Chapter 23. Botulinum Toxins for the Treatment of Headaches

Since the 1980s, botulinum toxins (BTX) have been used for many putative conditions that cause pain. The U.S. Food and Drug Administration (FDA) has not yet approved their use for any specific pain disorders, although two forms of BTX (A and B) have been approved by the FDA for other medical conditions associated with pain and discomfort. However, BTX continues to be used successfully by a range of specialists to address pain control.

Although there are many case reports and open-label studies on the effectiveness of BTX in treating painful conditions, a dearth of double-blind, placebo-controlled, randomized clinical trials exist that directly addresses its use for pain management. Some double-blind, placebo-controlled, randomized clinical studies show that botulinum toxin type A (BTX-A) injections are effective in treating various headache disorders (Table 23-1). However, there are no published clinical trials showing its effectiveness in cluster headaches.

All of the data presented in this chapter, and most of the published experience in headache management is from BTX-A studies, but botulinum toxin type B (BTX-B) also may be effective, given the similarity of the two serotypes.

Headache is one of the most common types of pain disorder, responsible for more than 10 million physician visits annually in the United States. Although the terminology of various types of headaches may be confusing, we limit our discussion here to primary headaches, for which BTX data is available to make preliminary recommendations until more information is available from ongoing large, multi-center, double-blind, randomized, placebo-controlled trials.

Migraine is a neurologic disorder that features recurrent attacks of headache, most often occurring unilaterally. It accompanies various combinations of symptoms, such as nausea, vomiting, and sensitivity to light, sound, and other stimuli. Migraine attacks can occur at any time of day or night. Episodes may last from several hours to days, 4 to 72 hours by International Headache Society (IHS) criteria, and are often disabling. Even routine activity or slight head movement can exacerbate the pain. Pain can migrate from one part of the head to another and may radiate down the neck or shoulder. The majority of patients also experience scalp tenderness during or after an attack.

Tension-type headache has two subcategories: episodic and chronic. The episodic tension-type headache (ETTH) is defined by the IHS13 as headache frequency of greater than 10 lifetime attacks, but fewer than 15 attacks per month; With an average attack duration of 30 minutes to 7 days; and at least two features that may include mild to moderate pain intensity, pressing, tightening, a bandlike sensation bilaterally, nonpulsatile quality, and no exercise-induced exacerbation.

The IHS chronic tension-type headache (CTTH) criteria are identical to those for ETTH except that the attack frequency is 15 or more attacks per month for at least 6 months. CTTH definition permits one migraine-associated symptom of nausea, photophobia, or phonophobia, in contrast to that of ETTH. Patients who have two different headaches that both meet criteria for ETTH are defined as having CTTH if the sum of the attack frequencies for the two headaches is 15 or more attacks per month.

Chronic daily headache has not been satisfactorily characterized by the IHS but Silberstein and colleagues14 have proposed that this condition represents a group of disorders that includes CTTH, transformed migraine, new daily persistent headache, and hemicrania continua. Chronic daily headaches usually evolve over a period of months or years but can be of sudden onset. The chronic daily headache spectrum may include transformed migraines that occur more than 4 hours per day, and 15 days per month. There is usually a slow increase in tension-type headache and a concomitant decrease in migraine features. Chronic daily headaches often are associated with analgesic abuse or overuse in many patients.

The existence of BTX has been known for centuries, but its positive effects have only recently been realized. Justinus Kerner, a German physician and poet (1786–1862),coined the term “sausage poison,” later called “botulism” for the Latin form botulus, which means sausage. Professor Emile Pierre van Ermengem, of Ellezelles, Belgium, identified the bacterium Bacillus botulinus in 1885 that was later renamed Clostridium botulinum. In 1944, Edward Schantz cultured C. botulinum and isolated the neurotoxin. In 1949, Burgen and associates discovered that BTX blocks neuromuscular transmission. Dr. Vernon Brooks, in the 1950s, discovered that BTX-A could be injected into hyperactive muscle causing temporary “paralysis” by blocking the release of acetylcholine at the motor nerve ending.

In 1973, Alan B. Scott, MD, of Smith-Kettlewell Eye Research Institute, used BTX-A in monkey experiments, and, in 1980, he was the first to use BTX-A to treat strabismus in humans. In 1988, Allergan acquired the rights to distribute Scott’s BTX-A product, Oculinum, and the responsibilities to conduct clinical trials of the drug’s effectiveness for other indications, including cervical dystonia. In 1989, the FDA approved Oculinum (renamed Botox in the United States and Dysport in Europe) as an orphan drug to treat strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or eighth cranial nerve disorder (hemifacial spasms) in patients 12 years of age and older. BTX-A received FDA approval in 2000 for cervical dystonia, and in 2002 for improvement in the appearance of glabellar lines. The newest form of the botulinum toxin, BTX-B, was studied recently, and several products currently are available commercially (MyoBloc in the United States; NeuroBloc in Europe). BTX-B (MyoBloc) was approved by the FDA in 2000 for treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain. Clinicians are also using BTX-B when patients become immunologically resistant to serotype A.

The BTX molecule is produced by C. botulinum, which is a gram-positive anaerobic bacterium. BTX can be divided into seven neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G) that are antigenically and serologically distinct but structurally similar. BTX-A, -B, -E, and, -F (rarely) can cause the clinical syndrome of “botulism,” which may occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from an infected wound. BTX-C and -D cause toxicity only in animals.

BTX is synthesized as a single chain (150 kDa) and cleaved to form a dichain molecule with a disulfide bridge. The light chain (~50 kDa) acts as a zinc (Zn2+) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end. The heavy chain (~100 kDa) provides cholinergic specificity and binding to the presynaptic receptors. This promotes light chain translocation across the endosomal membrane.

BTX acts by binding presynaptically on the cholinergic nerve terminals, thus decreasing the release of acetylcholine and causing a neuromuscular blocking effect. This effect is temporary, and recovery occurs through proximal axonal sprouting and muscle reinnervation by the formation of new neuromuscular junctions. BTX-A and -E cleave synaptosome-associated protein (SNAP-25), a presynaptic membrane protein required for fusion of neurotransmitter-containing vesicles. BTX-B, -D, and -F cleave a vesicle-associated membrane protein (VAMP), also known as synaptobrevin. BTX-C acts by cleaving syntaxin, a target membrane protein.

Clinicians began using BTX with the prospect of reducing pericranial muscular tension and contractions that are thought to contribute to headaches. BTX may reduce muscle spindle activity, and this, in turn, may decrease the sensory feedback. BTX may also directly affect sensory nerves by possibly inhibiting the neuropeptide-containing fibers. Although large multi-center, double-blind, randomized data are lacking, the evidence so far shows that BTX is an effective anti-headache medication when certain criteria are met.

Although there are numerous case studies focusing on use of BTX-A for treating migraines,1,3 chronic daily headaches with migraine features,11 and chronic tension-type headache,4–6,8,9,15 there is no uniformity with the injection techniques or dosages. The studies use two general injection paradigms for treating headaches. In the fixed-site paradigm (Fig. 23-1), BTX is injected in sites that are predetermined and the same for everyone in the study. In the follow-the-pain paradigm, BTX is injected into or around the tender points that are reported by the patients and confirmed on physical examination.

Recent double-blind, placebo-controlled studies have shown consistency and homogeny with injection technique and dosage, allowing better comparative data analysis. An upcoming wave of large multi-center, double-blind, randomized placebo-controlled trials will further clarify the role of BTX in the prophylactic treatment of a variety of headache disorders.

Migraine Studies

Silberstein and colleagues, in 2000,1 reported a double-blind, placebo-controlled study in which 123 patients were randomly assigned into three groups, as follows: placebo (n = 42), BTX-A, 25 units (n = 42), and BTX-A, 75 units (n = 40). Patients who had two to eight moderate to severe, IHS-defined migraine attacks per months were enrolled. BTX-A injection sites were fixed-site and included frontalis, glabellar, and bilateral temporalis muscles. BTX-A decreased the frequency of moderate to severe migraines per month but failed to reach statistical significance. This study also showed a decrease in the number of days of acute medication usage. All treatment-related adverse events were transient, and more commonly associated with the 75-unit dose.

Binder, also in 2000,2 reported an open-label study that included 77 patients with migraine. Results confirmed the efficacy of BTX-A in reducing the number and severity of acute attacks per month.

In 1998, Binder and colleagues3 performed a retrospective review of 96 patients who had chronic migraines but were treated with BTX-A for their movement disorder or were seen in the cosmetic surgery clinics. This study evaluated patients who received BTX-A injections into glabellar, temporalis, and occipitalis regions. The mean total dosage of BTX-A was 26 ± 14 units. This study reported that 51% of the 96 patients had complete elimination of their headaches, while 28% of the subjects had more than 50% reduction in the frequency or severity of their headaches. The remaining 21% of the 96 patients either had less than 50% response in headache frequency and severity, or were lost to follow-up. The duration of benefit in the complete responders group was 3.6 ± 2.4 months. The partial responders group (≥ 50% decrease in headache frequency or severity) was 2.9 ± 1.6 months. Adverse effects reported were ecchymosis and transient, local pain at the injection site.

Tension-Type Headaches

The first reported study, by Zwart and colleagues in 1994,10 showed no effect in six patients with tension-type headache, not using the IHS criteria. This study was carried out using the follow-the-pain paradigm, with BTX-A injected unilaterally into the temporal muscle.

Since then, Rollnik and colleagues,4 in 2000, conducted a double-blind placebo-controlled study involving 21 patients with CTTH or ETTH. The injection sites were specified as follows: “pericranial muscles around the head (2 injections into the fronto-occipital muscle and 3 into the temporal muscles bilaterally).” This study used BTX-A (Dysport) from Ipsen. The total dose used was 200 units. These investigators found no significant difference (P > .5) between the BTX-A and saline-treated groups. The study evaluated the pain intensity (visual analog scale), clinical global impression, headache frequency, and consumption of analgesics. Both groups tended to improve on several measures; however, the pain intensity (P = .051) and clinical global impression (probability not given) at 4 weeks. The authors of this study suggest that given that Dysport is freeze dried and susceptible to breakdown, in contrast to the Botox (an American BTX-A) that is vacuum dried, a higher dose of Dysport may be needed to obtain a successful outcome.

Smuts and colleagues,6 in 1999, reported a double-blind, placebo-controlled study in which 37 patients with CTTH were randomized into one of two groups: placebo (n= 15) or BTX-A (n = 22). Of the 37 patients, 38% also had history of migraines. The BTX-A injection sites were fixed and included 100 units into bilateral trapezius, splenius capitis, and temporalis muscles. At 3 months, 59% of the patients in the BTX-A group had ≥ 25% improvement in their headache severity score and number of headache-free days, whereas only 13% of the placebo had the same response.

Schulte-Mattler and colleagues,7 also in 1999, in an open-label prospective study, injected nine patients who had ETTH and CTTH with BTX-A. They reported that eight of the nine patients showed improvement of their headache symptoms.

Wheeler,8 in 1998, reported four case studies of patients with CTTH for whom previous multiple therapies had been unsuccessful. BTX-A was injected in a follow-the-pain paradigm, using variable doses (20 units to 100 units) at the tender sites. All four patients had subjective pain relief.

Relja,9 in 1997, did a preliminary open-label study in which 10 patients with CTTH were injected with 15 to 35 units of BTX-A in up to six sites based on local tenderness. All of the patients were refractory to previous pain medications, and all reported elimination or reduction in severity and duration of headaches at 2 weeks.

Relja and Korsic,5 in 1999, enrolled 16 CTTH patients in a double-blind, placebo-controlled, crossover study. The 35 to 80 units of BTX-A or placebo were injected in up to six sites into bilateral frontalis, trapezius, or sternocleidomastoid muscles based on local tenderness. The patients were followed 1, 2, 4, and 8 weeks post-injection. BTX-A significantly decreased tenderness scores, as recorded in patient diaries, and also decreased severity and duration of attacks (probability values not listed). Adverse events included local pain at the injection site, which occurred in some patients (number not specified) following BTX-A and saline.

Chronic Daily Headaches

Klapper and Klapper,11 in 1999, reported five case studies of patients who had chronic daily headache with migrainous features. All five received 75 units of BTX-A at 11 fixed injection sites into the frontalis, glabellar, and temporalis muscles. Three of the five patients showed more than 75% subjective improvement. One patient had no response, and one showed only 35% subjective improvement.

Freund and Schwartz,12 in 2000, reported a double-blind, placebo-controlled study in which 26 patients (n = 14 BTX-A, n = 12 placebo) with daily headaches secondary to cervical whiplash injuries were randomly assigned to one of two groups. The inclusion criteria included neck pain with musculoskeletal signs for more than 6 months. All of the patients were 2 years post-injury and had failed conservative therapy. BTX-A injection involved fixed doses of 100 units and the follow-the-pain paradigm. After 4 weeks, 11 of 14 patients showed a significant decrease in pain, and there was significant improvement in neck pain and range of motion. No adverse effects were reported.

Current data suggest that BTX is potentially effective as an agent for treating severe headaches. It has been successfully used to treat not only myofascial pain syndrome but also headaches, although in the United States this use is off-label at the present time. BTX appears to work primarily at the neuromuscular junction by binding presynaptically to the cholinergic nerve terminals, causing a neuromuscular blocking effect. Researchers are also evaluating its effect on substance P and other neurotransmitters involved in pain transmission. It may have a potential direct effect on pain perception.

Although, large multi-center data are yet to be published, based on the current available data on the use of BTX for headaches, we suggest the following guidelines:

• 1. BTX should be considered in treating migraines that are moderate to severe, resistant to conventional treatments, or cause more than 4 days of disability per month.
• 2. BTX injections may be efficacious in treating chronic severe tension-type headaches causing missed work or school.
• 3. BTX may potentially be the most efficacious agent in patients with chronic daily headaches.
• 4. BTX may be effective in patients with cervicogenic headaches and cervicothoracic myofascial pain syndromes associated with frequent headaches.

All of the headache studies carried out thus far have shown that BTX is a safe drug. The adverse effects are limited to localized pain at the injection site, muscle weakness, and flulike symptoms. There is a possibility of developing immunity to BTX-A, in which case this form of the toxin could be replaced with BTX-B. Current data suggest that headaches can be treated using a relatively low dose, thus further decreasing the potential for developing antibodies. BTX-A doses closer to 100 units show more favorable results in reducing headache frequency and intensity. Data also suggest that the fixed-injection paradigm may be more effective, and it appears to be gaining popularity among headache specialists.