from the obvious limitation of a reduced in the BoNT-A group compared with placebo.retrospective review or open-label design, the weak- At the end of the 3-month study, the BoNT-A – treatednesses of many of these study reports include small group reported a significant decrease in the use ofpatient number; poorly defined end points; and often nonsteroidal anti-inflammatory drugs and triptanheterogeneous patient populations (episodic-chronic medications for acute headache treatment comparedmigraine, tension-type or chronic headaches). with placebo. This supports the previous clinical data that BoNT-A is effective and well tolerated for pre- ventive migraine treatment.Clinical efficacy: placebo-controlled trials A small, double-blind, placebo-controlled study of BoNT-A conducted by Brin et al  further supports Currently, few well-conducted clinical trials of the efficacy of BoNT-A in migraine. In this trial,BoNT-A in migraine prevention exist. The first 56 subjects with a history of two to six migraines perdouble-blind, placebo-controlled, randomized clinical month were randomized into four groups receiving (1)trial was published by Silberstein et al . In this study, BoNT-A in frontal-temporal regions, (2) BoNT-A in123 patients who had experienced between two to frontal and placebo in temporal, (3) placebo in frontaleight moderate-to-severe migraine headaches over a and BoNT-A in temporal, and (4) placebo in frontal-3-month period were randomized to receive a single temporal regions. Migraine frequency was reduced byinjection of either placebo, low-dose (25 units), or a median of 1.8 headaches per month in BoNT-A –high-dose (75 units) BoNT-A. This single dose was treated groups (groups 1 to 3) compared with a medianinjected into multiple sites of pericranial muscles reduction of 0.2 headaches per month in the placeboduring the injection visit. Injections were performed group (group 4). This study is limited, however, by itsanteriorly, in the frontalis, glabellar region, and tem- small population size.
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 173 Recently, Ondo et al  conducted a randomized, For patients with only tension-type headaches, thedouble-blind, placebo-controlled, parallel clinical trial follow-the-pain approach is used. Even in these cases,that examined the effect of BoNT-A treatment on pa- cosmetic effects in the frontal region need to betients with chronic daily headache, including chronic obtained, but asymmetric injections can be given intension-type headache and chronic migraine. Sixty the temporalis, occipitalis, splenius capitus, cervical,patients who experienced chronic headache more than and subcervical paraspinal muscles. The doses injected15 days each month were enrolled and randomized to in the cervical-shoulder girdle muscles are low to pre-receive, based on the ‘‘follow-the-pain’’ rationale, vent any possible weakness, which could cause head-either 200 units of BoNT-A or matching placebo and ache. Patients need to be assessed carefully forat 12 weeks, if patient consented, a second open-label associated cervical dystonia, which requires injectionBoNT-A injection. Following the first injection, of the dystonic muscles.patients treated with BoNT-A had significantly fewer Current available data do not seem to indicate aheadache days from week 8 to 12 compared with dose response-benefit [8,21,23,24]. There is need forplacebo. In addition, 10% of patients treated with further randomized, placebo-controlled clinical trialsBoNT-A reported a dramatic improvement and 24% to identify the optimal dosing regimen and injectionreported a marked improvement compared with 3% sites for BoNT-A. Some data, however, report greaterand 7%, respectively, in the placebo-treated group. At efficacy with repeated dosing. In the Ondo et al week 24, patients who had received two BoNT-A trial, patients who received a repeat BoNT-A injectioninjections had significantly fewer headache days over reported better improvement than patients who re-the second 12-week period than those receiving one ceived only a single BoNT-A injection ; these datainjection (40 versus 19 days, P < .05). are also supported by results from retrospective chart reviews [26,28]. Until results of large, well-conducted trials are available, optimal method of BoNT-A deliv-Use of botulinum toxin A: dosage and ery remains unresolved.administration The most common sites of injections include the Tolerabilityglabellar (procerus and corrugators), frontal, temporal,and sometimes the occipital regions (Figs. 1 – 3). The clinical dose of BoNT-A commonly used forBoNT-A is administered either at fixed injection sites; migraine therapy is between 25 and 100 units, which isat sites of pain or tenderness (‘‘follow the pain’’); or a 30 to 120 times below the toxic limit . Mostcombination of both. The total dosage of toxin, the published trials have reported minimal to no AEs. Innumber of units per site of injection, dilution of toxin, a placebo-controlled, double-blind trial, Silbersteinand sites of injection varied widely, however, between et al  found that although no serious AEs occurred,studies (Table 2). The total dosage ranged from 25 to some patients receiving BoNT-A injections experi-300 units over several injection sites. enced transient minor AEs, including blepharoptosis, The fixed-site approach consists of bilateral in- diplopia, and injection site weakness. The authors alsojections, even if the patient has strictly unilateral found that injection of high doses of BoNT-Aheadaches. The muscles injected are the procerus, (75 units) resulted in a dose-dependent increase incorrugators, frontalis, and temporalis. Follow-the-pain the side effect profile of BoNT-A. In an open-labelinjection sites are identified by history (‘‘Where does it study, Binder et al  also reported only minimal andhurt when you have a headache’’? and ’’ Show me with transient AEs, including brow ptosis, local injectionyour hands where the pain is’’) and by examination of discomfort, and ecchymosis at the injection site. Over-the cervical-shoulder girdle and temporomandibular all, clinical studies and retrospective reviews confirmmusculature. These sites include the frontalis, tempo- the tolerable side effect profile of BoNT-A and thatralis, occipitalis, trapezius, splenius capitus, suboccipi- associated AEs are typically mild and transient.tal, and cervical paraspinal muscles. For patients with migraine or migrainous headachefeatures by history, treatment with a fixed-site ap- Summaryproach may be required for successful results. Whenonly a follow-the-pain approach is used in patients Clinical data and experience to date have demon-with migraine or migrainous headache, two problems strated that BoNT-A is an effective and well-toleratedarise: first, a poor cosmetic outcome; and second, the therapy for the prevention of migraine and otherheadaches often shift to the previously unaffected side. headache disorders. It has a long duration of action
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