New AAN Guideline on Botulinum Neurotoxins in Neurologic Disease

Susan Jeffrey

April 18, 2016

VANCOUVER — The American Academy of Neurology (AAN) has released a new guideline looking at the use of botulinum neurotoxins for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache.

The document updates guidelines that were last revised in 2008 using the most recent literature and for the first time assesses the data available for each condition for each of the four US Food and Drug Administration (FDA)-approved formulations of botulinum toxin.

The guidelines were presented here at a press conference during the AAN 2016 Annual Meeting, and are published online April 18 in Neurology. The guideline is also endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Society of Plastic Surgeons.

Dr David M. Simpson

Findings were presented by guideline author David M. Simpson, MD, Icahn School of Medicine at Mount Sinai, New York, New York, and coauthor Mark Hallett, MD, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Dr Mark Hallett

"In 2008, we reviewed the four US FDA-approved formulations of botulinum toxin as a class, and generated a single set of conclusions concerning all four of them with all the data essentially combined together," Dr Simpson said. "We took a different approach in this update, in that we now have looked at each of the four formulations individually, and have looked at the data and the evidence for each toxin on its own and generated conclusions for each of those toxins separately."

Currently there are three formulations of botulinum toxin (serotype A, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one of serotype B (rimabotulinumtoxinB).

Table. FDA-Approved Indications for Botulinum Toxin Products

Product (Brand Name, Manufacturer) FDA-Approved Indications
OnabotulinumtoxinA (Botox, Allergan Inc) Blepharospasm, cervical dystonia, upper-extremity spasticity, lower-extremity spasticity, chronic migraine
AbobotulinumtoxinA (Dysport, Ipsen Ltd) Cervical dystonia, upper-extremity spasticity
IncobotulinumtoxinA (Xeomin, Merz Pharmaceuticals Blepharospasm, cervical dystonia, upper-extremity spasticity
RimabotulinumtoxinB (Myobloc/NeuroBloc, US WorldMeds/Solstice Neurosciences Cervical dystonia

 

"At the time of the 2008 guideline, we gave a Level B [recommendation] for blepharospasm, and now looking at the agents individually, there is Level B, that is, moderate evidence or probably effective for onabotulinumtoxinA and incobotulinumtoxinA, and weak evidence, Level C, that is, possibly effective for abobotulinumtoxinA," Dr Hallett noted. All three A serotype agents are viewed as relatively equivalent to each other, he said.

There is no evidence in blepharospasm and so no recommendation is made for rimabotulinumtoxinB, he added.

The evidence has increased most since the prior guideline for use of botulinum toxins in blepharospasm and cervical dystonia, Dr Hallett noted. Blepharospasm was one of the first approved indications for use of these agents, so the evidence dates back a long way, he said. However, interestingly, there are still few well-designed studies in blepharospasm, so it could not achieve a Level A level of evidence.

"Once a drug has gotten formal FDA approval for a particular indication, there is less reason for doing additional formal studies," Dr Hallet said. In the case of blepharospasm, clinical trials at that time were not of the quality of current-day trials, he added, "and additionally, the magnitude of the benefit is so powerful in blepharospasm that it didn't almost seem like it was necessary to have quite as strict trials, so the level of evidence in blepharospasm has never built up to the level has been in other areas.

"That doesn't mean that it doesn't work, and that's why we have the Clinical Context section [in the guideline] to keep that clear," he added.

For cervical dystonia, in the past guideline there was Level A evidence for the effectiveness of these agents as a class and a recommendation that they should be offered. In the current guideline looking at individual agents, "there is strong evidence, Level A, for abobotulinumtoxinA and rimabotulinumtoxinB, and only moderate evidence, Level B, for onabotulinumtoxinA and incobotulinumtoxinA," probably effective and should be considered, he noted.

In terms of spasticity, often seen in association with neurologic conditions such as brain and spinal cord injury, stroke, or multiple sclerosis, the current guideline looks only at adult spasticity because separate guidelines were published by the AAN on spasticity in children in the interim, Dr Simpson noted.

For upper-limb spasticity, all three of the serotype A formulations —abobotulinumtoxinA, incobotulinumtoxinA, and onabotulinumtoxinA — reached Level A evidence showing they are effective in reducing excess muscle tone and should be offered. RimabotulinumtoxinB is probably effective (Level B) and should be considered.

"Importantly, when one looks at the type of function that improved in these patients with spasticity, it related to what is known as passive functional gains," Dr Simpson said. These are things that are done for the patient — getting them dressed, for example, or getting braces on — but active functional gains, things patients can do for themselves, such as dressing and buttoning, have not been shown in the current trials.

For lower-limb spasticity, abobotulinumtoxinA and onabotulinumtoxinA have Level A evidence that they are effective and should be offered, Dr Simpson said. There is insufficient evidence in the lower limb for either incobotulinumtoxinA or rimabotulinumtoxinB, they concluded.

For this review, there was also available a Class I study comparing onabotulinumtoxinA with medical treatment for spasticity, tizanidine, which found that onabotulinumtoxinA was superior in improving wrist and flexor tone, while the drug showed no benefit over placebo. There was also a high incidence of adverse effects with tizanidine that limited dose titration. As a result, they conclude that onabotulinumtoxinA is "probably superior" to tizanidine and should be considered as a treatment option ahead of the drug for adult upper extremity spasticity (Level B).

Finally, for headache, there was a "major difference between the 2008 guidelines and 2016," Dr Simpson said. "In 2008, the data available for virtually all types of headache with botulinum toxin did not support any ability to conclude efficacy, including migraine." Since then, two pivotal Class I studies have bee published for onabotulinumtoxinA in the treatment of chronic migraine, defined as 15 or more headache days per month, resulting in FDA approval in that indication.

"Now, it's important to qualify that the magnitude of the efficacy was small," he added, a 15% reduction in headache days in the 4 weeks after the first treatments vs placebo.

For other forms of headache, "there is Level A strong evidence indicating lack of effectiveness of onabotulinumtoxinA in episodic migraine," Dr Simpson said. Further, "there is moderate Level B evidence again against any efficacy of botulinum toxins in the treatment of tension-type headaches."

The 2008 guidelines also covered other disorders, such as essential tremor, hemifacial spasm, and disorders of the voice. For those other disorders, no new evidence was available at the time the guideline update was initiated that would change the conclusions, and so these disorders were not included in this update.

Specifically, the guideline conclusions are as follows:

  • Blepharospasm

    • OnabotulinumtoxinA and incobotulinumtoxinA are probably effective and should be considered (Level B).

    • AbobotulinumtoxinA is possibly effective and may be considered (Level C).

  • Cervical dystonia

    • AbobotulinumtoxinA and rimabotulinumtoxinB are established as effective and should be offered (Level A).

    • OnabotulinumtoxinA and incobotulinumtoxinA are probably effective and should be considered (Level B).

  • Adult spasticity

    • AbobotulinumtoxinA, incobotulinumtoxinA, and onabotulinumtoxinA are established as effective and should be offered (Level A), and rimabotulinumtoxinB is probably effective and should be considered (Level B), for upper-limb spasticity.

    • AbobotulinumtoxinA and onabotulinumtoxinA are established as effective and should be offered (Level A) for lower-limb spasticity.

  • Headache

    • OnabotulinumtoxinA is established as effective and should be offered to increase headache-free days (Level A) and is probably effective and should be considered to improve health-related quality of life (Level B) in chronic migraine.

    • OnabotulinumtoxinA is established as ineffective and should not be offered for episodic migraine (Level A) and is probably ineffective for chronic tension-type headaches (Level B).

Ambiguities in Evidence

Published along with the guideline are two companion commentaries on this subject.

In a companion article published in Neurology: Clinical Practice, Raghav Govindarajan, MD, from the University of Missouri, Columbia, and colleagues attempt to identify, they write, "ambiguities in the evidence for efficacy among various brand names for a given clinical indication, their dosing equivalencies, as well as different clinical indications."

Dr Raghav Govindarajan

"The guidelines are derived from the research or the evidence that's available but not all clinical things that we do have research evidence," Dr Govindarajan said an interview with Medscape Medical News. "We treat patients with multiple conditions with different medications, but not all of them if you ask is there a randomized placebo controlled trial to back up what we do clinically, in some cases we have it and in many cases we don't have it. That doesn't mean it doesn't work.

"This companion article is to provide recommendations in those cases where there is a gap in research so that we continue taking care of our patients, and make sure that the coverage for botulinum toxin is not affected," he added. "At the same time, if they are facing trouble with coverage, we provide information on how to troubleshoot that."

In a second companion article also in Neurology: Clinical Practice, Richard L. Barbano, MD, PhD, Movement Disorders Division, University of Rochester Medical Center, New York, further discusses the gaps in knowledge brought to light by these new guidelines.

"In this updated guideline, the botulinum toxins are addressed as unique products, noting pharmacologic differences between the various preparations such as potency and duration of action, for which evidence exists in animal models," Dr Barbano writes. "Each product has its own unique properties including molecular weight and complexing proteins, which can lead to varying clinical properties and side effect profiles.

"While the approach of addressing each preparation for different indications is laudable, it does result in questions regarding the interchangeability of the different formulations as well as the use in other indications not covered by the guideline," he adds. "Lack of evidence of certain preparations in particular indications reminds one of the old adage that 'absence of evidence is not evidence of absence.'"

The guideline was developed with financial support from the AAN. Dr Simpson has received research grants from and served as a consultant for Allergan Inc, Ipsen Ltd, Merz Pharmaceuticals, and Acorda Therapeutics. Dr Hallett serves as a chair of the Neurotoxin Institute Advisory Council and has received research grants from Allergan Inc and Merz Pharmaceuticals. Dr Govindarajan has disclosed no relevant financial relationships. Dr Barbano served on a scientific advisory board for Allergan; serves as an associate editor for Neurology: Clinical Practice; performs botulinum toxin injections at the University of Rochester (30% effort); receives research support from Allergan, Vaccinex, and Biotie; has received research support from the National Institutes of Health, National Institute of Neurologic Disorders and Stroke, ORDR: Dystonia Coalition Projects, site principal investigator; holds stock/stock options in VisualDx; and has served as an expert witness in legal proceedings including malpractice, not involving commercial entities.

Neurology. Published online April 18, 2016. Guideline abstract

Neurol Clin Pract. Published online April 18, 2016. Govindarajan abstract Barbano abstract

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