Chapter 8: Botulinum Toxins

BACKGROUND

Botulinum toxins are neurotoxins produced by the gram-positive, spore-forming, anaerobic bacteria, Clostridium botulinum, as well as C butyricum, C baratii, and C argentinense.^1,2 These toxins are the most deadly human neurotoxins known. Clinically, botulism can occur following ingestion of contaminated food or from a wound infection. The clinical signs of botulism include limb paralysis, facial weakness, ophthalmoplegia, dysarthria, dysphagia, dyspnea progressing to respiratory arrest, constipation progressing to ileus, and urinary retention.³ C botulinum produces 7 antigenically (immunologically) distinct neurotoxins: A, B, C1, D, E, F, and G.

• Varied mechanisms of action of botulinum neurotoxin (BoNT) subtype are believed to be due to its ability to inhibit multiple neurotransmitters from presynaptic vesicles. Specific proteins involved in this process are affected by different toxins and thus different strains of toxin do not necessarily work via the same mechanism.

• Only types A and B toxin are currently routinely used in clinical practice.

• Currently, there are 3 types of botulinum toxin type A commercially available in the United States including onabotulinum toxin A (Botox), abobotulinum toxin A (Dysport), and incobotulinum toxin A (Xeomin).

• Rimabotulinum toxin B (Myobloc) is the only botulinum toxin type B currently available in the United States.

• Each toxin has been developed with different dosing units and they are not interchangeable—this is clinically important to remember. Synaptosomal-associated protein (SNAP 25) is inactivated by botulinum toxin type A and vesicle associated membrane protein (VAMP) is inactivated by botulinum toxin type B.

• Its effect on motor function through inhibition of release of acetylcholine has been well documented. Cleavage of either one of these proteins results in inhibition of acetylcholine release, disruption of neuromuscular transmission, and paralysis of the muscle.

• Most important recent scientific discovery is of SNAP 25 on motor and sensory neurons.

• Several animal studies demonstrating the toxin’s inhibition of substance P, calcitonin-gene related peptide (CGRP), glutamate, bradykinin, ATP, and purinergic receptors.

• Additional animal studies have suggested a clinically relevant central analgesic effect of type A toxin as well.

The only FDA-approved specific pain indication for any current commercially available botulinum toxin is chronic migraine for onabotulinum toxin A (Botox).⁴ The “off-label” use of botulinum toxin for the treatment of other chronic painful conditions has been reported for cervical dystonia–associated neck pain, chronic low back pain, and chronic lateral epicondylitis. Jabbari and Machado have recently published a review of the use of botulinum toxin for refractory pain based on the evidence according to the AAN evidence rating approach. The reader can review these references for additional information regarding the use of botulinum toxins for chronic pain.

BOTULINUM TOXIN FOR THE TREATMENT OF CHRONIC MIGRAINE

The most evidence for treatment with botulinum toxin is for the specific condition, chronic migraine. The importance of defining this group has become vital for proper patient selection. The FDA has approved the use of ...