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## Complete Summary

#### GUIDELINE TITLE

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.

#### BIBLIOGRAPHIC SOURCE(S)

Naumann M, So Y, Argoff CE, Childers MK, Dykstra DD, Gronseth GS,
Jabbari B, Kaufmann HC, Schurch B, Silberstein SD, Simpson DM,
Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology. 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 May 6;70(19):1707-14. \[34
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=18458231)

#### GUIDELINE STATUS

This is the current release of the guideline.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   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

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Technology Assessment\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Neurology\
Pharmacology\
Physical Medicine and Rehabilitation\
Urology

#### INTENDED USERS

Pharmacists\
Physicians

#### GUIDELINE OBJECTIVE(S)

-   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

#### TARGET POPULATION

-   Adult patients with autonomic and urologic disorders

-   Adult patients with low back pain and headache

#### INTERVENTIONS AND PRACTICES CONSIDERED

Botulinum neurotoxin (BoNT) injection

#### MAJOR OUTCOMES CONSIDERED

-   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

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

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

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

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.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**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).

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

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.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Other

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

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.

#### RATING SCHEME FOR THE STRENGTH OF THE 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 and/or 2) the magnitude
of effect is large (relative rate improved outcome \>5 and the lower
limit of the confidence interval is \>2.

#### COST ANALYSIS

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

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

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.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

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]{.underline}**

**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]{.underline}**:

**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 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 and/or 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).

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

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

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

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

#### POTENTIAL HARMS

-   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

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

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.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Patient Resources\
Quick Reference Guides/Physician Guides\
Slide Presentation\
Staff Training/Competency Material

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Patient-centeredness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Naumann M, So Y, Argoff CE, Childers MK, Dykstra DD, Gronseth GS,
Jabbari B, Kaufmann HC, Schurch B, Silberstein SD, Simpson DM,
Therapeutics and Technology Assessment Subcommittee of the American
Academy of Neurology. 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 May 6;70(19):1707-14. \[34
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=18458231)

#### ADAPTATION

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

#### DATE RELEASED

2008 May 6

#### GUIDELINE DEVELOPER(S)

American Academy of Neurology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

American Academy of Neurology (AAN)

#### GUIDELINE COMMITTEE

Therapeutics and Technology Assessment Subcommittee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*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

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The American Academy of Neurology (AAN) is committed to producing
independent, critical and truthful clinical practice guidelines (CPGs).
Significant efforts are made to minimize the potential for conflicts of
interest to influence the recommendations of this CPG. To the extent
possible, the AAN keeps separate those who have a financial stake in the
success or failure of the products appraised in the CPGs and the
developers of the guidelines. Conflict of interest forms were obtained
from all authors and reviewed by an oversight committee prior to project
initiation. AAN limits the participation of authors with substantial
conflicts of interest. The AAN forbids commercial participation in, or
funding of, guideline projects. Drafts of the guidelines have been
reviewed by at least three AAN committees, a network of neurologists,
*Neurology*^®^ peer reviewers, and representatives from related fields.
The AAN Guideline Author Conflict of Interest Policy can be viewed at
[www.aan.com](http://www.aan.com/).

The authors report the following conflicts: Dr. Naumann has received
speaker honoraria from Ipsen and Allergan and performs botulinum toxin
injections. Dr. So holds financial interest in Satoris Inc., and has
received research support from NIH, Pfizer, Inc., and NeurogesX, Inc.
Dr. Argoff performs botulinum toxin injections. Dr. Childers has
received speaker honoraria and research support from Allergan and
performs botulinum toxin injections. Dr. Dykstra has received speaker
honoraria from Allergan and Solstice, research support from Allergan,
and performs botulinum toxin injections. Dr. Gronseth has received
speaker honoraria from Pfizer, GlaxoSmithKline, Boehringer Ingelheim,
and Ortho-McNeil. Dr. Jabbari has received research support from
Allergan and performs botulinum toxin injections. Dr. Kaufmann has
received speaker honoraria from Chelsea Therapeutics, research support
from NIH, payment for expert testimony, and performs autonomic testing.
Dr. Schurch has received speaker honoraria from Pfizer, Astellas, and
Allergan; research support from Allergan, IFP, NCCR, and SNF; and
performs autonomic testing and botulinum toxin injections. Dr.
Silberstein has received speaker honoraria from GlaxoSmithKline,
Allergan, AstraZeneca, Endo, Medtronic, Merck, J&J, Pfizer, Pozen, and
Valeant Pharmaceuticals International; research support from Allergan,
and performs botulinum toxin injections. Dr. Simpson has received
speaker honoraria and research support from Allergan, Merz, and
Solstice, Inc., and performs botulinum toxin injections.

#### ENDORSER(S)

American Academy of Physical Medicine and Rehabilitation - Medical
Specialty Society

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: A list of American Academy of Neurology (AAN)
guidelines, along with a link to a Portable Document Format (PDF) file
for this guideline, is available at the [AAN Web
site](http://www.aan.com/go/practice/guidelines).

Print copies: Available from the AAN Member Services Center, (800)
879-1960, or from AAN, 1080 Montreal Avenue, St. Paul, MN 55116.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Use of botulinum neurotoxin for the treatment of autonomic disorders
    and pain. AAN summary of evidence-based guidelines for clinicians.
    St. Paul (MN): American Academy of Neurology. 2008. 2 p. Available
    in Portable Document Format (PDF) from the [AAN Web
    site](http://www.aan.com/practice/guideline/uploads/281.pdf).

-   Assessment: botulinum neurotoxin for the treatment of autonomic
    disorders and pain, movement disorders, and spasticity (an
    evidence-based review). Slide presentation. St. Paul (MN): American
    Academy of Neurology. 2008. 146 p. Available from the [AAN Web
    site](http://www.aan.com/practice/guideline/uploads/299.ppt).

-   Assessment: botulinum neurotoxin for the treatment of autonomic
    disorders and pain, movement disorders, and spasticity (an
    evidence-based review). Case study and coding. St. Paul (MN):
    American Academy of Neurology. 2008. 3 p. Available from the [AAN
    Web
    site](http://www.aan.com/practice/guideline/index.cfm?fuseaction=home.view&guideline=288).

-   AAN guideline development process \[online\]. St. Paul (MN):
    American Academy of Neurology. Available from the [AAN Web
    site](http://www.aan.com/go/practice/guidelines/development).

#### PATIENT RESOURCES

The following is available:

-   Use of botulinum neurotoxin injections to treat autonomic disorders
    and pain. AAN summary of evidence-based guideline for patients and
    their families. St. Paul (MN): American Academy of Neurology
    (AAN). 2008. 2 p.

Electronic copies: Available in Portable Document Format (PDF) from the
[AAN Web site](http://www.aan.com/practice/guideline/uploads/284.pdf).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This summary was completed by ECRI Institute on November 3, 2008. The
information was verified by the guideline developer on December 30,
2008.

#### COPYRIGHT STATEMENT

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

### DISCLAIMER

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Date Modified: 1/26/2009