This is the current release of the guideline.

• Hypersecretory disorders
  • Axillary hyperhidrosis
  • Palmer hyperhidrosis
  • Gustatory sweating
  • Drooling in neurodegenerative diseases
  • Hyperlacrimation
• Neuro-urologic disorders
  • Detrusor sphincter dyssynergia
  • Neurogenic detrusor overactivity
• Low back pain
• Headache
  • Episodic migraine
  • Chronic daily headache
  • Chronic tension-type headache

Assessment of Therapeutic Effectiveness
Technology Assessment
Treatment

Family Practice
Internal Medicine
Neurology
Pharmacology
Physical Medicine and Rehabilitation
Urology

Pharmacists
Physicians

• To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain
• To make evidence-based recommendations

• Adult patients with autonomic and urologic disorders
• Adult patients with low back pain and headache

Botulinum neurotoxin (BoNT) injection

• Response rate (reduction in sweating; reduction in drooling)
• Quality of life
• Post-voiding residual urine volume
• Urethral or detrusor pressure
• Urodynamic measures
• Urinary frequency and average voided volume
• Level of pain
• Functional improvement
• Frequency of moderate to severe migraines per month
• Headache-free days per month

Hand-searches of Published Literature (Primary Sources)
Searches of Electronic Databases

The literature search used MEDLINE and Current Contents for relevant, fully published, peer-reviewed articles up to April 2007 and was supplemented through manual searches by panel members. The search terms used were botulinum toxin and movement disorders, dystonia, tics, tremors, hemifacial spasm, blepharospasm, cerebral palsy, spasticity, autonomic, Frey's syndrome, sweating, hyperhidrosis, drooling, headache, back pain, pain, laryngeal disorders, dysphonia, and urologic disorders. The following criteria were used: 1) relevant to the clinical questions of efficacy, safety, tolerability, or mode of use; 2) limited to human subjects; 3) limited to therapeutic studies. Abstracts, reviews, and meta-analyses were excluded.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Classification of Evidence for Therapeutic Intervention

Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion, or a case report.

*Objective outcome measurement: An outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Systematic Review with Evidence Tables

The panel was comprised of specialists with experience in the therapeutic use of botulinum neurotoxin (BoNT) for the indications under consideration or with expertise in guideline methodology. Each article was reviewed by at least two panelists who did not participate in the trial reported. The articles were classified as Class I through IV using the American Association of Neurology (AAN) guideline process (see "Rating Scheme for the Strength of the Evidence"). Disagreements on article classification were resolved by discussion and consensus.

Other

Conclusions and recommendations were made according to the American Academy of Neurology (AAN) criteria for translating the quality of evidence for therapeutic interventions into recommendations.

Classification of Recommendations

The strength of practice recommendations is linked directly to the level of evidence:

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or at least two consistent Class III studies)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I–Class III).

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Draft guidelines were reviewed for accuracy, quality, and thoroughness by the American Academy of Neurology members, topic experts, and pertinent physician organizations.

The guideline was approved by the Therapeutics and Technology Assessment Subcommittee on March 31, 2007; by the Practice Committee on July 12, 2007; and by the American Academy of Neurology (AAN) Board of Directors on January 30, 2008.

Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I through Class IV) are provided at the end of the "Major Recommendations" field.

Hypersecretory Disorders

Conclusions

Botulinum neurotoxin (BoNT) is established as safe and effective for the treatment of axillary hyperhidrosis (two Class I studies), is probably safe and effective for palmar hyperhidrosis (two Class II studies) and in drooling in patients with Parkinson's disease (PD) (four Class II studies), and is possibly effective for gustatory sweating (five Class III studies). There is insufficient evidence to support the effectiveness of BoNT in hyperlacrimation (Class IV studies).

Recommendations

• BoNT should be offered as a treatment option to patients with axillary hyperhidrosis (Level A).
• BoNT should be considered as a treatment option for palmar hyperhidrosis and drooling (Level B).
• BoNT may be considered for gustatory sweating (Level C).

Neuro-urologic Disorders

Conclusions

BoNT is established as safe and effective for the treatment of neurogenic detrusor overactivity in adults (two Class I studies, one Class II study). Data on the use of BoNT for detrusor sphincter dyssynergia (DSD) are conflicting. BoNT is probably safe and effective for the treatment of DSD in patients with spinal cord injury (two Class II studies). However on the basis of one Class I study, BoNT does not provide significant benefit for the treatment of DSD in patients with multiple sclerosis (MS).

Recommendations

• BoNT should be offered as a treatment option for neurogenic detrusor overactivity (Level A).
• BoNT should be considered for DSD in patients with spinal cord injury (Level B).

Low Back Pain

Conclusions

BoNT is possibly effective for the treatment of chronic predominantly unilateral low back pain (LBP) (one Class II study).

Recommendation

BoNT may be considered as a treatment option of patients with chronic predominantly unilateral LBP (Level C).

Headache

Episodic Migraine

Conclusions

Based on published Class I and Class II studies, BoNT injection is probably ineffective in the treatment of episodic migraine (Level B).

Chronic Daily Headache

Conclusions

Based on inconsistent results from four Class II studies, there is insufficient evidence to support or refute a benefit of BoNT for the treatment of chronic daily headache (Level U).

Chronic Tension-type Headache

Conclusions

Based on the results of two Class I studies, at least one of which was adequately powered, BoNT injection is probably ineffective for patients with chronic tension-type headaches (Level B).

Recommendation

BoNT injections should not be considered in patients with episodic migraine and chronic tension-type headaches (Level B).

Definitions:

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given conition in the specified population. (Level C rating requires at least one Class II study or at least two consistent Class III studies)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I–Class III).

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Classification of Evidence for Therapeutic Intervention

Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion, or a case report.

*Objective outcome measurement: An outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Appropriate use of botulinum neurotoxin for treatment of autonomic disorders and pain

• Undesirable effects associated with administration of botulinum neurotoxin (BoNT) fall into three broad categories. First, diffusion of the toxin from the intended sites of action can lead to unwanted inhibition of transmission at neighboring nerve endings. Second, sustained blockade of transmission can produce effects similar to anatomic denervation, including muscle atrophy. The third undesirable effect is immunoresistance to BoNT.
• Adverse events reported for BoNT in the treatment of autonomic disorders and pain include:
  • Mild or transient muscle weakness
  • Pain at the injection site
  • Dry mouth
  • Urinary retention
  • Ptosis
  • Diplopia
  • Bruising
  • Local skin tension
  • Flu-like symptoms

This statement is provided as an educational service of the American Academy of Neurology (AAN). It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved. The clinical context section is made available in order to place the evidence-based guildeline(s) into perspective with current practice habits and challenges. No formal practice recommendations should be inferred.

An implementation strategy was not provided.

Getting Better
Living with Illness

Effectiveness
Patient-centeredness
Safety

Not applicable: The guideline was not adapted from another source.

2008 May 6

American Academy of Neurology - Medical Specialty Society

American Academy of Neurology (AAN)

Therapeutics and Technology Assessment Subcommittee

Primary Authors: M. Naumann, MD; Y. So, MD, PhD; C.E. Argoff, MD; M.K. Childers, DO, PhD; D.D. Dykstra, MD, PhD; G.S. Gronseth, MD; B. Jabbari, MD; H.C. Kaufmann, MD; B. Schurch, MD; S.D. Silberstein, MD; D.M. Simpson, MD

American Academy of Physical Medicine and Rehabilitation - Medical Specialty Society

This is the current release of the guideline.

This summary was completed by ECRI Institute on November 3, 2008. The information was verified by the guideline developer on December 30, 2008. This summary was updated by ECRI Institute on May 26, 2009, following the U.S. Food and Drug Administration advisory on Botox, Botox Cosmetic (Botulinum toxin Type A), and Myobloc (Botulinum toxin Type B). This summary was updated by ECRI Institute on August 17, 2009, following the updated FDA advisory on Botox and Botox Cosmetic (Botulinum toxin Type A), and Myobloc (Botulinum toxin Type B).

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.