| Coverage Policy Manual | |
| Policy #: | 2018002 |
| Category: | Pharmacy |
| Initiated: | January 2018 |
| Last Review: | October 2024 |
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| Chemodenervation, Botulinum Toxins | |
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| 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 (e.g., Botox), abobotulinumtoxinA (e.g., Dysport), and incobotulinumtoxinA (e.g., 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 (e.g., 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.
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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 December 4, 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:
Documentation should include the following:
CONTINUATION OF THERAPY for 12 months:
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 3 months.
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 16, 2024 to December 3, 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:
Documentation should include the following:
CONTINUATION OF THERAPY for 12 months:
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.
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 February 28, 2024 to October 15, 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:
Documentation should include the following:
CONTINUATION OF THERAPY for 12 months:
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.
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 February 28, 2024, are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| 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)
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2024.
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