Since the 1980s, botulinum toxins (BTXs) have been used for many putative conditions that cause pain. The U.S. Food and Drug Administration (FDA) has approved BTX type A as a prophylactic treatment for headaches due to chronic migraines and approved both BTX type A and B for other medical conditions associated with pain and discomfort. Although BTX is currently not approved for any other headache disorders, it 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 34-1). However, so far, an open study has shown BTX is ineffective for patients with episodic cluster headaches.¹³

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 mostly primary headaches, for which BTX data are available. More research continues, with the largest chronic migraine study to date done in 2010, leading to FDA approval of BTX. Other large, double-blind, randomized, placebo-controlled trials are coming forward for other types of headaches.

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 IHS¹⁴ 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. The 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 colleagues¹⁵ 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.

Although not a primary headache, new research has shed light on BTX for the treatment of a nummular headache. According to the IHS, a nummular headache is defined as pain coming from a small circumscribed area of the head where there is no sign of any lesion of the underlying structures. Mild to moderate pain can be felt and is confined to a rounded area usually ranging from 2 to 6 cm, and the affected area may present with paraesthesia, hypesthesia, dysesthesia, and/or tenderness. The area of pain in a nummular headache is usually found in the parietal region and is slightly more predominant in females.

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 for improvement in the appearance of glabellar lines in 2002. 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. Recently, the FDA has approved BTX-A for therapeutic use in patients with moderate to severe glabellar lines (2002) and for the prophylactic treatment of chronic migraine in adults (2010).

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.