Botulinum Toxins

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for botulinum toxins. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for botulinum toxins and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
• Chapter 1, Section 30 Drugs and Biologicals
• Chapter 6, Section 20.5.2 Coverage of Outpatient Therapeutic Services Incident to a Physician’s Services Furnished on or After January 1, 2010
• Chapter 15, Section 50 Drugs and Biologicals, Section 60 Services and Supplies Furnished Incident To a Physician’s/NPP’s Professional Service
• Chapter 16, Section 120 Cosmetic Surgery
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
• Chapter 13, Section 13.5.4 Reasonable and Necessary Provisions in LCDs

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.
• Title XVIII of the Social Security Act, Section 1862(a)(10) excludes coverage for cosmetic surgery.
• Title XVIII of the Social Security Act, Section 1861(t). This section addresses drugs and biologicals definitions.

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

Clostridium botulinum toxin describes a family of neurotoxins produced by the anaerobic bacteria of the species C. botulinum. There are 7 distinct serotypes of botulinum toxin: A, B, C, D, E, F and G. All botulinum neurotoxin serotypes are understood to produce their clinical effect by blocking the release of the neurotransmitters, principally acetylcholine, from nerve endings.¹ There are 5 distinct serotype A botulinum toxin products, onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), prabotulinumtoxinA-xvfs (Jeuveau), and daxibotulinum toxin A (Daxxify) and 1 serotype B botulinum toxin product, rimabotulinumtoxinB (Myobloc) that have been approved by the US Food and Drug Administration (FDA). Jeuveau is indicated for cosmetic use only.²

Whether a botulinum toxin is produced from the same or a different serotype producing strain, they undergo different manufacturing processes which yield differences in the size and weight of the molecules. Because of this, Botox, Dysport, Xeomin, Myobloc, and Daxxify, as well as other botulinum toxin products available internationally, are not interchangeable. They are chemically, pharmacologically and clinically distinct.¹

Botulinum toxin injections are commonly used to treat a wide variety of conditions in which the main therapeutic effect is to decrease undesired or excessive contraction of striated or smooth (involuntary) muscle. They produce a presynaptic neuromuscular blockade by preventing the release of acetylcholine from the nerve endings.¹ The resulting chemical-denervation of muscle produces local paresis or paralysis and allows individual muscles to be weakened selectively.

The overall coverage of drugs is addressed in the CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Sections 50.4.1 and 50.4.2 and includes coverage for FDA-approved drugs and unlabeled use of a drug.

Covered Indications

NOTE: The 5 botulinum therapies are not interchangeable and are only covered as listed below.

Botulinum toxins (Botox, Dysport, Xeomin, Myobloc, and Daxxify), will be considered reasonable and necessary when administered for treatment of FDA-labeled indications and Off-label indications (as applicable) below:

1. FDA³ indications for onabotulinumtoxinA (Botox) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103000
2. Off-Label indications for onabotulinumtoxinA (Botox) are considered reasonable and necessary in patients for the following conditions:
   • Esophageal achalasia in the following circumstances:
     • Medically high-risk patients who cannot undergo other invasive treatments (peroral endoscopic myotomy [POEM], Heller myotomy, pneumatic dilation [PD])^{4,5,6,7,8,9,10,11,12}
     • As a bridge for those awaiting more effective treatments such as Heller myotomy, pneumatic dilations or POEM¹⁰
     • During work-up and treatment planning of definitive treatments for achalasia^13,14
   • Chronic anal fissure for patients with inadequate response to conservative or pharmacologic treatment¹⁵
   • Essential hand tremor for patients with a high amplitude tremor that disrupts activities of daily living and have had inadequate response to oral pharmacotherapy such as propranolol and primidone¹⁶
   • Focal hand and limb dystonia¹⁶
   • Hemifacial spasm in adults (cranial nerve VII disorder)¹⁶
   • Isolated oromandibular dystonia (also known as orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome) in adults¹⁷
   • Laryngeal dystonia (spastic dysphonia) for adductor type (ADSD)¹⁶
   • Bothersome simple motor tics in adolescents and adults when the benefits of treatment outweigh the risks¹⁸
   • Severely disabling or aggressive vocal tics in older adolescents and adults when the benefits of treatment outweigh the risks¹⁸
3. FDA¹⁹ indications for abobotulinumtoxinA (Dysport) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274
4. Off-label indications for abobotulinumtoxinA (Dysport) may be considered reasonable and necessary in patients for the following conditions:
   • Blepharospasm in adults^16,17
   • Hemifacial spasm in adults (cranial nerve VII disorder)¹⁶
   • Isolated oromandibular dystonia (also known as orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome) in adults¹⁷
5. FDA²⁰ indications for incobotulinumtoxinA (Xeomin) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125360
6. FDA²¹ indications for rimabotulinumtoxinB (Myobloc) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103846
7. FDA²² indications for daxibotulinumtoxinA-lanm (Daxxify) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761127.

Limitations

1. Localization procedures would not be expected for easily targeted muscles and, therefore, would not be considered reasonable and necessary.¹⁷
2. Administration of onabotulinumtoxinA (Botox) for achalasia in the following circumstances is not considered reasonable and necessary:

• Patients with contraindications for botulinum toxin injections (BTI) or upper endoscopy.²³
• Injection of botulinum toxin in the esophageal body.^6,8,9,10

3. Treatment of isolated lower limb dystonia and isolated exercise-associated lower limb dystonia is not considered reasonable and necessary.²⁴
4. Treatment of abductor spasmodic dysphonia is not considered reasonable and necessary.²⁵
5. Treatment of wrinkles, also called glabellar lines, smoker’s lines, crow’s feet, laugh lines and aging neck, using botulinum toxins, are considered cosmetic procedures and not covered under Medicare.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

Off-Label Indications Supported by Evidence-Based Guidelines

Botulinum toxin is used therapeutically to reduce pathologic muscle contraction. Health outcomes of interest are improved function and improved quality of life.

The American Academy of Neurology (AAN)²⁶ has produced a clinical practice guideline process manual that includes a discussion regarding elements of recommendations and levels of evidence (see tables below).

Note: When there is insufficient evidence to support an inference for the use of an intervention (i.e., the balance of benefits and harms is unknown), a Level U is appropriate. A Level U indicates that the available evidence is insufficient to support or refute the efficacy of an intervention.²⁶

Gastrointestinal

Achalasia

Achalasia is a relatively rare primary motor esophageal disorder, characterized by incomplete relaxation of the gastroesophageal junction coupled with the absence of organized peristalsis along the esophageal body. The gold standard for diagnosing achalasia is high-resolution esophageal manometry. The treatment options for patients with achalasia aim to improve symptoms by reducing the functional obstruction at the level of the gastroesophageal junction. Injection of botulinum toxin (BTI) reduces lower esophageal sphincter (LES) pressure by inhibiting release of acetylcholine from nerve endings.^{4,5,6,7,8,9,10}

In the management of achalasia, BTI is an FDA off-label use consisting of endoscopic injections of the toxin into 4 quadrants of the LES.^{4,5,6,7,8,9,10}

We performed a literature search in PubMed and Google scholar in the past 10 years with terms including “achalasia” and “botulinum toxin”. We conducted a multi-MAC Contract Advisory Committee in October 2023 with subject matter experts (SME) and included additional articles selected by them. We also included 4 society guidelines and 5 additional systematic reviews (SR) in our analysis.

Intra-sphincteric BTI is effective for esophageal achalasia treatment but is limited by its short-term efficacy. Four society guidelines (from the American Society for Gastrointestinal Endoscopy [ASGE],⁶ the International Society for Diseases of the Esophagus [ISDE],¹⁰ the American College of Gastroenterology [ACG],⁸ and the European Society of Gastrointestinal Endoscopy [ESGE])⁹ support the use of BTI as a treatment for achalasia only in patients who are not candidates for alternative invasive therapies, such as PD, laparoscopic Heller myotomy (LHM), or POEM. Four additional SR and meta-analyses comparing the use of BTI with alternative treatments have found that while BTI may provide short-term symptom relief and is associated with low complication rates, its results are inferior in both medium- and long-term compared to all other non-pharmacological alternatives.^4,11,12,27

The 2018 ISDE achalasia guidelines also recommend the use of BTI as a bridge for those awaiting more effective treatments such as Heller myotomy, PD or POEM.¹⁰

The use of BTI during work-up and treatment planning of definitive treatments for achalasia is recommended by SMEs and Katzka et al.¹³

In non-achalasia esophageal motility disorders the evidence of BTI is inconsistent but the SMEs support its use. A few non-randomized small trials favor this approach²⁸ while others do not.²⁹ European Society of Gastrointestinal Endoscopy guidelines specifically do not recommend BTI in those cases, but state that if in individual patients the decision of BTI is chosen, they recommend performing additional BTI in the lower third of the esophagus.⁹

Botulinum toxin injection in achalasia is safe overall.^10,11,12 Patients with contraindications for upper endoscopy should not undergo BTI.²³

Botulinum toxin injection in the esophageal body is not recommended in the treatment of idiopathic achalasia.¹⁰

The ESGE recommends that BTI should be performed using 100 units of the toxin diluted in preservative-free saline that is injected in aliquots of 0.5–1mL using an injection needle in at least 4 quadrants of the LES.⁹ Additionally, higher doses and escalating doses above 100 U of onabotulinumtoxinA (or equivalent) at subsequent injections have not been shown to have superior treatment benefit.^9,10

Frequency intervals of BTI vary. European Society of Gastrointestinal Endoscopy guidelines found that although the initial (1 month) response rate is high (> 75%), the therapeutic effect of repeated treatments substantially reduces over time and about half of patients required further injections at intervals of 6 – 24 months with some reporting long lasting effects when repeating BTI after a month.⁹ Thus, it is recommended to perform no more than 3 BTI per year for the treatment of achalasia.

A Cochrane database review of 7 studies included 178 patients and discovered no significant difference in remission between PD and botulinum toxin treatment within 4 weeks of the initial intervention.¹² Four studies included in the review had 12-month data with remission in 55 of 75 PD patients compared with 27 of 72 botulinum toxin patients (risk ratio of 1.88 [95% confidence interval 1.35 to 2.61, p = 0.0002]). These outcomes provide strong evidence that PD is more successful than botulinum toxin in the long term for patients with achalasia.

Chronic Anal Fissure

Current evidenced-based recommendations indicate chronic anal fissure should be treated with topical medications like calcium channel blockers or nitrates. In situations where patients do not respond to conservative or pharmacologic treatment, local injections of botulinum toxin have been shown to be as effective in healing fissures and are therefore recommended as an alternative treatment. Thus, consistent with evidence-based guidelines, off-label coverage has been extended for onabotulinumtoxinA as a treatment option for chronic anal fissure in patients with inadequate response to conservative or pharmacologic treatment.¹⁵

Blepharospasm

Studies show Botox and Xeomin may be comparable for the treatment of blepharospasm following dose modification. Studies signify Botox and Dysport may be equivalent for the treatment of blepharospasm. Dysport has backing in the IBM Micromedex compendium DrugDex for off-label treatment of blepharospasm in adults.²⁵ Accordingly, off-label coverage has been extended for Dysport for the treatment of blepharospasm in adults.

First Coast received a reconsideration request to expand coverage for Myobloc to include the treatment of benign essential blepharospasm in patients refractory to Botox. A single prospective case series publication was submitted for reconsideration of the LCD to expand coverage.³⁰ An additional search of PubMed revealed 10 studies. Four studies only briefly mentioned botulinum toxin type B and possible use for blepharospasm but do not examine its use in depth; 1 study examined the cosmetic use of botulinum toxin type B, and another study focused on the use of zinc with botulinum toxins. There were 4 other studies that do mention and analyze Myobloc’s use in some capacity, but all 4 studies establish reasons not to cover Myobloc for blepharospasm.^17,31,32 The study by Jankovic et al states that Myobloc for blepharospasm treatment has an insufficient level of evidence to establish its efficacy and use in the treatment of blepharospasm.³³ The paper by Hellman et al notes that Myobloc is available in a solution which is acidic and can result in more painful njections, dry mouth, and constipation than type A botulinum toxins. The experience and level of evidence on BoNT-B is much smaller than that of BoNT-A preparations, likely because the former produces more painful injections. Overall, it was determined that there was a low certainty of evidence in the submitted literature as well as in the search performed by the MAC to support the addition of Myobloc for the treatment of blepharospasm in the covered indications.

Hemifacial Spasm

The literature indicates botulinum neurotoxin may be considered as a treatment for hemifacial spasm with minimal side effects. Studies show Botox and Dysport, after dosage modification, may be equal in effectiveness.²⁵ Subsequently, off-label coverage has been extended for Botox and Dysport as a treatment of hemifacial spasm in adults.

Focal Hand and Limb dystonia

Focal hand dystonia (FHD) is a disabling task-specific movement disorder, that can generalize across tasks and be present at rest. It is also referred to as writer’s cramp, musician’s dystonia, and other occupational hand dystonias. A patient’s history and clinical examination are both critical for its diagnosis and for identification of dystonic muscles.

The treatment options for FHD aim to improve symptoms by reducing the signals that cause muscle spasms. Botulinum toxin injections (BTI) in FHD require guidance either by ultrasound or by electromyography with or without electrostimulation. Molloy 2002³⁴ Botulinum toxin injections dosing in FHD is highly individualized due to different activity types, levels, multiple potential target muscles with varying BTI doses and intervals.³⁵ Currently, no effective alternative medical or proven surgical therapies have been established for FHD.^{36,37,38,39,40,41}

In the management of FHD, BTI is considered reasonable and necessary as an FDA off-label use consisting of focal injections of the toxin into the muscles responsible for the abnormal postures.

We performed a literature search in PubMed and Google scholar in the past 10 years with terms including FHD and botulinum toxin. We also conducted a multi-MAC Contract Advisory Committee in October 2023 with SMEs and included additional articles selected by them. The SMEs concluded that BTI should be offered as a first-line treatment for focal hand dystonia. We included a total of 6 studies in our analysis. (Class I and II strength of recommendations).²⁶ They all support the use of BTI as a first line treatment of FHD. The efficacy of botulinum toxin injection use in isolated lower limb dystonia and isolated exercise-associated lower limb dystonia has a class III level of scientific evidence.²⁴

Laryngeal dystonia

Laryngeal dystonia (spasmodic dysphonia) commonly presents as adductor type (ADSD) and less commonly as abductor type of spasmodic dysphonia (ABSD). Presently no effective alternative medical or surgical therapies have been established for spasmodic dysphonia. Studies show botulinum neurotoxin should be recommended as a treatment option for adductor spasmodic dysphonia (ADSD); however, there is inadequate evidence to support the effectiveness of botulinum neurotoxin in abductor spasmodic dysphonia (ABSD). Botox has support in the IBM Micromedex compendium DrugDex for off-label treatment of spastic dysphonia in adults.²⁵ Consequently, consistent with evidence-based guidelines, off-label coverage has been extended for Botox.

Essential hand tremor

Studies indicate botulinum neurotoxin injection of forearm muscles may be helpful in reducing the tremor amplitude in patients with a high amplitude essential hand tremor that disrupts activities of daily living and have had an inadequate response to oral agents including propranolol and primidone.¹⁶ Therefore, consistent with evidence-based guidelines, off-label coverage has been extended for Botox as a treatment for essential hand tremor for patients with a high amplitude tremor that disrupts activities of daily living and have had an inadequate response to oral pharmacotherapy such as propranolol and primidone.

Oromandibular Dystonia

Oromandibular dystonia (OMD) is a rare neurological movement disorder characterized by involuntary and often forceful contractions of the muscles of the jaw and tongue. Oromandibular dystonia is described by several different terminologies. Those include, orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome.⁴² Oromandibular dystonia can present along with involuntary muscle spasms and contractions of the muscles around the eyes (blepharospasm) and is known as Meige Syndrome.⁴³ Overall, half of all blepharospasm subjects experience symptoms to different parts of the body over a period of 5 years.⁴⁴

Oromandibular dystonia (OMD) has various treatment choices consisting of botulinum toxin therapy, medication, and surgical intervention. Medications, like anticholinergics (trihexyphenidyl and benztropine), benzodiazepines, VMAT2 inhibitors (tetrabenazine), levodopa, and baclofen have been utilized with varying success. The effectiveness of medication therapy is limited and does not show the same level of value when compared to botulinum toxin. Oral medication treatments are also restricted by systemic side effects not typically experienced with botulinum toxin.

Current practice guidelines for botulinum toxins show support for Botox and Dysport for the treatment of OMD. In addition to the literature, Botox has support in the IBM Micromedex compendium DrugDex for off-label treatment of isolated oromandibular dystonia in adults.²⁵ Thus, consistent with evidence-based guidelines, off-label coverage has been extended for Botox and Dysport as a treatment for isolated oromandibular dystonia in adults.

Chronic motor tics and disabling or aggressive vocal tics

The treatment of tics must be personalized and based on collaborative determinations among patients, caregivers, and clinicians. Many individuals with tic disorders have psychiatric comorbidities, which require clinicians to set treatment priorities. The management of comorbid conditions is of chief concern in determining treatment options for tics in individuals with Tourette’s Syndrome. Medications, behavioral therapy, and neurostimulation have been shown to significantly decrease tics; however, these treatments seldom fully terminate tics.²⁵ Evidence-based guidelines indicate: 1) OnabotulinumtoxinA (Botox) injections are recommended for the treatment of adolescents and adults with localized and bothersome simple motor tics when the benefits of treatment outweigh the risks; and 2) OnabotulinumtoxinA (Botox) injections are recommended for the treatment of older adolescents and adults with severely disabling or aggressive vocal tics when the benefits of treatment outweigh the risks. In addition to the current guidelines, the IBM Micromedex compendium DrugDex²⁵ lends support for Botox as an off-label treatment of Gilles de la Tourette’s syndrome in adults. Therefore, off-label coverage has been extended for Botox consistent with current evidence-based guidelines.

The quality of evidence in the literature is insufficient to support botulinum toxin injection for the treatment of defecatory disorders (DD), chronic proctalgia, phonic tics, head tremor, and voice tremor. Further research is needed to clarify the utility and efficacy of botulinum toxin therapy for these conditions.¹⁶

Botulinum toxin can improve quality of life through reducing muscle rigidity and contraction and is a treatment for voluntary and involuntary muscle dysfunction. Reduction of painful contractions is important for an improved quality of life.

Dosing and frequency are important considerations. While botulinum toxins have a wide therapeutic window, all botulinum toxin products have a black box warning about the potential for distant spread of toxin effect. These symptoms can occur hours to weeks after administration. Symptoms may include swallowing and breathing difficulties which can be life threatening and can lead to death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms.^3,19,20,21 Therefore, the lowest effective dose that produces the desired clinical effect should be used. Treatment effect can last from 12 to 16 weeks, with labeled use suggesting a minimum interval of 12 weeks. Dosing frequency should be at the longest interval that produces the desired clinical effect.

Medical utilization of botulinum toxins has increased in the past 30 years with an extensive track record of safety and efficacy.¹ The mechanism of action is well understood. However, the benefits of botulinum toxin must be balanced with the risk. Professional societies have evidence-based guideline recommendations to assist providers in maximizing patient outcomes.

There are important differences between the botulinum toxin preparations that include potency and duration of effect. They are chemically, pharmacologically and clinically distinct and are not interchangeable.

Achalasia

BTI in the treatment of achalasia

Society guidelines:

Of these guidelines 3 were based on results of systematic reviews (SRs, 2020 ASGE,⁶ 2018 ISDE,¹⁰ 2020 ESGE⁹) and 1 was a position statement (ACG).⁸ The ASGE guideline on the management of achalasia 2020,⁶ 2018 ISDE achalasia guidelines,¹⁰ ACG Clinical Guidelines: Diagnosis and Management of Achalasia, 2020,⁸ and ESGE Guideline, 2020⁹ all support BTI into the distal esophageal sphincter as an effective short-term treatment for achalasia, in medically high-risk patients who are not candidates for other invasive therapies.

Overall, the SRs included open label trials with small numbers of participants due to the rarity of achalasia and the invasiveness of treatments.

American Society for Gastrointestinal Endoscopy guidelines⁶ were based on a SR and meta-analysis by Khashab et al of 22 uncontrolled studies published from inception to October 2017, in 730 achalasia patients who were treated with BTI. Clinical success, defined by an Eckardt score of less than or equal to 3, was achieved in 77% (95% confidence interval [CI], 72%-81%; I 2 value 35; P= 0.04) over a follow-up period ranging from 1 to 6 months. There was a statistically significant decrease in average LES pressure from 38.23 mm Hg (range, 34.40-42.06) before the procedure to 23.30 mm Hg (range, 20.79-25.81) after BTI (P < .01). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), for PD and BTI respectively (Risk ratio, 1.88; 95% CI, 1.35-2.61; P= 0.0002). Serious adverse events were uncommon, with transient chest pain reported after 4.4% of injections. The authors recommended against the use of BTI as definitive therapy for achalasia patients (Assessing the Methodological Quality of Systematic Reviews-2 AMSTAR-2 moderate quality of evidence or moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different).

The ESGE⁹ performed a systematic review (see Weusten SR below) and Delphi consensus and aligned with previous recommendations. They additionally made specific dosing recommendations of 100 units onabotulinumtoxin A or equivalent of the toxin diluted in preservative-free saline that is injected in aliquots of 0.5–1mL using an injection needle in forward view just above the squamocolumnar junction in at least 4 quadrants. This was a strong recommendation, high quality of evidence, level of agreement 100%. A multicenter randomized trial with injection of 50, 100, and 200 units of BTI resulted in similar short-term results in LES pressure 1 month after injection⁵ and in a SR review, a dose of 100 units of botulinum toxin was used most frequently⁴⁵ supporting this dosing recommendation.

2018 ISDE achalasia guidelines were based on Zaninotto et al SR (see below)¹⁰, and the strength of recommendation was graded according to the Grading of Recommendations Assessment and Evaluation (GRADE). Based on a moderate GRADE rating of the evidence, the authors support BTI for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation.

American College of Gastroenterology Clinical Guidelines, 2020⁸ performed a literature review and generated consensus-based recommendations using a modified Delphi process. They recommend BTI as first-line therapy for patients with achalasia that are unfit for definitive therapies compared with other less-effective pharmacological therapies.

Systematic reviews:

Recent SR and meta-analyses comparing the use of BTI with alternative treatments have found that, while BTI may provide short-term symptom relief and is associated with low complication rates, its results are inferior in both the medium- and long-term compared to all other non-pharmacological alternatives.

Andolfi et al⁴ conducted a SR of articles published between 2008 and 2018 comparing the effect of different invasive treatments on symptomatic outcomes across achalasia subtypes. Their search strategy included PubMed and MEDLINE only. They included 20 studies (1,575 participants) reporting clinical outcomes after BTI, PD, LHM and POEM based on manometric subtypes. The authors performed a meta-analysis. Three studies reported data on botulinum toxin (58 patients). Botulinum toxin injection was the treatment modality with the worse outcomes (18 percent for type I, 59 percent for type II and 21 percent for type III). About half of the patients needed further injections at intervals of 6–24 months.

Gong et al¹¹ conducted a SR comparing the efficacy of 9 interventional treatments (BTI, PD, BTI + PD, LHM + Toupet, LHM + anterior wrap [D], anterior POEM [APOEM], traditional posterior POEM, double-scope POEM, and waterjet assisted [JPOEM]) for achalasia. The authors included 27 RCTs published from 1990 to December 2020 with 2,278 achalasia patients (BTI [n = 158], BTI + PD [n =72]) in a meta-analysis. Primary outcome was comparisons of the induction of clinical remission after 1-year follow-up. Results indicated that APOEM was the most effective (rank 1,50%) strategy to significantly relieve achalasia symptoms, while BTI ranked last (rank 9 [99%]), although BTI had the highest safety profile.

Leyden et al¹² conducted a Cochrane SR and meta-analysis comparing the efficacy and safety of 2 endoscopic treatments, PD and BTI. They included 7 randomized controlled trials (RCT) with 178 patients published from 1946 through March 2014. The authors examined symptom remission rates within the first month, at 6 months, and at 12 months. Based on the AMSTAR-2 critical appraisal tool, the overall confidence in the result of this meta-analysis was deemed to be “high.” The overall methodological quality of the studies was good although the risk of bias is high. Only 1 of the studies included was double blinded. There was no significant difference between pneumatic dilation and BTI arms in clinical success rates or LES pressures within 4 weeks of the initial intervention (risk ratio of remission, 1.11; 95% CI, 0.97-1.27) with a weighted mean difference for PD of –0.77 (95% CI, –2.44 to .91; P = 0.37). Clinical success rates beyond 4 weeks were available for 3 studies at 6 months and 4 studies at 12 months. At 6 months, clinical success was achieved in 80.7% of patients (46/57) who underwent PD as compared with 51.8% of patients (29/56) who underwent BTI (risk ratio, 1.57; 95% CI, 1.19-2.08; P 0.0015). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), respectively (risk ratio, 1.88; 95% CI, 1.35-2.61; P =0.0002). There were no adverse events in the botulinum injection arm (total of 151 injection procedures), whereas perforation occurred in 3 cases (total of 188 pneumatic dilation procedures) in the pneumatic dilation arm.

These data demonstrate that pneumatic dilation is a more effective long-term (>6 months) endoscopic treatment option compared with BTI for patients with achalasia.

Shiu et al²⁷ conducted a SR and meta-analysis of RCTs published between January 2000 and June 2021 to compare the efficacy of 8 treatments for achalasia. Twenty-four studies involved 1,987 participants for analysis. LHM+Dor (OR 2.29, 95% CI: 1.50–3.49) all showed significantly greater efficacy and were at least twice as effective as the reference group with only BTI (OR 0.33, 95% CI: 0.17–0.63) showing significantly lower efficacy. The medians (IQRs) for short-term clinical success rates (%) of Anterior POEM, Posterior POEM, LHM+Toupet, BTI+PD, LHM+Dor, PD, and BTI were 91.1 (IQR, 84.4–95.4), 92.1 (IQR, 87.0–93.0), 93.9 (IQR, 90.2–97.0), 85.4 (IQR, 84.4–86.5), 86.7 (IQR, 79.7–88.7), 66.35 (IQR, 56.0–77.7), and 53.3 (IQR, 37.5–60.0), respectively.

Zaninotto et al¹⁰ conducted a SR with interdisciplinary and international authors to establish best evidence-based principles for the diagnosis and management of achalasia. The authors included 466 articles in their analysis. Regarding BTI results, the authors found that BTI has a high safety profile with mild adverse events (heartburn or chest pain) observed in less than 10% of patients treated. At 2-year follow up, only 34% of BTI patients versus 87.5% of the Heller patients were asymptomatic. Similarly, 4 randomized trials and a Cochrane meta-analysis comparing BTI with PD consistently reported a higher cumulative rate of remission rate at 1 year after treatment after PD. Based on the moderate GRADE rating of the evidence, the authors recommended against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for surgery (LHM) or PD.

Repeated BTI may be successful, if there are contraindications to invasive, but more durable treatments. The authors also found that BTI efficacy may decrease over time.

Weusten et al, 2020⁹ conducted a SR of the technical aspects of the endoscopic management of gastrointestinal motility disorders (including achalasia). Evidence levels and recommendation strengths were assessed using the GRADE system. The total number of studies included was unclear as were the methods for analysis and combination of study results. This is based on a moderate GRADE rating of the evidence.

BTI in the work-up and treatment planning of achalasia

Although the literature is sparse with small samples studies, expert consensus supports that BTI may be used during work-up and treatment planning of definitive treatments for achalasia.¹⁴ Katzka DA et al¹³ followed a retrospective cohort of 11 patients evaluating BTI in patients with: 1) symptoms consistent with achalasia but insufficient manometric criteria to make the diagnosis; 2) complex clinical situations in which there were factors in addition to achalasia that may be contributing to the patient’s symptoms and that required different treatment; 3) atypical manifestations of achalasia; 4) advanced achalasia in which it was unclear that sphincter-directed therapy (vs esophagectomy) would be of benefit; and 5) after Heller myotomy.

Chronic anal fissure

Anal fissure is defined as an ulcer-like, longitudinal tear in the midline of the anal canal, distal to the dentate line. Treatments for anal fissure lean heavily on adaptations from the American Society of Colon and Rectal Surgeons Practice Parameters from the most recent published guidelines in 2010 and 2011 and are supplemented with subsequent publications through 2023.⁴⁶ Generally, treatment for chronic anal fissure is targeted at reducing the sphincter spasms caused by this condition. Recommended therapy includes topical medications like calcium channel blockers or nitrates. For patients who do not respond to conservative or pharmacologic treatment, local injections of botulinum toxin are strongly recommended for relief of painful spasms. Surgery (internal anal sphincterotomy) is recommended for medically refractory situations.

Wald et al¹⁵ released the American College of Gastroenterology practice guideline for management of benign anorectal disorders which discusses the definitions, diagnostic criteria, differential diagnoses, and treatments of a set of benign disorders of anorectal function and/or structure. Studies show that injection of botulinum toxin into the internal anal sphincter allows healing in 60% to 80% of fissures, and at a greater rate than a placebo. Usual side effects include temporary incontinence of flatus in up to 18%, and of stool in 5%. Relapse may occur in up to 42%; however, patients have shown similar outcomes to initial therapy.

Currently, a consensus has not been reached on dosage, exact site of administration, number of injections, or effectiveness. The effects of botulinum toxin may be potentiated by topical nitrate medications in patients with refractory anal fissure. Botulinum toxin is reserved for patients who fail pharmacologic treatment with nitrates or calcium channel blockers. Lateral internal sphincterotomy (LIS) is recommended for patients who have failed botulinum toxin injection therapy.

Blepharospasm

The American Academy of Neurology has provided recommendations for the use of botulinum neurotoxin in blepharospasm based on the following studies:

One Class II⁴⁷ and 1 Class III study⁴⁸ compared 2 different serotype A botulinum neurotoxins (Botox and Dysport). In the Class II study, 212 participants were assessed in a crossover design using a 4:1 dose ratio of Dysport to Botox. The primary clinical outcome, duration of effect, was similar for the 2 botulinum neurotoxins. The Class III trial, a parallel design of 42 patients without blinded raters, used a dose ratio of 4:1. Duration of action was the primary clinical outcome, and this outcome and others including number of booster doses needed, latency of effect, clinical efficacy, and adverse reactions were comparable for the 2 botulinum toxin products. A Class I trial performed a comparison of Xeomin and Botox injecting equal doses in 300 study participants (256 participants finished the trial). Results showed identical effectiveness and side effects (Simpson 2008).

The conclusion for these studies indicates Botox and Xeomin have level B evidence, Dysport has level C evidence. These studies signify that following dose modifications, Botox and Xeomin may be equal and Botox and Dysport may be comparable for the treatment of blepharospasm.

Hemifacial spasm

Hemifacial spasm is illustrated by a combination of unilateral clonic and tonic spasms of the muscles innervated by the facial nerve. Treatment choices include oral pharmacologic treatments (including carbamazepine, baclofen, and benzodiazepine) that have limited effectiveness, and microvascular decompression of the facial nerve, which is a highly invasive technique.

A Class II study⁴⁹ comprised of 11 patients was a prospective, blinded trial with 4 arms: a random dose based on clinical experience of between 2.5 and 10 units of BoNT-A (Botox), half the dose, double the dose, and saline placebo. Patients went through the 4 treatment arms in random order. Utilization of a clinical scale to rate videotapes and a patient subjective scale, 84% had objective improvement with a minimum of 1 of the active doses with a tendency for an improved response with higher dose; only 1 participant improved on placebo. Seventy-nine percent described subjective improvement lasting an average of 2.8 months with active treatment. The principal side effect was weakness of the face, generally mild (97%). Other side effects included bruising, diplopia, ptosis, and headache.

A Class III study⁵⁰, a double-blind, prospective, parallel design including only 4 participants per group used individualized therapy (dose range 2.5 to 40 units) with BoNT-A (Botox) in the active arm. In addition, 93 patients studied in an open label fashion were reported. More improvement was shown on a clinical scale with BoNT than with a saline placebo. Improvement continued an average of 3.8 months. Side effects, reported in 63% of participants, were usually mild and involved dry eye, mouth droop, and ptosis.

One Class II study⁴⁸ contrasted Botox and Dysport in a parallel design without placebo control or blinded raters. A dose ratio of 4:1 was used for Dysport to Botox. The primary clinical outcome (duration of action) and other clinical outcomes (number of booster doses needed, latency of effect, clinical efficacy, and frequency of adverse reactions) were comparable for the two products. Therapeutic effects lasted 2.6–3.0 months.¹⁶

The conclusion of these studies signifies botulinum neurotoxin may be considered as a treatment for hemifacial spasm. Botox and Dysport have level C evidence and after dosage modification, are comparable in effectiveness.

Focal Hand and Limb dystonia

A Class I trial randomized 40 study participants with writer’s cramp in a double-blind design for botulinum neurotoxin (BoNT) or an equal amount of saline placebo.⁵¹ The primary outcome measure was the patient’s indicated request to continue injection therapy. In patients randomized to BTI, 70% requested to maintain treatment in comparison to 31.6% of those who received a placebo (p = 0.03). Patients injected with BTI also had considerable improvement in comparison to patients who had been given a placebo in secondary clinical outcome measures including a visual analog scale, symptoms severity scale, writer’s cramp rating scale, and assessment of writing speed, but not in the functional status scale. The only adverse effects reported were temporary weakness and pain at the injection site.

A Class II study utilized a placebo-controlled, double-blind, crossover design for 20 individuals with writer’s cramp.⁵² Clinical assessment was utilized in selecting the muscle to be injected and the dose of BoNT-A was founded on investigator experience. Outcome evaluations included assessment of writing speed, accuracy, writing samples, and patients’ subjective report of pain. There was substantial improvement with BTI in the objective measures, but not in patients’ own evaluations. The only adverse effect was focal weakness, although this was severe enough to worsen pen control in one participant. This study only evaluated the first active therapy session for study participants; therefore, the therapeutic effects achieved were not optimal.

A Class II trial¹ was a double-blind, placebo-controlled, crossover design with 10 study participants with focal hand dystonia.⁵³ Muscles and BTI-A (Botox) doses were selected and optimized during a time of open treatment before the trial. Outcome measures were based on study participant’s subjective ratings and observer ratings of videotapes taken during actions relevant to the individual dystonia. Eight participants had improved subjective ratings and 6 had improved videotape ratings with BTI in comparison with placebo. Weakness was noted in the injected muscles of 80% of study participants with active treatment.

Three Class II studies assessed technical issues of BTI administration. In 1 trial, a blinded, randomized, crossover design was utilized to contrast continuous muscle activation to immobilization immediately following BTI.⁵⁴ Blinded assessment of handgrip strength and writing showed a substantial increase in focal weakness with continuous muscle activity, but no subjective or objective improvement in writing. In a similar study,⁵⁵ participants were randomized to 1 of 2 muscle localization methods: electromyography (EMG) recording or electrical stimulation. Injections guided by both techniques were similarly effective in producing weakness in the target muscle. In a third trial, the precision of muscle localization with and without EMG was assessed. In needle placements without EMG, only 37% were localized in the targeted muscle.³⁴

Because FHD is a rare and heterogenous disease, studies had small sample sizes and different BTI dosing schemes. Most studies used subjective scales involving either patient or clinician ratings. None of the scales have been rigorously evaluated for clinical utility or validity. Whether studies involved treatments or pathophysiologic assays, there was a heterogeneous choice of rating scales used with no clear standard. As a result, the collective interpretive value of those studies is limited because the results are confounded by measurement effects.

The therapy for FHD with BTI is challenging, but SME opinion and the included studies signify that BTI should be considered as a first line treatment for FHD.

Laryngeal dystonia

Laryngeal dystonia (spasmodic dysphonia) commonly presents as adductor type (ADSD) and less commonly as abductor type (ABSD). The voice of an individual with ADSD is described as strained or strangled, while ABSD generates a weak and breathy voice. Currently, no effective alternative medical or surgical therapies have been established for spasmodic dysphonia.

One Class I trial⁵⁶ of botulinum neurotoxin (BoNT) for 13 study participants with ADSD, a double-blind, randomized, parallel group study, compared 7 patients who received BoNT with 6 patients who received saline. Outcome measures included instrumental quantitative measures of voice function and patient ratings. Substantial benefit was achieved in the study participants who received BoNT (p = 0.01).

One Class III trial⁵⁷ discovered that adding voice therapy after BoNT therapy in ADSD patients extended improvements from the BoNT treatment. One Class III study of 15 participants with ABSD did not observe a noteworthy distinction between using percutaneous or endoscopic injection technique.⁵⁸

The conclusion for these studies signifies Botox has level B evidence and should be recommended as a treatment option for ADSD; however, there is inadequate evidence to support the effectiveness for botulinum neurotoxin in ABSD.

Essential hand tremor

Tremor, an involuntary rhythmic movement caused by alternating or synchronous contractions of opposing muscles, is a common movement disorder. While pharmaceutical interventions may provide relief for mild or moderate essential tremors, they often fall short for severe tremors that interfere with daily activities. For patients with debilitating tremors, injecting botulinum neurotoxin (BoNT) locally may be considered before more invasive treatments such as thalamic deep brain stimulation.⁶⁰

In a Class II placebo-controlled trial,⁵⁹ 25 participants with moderate to severe hand tremors were randomly assigned to receive either 50 units of BoNT-A (Botox) or a placebo in wrist muscles of their dominant limb. If the initial injection showed no improvement, a second 100-unit injection could be given after 4 weeks. Over 16 weeks, tremor severity was assessed using rating scales, accelerometry, and disability evaluations every 2 to 4 weeks. Participants treated with BoNT showed significant improvement in tremor severity compared to those who received placebo, which persisted throughout the study. Four weeks after injection, 75% of BoNT-treated participants reported mild to moderate improvement, compared to 27% in the placebo group (p < 0.05). Accelerometry measurements indicated a 30% decrease in tremor amplitude in 9 out of 12 BoNT-treated patients versus 1 out of 9 in the placebo group (p < 0.05). Although BoNT caused mild finger weakness in all patients, no severe, irreversible, or unexpected adverse effects were reported.

Similar findings were observed in another Class II multicenter, double-blind study involving 133 participants with essential tremor.⁶⁰ Participants received either 50 or 100 units of Botox injected into wrist muscles and were followed for 4 months. While postural tremor showed substantial improvement, kinetic tremor and functional assessments saw only minor enhancements.

Additional studies, including a systematic review published in 2019,⁶¹ provide further support for the use of onabotulinumtoxinA in the treatment of patients with essential hand tremor for whom conservative treatment options were unsuccessful.

Oromandibular dystonia (OMD)

Hassel and Charles¹⁷ conducted a systematic literature review to give a summary of the history of oromandibular dystonia, botulinum neurotoxin (BoNT), and the utilization of BoNT to treat this focal cranial dystonia. Oromandibular dystonia (OMD) has various treatment choices consisting of BoNT therapy, medication, and surgical intervention. Botulinum neurotoxin is commonly recognized as a first-line therapy.

The effectiveness of medication therapy is limited and does not show the same level of value when compared to BoNT. Oral medication treatments are also restricted by systemic side effects not typically experienced with botulinum toxin. Benzodiazepine use is also problematic due to potential tolerance and addiction.

For the treatment of OMD, OnaBoNT/A (Botox) and aboBoNT/A (Dysport) carry the highest evidence (level of evidence C for both). While IncoBoNT/A (Xeomin) and RimaBoNT/B (Myobloc) have insufficient evidence to support therapy for OMD (level of evidence U for both).¹⁷

Chronic motor tics and disabling or aggressive vocal tics

Tics, generally linked with Tourette syndrome, are characterized as short, sporadic movements (motor tics) or sounds (vocal or phonic tics), generally led by a premonitory sensation. Current treatment includes anti-dopaminergic drugs (neuroleptics) which are normally successful for multifocal tics. However, the side effects are considered unfavorable especially in individuals with focal tics like blinking, blepharospasm, head jerking, neck twisting, and loud vocalizations, including the involuntary and repetitive use of obscene language.

In preliminary open label Class IV trials,¹⁶ the muscles involved in the motor and phonic tics were injected with botulinum neurotoxin (BoNT) and showed an adequate to significant decrease in the strength and occurrence of the tics, and almost full elimination of the premonitory sensation. In a Class IV trial of 35 study participants treated in 115 sessions for bothersome or incapacitating tics, the average peak effect response was 2.8 (range: 0=no effect, 4=marked improvement in both severity and function). The average length of improvement was 3.4 months (up to 10.5).⁶² The dormancy to start of improvement was 3.8 days (up to 10). Twenty-one participants out of 25 (84%) with significant premonitory sensory symptoms obtained noticeable relief of these symptoms with BoNT (average improvement 70.6%).

A class II trial⁶³ with 18 study participants with simple motor tics achieved a 39% decrease in the number of tics per minute in 2 weeks following BoNT injection in comparison to a 6% rise in the placebo participants (p=0.004). Also, a 0.46 decrease in “urge scores” with BoNT in comparison to a 0.49 rise in the placebo participants (p=0.02). This underpowered study was unable to reveal sufficient differences in measured variables like severity score, tic suppression, pain, and patient global impression. The maximum results derived from BoNT may not have been realized at 2 weeks. Also, it was noted that the study participants did not score themselves as considerably compromised because of their tics, so their symptoms may have been reasonably mild at baseline.

The conclusion for these studies indicates Botox has level C evidence and may be effective for the treatment of motor tics (one Class II study). There is insufficient data to conclude the effectiveness of BoNT in phonic tics (one Class IV study).

Pringsheim et al¹⁸ provided a systematic review of the literature to make recommendations on the assessment and management of tics in individuals with Tourette syndrome (TS) and chronic tic disorders. A multidisciplinary panel consisting of 9 physicians, 2 psychologists, and 2 patient representatives developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

The systematic review integrates the evidence supporting the effectiveness and detriments of medical, behavioral, and neurostimulation treatments for tics. The treatment of tics must be personalized and based on collaborative determinations among patients, caregivers, and clinicians. Many individuals with tic disorders have psychiatric comorbidities, which require clinicians to set treatment priorities. The management of comorbid conditions is of chief concern in determining treatment options for tics in individuals with TS. Medications, behavioral therapy, and neurostimulation have been shown to significantly decrease tics; however, these treatments seldom fully terminate tics.

The literature shows that botulinum toxin injections with onabotulinumtoxinA are probably more likely than a placebo to reduce tic severity in adolescents and adults. Botulinum toxin injections may also improve premonitory urges.¹⁸ OnabotulinumtoxinA is associated with greater rates of weakness relative to placebo. Also, a common side effect of injecting botulinum toxin in the laryngeal muscles for vocal tics is hypophonia. Botulinum toxin effects generally last for 12-16 weeks, after which injections would need to be repeated.

Recommendations based on the study from Pringsheim et al¹⁸ include: 1) Botulinum toxin injections are recommended for the treatment of adolescents and adults with localized and bothersome simple motor tics when the benefits of treatment outweigh the risks (Level C). 2) Botulinum toxin injections are recommended for the treatment of older adolescents and adults with severely disabling or aggressive vocal tics when the benefits of treatment outweigh the risks (Level C). In addition, providers must advise patients with tics that treatment with botulinum toxin may cause temporary weakness and hypophonia.

Please refer to the related Draft Local Coverage Article: Billing and Coding: Billing and Coding: Botulinum Toxins (DA57715) for documentation requirements, utilization parameters and all coding information as applicable.

N/A

This bibliography presents those sources that were obtained during the development of this policy. The Contractor is not responsible for the continuing viability of Website addresses listed below.

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