Botulinum is a family of toxins produced by the anaerobic organism Clostridia botulinum. Multiple formulations of botulinum toxin have been approved by the U.S. Food and Drug Administration (FDA). Labeled indications of these agents differ. Botulinum toxin products are also used for a range of off-label indications. The scope of the evidence review is limited to off-label use of 4 botulinum toxin agents currently available and approved by the FDA for medical use. These include onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), and rimabotulinumtoxinB (Myobloc).
For individuals who have esophageal achalasia who fail initial treatment with medications who receive botulinum toxin injections, the evidence includes 3 meta-analysis that included randomized controlled trials (RCTs) comparing endoscopic pneumatic dilation (PD) or laparoscopic myotomy with botulinum toxin. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. The systematic review reported that PD, as well as laparoscopic myotomy, afforded higher and statistically significant greater symptom remission rates. OnabotulinumtoxinA was not associated with any serious adverse events while PD resulted in perforation in a few cases. While the evidence was suggestive that PD and surgical myotomy are definitive therapies for esophageal achalasia and are 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 and can be easily performed during routine endoscopy. Initial success rates with botulinum toxin are comparable to PD and surgical myotomy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with chronic anal fissure who fail medical treatment who receive botulinum toxin injections, the evidence includes a systematic reviewand 2 meta-analyses. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. Results suggest that sphincterotomy is a more effective treatment option for chronic anal fissure compared with botulinum toxin A and is associated with a significantly higher healing rate as well as a lower recurrence rate. However, these meta-analyses report higher fecal incontinence rates with surgical procedures. Since botulinum toxin A injections are less invasive and do not require the internal sphincter muscle to be divided and, thereby, reduce the risk of fecal incontinence, the injections are preferred for patients who are not good surgical candidates or who want to minimize the likelihood of incontinence. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with Hirschsprung disease who develop obstructive symptoms after a pull-through operation who receive botulinum toxin injections, the evidence includes a meta-analysis and 2 later published retrospective cohort studies.. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity.. There was evidence for improvement of obstructive symptoms after botulinum toxin injections in patients that underwent surgery for Hirschsprung disease, although this effect was often transient and most patients needed multiple injections. Long- term follow-up is suggestive of durability of response. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have other indications such as neurological indications (non-migraine headaches, essential tremor, tinnitus, Tourette syndrome), urological indications (benign prostatic hyperplasia, interstitial cystitis, detrusor sphincteric dyssynergia), pain due to multiple etiologies (including neuropathic pain), gastrointestinal motility disorders (internal anal sphincter achalasia, anismus, gastroparesis) and miscellaneous other conditions ( , depression, facial wound healing) who receive botulinum toxin injections, the evidence includes systematic reviews and RCTs. Relevant outcomes are symptoms, functional outcomes, medication use, and treatment-related morbidity. Generally, botulinum toxin has been evaluated in clinical settings where patients have failed the standard of care or in whom standard of care interventions are contraindicated. However, in multiple indications with high prevalence rates (eg, benign prostatic hyperplasia, low back pain, depression, tinnitus, etc.), where multiple effective treatments supported by an adequate quality evidence base are available, studies using a placebo comparator that lack scientific rigor do not permit conclusions about the net health benefit of botulinum toxin. Future studies in these clinical indications should use appropriate comparators in adequately powered prospective studies using a standardized treatment dose and adequate follow-up. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
The following policy statements do not apply to prabotulinumtoxinA.
On-label indications: Implies at least 1 of the 4 Food and Drug Administration (FDA) approved botulinum toxin agents are approved for the indications below.
Botulinum toxin may be considered medically necessary for:
Treatment of cervical dystonia (spasmodic torticollis; applicable whether congenital, due to childbirth injury, or traumatic injury). For this use, cervical dystonia must be associated with sustained head tilt or abnormal posturing with limited range of motion in the neck AND a history of recurrent involuntary contraction of 1 or more of the muscles of the neck, eg, sternocleidomastoid, splenius, trapezius, or posterior cervical muscles.
Treatment of dystonia resulting in functional impairment (interference with joint function, mobility, communication, nutritional intake) and/or pain in individuals with any of the following:
Focal upper-limb dystonia (eg, organic writer’s cramp)
Oromandibular dystonia (orofacial dyskinesia, Meige syndrome)
Laryngeal dystonia (adductor spasmodic dysphonia)
Idiopathic (primary or genetic) torsion dystonia
Symptomatic (acquired) torsion dystonia.
Treatment of upper and lower limb spasticity as well spastic conditions related to:
Cerebral palsy
Stroke
Acquired spinal cord or brain injury
Hereditary spastic paraparesis
Spastic hemiplegia
Neuromyelitis optica.
Multiple sclerosis or Schilder disease.
(For additional details on dystonia and spastic condition, see “A” in the Policy Guidelines section).
Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition ( eg, spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant to an anticholinergic medication.
Prophylaxis of chronic migraine headache in the following situations:
Initial 6-month trial: Adults who:
meet International Classification of Headache Disorders diagnostic criteria for chronic migraine headache and
have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications used in the treatment of chronic migraine headaches (eg, antidepressants, antihypertensives, antiepileptics). Individuals who have contraindications to preventive medications are not required to undergo a trial of these agents.
Continuing treatment beyond 6 months:
Migraine headache frequency reduced by at least 7 days per month compared with pretreatment level, or
Migraine headache duration reduced at least 100 hours per month compared with pretreatment level.
(For additional details on chronic migraine headache, see “B” in the Policy Guidelines section).
Treatment of severe axillary hyperhidrosis when potential causes of secondary hyperhidrosis have been ruled out ( eg, hyperthyroidism) and is inadequately managed by topical agents in adults.
Treatment of blepharospasm associated with dystonia or facial nerve (VII) disorders (including hemifacial spasm).
Treatment of strabismus.
Treatment of chronic sialorrhea associated with amyotrophic lateral sclerosis or atypical parkinsonian disorders or cerebral palsy or Parkinson disease or stroke or traumatic brain injury AND has experienced excessive salivation for 3 or more months AND refractory to at least 2 months of continuous treatment with at least 1 oral pharmacotherapy ( eg, anticholinergics).
Off-label use (Implies none of the 4 FDA approved botulinum toxin agents are approved or preferred for any of the indications below).
Botulinum toxin may be considered medically necessary for:
Treatment of esophageal achalasia in individuals who have not responded to dilation therapy or who are considered poor surgical candidates.
Treatment of chronic anal fissure in individuals with a history of failure, contraindication, or intolerance to 1 of the following conventional therapies: a. topical nitrates b. topical calcium channel blockers ( eg, diltiazem, nifedipine).
Treatment of individuals with Hirschsprung disease who develop obstructive symptoms after a pull-through operation.
Use of botulinum toxin is considered investigational for all other indications not specifically mentioned above, including, but not limited to:
Neurological indications such as
Headaches, except as noted above for prevention of chronic migraine headache including maintenance therapy
Essential tremor
Tinnitus
Chronic motor tic disorder and tics associated with Tourette syndrome (motor tics).
Urological indications such as
Benign prostatic hyperplasia
Interstitial cystitis
Detrusor sphincteric dyssynergia (after spinal cord injury).
Pain due to multiple etiologies such as
Chronic low back pain
Pelvic and Genital Pain in Women
Neuropathic pain
Trigeminal neuralgia
Prevention of pain associated with breast reconstruction after mastectomy
Gastrointestinal motility disorders such as
Internal anal sphincter achalasia
Anismus
Other miscellaneous conditions such as
Facial wound healing
Depression.
The use of botulinum toxin may be considered investigational as a treatment of wrinkles or other cosmetic indications.
| CPT | 31513 | Laryngoscopy, indirect, with vocal cord injection |
| 31570 | Laryngoscopy, direct, with injection into vocal cords, therapeutic | |
| 31571 | Laryngoscopy, direct, with injection into vocal cords, therapeutic; with operating microscope or telescope | |
| 43201 | Esophagoscopy, rigid or flexible; diagnostic with or without collection of specimen(s) by brushing or washing, with directed submucosal injection(s) any substance | |
| 43236 | Upper gastrointestinal endoscopy including esophagus, stomach, and either the duodenum or jejunum as appropriate; diagnostic, with or without washing, with directed submucosal injection(s) any substance | |
| 52287 | Cystourethroscopy, with injection(s) for chemodenervation of the bladder | |
| 64611 | Chemodenervation of parotid and submandibular salivary glands, bilateral | |
| 64612 | Chemodenervation of muscle(s); innervated by facial nerve (eg, for blepharospasm or hemifacial spasm) | |
| 64615 | ; muscle(s) innervated by facial, trigeminal, cervical spinal and accessory nerves, bilateral (eg, for chronic migraine) | |
| 64616 | ; neck muscle(s), excluding muscles of the larynx, unilateral (eg, for cervical dystonia, spasmodic torticollis) | |
| 64617 | ; larynx, unilateral, percutaneous (eg, for spasmodic dysphonia), includes guidance by needle electromyography, when performed | |
| 64642-64645 | Chemodenervation of one extremity code range | |
| 64646-64647 | Chemodenervation of trunk muscle(s) code range |
| HCPCS | J0585 | Injection, onabotulinumtoxinA, 1 unit |
| J0586 | Injection, abobotulinumtoxinA, 5 units | |
| J0587 | Injection, rimabotulinumtoxinB, 100 units | |
| J0588 | Injection, incobotulinumtoxinA, 1 unit |
| ICD-10-CM | G11.4 | Hereditary spastic paraplegia |
| G24.01-G24.9 | Dystonia code range (includes blepharospasm) | |
| G35 | Multiple sclerosis | |
| G51.0-G51.9 | Facial nerve disorders (includes disorders of the 7th cranial nerve) | |
| G80.0-G80.9 | Cerebral palsy code range | |
| G81.10-G81.14 | Spastic hemiplegia code range | |
| G43.011; G43.019 | Migraine without aura, intractable codes | |
| G43.111; G43.119 | Migraine with aura, intractable codes | |
| G43.411; G43.419 | Hemiplegic migraine, intractable codes | |
| G43.511; G43.519 | Persistent migraine aura without cerebral infarction, intractable codes | |
| G43.611; G43.619 | Persistent migraine aura with cerebral infarction, intractable codes | |
| G43.711; G43.719 | Chronic migraine without aura, intractable codes | |
| G43.B1 | Ophthalmoplegic migraine, intractable codes | |
| G43.D1 | Menstrual migraine, intractable codes | |
| G43.811; G43.819 | Other migraine, intractable codes | |
| G43.911; G43.919 | Migraine, unspecified, intractable codes | |
| G44.86 | Cervicogenic headache | |
| G80.0-G80.9 | Cerebral palsy code range | |
| G81.10-G81.14 | Spastic hemiplegia code range | |
| H49.00-H50.9 | Strabismus code range (Includes H50.621-H50.689 eff 10/1/2023) | |
| I69.951-I69.959 | Hemiplegia and hemiparesis following unspecified cerebrovascular disease code range | |
| K11.7 | Disturbances of salivary secretion | |
| K22.0 | Achalasia of cardia | |
| K60.1 | Chronic anal fissure | |
| N31.9 | Neuromuscular dysfunction of bladder, unspecified | |
| N32.81 | Overactive bladder | |
| N39.81 | Urge incontinence | |
| R25.0-R25.9 | Abnormal involuntary movements code range |
Dystonia is a general term describing a state of abnormal or disordered tonicity of muscle. As an example, achalasia is a dystonia of the lower esophageal sphincter, while cervical dystonia is also known as torticollis. Spasticity is a subset of dystonia, describing a velocity-dependent increase in tonic-stretch reflexes with exaggerated tendon jerks. Spasticity typically is associated with injuries to the central nervous system. Spasticity is a common feature of cerebral palsy.
International Classification of Headache Disorders (ICHD-3) diagnostic criteria for chronic migraine headache include the following:
Headaches at least 15 days per month for more than 3 months; have features of migraine headache on at least 8 days.
Features of migraine headache:
Lasts 4 to 72 hours.
Has at least 2 of the following 4 characteristics:
Unilateral
Pulsating
Moderate or severe pain intensity
Aggravates or causes avoidance of routine physical activity.
Associated with:
Nausea and/or vomiting
Photophobia and phonophobia.
(In ICHD-2, absence of medication overuse was 1 of the diagnostic criteria for chronic migraine. In the ICHD-3, this criterion was removed from the chronic migraine diagnosis and “medication overuse headache” is now a separate diagnostic category.)
Continuing treatment with botulinum toxin beyond 6 months for chronic migraine includes the following:
The policy includes the requirement that migraine headache frequency be reduced by at least 7 days per month compared with pretreatment level, or that migraine headache duration be reduced by at least 100 hours per month compared with pretreatment level in order to continue treatment beyond 6 months. The 7 days per month represents a 50% reduction in migraine days for individuals who have the lowest possible number of migraine days (ie, 15) that would allow them to meet the ICHD-3 diagnostic criteria fewest chronic migraine. A 50% reduction in frequency is a common outcome measure for assessing the efficacy of headache treatments.
This policy refers to the following botulinum toxin types A and B drug products: abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox), and rimabotulinumtoxinB (Myobloc). PrabotulinumtoxinA-xvfs (Jeuveau®) was approved by the U.S. Food and Drug Administration (FDA) on February 1, 2019 for cosmetic use and is considered out of scope of the review.
On December 9, 1989, onabotulinumtoxinA (Botox) was approved by the FDA for treatment of ocular dystonias. Since then, its use has been expanded for multiple indications.
On December 8, 2000, rimabotulinumtoxinB (Myobloc) was approved by the FDA for treatment of cervical dystonias. Since then, its use has also been expanded for multiple indications.
On April 29, 2009, abobotulinumtoxinA (Dysport) was approved by the FDA for treatment of cervical dystonias. Since then, its use has been expanded for multiple indications.
On July 30, 2010, incobotulinumtoxinA (Xeomin) was approved by the FDA for treatment of cervical dystonias and blepharospasm. Since then, its use has been expanded for multiple indications.
The FDA-approved indications for the various botulinum toxin products are summarized in Table 1. The evidence for the FDA approved indications for botulinum toxin is not reviewed.
| FDA Approved Indicationa | Botox | Dysport | Myobloc | Xeomin | |
| 1 | Overactive bladder | Approved for adults | |||
| 2 | Urinary incontinence | Approved for adults and pediatric patients ≥5 years | |||
| 3 | Limb spasticity | Approved for ≥2 years of age (upper limb and lower limb) | Approved for ≥2 years of age (upper limb and lower limb) | Approved for adults (upper limb) Approved for 2 to 17 years of age (upper limb) excluding spasticity caused by cerebral palsy |
|
| 4 | Chronic migraine | Approved for adults | |||
| 5 | Cervical dystonia | Approved for adults | Approved for adults | Approved for adults | Approved for adults |
| 6 | Severe axillary hyperhidrosis | Approved for adults | |||
| 7 | Blepharospasm | Approved for ≥12 years of age | Approved for adults | ||
| 8 | Strabismus | Approved for ≥12 years of age | |||
| 9 | Chronic sialorrhea | Approved for adults | Approved for ≥2 years of age |
FDA: U.S. Food and Drug Administration.
a 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 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.
