Botulinum Toxin In The Treatment Of Headaches

Victor A. Maquera, M.D.
Victor Maquera, M.D. is a Neurologist in private practice
in Jacksonville with the Jacksonville Neurological Clinic.

Introduction

Clostridium Botulinum is the microorganism responsible for Botulism. Neuroparalysis due to the toxin produced by this organism was recognized as a cause for Botulism in 1793.1 The concept that this toxin might be useful in the treatment of excitatory states of the central nervous system was described in the early part of the 19th-century. Since then, the 900 kDa structure of the toxin has been elucidated.2

BOTOX® (Allergan Inc., Irvine, CA, USA) was licensed by the Food and Drug Administration in 1989 for the treatment of strabismus and blepharospam. This formulation has since been used the treatment of cervical dystonia, cerebral palsy and a number of other conditions (Table 1). Recently, several authors have described its use in the treatment of headaches. This article will summarize its use for these conditions.

Table 1. Conditions Treated
With Botulinum Toxin

  • Blepharospam
  • Hemifacial spasm
  • Torticollis
  • Spastic Dysphonia
  • Writer's Cramp and other focal dystonias
  • Spasticity due to Stroke
  • Spasticity due to Multiple Sclerosis
  • Spasticity due to Cerebral Palsy
  • Focal Hyperhydrosis
  • Myofascial Pain Syndrome
  • Detruser-Sphincter Dyssynergia

Mechanism

Clostridium Botulinum produces seven distinct types of neurotoxins (BTX-A through G). Each type is antigenically distinct with its own characteristics.

The neurotoxins act at the neuromuscular junction inhibiting the release of acetylcholine. Botulinum toxin is formed as a single-chain molecule that is cleaved to form a dichain molecule. This dichain molecule is composed of a light chain linked by a disulfide bond to a heavy chain. Four steps are required in the cellular action of this neurotoxin3. (Figure 1).

Figure 1. Botulinum Toxin Mechanism Of Action.
The Botox light chains block specific proteins, which are used in binding the Acetylcholine vesicle to the cell membrane.

botox_fi.jpg (22212 bytes)
  1. Binding. The heavy chain of the toxin enables binding of the toxin to the presynaptic terminal through high-affinity acceptors that are specific for the various distinct serotypes.
  2. Internalization. The neurotoxin is then internalized into the nerve terminal through endocytosis.
  3. Translocation. When the vesicle containing the neurotoxin becomes acidic, the structure of the toxin molecule changes and the light chain is moved across the vesicle membrane into the cytoplasm of the nerve terminal.
  4. Metalloprotease Activity. Once the light chain is in the cytoplasm of the nerve terminal, it acts by cleaving specific peptide bonds of specific synaptic proteins.
These proteins are required for fusion of synaptic vesicles with the presynaptic membrane, allowing release of the vesicle contents i.e. Acetylcholine. When the synaptic fusion proteins are rendered non-functional, acetylcholine is not released and the muscle no longer receives a signal to contract. The neurotoxins are very specific and cleave only one specific peptide bond (Table 2).

 
Table 2. Specificity Of Protein Cleavage
BTX-A,E cleave SNAP-25 (25kDa synaptosomal associated protein)

BTX-B,D,F cleave VAMP (vesicle associated membrane protein)

Intuitively, treatment with Botulinum Toxin would not appear to be a physiologic mechanism for treating migraines. However, the findings of the Botox Migraine Study Group suggest that in a group of 123 patients diagnosed with the International Headache Society classification of migraines, Botulinum Toxin reduced the frequency of migraine attacks by half. This group of patients was randomized to receive 0, 25 or 75 units of Botulinum Toxin injected into the glabellar, frontalis or temporalis muscles. Of interest, this particular study also noted that 25 units of Botulinum Toxin seemed to be more effective than 75 units. Side effects included blepharoptosis, especially with the larger dose, which was transient and mild.

Botox may not only affect the neuromuscular junction directly, but may also have intrinsic pain controlling effects by acting on afferent pathways affecting pain perception5, 6.

Tension Type Headaches

Tension type headaches are described as a band-like pain that encompasses the frontal to occipital region. Associated with this type of headache, there may be an associated Cervical Myofascial Pain Syndrome (MPS). MPS is characterized by acute pain in one or more trigger points located within the affected muscles7.

The goal for treatment of these conditions is to provide relaxation to the affected muscles. Standard therapies have included non-steroidal anti-inflammatory drugs, corticosteroids, antidepressants, injections of local anesthetic in combination with or without corticosteroids. Additional therapies have included "dry needling" and physical therapy.

Migraines

Recently Botulinum Toxin has come into vogue as a treatment for facial wrinkles. In the course of treating these wrinkles, it was discovered that people who suffered from migraines had a decrease in the frequency and severity of these types of headaches. Since then several authors have described the treatment of migraines with Botulinum Toxin4.

Botulinum Toxin has demonstrated its efficacy in a number of conditions associated with dysregulated muscle contractions (Table 1). In addition to the muscle relaxation, secondary effects include release of entrapped nerves and pain relief5-7. Physiotherapy associated with this treatment will assist in breaking the cycle of pain and spasm. This combination of effects is designed to achieve neuromuscular re-education, improving posture and restoring normal muscle and tendon movement.

Summary

Botulinum Toxin is a relatively recent novel approach to the treatment of chronic headache conditions. Additional studies are necessary in order to validate the effects of Botulinum Toxin in the treatment of migraines. The treatment of Tension-type headaches is an extension of the current treatment for Cervical Dystonias. Botulinum Toxin will most likely play an adjunctive role in the standard treatment of these conditions.

REFERENCES

  1. Guyer B. Botulinum toxin type A: new therapeutic directions. Eur J Neurol. 1999; 6:S121-123.
  2. Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus. 1973; 17:21-25.
  3. Montecucco C. Mechanism of Action of Clostridial Neurotoxins. Toxins 99 Meeting Report. 1999; 2.
  4. Botox Migraine Study Group. Am Acad Neurol Annual Meeting. 1999.
  5. Gordh T, Karlsten R, Christiansen J. Intervention with spinal NMDA, adenosine and NO systems for pain modulation. Ann Med. 1995; 27: 229-234.
  6. Choi Y, Raja SN, Morre LC, Tobin JR. Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue. J Neurol Sci. 138:14-20.
  7. Porta M. Botulinum toxin type A injections for myofascial pain syndrome and tension-type headache. Eur J Neurol. 1999; 6:S103-109.
  8. Smuts JA et al. Prophylactic treatment of chronic tension-type headache using Botulinum Toxin type A. Eur J Neurol. 1999; 6:S99-102.

Jacksonville Medicine / April 2000

 

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