Dr. Silberstein discusses the distinction between acute and preventive treatments and specific acute pharmacologic approaches to managing migraine. Advisory Editor
Stephen D. Silberstein, MD, FACP
Director, Jefferson Headache Center
Thomas Jefferson University Hospital
Professor of Neurology
Jefferson Medical College
Philadelphia, Pennsylvania
According to the National Headache Foundation, chronic, recurring headaches affect roughly 45 million Americans (NHF Fact Sheet). The American Migraine Study II (AMS II) estimated that 28 million Americans suffer from migraine—approximately 18% of women and 7% of men (Lipton et al, 2001a). Another study found a 1-year prevalence of 17% of women and 6% of men (Lipton et al, 2002).Episodic and chronic tension-type headache (TTH) affect 38.3% and 2.2% of Americans each year (Schwartz et al, 1998). Approximately 5% of the population (9% of women) suffer from chronic daily headache (CDH), which comprises transformed migraine, chronic TTH, new daily persistent headache, and hemicrania continua that occur more than 15 days per month and last at least 4 hours daily (Castillo et al, 1999).
The significant impact of migraine and other headache disorders—on pain, disability, impaired social function, quality of life, and general health—imposes a large burden on the utilization of healthcare services, society, and the affected individuals (Hu et al, 1999). Migraine alone has been reported to cost the US economy billions of dollars, with $13 billion a year as a result of missed workdays and impaired work function (Hu et al, 1999). The direct medical costs associated with migraine have been estimated at $9.5 billion (Ferrari, 1998). One managed healthcare study found patients with migraine generated nearly twice as many medical claims as those without and incurred healthcare costs (medical and pharmaceutical) that were 64% higher (Clouse and Osterhaus, 1994). Migraine sufferers use 2.5 times more prescription drugs than nonmigraine sufferers (Clouse and Osterhaus, 1994), at a cost of $2.7 billion annually in the US (Ferrari, 1998). A recent survey of urgent care/emergency department (UC/ED) utilization found that 10% of patients who visited the UC/ED for headache-related reasons accounted for 50% of headache-related visits, most for acute care of headache (Maizels, 2002). The reported cost of ED visits for migraine-related treatment in the US ranges from $646 million to $1.94 billion annually (Barron et al, 2003).
Effective headache treatment can reduce disability, increase productivity in the workplace, and improve health-related quality of life. Adding an effective preventive headache medication to a migraine management regimen has been shown to reduce the use of acute medications and number of headache-related visits to physician offices and EDs (Silberstein et al, 2003). However, migraine and other headache disorders are underdiagnosed and undertreated. The AMS II, conducted in 1999, found that only 48% of survey participants who met International Headache Society (IHS) criteria for migraine had received a physician’s diagnosis of migraine. Many sufferers continue to rely solely on over-the-counter (OTC) medications to treat their migraines: the AMS II found 57% used only OTC drugs (Lipton et al, 2001b); another study put the figure at 49% (Lipton et al, 2002).
Medications used to prevent migraine include anticonvulsants such as valproate and topiramate, antidepressants such as amitriptyline (TCA) and fluoxetine (SSRI), β-blockers such as propranolol and metoprolol, calcium channel blockers such as verapamil, and nonsteroidal anti-inflammatory drugs (NSAIDs) (Ramadan et al, 2005; Silberstein and Goadsby, 2002). These medications have limited efficacy or varying degrees of efficacy and are associated with numerous, sometimes serious, adverse events (AEs).
Of these drugs, topiramate is the most recently approved by the FDA as a migraine preventive treatment based on evidence from controlled clinical trials. Silberstein and colleagues assessed the efficacy and safety of topiramate as a migraine-preventive therapy in a 26-week, randomized, double-blind, placebo-controlled, multicenter study of 487 patients. Patients with between 3 and 12 migraines per month on 15 or fewer days per month during the 28-day baseline period were randomized to topiramate at 50 mg/d, 100 mg/d, 200 mg/d, or placebo. Mean monthly migraine frequency decreased significantly for the 100-mg/d group (from 5.4 to 3.3; P < 0.001) and the 200-mg/d group (from 5.6 to 3.3; P < 0.001) versus the placebo group (from 5.6 to 4.6). Significantly more patients in the topiramate 100 mg/d group (54.0%; P < 0.001), 200 mg/d group (52.3%; P < 0.001), and 50 mg/d group (35.9%; P = 0.04) exhibited a 50% or more reduction in monthly migraine frequency than patients in the placebo group (22.6%). Most common AEs (occurring in ≥10% of patients) included paresthesia, fatigue, anorexia, and nausea. In the placebo and topiramate 50 mg/d, 100 mg/d, and 200 mg/d groups, the discontinuation rate resulting from AEs was 10%, 18%, 19%, and 34%, respectively (Silberstein et al, 2004).
In a similarly designed trial of 483 patients, Brandes and colleagues found that the mean monthly migraine frequency decreased significantly for patients receiving topiramate at 100 mg/d (from 5.8 to 3.5; P = 0.008) and 200 mg/d (from 5.1 to 3.0; P < 0.001) versus placebo (from 5.6 to 4.5). The responder rate was significantly greater with topiramate at 50 mg/d (39%; P = 0.01), 100 mg/d (49%; P < 0.001), and 200 mg/d (47%; P < 0.001) versus placebo (23%). AEs occurring in ≥10% of patients with use of topiramate 100 mg/d were paresthesia (50%), fatigue (14%), anorexia (13%), diarrhea (11%), difficulty with memory (10%), and nausea (10%). In the placebo and topiramate 50 mg/d, 100 mg/d, and 200 mg/d groups, the discontinuation rate due to AEs was 12%, 17%, 27%, and 21%, respectively (Brandes et al, 2004).
To evaluate the drug’s efficacy in chronic migraine, Silvestrini and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group study. Twenty-eight patients suffering from chronic migraine with analgesic overuse were randomly assigned to receive 50 mg/d topiramate or placebo. After a baseline phase of 8 weeks to determine mean 4-week headache frequency, the study drug was titrated in 25-mg increments over 1 week to 50 mg daily. The titration phase was followed by an 8-week maintenance phase, divided into two 4-week phases. During the last 4-week maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency compared with those treated with placebo (mean number of headache days: 8.1 versus 20.6; P < 0.0005) and with baseline (P < 0.0007). Both endpoints were significantly better for topiramate at 4 weeks as well. Only 1 topiramate patient dropped out, due to gastric intolerance (Silvestrini et al, 2003). It must be noted that the 50-mg dose given in this small trial did not significantly reduce mean monthly migraine frequency in the larger, episodic-migraine trials.
When topiramate and other available preventive medications are given at efficacious doses, AEs are common. Topiramate and other antiepileptic drugs can cause gastrointestinal distress, fatigue, anorexia, paresthesia, and tremor. Tricyclic antidepressants are known to cause sedation, weight gain, dry mouth, constipation, tremor, dizziness, mental confusion, palpitations, blurred vision, and urinary retention. Calcium channel blockers can cause dizziness, headache, depression, gastrointestinal complaints, vasomotor changes, tremor, peripheral edema, and an initial increase in headache pain. Use of β-blockers is associated with drowsiness, fatigue, lethargy, sleep disorders, and depression. NSAIDs must be used with caution because of their adverse effects on gastrointestinal and renal function (Silberstein and Goadsby, 2002). In recently conducted trials of topiramate to prevent episodic migraine, the patient withdrawal rate related to AEs was 19% to 34% at the effective doses (Silberstein et al, 2004; Brandes et al, 2004).
The experience of intolerable AEs may limit patients’ adherence to their headache medication regimens. In a recent survey of migraine patients, 2 of 3 (67%) sufferers reported that they had delayed or avoided taking a current prescription migraine medication because of concerns about AEs. Prescription medications almost always or often caused AEs in 16% of study respondents or had in the past (37%). The result of delaying or avoiding the use of prescription medication was more intense pain and extended duration of headache in 60% and 59% of respondents, respectively, as well as suboptimal performance at work and absence from work in 25% and 21%, respectively (Gallagher and Kunkel, 2003). There is an obvious need for effective, long-term, and well-tolerated prophylactic treatment regimens for migraine and chronic headache.
Individuals affected by episodic and chronic headache disorders remain underdiagnosed and undertreated, in part because of the limited use of preventive therapies and the limited clinical efficacy and intolerable side effects of some of these treatments. The use of botulinum neurotoxin (BoNT) is a promising new approach to preventive headache therapy that may potentially address some of the currently unmet needs in this therapeutic area.
In migraine, following stimulation of the trigeminal nerve by electrically, chemically, or immunologically induced activation, the neuroinflammatory nociceptive vasoactive peptides substance P, calcitonin gene-related peptide (CGRP), and neurokinin A are released from perivascular nerve fibers (Figure 1) (Moskowitz, 1993). The release of nociceptive mediators triggers the sensory fibers of the trigeminovascular system to transmit nociceptive information to the trigeminal nucleus caudalis in the brain stem via the action of glutamate, perhaps the most important neurotransmitter conveying nociceptive information to the brain (Ramadan 2003; Moskowitz 1993). It has been hypothesized that migraineurs have an altered peripheral glutamate homeostasis and persistent neuronal hyperexcitability that becomes heightened during migraine attacks (Ramadan, 2003). Neurogenic inflammation eventually leads to the pain associated with a migraine.
Figure 1. Neurogenic inflammation: Following stimulation of the trigeminal nerve, neuroinflammatory peptides, such as substance P, CGRP, and neurokinin A, are released from perivascular nerve fibers, triggering neurogenic inflammation, which eventually leads to the pain of migraine. Reproduced with permission from Silberstein SD, et al. Headache in Clinical Practice. Oxford, UK: Isis Medical Media; 1998:41-55.
The mechanisms by which BoNT may alleviate migraine and headache pain are not clearly established at present. However, its therapeutic effect is probably more complex than simple muscle relaxation, which results from the inhibition of acetylcholine release via cleavage of SNAP-25 (synaptosomal protein with a molecular weight of 25 kDa) at the neuromuscular junction. There is increasing evidence suggesting that BoNT has distinct antinociceptive effects though its mechanism of action is the same (cleavage of SNAP-25). Recently published in vitro and in vivo data provide evidence that BoNT cleavage of SNAP-25 may also inhibit the release of substance P, glutamate, and CGRP (Aoki, 2003; Dolly, 2003) (Figure 2).
Figure 2. BoNT inhibition of vesicle-dependent neurotransmitter release: BoNT SNAP-25 cleavage in sensory neurons inhibits the release of substance P, CGRP, and glutamate, which may be the foundation of its antinociceptive properties. Basic Science of Botulinum Neurotoxins [DVD]. New York, NY: Neurotoxin Institute; 2004.
Welch and colleagues found that in vitro administration of BoNT type A in rat dorsal root ganglia cells significantly inhibited substance P secretion (Welch et al, 2000). Cui and colleagues, using a rat formalin model, examined the effect of BoNT type A on inflammatory pain behaviors (paw licking and paw lifting) and the release of nociceptive mediators such as substance P and glutamate. BoNT type A in doses of 3.5, 7, 15, and 30 unit/kg (U) or vehicle was administered to the plantar surface of the right hindpaw of rats from 2 hours to 12 days before formalin challenge. BoNT significantly ( P < 0.05) inhibited formalin-induced nociceptive behavior. It was found that peripheral but not acute pain was relieved by BoNT type A (3.5, 7, and 15 U/kg) when administered 5 days before formalin challenge. In addition, peripheral glutamate release was significantly ( P < 0.05) reduced by BoNT type A (3.5, 7, or 15 U/kg) compared with vehicle, with a dose-dependent trend. At 30 U/kg both acute and peripheral pain were significantly reduced, but the mice had significant motor difficulty when compared with either control rats or the rats administered the lower doses of BoNT type A. Thus, the antinociceptive efficacy of BoNT was independent of its effects on muscle relaxation. This antinociceptive effect is associated with inhibition of formalin-induced release of glutamate (and/or neuropeptides) from primary afferent terminals (Cui et al, 2004).
A pilot study by Smuts and colleagues, in which 7 of 10 patients reported at least a 50% decline in migraine frequency by day 60 and intensity decrease in these 7 patients by day 30, also found that the migraine response observed did not correspond with the electrophysiologic evidence of denervation as measured by the decrease in compound muscle action potential. In addition, electrophysiologic evidence of reinervation after days 60 and 90 was not coincident with a return of migraine symptoms (Smuts et al, 2004).
Morris and colleagues demonstrated that BoNT type A inhibited CGRP release from autonomic vasodilator neurons (Morris et al, 2001). Durham and colleagues found that incubation of primary cultures of rat trigeminal ganglia with BoNT type A greatly reduced the stimulated release of CGRP almost to basal levels following chemical depolarization with KCl or activation with capsaicin, while the control vehicle had no effect (Durham et al, 2004).
Based on the available evidence and what is known of its mechanism of action, BoNT type A may inhibit the induction of centralized mechanisms of pain transmission by peripheral inhibition of substance P, CGRP, and glutamate secretion. The nociceptive effects of BoNT type A are thus most likely to the result of its inhibitory actions at peripheral, but not central, neurons. A study of the diffusion of radiolabeled BoNT type A found that most of the neurotoxin did not diffuse from the injection site, which may reduce the potential for systemic effects (Tang-Liu et al, 2003).
For a more detailed review of BoNT mechanism of action in the nociceptive pathways, please see the Botulinum Neurotoxin Mechanism of Action section of www.neurotoxininstitute.org.
Three evidence-based reviews evaluated the use of BoNT therapy in the treatment of headache. Gobel and Jost concluded there is positive SIGN level I evidence (Brin et al, 2000; Silberstein et al, 2000) and positive level III evidence (Binder et al, 2000; Mauskop and Basdeo, 2000; Smuts and Barnard, 2000; Guyuron et al, 2002) supporting the use of BoNT for the treatment of migraine. They also found positive level I and IV evidence for treatment of migraine plus TTH (Wheeler et al, 1998; Klapper et al, 2000; Gobel and Jost, 2003).
Reviewing the same body of evidence, with the exception of the study by Guyeron et al, Evers et al concluded that the strongest evidence for the efficacy of BoNT in headache is in migraine, with positive class I evidence for the 25 U dose in both intensity and frequency reduction and negative evidence for the 75 U dose (Silberstein et al, 2000), positive class II evidence for intensity but not frequency reduction (Brin et al, 2000), and positive class III evidence (Binder et al, 2000; Mauskop and Basdeo, 2000; Smuts and Barnard, 2000). For TTH, they found 2 class I studies were negative with respect to the primary endpoint of headache frequency (Burch et al, 2001; Schmitt et al, 2001), although Burch et al found a significant decrease in pain intensity with BoNT type A, while 3 class II studies provide mixed results: 1 showing no reduction in either endpoint, the other 2 showing reductions in both intensity and frequency (Rollnick et al, 2000; Smuts et al, 1999; Relja and Klepac, 2001), and small class III studies that show more positive than negative results. The authors note the inconsistency of results may in part be a result of the varying quality of the studies and methodological differences in the BoNT administration. They note a variety of positive case reports with use of BoNT for cluster and cervicogenic headache and chronic paroxysmal hemicrania, and that an assessment of BoNT efficacy in these types of headache awaits evidence from controlled trials (Evers et al, 2002).
Mathew and Kaup concluded that the currently available evidence and the clinical experience of physicians support the idea that BoNT therapy seems to be a safe and effective option for chronic migraine and TTH patients that reduces use of acute medications and improves quality of life (Mathew and Kaup, 2002). All of these evidence-based reviews indicate the need for further randomized clinical trials sufficiently powered to evaluate the efficacy of BoNT headache therapy within specific headache classes and to identify the subgroups of subjects most likely to benefit from BoNT treatment, the best injection sites, and optimum doses. Since the last of these reviews was published in 2003, the results of several such trials have been published, as are discussed below.
A number of studies, most of them open-label or retrospective, have evaluated BoNT therapy with bilateral injections for TTH in adults. Results of randomized, placebo-controlled studies have been inconsistent. In a study of patients with chronic TTH, Smuts et al noted that treatment with 100 U BoNT type A (Botox ®; Allergan, Inc., Irvine, CA) administered to the cervical and temporalis muscles reduced pain scores by at least 25% in many more BoNT-treated patients than placebo patients (13/22 and 2/15, respectively), although the percentage of patients with at least 50% reduction in pain scores did not differ significantly from placebo. By month 3, patients in the BoNT-treated group had significantly improved monthly average headache severity scores compared with baseline (P = 0.002). Patients in the BoNT-treated group also had more headache-free days compared with the placebo group after 3 months (P = 0.001). No serious AEs were reported. A number of patients reported muscle cramps, flu-like symptoms, and feelings of weakness in the neck muscles, but no significant between-group differences were reported (Smuts et al, 1999).
In a study of 41 patients with episodic or chronic frontal tension headache, Burch et al noted that BoNT type A (Botox ®) 50 U injected into the glabella and forehead region did not reduce headache frequency significantly more than placebo but did reduce headache intensity significantly (Burch et al, 2001). Rollnik et al administered 10 injections of BoNT type A (Dysport ®; Slough, Berkshire, UK) 20 U each or placebo into the fronto-occipital and temporal muscles of 21 patients with chronic and episodic TTH and Schmitt et al administered 8 injections of BoNTA (Botox ®) 2.5 U each or placebo into the frontal and temporal superficial muscles of 59 patients with chronic TTH; neither found significant differences in headache intensity or frequency, or in analgesic use, between BoNT and placebo (Rollnik et al, 2000; Schmitt et al, 2001). Similarly, Gobel et al found no significant improvement versus placebo in any of these endpoints after 6 weeks in patients with chronic TTH treated with BoNT type A (Botox ®) 10 U in the frontal and auricular muscles and 20 U in the splenius capitis muscle (Gobel et al, 1999).
In a study of 300 patients with chronic TTH, Silberstein and colleagues conducted a randomized, double-blind, placebo-controlled study of a single treatment of BoNT type A (Botox ®) versus placebo injected into 5 muscle groups using a fixed-site injection protocol (as opposed to Blumenfeld’s “follow-the-pain” approach). Patients received 50 U, 100 U, or 150 U BoNT; a combination of 86 U BoNT and placebo or 100 U BoNT and placebo (to be referred to as 86 Usub and 100 Usub), with 3 muscle groups receiving active treatment and 2 placebo; or placebo into all 5 muscle groups. The mean change from baseline in the number of TTH-free days at day 60 was the primary outcome measure. All treatment groups showed improvement in the mean change from baseline for number of headache days but no significant difference in BoNT and placebo results, except for the 150 U group at day 60, which was significantly less improved versus placebo (4.5 versus 2.8 d/mo; P = 0.007). At day 90, significantly more patients in the following BoNT-A groups reported a 50% decrease in headache days versus the placebo group (in which 12% achieved the decrease): the 100 U group (31.9%; P = 0.017), the 100 Usub group (30.6%; P = 0.024), and the 86 Usub group (31.9%; P = 0.017). No significant results had been observed at day 60, indicating that a longer period of observation is needed in future studies. There were no significant differences in headache severity, percentage of the day with headache, or other secondary endpoints. There were no treatment-related discontinuations or serious AEs. The incidence of treatment-related AEs overall was significantly higher only for BoNT 100 U versus placebo (45.1% versus 22.0%; P = 0.014) (Silberstein et al, 2005a).
Blumenfeld et al conducted a retrospective chart review of 271 patients diagnosed with episodic migraine, episodic TTH, mixed headache (combination of migraine and TTH), and CDH, the majority (77%) refractory to oral medications. A fixed-site, follow-the-pain, or combination approach was used according to patient need. The mean BoNT type A dose was 63.2 U, and mean total treatment duration was 8.6 months, during which time patients received an average of 3.4 treatments, approximately 3 months apart. The study found that BoNT type A treatment significantly reduced headache frequency and intensity. The number of headache days per month decreased from 18.9 at baseline to 8.3 at last treatment (n = 256; P < 0.001), a 56% reduction. Headache frequency was reduced significantly regardless of headache type ( P < 0.001). On a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), BoNT type A treatment reduced headache intensity by 25%, from 2.4 at baseline to 1.8 at last treatment (n = 117; P < 0.001). Significant reductions were achieved in patients with episodic migraine (n = 15; P < 0.001), CDH (n = 67; P < 0.001), and mixed headache (n = 29; P < 0.05) but not in those with episodic TTH (n = 6; P = 0.09). Of 263 patients surveyed, 225 (85.6%) reported improvement in headache frequency and intensity. Approximately 95% reported no AEs (Blumenfeld, 2003a).
In an ongoing prospective, 3-year, open-label trial of BoNT type A treatment of intractable CDH, migraine, and TTH (>15 days a month), more than 2300 injections had been performed in over 640 patients at the time of publication in 2004. In a preliminary analysis of 436 patients, 91% reported some improvement in their headache symptoms as a result of treatment, with 75% of patients reporting good to excellent improvement. Patients who were administered 2 treatments noted significantly greater improvement than those who had received only 1 treatment, and those administered 3 treatments noted significantly greater improvements than those administered 2 treatments. CHD patients showed cumulative improvement through 3 treatments that was maintained at 12 months. In general, it appeared that use of BoNT therapy brought about a major reduction in use of other analgesic medication (Troost, 2004).
Brin and colleagues demonstrated a significantly greater reduction in migraine pain intensity versus placebo in patients treated with BoNT type A (dose unspecified). In this trial, 56 patients with a history of 2 to 6 migraines per month were randomized into 4 groups: group 1 received BoNT type A in the frontal/temporal regions, group 2 received BoNT type A in the frontal region and placebo in the temporal region, group 3 received placebo in the frontal region and BoNT type A in the temporal region, and group 4 received placebo in the frontal/temporal regions. Group 1 (full BoNT treatment) versus group 4 (full placebo) at week 12 was the primary comparison; the other groups were considered exploratory. On a pain intensity scale of 0 to 10, maximum pain decrease occurred at week 12 for group 1, with a median reduction (range) of –4.0 (–7.5, 0.0) versus a placebo reduction of –0.2 (–5.6, 2.6) (P = 0.04). Monthly migraine frequency was reduced by a median of 1.8 headaches in BoNT type A groups 1, 2, and 3 versus a median reduction of 0.2 headaches in the placebo group. The differences among groups 1, 2, and 3 were not significant (Brin et al, 2000; Dodick, 2003).
Silberstein and colleagues studied the efficacy of 25 U and 75 U of BoNT type A versus placebo as preventive treatment in 123 patients with a history of moderate-to-severe migraine. A fixed-site injection protocol was used in 4 frontalis sites, 2 temporalis sites, and 5 glabellar sites. Patients in the 3 groups had mean migraine frequencies of 4.8, 4.3, and 4.0 and mean headache durations of 35.9, 32.9, and 32.2 hours, respectively (differences were not significant). The 25 U group, but not the 75 U group, showed a significantly greater reduction in moderate-to-severe migraine frequency versus placebo at months 2 (– 1.57 versus – 0.37; P = 0.008) and 3 (– 1.88 versus – 0.98; P = 0.042) and in migraines of any severity at month 3 (– 2.12 versus – 0.90; P = 0.014). A trend in reductions of any migraine was also reported for month 2 (– 1.55 versus – 0.37; P = 0.072). Significantly more BoNT 25 U patients than placebo patients reported at least 2 fewer migraines of any severity at month 3 (P = 0.01). Significantly more BoNT type A patients than placebo patients reported a decrease in migraine frequency of at least 50% at month 3 (45% versus 24%; P = 0.046). In addition, there was a significant reduction in mean headache intensity for BoNT type A versus placebo at months 1 and 2 ( P ≤ 0.029), in the number of patients experiencing migraine-associated vomiting (10% versus 31%; P = 0.012), and in days on which patients used acute medication at month 2 (– 2.45 versus – 0.76; P = 0.028). Both the 25-U and 75-U BoNT type A groups improved significantly more than the control vehicle group on subject global assessment (P ≤ 0.041). The duration of the BoNT type A effect was sustained for 12 weeks after injection and was well tolerated, with no serious treatment-related AEs and only the 75-U treatment group reporting a significantly higher rate of treatment-related AEs than the vehicle. The authors suggested the lack of effect in the 75-U group might be attributable to the lower baseline frequency of migraines in these patients (Silberstein et al, 2000).
Barrientos and Chana conducted a 90-day study of BoNT type A 50 U versus placebo injected into multiple pericranial muscles in 30 migraine patients. Treatment resulted in a significant reduction for BoNT versus placebo in the number of attacks per month of any severity at day 90 (–3.14 versus –0.53; P < 0.05) and the frequency of severe attacks per month at day 60 (–1.4 versus –0.54; P < 0.05) and day 90 (–1.8 versus –0.20; P < 0.02). Significant reductions ( P < 0.005) in frequency versus baseline of severe migraines and migraines of any severity occurred in the BoNT group at 30, 60, and 90 days, but not in the placebo group. Significant reductions ( P < 0.05) for BoNT versus placebo also occurred in duration of attacks, use of acute migraine treatments, and number of attacks with nausea; BoNT patients also noted significantly greater improvements from baseline on a global effectiveness scale. AE information is limited; the authors note only that BoNT type A treatment was well tolerated, except for 1 case of transient frontalis asymmetry that lasted approximately 30 days (Barrientos and Chana, 2003).
In an 11-month multicenter trial, Mathew and colleagues studied the efficacy of BoNT type A in 355 patients with CDH. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders (found to comprise 21% of the group), eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT type A or placebo using a follow-the-pain protocol. Physicians could adjust the dose of BoNT in accordance with each patient’s headache features. The injections were repeated every 90 days at the same sites with the same doses, usually by the same physicians, and assessed every 30 days for 9 months, a period encompassing 3 treatment cycles. The primary efficacy measure was the mean change from baseline in the frequency of headache-free days per 30-day period for the placebo nonresponder group at day 180. At that timepoint, placebo nonresponders treated with BoNT type A (mean, 190.7 U) had an improved mean change from baseline of 6.7 headache-free days per 30-day period versus 5.2 headache-free days for placebo-treated nonresponders. Although the between-group difference of 1.5 headache-free days favored BoNT type A, the difference was not statistically significant. Significant results were evident in some secondary endpoints. A higher percentage of BoNT patients versus placebo patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% versus 15.0%; P = 0.027), although other timepoints showed no significant difference. Also, the mean reduction from baseline in the frequency of headaches per 30-day period at day 180 was significantly greater for placebo nonresponders given BoNT versus those given placebo (–6.1 versus –3.1; P = 0.013), as well as at days 30 through 240. Placebo responders given BoNT versus those given placebo also had greater reductions in 30-day frequency (–9.9 versus –5.6; P = 0.004). Treatment-related AEs occurred in a significantly higher number of BoNT patients versus placebo patients (51% versus 23%; P < 0.001). The authors note that the majority of AEs were transient and mild to moderate in severity and that only 4 of 173 BoNT patients (2.3%) discontinued because of AEs (Mathew et al, 2005).
A subset analysis that pooled both initial placebo responders and nonresponders who were not receiving prophylactic headache medication (n = 228, 64% of the full study population) revealed statistically significant differences between the BoNT- and placebo-treated groups on several outcome measures. Mean change in headache-free days improved over the study course in both treatment groups, although always more in the BoNT group, with the increase achieving statistical significance at day 180 (BoNT 10.0 d/mo versus placebo 6.7 d/mo; P = 0.038). After 2 injection sessions, the maximum change in the mean frequency of headaches per 30 days was –7.8 in the BoNT type A group versus –4.5 in the placebo group ( P = 0.032). After 3 injections, the between-group difference improved to 4.2 headaches ( P = 0.023). The difference in mean usual headache severity was greater with BoNT throughout the study and was statistically significant from days 180 through 270. BoNT treatment reduced the frequency of headaches at least 50% from baseline in over 50% of patients after 3 injection sessions. Significant differences between BoNT and placebo were evident for the change from baseline in headache frequency and headache severity for most timepoints from day 180 through day 270 (Dodick et al, 2005).
In a trial using a fixed-site protocol, Silberstein and colleagues assessed the efficacy of BoNT type A 225 U, 150 U, and 75 U injections versus placebo in 702 CDH patients, the largest controlled trial in this headache population to date (Silberstein et al, 2005b). As in the Mathew trial, the study began with a 30-day single-blind placebo run-in to detect placebo responders (163/702 patients [23.4%]). Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were observed in the placebo nonresponder stratum treated with BoNT type A 225 U, 150 U, and 75 U, and placebo, respectively, but the primary endpoint results were not significant (P = 0.44). Significant results occurred in the following secondary endpoints: at day 30, patients given BoNT 75 U had a significantly larger mean increase in headache-free days (5.0) versus those given BoNT 225 U, 150 U, or placebo (3.1, 3.0, and 2.9 days, respectively; P = 0.01). In the placebo nonresponder groups, the numbers of 50% responders were similar. At day 60 in the placebo responder group, however, a significantly higher percentage of patients given BoNT 225 U had at least a 50% decrease from baseline in number of headache-free days (70%) versus those given BoNT 150 U (44%; P = 0.02) or placebo (37%; P = 0.004). An a priori pooled analysis of placebo nonresponders and responders revealed that BoNT A 225 U or 150 U resulted in statistically significantly greater reductions from baseline in headache frequency compared with placebo at day 240 (–8.4, –8.6, and –6.4, respectively; P = 0.033 analysis of covariance) and that BoNT 225 U also achieved significance in this endpoint versus placebo at day 210 ( P = 0.03). Reduction in number of migraines or probable migraines was also significant (P ≤ 0.02) versus placebo for BoNT 225 U at days 30, 210, and 240; for BoNT 150 U at days 240 and 270; and for BoNT 75 U at days 90, 150, 210, 240, and 270. Only 3.8% of patients discontinued because of AEs (9, 13, 3, and 2 patients in the BoNT 225 U, 150 U, 75 U, and placebo groups, respectively) (Silberstein et al, 2005b).
The results of clinical trials involving over 2000 headache patients have demonstrated that focal injections of BoNT type A as preventive treatment of headache have been safe and very well tolerated, with a notable lack of the systemic effects of other headache medications. BoNT type A treatment-related AEs such as muscle weakness, injection site pain, headache, rash, bruising, and eyebrow and eyelid ptosis are generally transient and mild to moderate in severity (Silberstein et al, 2000; Blumenfeld 2003b; Barrientos and Chana, 2003; Troost, 2004; Mathew et al, 2005; Silberstein et al, 2005a; Silberstein et al, 2005b). In the controlled CDH trials, the withdrawal rates due to AEs were less than 4% (Mathew et al, 2005; Silberstein et al, 2005b).
The safety and tolerability of BoNT therapy for headache distinguish it from a number of other headache treatments. Accordingly, in an overall evaluation of the risks and benefits of BoNT, it is worth considering the extent to which use of BoNT therapy avoids AEs caused by other therapies, either because it is administered as an alternative preventive therapy or because it reduces the use of, and therefore exposure to, acute medications.
In an article for Headache published in 2003, Blumenfeld et al detail procedures for administering BoNT type A in patients with migraine and TTH. The selection of appropriate candidates for BoNT type A is based on an accurate diagnosis and headache classification derived from a comprehensive headache history. Secondary headaches resulting from other causes such as tumor, infection, metabolic disorders, or other systemic illness should be ruled out. Patients most likely to benefit from BoNT type A treatment include those with recurring migraines that significantly interfere with their daily routine despite acute treatment; those with frequent headaches; those concerned about the high cost of acute therapies; those with extant uncommon migraine conditions including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction; those refractory to other treatments; those who overuse, cannot tolerate, or do not comply well with acute treatment regimens; those in whom other preventive treatments are poorly tolerated or contraindicated; and those who simply prefer this treatment. Those with headache and jaw, neck, or head muscle pain should also be considered candidates. Contraindications to BoNT type A use include sensitivity to toxin or neuromuscular disorders such as myasthenia gravis or Eaton-Lambert syndrome (Blumenfeld et al, 2003b).
Physicians should discuss the known AEs that may occur with BoNT type A treatment (eg, headache, bruising, ptosis) and obtain informed consent. They should also inform patients that multiple treatment cycles may be needed to achieve optimal therapeutic effect.
Patients should indicate the principal sites of their head pain, pointing to the anatomical locations most frequently affected. The face and neck should be examined to assess muscle tone, asymmetry, and brow position. Palpating the frontalis, temporalis, and posterolateral neck and shoulder regions will help identify areas of tenderness and anatomical sites that produce pain on palpation. Patients can either sit or lie down for injection of the frontal and temporal regions and should be seated for injection of the posterior neck region and trapezius.
The total dose of BoNT type A to be administered should be individualized by taking into account the specific features of each patient, including type of headache, severity of symptoms, and body size (Blumenfeld et al, 2003b).
Sterile injection technique should be observed for the entire procedure. Injections should be intramuscular; avoid injecting the periosteum and injecting intradermally to minimize discomfort and the risk of intra-arterial injection. To avoid facial asymmetry, inject symmetrically in the frontalis region. Visualization and avoidance of the superficial blood vessels can help minimize the risk of bruising. If the patient has no pain in the inferolateral frontalis regions (lateral suprabrow areas), avoid injection there to minimize the risk of ptosis (Blumenfeld et al, 2003b).
The injection sites commonly used for BoNT type A treatment of headache are the glabellar and frontal regions, the temporalis muscle, the occipitalis muscle, and the cervical paraspinal region (Figure 3). There are 3 recommended injection protocols: a fixed-site approach, a follow-the-pain approach, and a combination approach (Table 1). In general, choice of protocol depends on the patient’s headache features (Blumenfeld et al, 2003b).
Figure 3. Typical sites of BoNT injections for headache treatment. Reproduced with permission from Nucleus Medical Art. Copyright © 2003. All rights reserved. www.nucleusinc.com.
Table 1. Summary of injection protocols and clinical indications.
Injection protocol |
Clinical features on history or examination |
Fixed-site: “Follow the trigeminal nerve” |
Migraine or migrainous headache |
“Follow the pain” |
TTH |
Combination approach |
Coexisting migraine and TTH |
“Follow the muscles of mastication” |
Temporomandibular disease |
“Follow the dystonia/postural abnormality” |
Headache caused by cervical dystonia (head forward position) |
Adapted from Blumenfeld et al, 2003c.
The fixed-site method is often used for patients with migraine or migrainous headache and uses fixed symmetrical injection sites with a range of predetermined doses. The follow-the-pain approach, most often used to treat TTH, adjusts the sites and doses depending on where the patient feels pain and where the examiner can elicit pain and tenderness on palpation of the muscle. Injections are often asymmetrical. For patients with coexisting migraine and TTH, a combination of injections at fixed trigeminal sites is supplemented with follow-the-pain injections. These patients generally receive higher doses of BoNT type A. Cervical dystonia can also be a cause of head and neck pain; in this case a follow-the-dystonia approach is recommended. The dystonic muscles should be the focus of injection, with lower doses in the compensatory muscles to avoid weakening them (Blumenfeld et al, 2003c). Recommended anatomical sites of injection for headache and the BoNT type A dose per site are listed in Table 2.
Table 2. Anatomical sites of injection and BoNT type A dose.
Muscle |
BoNT type A U/Site |
Number of injection sites |
Procerus* |
2.5-5.0 |
1 |
Corrugator* Medial Lateral |
2.5 2.5 |
2 (1 per side) 2 (1 per side) |
Frontalis* |
2.5 |
8-12 (4-6 per side) |
Temporalis* |
2.5-5.0 |
8-10 (4-5 per side) |
Occipitalis † |
2.5-5.0 |
2 (1 per side) |
Splenius capitis area *† |
5.0-10.0 |
2 |
Masseter † |
10.0 |
1-2 |
Trapezius † |
5.0-10.0 |
2-6 (1-3 per side) |
Sternocleidomastoid † |
5.0-10.0 |
2 |
Cervical paraspinal muscles † |
2.5 |
1-3 per side |
*For fixed-site or follow-the-trigeminal-nerve protocol; injections should be bilateral. |
||
† For follow-the-pain protocol; injections may be unilateral or bilateral, depending on signs and symptoms. |
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Adapted from Blumenfeld et al, 2003b.
The stepped-care approach to headache treatment initiates therapy with the safest standard medication and progresses to more costly treatments only after the initial approach fails. In contrast, stratified care provides treatments tailored to patients’ individual needs and may be more likely to match preventive headache therapies to the most appropriate candidates based on headache frequency, severity, patterns of medication usage, and contraindications of other treatments. Two recent studies provide compelling evidence that the stratified care approach to headache therapy improves clinical outcomes compared with traditional stepped care and that from a societal perspective stratified care is cost-effective (Lipton et al, 2000; Sculpher et al, 2002). As treatment algorithms are formulated in the future, some of which may incorporate specific recommendations regarding BoNT and other preventive therapies, the issue of stepped versus stratified care will probably influence treatment recommendations. Further study is needed to establish the role of individual therapeutic agents within a stratified care algorithm and to determine whether stratification to preventive versus abortive treatment is associated with enhanced cost-effectiveness.
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