Botulinum neurotoxin for the treatment of migraine and other primary headache disorders

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1 Dermatol Clin 22 (2004) Botulinum neurotoxin for the treatment of migraine and other primary headache disorders Andrew M. Blumenfeld, MD a, *, David W. Dodick, MD, FRCP(C), FACP b,c, Stephen D. Silberstein, MD, FACP d 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, 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 afflicts 2% to 15% of the world s population. In the United States there are an estimated 28 million migraine sufferers, with women being affected three times as often as men [1]. It is characterized by severe headaches and is often associated with nausea, vomiting, and heightened sensitivity to sound and light at the peak of the attack. Migraine is considered to cause more disability than epilepsy, and severe migraine has been judged by the World Health Organization to be as disabling as quadriplegia, psychosis, and dementia [2]. Most sufferers are in their most socially active and productive years (25 to 55) [1]. Not only is migraine painful and disabling for the sufferer, but it exerts a significant economic burden on society. It causes 112 million bedridden days each year and costs $14 billion in reduced productivity and missed workdays [3]. The economic burden of migraine is comparable with that of diabetes [4] and higher than that of asthma [5]. Even among migraineurs who consult a physician, many are not satisfied with their therapy and report that prescribed medications are not always optimal. Triptan medications, the most effective therapy for acute migraine attacks, are only effective in improving the pain and associated migraine symptoms, such as photophobia and nausea, in up to two thirds of patients * Corresponding author. address: Andrew.m.Blumenfeld@kp.org (A.M. Blumenfeld). [6]. There is a significant need to develop more effective therapies for migraine prevention because 35% of migraineurs suffer from two to three severe attacks per month, whereas 25% suffer from more than four attacks per month [6]. Furthermore, more than 4% of the United States population suffers from chronic daily headache [7]. Patients with frequent, disabling, or refractory migraine should be considered for prophylactic treatment. Current United States guidelines recommend preventive therapy in one or more of the following situations: (1) frequent headaches; (2) recurring migraines that significantly interfere with daily routine; (3) failure of, a contraindication to, overuse of, or adverse events (AEs) with acute migraine therapies; (4) cost of acute and preventive therapies; (5) patient preference; and (6) the presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infraction [8]. Although numerous therapies are currently available for the prevention and treatment of migraine, most of these agents have significant side effects. Commonly used agents for migraine prophylaxis include b-adrenergic blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants (Table 1). Moderate to severe AEs are not uncommon with all available prophylactic medications. b-blockers are known to produce a wide array of AEs, including drowsiness, fatigue, lethargy, sleep disorders, and depression. AEs typically associated with the calcium channel blockers include constipa /04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi: /s (03)

2 168 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) Table 1 Preventive therapeutics commonly prescribed for migraine Quality of Evidence a Scientific Effect b Clinical Impression c Anticonvulsants Divalproex sodium A Topiramate A Gabapentin B Antidepressants Amitriptyline A Fluoxetine B + + b-blockers Propranolol A Metoprolol B Timolol A Atenolol B Calcium channel blockers Verapamil B + + Nimodipine B + + a A, Multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings; B, some evidence from randomized clinical trials supported the recommendation, but scientific support was not optimal. b +, Effect of medication is either statistically or not clinically significant; ++, effect of medication is statistically significant and exceeds the minimally clinically significant benefit; +++, effect is statistically significant and far exceeds the minimally clinically significant benefit. c +, Somewhat effective: few people get clinically significant improvement; ++, effective: some people get clinically significant improvement; +++, very effective: most people get clinically significant improvement. Adapted from Silberstein SD, Goadsby PJ. Migraine: Preventive treatment. Cephalalgia 2002;22: tion, peripheral edema, and weight gain [9], whereas the tricyclic antidepressants commonly are associated with a variety of AEs, including sedation, weight gain, dry mouth, constipation, dizziness, mental confusion, palpitations, blurred vision, and urinary retention. The AEs associated with antiepileptic drugs are unique to each medication, but the most common AEs include nausea, vomiting, and gastrointestinal distress [9]. Because of the AE profile and limited efficacy of currently available preventive therapies, there is a need for novel and improved prophylactic therapies. Recently, the potent neurotoxin botulinum toxin type-a (BoNT-A) has been under intensive clinical investigation for the treatment of migraine and other types of headache. Over the last 20 years, BoNT-A has been used to treat a variety of disorders characterized by inappropriate and involuntary muscle contraction [10]. BNT-A is currently approved for blepharospasm, strabismus, cervical dystonia, and, more recently, for the treatment of glabellar lines [11]. Although not currently indicated, it has also been safely used for spasticity; hyperkinetic disorders, such as tremor; autonomic disorders, such as hyperhidrosis; and cosmetically troublesome hyperfunctional facial lines (crow s feet, forehead lines) [12,13]. The analgesic effect of BoNT-A has long been observed in the treatment of dystonia and spasticity [14,15]. This led to further investigation of the efficacy of BoNT-A for other painful conditions, including migraine and tension-type headaches. Because most clinical experience with the use of BoNT for the treatment of headache has been with BoNT-A, this article describes the potential antinociceptive mechanism of action of BoNT-A, summarizes the clinical evidence to date for BoNT-A as effective migraine prophylactic therapy, and reviews the injection technique and strategies used in treating headache and cervical myofascial pain. Mechanism of action Botulinum toxins are exotoxins of the anaerobic bacterium Clostridium botulinum. This bacterium has eight serotypes: A, B, C-alpha, C-beta, D, E, F, and G. Seven serologically separate exotoxins are produced. The intracellular targets of each of these toxins vary; however, their biologic activity at the neuromuscular junction is similar [16]. Injection of BoNT-A directly affects neuromuscular signaling processes. On injection, the toxin enters the nerve terminals by endocytosis; interacts with intracellular proteins (snare proteins); and inhibits the vesicular release of the acetylcholine neurotransmitter at the neuromuscular junction. Inhibition of acetylcholine produces chemical denervation and paralysis of the striated muscles. Paralysis usually peaks 2 weeks postinjection. Because of molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return at 3 months, with complete function at approximately 6 months [17]. Although neuromuscular activity inhibition may alleviate a portion of the pain associated with headache disorders, it does not fully explain the pain relief mechanisms mediated by BoNT-A. Intensive research on BoNT-A has begun to suggest that this toxin may interact with several other neuronal signaling pathways, although the exact mechanisms remain elusive. Current data suggest that BoNT-A modifies the sensory feedback loop to the central nervous system by blocking intrafusal fibers, resulting in decreased activation of muscle spindles. This effectively alters the

3 sensory afferent system by reducing the traffic along Ia spindle afferent fibers [18]. This toxin also seems to inhibit the release of glutamate from primary afferent nociceptive fibers, reduce the firing of wide dynamic range neurons within the dorsal horn of the spinal cord, and reduce the activity of central nociceptive neurons as measured by a reduction in the expression of immediate early genes (c-fos) after nociceptor stimulation [19]. A reduction in afferent sensory activity coming from pericranial and cervical muscles, and inhibition of peripheral and central trigeminal sensitization, may represent the potential mechanisms by which BoNT-A exerts its therapeutic effect in migraine, tension-type headache, and other primary headache disorders [20]. A.M. Blumenfeld et al / Dermatol Clin 22 (2004) Clinical efficacy: retrospective reviews and openlabel trial Historically, while conducting the initial clinical trials of BoNT-A for the treatment of hyperfunctional facial lines, Binder et al [21] noted a correlation between pericranial BoNT-A injections and alleviation of migraine headache symptoms. Based on these initial findings, the authors conducted a combined, multicenter, open-label trial that evaluated the efficacy of Fig. 2. Injection site: temporalis and masseter muscles. Fig. 1. Injection sites: glabellar and frontal regions. Fig. 3. Injection site: occipital, suboccipital, and trapezius muscles.

4 170 Table 2 Retrospective/open-label and placebo-controlled trials of botulinum toxin A treatment for migraine Study Design (N) and Patient Type a Dose Injection site Primary result reported Retrospective Reviews/Prospective Open-label Trials Binder et al (2000) Mauskop and Basedo (2000) Mauskop (2002) Miller and Denny (2002) Blumenfeld (2002) Mathew et al (2002) Retrospective chart review (N=77) Retrospective chart review (N=27) Retrospective chart review (N=78) Episodic migraine, N=32 Chronic migraine, N=46 Retrospective chart review (N=48) All patients were chronic headache patients who had failed previous therapy Retrospective chart review (N=271) Headache types include b Chronic daily Episodic-tension Episodic-migraine Mixed Retrospective chart review (N=112) All patients diagnosed with chronic migraine Mean dose 31 units (range units) Fixed injection sites Glabellar Frontal Temporal units Fixed injection sites (frontalis, glabellar, and temporalis) Some patients received a combination of fixed injections and follow-the-pain injections Varying dose from Follow-the-pain protocol units Varying dose from units Average dose 63.2 units Fixed injection site (frontalis, corrugator, temporalis, splenius captis) with follow-the-pain as needed Injection sites were either fixed or follow-the-pain units Combination of fixed injection sites (frontal/ glabellar/ temporal/ occipital/ suboccipital) and follow-the-pain 51% of migraine patients reported complete response 85% (23 of 27) of patients reported significant reduction in frequency and intensity Most patients reported partial to complete response (no percentage improvement given in this study) 86% of patients treated with BTX-A reported nominal benefit with 35% reporting good and 27% very good benefits 25% reduction in headache intensity ( P <.001) 56% reduction in headache days per month ( P <.0001) 85.6% of patients reported symptomatic improvement Three months after third injection a significant decrease in the number of headache days ( P <.05) and a decrease in mean MIDAS scores ( P <.01) were observed A.M. Blumenfeld et al / Dermatol Clin 22 (2004)

5 Smuts and Barnard (2000) Eross and Dodick (2002) Prospective, open-label (N=19) Prospective, open-label (N=73) Episodic migraine, N=12 Chronic migraine, N= units Variable sites (no specific protocol mentioned in abstract) 25 units If required based on pain, additional units injected into cervical paraspinals Fixed injection sites Frontalis Temporalis Procerus Corrugator Placebo-Controlled Trials Barrientos and Chana (2002) Placebo-controlled (N=30) 50 units Fixed injection sites Glabellar Frontal Temporal Procerus Trapezius Splenium capitis Silberstein et al (2000) Brin et al (2000) Ondo et al (2002) Placebo-controlled/ double-blind (N=123) Placebo-controlled/ double-blind (N=56) Placebo-controlled/ double-blind (N=60) Chronic migraine, N=19 Chronic tension headache, N=22 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. 25 units (low dose) 75 units (high dose) Dose not given in study Fixed injection sites Glabellar Frontal Temporal Fixed injection sites Frontal Temporal 200 units Individual injection choice using followthe-pain protocol 68% (13 of 19) of migraine patients reported positive response Of patients who responded > 50% reported an improvement in disability 61% of responders reported decrease in headache frequency and 27% reported decrease in headache severity Significant reduction in frequency (P<.001), severity (P <.02), and adjunct medications (P <.001) compared with placebo 45% of patients in low-dose group (25 units) reported a >50% decrease in frequency BTX-A was superior than placebo in reducing severity (P=.04) 10% of patients reported a dramatic improvement and 24% a marked improvement. Significant reduction in the number of headache days (weeks 8 12) compared with placebo (P <.05) A.M. Blumenfeld et al / Dermatol Clin 22 (2004)

6 172 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) BoNT-A for migraine management. Efficacy was categorized as either complete response with total symptom elimination, partial response with greater than 50% reduction in headache severity and frequency, or no beneficial response. In this study, 51% of patients treated with BoNT-A as migraine prophylaxis reported a complete response to localized head and neck BoNT-A injections with a mean duration of 4.1 months. An additional 38% reported partial improvement with a mean response period of 2.7 months [21]. Since then, many researchers have reported their experience with BoNT-A. Mauskop and Basedo [22] reviewed chart records of 27 patients treated with BoNT-A for migraine prophylaxis by injections in the pericranium. A decrease in headache frequency and severity was reported in 85% (N = 23) of patients. Rather than focusing solely on the end point of severity and frequency of headache, Eross and Dodick [23] evaluated the effect of BoNT-A (25 to 100 units) on reducing disability in 47 patients with either episodic or chronic migraine. Using a well-validated tool to assess migraine-related disability (the MIDAS questionnaire), 58% of all patients reported a decrease in migraine-associated disability. Episodic migraine patients (N = 12) seemed to show the most benefit, with 75% reporting a decrease in migraine frequency compared with 53% of chronic migraine patients [23]. Other retrospective reviews [24 28] further support the beneficial role of BoNT-A for the preventive treatment of episodic migraine, chronic tension-type headache, and treatment-refractory chronic migraine headaches. Aside from the obvious limitation of a retrospective review or open-label design, the weaknesses of many of these study reports include small patient number; poorly defined end points; and often heterogeneous patient populations (episodic-chronic migraine, tension-type or chronic headaches). Clinical efficacy: placebo-controlled trials Currently, few well-conducted clinical trials of BoNT-A in migraine prevention exist. The first double-blind, placebo-controlled, randomized clinical trial was published by Silberstein et al [8]. In this study, 123 patients who had experienced between two to eight moderate-to-severe migraine headaches over a 3-month period were randomized to receive a single injection of either placebo, low-dose (25 units), or high-dose (75 units) BoNT-A. This single dose was injected into multiple sites of pericranial muscles during the injection visit. Injections were performed anteriorly, in the frontalis, glabellar region, and temporalis muscle. At the end of the 3-month follow-up period postinjection, the low-dose BoNT-A group experienced a mean decrease of 1.88 moderate-tosevere migraines compared with the placebo group (P =.042). Furthermore, patients in the low-dose group had a significant reduction in the incidence of migraine-associated vomiting compared with placebo (P =.012). The high-dose BoNT-A group, however, did not have a significant effect on migraine pain and associated symptoms. In fact, at the higher dose, there was an increase in AEs. The authors suggest that the lack of BoNT-A activity at this higher concentration may actually be caused by a lower number of migraine headaches at baseline compared with the low-dose BoNT-A group [8]. In this trial, BoNT-A was well tolerated with no AEs observed in the low-dose group compared with placebo. Barrientos and Chana [29] also conducted a randomized, placebo-controlled trial (no indication of being double-blinded) that evaluated the efficacy and tolerability of BoNT-A as prophylaxis for episodic migraine. Thirty patients with a history of two to eight migraine attacks per month were enrolled and randomized to receive placebo or 50 units of BoNT-A injected in 15 pericranial muscle sites. During the 3-month study, when compared with baseline, patients treated with BoNT-A experienced fewer attacks at day 30 (3.7 versus 5.8, P <.02); day 60 (3.2 versus 5.8, P <.2); and day 90 (2.5 versus 5.8, P <.01). In comparison, no significant reduction from baseline was observed in the placebo group. Severity and duration of migraine attacks also were significantly reduced in the BoNT-A group compared with placebo. At the end of the 3-month study, the BoNT-A treated group reported a significant decrease in the use of nonsteroidal anti-inflammatory drugs and triptan medications for acute headache treatment compared with placebo. This supports the previous clinical data that BoNT-A is effective and well tolerated for preventive migraine treatment. A small, double-blind, placebo-controlled study of BoNT-A conducted by Brin et al [30] further supports the efficacy of BoNT-A in migraine. In this trial, 56 subjects with a history of two to six migraines per month were randomized into four groups receiving (1) BoNT-A in frontal-temporal regions, (2) BoNT-A in frontal and placebo in temporal, (3) placebo in frontal and BoNT-A in temporal, and (4) placebo in frontaltemporal regions. Migraine frequency was reduced by a median of 1.8 headaches per month in BoNT-A treated groups (groups 1 to 3) compared with a median reduction of 0.2 headaches per month in the placebo group (group 4). This study is limited, however, by its small population size.

7 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) Recently, Ondo et al [31] conducted a randomized, double-blind, placebo-controlled, parallel clinical trial that examined the effect of BoNT-A treatment on patients with chronic daily headache, including chronic tension-type headache and chronic migraine. Sixty patients who experienced chronic headache more than 15 days each month were enrolled and randomized to receive, based on the follow-the-pain rationale, either 200 units of BoNT-A or matching placebo and at 12 weeks, if patient consented, a second open-label BoNT-A injection. Following the first injection, patients treated with BoNT-A had significantly fewer headache days from week 8 to 12 compared with placebo. In addition, 10% of patients treated with BoNT-A reported a dramatic improvement and 24% reported a marked improvement compared with 3% and 7%, respectively, in the placebo-treated group. At week 24, patients who had received two BoNT-A injections had significantly fewer headache days over the second 12-week period than those receiving one injection (40 versus 19 days, P <.05). Use of botulinum toxin A: dosage and administration The most common sites of injections include the glabellar (procerus and corrugators), frontal, temporal, and sometimes the occipital regions (Figs. 1 3). BoNT-A is administered either at fixed injection sites; at sites of pain or tenderness ( follow the pain ); or a combination of both. The total dosage of toxin, the number of units per site of injection, dilution of toxin, and sites of injection varied widely, however, between studies (Table 2). The total dosage ranged from 25 to 300 units over several injection sites. The fixed-site approach consists of bilateral injections, even if the patient has strictly unilateral headaches. The muscles injected are the procerus, corrugators, frontalis, and temporalis. Follow-the-pain injection sites are identified by history ( Where does it hurt when you have a headache? and Show me with your hands where the pain is ) and by examination of the cervical-shoulder girdle and temporomandibular musculature. These sites include the frontalis, temporalis, occipitalis, trapezius, splenius capitus, suboccipital, and cervical paraspinal muscles. For patients with migraine or migrainous headache features by history, treatment with a fixed-site approach may be required for successful results. When only a follow-the-pain approach is used in patients with migraine or migrainous headache, two problems arise: first, a poor cosmetic outcome; and second, the headaches often shift to the previously unaffected side. For patients with only tension-type headaches, the follow-the-pain approach is used. Even in these cases, cosmetic effects in the frontal region need to be obtained, but asymmetric injections can be given in the temporalis, occipitalis, splenius capitus, cervical, and subcervical paraspinal muscles. The doses injected in the cervical-shoulder girdle muscles are low to prevent any possible weakness, which could cause headache. Patients need to be assessed carefully for associated cervical dystonia, which requires injection of the dystonic muscles. Current available data do not seem to indicate a dose response-benefit [8,21,23,24]. There is need for further randomized, placebo-controlled clinical trials to identify the optimal dosing regimen and injection sites for BoNT-A. Some data, however, report greater efficacy with repeated dosing. In the Ondo et al [31] trial, patients who received a repeat BoNT-A injection reported better improvement than patients who received only a single BoNT-A injection [31]; these data 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 delivery remains unresolved. Tolerability The clinical dose of BoNT-A commonly used for migraine therapy is between 25 and 100 units, which is 30 to 120 times below the toxic limit [17]. Most published trials have reported minimal to no AEs. In a placebo-controlled, double-blind trial, Silberstein et al [8] found that although no serious AEs occurred, some patients receiving BoNT-A injections experienced transient minor AEs, including blepharoptosis, diplopia, and injection site weakness. The authors also found that injection of high doses of BoNT-A (75 units) resulted in a dose-dependent increase in the side effect profile of BoNT-A. In an open-label study, Binder et al [21] also reported only minimal and transient AEs, including brow ptosis, local injection discomfort, and ecchymosis at the injection site. Overall, clinical studies and retrospective reviews confirm the tolerable side effect profile of BoNT-A and that associated AEs are typically mild and transient. Summary Clinical data and experience to date have demonstrated that BoNT-A is an effective and well-tolerated therapy for the prevention of migraine and other headache disorders. It has a long duration of action

8 174 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) that may last over 4 months with no systemic or serious AEs. Several issues remain to be defined, however, including dosing, location, and number of injections; optimal dilution of BoNT-A; specific headache types that respond best to BoNT-A; and long-term efficacy and safety. Data from ongoing well-designed trials that include a larger patient population investigating these issues may confirm a role for BoNT-A as a first-line agent for migraine prevention. Neurotoxin therapy is part of a broader headache management approach. Because the injection techniques for headache are unique and vary depending on the primary headache disorder being treated and the location and pattern of pain referral, the use of BoNT-A for headache is not simply an extension of its use for cosmesis. The use of BoNT-A in the overall management of primary headache disorders should be reserved for medical practitioners who not only have experience with BoNT-A injections, but possess the expertise in the diagnosis and management of complex headache disorders. Educating patients and addressing headache triggers and optimizing acute treatment improve the outcome of any preventive program. References [1] Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001;41: [2] Menken M, Munsat TL, Toole JF. The global burden of disease study: implications for neurology. Arch Neurol 2000;57: [3] Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med 1999;159: [4] Thom TJ. Economic costs of neoplasms, arteriosclerosis, and diabetes in the United States. In Vivo 1996;10: [5] Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med 1992;326: [6] Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med 2002;346: [7] Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache 1998;38: [8] Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40: [9] Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002;22: [10] Gobel H, Heinze A, Heinze-Khun K, Jost WH. Evidence-based medicine: botulinum toxin A in migraine and tension type headache. J Neurol 2001; 248(suppl 1):34 8. [11] Allergan Pharmaceuticals. BOTOX (botulinum toxin type A) prescribing information. Irvine, CA: Allergan Pharmaceuticals. [12] Heckmann M, Ceballos-Baumann AO, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001;344: [13] Carruthers J, Carruthers A. Botulinum toxin (Botox) chemodenervation for facial rejuvenation. Facial Plast Surg Clin North Am 2001;9: [14] Tsui JKC, Eisen A, Stoessl AJ, Calne DB. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2: [15] Dunne JW, Heye N, Dunne SL. Treatment of chronic limb spasticity with botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;58: [16] Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon 2002;48: [17] Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. Muscle Nerve 1997; 20(suppl 6):S [18] Rosales R, Arimura K, Takenaga S, Osame M. Extrafusal and intrafusal muscle effects in experimental botulinum toxin-a injection. Muscle Nerve 1996;19: [19] Aoki R. The antinociceptive mechanism of action of botulinum toxin A. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, [20] Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47: [21] Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg 2000;123: [22] Mauskop A, Basdeo R. Botulinum toxin A is an effective prophylactic therapy for migraines. Cephalalgia 2000;20:422. [23] Eross EG, Dodick DW. The effects of botulinum toxin type A on disability in episodic and chronic migraine [abstract S108]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, [24] Blumenfeld A. Botulinum toxin type A (BOTOX) as an effective prophylactic treatment in headache [abstract 81]. Presented at the 6th headache congress: European Headache Federation. Istanbul, Turkey, June 26 30, [25] Mauskop A. The use of botulinum toxin in the treatment of headaches. Curr Pain Headache Rep 2002a;6: [26] Mauskop A. Long-term use of botulinum toxin type A (BOTOX) in the treatment of episodic and chronic migraine headaches [abstract S105]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002.

9 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) [27] Mathew NT, Kallasam J, Kaupp A, Meadors L. Disease modification in chronic migraine with botulinum toxin type A: long-term experience [abstract S107]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, [28] Miller T, Denny L. Retrospective cohort analysis of 48 chronic headache patients treated with botulinum toxin type A (BOTOX) in a combination fixed-injection-site and follow the pain protocol [abstract S138]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, [29] Barrientos N, Chana P. Efficacy and safety of botulinum toxin type A (BOTOX) in the prophylactic treatment of migraine [abstract S106]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, [30] Brin MF, Binder WJ, Blitzer A, Schenrock L, Pogoda JM. Botulinum toxin type A for pain and headache. In: Brin MF, Hallett M, Jankovic J, editors. Scientific and therapeutic aspects of botulinum toxin. New York: Lippincott Williams & Wilkins; p [31] Ondo WG, Vuong KD, Derman HS. Botulinum toxin A (BOTOX) for chronic daily headache: a randomized placebo-controlled, parallel design study [abstract S131]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002.