Summary Of Evidence

Migraine
The Health technology assessment for the acute and preventive treatment of migraine: A position statement of the International Headache Society indicates that the frequency of headaches is an important factor of classifying chronic migraines. Chronic migraine is defined as at least 3 months with 15 or more monthly headache days (MHDs), at least eight of which satisfy criteria for migraine.

“It is recommended that HTAs assess migraine frequency by counting days with migraine per month or days with headache per month, and the respective units of measure should be monthly migraine days (MMDs) and monthly headache days (MHDs). A migraine day is defined as any calendar day on which the patient had onset, continuation, or recurrence of a migraine headache.”³

FDA labels indicate that the safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month).

Achalasia
ACG Clinical Guidelines: Diagnosis and Management of Achalasia recommends “botulinum toxin injection as first-line therapy for patients with achalasia that are unfit for definitive therapies compared with other less-effective pharmacological therapies.” “Botulinum toxin is the best studied pharmacotherapy in achalasia, and it is the most effective pharmacological treatment that can be offered; however, its benefits are short lived, and the medication should not be offered as first-line treatment to patients who are fit for myotomy.”⁴

Anal Fissures
“Lateral internal sphincterotomy is still regarded as the gold standard treatment for chronic fissures, despite known potential for serious morbidity, namely fecal incontinence. Therefore, a search for less invasive procedures has been ongoing, including topical nitrates and botulinum toxin injections. However, nitrates are poorly tolerated due to their association with headaches. This chemical denervation is not permanent, and the clinical efficacy generally lasts for 2-3 months, which is enough time for sphincter resting pressure reduction to allow for healing.”⁵

Analysis of Evidence

N/A

Botulinum toxins are potent neuromuscular blocking agents that are useful in treating various focal muscle spastic disorders and excessive muscle contractions, such as dystonia, spasms, and twitches. They produce a presynaptic neuromuscular blockade by preventing the release of acetylcholine from the nerve endings. Since the resulting chemical denervation of muscle produces local paresis or paralysis, selected muscles can be treated. Botulinum toxins are used in the treatment of overactive skeletal muscles (e.g., Hemifacial spasm, dystonia and spasticity), smooth muscles (e.g., Detrusor overactivity and achalasia), glands (e.g., Sialorrhoea and hyperhidrosis) and additional conditions that are being investigated.

There are currently 4 botulinum toxin products commercially available in the United States: onabotulinumtoxinA, rimabotulinumtoxinB, abobotulinumtoxinA, and incobotulinumtoxinA. Each preparation has distinct pharmacological and clinical profiles specified on the product insert. Dosing patterns are specific to the preparation of neurotoxin and varies between different serotypes. Failure to recognize the unique characteristics of each formulation of botulinum toxin can lead to undesired patient outcomes. It is expected that physicians will be familiar with and experienced in the use of these agents and utilize evidence-based medicine to select the appropriate drug and dose regimen for each patient condition. A patient who is not responsive or who ceases to respond to one serotype may respond to the other.

Limitations
Voluntary muscular contraction depends upon the release of acetylcholine from vesicles within a nerve ending following stimulation of the nerve. The acetylcholine is released into the neuromuscular junction, binding to specific proteins called receptors in the membrane of the muscle fiber. The effect of the acetylcholine at these receptors is to cause the muscle to contract. When a sufficient amount of acetylcholine has been released with subsequent binding to the muscle fiber proteins, muscle contraction occurs. Botulinum toxin type A and botulinum toxin type B create a chemical blockade by inhibiting the release of acetylcholine from the nerve ending vesicles thereby preventing the acetylcholine from binding to the proteins in the receptor site on the muscle. Localized weakness or paralysis occurs in the muscle injected with botulinum toxin.

Approved indications for botulinum toxin type A and toxin type B differ. WPS GHA has determined that the separate accepted indications for the botulinum toxin products will be combined into a single list of covered indications in this Local Coverage Determination (LCD). It is the responsibility of providers to use each drug in accordance with approved indications. While this policy contains a single list of covered indications, this is not meant to imply that botulinum toxin products are interchangeable.

1. Coverage of botulinum toxin for certain spastic conditions (e.g., cerebral palsy, stroke, head trauma, spinal cord injuries, and multiple sclerosis) will be limited to those conditions listed in the Billing and Coding: Botulinum Toxin Type A & B (A57474).  All other uses in the treatment of other types of spasm will be considered as investigational and therefore, non-covered by Medicare.
2. Since organic writer's cramp is uncommon, Medicare would not expect to see the treatment of this condition to be billed frequently.
3. The patient who has a spastic or excessive muscular contraction condition is usually started with a low dose of botulinum toxin.  Other spastic or muscular contraction conditions, such as eye muscle disorders, (e.g., blepharospasm) may require lesser amounts of botulinum toxin.  For larger muscle groups, it is generally agreed that once a maximum dose per site has been reached and there is no response, the treatment is discontinued.  The treatments may be resumed at a later date.  With response, the effect of the injections generally lasts for 3 months at which time the patient may require repeat injections to control the spastic or excessive muscular condition. 
4. It is usually considered not medically necessary to give botulinum toxin injections for spastic conditions more frequently than every 12 weeks.
5. Coverage of treatments provided may be continued unless any 2 treatments in a row, utilizing an appropriate or maximum dose of botulinum toxin failed to produce satisfactory clinical response. 
6. Botulinum toxin may be covered in the treatment of achalasia. According to the 2018 ISDE achalasia guidelines, botulinum injections should mainly be used in patient’s age 50 or greater and for patients that are unfit for surgery or as a bridge to more definitive therapies such as surgery or balloon dilatation.¹
7. Chronic migraine is defined as a “headache occurring on 15 or more days a month for more than three months, which, on at least eight days/month has the features of migraine headache.²”. Treatment of chronic migraines will be covered when they meet the following diagnostic criteria: for migraine with aura and /or criteria for migraine without aura. Treatment with botulinum toxin may be given every 12 weeks as multiple injections around the head and neck.

   1. Migraine with aura²:

      1. At least two attacks fulfilling the following criteria a and b
         1. One or more of the following fully reversible aura symptoms
            • Visual (aura, changes in vision)
            • sensory (e.g., tingling in hands or face, pins and needles, numbness
            • speech and/or language difficulties)
            • motor (e.g., weakness)
            • brainstem (e.g., vertigo, tinnitus, loss of hearing, diplopia, ataxia not attributable to sensory deficit, and decreased level of consciousness)
            • retinal (visual disturbance, flash of light, blind spot)
         2. At least three of the following six characteristics:
            • at least 1 aura symptom spreads gradually over > 5 minutes
            • 2 or more aura symptoms occur in succession
            • each individual aura symptoms last 5-60 minutes
            • at least 1 aura symptom is unilateral
            • at least 1 aura symptom is positive
            • the aura is accompanied, or followed within 60 minutes, by headache
   2. Migraine without aura²:
      1. At least 5 attacks fulfilling the following criteria
         • Headache attacks lasting 4-72 hours (when untreated or unsuccessfully treated)
         • Headache has at least two of the following:
           • unilateral location
           • pulsating quality
           • moderate or severe pain intensity
           • aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
         • During headache at least one of the following:
           • nausea and/or vomiting
           • photophobia and phonophobia
8. Botulinum toxin for chronic anal fissure may be considered for the patient who has not responded satisfactorily to conservative treatment. Conservative treatment may include the use of bulking agents, sitz baths or topical agents.
9. Botulinum toxin is covered for hyperhidrosis that significantly affects one’s quality of life and cannot be managed adequately with topical agents.