New Guidelines From AAN on Botulinum Neurotoxin Issued

Susan Jeffrey

May 09, 2008

May 9, 2008 – Three new guidelines documents from the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review the use of botulinum neurotoxin (BoNT) in spasticity, movement disorders, and autonomic disorders and pain.

The documents endorse the use of BoNT in many disorders but conclude, to the surprise of some, perhaps, that treatment is "probably ineffective" for episodic migraine and chronic tension-type headache.

David M. Simpson, MD, professor of neurology at Mount Sinai School of Medicine, in New York, chaired the panel. "Under the auspices of the American Academy of Neurology, this type of evidence-based review has not been done for many years, over 15 years, so this is at least for the AAN, a new and unique review," he told Medscape Neurology & Neurosurgery.

The guidelines are published as 3 documents in the May 6 issue of Neurology.

BoNT in Spasticity

In the first document, the subcommittee reviews the use of BoNT for adult and childhood spasticity. The literature review showed 14 class 1 studies were available in adult spasticity, the highest level of evidence based on randomized clinical trials, and 6 of spastic equinus and adductor spasticity in pediatric cerebral palsy. On the basis of these, they concluded that "BoNT should be offered as a treatment option for the treatment of spasticity in adults and children (level A)."

Despite the high level of evidence, Dr. Simpson noted, this indication is not yet approved by the Food and Drug Administration (FDA). Manufacturers are continuing studies aimed at gaining approval, he said. "I would also add that despite the lack of FDA approval, most of the insurers, including Medicare and other third-party payers, do reimburse for the use of botulinum toxin in spasticity."

A recent FDA early communication was issued regarding cases of respiratory compromise or death with the use of botulinum toxin type A (Botox, Allergan), and botulinum toxin type B (Myobloc, Solstice Neurosciences Inc.). The most serious cases were reportedly among children treated for limb spasticity, although cases were also seen in other conditions.

Dr. Simpson pointed out that these were rare reactions. "And although those do need to be considered and physicians need to be skilled in their knowledge and use of botulinum toxin, that should not detract from the very good safety profile with this drug for over 25 years."

BoNT in Movement Disorders

In the second document, the subcommittee reviews the use of BoNT in movement disorders. They conclude that BoNT treatment should be offered as a treatment option in cervical dystonia (level A); "may" be offered for blepharospasm, focal upper-extremity dystonia, adductor laryngeal dystonia, and upper-extremity essential tremor (level B); and "may be considered" for hemifacial spasm, focal lower-limb dystonia, and motor tics (level C).

"While clinicians' practice may suggest stronger recommendations in some of these indications," they note, "evidence-based conclusions are limited by the availability of the data."

Autonomic Disorders and Headache

Finally, the subcommittee considered evidence for BoNT in autonomic disorders and pain, including headache.

They recommend that BoNT be offered as an option for treatment of axillary hyperhidrosis and detrusor overactivity (level A); "should be considered" for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal-cord injury (level B); and "may be considered" for gustatory sweating and low back pain (Level C).

In a statement from the AAN, Markus Naumann, MD, professor of neurology at Augsburg Hospital, in Germany, and first author on this document, said that BoNT is "possibly effective in low back pain and therefore may be considered as a treatment option. However," he added, "our recommendation is based on data from only 1 study in a small number of patients. More research is needed to define the place of botulinum toxin in treating this condition, in comparison with other treatment options."

Based on currently available data, though, the authors of this document conclude that BoNT is "probably ineffective" in episodic migraine and chronic tension-type headache (level B). "Based on currently available data, botulinum toxin injections should not be offered to patients with episodic migraine and chronic tension-type headache," Dr. Naumann said in the AAN statement. "It is no better than placebo injections for these types of headache."

Finally, they note, there is "no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (level U)." Again, they note, "although clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data."

Benefit for a Subset of Patients?

Asked for comment on the conclusions regarding headache, Randolph W. Evans, MD, clinical professor of neurology at Baylor College of Medicine, in Houston, Texas, and a member of the editorial advisory board (uncompensated) for Medscape Neurology & Neurosurgery, agreed that studies of botulinum toxin in headache have been disappointing to date, after some initial enthusiasm.

"However, many headache specialists, including myself, believe that there is a subset of patients with chronic migraine who do benefit from botulinum toxin who may not benefit from other treatments," Dr. Evans said. "Patients with chronic migraine can be especially resistant to treatment. Many of us have a number of these patients who did not respond to numerous medications but had a dramatic response to botulinum toxin — for which many of them are paying cash — that we doubt is a placebo response."

He concurs, however, that additional studies would be helpful to further identify subgroups with migraine that may benefit. "Prior studies have suggested that patients with medication overuse might be less responsive, and those with 'imploding pain,' unilateral headache, or cutaneous allodynia might be more responsive," Dr. Evans noted.

Dr. Simpson reports that he has received speaker honoraria and research support from Allergan, Merz, and Solstice and performs botulinum toxin injections. Dr. Naumann reports that he has received speaker honoraria from Ipsen and Allergan and performs botulinum toxin injections. Other author disclosures appear in the published papers. Dr. Evans reports that he has served as an advisor or consultant to Abbott, GlaxoSmithKline, Merck, Ortho-McNeil, Pfizer, and Valeant.

Neurology. 2008;70:1691-1698, 1699-1706, 1707-1714.

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