A Neurotoxin With Many Uses

STOWE, VT—From FDA-approved uses such as treatment of cervical dystonia to off-label uses such as headache, from blepharospasm to back pain, botulinum toxin types A and B continue to find roles in the therapeutic armamentarium. At the Headache Cooperative of New England’s 20th Annual Headache Symposium, Thomas N. Ward, MD, discussed the history of the unique toxin and some of its clinical uses. Dr. Ward is Professor of Neurology and Co-Director of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The Most Potent Toxin Known
There are seven antigenic types of botulinum toxin in nature—A, B, C1, D, E, F, and G—and they vary based on the complex proteins within them. The common theme with all of them is their heavy chain that binds with cholinergic nerve terminals and their light chain then gets internalized and cleaves one of the docking compounds, which for botulinum toxin A is synaptosome-associated protein 25 (SNAP-25). “What happens is vesicles cannot fuse with the membrane and dump out the neurotransmitter. The best studied is acetylcholine, and that’s the mechanism that affords clinicians the most benefit, particularly for dystonia,” Dr. Ward said. Very simply put, botulinum toxin acts therapeutically by preventing the release of acetylcholine at synaptic nerve terminals.

Botulinum toxin type A was first FDA approved in 1989. It was known as Oculinum, better known as Botox, and now called onabotulinumtoxinA. In the early 1990s, botulinum toxin type B was being studied. Type B was known as Neurobloc in just about every country in the world except the United States, where it was known as Myobloc. Generically it is now known as rimabotulinumtoxinB. There is also now a second type A in the United States called Dysport (abobotulinumtoxinA).

“All these products are not interchangeable,” Dr. Ward stressed. “The dosing is different. If you use any of them, you better know what you’re doing.” While botulinum toxin can be very effective, it can also cause botulism, although that requires massive doses compared to the tiny therapeutic doses commonly used. “It’s the most potent toxin known … and there’s a fairly narrow therapeutic window,” Dr. Ward cautioned.

Clinically, botulinum toxin is used for many things: strabismus, cervical dystonia, blepharospasm, excessive sweating, wrinkles, and hemifacial spasm—these all have an FDA indication. It’s also used for action dystonias, tics, spasmodic dysphonia, trigeminal neuralgia, headaches, rigidity, low back pain, anal fissure, and excessive salivation.

How does botulinum toxin work? “There’s good evidence that it prevents the release of acetylcholine,” Dr. Ward said. Beyond that the quality of information and data starts to slide. It is believed to prevent glutamate and CGRP release, although some are still skeptical that these changes can occur clinically. It has also been shown to act quickly—in less than two hours—on muscle spindles.

Management of Dystonia
Dystonia is a movement disorder that causes the muscles to contract and spasm involuntarily and inappropriately. “The neurologic mechanism that makes muscles relax when they are not in use does not function properly, so you often get agonism/antagonism contracting at the same time and you may end up with very unusual body postures,” Dr. Ward said. Treatment used to be pharmacologic. Various drugs were used; with near toxic doses, patients may have seen some benefit along with a host of side effects. At one time surgery was the mainstay for dystonia, but these procedures have fallen by the wayside. “The breakthrough in therapy came with botulinum toxin,” he said. “It’s been in widespread use for about two decades now. It’s the most effective therapy.” One of its many advantages is the flexibility in injection strategies. The dose and injection site can be changed until the patient responds. “And most patients will respond.”

In cervical dystonia, “there’s a disconnect in pain,” Dr. Ward said. The pain varies in severity and it doesn’t always correlate with severity of the posture deformity. Similar to most movement disorders, it is gone when the patient is asleep. And in part, in some people, it seems to be related to muscle spasms. It has been noted clinically that sometimes the pain of cervical dystonia is reduced by botulinum toxin administration way before the spasm changes.

Also, the amount of pain relief can be disproportionate to the change in the position of the head, and it can also occur long before the posture gets the maximum benefit at seven to 10 days. “Some patients will claim that their pain starts to get better in an hour or two and no one can fully explain that, although there is some evidence that it may be a direct effect on muscle spindles that kicks in at about 45 minutes,” Dr. Ward said.

Headache Pain
Botulinum toxin can be and is used for headache. “Let me emphasize it is off label, at least for now. I would describe it as very controversial,” Dr. Ward said. “There is good evidence that it does not work for tension-type headache.” Conflicting evidence exists regarding other headache types. It may be effective in chronic migraine if the patients are not on preventive treatments. “There is an [American Academy of Neurology] assessment that basically outlines what it thinks are the flaws in the evidence—that it doesn’t work for tension-type headache, that maybe it works in some cases in some types of migraine—and I would recommend that you read that because it is evidence based.”

—Glenn S. Williams

Suggested Reading
Dodick DW, Turkel CC, Degryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010 May 17; [Epub ahead of print].

Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1707-1709.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Gracies JM, Graham HK, et al. Assessment: Botulinum neurotoxin in the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1691-1698.

STOWE, VT—From FDA-approved uses such as treatment of cervical dystonia to off-label uses such as headache, from blepharospasm to back pain, botulinum toxin types A and B continue to find roles in the therapeutic armamentarium. At the Headache Cooperative of New England’s 20th Annual Headache Symposium, Thomas N. Ward, MD, discussed the history of the unique toxin and some of its clinical uses. Dr. Ward is Professor of Neurology and Co-Director of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The Most Potent Toxin Known
There are seven antigenic types of botulinum toxin in nature—A, B, C1, D, E, F, and G—and they vary based on the complex proteins within them. The common theme with all of them is their heavy chain that binds with cholinergic nerve terminals and their light chain then gets internalized and cleaves one of the docking compounds, which for botulinum toxin A is synaptosome-associated protein 25 (SNAP-25). “What happens is vesicles cannot fuse with the membrane and dump out the neurotransmitter. The best studied is acetylcholine, and that’s the mechanism that affords clinicians the most benefit, particularly for dystonia,” Dr. Ward said. Very simply put, botulinum toxin acts therapeutically by preventing the release of acetylcholine at synaptic nerve terminals.

Botulinum toxin type A was first FDA approved in 1989. It was known as Oculinum, better known as Botox, and now called onabotulinumtoxinA. In the early 1990s, botulinum toxin type B was being studied. Type B was known as Neurobloc in just about every country in the world except the United States, where it was known as Myobloc. Generically it is now known as rimabotulinumtoxinB. There is also now a second type A in the United States called Dysport (abobotulinumtoxinA).

“All these products are not interchangeable,” Dr. Ward stressed. “The dosing is different. If you use any of them, you better know what you’re doing.” While botulinum toxin can be very effective, it can also cause botulism, although that requires massive doses compared to the tiny therapeutic doses commonly used. “It’s the most potent toxin known … and there’s a fairly narrow therapeutic window,” Dr. Ward cautioned.

Clinically, botulinum toxin is used for many things: strabismus, cervical dystonia, blepharospasm, excessive sweating, wrinkles, and hemifacial spasm—these all have an FDA indication. It’s also used for action dystonias, tics, spasmodic dysphonia, trigeminal neuralgia, headaches, rigidity, low back pain, anal fissure, and excessive salivation.

How does botulinum toxin work? “There’s good evidence that it prevents the release of acetylcholine,” Dr. Ward said. Beyond that the quality of information and data starts to slide. It is believed to prevent glutamate and CGRP release, although some are still skeptical that these changes can occur clinically. It has also been shown to act quickly—in less than two hours—on muscle spindles.

Management of Dystonia
Dystonia is a movement disorder that causes the muscles to contract and spasm involuntarily and inappropriately. “The neurologic mechanism that makes muscles relax when they are not in use does not function properly, so you often get agonism/antagonism contracting at the same time and you may end up with very unusual body postures,” Dr. Ward said. Treatment used to be pharmacologic. Various drugs were used; with near toxic doses, patients may have seen some benefit along with a host of side effects. At one time surgery was the mainstay for dystonia, but these procedures have fallen by the wayside. “The breakthrough in therapy came with botulinum toxin,” he said. “It’s been in widespread use for about two decades now. It’s the most effective therapy.” One of its many advantages is the flexibility in injection strategies. The dose and injection site can be changed until the patient responds. “And most patients will respond.”

In cervical dystonia, “there’s a disconnect in pain,” Dr. Ward said. The pain varies in severity and it doesn’t always correlate with severity of the posture deformity. Similar to most movement disorders, it is gone when the patient is asleep. And in part, in some people, it seems to be related to muscle spasms. It has been noted clinically that sometimes the pain of cervical dystonia is reduced by botulinum toxin administration way before the spasm changes.

Also, the amount of pain relief can be disproportionate to the change in the position of the head, and it can also occur long before the posture gets the maximum benefit at seven to 10 days. “Some patients will claim that their pain starts to get better in an hour or two and no one can fully explain that, although there is some evidence that it may be a direct effect on muscle spindles that kicks in at about 45 minutes,” Dr. Ward said.

Headache Pain
Botulinum toxin can be and is used for headache. “Let me emphasize it is off label, at least for now. I would describe it as very controversial,” Dr. Ward said. “There is good evidence that it does not work for tension-type headache.” Conflicting evidence exists regarding other headache types. It may be effective in chronic migraine if the patients are not on preventive treatments. “There is an [American Academy of Neurology] assessment that basically outlines what it thinks are the flaws in the evidence—that it doesn’t work for tension-type headache, that maybe it works in some cases in some types of migraine—and I would recommend that you read that because it is evidence based.”

—Glenn S. Williams

Suggested Reading
Dodick DW, Turkel CC, Degryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010 May 17; [Epub ahead of print].

Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1707-1709.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Gracies JM, Graham HK, et al. Assessment: Botulinum neurotoxin in the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1691-1698.

STOWE, VT—From FDA-approved uses such as treatment of cervical dystonia to off-label uses such as headache, from blepharospasm to back pain, botulinum toxin types A and B continue to find roles in the therapeutic armamentarium. At the Headache Cooperative of New England’s 20th Annual Headache Symposium, Thomas N. Ward, MD, discussed the history of the unique toxin and some of its clinical uses. Dr. Ward is Professor of Neurology and Co-Director of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The Most Potent Toxin Known
There are seven antigenic types of botulinum toxin in nature—A, B, C1, D, E, F, and G—and they vary based on the complex proteins within them. The common theme with all of them is their heavy chain that binds with cholinergic nerve terminals and their light chain then gets internalized and cleaves one of the docking compounds, which for botulinum toxin A is synaptosome-associated protein 25 (SNAP-25). “What happens is vesicles cannot fuse with the membrane and dump out the neurotransmitter. The best studied is acetylcholine, and that’s the mechanism that affords clinicians the most benefit, particularly for dystonia,” Dr. Ward said. Very simply put, botulinum toxin acts therapeutically by preventing the release of acetylcholine at synaptic nerve terminals.

Botulinum toxin type A was first FDA approved in 1989. It was known as Oculinum, better known as Botox, and now called onabotulinumtoxinA. In the early 1990s, botulinum toxin type B was being studied. Type B was known as Neurobloc in just about every country in the world except the United States, where it was known as Myobloc. Generically it is now known as rimabotulinumtoxinB. There is also now a second type A in the United States called Dysport (abobotulinumtoxinA).

“All these products are not interchangeable,” Dr. Ward stressed. “The dosing is different. If you use any of them, you better know what you’re doing.” While botulinum toxin can be very effective, it can also cause botulism, although that requires massive doses compared to the tiny therapeutic doses commonly used. “It’s the most potent toxin known … and there’s a fairly narrow therapeutic window,” Dr. Ward cautioned.

Clinically, botulinum toxin is used for many things: strabismus, cervical dystonia, blepharospasm, excessive sweating, wrinkles, and hemifacial spasm—these all have an FDA indication. It’s also used for action dystonias, tics, spasmodic dysphonia, trigeminal neuralgia, headaches, rigidity, low back pain, anal fissure, and excessive salivation.

How does botulinum toxin work? “There’s good evidence that it prevents the release of acetylcholine,” Dr. Ward said. Beyond that the quality of information and data starts to slide. It is believed to prevent glutamate and CGRP release, although some are still skeptical that these changes can occur clinically. It has also been shown to act quickly—in less than two hours—on muscle spindles.

Management of Dystonia
Dystonia is a movement disorder that causes the muscles to contract and spasm involuntarily and inappropriately. “The neurologic mechanism that makes muscles relax when they are not in use does not function properly, so you often get agonism/antagonism contracting at the same time and you may end up with very unusual body postures,” Dr. Ward said. Treatment used to be pharmacologic. Various drugs were used; with near toxic doses, patients may have seen some benefit along with a host of side effects. At one time surgery was the mainstay for dystonia, but these procedures have fallen by the wayside. “The breakthrough in therapy came with botulinum toxin,” he said. “It’s been in widespread use for about two decades now. It’s the most effective therapy.” One of its many advantages is the flexibility in injection strategies. The dose and injection site can be changed until the patient responds. “And most patients will respond.”

In cervical dystonia, “there’s a disconnect in pain,” Dr. Ward said. The pain varies in severity and it doesn’t always correlate with severity of the posture deformity. Similar to most movement disorders, it is gone when the patient is asleep. And in part, in some people, it seems to be related to muscle spasms. It has been noted clinically that sometimes the pain of cervical dystonia is reduced by botulinum toxin administration way before the spasm changes.

Also, the amount of pain relief can be disproportionate to the change in the position of the head, and it can also occur long before the posture gets the maximum benefit at seven to 10 days. “Some patients will claim that their pain starts to get better in an hour or two and no one can fully explain that, although there is some evidence that it may be a direct effect on muscle spindles that kicks in at about 45 minutes,” Dr. Ward said.

Headache Pain
Botulinum toxin can be and is used for headache. “Let me emphasize it is off label, at least for now. I would describe it as very controversial,” Dr. Ward said. “There is good evidence that it does not work for tension-type headache.” Conflicting evidence exists regarding other headache types. It may be effective in chronic migraine if the patients are not on preventive treatments. “There is an [American Academy of Neurology] assessment that basically outlines what it thinks are the flaws in the evidence—that it doesn’t work for tension-type headache, that maybe it works in some cases in some types of migraine—and I would recommend that you read that because it is evidence based.”

—Glenn S. Williams

Suggested Reading
Dodick DW, Turkel CC, Degryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010 May 17; [Epub ahead of print].

Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1707-1709.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Gracies JM, Graham HK, et al. Assessment: Botulinum neurotoxin in the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1691-1698.