An Invited Review

s of Botulinum Toxin Type A in Migraine Headache In 2003, Blumenfeld (32) reported on the efficacy of BT-A in reducing headache frequency and intensity in a retrospective, open-label analysis that included 271 patients. All participants had disabling, chronic migraine. BT-A was administered at an average, fixed dose of 63.2 U either at a fixed site or in a pattern that followed the pain. A response to treatment was reported by 80% of patients, and significant reductions in the frequency of headache occurred (from 18.9 to 8.3 days/month). Headache intensity was diminished by 25%. The author concluded that BT-A provides “efficacious and safe” preventive treatment for headaches. Mathew et al (33) reported on their long-term experience with BT-A in patients with chronic headache in a retrospective, open-label trial of 208 patients. All participants had disabling, chronic migraine and were treated with 50 to 100 U of the study medication administered at fixed sites or at sites that corresponded to the location of pain. According to the physician’s global assessment, the 100U dose was more effective than the 50-U dose. The incidence of severe, disabling migraine was greatly reduced compared with the incidence of less severe headache. Patients returned for treatment as the effects of an injection wore off, and there was no evidence of tachyphylaxis. This observation also suggests that the benefits were not attributable to a placebo effect. Botox therapy significantly reduced the disability associated with migraine, as well as migraine frequency and the need for other, acute medications. No patient dropped out of the study because of a lack of efficacy. A randomized, double-blind, placebo-controlled trial enrolling 30 patients was reported by Barrientos et al (34) in 2002. Using a follow the pain approach, 50 U of BT-A was administered. The frequency, duration, acute use of migraine medications, and the incidence of migraine with nausea were decreased among patients receiving the study medication. Improvements lasted up to 3 months. One patient experienced frontal asymmetry that lasted for 30 days. The authors concluded that BT-A provided effective treatment of migraine in this patient group and that it warrants additional study. A prospective, open-label disability study was reported by Eross et al (35) in 2002. Fifty-four patients completed the study, which investigated the effects of BT-A on disability in patients suffering from chronic and episodic migraine. The dosage of study drug ranged from 25 to 75 U; it was administered at multiple sites. Improvements lasted up to 3 months, the frequency of headaches was diminished, and disability was lessened. The efficacy of BT-A for the treatment of patients with cervicogenic migraine was studied in a prospective, openlabel by Krusz (36) in 2002. The study dose was 100 U administered at 4 to 6 posterior cervical injection sites. Headache frequency was reduced by more than 70%, and migraine severity was judged to be diminished by 50%. The investigators concluded that BT-A was effective in reducing headache and spasm symptoms in this patient population. This author evaluated the long-term efficacy of Botox in the treatment of episodic and chronic migraine headaches in a retrospective, open-label trial in patients treated multiple times and over long periods of time (12). In some, multiple other treatments had failed. Dosages of 25 to 200 U were administered in a follow-the-pain pattern. Among the findings were that improvements lasted up to 15 months, headaches were completely eliminated in some patients, and symptom relief from abortive drugs was improved by Botox treatment. In addition, headache frequency and intensity, as well Mauskop • Botulinum Toxin in Headache 380 Pain Physician Vol. 7, No. 3, 2004 Mauskop • Botulinum Toxin in Headache 381 Pain Physician Vol. 7, No. 3, 2004 as triptan use, were diminished. Adverse events included transient neck pain and weakness in 2 patients, acute headache in 2 patients, and neck weakness and a fainting feeling in 1 patient each. At the time of this review the author has treated over 900 headache patients with Botox in clinical practice. ABSTRACTS AND PUBLISHED ARTICLES OF BOTULINUM TOXIN TYPE A IN TENSIONTYPE HEADACHE, CHRONIC MIGRAINE, CHRONIC DAILY HEADACHE AND OTHER HEADACHE TYPESS AND PUBLISHED ARTICLES OF BOTULINUM TOXIN TYPE A IN TENSIONTYPE HEADACHE, CHRONIC MIGRAINE, CHRONIC DAILY HEADACHE AND OTHER HEADACHE TYPES BT has also been the subject of numerous investigations conducted in patients with tension-type headaches, chronic daily headache, and other forms of headache. In 1999, Smuts et al (37) assessed the efficacy of Botox in the prophylaxis of chronic tension-type headaches. This double-blind, randomized, placebocontrolled study enrolled 37 patients, and outcomes included changes in headache intensity, headache-free days, and chronic pain index. Patients were randomized to receive 100 U of Botox or placebo. The number of headache-free days improved significantly in the Botox group relative to the placebo group, and patients randomized to Botox reported improvement in quality of life after the injections. Improvements lasted for 3 months, and no serious side effects were reported. A similar double-blind, placebo controlled trail of BT-A was conducted in 16 patients by Relja (18). The study agent was administered in doses of 35 to 80 U in a follow the pain approach and at multiple sites. The conclusion was that BTA provided safe and effective prophylaxis of tension-type headache. Improvement lasted for up to 2 months, and no adverse events were reported. In a study of chronic cervical-associated headache associated with whiplash injuries, Freund et al (38) conducted a randomized, double-blind, placebo-controlled trail in 26 patients who received BT-A at a dose of 100 U or placebo. Pain was diminished and cervical range of motion increased, but the authors made no conclusions about efficacy because of the short follow-up and small sample size. Porta (39) compared the efficacy of Botox with that of methylprednisolone in a randomized, single-blind trial conducted in 20 patients with tension-type headaches. The test regimens were Botox, 5 to 15 U in lidocaine versus methylprednisolone, 40 mg plus lidocaine. The corticosteroid decreased pain at 30 days, while Botox was associated with diminished pain at 30 days and 60 days. Botox was also associated with improvements in the symptom profile for up to 60 days. No adverse events were reported. According to the authors, the results confirmed the effectiveness of Botox for the treatment of tension headache and Botox produced more prolonged pain relief than methylprednisolone. Among the published, peer-reviewed abstracts on this subjects is that of McAllister (40), who reported on improvements in headache and changes in headache medications among 116 patients with a variety of headache types (migraine with or without aura, episodic tension-type headache, cervicogenic headache, and cervical myofascial pain) who were treated with Botox in a retrospective, open-label analysis. Injections were administered both at fixed sites and in a follow the pain pattern, and dosages ranged from 40 to 280 U. Of note, all patients reported some degree of headache improvement, with 76% reporting an improvement of 75% or more; 9% reported a complete remission of headache. The monthly cost of headache medications decreased from $253 to $97. The investigators called for larger trials to confirm these results. Using the Migraine Disability Assessment Scale (MIDAS), Tepper et al (41) assessed the effect of Botox on the disability caused by refractory headache in 100 patients included in a retrospective, open-label trial. Participants in this trial had previous failures of at least 4 preventive treatments. The headache types represented in this group included chronic daily headache with analgesic rebound headache, chronic daily headache without analgesic rebound headache, and chronic, posttraumatic headache. Botox was administered in a dose of 25 U. The mean MIDAS score dropped from 34. 5 to 15.9, a difference that was statistically significant at the level of P < 0.001. The efficacy of Botox in patients with chronic, intractable headache with or without concomitant neck pain was the subject of a study by Miller et al (42), who conducted a prospective, open-label study in 68 patients. All subjects had unsuccessful trials with other treatment modalities. Botox was administered at a dosage of 100 U in a follow the pain protocol. A total of 75% of patients reported 50% to 100% pain relief. A total of 13% reported no benefit, and 12% judged their improvements to be of little clinical use. Treatment efficacy was similar in patients with and without neck pain. Ten adolescent females were the subjects of a study by Tomosovic et al (43). All subjects had chronic daily headaches that had been refractory to other modalities. Symptom improvements were assessed with MIDAS. Botox, 100 U, was administered in a follow the pain approach. All participants reported improvement, and 8 of the 10 had sustained improvement at 90 days. The use of other medications was reduced, as well. Stiff person syndrome was the subject of a study by Loder (44) in 2003. This case report described the response to Botox in a patient with stiff person syndrome accompanied by headache and neck pain. Botox, 100 U, was administered. At 3 weeks postinjection, the patient reported complete resolution of the headache. Muscle relaxation was credited as the most likely mechanism of action, although other mechanisms were considered possible. Troost (45) studied the impact of repeated Botox treatments in 436 patients with intractable migraine or episodic tension-type headaches. Botox dosages were in the range of 25 to 300 U and were given at fixed and multiple sites. A total of 91% of patients reported improvements, and the more cycles of treatment a patient had, the greater the improvements. Improvements were cumulative through 3 cycles of treatment and sustained through 8 treatments. Minor injection-site pain was the only adverse reaction reported in this series. Importantly, tachyphylaxis was not observed. In 1998, Wheeler (46) published 4 case reports of the use of BT-A as adjunctive therapy for refractory headache associated with pericranial muscle tension. The medication was injected at multiple sites corresponding to the pain patterns. The frequency and severity of headaches diminished, as did the need for subsequent medical and physical therapy interventions. In contrast, Sebastian et al (47) were unable to show a benefit for Botox in their 12-week, double-blind, placebo-controlled trial in 40 patients with chronic, tension-type headache. Subjects were treated with 100 U of Botox or placeMauskop • Botulinum Toxin in Headache380 Pain Physician Vol. 7, No. 3, 2004 Mauskop • Botulinum Toxin in Headache 381 Pain Physician Vol. 7, No. 3, 2004 bo. No significant difference between the groups was apparent with respect to average headache days, headache hours each day, requirements for additional symptom management, or the patient global assessments. Blumenfeld (48) assessed the efficacy of Botox as prophylactic therapy in 271 patients with a range of headache types, including chronic daily, episodic tension, episodic migraine, or mixed headache. Mean Botox dose was 63.2 U administered at multiple sites. Headache intensity and frequency was diminished by treatment, and improvements persisted for more than 8 months. Three patients experienced transient ptosis. To evaluate the possibility that Botox is associated with progressive and cumulative treatment effects, Troost (49) administered the drug in doses of 30 to 240 U to 134 patients enrolled in a prospective, open label study. The subjects represented an array of headache types. No adverse events were reported, but pain was diminished. Headache scores improved according to both patient and clinical ratings. Improvements again persisted beyond 8 months. Fifty-six patients with chronic daily headache were enrolled in Klapper’s (23, 25) double-blind, placebo-controlled study of Botox for the prophylaxis of chronic daily headache. Treatment groups included Botox 100 U, Botox 27.5 U plus placebo, Botox 72.5 U plus placebo, or placebo alone. Both headache duration and frequency were reduced by active treatment. Padberg et al (50) reported nonsignificant improvements in headache intensity and frequency, headache-free days, and medication days among 40 patients with chronic, tension-type headaches who were enrolled in a randomized, double-blind, placebo-controlled study. The Botox dosage was 100 U administered at multiple, individualized sites. Improvements persisted for up to 3 months. Sixty patients with chronic daily headache were enrolled in Ondo’s (51) double-blind, placebo-controlled trial that employed a Botox dose of 200 U or placebo in a follow the pain approach. Based on improvements in headachefree days, frequency, the need for abortive medications, and global impressions that persisted for up to 3 months, the authors concluded that Botox was a potentially helpful approach to this form of headache and that its effects appeared to be cumulative. Smuts (10) investigated the efficacy of Botox in 79 patients with a variety of headache types enrolled in a prospective, open-label trial of Botox, 100 U. Positive outcomes were reported in 50% to 68% of patients with chronic tension-type headaches, migraine, cluster headache, and cervicogenic headaches. The authors concluded that Botox could be considered an alternative therapy in patients with a variety of refractory headache syndromes. Improvements lasting longer than 3 months and decreases in pain frequency, intensity, tenderness and duration of pain were among the findings of Lopez-Lozano (52), who studied Botox in 10 patients with chronic tension-type headaches accompanied by pericranial muscle tenderness. The dose of Botox was unspecified, and a single treatment at a single site was administered. Only the improvement in duration of pain was nonsignificant, and the authors concluded that Botox had produced “significant” improvements in patients with chronic tension-type headache associated with pericranial muscle tension. A retrospective case review of 10 patients also with chronic tension-type headache was reported by Lin and Chang (53) in 2002. Botox was administered at doses of 20 U to 100 U at multiple sites and for multiple treatments. Pain severity and disability were diminished, and patients reported pain relief. The improvements persisted for more than 3.5 months. The authors took this as confirmation of the clinical benefit of Botox in treating this type of headache. Miller and Denny (54) conducted a retrospective cohort analysis in 48 patients with chronic headache who were treated with Botox in a combination fixed injection and follow-the-pain protocol. The patients had not obtained adequate headache relief from other therapies. All received multiple treatments of 50 to 300 U of Botox. The response to Botox was rated as good, very good, or full in 71% of participants; 8% reported being headache-free after treatment. These investigators concluded that Botox therapy may be beneficial in patients who have not benefited from other headache therapies and that multiple regimens may be more effective than single treatments. Twenty patients with chronic daily headache refractory to other treatment modalities were enrolled in a prospective, open-label study conducted by Edwards (55) in 2002. Botox was administered in dosages of 20 to 100 U. The mean headache frequency dropped from 7 to 3.5 days per week. No clinical weakness was observed, and the side effects were limited to injection site discomfort. The authors considered the benefits of Botox to be “highly significant.” They noted that Botox might represent an alternative treatment for patients with chronic daily headache that poses no risk of drug abuse, drug-drug interaction, sedating effects, or other systemic toxicities. The useful of Botox as prophylaxis for chronic tension-type headache was examined by Relja et al (19) in a 10month randomized, double-blind, placebo-controlled phase and in an 18-month, prospective, open-label phase. Thirty patients were enrolled. Botox was administered at doses of 40 to 95 U in a followthe-pain pattern at multiple sites. During the placebo-controlled phase, the number of headache-free days was increased, while headache severity was diminished. During the open label period, tenderness diminished. Adverse events were rare. Freund and Schwartz (56) reported on an open-label, prospective investigation of 8 patients with whiplash-associated neck pain who were treated with Botox. Botox doses were 100 U or less. Pain was diminished, and range-of-motion improved. The investigators termed the acute improvements “profound” and called for blinded, placebo-controlled trials so that the efficacy of the agent in chronic whiplash can pain can be assessed. Wollina (57) published the cases of 8 patients who reported that their tension headaches were relieved after they received Botox for cosmetic purposes (wrinkles). Johnstone et al (58) reported on one patient who received Botox for relief of facial pain, headache and blepharospasm. The improvements associated with a 27.5 U dose at multiple locations lasted for 3 months. Headaches were relieved, and pain and blepharospasm were diminished. Review Articles: The Application of Botulinum Toxin Type-A in Headache At least 5 review articles on the use of BTX-A in patients with headache have been published to date. Silberstein (59) suggested that before BTX-A could be Mauskop • Botulinum Toxin in Headache 382 Pain Physician Vol. 7, No. 3, 2004 Mauskop • Botulinum Toxin in Headache 383 Pain Physician Vol. 7, No. 3, 2004 considered a first-line agent for the treatment of migraine, larger studies would be required to determine the optimal dosing and administration sites. This author published a review in 2002 stating that BTX-A is the preferred agent for many patients with migraine, since prophylactic pharmacotherapy of migraine has limited efficacy and because of the possibility of systemic side effects (12). In contrast, BTX-A is simple to administer, has few systemic effects, and the beneficial effects of a single dose may last for 3 months. In their summary of the numerous clinical uses for which BTX-A has been reported, Royal et al (60) noted that major benefit of BTX-A may be its duration of efficacy. Nonetheless, BTX-A was not recommended for first-line use. Instead, they suggested reserving its use for patients whose headaches are refractory to other modalities. Mathew et al advised clinicians to consider using BTX-A in patients with refractory forms of chronic migraine and chronic tension-type headaches, noting that the agent reduces the frequency and severity of headaches, improves disability scores and quality of life, and reduces the need for acute medication, all without the development of tachyphylaxis to repeated doses (61). A thorough review by Gobel et al (8) stressed excellent tolerability, safety and efficacy of BT-A in the treatment of headache syndromes and its advantages over pharmacotherapy. TREATMENT OF MIGRAINES Nonpharmacologic Management In addition to trigger avoidance, mind-body techniques and alternative and complementary methods may help improve migraine symptoms. Patients need to understand the benefits and potential problems associated with these methods.