Coverage Policy Manual
Policy #: 2018002
Category: Pharmacy
Initiated: January 2018
Last Review: October 2023
  Chemodenervation, Botulinum Toxins

Description:
Botulinum is a family of toxins produced by the anaerobic organism Clostridia botulinum. The U.S. Food and Drug Administration (FDA) has approved four formulations. Botulinum Toxin  injections have been used to treat various focal muscle spastic disorders and excessive muscle contractions such as dystonias, spasms, twitches, etc. Although labeled indications of these agents differ; all are FDA-approved for treating cervical dystonia in adults. Botulinum toxin products are also used for a range of off-label indications.
 
There are 7 distinct botulinum serotypes designated as type A, B, C-1, D, E, F, and G. In the United States, 4 preparations of botulinum are commercially available, three using type A serotype and one using type B. The brand names of the botulinum toxin products were changed in 2009; trade names and product formulations did not. The 3 formulations of botulinum toxin type A are currently called onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin). Botox has been available on the U.S. market the longest and has been the most widely used formulation. Xeomin, the newest product marketed in the United States, consists of the pure neurotoxin without complexing proteins and is the only product stable at room temperature for up to 4 years. RimabotulinumtoxinB contains botulinum toxin type B, currently marketed as Myobloc.
 
Among the botulinum toxin products, onabotulinumtoxinA (Botox) is approved by the Food and Drug Administration (FDA) for the most indications.
 
All botulinum toxin products carry black box warnings of the potential for a distant spread of the toxin effect. The warning notes that the risk of symptoms may be greatest in children treated for spasticity but symptoms can also occur in adults.
 
Three products, Botox (marketed as Botox Cosmetic), Dysport, and Xeomin are approved for temporarily improving the appearance of glabellar (frown) lines in adults.
 
The botulinum toxin products have also been used for a wide variety of off-label indications.
 
In rare cases, individuals do not respond to botulinum toxin (primary resistance), and a small percentage of adults develop secondary resistance after long-term treatment. Reasons for resistance include injection of incorrect muscles, unrealistic expectations of a complete cure, and interference from associated disorders that mask perception of response (Hyman, 2004). In 3% to 10% of adults, true secondary resistance arises due to the development of antibodies that specifically neutralize the activity of botulinum toxin (Hsiung, 2002; Mejia, 2005). That neutralizing antibodies directly cause resistance has been shown in a case study in which an individual with severe dystonia, secondary resistance, and detectable neutralizing antibodies was treated with repeated plasma exchange and depletion of serum antibodies; subsequent treatment with the same botulinum toxin type was successful (Naumann, 1998). Non-neutralizing antibodies may also develop in individuals but have no effect on outcomes. The predisposing factors are not completely understood but include the use of higher doses, shorter intervals between repeat treatments, and younger age (Mahant, 2000). In 2 studies of pediatric individuals treated for spasticity, neutralizing antibodies were detected in 28% to 32% of individuals (Herrman, 2004; Koman, 2001). Recommendations for avoiding eventual resistance are using the lowest dose possible to obtain a clinical response and scheduling intervals of 10 to 12 weeks between injections, if possible.
 
Individuals who develop secondary resistance to botulinum toxin type A may stop treatment for several months and then undergo retreatment with likely success; however, the duration of response is often short, because neutralizing antibodies may redevelop quickly (Sankhla, 1998). Alternatively, the individual may be administered botulinum toxin type B, with which neutralizing antibodies to toxin type A will not interfere. However, the duration of effect is shorter, and adverse effects have occurred at higher frequencies than for botulinum toxin type A (Mahant, 2000; Dutton,2006).
 
Confirmation of neutralizing antibodies to botulinum toxin type A in research studies (mice) has most often been accomplished using 2 techniques: (1) an injection of individual serum (Pearce, 1994) or (2) an in vitro toxin-neutralizing assay based on a mouse diaphragm nerve-muscle preparation (Goschel, 1997). While sensitive, neither assay is appropriate for a clinical laboratory setting. Other assay formats have been explored, such as immunoprecipitation, Western blot, and enzyme-linked immunosorbent assay. However, unless only the protein sequences that specifically react with neutralizing antibodies are employed, these formats detect both neutralizing and non-neutralizing antibodies (Herrmann, 2004; Cordivari, 2006; Hanna, 1998), and would therefore result in significant numbers of false-positive results. An option for some individuals might be to inject toxin into the frontal muscle above 1 eyebrow; a toxin-responsive individual would have asymmetry of the forehead on attempted frowning, whereas a nonresponsive individual would not (Hanna, 1998).
 
Regulatory Status
 
In 1991, Botox® (Allergan, Irvine, CA) was approved by FDA. In 2000, Myobloc® (Solstice Neurosciences [South San Francisco, CA]) was approved by FDA. In 2009, Dysport® (Medicis Pharmaceutical, now Ipsen Biopharm [Basking Ridge, NJ]) was approved by FDA. In 2010, Xeomin® (Merz Pharmaceuticals [Raleigh, NC]) was approved by FDA (FDA, 2009).
 
On June 20, 2019, the U.S. Food and Drug Administration approved the use of onabotulinumtoxinA (e.g., Botox)) for the treatment of upper limb spasticity in pediatric individuals 2 to 17 years of age.
 
On October 18, 2019, the U.S. Food and Drug Administration approved the use of onabotulinumtoxinA (e.g., Botox) for the treatment of lower limb spasticity in pediatric individuals 2 to 17 years of age excluding spasticity caused by cerebral palsy.
 
On August 11, 2023, the U.S. Food and Drug Administration approved the use of daxibotulinumtoxinA-lanm (e.g., Daxxify) for the treatment of cervical dystonia in adults with up to 250 units via intramuscular injection.
 
Coding
 
See CPT/HCPCS Code section below.
 
Treatment of hyperhidrosis with other than botox is addressed in coverage policy 2000034.
 

Policy/
Coverage:
For the treatment of hyperhidrosis with other than botox, see coverage policy 2000034.
 
Effective April 01, 2022 Prior Approval is required for Botulinum Toxin.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective February 28, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Before consideration of coverage may be made, it should be established that the individual has been unresponsive to conventional methods of treatment, such as medication, physical therapy and other appropriate methods used to control and/or treat the specified covered condition(s).
  
There may be individuals who require electromyography in order to determine the proper injection site(s).  CPT 95874 is the appropriate code for reporting electromyography in conjunction with chemodenervation.
 
The use of botulinum toxin meets primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Disorders associated with spasticity or dystonia:
a. Blepharospasm associated with dystonia in individuals 12 years of age and older (Jankovic, 2009; Nussgens, 1997; Roggenkamper, 2006)
b. Facial nerve (VII) disorder (Soares, 2014)
c. Hereditary spastic paraparesis (Shribman, 2019)
d. Idiopathic torsion dystonia (Duarte, 2016)
e. Laryngeal spasm (Simpson, 2008)
f. Multiple sclerosis or Schilder’s disease (deSeze, 2002)
g. Neuromyelitis optica (Esquenazi, 2013)
h. Organic writer’s cramp (FDA, 2021)
i. Orofacial dyskinesis, Meige syndrome (Soares, 2014)
j. Spastic hemiplegia (Shribman, 2019)
k. Symptomatic torsion dystonia (Duarte, 2016)
l. Treatment of upper and lower limb spasticity in individuals 2 years of age and older (FDA, 2021)
m. Treatment of upper limb spasticity in children 2 years of age and older (FDA, 2021)
n. Treatment of lower limb spasticity in children 2 years of age and older (FDA, 2021)
2. Disorders of the bladder:
a. Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
b. Treatment of urinary incontinence due to detrusor overactivity associated with neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
c. Treatment of neurogenic detrusor overactivity (NDO) in pediatric individuals 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. (FDA, 2021)
3. Prophylaxis of chronic migraine headaches in the following situations:
a. Initial approval for 12 months in adult individuals who:
i. Meet International Headache Classification (KCHD-2) diagnostic criteria for chronic migraine headache (e.g., migraine headache lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months) (FDA, 2021); AND  
ii. Have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications in the treatment of chronic migraine headaches (e.g., antidepressants, antihypertensives, and antiepileptics) (Garza, 2021)
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g., Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g., Nurtec) 75 mg every other day); and Atogepant (e.g., Qulipta) 10 mg, 30, or 60 mg daily.; (AAN 2016)
b. Continuing treatment beyond 12 months:
i. Migraine headache frequency reduced by at least 7 days per month (represents a 50% reduction in migraine days); OR  
ii. Migraine headache duration reduced at least 100 hours per month.
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g.,  Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g.,  Nurtec) 75 mg every other day; and Atogepant (e.g., Qulipta 10 mg, 30 mg, or 60 mg daily (AAN 2016)
4. Treatment of cervical dystonia (spasmodic torticollis) in adult individuals, to reduce the severity of abnormal head position and neck pain. (FDA, 2021)
5. Treatment of strabismus in individuals 12 years of age and older. (FDA, 2021)
6. Achalasia unresponsive to dilation therapy or who are poor surgical candidates (Friedmacher, 2012)
7. Chronic anal fissure (Brisinda, 1999)
8. Chronic sialorrhea that is associated with amyotrophic lateral sclerosis or atypical parkinsonian disorders or cerebral palsy (Sialorrhea, 2017) or Parkinson disease or stroke or traumatic brain injury; AND
a. Individual has experienced excessive salivation for 3 or more months; AND   
b. Individual is refractory to at least 2 months of continuous treatment with at least one oral pharmacotherapy (e.g., anticholinergics)
9. Hirschsprung disease with the development of obstructive symptoms after pull-through operation. (Langer, 2017)
10. Primary axillary hyperhidrosis when all the following are met:
a. Individual is 18 years of age or older; AND
b. Individual has failed a trial of at least one week or intolerant of at least one prescription strength antiperspirants or anticholinergics.
11. Coverage is not provided for the following conditions:
a. Neurologic indications such as:
i. Headaches, except as noted above for prevention of chronic migraine headache including maintenance therapy
ii. Essential tremor
iii. Tinnitus
iv. Chronic motor tic disorder and tic associated with Tourette syndrome (motor tics)
b. Urological indications such as:
i. Benign prostatic hyperplasia
ii. Interstitial cystitis
iii. Detrusor sphincteric dyssynergia (after spinal cord injury)
c. Pain due to multiple etiologies such as:
i. Chronic low back pain
ii. Joint pain
iii. Mechanical neck disorders
iv. Neuropathic pain after neck dissection
v. Myofascial pain syndrome
vi. Temporomandibular joint disorders
vii. Trigeminal neuralgia
viii. Pain after hemorrhoidectomy or lumpectomy
ix. Lateral epicondylitis
x. Prevention of pain associated with breast reconstruction after mastectomy
xi. Chronic pelvic/perineal pain
d. Ano-rectal conditions such as:
i. Internal anal sphincter achalasia
ii. Anismus (pelvic floor dyssynergia)
e. Any cosmetic purpose/indication
f. Other miscellaneous conditions such as:
i. Gastroparesis
ii. Facial wound healing
iii. Depression
 
Documentation should include the following:
    1. Support for the medical necessity of the injection; AND
    2. A covered diagnosis; AND
    3. A statement that traditional methods of treatments have been tried and proven unsuccessful; AND
    4. Dosage and frequency of the injections; AND
    5. Support of the clinical effectiveness of the injections; AND
    6. Specify the site(s) injected.
 
CONTINUATION OF THERAPY for 12 months:
    1. Individual meets criteria for initial approval based on indication.
    2. Individual has experienced a positive clinical response to botulinum toxin.
    3. Dosed in accordance with FDA labeling.
 
Dosage and Administration
Dosing per FDA Guidelines
 
NOTE: The botulinum toxin preparations are not interchangeable. Dosing will vary according to the product used.  Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.  Botulinum Toxin treatment cycle for indications listed other than chronic migraine, will be separated by a minimum of 90 days.
 
    1. Onabotulinumtoxin A (e.g., Botox) is available as 100 units or 200 units vacuum-dried powder in a single-dose vial for the following conditions:
*Follow indication-specific dosage and administration recommendations. In a 3-month interval, do not exceed a total dose of:
      • Adults: 400 units
      • Pediatrics: the lesser of 10 units/kg or 30 units.
 
a. Overactive Bladder: Recommended total dose 100 units, as 0.5 mL (5 units) injections across 20 sites into the detrusor
b. Adult Detrusor Overactivity associated with a Neurological Condition: Recommended total dose 200 units, as 1 mL (~6.7 units) injections across 30 sites into the detrusor.
c. Pediatric Detrusor Overactivity associated with Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor.
i. Greater than or equal to 34 kg: Recommended total dose is 200 units
ii. Less than 34 kg: Recommended total dose is 6 units/kg.
d. Chronic Migraine: Recommended total dose 155 units, as 0.1 mL (5 units)injections per each site divided across 7 head/neck muscles. The safety and efficacy are not established in individuals under 18 years of age for the prophylaxis of headaches in chronic migraine. Each Botulinum Toxin treatment cycle for chronic migraine headaches, will be separated by a minimum of 12 weeks.
e. Adult Upper Limb Spasticity: Recommended total dose up to 400 units divided among affected muscles.
f. Adult Lower Limb Spasticity: Recommended total dose 300 units to 400 units divided across ankle  and toe muscles.
g. Pediatric Upper Limb Spasticity: Recommended total dose 3 Units/kg to 6 Units/kg (maximum 200 Units) divided among affected muscles.
h. Pediatric Lower Lib Spasticity: Recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles.
i. Cervical Dystonia:  Base dosing on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients.
j. Axillary Hyperhidrosis: 50 Units per axilla.
k. Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye. At repeat treatment sessions, this dose may be increased up to 2-fold if the response from the initial treatment is considered insufficient, which is usually defined as an effect that does not last longer than 2 months.
l. Strabismus: The dose is based on prism diopter correction or previous response to treatment with onabotulinumtoxin A.
 
2. Abobutulinumtoxin a (e.g., Dysport) is available as 300 units or 500 units lyophilized powder in a single-dose vial for the following conditions:
a. Cervical Dystonia:
i. Initial dose is 500 units given intramuscularly as a divided dose among the affected muscles.
ii. Re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 nits and 1000 units to optimized clinical benefit.
iii. Re-treatment should not occur intervals of less than 12 weeks.
iv. Titrate in 250-unit steps according to individual’s response.
b. Spasticity in Adults:
i. Select dose based on muscles affected, severity of spasticity, and treatment and adverse reaction history with botulinum toxins.
ii. Dosing for upper limb spasticity: between 500 Units and 1000 Units.
iii. Dosing for lower limb spasticity: up to 1500 Units.
iv. The maximum recommended total dose per treatment session (upper and lower limb combined) in adults is 1500 Units.
v. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 12 weeks.
c. Spasticity in Pediatric Individuals:
i. Select dose based on the affected muscle, severity of spasticity, and treatment and adverse reaction history with all botulinum toxins.
ii. Recommended dosing for upper limb spasticity: 8 Units/kg to 16 Units/kg per limb. The maximum recommended total dose administered per treatment session must not exceed 16 Units/kg or 640 Units, whichever is lower.
iii. Recommended dosing for lower limb spasticity: 10 Units/kg to 15 Units/kg per limb. Total dose per treatment session must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral injections, or 1000 Units, whichever is lower.
iv. The maximum recommended total dose per treatment session is 30 Units/kg or 1000 Units, whichever is lower. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 3 months.
 
3. Rimabotulinumtoxin B (e.g., Myobloc) is available as 2,500 units/0.5 mL; 5,000 units/mL; or 10,000 units/2 mL (5,000 units/mL) in a single-dose vial for the following conditions:
a. Cervical Dystonia: for individuals with demonstrated tolerance of botulinum toxin injection, recommended total dosage is 2,500 Units to 5,000 Units divided among effected muscles with frequency no sooner than every 12 weeks.
i. Individuals without a prior history of tolerating botulinum toxin injections should receive a lower initial dosage. Subsequent dosing should be determined by individual response.
b. Chronic Sialorrhea: recommended dosage is 1,500 Units to 3,500 Units; 500 Units to 1,500 Units per parotid gland and 250 Units per submandibular gland; no more frequent than every 12 weeks.
 
4. Incobotulinumtoxin a (e.g., Xeomin) is available as 50 units, 100 units, or 200 units lyophilized powder in a single-dose vial for the following conditions:
a. Chronic Sialorrhea:
i. Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks.
ii. Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks.
b. Upper lib spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency (no sooner than every 12 weeks), and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient:
i. Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles.
ii. Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles.
iii. Cervical Dystonia: the recommended initial dose is 120 Units per treatment session.
iv. Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye).
 
5. DaxibotulinumtoxinA-lanm (e.g., Daxxify) is available as 50 units or 100 units sterile lyophilized powder in a single-dose vial for the following condition:
a. Cervical Dystonia: the recommended dose is 125 units to 250 units given intramuscularly as a divided dose among affected muscles with frequency no sooner than every 12 weeks.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of botulinum toxins for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the use of botulinum toxins for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefits certificates of coverage.
 
The use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
  
The use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
Effective January 24, 2024 to February 27, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Before consideration of coverage may be made, it should be established that the individual has been unresponsive to conventional methods of treatment, such as medication, physical therapy and other appropriate methods used to control and/or treat the specified covered condition(s).
  
There may be individuals who require electromyography in order to determine the proper injection site(s).  CPT 95874 is the appropriate code for reporting electromyography in conjunction with chemodenervation.
 
The use of botulinum toxin meets primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
    1. Disorders associated with spasticity or dystonia:
a. Blepharospasm associated with dystonia in individuals 12 years of age and older (Jankovic, 2009; Nussgens, 1997; Roggenkamper, 2006)
b. Facial nerve (VII) disorder (Soares, 2014)
c. Hereditary spastic paraparesis (Shribman, 2019)
d. Idiopathic torsion dystonia (Duarte, 2016)
e. Laryngeal spasm (Simpson, 2008)
f. Multiple sclerosis or Schilder’s disease (deSeze, 2002)
g. Neuromyelitis optica (Esquenazi, 2013)
h. Organic writer’s cramp (FDA, 2021)
i. Orofacial dyskinesis, Meige syndrome (Soares, 2014)
j. Spastic hemiplegia (Shribman, 2019)
k. Symptomatic torsion dystonia (Duarte, 2016)
l. Treatment of upper and lower limb spasticity in individuals 2 years of age and older (FDA, 2021)
m. Treatment of upper limb spasticity in children 2 years of age and older (FDA, 2021)
n. Treatment of lower limb spasticity in children 2 years of age and older (FDA, 2021)
2. Disorders of the bladder:
a. Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
b. Treatment of urinary incontinence due to detrusor overactivity associated with neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
c. Treatment of neurogenic detrusor overactivity (NDO) in pediatric individuals 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. (FDA, 2021)
3. Prophylaxis of chronic migraine headaches in the following situations:
a. Initial approval for 12 months in adult individuals who:
i. Meet International Headache Classification (KCHD-2) diagnostic criteria for chronic migraine headache (e.g., migraine headache lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months) (FDA, 2021); AND  
ii. Have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications in the treatment of chronic migraine headaches (e.g., antidepressants, antihypertensives, and antiepileptics) (Garza, 2021)
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g., Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g., Nurtec) 75 mg every other day); and Atogepant (e.g., Qulipta) 10 mg, 30, or 60 mg daily.; (AAN 2016)
b. Continuing treatment beyond 12 months:
i. Migraine headache frequency reduced by at least 7 days per month (represents a 50% reduction in migraine days); OR  
ii. Migraine headache duration reduced at least 100 hours per month.
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g.,  Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g.,  Nurtec) 75 mg every other day; and Atogepant (e.g., Qulipta 10 mg, 30 mg, or 60 mg daily (AAN 2016)
4. Treatment of cervical dystonia (spasmodic torticollis) in adult individuals, to reduce the severity of abnormal head position and neck pain. (FDA, 2021)
5. Treatment of strabismus in individuals 12 years of age and older. (FDA, 2021)
6. Achalasia unresponsive to dilation therapy or who are poor surgical candidates (Friedmacher, 2012)
7. Chronic anal fissure (Brisinda, 1999)
8. Chronic sialorrhea that is associated with amyotrophic lateral sclerosis or atypical parkinsonian disorders or cerebral palsy (Sialorrhea, 2017) or Parkinson disease or stroke or traumatic brain injury; AND
a. Individual has experienced excessive salivation for 3 or more months; AND   
b. Individual is refractory to at least 2 months of continuous treatment with at least one oral pharmacotherapy (e.g., anticholinergics)
9. Hirschsprung disease with the development of obstructive symptoms after pull-through operation. (Langer, 2017)
10. Primary axillary hyperhidrosis when all the following are met:
a. Individual is 18 years of age or older; AND
b. Individual has failed a trial of at least one week or intolerant of at least one prescription strength antiperspirants or anticholinergics.
11. Coverage is not provided for the following conditions:
a. Neurologic indications such as:
i. Headaches, except as noted above for prevention of chronic migraine headache including maintenance therapy
ii. Essential tremor
iii. Tinnitus
iv. Chronic motor tic disorder and tic associated with Tourette syndrome (motor tics)
b. Urological indications such as:
i. Benign prostatic hyperplasia
ii. Interstitial cystitis
iii. Detrusor sphincteric dyssynergia (after spinal cord injury)
c. Pain due to multiple etiologies such as:
i. Chronic low back pain
ii. Joint pain
iii. Mechanical neck disorders
iv. Neuropathic pain after neck dissection
v. Myofascial pain syndrome
vi. Temporomandibular joint disorders
vii. Trigeminal neuralgia
viii. Pain after hemorrhoidectomy or lumpectomy
ix. Lateral epicondylitis
x. Prevention of pain associated with breast reconstruction after mastectomy
d. Ano-rectal conditions such as:
i. Internal anal sphincter achalasia
ii. Anismus (pelvic floor dyssynergia)
e. Any cosmetic purpose/indication
f. Other miscellaneous conditions such as:
i. Gastroparesis
ii. Facial wound healing
iii. Depression
 
Documentation should include the following:
    1. Support for the medical necessity of the injection; AND
    2. A covered diagnosis; AND
    3. A statement that traditional methods of treatments have been tried and proven unsuccessful; AND
    4. Dosage and frequency of the injections; AND
    5. Support of the clinical effectiveness of the injections; AND
    6. Specify the site(s) injected.
 
CONTINUATION OF THERAPY for 12 months:
    1. Individual meets criteria for initial approval based on indication.
    2. Individual has experienced a positive clinical response to botulinum toxin.
    3. Dosed in accordance with FDA labeling.
 
Dosage and Administration
Dosing per FDA Guidelines
 
NOTE: The botulinum toxin preparations are not interchangeable. Dosing will vary according to the product used.  Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.  Botulinum Toxin treatment cycle for indications listed other than chronic migraine, will be separated by a minimum of 90 days.
 
    1. Onabotulinumtoxin A (e.g., Botox) is available as 100 units or 200 units vacuum-dried powder in a single-dose vial for the following conditions:
*Follow indication-specific dosage and administration recommendations. In a 3-month interval, do not exceed a total dose of:
      • Adults: 400 units
      • Pediatrics: the lesser of 10 units/kg or 30 units.
 
a. Overactive Bladder: Recommended total dose 100 units, as 0.5 mL (5 units) injections across 20 sites into the detrusor
b. Adult Detrusor Overactivity associated with a Neurological Condition: Recommended total dose 200 units, as 1 mL (~6.7 units) injections across 30 sites into the detrusor.
c. Pediatric Detrusor Overactivity associated with Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor.
i. Greater than or equal to 34 kg: Recommended total dose is 200 units
ii. Less than 34 kg: Recommended total dose is 6 units/kg.
d. Chronic Migraine: Recommended total dose 155 units, as 0.1 mL (5 units)injections per each site divided across 7 head/neck muscles. The safety and efficacy are not established in individuals under 18 years of age for the prophylaxis of headaches in chronic migraine. Each Botulinum Toxin treatment cycle for chronic migraine headaches, will be separated by a minimum of 12 weeks.
e. Adult Upper Limb Spasticity: Recommended total dose up to 400 units divided among affected muscles.
f. Adult Lower Limb Spasticity: Recommended total dose 300 units to 400 units divided across ankle  and toe muscles.
g. Pediatric Upper Limb Spasticity: Recommended total dose 3 Units/kg to 6 Units/kg (maximum 200 Units) divided among affected muscles.
h. Pediatric Lower Lib Spasticity: Recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles.
i. Cervical Dystonia:  Base dosing on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients.
j. Axillary Hyperhidrosis: 50 Units per axilla.
k. Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye. At repeat treatment sessions, this dose may be increased up to 2-fold if the response from the initial treatment is considered insufficient, which is usually defined as an effect that does not last longer than 2 months.
l. Strabismus: The dose is based on prism diopter correction or previous response to treatment with onabotulinumtoxin A.
 
2. Abobutulinumtoxin a (e.g., Dysport) is available as 300 units or 500 units lyophilized powder in a single-dose vial for the following conditions:
a. Cervical Dystonia:
i. Initial dose is 500 units given intramuscularly as a divided dose among the affected muscles.
ii. Re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 nits and 1000 units to optimized clinical benefit.
iii. Re-treatment should not occur intervals of less than 12 weeks.
iv. Titrate in 250-unit steps according to individual’s response.
b. Spasticity in Adults:
i. Select dose based on muscles affected, severity of spasticity, and treatment and adverse reaction history with botulinum toxins.
ii. Dosing for upper limb spasticity: between 500 Units and 1000 Units.
iii. Dosing for lower limb spasticity: up to 1500 Units.
iv. The maximum recommended total dose per treatment session (upper and lower limb combined) in adults is 1500 Units.
v. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 12 weeks.
c. Spasticity in Pediatric Individuals:
i. Select dose based on the affected muscle, severity of spasticity, and treatment and adverse reaction history with all botulinum toxins.
ii. Recommended dosing for upper limb spasticity: 8 Units/kg to 16 Units/kg per limb. The maximum recommended total dose administered per treatment session must not exceed 16 Units/kg or 640 Units, whichever is lower.
iii. Recommended dosing for lower limb spasticity: 10 Units/kg to 15 Units/kg per limb. Total dose per treatment session must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral injections, or 1000 Units, whichever is lower.
iv. The maximum recommended total dose per treatment session is 30 Units/kg or 1000 Units, whichever is lower. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 3 months.
 
3. Rimabotulinumtoxin B (e.g., Myobloc) is available as 2,500 units/0.5 mL; 5,000 units/mL; or 10,000 units/2 mL (5,000 units/mL) in a single-dose vial for the following conditions:
a. Cervical Dystonia: for individuals with demonstrated tolerance of botulinum toxin injection, recommended total dosage is 2,500 Units to 5,000 Units divided among effected muscles with frequency no sooner than every 12 weeks.
i. Individuals without a prior history of tolerating botulinum toxin injections should receive a lower initial dosage. Subsequent dosing should be determined by individual response.
b. Chronic Sialorrhea: recommended dosage is 1,500 Units to 3,500 Units; 500 Units to 1,500 Units per parotid gland and 250 Units per submandibular gland; no more frequent than every 12 weeks.
 
4. Incobotulinumtoxin a (e.g., Xeomin) is available as 50 units, 100 units, or 200 units lyophilized powder in a single-dose vial for the following conditions:
a. Chronic Sialorrhea:
i. Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks.
ii. Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks.
b. Upper lib spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency (no sooner than every 12 weeks), and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient:
i. Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles.
ii. Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles.
iii. Cervical Dystonia: the recommended initial dose is 120 Units per treatment session.
iv. Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye).
 
5. DaxibotulinumtoxinA-lanm (e.g., Daxxify) is available as 50 units or 100 units sterile lyophilized powder in a single-dose vial for the following condition:
a. Cervical Dystonia: the recommended dose is 125 units to 250 units given intramuscularly as a divided dose among affected muscles with frequency no sooner than every 12 weeks.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of botulinum toxins for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the use of botulinum toxins for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefits certificates of coverage.
 
The use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
  
The use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
Effective October 24, 2023 to January 23, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Before consideration of coverage may be made, it should be established that the individual has been unresponsive to conventional methods of treatment, such as medication, physical therapy and other appropriate methods used to control and/or treat the specified covered condition(s).
  
There may be individuals who require electromyography in order to determine the proper injection site(s).  CPT 95874 is the appropriate code for reporting electromyography in conjunction with chemodenervation.
 
The use of botulinum toxin meets primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
    1. Disorders associated with spasticity or dystonia:
a. Blepharospasm associated with dystonia in individuals 12 years of age and older (Jankovic, 2009; Nussgens, 1997; Roggenkamper, 2006)
b. Facial nerve (VII) disorder (Soares, 2014)
c. Hereditary spastic paraparesis (Shribman, 2019)
d. Idiopathic torsion dystonia (Duarte, 2016)
e. Laryngeal spasm (Simpson, 2008)
f. Multiple sclerosis or Schilder’s disease (deSeze, 2002)
g. Neuromyelitis optica (Esquenazi, 2013)
h. Organic writer’s cramp (FDA, 2021)
i. Orofacial dyskinesis, Meige syndrome (Soares, 2014)
j. Spastic hemiplegia (Shribman, 2019)
k. Symptomatic torsion dystonia (Duarte, 2016)
l. Treatment of upper and lower limb spasticity in individuals 2 years of age and older (FDA, 2021)
m. Treatment of upper limb spasticity in children 2 years of age and older (FDA, 2021)
n. Treatment of lower limb spasticity in children 2 years of age and older (FDA, 2021)
2. Disorders of the bladder:
a. Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
b. Treatment of urinary incontinence due to detrusor overactivity associated with neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication. (FDA, 2021)
c. Treatment of neurogenic detrusor overactivity (NDO) in pediatric individuals 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. (FDA, 2021)
3. Prophylaxis of chronic migraine headaches in the following situations:
a. Initial approval for 12 months in adult individuals who:
i. Meet International Headache Classification (KCHD-2) diagnostic criteria for chronic migraine headache (e.g., migraine headache lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months) (FDA, 2021); AND  
ii. Have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications in the treatment of chronic migraine headaches (e.g., antidepressants, antihypertensives, and antiepileptics) (Garza, 2021)
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g., Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g., Nurtec) 75 mg every other day); and Atogepant (e.g., Qulipta) 10 mg, 30, or 60 mg daily.; (AAN 2016)
b. Continuing treatment beyond 12 months:
i. Migraine headache frequency reduced by at least 7 days per month (represents a 50% reduction in migraine days); OR  
ii. Migraine headache duration reduced at least 100 hours per month.
iii. Individual must not be taking concurrently with any preventive CGRP inhibitor including but not limited to Galcanezumab-gnlm (e.g., Emgality) 120 mg once monthly; Erenumab-aooe (e.g., Aimovig) 70 to 140 mg once monthly; Fremanezumab-vfrm (e.g., Ajovy) 225 mg monthly or 675 mg every 3 months; Eptinezumab-jjmr (e.g.,  Vyepti) 100 mg to 300 mg every 3 months; Rimegepant (e.g.,  Nurtec) 75 mg every other day; and Atogepant (e.g., Qulipta 10 mg, 30 mg, or 60 mg daily (AAN 2016)
4. Treatment of cervical dystonia (spasmodic torticollis) in adult individuals, to reduce the severity of abnormal head position and neck pain. (FDA, 2021)
5. Treatment of strabismus in individuals 12 years of age and older. (FDA, 2021)
6. Achalasia unresponsive to dilation therapy or who are poor surgical candidates (Friedmacher, 2012)
7. Chronic anal fissure (Brisinda, 1999)
8. Chronic sialorrhea that is associated with amyotrophic lateral sclerosis or atypical parkinsonian disorders or cerebral palsy (Sialorrhea, 2017) or Parkinson disease or stroke or traumatic brain injury; AND
a. Individual has experienced excessive salivation for 3 or more months; AND   
b. Individual is refractory to at least 2 months of continuous treatment with at least one oral pharmacotherapy (e.g., anticholinergics)
9. Hirschsprung disease with the development of obstructive symptoms after pull-through operation. (Langer, 2017)
10. Primary axillary hyperhidrosis when all the following are met:
a. Individual is 18 years of age or older; AND
b. Individual has failed a trial of at least one week or intolerant of at least one prescription strength antiperspirants or anticholinergics.
11. Coverage is not provided for the following conditions:
a. Neurologic indications such as:
i. Headaches, except as noted above for prevention of chronic migraine headache including maintenance therapy
ii. Essential tremor
iii. Tinnitus
iv. Chronic motor tic disorder and tic associated with Tourette syndrome (motor tics)
b. Urological indications such as:
i. Benign prostatic hyperplasia
ii. Interstitial cystitis
iii. Detrusor sphincteric dyssynergia (after spinal cord injury)
c. Pain due to multiple etiologies such as:
i. Chronic low back pain
ii. Joint pain
iii. Mechanical neck disorders
iv. Neuropathic pain after neck dissection
v. Myofascial pain syndrome
vi. Temporomandibular joint disorders
vii. Trigeminal neuralgia
viii. Pain after hemorrhoidectomy or lumpectomy
ix. Lateral epicondylitis
x. Prevention of pain associated with breast reconstruction after mastectomy
d. Ano-rectal conditions such as:
i. Internal anal sphincter achalasia
ii. Anismus (pelvic floor dyssynergia)
e. Any cosmetic purpose/indication
f. Other miscellaneous conditions such as:
i. Gastroparesis
ii. Facial wound healing
iii. Depression
 
Documentation should include the following:
    1. Support for the medical necessity of the injection; AND
    2. A covered diagnosis; AND
    3. A statement that traditional methods of treatments have been tried and proven unsuccessful; AND
    4. Dosage and frequency of the injections; AND
    5. Support of the clinical effectiveness of the injections; AND
    6. Specify the site(s) injected.
 
CONTINUATION OF THERAPY for 12 months:
    1. Individual meets criteria for initial approval based on indication.
    2. Individual has experienced a positive clinical response to botulinum toxin.
    3. Dosed in accordance with FDA labeling.
 
Dosage and Administration
Dosing per FDA Guidelines
 
NOTE: The botulinum toxin preparations are not interchangeable. Dosing will vary according to the product used.  Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.  Botulinum Toxin treatment cycle for indications listed other than chronic migraine, will be separated by a minimum of 90 days.
 
    1. Onabotulinumtoxin A (e.g., Botox) is available as 100 units or 200 units vacuum-dried powder in a single-dose vial for the following conditions:
*Follow indication-specific dosage and administration recommendations. In a 3-month interval, do not exceed a total dose of:
      • Adults: 400 units
      • Pediatrics: the lesser of 10 units/kg or 30 units.
 
a. Overactive Bladder: Recommended total dose 100 units, as 0.5 mL (5 units) injections across 20 sites into the detrusor
b. Adult Detrusor Overactivity associated with a Neurological Condition: Recommended total dose 200 units, as 1 mL (~6.7 units) injections across 30 sites into the detrusor.
c. Pediatric Detrusor Overactivity associated with Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor.
i. Greater than or equal to 34 kg: Recommended total dose is 200 units
ii. Less than 34 kg: Recommended total dose is 6 units/kg.
d. Chronic Migraine: Recommended total dose 155 units, as 0.1 mL (5 units)injections per each site divided across 7 head/neck muscles. The safety and efficacy are not established in individuals under 18 years of age for the prophylaxis of headaches in chronic migraine. Each Botulinum Toxin treatment cycle for chronic migraine headaches, will be separated by a minimum of 12 weeks.
e. Adult Upper Limb Spasticity: Recommended total dose up to 400 units divided among affected muscles.
f. Adult Lower Limb Spasticity: Recommended total dose 300 units to 400 units divided across ankle  and toe muscles.
g. Pediatric Upper Limb Spasticity: Recommended total dose 3 Units/kg to 6 Units/kg (maximum 200 Units) divided among affected muscles.
h. Pediatric Lower Lib Spasticity: Recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles.
i. Cervical Dystonia:  Base dosing on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients.
j. Axillary Hyperhidrosis: 50 Units per axilla.
k. Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye.
l. Strabismus: The dose is based on prism diopter correction or previous response to treatment with onabotulinumtoxin A.
 
2. Abobutulinumtoxin a (e.g., Dysport) is available as 300 units or 500 units lyophilized powder in a single-dose vial for the following conditions:
a. Cervical Dystonia:
i. Initial dose is 500 units given intramuscularly as a divided dose among the affected muscles.
ii. Re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 nits and 1000 units to optimized clinical benefit.
iii. Re-treatment should not occur intervals of less than 12 weeks.
iv. Titrate in 250-unit steps according to individual’s response.
b. Spasticity in Adults:
i. Select dose based on muscles affected, severity of spasticity, and treatment and adverse reaction history with botulinum toxins.
ii. Dosing for upper limb spasticity: between 500 Units and 1000 Units.
iii. Dosing for lower limb spasticity: up to 1500 Units.
iv. The maximum recommended total dose per treatment session (upper and lower limb combined) in adults is 1500 Units.
v. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 12 weeks.
c. Spasticity in Pediatric Individuals:
i. Select dose based on the affected muscle, severity of spasticity, and treatment and adverse reaction history with all botulinum toxins.
ii. Recommended dosing for upper limb spasticity: 8 Units/kg to 16 Units/kg per limb. The maximum recommended total dose administered per treatment session must not exceed 16 Units/kg or 640 Units, whichever is lower.
iii. Recommended dosing for lower limb spasticity: 10 Units/kg to 15 Units/kg per limb. Total dose per treatment session must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral injections, or 1000 Units, whichever is lower.
iv. The maximum recommended total dose per treatment session is 30 Units/kg or 1000 Units, whichever is lower. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 3 months.
 
3. Rimabotulinumtoxin B (e.g., Myobloc) is available as 2,500 units/0.5 mL; 5,000 units/mL; or 10,000 units/2 mL (5,000 units/mL) in a single-dose vial for the following conditions:
a. Cervical Dystonia: for individuals with demonstrated tolerance of botulinum toxin injection, recommended total dosage is 2,500 Units to 5,000 Units divided among effected muscles with frequency no sooner than every 12 weeks.
i. Individuals without a prior history of tolerating botulinum toxin injections should receive a lower initial dosage. Subsequent dosing should be determined by individual response.
b. Chronic Sialorrhea: recommended dosage is 1,500 Units to 3,500 Units; 500 Units to 1,500 Units per parotid gland and 250 Units per submandibular gland; no more frequent than every 12 weeks.
 
4. Incobotulinumtoxin a (e.g., Xeomin) is available as 50 units, 100 units, or 200 units lyophilized powder in a single-dose vial for the following conditions:
a. Chronic Sialorrhea:
i. Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks.
ii. Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks.
b. Upper lib spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency (no sooner than every 12 weeks), and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient:
i. Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles.
ii. Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles.
iii. Cervical Dystonia: the recommended initial dose is 120 Units per treatment session.
iv. Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye).
 
5. DaxibotulinumtoxinA-lanm (e.g., Daxxify) is available as 50 units or 100 units sterile lyophilized powder in a single-dose vial for the following condition:
a. Cervical Dystonia: the recommended dose is 125 units to 250 units given intramuscularly as a divided dose among affected muscles with frequency no sooner than every 12 weeks.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of botulinum toxins for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the use of botulinum toxins for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefits certificates of coverage.
 
The use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
  
The use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have primary coverage criteria, the use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to January 24, 2024 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
DYSTONIA AND SPASTICITY
This evidence review section is based on a 1996 TEC Assessment (updated in 2004) that focused on the use of botulinum toxin for the treatment of focal dystonia or spasticity, the American Academy of Neurology (AAN) 2008 assessment of movement disorders and spasticity (Naumann, 2008; Simpson, 2008), and additional controlled trials and systematic reviews identified by MEDLINE literature searches.
 
The AAN assessment concluded that the evidence was AAN level A (established as effective, should be done) for equinus varus deformity in children with cerebral palsy and AAN level B (probably effective, should be considered) for upper extremity, for adductor spasticity, and for pain control in conjunction with adductor-lengthening surgery in children with cerebral palsy. The evidence was rated level B for treatment of adult spasticity in the upper- and lower-limb for reducing muscle tone and improving passive function, but insufficient evidence to recommend an optimum technique for muscle localization at the time of injection. The evidence was rated level B for upper-limb focal dystonia but insufficient for lower-limb focal dystonia, and was rated level B for adductor laryngeal dystonia but insufficient for abductor laryngeal dystonia (Simpson, 2008).
  
STRABISMUS
Strabismus is a condition in which the eyes are not in proper alignment. In 2012, a Cochrane review by Rowe and Noonan evaluated the literature on botulinum toxin for strabismus (Rowe, 2012). Reviewers identified 4 RCTs, all of which were published in the 1990s. Three trials compared botulinum toxin injection with surgery, and one compared botulinum toxin injection with a noninvasive treatment control group. Among the trials that used surgery as a comparator intervention, 2 studies found no statistically significant differences in outcomes between the 2 groups, and one found a higher rate of a satisfactory outcome in the surgery group (defined as <8 prism diopters). The study comparing botulinum toxin with no intervention did not find a significant difference in outcomes in the 2 groups. Complications after botulinum toxin included transient ptosis and vertical deviation; combined complication rates ranged from 24% to 56% in the studies.
 
BLEPHAROSPASM
Blepharospasm is a progressive neurologic disorder characterized by involuntary contractions of the eyelid muscles; it is classified as a focal dystonia. RCTs have evaluated Botox, Dysport, and Xeomin for the treatment of blepharospasm and found these agents to be effective at improving symptoms(Jankovic, 2009; Nussgens, 1997; Roggenkamper, 2006). No RCTs evaluating Myobloc for treating blepharospasm were identified in literature searches. Dashtipour et al (2015) reported on the results of a systematic review that included 5 RCTs (374 with blepharospasm, 172 with hemifacial spasm) of abobotulinumtoxinA (Dashtipour, 2015). All trials showed statistically significant benefits for the treatment of blepharospasm and hemifacial spasm.
 
HEADACHE
Botulinum toxin for treatment of pain from migraine and from chronic tension-type headaches was addressed in a 2004 TEC Assessment. Both Assessments concluded that the evidence was insufficient for either indication. Because the placebo response rate is typically high in patients with headache, assessment of evidence focuses on randomized, placebo-controlled trials. More recent literature is discussed below, organized by type of headache. Recent studies have focused on frequency of headache as an outcome measure in addition to pain and headache severity.
 
Migraine Headache
Migraines can be categorized by headache frequency. According to the Third Edition of the International Headache Classification (ICHD-3), migraine without aura (previously known as common migraine) is defined as at least 5 attacks per month meeting other diagnostic criteria (Headache Classification Committee of the IHS, 2013). Chronic migraine is defined as attacks on at least 15 days per month for more than 3 months, with features of migraine on at least 8 days per month.
 
Several RCTs and systematic reviews of RCTs have been published. In 2013, the Agency for Healthcare Research and Quality published a comparative effectiveness review on preventive pharmacologic treatments for migraine in adults (Shamliyan, 2013). The investigators identified 15 double-blind RCTs evaluating botulinum toxin for migraine prevention: 13 used onabotulinumtoxinA and two used abobotulinumtoxinA. In a meta-analysis of 3 RCTs, onabotulinumtoxinA was more effective than placebo in reducing the number of chronic migraine episodes per month by at least 50% (relative risk [RR], 1.5; 95% CI, 1.2 to 1.8). In another pooled analysis, onabotulinumtoxinA was associated with a significantly higher rate of treatment discontinuation due to adverse effects than placebo (RR=3.2; 95% CI, 1.4 to 7.10). Five RCTs compared the efficacy of onabotulinumtoxinA with another medication (topiramate or divalproex sodium). Findings were not pooled, but, for the most part, there were no statistically significant differences in outcomes between the 2 drugs.
 
The primary end point in PREEMPT 1 was mean change from baseline in frequency of headache episodes for 28 days ending with week 24. A headache episode was defined as a headache with a start and stop time indicating that pain lasted at least 4 hours. Prespecified secondary outcomes included, among others, change in frequency of headache days (calendar days in which pain lasted at least 4 hours), migraine days (calendar days in which a migraine lasted at least 4 hours), and migraine episodes (migraine with a start and stop time indicating that pain lasted at least 4 hours). Based on availability of data from PREEMPT 1 and other factors, the protocol of the PREEMPT 2 trial was amended (after study initiation but before unmasking) to make frequency of headache days the primary end point of this study. The authors noted that, to control for potential type I error related to changes to the outcome measures, a more conservative p-value (0.01) was used. Several QOL measures were also included in the trials, including the 6-item Headache Impact Test-6 (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ v.2). Key findings of the 2 studies are described below.
 
PREEMPT 1 randomized 679 patients (Aurora, 2010). Mean number of migraine days during baseline was 19.1 in each group. The mean number of headache episodes during the 28-day baseline period was 12.3 in the Botox group and 13.4 in the placebo group. Approximately 60% of patients had previously used at least 1 prophylactic medication and approximately 68% overused headache pain medication during baseline. A total of 296 (87%) of 341 patients in the Botox group and 295 (87%) of 338 patients in the placebo group completed the 24-week double-blind phase. The primary outcome (change from baseline in frequency of headache episodes over a 28-day period) did not differ significantly between groups. The number of headache episodes decreased by a mean of 5.2 in the Botox group and 5.3 in the placebo group (p=0.344). Similarly, the number of migraine episodes did not differ significantly. There was a decrease of 4.8 migraine episodes in the Botox group and of 4.9 in the placebo group (p=0.206). In contrast, there was a significantly greater decrease in the number of headache days and the number of migraine days in the Botox group than in the placebo group. The decrease in frequency of headache days was 7.8 in the Botox group and 6.4 in the placebo group, a difference of 1.4 headache days per 28 days (p=0.006). Corresponding numbers for migraine days were 7.6 and 6.1, respectively (p=0.002). There was significantly greater improvement in QOL in the Botox group vs the placebo group. The proportion of patients with severe impact of headaches (ie, HIT-6 score, ³60) in the Botox group decreased from 94% at baseline to 69% at 24 weeks; in the placebo group, it decreased from 95% at baseline to 80%, a between-group difference of 11% (p=0.001). The authors did not report MSQ scores, but stated that there was statistically significant greater improvement in the 3 MSQ role function domains at week 24 (restrictive, p<0.01; preventive, p=0.05; emotional, p<0.002). Adverse events were experienced by 203 (60%) patients in the Botox group and 156 (47%) patients in the placebo group. Eighteen (5%) patients in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. Treatment-related adverse events were consistent with the known safety profile of Botox.
 
PREEMPT 2 randomized 705 patients (Diener, 2010). Mean number of migraine days during baseline period was 19.2 in the Botox group and 18.7 in the placebo group. Mean number of headache episodes during the 28-day baseline period was 12.0 in the Botox group and 12.7 in the placebo group. Approximately 65% of patients had previously used at least 1 prophylactic medication and approximately 63% overused headache pain medication during baseline. A total of 311 (90%) of 347 patients in the Botox group and 334 (93%) of 358 patients in the placebo group completed the 24-week, double-blind phase. The primary outcome, change from baseline frequency of headache days over a 28-day period (a different primary outcome from PREEMPT 1), differed significantly between groups and favored Botox treatment. The number of headache days decreased by a mean of 9.0 in the Botox group and 6.7 in the placebo group, an absolute difference of 2.3 days per 28 days (p<0.001). Mean number of migraine days also decreased significantly, more in the Botox group (8.7) than in the placebo group (6.3; p<0.001). Unlike PREEMPT 1, there was a significantly greater decrease in headache episodes in PREEMPT 2 in the Botox group (5.3) than in the placebo group (4.6; p=0.003). Change in frequency of migraine episodes was not reported.
 
Medication Overuse Headache
According to the ICHD-2, medication overuse headache is a different diagnostic classification than chronic migraine (Silberstein, 2005). In 2013, Silberstein et al published a subanalysis of pooled PREEMPT data limited to patients with headache medication overuse at baseline (Dilberstein, 2013). A total of 904 patients who indicated they had medication overuse headache were included; 445 were randomized to the botulinum toxin group and 459 to the placebo group. At the end of week 24, there was a significantly greater reduction in outcomes, including headache days, headache episodes, and moderate-to-severe headache days, in the botulinum toxin group than in the placebo group. For example, the number of headache days per month decreased by a mean of 8.2 in the botulinum toxin group and 6.2 in the placebo group (p<0.001). This is a single analysis of RCT data and provides insufficient evidence that botulinum toxin is effective for patients with the diagnosis of medication overuse headache.
 
Tension Headache
The 2012 meta-analysis by Jackson et al (discussed above) identified 7 RCTs evaluating botulinum toxin for treating chronic tension-type headaches; all were placebo-controlled (Jackson, 2012). A pooled analysis of these 7 studies did not find a statistically significant difference in change in the monthly number of headache days in the botulinum toxin group vs the placebo group (difference, -1.43; 95% CI, -3.13 to 0.27). The trial with the largest sample size (Silberstein et al, 2006) included 300 patients randomized to 1 of 4 doses of botulinum toxin or placebo. Overall, there was no statistically significant difference between the botulinum toxin groups and the placebo group in mean change from baseline to 90 days in number of headache days per month.
 
Chronic Daily Headache
Although chronic daily headache is not recognized in the ICHD, it is commonly defined to include different kinds of chronic headache (eg, chronic or transformed migraine, daily persistent headache). It may also include chronic tension-type headache, addressed above. The 2102 meta-analysis by Jackson identified 3 RCTs comparing botulinum toxin type A with placebo in patients having at least 15 headaches per month (Jackson, 2012). A pooled analysis of data from these 3 trials found a significantly greater reduction in the number of headaches per month with botulinum toxin than with placebo (absolute difference, -2.06; 95% CI, -3.56 to -0.56). Individually, only 1 (Ondo et al, 2004) of the 3 trials found a statistically significant benefit with botulinum toxin treatment. Ondo included 60 patients, some with chronic migraines and chronic tension-type headache. The Ondo study found significantly greater reduction in the number of headache-free days over weeks 8 to 12 with botulinum toxin than with placebo (p<0.05), but there was no statistically significant between-group difference in reduction in headache-free days over the entire 12-week study period (p=0.07). The other 2 studies evaluated more patients: 355 in Mathew et al (2005) and 702 in Silberstein et al (2005). Neither found a statistically significant difference in the reduction in the number of headache days per month with botulinum toxin. The available evidence from RCTs is conflicting and insufficient for conclusions.
 
Cluster Headache
No controlled trials were identified for cluster headache.
 
Cervicogenic Headache
In 2011, Linde et al published a double-blind, placebo-controlled crossover study that included 28 patients with treatment-resistant cervicogenic headache (Linde, 2011). Patients were randomized to botulinum toxin type A or placebo; there was at least an 8-week period between treatments. The trial did not find significant differences between active and placebo treatment in the primary outcome, reduction in the number of days with moderate-to-severe headache. Three other RCTs, published between 2000 and 2008, randomized patients with chronic, whiplash-related headache to botulinum toxin type A treatment or placebo (Braker, 2008; Freund, 2000; Padberg, 2007). One trial reported trends toward improvement with treatment for various outcomes; most were not statistically significant (Braker, 2008). Another reported no significant differences for several pain-related outcomes (Padberg, 2007). One trial reported a significant improvement in pain with treatment while the placebo group reported no improvement, but trial design was flawed because the placebo group reported less pain at baseline (Freund, 2000), A Cochrane review of treatment of mechanical neck disorders, published in 2007, included 6 RCTs (total N=273 patients) assessing botulinum toxin and placebo for chronic neck disorders with or without radicular findings or headache (Peloso, 2007). A meta-analysis of 4 studies (n=139 patients) for pain outcomes found no statistically significant results. Reviewers concluded that a range of doses did not show significant differences compared with placebo or other comparators.
 
ESOPHAGEAL ACHALASIA
Esophageal achalasia is a primary motor disorder characterized by abnormal lower esophageal sphincter relaxation. A 2014 Cochrane review by Leyden et al identified 7 RCTs (total N=178 participants) on treatment of primary esophageal achalasia with botulinum toxin or endoscopic pneumatic dilation (Leyden, 2014). A pooled analysis of data from 5 trials did not find a statistically significant difference in the rate of initial remission with pneumatic dilation vs botulinum toxin injection (RR=1.11; 95% CI, 0.97 to 1.27). Remission at 6 and 12 months favored the pneumatic dilation group. No serious adverse events were reported after botulinum toxin injection; however, there were 3 cases of perforation after pneumatic dilation.
 
SIALORRHEA
Sialorrhea (Drooling) Associated With Parkinson Disease
Several RCTs have evaluated botulinum toxin injections in patients with Parkinson disease. For example, in 2006, Lagalla et al randomized 32 patients with Parkinson disease to placebo or botulinum toxin type A; evaluation at 1 month postinjection resulted in significant improvements compared with placebo in drooling frequency, saliva output, and familial and social embarrassment (Lagalla, 2006). Dysphagia scores were not significantly improved. Moreover, Ondo et al (2004) randomized 16 patients with Parkinson disease to botulinum toxin type B or placebo (Ondo, 2004). The botulinum toxin group had significantly better outcomes than the placebo group at 1 month on 4 drooling outcomes. Groups did not differ on salivary gland imaging or on a dysphagia scale. Mancini et al (2003) assigned 20 patients with Parkinson disease to injections of either a saline placebo or botulinum toxin type A (Mancini, 2003). The treatment group had significantly better outcomes than the placebo group on a drooling scale at 1 week; the effect disappeared by 3 months.
 
Sialorrhea (Drooling) Not Associated With Parkinson Disease
Several systematic reviews have evaluated botulinum toxin for treating sialorrhea in people with conditions other than Parkinson disease. In 2014, Squires et al reviewed the research on botulinum toxin injections for drooling in patients with amyotrophic lateral sclerosis/motor neuron disease (Squires, 2014). Reviewers included RCTs and controlled and uncontrolled observational studies. They identified 12 studies, of which 8 had no control groups. There were 2 small RCTs, each with fewer than 20 patients. Sample sizes in the non-RCTs ranged from 5 to 26 patients. Due to heterogeneity, study findings were not pooled. Only one of the 2 RCTs reported drooling outcomes; it found a significantly greater reduction in saliva volume with botulinum toxin than with placebo at 2 weeks.
 
In 2012, Rodwell et al published a systematic review evaluating botulinum toxin injections in the salivary gland to treat sialorrhea in children with cerebral palsy and neurodevelopment disability (Rodwell, 2012). Reviewers identified 5 RCTs; sample sizes in individual trials ranged from 6 to 48 participants. One of the RCTs (N=6) was terminated due to adverse events. In a pooled analysis of data 4 weeks postintervention in 3 RCTs, the mean score on the Drooling Frequency and Severity Scale was significantly lower in children who received botulinum toxin injections than a control intervention (MD = -2.71 points; 95% CI, -4.82 to -0.60; p<0.001). The clinical significance of this difference in Drooling Frequency and Severity Scale scores is not clear. Data were not pooled for other outcomes. The systematic review also identified 11 prospective case series. The rate of adverse events associated with botulinum toxin injection in the RCTs and case series ranged from 2% to 41%. Dysphagia occurred in 2 (33%) of the 6 participants in an RCT terminated early and in 2 (2%) of 126 patients in a case series. There was 1 reported chest infection, 1 case of aspiration pneumonia, and, in 1 case series, 6 (5%) of 126 patients experienced an increased frequency of pulmonary infections. In 7 studies, there were reports of patients with difficulty swallowing and/or chewing following botulinum toxin treatment.
 
The largest RCT on botulinum toxin for treating sialorrhea in children with cerebral palsy was published in 2008 by Reid et al (Reid, 2008). Forty-eight children with cerebral palsy (n=31) and other neurologic disorders (n=17) were randomized to a single injection of botulinum toxin type A 25 U compared with no treatment. Drooling was assessed by using the Drooling Impact Scale. Scores differed significantly between groups at 1 month, and a beneficial effect of botulinum toxin injection remained at 6 months. Gonzalez et al (2017) reported the results of an RCT in which 40 adults with cerebral palsy were randomized to onabotulinumtoxinA or observation (Gonzalez, 2017). The trial had greater than 80% power to detect a 39% difference in the proportion of patients who achieve at least a 50% reduction in drooling quotient. The primary efficacy outcome was drooling quotient. This quotient, measured as a proportion, is a semi-quantitative method that assesses the presence of newly formed saliva on the lips every 15 seconds with 40 observations in 10 minutes, expressed as a percentage based on the ratio between the number of observed drooling episodes and the total number of observations. The proportion of patients who achieved at least a 50% reduction in drooling quotient in the treated group vs control after 8 weeks and 80 weeks was 45% vs 0.0% (p=0.001) and 20% vs 0% (p=0.106). While the treatment effect was large, the trial did not use a placebo group and was unblinded.
 
A 2013 retrospective review focused on the long-term safety of botulinum toxin type A injection for treating sialorrhea in children (Chan, 2013). Reviewers included 69 children; 47 (68%) had cerebral palsy. Children received their first injection of botulinum toxin type A at a mean age of 9.9 years; mean follow-up was 3.1 years. During the study period, the children received a total of 120 botulinum toxin injections. Complications occurred in 19 (28%) of 69 children and in 23 (19%) of 120 injections. Fifteen of 23 complications were minor, including 6 cases of dysphagia. There were 8 major complications: 3 cases of aspiration pneumonia, 2 cases of severe dysphagia, and 3 cases of loss of motor control of the head. Complications were associated with 5 hospitalizations and 2 cases of nasogastric tube placement.
 
ANAL APPLICATIONS  
Internal Anal Sphincter Achalasia
Internal anal sphincter (IAS) achalasia is a defecation disorder in which the internal anal sphincter is unable to relax. Symptoms include severe constipation and soiling. A meta-analysis of studies on treatment of IAS achalasia was published in 2012 by Friedmacher and Puri (Friedmacher, 2012). Reviewers did not identify any RCTs of Botox treatment. Two prospective case series and 14 retrospective case series (total N=395 patients) of IAS achalasia were identified. Most patients (229/395 [58%]) in the series were treated with posterior IAS myectomy and 166 (42%) were treated with intrasphincteric botulinum toxin injection. A meta-analysis of data from the observational studies found that regular bowel movements were more frequent after myectomy (odds ratio [OR], 0.53; 95% CI, 0.29 to 0.99; p=0.04). Moreover, the rate of transient fecal incontinence was significantly higher after botulinum toxin injection (OR=0.07; 95% CI, 0.01 to 0.54; p<0.01) and the rate of subsequent surgical intervention was higher after botulinum toxin injection (OR=0.18; 95% CI, 0.07 to 0.44; p<0.001). Other outcomes, including continued use of laxatives or rectal enemas and overall complication rates, did not differ between treatments. Emile et al (2016) reported the results of a systematic review that included 7 studies comprising 189 patients with a follow-up period greater than 6 months in each of the individual studies (Emile, 2016). Of the 7 included studies, 2 were RCTs and remaining were comparative and observational studies. Both RCTs were single site from the same author group and conducted in Egypt, enrolling 15 and 24 patients, respectively (Farid, 2009; Farid, 2009). Improvement was defined as patients returning to their normal habits. The first RCT used biofeedback and the other used surgery as the comparator. In the first RCT, 50% of individuals in the biofeedback group reported improvement initially at 1 month but it dropped down to 25% by the end of year. The respective proportions of patients in the botulinum toxin arm were 70.8% and 33.3%. In the second RCT, surgery led to improved outcomes in all patients at 1 month but that percentage dropped to 66.6% at 1 year. The respective proportions of patients in the botulinum toxin arm were 87% and 40%. While these results suggest temporary improvement, methodologic limitations, including small sample size, lack of blinded assessment, and use of validated outcome measure, limit the interpretation of these RCTs.
 
Anal Fissure
Chronic anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the IAS and is treated surgically with an internal sphincterotomy. Because the anal sphincter contraction could be characterized as a dystonia, botulinum toxin is a logical medical approach.
 
In 1998, Maria et al randomized 30 patients with chronic anal fissure to 2 injections of botulinum toxin type A, on either side of the fissure, or 2 injections of saline (Maria, 1998). After 2 months, 11 (73%) patients in the treated group and 2 (13%) patients in the control group had healed fissures (p=0.003); 13 (87%) patients in the treated group and 4 (26%) in the control group had symptomatic relief (p=0.003). Four patients in the treated group were later retreated. No relapses occurred during an average of 16 months of follow-up. Nitroglycerin ointment has also been used to successfully treat anal fissure. In 1999, Brisinda et al in Italy compared the results of nitroglycerin ointment with botulinum toxin type A in a randomized trial of 50 patients (Brisinda, 1999). After 2 months, 96% of the fissures were healed in the botulinum group compared with 60% in the nitroglycerin group. Brisinda et al conducted a second, similar trial in 2007 and reported 92% healing rates for botulinum toxin type A and 70% for nitroglycerin ointment (p<0.001) (Brisinda, 2007). Another trial by Brisinda et al (2004) found that 2 botulinum type A formulations (onabotulinumtoxinA, abobotulinumtoxinA) used to treat anal fissures were similar in terms of efficacy and tolerability (Brisinda, 2004). Others have reported both supportive (De Nardi, 2006) and contradictory (Fruehauf, 2006) data from randomized trials comparing the same treatments. RCTs of botulinum toxin vs sphincterotomy, and a meta-analysis of these studies, have reported significantly better healing rates with sphincterotomy, but authors concluded that botulinum toxin was a viable first option for patients who are not good surgical candidates or who want to minimize the likelihood of incontinence (Iswariah, 2005; Nasr, 2010, Chen, 2014).
 
UROLOGIC APPLICATIONS
Overactive Bladder and Neurogenic Detrusor Overactivity
Several meta-analyses of RCTs have been published on overactive bladder and neurogenic detrusor overactivity (Cui, 2013; Cui 2015; Duthie, 2011). Drake et al (2017) reported on the results of a network meta-analysis of 56 RCTs that compared the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (Drake, 2017). While all treatments were more efficacious than placebo after 12 weeks, patients who received onabotulinumtoxinA (100 U) reported the greatest reductions in urinary incontinence episodes, urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and 50% or greater from baseline in urinary incontinence episodes per day. The exclusion of studies with a high risk of bias had little impact on the conclusions. Freemantle et al (2016) also reported on the results of a network meta-analysis of 19 RCTs comparing any licensed dose of onabotulinumtoxinA, mirabegron, anticholinergic drugs, or placebo (Freemantle, 2016). Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination, and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 mg and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency, and urination.
 
 
Other Urologic Issues
 
Detrusor Sphincter Dyssynergia
In 2002, de Seze et al studied 13 patients with chronic urinary retention due to detrusor sphincter dyssynergia from spinal cord disease (traumatic injury, multiple sclerosis, congenital malformations) who were randomized to perineal botulinum toxin type A or lidocaine injections into the external urethral sphincter (deSeze, 2002). In the botulinum group, there was a significant decrease in the primary outcome of postvoid residual volume compared with no change in the control group (lidocaine injection). Improvements were also seen in satisfaction scores and other urodynamic outcomes.
 
Systematic reviews have addressed treating detrusor sphincter dyssynergia with botulinum toxin injection. In 2012, Mehta et al conducted a meta-analysis on botulinum toxin injection as a treatment of detrusor external sphincter dysfunction and incomplete voiding after spinal cord injury (Mehta, 2012). Reviewers identified 2 RCTs and multiple uncontrolled studies. The RCTs included the de Seze study (discussed above) and a second study of 5 patients. A 2006 systematic review by Karsenty et al reviewed trials of botulinum toxin type A injected into the urethral sphincter to treat different types of lower urinary tract dysfunction, grouped into neurogenic detrusor sphincter dyssynergia and non-neurogenic obstructive sphincter dysfunction (Karsenty, 2006). In the former group, reviewers cited 10 small studies (N range, 3-53 patients; 3 studies included patients in both categories). Most patients were quadriplegic men unable to self-catheterize or patients (of both genders) with multiple sclerosis. All studies except two were case reports or case series; the two exceptions were controlled studies and were included in the Mehta meta-analysis. The authors of both reviews noted that, while most of the available studies have reported improvements with botulinum toxin injections, there are few published studies, and those published have small sample sizes.
 
Benign Prostatic Hyperplasia
The use of botulinum toxin to treat symptoms of benign prostatic hyperplasia (BPH) is premised in part on a static component related to prostate size and a dynamic component related to the contraction of smooth muscle within the gland. Botulinum therapy addresses this latter component. In 2012, Marchal et al published a systematic review on use of botulinum toxin to treat BPH (Marchal, 2012). Reviewers identified 25 studies, including controlled and uncontrolled studies and abstracts in journal supplements. There were 6 RCTs; three were published as full articles and three were published as abstracts (two RCTs were included in a meta-analysis). Reviewers reported that the mean postvoiding residue, both in pre- and posttreatment, did not differ significantly; pooled results were not reported for between-group outcomes. One of the RCTs, by Maria et al (2003), reported on 30 patients with BPH randomized to intraprostatic botulinum toxin type A or saline injection (Maria, 2003). Inclusion criteria were moderate-to-severe symptoms of BPH based on the American Urological Association score and a mean peak urinary flow rate of no more than 15 mL per second with a void volume of 150 mL or less. After 2 months, the American Urological Association symptom score decreased by 65% among those receiving botulinum toxin compared with no significant change in the control group. Mean peak urinary flow rate was significantly increased in the treatment group.
 
2019 Update
A literature search conducted through October 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
December 2019 Update
Hirschsprung Disease
Hirschsprung disease is a rare genetic birth defect that results in motor disorder of the gut due to failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during intestinal development during fetal life. The resulting aganglionic segment of the colon fails to relax, causing a functional obstruction.In a retrospective case series by Han-Geurts et al (2014), 33 children with surgically treated Hirschsprung disease treated with intrasphincteric botulinum toxin A injections for obstructive symptoms was analyzed with a retrospective chart review between 2002 and 2013 in the Netherlands. More than half of the patients reported good or excellent long-term outcomes after a median follow-up of 126 months. In a retrospective case series by Patrus et al (2011) outcomes in 22 patients with Hirschsprung disease treated over 10 years were reviewed. At the time of the chart review, 2 of 22 patients had persistent symptoms. Eighteen children had a “good response” to the initial treatment (not defined), and 15 (68%) had additional injections. It was noted that the number of hospitalizations for obstructive symptoms decreased significantly after onabotulinumtoxinA injection compared with preinjection.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Esophageal Achalasia
Wang et al conducted a meta-analysis of RCTs that compared the efficacy of different treatments for primary achalasia (Wang, 2009). Five RCTs compared botulinum toxin A injection with PD in patients with untreated achalasia, and also examined both subjective and objective parameters of esophageal improvement in all patients over 12 months. Authors reported that symptom remission rate was significantly higher in patients treated with PD vs botulinum toxin A injection (65.8% vs 36% respectively. Proportion of patients who relapsed within a year was 16.7% with PD vs 50% with botulinum toxin injection. Moreover, relapse time of botulinum toxin injection was shorter than that of PD after first therapy. Two RCTs compared efficacy of laparoscopic myotomy with botulinum toxin A injection in patients with untreated achalasia. Authors reported that the symptom remission rate of botulinum toxin injection rapidly decreased and nearly 50% of patients were symptomatic again after 1 year of treatment. Laparoscopic myotomy had superior efficacy to botulinum toxin injection (laparoscopic myotomy 83.3% vs botulinum toxin injection 64.9%, RR 1.28; 95% CI 1.02–1.59; P=0.03). Patients treated with onabotulinumtoxinA had more frequent relapse and shorter time to relapse than those treated with laparoscopic myotomy. Some limitations of this meta-analysis include small number of cohorts in each trial, poor randomization techniques, and inadequate follow-up.
 
While the evidence is suggestive that PD and surgical myotomy are definitive therapies for esophageal achalasia and associated with superior long-term outcomes compared with botulinum toxin A, in patients who are not good candidates for PD and/or surgical myotomy, botulinum toxin A may be a reasonable option. Further, botulinum toxin injection has the advantage of being less invasive as compared with surgery, can be easily performed during routine endoscopy. Initial success rates with botulinum toxin are comparable to PD and surgical myotomy (Wang, 2009). However, patients treated with botulinum toxin have more frequent relapses and a shorter time to relapse (Wang, 2009). Greater than 50% of patients with achalasia treated with botulinum toxin A require retreatment within 6 to 12 months. Repeated botulinum toxin injections may also make a subsequent Heller myotomy more challenging (Smith, 2006).
 
Chronic anal fissure
Chen et al compared outcomes of onabotulinumtoxinA injection with lateral internal sphincterotomy based on 7 RCTs (Chen, 2014). Treatment with botulinum toxin injection was associated with lower healing rate and a higher recurrence rate compared with lateral internal sphincterotomy. Sphincterotomy also resulted in higher complication rates but the difference was not statistically significant (p-value=0.35). The meta-analysis suggests that internal sphincterotomy is more effective to treat anal fissure but onabotulinumtoxinA injection was associated with lower rates of incontinence. Authors reported multiple limitations in the evidence pooled for the meta-analysis including various dose of onabotulinumtoxinA used in different trials, inconsistent definition of chronic anal fissure used in the RCTs and none of the included RCTs were blinded. In addition, results of included studies were not consistent. The total complication rate varied from 0 to 64 % among the trials, while the incontinence rate varied from 0 to 48%. Nelson et al published a Cochrane review that compared multiple treatment options for chronic anal fissure (Nelson, 2012). Reported results for comparison of botulinum toxin injection with sphincterotomy are consistent with those reported by Chen et al (Chen, 2014). Botulinum toxin A injection is therefore preferably used for patients who are at a high-risk of developing fecal incontinence (eg, multiparous women or older patients).
 
Interstitial Cystitis
Interstitial cystitis is a chronic condition characterized by pain, urgency, and frequent urination of small volumes. Intravesical injection of botulinum toxin A has been evaluated in patients with interstitial cystitis/bladder pain syndrome for patients with symptoms that significantly affect quality of life, who have failed other measures, and who are aware of and willing to accept the risk of adverse effects (Hanno, 2015).
 
A network meta-analysis of 16 trials including 905 patients published in 2016 indicated that botulinum toxin-A treatment had the highest probability of being the best treatment course based on global response assessment and significantly ameliorates bladder capacity in patients with interstitial cystitis (Zhang, 2017). However, botulinum toxin A showed no treatment advantages with regard to pain, urinary frequency, and urgency results. Wang et al who reported the findings of a systematic review that included 7 RCTs and a retrospective study on onabotulinumtoxinA and abobotulinumtoxinA rated only 1 of the 7 RCTs as high-quality (ie, low-risk of bias) while 5 were rated as moderate, and the other was rated as a high-risk of bias (Wang, 2016). Kuo et al reported the results of an RCT that included 60 Taiwanese patients (52 women, 8 men) with IC/painful bladder syndrome who had failed at least 6 months of conventional therapy (Kuo, 2016). In this trial, at a higher dose (200 units of botulinum toxin A), adverse reactions occurred in 9 of 15 patients (4 patients had acute or chronic urinary retention, 7 had severe dysuria) (Kuo, 2016). Later, the dose was decreased to 100 units that resulted in reduction of adverse events but they still occurred more frequent than hydrodistention alone.
 
Depression
Magid et al published a pooled analysis of individual patient data from 3 randomized trials evaluating injections of onabotulinumtoxinA in the glabellar region (forehead) for treating unipolar major depressive disorder as an adjunctive treatment (Magid, 2015; Wollmer, 2012; Finzi, 2014; Magid, 2014). The response rate (defined as ≥ 50% improvement from baseline scores in the depression score) was higher in the onabotulinumtoxinA group compared with placebo (54.2% vs 10.7%; OR=11.1; 95% CI 4.3 to 28.8). The respective remission rate (defined as score ≤ 7 for the Hamilton Depression Rating scales, ≤ 10 for the Montgomery-Asberg Depression Rating Scale) was 30.5% vs 6.7% (7.3; 95% CI, 2.4 to 22.5). While the effect size of the treatment observed in the pooled analysis and individual RCTs is clinically meaningful and large, there are multiple limitations that preclude drawing meaningful conclusions about net health benefit. Limitations in study design and conduct include potential of unblinding due to changes in cosmetic appearance, small sample size, lack of power analysis, short duration of follow-up in two out of three RCTs, lack of clarity on allocation concealment and lack of intention-to-treat analysis (Wollmer, 2012; Finzi, 2014; Magid, 2014). More importantly, patients with a history of major depressive order presenting with acute depression episode prior to enrollment in the trial were evaluated, it is unclear if botulinum toxin A treatment is intended to be used as a short-term treatment of a depressive episode or as a maintenance treatment for depression. Further, a large trial (NCT02116361) with 258 patients to evaluate the efficacy of OnabotulinumtoxinA as treatment for major depressive disorder in adult females was completed in 2016 but has not been published which raises concerns about potential for publication bias.
 
American Urological Association
The American Urological Association guideline on non-neurogenic overactive bladder states, “clinicians may offer intradetrusor onabotulinumtoxinA (100U) as third-line treatment in the carefully-selected and thoroughly-counseled patient who has been refractory to first- and second-line overactive bladder treatments. The patient must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary. Standard (Evidence Strength Grade B) (Lightner, 2019).”
 
American Pediatric Surgical Association
The American Pediatric Surgical Association published guidelines based on group discussions, literature review and expert consensus for the management of postoperative obstructive symptoms in children with Hirschsprung disease. These guidelines recommend that if there is no mechanical obstruction and rectal biopsy is normal, botulinum toxin injection into the internal anal sphincter should be tried. If a patient shows significant improvement, the patient can receive botulinum toxin injection every 3–6 months as many times as necessary depending on symptoms. In most cases, the symptoms will gradually improve with age (Langer, 2017).
 
2020 Update
The efficacy and safety of BOTOX for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 1 (NCT01603602), a randomized, multi-center, double-blind, placebo-controlled study. Study 1 included 234 pediatric patients (78 BOTOX 3 Units/kg, 77 BOTOX 6 Units/kg, and 79 placebo) with upper limb spasticity (modified Ashworth Scale elbow or wrist score of at least 2) because of cerebral palsy or stroke. A total dose of 3 Units/kg BOTOX (maximum 100 Units), 6 Units/kg BOTOX (maximum 200 Units), or placebo was injected intramuscularly and divided between the elbow or wrist and finger muscles. Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection.
 
The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) principal muscle group score (elbow or wrist) at Week 4 and Week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement).
 
Compared to placebo, significant improvements in MAS change from baseline were observed at all timepoints for BOTOX-treated patients. Although CGI scores numerically favored BOTOX over placebo, the difference was not statistically significant. (FDA, 2020)
 
The efficacy and safety of BOTOX for the treatment of lower limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 2 (NCT01603628), a randomized, multi-center, double-blind, placebo-controlled study. Study 2 included 381 pediatric patients (125 BOTOX 4 Units/kg, 127 BOTOX 8 Units/kg, and 129 placebo) with lower limb spasticity (modified Ashworth Scale ankle score of at least 2). A total dose of 4 Units/kg BOTOX (maximum 150 Units), 8 Units/kg BOTOX (maximum 300 Units), or placebo was injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior. Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection.
 
The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) ankle score at Week 4 and Week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement).
 
Compared to placebo, improvements in mean change from baseline for the MAS, and mean CGI score for lower limb spasticity were observed at timepoints up to Week 12 for BOTOX-treated patients. (FDA, 2020)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement.
 
May 2022 Update
Chen et al (2015) summarized the evidence assessing the efficacy of botulinum toxin A for treatment of temporomandibular joint disorders in a systematic review that included 5 RCTs. Sample size in majority of trials was 30 or less except for 1. Three of the 5 studies were judged to be at high-risk of bias. All studies administered a single injection of onabotulinumtoxinA or abobotulinumtoxinA and followed patients up at least 1 month later. Four studies used a placebo (normal saline) control group and the fifth used abobotulinumtoxinA to fascial manipulation. Data were not pooled due to heterogeneity among trials. In a qualitative review of the studies, 2 of the 5 trials found a significant short-term (1-2 months) benefit of onabotulinumtoxinA compared with control on pain reduction.
 
October 2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
The efficacy of DAXXIFY was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in a total of 301 patients (NCT03608397). The mean age of patients was 58 years, 65% were women, and 96% were White. At study baseline, 84% of patients had previously received a botulinum toxin as treatment for cervical dystonia. Patients had a clinical diagnosis of cervical dystonia with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, TWSTRS severity score ≥15, TWSTRS disability score ≥3, and TWSTRS pain score ≥1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥14 weeks had passed since the most recent botulinum toxin administration.
 
Patients were randomized (3:3:1) to receive a single administration of 2.5 mL of either DAXXIFY 125 Units (n=125), DAXXIFY 250 Units (n=130), or placebo (n=46), divided amongst the affected muscles as selected by the investigator.
 
The primary efficacy endpoint was the mean change in the TWSTRS total score from baseline averaged over weeks 4 and 6. TWSTRS evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain, with a range of possible scores from 0 to 85. The mean change from baseline in the total TWSTRS score was significantly greater for both dosage groups of DAXXIFY than for placebo. (FDA, 2023)

CPT/HCPCS:
31513Laryngoscopy, indirect; with vocal cord injection
31570Laryngoscopy, direct, with injection into vocal cord(s), therapeutic;
31571Laryngoscopy, direct, with injection into vocal cord(s), therapeutic; with operating microscope or telescope
43201Esophagoscopy, flexible, transoral; with directed submucosal injection(s), any substance
43236Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection(s), any substance
46505Chemodenervation of internal anal sphincter
52287Cystourethroscopy, with injection(s) for chemodenervation of the bladder
53899Unlisted procedure, urinary system
64612Chemodenervation of muscle(s); muscle(s) innervated by facial nerve, unilateral (eg, for blepharospasm, hemifacial spasm)
64615Chemodenervation of muscle(s); muscle(s) innervated by facial, trigeminal, cervical spinal and accessory nerves, bilateral (eg, for chronic migraine)
64616Chemodenervation of muscle(s); neck muscle(s), excluding muscles of the larynx, unilateral (eg, for cervical dystonia, spasmodic torticollis)
64642Chemodenervation of one extremity; 1 4 muscle(s)
64643Chemodenervation of one extremity; each additional extremity, 1 4 muscle(s) (List separately in addition to code for primary procedure)
64644Chemodenervation of one extremity; 5 or more muscles
64645Chemodenervation of one extremity; each additional extremity, 5 or more muscles (List separately in addition to code for primary procedure)
64646Chemodenervation of trunk muscle(s); 1 5 muscle(s)
64647Chemodenervation of trunk muscle(s); 6 or more muscles
64650Chemodenervation of eccrine glands; both axillae
64653Chemodenervation of eccrine glands; other area(s) (eg, scalp, face, neck), per day
64999Unlisted procedure, nervous system
67345Chemodenervation of extraocular muscle
92265Needle oculoelectromyography, 1 or more extraocular muscles, 1 or both eyes, with interpretation and report
95869Needle electromyography; thoracic paraspinal muscles (excluding T1 or T12)
95873Electrical stimulation for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
95874Needle electromyography for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
J0585Injection, onabotulinumtoxina, 1 unit
J0586Injection, abobotulinumtoxina, 5 units
J0587Injection, rimabotulinumtoxinb, 100 units
J0588Injection, incobotulinumtoxin a, 1 unit
S2341Chemodenervation of adductor muscle(s) of vocal cord

References: AACPDM Sialorrhea Care Pathway Team: L Glader (team lead), C Delsing, A Hughes, J Parr, L Pennington, D Reddihough, K van Hulst, J van der Burg.(2017) Sialorrhea in Cerebral Palsy. 2017. Available at: https://www.aacpdm.org/publications/care-pathways/sialorrhea

Abbott JA, Jarvis SK, Lyons SD, et al.(2006) Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. Oct 2006;108(4):915-923.

Allergan.(2018) “BOTOX Treatment in Pediatric Upper Limb Spasticity: Double-Blind Study.” Clinicaltrials.Gov, 16 July 2018, linicaltrials.gov/ct2/show/results/NCT01603605&draw=2&rank=1. Accessed 9 Oct. 2020

American Academy of Neurology.(2017) 2010 Pharmacologic Treatment of Spasticity in Children and Adolescents with Cerebral Palsy. Reaffirmed 2013. 2017 Available online at https://www.aan.com/Guidelines/. Accessed September 11, 2017.

American Academy of Neurology.(2017) 2011 Update: Treatment of Essential Tremor. Reaffirmed on April 30, 2014 Available online at https://www.aan.com/Guidelines/. Accessed September 11, 2017.

American Urological Association (AUA), Hanno PH, Burks DA, et al.(2017) Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome. 2011; amended 2014 Available online at https://www.auanet.org/education/guidelines/ic-bladder-pain-syndrome.cfm. Accessed October 16, 2017.

American Urological Association (AUA).(2015) Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. 2012, amended in 2014 Available online at http://www.auanet.org/education/guidelines/overactive-bladder.cfm. Accessed July 30, 2015.

Amundsen CL, Richter HE, Menefee SA, et al.(2016) OnabotulinumtoxinA vs sacral neuromodulation on refractory urgency urinary incontinence in women: a randomized clinical trial. JAMA. Oct 04 2016;316(13):1366-1374.

Anandasabapathy S, Sontag S, Graham DY, et al.(2011) Computer-assisted brush-biopsy analysis for the detectionof dysplasia in a high-risk Barrett's esophagus surveillance population. Dig Dis Sci. 2011; 56(3):761-766.

Arts J, Holvoet L, Caenepeel P, et al.(2007) Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther. Nov 1 2007;26(9):1251-1258.

Aurora SK, Dodick DW, Turkel CC, et al.(2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. Jul 2010;30(7):793-803.

Bai Y, Xu MJ, Yang X, et al.(2010) A systematic review on intrapyloric botulinum toxin injection for gastroparesis. Digestion. Dec 2010;81(1):27-34.

Baker JA, Pereira G.(2013) The efficacy of botulinum toxin A for spasticity and pain in adults: a systematic review and meta-analysis using the Grades of Recommendation, Assessment, Development and Evaluation approach. Clin Rehabil. Dec 2013;27(12):1084-1096.

Baker JA, Pereira G.(2016) The efficacy of Botulinum Toxin A for limb spasticity on improving activity restriction and quality of life: a systematic review and meta-analysis using the GRADE approach. Clin Rehabil. Jun 2016;30(6):549-558.

Blue Cross Blue Shield Association Technology Evaluation Center (TEC).(1996) Botulinum-A toxin for treatment of chronic spasticity. TEC Assessments 1996;Volume 11, Tab 6.

Blue Cross Blue Shield Association Technology Evaluation Center (TEC).(2004) Botulinum toxin for treatment of primary chronic headache disorders. TEC Assessments. 2004;Volume 19, Tab 10.

Braker C, Yariv S, Adler R, et al.(2008) The analgesic effect of botulinum-toxin A on postwhiplash neck pain. Clin J Pain. Jan 2008;24(1):5-10.

Brin MF, Lyons KE, Doucette J, et al.(2001) A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology. Jun 12 2001;56(11):1523-1528.

Brisinda G, Albanese A, Cadeddu F, et al. (2004) Botulinum neurotoxin to treat chronic anal fissure: results of a randomized "Botox vs. Dysport" controlled trial. Aliment Pharmacol Ther. Mar 15 2004;19(6):695-701

Brisinda G, Cadeddu F, Brandara F, et al.(2007) Randomized clinical trial comparing botulinum toxin injections with 0.2 per cent nitroglycerin ointment for chronic anal fissure. Br J Surg. Feb 2007;94(2):162-167.

Brisinda G, Maria G, Bentivoglio AR, et al.(1999) A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med. Jul 8 1999;341(2):65-69.

Cady RK, Schreiber CP, Porter JA, et al.(2011) A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache. Jan 2011;51(1):21-32.

Chan KH, Liang C, Wilson P, et al.(2013) Long-term safety and efficacy data on botulinum toxin type A: an injection for sialorrhea. JAMA Otolaryngol Head Neck Surg. Feb 2013;139(2):134-138.

Chapple C, Sievert KD, Macdiarmid S, et al.(2013) OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled tria. Eur Urol. Aug 2013;64(2):249-256.

Chen HL, Woo XB, Wang HS, et al.(2014) Botulinum toxin injection versus lateral internal sphincterotomy for chronic anal fissure: a meta-analysis of randomized control trials. Tech Coloproctol. Aug 2014;18(8):693-698.

Chen YW, Chiu YW, Chen CY, et al.(2015) Botulinum toxin therapy for temporomandibular joint disorders: a systematic review of randomized controlled trials. Int J Oral Maxillofac Surg. Aug 2015; 44(8): 1018-26. PMID 25920597

Chen YW, Chiu YW, Chen CY, et al.(2015) Botulinum toxin therapy for temporomandibular joint disorders: a systematic review of randomized controlled trials. Int J Oral Maxillofac Surg. Aug 2015;44(8):1018-1026

Cheng T, Shuang WB, Jia DD, et al.(2016) Efficacy and safety of onabotulinumtoxinA in patients with neurogenic detrusor overactivity: a systematic review and meta-analysis of randomized controlled trials. PLoS One. Jul 2016;11(7):e0159307.

Comella C, Barbano R, Singer C, et.al.,(2023) Efficacy and Safety of DaxibotulinumtoxinA for Injection Over Successive Treatments in Adults With Cervical Dystonia in the Phase 3 ASPEN-1 and ASPEN-OLS Trials. Neurology Apr 2023, 100 (17 Supplement 2) 3566; DOI: 10.1212/WNL. 0000000000203363

Cordivari C, Misra VP, Vincent A, et al.(2006) Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test. Mov Disord. Oct 2006;21(10):1737-1741.

Cui Y, Wang L, Liu L, et al.(2013) Botulinum toxin-A injections for idiopathic overactive bladder: a systematic review and meta-analysis. Urol Int. Aug 2013;91(4):429-438.

Cui Y, Zhou X, Zong H, et al.(2015) The efficacy and safety of onabotulinumtoxinA in treating idiopathic OAB: A systematic review and meta-analysis. Neurourol Urodyn. Jun 2015;34(5):413-419.

Dashtipour K, Chen JJ, Frei K, et al.(2015) Systematic literature review of AbobotulinumtoxinA in clinical trials for blepharospasm and hemifacial spasm. Tremor Other Hyperkinet Mov (N Y). 2015;5:338.

Dashtipour K, Chen JJ, Walker HW, et al.(2015) Systematic literature review of abobotulinumtoxinA in clinical trials for adult upper limb spasticity. Am J Phys Med Rehabil. Mar 2015;94(3):229-238.

Daxxify package insert. Newark, CA. Revance Therapeutics, Inc.

De Nardi P, Ortolano E, Radaelli G, et al.(2006) Comparison of glycerine trinitrate and botulinum toxin-a for the treatment of chronic anal fissure: long-term results. Dis Colon Rectum. Apr 2006;49(4):427-432.

de Seze M, Petit H, Gallien P, et al.(2002) Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol. Jul 2002;42(1):56-62.

Delgado MR, Bonikowski M, Carranza J, et al.(2017) Safety and Efficacy of Repeat Open-Label AbobotulinumtoxinA Treatment in Pediatric Cerebral Palsy. J Child Neurol. 2017 Nov;32(13):1058-1064. doi: 10.1177/0883073817729918. Epub 2017 Sep 15.

Delgado MR, Tilton A, Russman B, et al. (2016) AbobotulinumtoxinA for equinus foot deformity in cerebral palsy: a randomized controlled trial. Pediatrics. Feb 2016;137(2):e20152830.

Delgado MR, Tilton A, Russman B, et al.(2016) AbobotulinumtoxinA for equinus foot deformity in cerebral palsy: a randomized controlled trial. Pediatrics. Feb 2016;137(2):e20152830. PMID 26812925

Desai MJ, Shkolnikova T, Nava A, et al.(2014) A critical appraisal of the evidence for botulinum toxin type A in the treatment for cervico-thoracic myofascial pain syndrome. Pain Pract. Feb 2014;14(2):185-195.

Diener HC, Dodick DW, Aurora SK, et al.(2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. Jul 2010;30(7):804-814.

Dodick DW, Turkel CC, DeGryse RE, et al.(2010) OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. Jun 2010;50(6):921-936.

Dong Y, Wu T, Hu X, et al.(2017) Efficacy and safety of botulinum toxin type A for upper limb spasticity after stroke or traumatic brain injury: a systematic review with meta-analysis and trial sequential analysis. Eur J Phys Rehabil Med. Apr 2017;53(2):256-267.

Drake MJ, Nitti VW, Ginsberg DA, et al.(2017) Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis. BJU Int. Nov 2017;120(5):611-622.

Duarte GS, Castelao M, Rodrigues FB, et al.(2016) Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev. Oct 26 2016;10:CD004314.

Duthie JB, Vincent M, Herbison GP, et al.(2011) Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst Rev. Dec 07 2011(12):CD005493.

Dutton JJ, White JJ, Richard MJ.(2006) Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg. May-Jun 2006;22(3):173-177.

Dykstra DD, Presthus J.(2006) Botulinum toxin type A for the treatment of provoked vestibulodynia: an open-label, pilot study. J Reprod Med. Jun 2006;51(6):467-470.

Emile SH, Elfeki HA, Elbanna HG, et al.(2016) Efficacy and safety of botulinum toxin in treatment of anismus: A systematic review. World J Gastrointest Pharmacol Ther. Aug 06 2016;7(3):453-462.

Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, Smith CP, Ward AB.(2013) Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013 Jun 1;67:115-28.

Farid M, El Monem HA, Omar W, et al.(2009) Comparative study between biofeedback retraining and botulinum neurotoxin in the treatment of anismus patients. Int J Colorectal Dis. Jan 2009;24(1):115-120.

Farid M, Youssef T, Mahdy T, et al.(2009) Comparative study between botulinum toxin injection and partial division of puborectalis for treating anismus. Int J Colorectal Dis. Mar 2009;24(3):327-334.

Finzi E, Rosenthal NE.(2014) Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. J Psychiatr Res. May 2014;52:1-6. PMID 24345483

Foley N, Pereira S, Salter K, et al.(2013) Treatment with botulinum toxin improves upper-extremity function post stroke: a systematic review and meta-analysis. Arch Phys Med Rehabil. May 2013;94(5):977-989.

Food and Drug Administration (FDA).(2017) Information for Healthcare Professionals: OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc). 2009; Available online at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformationforheathcareprofessionals/ucm174949.htm. Accessed October 18, 2017.

Food and Drug Administration (FDA).(2019) Information for Healthcare Professionals: OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc). 2009; https://wayback.archive-it.org/7993/20170406044653/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm. Accessed October 24, 2019.

Food and Drug Administration (FDA).(2020) (2020) Botox. Available online at https://www.accessdata.fda.gov/drugsatfda_docs/lable/2019/1030000s5310lbl.pdf. Accessed September 13, 2021

Food and Drug Administration (FDA).(2020) Botox. Available online at https://www.accessdata.fda.gov/drugsatfda_docs/lable/2019/1030000s5310lbl.pdf. Accessed October 9, 2020.

Foster L, Clapp L, Erickson M, et al.(2001) Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology. May 22 2001;56(10):1290-1293.

Freemantle N, Ginsberg DA, McCool R, et al.(2016) Comparative assessment of onabotulinumtoxinA and mirabegron for overactive bladder: an indirect treatment comparison. BMJ Open. Feb 23 2016;6(2):e009122.

Freund BJ, Schwartz M.(2000) Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot study. Headache. Mar 2000;40(3):231-236.

Friedenberg FK, Palit A, Parkman HP, et al.(2008) Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol. Feb 2008;103(2):416-423.

Friedmacher F, Puri P.(2012) Comparison of posterior internal anal sphincter myectomy and intrasphincteric botulinum toxin injection for treatment of internal anal sphincter achalasia: a meta-analysis. Pediatr Surg Int. Aug 2012;28(8):765-771.

Fruehauf H, Fried M, Wegmueller B, et al.(2006) Efficacy and safety of botulinum toxin a injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure: a prospective randomized study. Am J Gastroenterol. Sep 2006;101(9):2107-2112.

Garza, I. and Schwedt, TJ.(2021) Chronic Migraines: Management. 2021. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed September 22, 2021)

Gassner HG, Brissett AE, Otley CC, et al.(2006) Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc. Aug 2006;81(8):1023-1028.

Ginsberg D, Gousse A, Keppenne V, et al.(2012) Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. Jun 2012;187(6):2131-2139.

Gonzalez LM, Martinez C, Bori YFI, et al.(2017) Factors in the Efficacy, Safety, and Impact on Quality of Life for Treatment of Drooling with Botulinum Toxin Type A in Patients with Cerebral Palsy. Am J Phys Med Rehabil. Feb 2017;96(2):68-76.

Goschel H, Wohlfarth K, Frevert J, et al.(1997) Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies--therapeutic consequences. Exp Neurol. Sep 1997;147(1):96-102.

Gracies JM, Brashear A, Jech R, et al.(2015) Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol. Oct 2015;14(10):992-1001.

Han-Geurts IJ, Hendrix VC, de Blaauw I, et. al.(2014) Outcome after anal intrasphincteric Botox injection in children with surgically treated Hirschsprung diease J Pediatr Gastroenterol Nutr. Nov 2014;59(5):604-607. PMID 25000353

Hanna PA, Jankovic J.(1998) Mouse bioassay versus Western blot assay for botulinum toxin antibodies: correlation with clinical response. Neurology. Jun 1998;50(6):1624-1629

Hanno PM, Erickson D, Moldwin R, et al.(2015) Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. May 2015;193(5):1545-1553. PMID 25623737

Headache Classification Committee of the International Headache Society.(2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. Jul 2013;33(9):629-808.

Herrmann J, Geth K, Mall V, et al.(2004) Clinical impact of antibody formation to botulinum toxin A in children. Ann Neurol. May 2004;55(5):732-735.

Hsiung GY, Das SK, Ranawaya R, et al.(2002) Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. Nov 2002;17(6):1288-1293.

Hyman N(2004) Botulinum toxin for focal dystonia. Pract Neurol 2004;4(1):30-35.

Int Urogynecol J. Oct 2010;21(10):1285-1300.(2015) Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response. Int J Urol. Sep 2015;22(9):835-841.

Iswariah H, Stephens J, Rieger N, et al.(2005) Randomized prospective controlled trial of lateral internal sphincterotomy versus injection of botulinum toxin for the treatment of idiopathic fissure in ano. ANZ J Surg. Jul 2005;75(7):553-555.

Jackson JL, Kuriyama A, Hayashino Y.(2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. Apr 25 2012;307(16):1736-1745.

Jankovic J, Schwartz K, Clemence W, et al.(1996) A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord. May 1996;11(3):250-256.

Jankovic J.(2009) Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm. Eur J Neurol. Dec 2009;16 Suppl 2:14-18.

Jarvis SK, Abbott JA, Lenart MB, et al.(2004) Pilot study of botulinum toxin type A in the treatment of chronic pelvic pain associated with spasm of the levator ani muscles. Aust N Z J Obstet Gynaecol. Feb 2004;44(1):46-50.

Johanson JF, Frakes J, Eisen D.(2011) Computer-assisted analysis of abrasive transepithelial brush biopsies increases the effectiveness of esophageal screening: a multicenter prospective clinical trial by the EndoCDx Collaborative Group. Dig Dis Sci. 2011; 56(3):767-772.

Kanovsky P, Slawek J, Denes Z, et al.(2009) Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol. Sep-Oct 2009;32(5):259-265.

Kanovsky P, Slawek J, Denes Z, et al.(2011) Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. J Rehabil Med. May 2011;43(6):486-492.

Karsenty G, Baazeem A, Elzayat E, et al.(2006) Injection of botulinum toxin type A in the urethral sphincter to treat lower urinary tract dysfunction: a review of indications, techniques and results. Can J Urol. Apr 2006;13(2):3027-3033.

Karsenty G, Denys P, Amarenco G, et al.(2008) Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review. Eur Urol. Feb 2008;53(2):275-287.

Koivusalo AI, Pakarinen MP, Rintala RJ.(2009) Botox injection treatment for anal outlet obstruction in patients with internal anal sphincter achalasia and Hirschsprung's disease. Pediatr Surg Int. Oct 2009;25(10):873-876.

Koman LA, Brashear A, Rosenfeld S, et al.(2001) Botulinum toxin type a neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial. Pediatrics. Nov 2001;108(5):1062-1071.

Krogh TP, Bartels EM, Ellingsen T, et al.(2013) Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials. Am J Sports Med. Jun 2013;41(6):1435-1446.

Kuo HC, Jiang YH, Tsai YC, et al.(2016) Intravesical botulinum toxin-A injections reduce bladder pain of interstitial cystitis/bladder pain syndrome refractory to conventional treatment - A prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. Neurourol Urodyn. Jun 2016;35(5):609-614.

Lagalla G, Millevolte M, Capecci M, et al.(2006) Botulinum toxin type A for drooling in Parkinson's disease: a double-blind, randomized, placebo-controlled study. Mov Disord. May 2006;21(5):704-707.

Langer JC, Rollins MD, Levitt M, et al.(2017) Guidelines for the management of postoperative obstructive symptoms in children with Hirschsprung disease. Pediatr Surg Int. May 2017;33(5):523-526. PMID 28180937

Langevin P, Lowcock J, Weber J, et al.(2011) Botulinum toxin intramuscular injections for neck pain: a systematic review and metaanalysis. J Rheumatol. Feb 2011;38(2):203-214.

Lee J, Harris S, Cohen J, et al.(1994) Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. J Pediatr Ophthalmol Strabismus. Sep-Oct 1994;31(5):283-286.

Leyden JE, Moss AC, MacMathuna P.(2014) Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia. Cochrane Database Syst Rev. 2014;12(12):CD005046.

Lightner DJ, Gomelsky A, Souter L, et al.(2019) Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment 2019. J Urol. Sep 2019;202(3):558-563. PMID 31039103

Lin YC, Wu WT, Hsu YC, et al.(2017) Comparative effectiveness of botulinum toxin versus non-surgical treatments for treating lateral epicondylitis: a systematic review and meta-analysis. Clin Rehabil. Mar 01 2017:269215517702517.

Linde M, Hagen K, Salvesen O, et al.(2011) Onabotulinum toxin A treatment of cervicogenic headache: a randomised, double-blind, placebo-controlled crossover study. Cephalalgia. May 2011;31(7):797-807.

Magid M, Finzi E, Kruger TH, et al.(2015) Treating depression with botulinum toxin: a pooled analysis of randomized controlled trial. Pharmacopsychiatry. Sep 2015;48(6):205-210.

Magid M, Reichenberg JS, Poth PE, et al.(2014) Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry. Aug 2014;75(8):837-844. PMID 24910934

Mahant N, Clouston PD, Lorentz IT.(2000) The current use of botulinum toxin. J Clin Neurosci 2000;7(5):389-394.

Mahowald ML, Singh JA, Dykstra D.(2006) Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res. Apr 2006;9(2-3):179-188.

Mancini F, Zangaglia R, Cristina S, et al.(2003) Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism. Mov Disord. Jun 2003;18(6):685-688.

Manning J, Dwyer P, Rosamilia A, et al.(2014) A multicentre, prospective, randomised, double-blind study to measure the treatment effectiveness of abobotulinum A (AboBTXA) among women with refractory interstitial cystitis/bladder pain syndrome. Int Urogynecol J. May 2014;25(5):593-599.

Marchal C, Perez JE, Herrera B, et al.(2012) The use of botulinum toxin in benign prostatic hyperplasia. Neurourol Urodyn. Jan 2012;31(1):86-92.

Maria G, Brisinda G, Civello IM, et al.(2003) Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology. Aug 2003;62(2):259-264; discussion 264-255.

Maria G, Cassetta E, Gui D, et al.(1998) A comparison of botulinum toxin and saline for the treatment of chronic anal fissure. N Engl J Med. Jan 22 1998;338(4):217-220.

Marques RE, Duarte GS, Rodrigues FB, et al.(2016) Botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev. May 13 2016(5):CD004315.

Marsh WA, Monroe DM, Brin MF, et al.(2014) Systematic review and meta-analysis of the duration of clinical effect of onabotulinumtoxinA in cervical dystonia. BMC Neurol. Apr 27 2014;14:91

Mathew NT, Frishberg BM, Gawel M, et al.(2005) Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. Apr 2005;45(4):293-307.

Mehta S, Hill D, Foley N, et al.(2012) A meta-analysis of botulinum toxin sphincteric injections in the treatment of incomplete voiding after spinal cord injury. Arch Phys Med Rehabil. Apr 2012;93(4):597-603.

Mehta S, Hill D, McIntyre A, et al.(2013) Meta-analysis of botulinum toxin A detrusor injections in the treatment of neurogenic detrusor overactivity after spinal cord injury. Arch Phys Med Rehabil. Aug 2013;94(8):1473-1481.

Mejia NI, Vuong KD, Jankovic J.(2005) Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord. May 2005;20(5):592-597.

Minkes RK, Langer JC.(2000) A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung's disease. J Pediatr Surg. Dec 2000;35(12):1733-1736.

Mittal SO, Machado D, Richardson D, et al.(2017) Botulinum toxin in Parkinson disease tremor: a randomized, double-blind, placebo-controlled study with a customized injection approach. Mayo Clin Proc. Sep 2017;92(9):1359-1367.

Morra ME, Elgebaly A, Elmaraezy A, et al.(2016) Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials. J Headache Pain. Dec 2016;17(1):63.

Nasr M, Ezzat H, Elsebae M.(2010) Botulinum toxin injection versus lateral internal sphincterotomy in the treatment of chronic anal fissure: a randomized controlled trial. World J Surg. Nov 2010;34(11):2730-2734.

Naumann M, So Y, Argoff CE, et al.(2008) 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. May 6 2008;70(19):1707-1714.

Naumann M, So Y, Argoff CE, et al.(2008) 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. May 6 2008;70(19):1707-1714.

Naumann M, Toyka KV, Mansouri Taleghani B, et al.(1998) Depletion of neutralising antibodies resensitises a secondary non-responder to botulinum A neurotoxin. J Neurol Neurosurg Psychiatry. Dec 1998;65(6):924-927.

Nelson RL, Thomas K, Morgan J, et al.(2012) Non surgical therapy for anal fissure. Cochrane Database Syst Rev. Feb 15 2012(2):CD003431. PMID 22336789

Nicol AL, Wu, II, Ferrante FM.(2014) Botulinum toxin type a injections for cervical and shoulder girdle myofascial pain using an enriched protocol design. Anesth Analg. Jun 2014;118(6):1326-1335.

Nitti VW, Dmochowski R, Herschorn S, et al.(2013) OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol. Jun 2013;189(6):2186-2193.

Nitti VW, Dmochowski R, Herschorn S, et al.(2017) OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol. Feb 2017;197(2S):S216-S223.

Nussgens Z, Roggenkamper P.(1997) Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol. Apr 1997;235(4):197-199.

Ondo WG, Hunter C, Moore W.(2004) A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease. Neurology. Jan 13 2004;62(1):37-40.

Ondo WG, Vuong KD, Derman HS.(2004) Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia. Jan 2004;24(1):60-65.

Padberg M, de Bruijn SF, Tavy DL.(2007) Neck pain in chronic whiplash syndrome treated with botulinum toxin. A double-blind, placebo-controlled clinical trial. J Neurol. Mar 2007;254(3):290-295.

Patrus B, Nasr A, Langer JC, et al.(2011) Intrasphincteric botulinum toxin decreases the rate of hospitalization for postoperative obstructive symptoms in children with Hirschsprung disease. J Pediatr Surg. Jan 2011;46(1):184-187.

Patrus B, Nasr A, Langer JC, et. al.(2011) Intrasphincteric botulinum toxin decreases the rate of hospitalization for postoperative obstructive symptoms in children with Hirschsprung disease J Pediatr Surg. Jan 2011;46(1):184-187. PMID 21238663

Patti R, Almasio PL, Arcara M, et al.(2006) Botulinum toxin vs. topical glyceryl trinitrate ointment for pain control in patients undergoing hemorrhoidectomy: a randomized trial. Dis Colon Rectum. Nov 2006;49(11):1741-1748.

Patti R, Almasio PL, Muggeo VM, et al.(2005) Improvement of wound healing after hemorrhoidectomy: a double-blind, randomized study of botulinum toxin injection. Dis Colon Rectum. Dec 2005;48(12):2173-2179.

Pearce LB, Borodic GE, First ER, et al(1994) Measurement of botulinum toxin activity: evaluation of the lethality assay. Toxicol Appl Pharmacol. Sep 1994;128(1):69-77.

Peloso P, Gross A, Haines T, et al.(2007) Medicinal and injection therapies for mechanical neck disorders. Cochrane Database Syst Rev. Jul 18 2007(3):CD000319.

Quality Standards Subcommittee of the American Academy of N, the Practice Committee of the Child Neurology S, Delgado MR, et al.(2010) Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. Jan 26 2010;74(4):336-343.

Reid SM, Johnstone BR, Westbury C, et al.(2008) Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders. Dev Med Child Neurol. Feb 2008;50(2):123-128.

Rodwell K, Edwards P, Ware RS, et al.(2012) Salivary gland botulinum toxin injections for drooling in children with cerebral palsy and neurodevelopmental disability: a systematic review. Dev Med Child Neurol. Nov 2012;54(11):977-987.

Roggenkamper P, Jost WH, Bihari K, et al.(2006) Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm. Mar 2006;113(3):303-312.

Rowe FJ, Noonan CP.(2012) Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev. Feb 15 2012;2(2):CD006499.

Sankhla C, Jankovic J, Duane D.(1998) Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord. Jan 1998;13(1):150-154.

Shamliyan TA, Kane RL, Taylor FR.(2013) Migraine in Adults: Preventive Pharmacologic Treatments (Comparative Effectiveness Review No. 103). Rockville MD: Agency for Healthcare Research and Quality; 2013.

Shaw LC, Price CI, van Wijck FM, et al.(2011) Botulinum Toxin for the Upper Limb after Stroke (BoTULS) Trial: effect on impairment, activity limitation, and pain. Stroke. May 2011;42(5):1371-1379.

Shehata HS, El-Tamawy MS, Shalaby NM, et al.(2013) Botulinum toxin-type A: could it be an effective treatment option in intractable trigeminal neuralgia? J Headache Pain. Nov 19 2013;14:92.

Shribman S, Reid E, Crosby AH, et al.(2019) Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 2019; 18:1136.

Shuhendler AJ, Lee S, Siu M, et al.(2009) Efficacy of botulinum toxin type A for the prophylaxis of episodic migraine headaches: a meta-analysis of randomized, double-blind, placebo-controlled trials. Pharmacotherapy. Jul 2009;29(7):784-791.

Sievert KD, Chapple C, Herschorn S, et al.(2014) OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder. Int J Clin Pract. Oct 2014;68(10):1246-1256.

Silberstein SD, Blumenfeld AM, Cady RK, et al.(2013) OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. Aug 15 2013;331(1-2):48-56.

Silberstein SD, Gobel H, Jensen R, et al.(2006) Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. Jul 2006;26(7):790-800.

Silberstein SD, Olesen J, Bousser MG, et al.(2005) The International Classification of Headache Disorders, 2nd Edition (ICHD-II)--revision of criteria for 8.2 Medication-overuse headache. Cephalalgia. Jun 2005;25(6):460-465.

Silberstein SD, Stark SR, Lucas SM, et al.(2005) Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. Sep 2005;80(9):1126-1137.

Simpson DM, Gracies JM, Graham HK, et al.(2008) Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. May 06 2008;70(19):1691-1698.

Simpson DM, Hallett M, Ashman EJ, et al.(2016) Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. May 10 2016;86(19):1818-1826.

Sims SE, Miller K, Elfar JC, et al.(2014) Non-surgical treatment of lateral epicondylitis: a systematic review of randomized controlled trials. Hand (N Y). Dec 2014;9(4):419-446.

Singer BJ, Silbert PL, Dunne JW, et al.(2006) An open label pilot investigation of the efficacy of Botulinum toxin type A [Dysport] injection in the rehabilitation of chronic anterior knee pain. Disabil Rehabil. Jun 15 2006;28(11):707-713.

Slengerik-Hansen J, Ovesen T.(2016) Botulinum toxin treatment of objective tinnitus because of essential palatal tremor: a systematic review. Otol Neurotol. Aug 2016;37(7):820-828.

Smith CD, Stival A, Howell DL, et al.(2006) Endoscopic therapy for achalasia before Heller myotomy results in worse outcomes than heller myotomy alone. Ann Surg. May 2006;243(5):579-584; discussion 584-576. PMID 16632991

Soares A, Andriolo RB, Atallah AN, et al.(2014) Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. Jul 25 2014;7(7):CD007533.

Soljanik I.(2013) Efficacy and safety of botulinum toxin a intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic review. Drugs. Jul 2013;73(10):1055-1066.

Squires N, Humberstone M, Wills A, et al.(2014) The use of botulinum toxin injections to manage drooling in amyotrophic lateral sclerosis/motor neurone disease: a systematic review. Dysphagia. Aug 2014;29(4):500-508.

Stewart DB, Sr., Gaertner W, Glasgow S, et al.(2017) Clinical practice guideline for the management of anal fissures. Dis Colon Rectum. Jan 2017;60(1):7-14.

Stidham KR, Solomon PH, Roberson JB.(2005) Evaluation of botulinum toxin A in treatment of tinnitus. Otolaryngol Head Neck Surg. Jun 2005;132(6):883-889.

Tejedor J, Rodriguez JM.(1999) Early retreatment of infantile esotropia: comparison of reoperation and botulinum toxin. Br J Ophthalmol. Jul 1999;83(7):783-787.

Tirumuru S, Al-Kurdi D, Latthe P.(2010) Intravesical botulinum toxin A injections in the treatment of painful bladder syndrome/interstitial cystitis: a systematic review. Int Urogynecol J. Oct 2010;21(10):1285-1300.

Vasan CW, Liu WC, Klussmann JP, et al.(2004) Botulinum toxin type A for the treatment of chronic neck pain after neck dissection. Head Neck. Jan 2004;26(1):39-45.

Wang J, Wang Q, Wu Q, et al.(2016) Intravesical botulinum toxin A injections for bladder pain syndrome/interstitial cystitis: a systematic review and meta-analysis of controlled studies. Med Sci Monit. Sep 14 2016;22:3257-3267.

Wang L, Li YM, Li L.(2009) Meta-analysis of randomized and controlled treatment trials for achalasia. Dig Dis Sci. Nov 2009;54(11):2303-2311. PMID 19107596

Winocour S, Murad MH, Bidgoli-Moghaddam M, et al.(2014) A systematic review of the use of Botulinum toxin type A with subpectoral breast implants. J Plast Reconstr Aesthet Surg. Jan 2014;67(1):34-41.

Wissel J, Ganapathy V, Ward AB, et al.(2016) OnabotulinumtoxinA improves pain in patients with post-stroke spasticity: findings from a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. Jul 2016;52(1):17-26.

Wittekindt C, Liu WC, Preuss SF, et al.(2006) Botulinum toxin A for neuropathic pain after neck dissection: a dose-finding study. Laryngoscope. Jul 2006;116(7):1168-1171.

Wollmer MA, de Boer C, Kalak N, et al.(2012) Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res. May 2012;46(5):574-581. PMID 22364892

Wu CJ, Lian YJ, Zheng YK, et al.(2012) Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. Apr 2012;32(6):443-450.

Yiannakopoulou E.(2012) Botulinum toxin and anal fissure: efficacy and safety systematic review. Int J Colorectal Dis. Jan 2012;27(1):1-9.

Zesiewicz TA, Elble RJ, Louis ED, et al.(2011) Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology. Nov 8 2011;77(19):1752-1755.

Zhang H, Lian Y, Ma Y, et al.(2014) Two doses of botulinum toxin type A for the treatment of trigeminal neuralgia: observation of therapeutic effect from a randomized, double-blind, placebo-controlled trial. J Headache Pain. Sep 27 2014;15:65.

Zhang W, Deng X, Liu C, et al.(2017) Intravesical treatment for interstitial cystitis/painful bladder syndrome: a network meta-analysis. Int Urogynecol J. Apr 2017;28(4):515-525. PMID 27614759

Ziade M, Domergue S, Batifol D, et al.(2013) Use of botulinum toxin type A to improve treatment of facial wounds: a prospective randomised study. J Plast Reconstr Aesthet Surg. Feb 2013;66(2):209-214.


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