|MP 5.01.05||Botulinum Toxin|
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
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, 3 using type A serotype and 1 using type B. The drug names of the botulinum toxin products were changed in 2009; trade names and product formulations did not change. The 3 formulations of botulinum toxin type A are currently called onabotulinumtoxinA (Botox®), abobotulinumtoxinA (Dysport®), and incobotulinumtoxinA (Xeomin®). Botox has been available for the longest time in the United States 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 that is stable at room temperature for up to 4 years. Myobloc® contains botulinum toxin type B; the current name of this drug is rimabotulinumtoxinB.
All 4 products are approved by FDA for the treatment of cervical dystonia in adults; this is the only FDA-approved indication for Myobloc. Dystonia is a general term describing a state of abnormal or disordered tonicity of muscle. As an example, esophageal 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. Botox is also approved for treating upper limb spasticity in adults.
Among the botulinum toxin products, onabotulinumtoxinA (Botox) is FDA-approved for the largest number of indications. Other than the indications mentioned above, this includes axillary hyperhidrosis in adults and in individuals at least 12 years of age, blepharospasm, and strabismus. On October 15, 2010, FDA approved Botox injection for prevention of chronic migraine. Chronic migraine is defined as episodes that otherwise meet criteria for migraine (eg, at least 4 hours in duration) that occur on at least 15 days per month for more than 3 months, in the absence of medication overuse. OnabotulinumtoxinA is also approved for treatment of urinary incontinence due to neurogenic conditions causing detrusor overactivity in patients unresponsive to or intolerant to anticholinergic medication. Most recently, in 2013, onabotulinumtoxinA received FDA approval for treatment of overactive bladder in adults who are unresponsive to or intolerant of anticholinergic medication.
The newest product, Xeomin, is approved for treating blepharospasm.
Two products, Botox (marketed as Botox Cosmetic) and Dysport, are approved for temporarily improving the appearance of glabellar (frown) lines in adults younger than 65 years of age.
The botulinum toxin products have also been used for a wide variety of off-label indications, ranging from achalasia, spasticity after strokes, cerebral palsy, and anal fissures.
Botox® (Allergan, Irvine, CA) was approved by the FDA in 1991, Myobloc® (Solstice Neurosciences) in 2000, Dysport® (Medicis Pharmaceutical Corporation, Scottsdale, AZ) in 2009, and Xeomin® (Merz Pharmaceuticals) in 2010(1).
The use of botulinum toxin may be considered medically necessary for the following:
- Cervical dystonia (spasmodic torticollis; applicable whether congenital, due to child birth 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 one or more of the muscles of the neck, eg, sternocleidomastoid, splenius, trapezius, or posterior cervical muscles.* (See additional details in Policy Guidelines section.)
- Blepharospasm or facial nerve (VII) disorders (including hemifacial spasm)*
- Upper limb spasticity*
- Prevention (treatment) of chronic migraine headache in the following situations*:
- Initial 6-month trial: Adult patients who:
- meet International Classification of Headache Disorders (ICHD-2) diagnostic criteria for chronic migraine headache (key criteria include migraine headaches lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months; absence of medication overuse); 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, and antiepileptics. Patients 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 to pretreatment level, or
- Migraine headache duration reduced at least 100 hours per month compared to pretreatment level.
- Dystonia/spasticity resulting in functional impairment (interference with joint function, mobility, communication, nutritional intake) and/or pain in patients with any of the following:
- Focal dystonias:
- 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
- Spastic conditions
- Cerebral palsy
- Spasticity related to stroke
- Acquired spinal cord or brain injury
- Hereditary spastic paraparesis
- Spastic hemiplegia
- Neuromyelitis optica
- Multiple sclerosis or Schilder disease
- Esophageal achalasia in patients who have not responded to dilation therapy or who are considered poor surgical candidates
- Sialorrhea (drooling) associated with Parkinson disease
- Chronic anal fissure
- Urinary incontinence due to detrusor overactivity associated with neurogenic causes (eg, spinal cord injury, multiple sclerosis) in patients unresponsive to or intolerant of anticholinergics*
- Overactive bladder in adults unresponsive to or intolerant of anticholinergics*
- Focal dystonias:
* FDA-approved indication for at least one of the agents.
With the exception of cosmetic indications, the use of botulinum toxin is considered investigational for all other indications not specifically mentioned above, including, but not limited to:
- headaches, except as noted above for prevention (treatment) of chronic migraine headache
- chronic low back pain
- joint pain
- mechanical neck disorders
- neuropathic pain after neck dissection
- myofascial pain syndrome
- trigeminal neuralgia
- pain after hemorrhoidectomy or lumpectomy
- tremors such as benign essential tremor (upper extremity
- sialorrhea (drooling) except that associated with Parkinson disease
- chronic motor tic disorder (ICD-9 307.22), and tics associated with Tourette syndrome (motor tics) (ICD-9 307.23)
- lateral epicondylitis
- benign prostatic hyperplasia
- interstitial cystitis
- detrusor sphincteric dyssynergia (after spinal cord injury)
- prevention of pain associated with breast reconstruction after mastectomy
- Hirschsprung’s disease
- Facial wound healing
- Internal anal sphincter (IAS) achalasia
The use of botulinum toxin may be considered not medically necessary as a treatment of wrinkles or other cosmetic indications.
The use of assays to detect antibodies to botulinum toxin is considered investigational.
Cervical dystonia is a movement disorder (nervous system disease) characterized by sustained muscle contractions. This results in involuntary, abnormal, squeezing and twisting muscle contractions in the head and neck region. These muscle contractions result in sustained abnormal positions or posturing. Sideways or lateral rotation of the head and twisting of the neck is the most common finding in cervical dystonia. Muscle hypertrophy occurs in most patients. When using botulinum toxin to treat cervical dystonia, the postural disturbance and pain must be of a severity to interfere with activities of daily living; and the symptoms must have been unresponsive to a trial of standard conservative therapy. In addition, before using botulinum toxin, alternative causes of symptoms such as cervicogenic headaches must have
been considered and excluded.
Continuing treatment with botulinum toxin beyond 6 months for chronic migraine: The policy includes the requirement that migraine headache frequency be reduced by at least 7 days per month compared to pretreatment level, or that migraine headache duration be reduced by at least 100 hours per month compared to pretreatment level in order to continue treatment beyond 6 months. The 7 days per month represents a 50% reduction in migraine days for patients who have the lowest possible number of migraine days (15) that would allow them to meet the ICHD-2 diagnostic criteria for chronic migraine. A 50% reduction in frequency is a common outcome measure for assessing the efficacy of headache treatments and is one of the endpoints of the PREEMPT study.
In 2014, CPT established new chemodenervation codes for neck, larynx, extremity and trunk muscles:
64616: Chemodenervation of muscle(s); 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: Chemodenervation of 1 extremity; 1-4 muscle(s)
64643: each additional extremity, 1-4 muscle(s) (List separately in addition to code for primary procedure)
64644: Chemodenervation of 1 extremity; 5 or more muscle(s)
64645: each additional extremity, 5 or more muscle(s) (List separately in addition to code for primary procedure)
64646: Chemodenervation of trunk muscle(s); 1-5 muscle(s)
64647: 6 or more muscle(s)
In 2013, CPT established specific codes for chemodenervation of the bladder and chemodenervation associated with treatment of chronic migraine:
52287: Cystourethroscopy, with injection(s) for chemodenervation of the bladder
64615: Chemodenervation of muscle(s); muscle(s) innervated by facial, trigeminal, cervical spinal and accessory nerves, bilateral (eg, for chronic migraine)
In 2003, CPT established 2 codes (43201 and 43236) for upper gastrointestinal endoscopy procedures with submucosal injection, any substance. These codes could apply to the use of botulinum toxin for the treatment of achalasia.
In 2011, CPT established a code for chemodenervation of parotid and submandibular salivary glands such as that to treat sialorrhea:
64611: Chemodenervation of parotid and submandibular salivary glands, bilateral
If fewer than 4 salivary glands are injected, code 64611 is to be reported with a modifier -52 to signify reduced service.
BlueCard/National Account Issues
Electromyographic (EMG) guidance may be used to direct the injection of the botulinum toxin, particularly for treatment of the larynx or esophagus. Beginning in 2006, there is a new CPT code for needle EMG guidance for chemodenervation (code 95874), as well as a code for electrical stimulation guidance (code 95873). Consideration of the guidance codes should be based on whether the botulinum toxin is being used for a medically necessary indication.
Injection of the vocal cords is done in association with laryngoscopic guidance. As indicated by the CPT code (31513, 31570, or 31571), laryngoscopy is considered an integral part of the procedure, and separate billing for laryngoscopy and injection is not warranted.
Botulinum toxin as a treatment of achalasia requires a separate endoscopy procedure, which is billed separately.
Botulinum toxin may be covered under the Drug or Medical benefit as determined by each individual Plan.
This policy was originally created in 1997 and was updated regularly with searches of the MEDLINE database. Most recently, the literature was reviewed through September 1, 2014. For studies published before 2000, it is assumed that Botox, the only Food and Drug Administration (FDA)‒approved agent at that time, was used.
This policy 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 assessments of movement disorders and spasticity,(2-4) and additional controlled trials identified by MEDLINE literature searches.
The AAN assessments concluded that the evidence was AAN level A (established as effective, should be done) for equinus varus deformity in children with cerebral palsy and level B (probably effective, should be considered) for upper-extremity and 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 focal limb dystonia but insufficient for lower focal limb dystonia, and was rated level B for adductor laryngeal dystonia but insufficient for abductor laryngeal dystonia.(2-4) The bulk of the literature is based on trials using onabotulinumtoxinA (ie, Botox).
In a 2013 meta-analysis, Foley et al identified 16 randomized controlled trials (RCTs) comparing injection of botulinum toxin to placebo injections or a nonpharmacologic treatment of moderate to severe upper-extremity spasticity following stroke.(5) Studies evaluated the impact of treatment on activity limitations. Ten trials with a total of 1000 patients had data suitable for pooling. In a pooled analysis of effect size, botulinum toxin was associated with a moderate treatment effect compared to comparison interventions (standardized mean difference [SMD], 0.54; 95% confidence interval [CI], 0.35 to 0.71; p<0.001). Another meta-analysis, also published in 2013, had similar findings; it identified 10 trials on botulinum toxin for limb spasticity and found moderate evidence of efficacy.(6)
The largest RCT was published in 2011 by Shaw et al and randomized 333 patients with poststroke upper-limb spasticity to physical therapy plus Dysport (n=170) or physical therapy alone (n=163).(7) The primary outcome, improved function at 1 month according to the Action Research Arm Test (ARAT), did not differ significantly among groups. Improved function according to ARAT scores also did not differ significantly between groups at 3 or 12 months. Change in muscle tone according to median change in the Motor Assessment Scale significantly favored the Dysport group over the placebo group at 1 month (mean change, -0.6 and -0.1, respectively, p<0.001), but not at 3 and 12 months.
Several European trials have evaluated Xeomin for poststroke upper-limb spasticity. Kanovsky et al randomized 148 patients with poststroke upper-limb spasticity to treatment with either Xeomin or placebo.(8) After 4 weeks, a significantly higher response rate was found in all treated flexor muscle groups among patients treated with Xeomin compared to placebo. The treatment benefit lasted through the week-12 visit. An open-label extension of this study with 145 participants was published in 2011.9 Patients received up to 5 additional sets of Xeomin injections, with 12-week intervals between injections. A total of 111 patients (77%) had at least 3 injections and 72 (50%) had 4 injections. Outcomes were assessed 4 weeks after each injection. Compared to baseline, patients consistently showed improved outcomes at each posttreatment visit. None of the patients developed neutralizing antibodies in either the double-blind or extension phases of the study.
A 2007 systematic review identified 70 studies that examined 2 botulinum toxin agents used to treat cervical dystonia.(10) There were 30 studies on Botox, 24 on Dysport, 11 on Myobloc, and 5 combining 2 agents. Xeomin for treating cervical dystonia has been evaluated in an RCT that found it to be noninferior to Botox.(11)
Multiple RCTs and meta-analyses support the efficacy of botulinum toxin for treating dystonia/spasticity and this is a labeled indication.
Strabismus is a condition in which the eyes are not in proper alignment with one another. In 2012, a Cochrane review was published by Rowe et al evaluating the literature on botulinum toxin for strabismus.(12) The investigators identified 4 RCTs, all of which were published in the 1990s. Three trials compared botulinum toxin injection to surgery, and 1 compared botulinum toxin injection to a noninvasive treatment control group. Among the trials that used surgery as a comparison intervention, 2 studies found no statistically significant differences in outcomes between the 2 groups, and 1 found a higher rate of a satisfactory outcome in the surgery group. The study comparing botulinum toxin to 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.
For patients who failed prior surgery, Tejedor and Rodriguez conducted a trial in 1999 that included 55 children with strabismus who remained symptomatic after surgical alignment.(13) Patients were randomly assigned to receive a second operation (28 patients) or botulinum toxin injection (n=27). Motor and sensory outcomes did not differ significantly in the 2 groups. At 3 years, for instance, 67.8% of children in the reoperation group and 59.2% of children in the botulinum toxin group were within 8 prism diopters of orthotropias (p=0.72). In 1994, Lee et al randomized 47 patients with acute unilateral sixth nerve palsy to botulinum toxin treatment or a no treatment control group.(14) The final recovery rate was 20 (80%) of 25 in the botulinum toxin group and 19 (86%) of 22 in the control group.
Several RCTs from the 1990s have mixed results concerning the efficacy of botulinum toxin for strabismus. This evidence has not established that botulinum toxin improves outcomes for patients with strabismus. However, because this treatment is a noninvasive alternative to surgery, it may be considered medically necessary.
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.(15-17) No RCTs that evaluated Myobloc for treating blepharospasm were identified in literature searches.
Due to evidence indicating that at least 1 botulinum toxin agent is an effective treatment of blepharospasm, botulinum toxin is considered medically necessary for this indication.
Esophageal achalasia is a primary motor disorder characterized by abnormal lower esophageal sphincter relaxation. Randomized, placebo-controlled trials initially validated the efficacy of botulinum toxin in treating esophageal achalasia. In 1999, Vaezi et al18 reported a trial that randomly assigned 42 patients with esophageal achalasia to either receive botulinum toxin or undergo pneumatic dilation. Pneumatic dilation resulted in a significantly higher cumulative remission rate. At 12 months, 70% of patients in the dilation group were still in remission compared to 32% of those in the botulinum toxin group. These results reflect the fact that the effects of botulinum toxin are known to be reversible but also the fact that pneumatic dilation can provide durable treatment effects. The authors concluded that while botulinum
toxin is an effective therapy, pneumatic dilation is the preferred medical treatment option. This conclusion is supported by a 2006 Cochrane systematic review and meta-analysis of 178 patients treated with either botulinum toxin or pneumatic dilation.(19)
An RCT by Annese et al in Italy with 78 patients found 100 units of Botox and 250 units of Dysport to have comparable efficacy for treating esophageal achalasia.(20)
Due to evidence indicating that at least 1 botulinum toxin agent is an effective treatment of esophageal achalasia, botulinum toxin is considered medically necessary for this indication.
Internal Anal Sphincter Achalasia
Internal anal sphincter (IAS) achalasia is a disorder of defecation in which the internal anal sphincter is unable to relax. Symptoms include severe constipation and soiling. A systematic review of studies on treatment of IAS achalasia was published in 2012 by Friedmacher and Puri.(21) The authors did not identify any RCTs of Botox treatment. Two prospective case series and 14 retrospective case series with a total of 395 patients with IAS achalasia were identified. The majority of patients in the series, 229 (58%) of 395, 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 the overall complication rates, did not differ with the 2 treatments.
Due to a lack of RCTs, and a meta-analysis of observational data suggesting that posterior IAS myectomy results in greater improvement in health outcomes than botulinum toxin injections, botulinum toxin for treating IAS achalasia is considered investigational.
Chronic anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the internal anal sphincter 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 randomly assigned 30 patients with chronic anal fissure to receive either 2 injections of 20 units of botulinum toxin, on either side of the fissure, or 2 injections of saline.(22) After 2 months, 11 patients (73%) in the treated group and 2 patients (13%) in the control group had healed fissures (p=0.003); 13 patients (87%) 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 and botulinum toxin in a randomized trial of 50 patients.(23) 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 with 92% versus 70%, respectively, healing rates for botulinum toxin A-treated versus nitroglycerin ointment-treated patients (p<0.001).(24) Another trial by Brisinda et al found that Botox and Dysport used to treat anal fissures were similar in terms of efficacy and tolerability.(25) Others have reported both supportive26 and contradictory27 data from randomized trials comparing the same treatments. RCTs of
botulinum toxin versus 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.(28-30)
A 2012 systematic review of the literature identified 2 RCTs comparing botulinum toxin with placebo, 1 RCT comparing botulinum toxin with lidocaine pomme, 5 RCTs comparing botulinum toxin with nitrates, and 8 RCTs comparing botulinum toxin with surgery.(31) A meta-analysis was not performed due to heterogeneity among studies. The author noted that the studies tended to be small and of short duration, and superiority of botulinum toxin over surgery has not been demonstrated. However, due to the fact that it is a minimally invasive option that can be repeated, it is a reasonable option prior to surgery.
Due to evidence of effectiveness in numerous small RCTs, combined with being a less invasive option than the gold standard of surgery, botulinum toxin is considered medically necessary for treatment of anal fissure.
Overactive Bladder/Neurogenic Detrusor Overactivity
Several meta-analyses of RCTs have been published.(32-34) In 2014, Cui et al identified 6 double-blind RCTs comparing botulinum toxin A with placebo for treating patients with idiopathic OAB.(33) In a pooled analysis of 3 studies, patients treated with botulinum toxin were significantly more likely to be incontinence-free at the end of the study (OR=4.89; 95% CI, 3.11 to 7.70). Moreover, a pooled analysis of 5 studies found significantly greater reduction in the number of incontinence episodes per day in the group treated with botulinum toxin (SMD=-1.68; 95% CI, -2.06 to -1.31). Previously, in 2011, Duthie et al published a Cochrane review of RCTs evaluating botulinum toxin injections for patients with idiopathic or neurogenic OAB.(34) The authors identified 19 trials that compared treatment with botulinum toxin to placebo or another intervention. Two studies included botulinum toxin B; the remainder included botulinum toxin A. The outcomes reported varied, which made it difficult for the authors to pool study findings. A pooled analysis of 3 studies reporting change in urinary frequency episodes at 4 to 6 weeks reported a significantly better outcome with botulinum toxin injection compared to placebo (pooled mean difference, -6.50; 95% CI, -8.92 to -4.07). A pooled analysis of 3 studies on change in incontinence episodes at 4-6 weeks also found a significantly greater improvement with botulinum toxin (mean difference, -1.58; 95% CI, -2.16 to -1.01).
Other systematic reviews have included both controlled and uncontrolled studies. A 2013 systematic review by Soljanik identified 28 studies evaluating onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity/neurogenic overactive bladder; 6 of the studies were RCTs.(35) The authors reported
that studies with comparative data found superior outcomes with onabotulinumtoxinA compared to placebo. Data from the RCTs were not pooled. Serious adverse events were not reported. However, adverse events after intradetrusor botulinum toxin injection included postvoid residual urine (50%), urinary retention (23.7%), and urinary tract infection (16.7%). Also in 2013, Mehta et al identified 14 studies evaluating botulinum toxin A for treating neurogenic detrusor overactivity after spinal cord injury; only one was an RCT.(36) The authors interpreted effect sizes as small, greater than 0.2; moderate, greater than 0.5; or large, greater than 0.8. Studies tended to have large effect sizes for outcomes including bladder capacity and reflex detrusor volume. Rate of incontinence episodes decreased after treatment with botulinum toxin A from 23% to 1.3% per day. Previously in 2008, Karsenty et al identified 18 studies evaluating botulinum toxin A to treat patients who were refractory to anticholinergics.(37) Most of the studies reported statistically significant improvement in clinical and urodynamic outcomes, without major adverse events.
Representative large, double-blind RCTs are described below.
In 2013, Nitti et al published data from an industry-supported study that included 557 patients with overactive bladder and urinary incontinence inadequately controlled by anticholinergics.(38) Patients were randomized to receive an intradetrusor injection of onabotulinumtoxinA 100 units or placebo. At the 12-week follow-up, there was a statistically significantly greater improvement in the daily frequency of urinary incontinence episodes in the group that received botulinum toxin than in the placebo group (-2.65 vs -0.87, p<0.001). The other primary end point was the proportion of patients with a positive response at week 12 according to the treatment benefit scale. A significantly larger proportion of patients in the botulinum toxin group than the placebo group reported a treatment benefit (60.8% vs 29.2%, p<0.001). A total of 22.9% of patients in the botulinum toxin group and 6.5% of patients in the placebo group became completely continent. In the first 12 weeks after injection, urinary tract infections occurred in 43 (15.5%) of 278 patients in the botulinum toxin group and 16 (5.9%) of 272 patients in the placebo group. Urinary retention was reported by 15 patients (5.4%) in the botulinum toxin group and 1 patient (0.4%) in the placebo group. Between-group p values were not reported for adverse effects.
A 2012 industry-supported RCT by Ginsberg et al included 416 patients with neurogenic detrusor activity associated with multiple sclerosis or spinal cord injury.(39) Patients were randomized to receive injections with 200 units of onabotulinumtoxinA, 300 units of onabotulinumtoxinA or placebo. Decrease in the mean number of weekly incontinence episodes at week 6, the primary end point, was significantly greater in both active treatment groups (-21 in the 200-unit group, -23 in the 300-unit group) than in the placebo group (-9, p<0.001). Urinary retention was a common adverse event. Among patients who did not catheterize at baseline, 35% in the 200-unit group, 42% in the 300-unit group and 10% on placebo initiated catheterization. A total of 329 (79%) of 416 patients completed the 52-week study; however, outcomes such as the number of weekly incontinence episodes were not reported at 52 weeks.
Numerous RCTs, as well as observational data, report improvements in outcomes following botulinum toxin treatment in patients with neurogenic detrusor overactivity or overactive bladder who are unresponsive to anticholinergic medication. Despite the risk of adverse events, including urinary retention and urinary tract infection, evidence suggests that botulinum toxin improves the net health outcome.
Detrusor Sphincter Dyssynergia
In 2002, deSeze 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 randomly assigned to receive perineal botulinum toxin A or lidocaine injections into the external urethral sphincter.(40) In the botulinum group, there was a significant decrease in the primary outcome of postvoid residual volume compared to no change in the control group receiving a lidocaine injection. Improvements were also seen in the satisfaction scores and other urodynamic outcomes.
Systematic reviews had addressed this potential indication for botulinum toxin injection. Most recently, in 2012, Mehta et al conducted a systematic review of literature on botulinum toxin injection as a treatment of detrusor external sphincter dysfunction and incomplete voiding after spinal cord injury.(41) The authors identified 2 RCTs in addition to uncontrolled studies. The RCTs included the deSeze study, discussed above and a second study that included only 5 patients. A 2008 systematic review by Karsenty et al reviewed trials of botulinum toxin 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.(42) In the former group, the authors cited 10 small studies (N range, 3-53;3 studies included patients in both categories). Most patients were quadriplegic men unable to perform self-catheterization or patients (of both genders) with multiple sclerosis. All except 2 studies were case reports or case series; the 2 controlled studies were the same ones included in the Mehta systematic review. Authors of both systematic reviews noted that, while most of the available studies have reported improvements with botulinum toxin injections, there are few published studies, and studies included small
numbers of patients.
There is insufficient evidence from RCTs on the impact of botulinum toxin on health outcomes for patients with detrusor sphincter dyssynergia; therefore, this indication is considered investigational.
Benign Prostatic Hyperplasia
The rationale for botulinum treatment is based on the theory that symptoms of benign prostatic hyperplasia are in part due to 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 of the literature on use of botulinum toxin in treating benign prostatic hyperplasia.(43) The authors identified 25 studies on this topic, including controlled and uncontrolled studies and abstracts published in journal supplements. There were 6 RCTs, 3 published as full articles and 3 as abstracts. Two of the 3 published RCTs were considered to be of sufficient quality for meta-analysis. The authors reported that pre- and posttreatment mean post-voiding residue did not differ significantly; pooled results were not reported for between-group outcomes. One of the RCTs was published by Maria et al in 2003.(44) The investigators reported on 30 patients with benign prostatic hyperplasia (BPH) randomly assigned to receive either intraprostatic botulinum toxin A or saline injection. Inclusion criteria for this trial included moderate-to-severe symptoms of BPH based on the American Urological Association (AUA) score and a mean peak urinary flow rate of no more than 15 mL
per second with a voided volume of 150 mL or less. After 2 months, the AUA symptom score decreased by 65% among those receiving botulinum toxin compared to no significant change in the control group. The mean peak urinary flow rate was significantly increased in the treatment group.
Given the prevalence of BPH, larger trials with good methodology that compare the role of botulinum toxin with other medical and surgical therapies for treating BPH are warranted before conclusions can be drawn about the impact of this technology on health outcomes.
Several case series (<20 participants) of botulinum toxin treatment of patients with interstitial cystitis for alleviation of chronic pain and improving bladder capacity have been published (eg,(45-47)). All report subjective improvement in a majority of patients and statistically significant improvement in various measured parameters, such as pain rated by visual analog scale (VAS), frequency, nocturia, and functional bladder capacity.
There is insufficient evidence from case series on small numbers of patients with interstitial cystitis. Controlled trials are needed to confirm efficacy and safety of botulinum toxin in this population.
Tremor may be defined as alternate or synchronous contractions of antagonistic muscles. Some patients may be disabled by severe or task-specific tremors. Tremors are also a frequent component of dystonias, and successful treatment of dystonias resulted in an improvement in tremors. Botulinum toxin has been investigated in patients with tremors unrelated to dystonias; however, most reports are case reports or case series. Two randomized, placebo-controlled studies addressed essential hand tremors; the 2001 trial enrolled 133 patients, and the 1996 trial enrolled 25 patients.(48,49) In both studies, inconsistent significant advantages for botulinum toxin were found on tremor symptom scales, but none were shown on functional outcomes.
The clinical significance of findings from 2 RCTs with inconsistent outcomes is unclear. Botulinum toxin is therefore considered investigational for treating tremors, such as benign essential tremor.
Sialorrhea (Drooling) Associated with Parkinson Disease
Several RCTs have evaluated botulinum toxin injection in patients with Parkinson disease. For example, in 2006, Lagalla et al. randomly assigned 32 patients with Parkinson disease to placebo or 50 units of botulinum toxin A; evaluation at 1 month postinjection resulted in significant improvements compared with placebo, in drooling frequency, saliva output, and in familial and social embarrassment.(50) Dysphagia scores were not significantly improved. Moreover, Ondo et al randomly assigned 16 patients with Parkinson disease to receive placebo or 2500 units of botulinum toxin B (Myobloc).(51) The botulinum toxin group had significantly better outcome 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(52) assigned 20 patients with Parkinson disease to injections of either a saline placebo or 450 units of Dysport. The treatment group was significantly better than placebo on a drooling scale at 1 week; the effect disappeared by 3 months.
RCTs have consistently found benefit of botulinum toxin injection on sialorrhea in patients with Parkinson disease.
Sialorrhea (Drooling) Not Associated with Parkinson Disease
Several systematic reviews have been published on 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 (ALS)/motor neuron disease (MND).(53) The review included both RCTs and controlled and uncontrolled observational studies. The authors identified 12 studies of which 8 did not have a control group. There were 2 small RCTs, 1 had 20 patients and was placebo-controlled and the other had 14 patients and compared botulinum toxin with radiotherapy. Sample sizes in the non-RCTs ranged from 5 to 26. Due to heterogeneity, study findings were not pooled. As reported in the systematic review, only 1 of the 2 RCTs reported drooling outcomes; this study found a significantly greater reduction in saliva volume in the botulinum toxin group than the placebo group at 2 weeks.
In 2012, Rodwell et al published a systematic review of published literature evaluating botulinum toxin injections in the salivary gland for treating sialorrhea in children with cerebral palsy and neurodevelopment disability.(54) The authors identified 5 RCTs; sample sizes in individual trials ranged from 6 to 48 participants. One of the RCTs, which had 6 participants, 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 (DFSS) was significantly lower in children who received botulinum toxin injections compared to a control intervention (mean difference, -2.71 points; 95% CI, -4.82 to -0.60; p<0.001). The clinical significance of this degree of difference in DFSS 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 that was 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 al55 Forty-eight children with cerebral palsy (n=31) and other neurologic disorders (n=17) were randomized to a single injection of 25 units of botulinum toxin A compared with no treatment. Drooling was assessed by administering the Drooling Impact Scale. Scores were significantly different between groups at 1 month, and a beneficial effect of botulinum toxin injection remained at 6 months.
A 2013 article focused on the long-term safety of botulinum toxin A injection for treating sialorrhea in children.(56) The study included 69 children; 47 (68%) had cerebral palsy. Children received their first injection of botulinum toxin at a mean age of 9.9 years, and 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. These included 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.
Although there is evidence of improvement in drooling scales following botulinum toxin injections in children with cerebral palsy, the clinical significance is uncertain, and there are concerns about the safety of injecting botulinum toxin into the salivary gland in this population. The evidence on botulinum toxin for treating sialorrhea in patients with ALS/MND is insufficient due to the small number of controlled studies, small sample sizes of available studies, and limited reporting of drooling outcomes.
Chronic Low Back Pain
Only 1 RCT of botulinum toxin A treatment in patients with low back pain has been published.(57) The trial, published in 2001, enrolled 31 consecutive patients with chronic low back pain of at least 6 months in duration and more predominant pain on 1 side. Patients were injected with 40 units of Botox (Allergan Inc.) at 5 lumbosacral locations for a total of 200 units (treated group) or saline placebo (placebo group). Injections were made on 1 side of the back only, depending on predominance of pain. At 8 weeks, 60% of treated patients and 12.5% of placebo patients showed improvement in VAS pain scores (p=0.009). Perceived functional status (Oswestry Disability Index) at 8 weeks showed that 66.7% of treated patients and 18.8% of placebo patients were responders (p=0.011).
The population with chronic low back pain is heterogeneous. Results of 1 small RCT in a group of selected subjects cannot be used to generalize results for the whole population with chronic low back pain. Furthermore, studies should examine the long-term effectiveness of using repeated courses of botulinum toxin to determine the durability of repeated treatments. Botulinum toxin is considered investigational for treatment of chronic low back pain.
Botulinum toxin for treatment of pain from migraine and from chronic tension-type headaches was addressed in a 2002 TEC Assessment that was updated in 2004.3 Both TEC Assessments concluded that the evidence was insufficient for either indication. Because of the typically high placebo response rate 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 variable in addition to pain or headache severity.
Migraines can be categorized, among other characteristics, according to headache frequency. According to the Second Edition of the International Headache classification (ICHD-2), migraine without aura (previously known as common migraine) is defined as at least 5 attacks per month meeting other diagnostic criteria.(58)
Chronic migraine is defined as attacks on at least 15 days per month for more than 3 months, in the absence of medication overuse.
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 pharmacological treatments for migraine in adults.(59) The investigators identified 15 double-blind RCTs evaluating botulinum toxin for migraine prevention; 13 used onabotulinumtoxinA and 2 used abobotulinumtoxinA. In a meta-analysis of 3 RCTs, onabotulinumtoxinA was found to be more effective than placebo in reducing the number of chronic migraine episodes per month by at least 50% (risk ratio [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 and 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.
In 2012, Jackson et al conducted a meta-analysis of RCTs on botulinum toxin A for the prophylactic treatment of headache in adults; the analysis addressed migraines, as well as other types of headache.(60) The investigators included RCTs that were at least 4 weeks in duration, had reduction in headache frequency or severity as an outcome, and used patient-reported outcomes. The investigators reviewed study eligibility criteria and categorized them as addressing episodic (<15 headaches/month) or chronic headache (at least 15 days/month). A total of 10 trials on episodic migraine and 7 trials on chronic migraine were identified. All of the trials on episodic migraine and 5 of 7 trials on chronic migraine were placebo-controlled; the other 2 trials compared botulinum toxin injections to oral medication. A pooled analysis of the studies on chronic migraine found a statistically significantly greater reduction in the frequency of headaches per month with botulinum toxin versus a control intervention (difference, -2.30; 95% CI, -3.66 to -0.94; 5 trials). In contrast, in a pooled analysis of studies on episodic migraine, there was no statistically significant difference between groups in the change in monthly headache frequency (difference, -0.05; 95% CI, -0.25 to 0.36; 9 trials).
Previously, in 2009, Shuhendler et al published a systematic review and meta-analysis of trials on botulinum toxin for treating episodic migraines.(61) The investigators identified 8 randomized double-blind placebo-controlled trials evaluating the efficacy of botulinum toxin A injections. A pooled analysis of the main study findings found no significant differences between the botulinum toxin A and placebo groups in change in the number of migraines per month. After 30 days of follow-up, the SMD was -0.06 (95% CI, -0.14 to 0.03; p=0.18). After 90 days, the SMD was -0.05 (95% CI, -0.13 to 0.04; p=0.28). A subgroup analysis that separately examined trials using low-dose botulinum toxin A (<100 units) separately from trials using high-dose botulinum toxin A (≥100 units) did not find a statistically significant effect of botulinum toxin A compared with placebo in either stratum.
A pair of multicenter RCTs that evaluated onabotulinumtoxinA (Botox) for chronic migraine was published in 2010. The trials reported findings from the double-blind portions of the industry-sponsored PREEMPT (phase 2 Research Evaluating Migraine Prophylaxis Therapy) studies 1 and 2.62,63 Study designs were similar. Both studies included a 24-week double-blind, placebo-controlled phase prior to an open-label phase. The trials recruited patients meeting criteria for migraine and excluded those with complicated migraine. To be eligible for participation, patients needed to report at least 15 headache days during the 28-day baseline period, each headache lasting at least 4 hours. At least 50% of the headaches needed to be definite or probable migraine. The investigators did not require that the frequent attacks occurred for
more than 3 months or exclude patients who overused pain medication, 2 of the ICHD-2 criteria for chronic migraine. Eligible patients were randomly assigned to receive 2 cycles of Botox injections 155 units or placebo, with 12 weeks between cycles. Randomization was stratified based on the frequency of acute headache pain medication used during baseline and whether or not patients overused acute headache pain medication. (Medication overuse was defined as baseline intake of simple analgesics on
at least 15 days, or other medications for at least 10 days, and medication use at least 2 days per week.)
The primary endpoint 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 endpoint 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 instead of 0.05, was used. Several quality-of-life measures were also included in the trials. This included the 6-item Headache Impact Test (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ v.2). Key findings of the 2 studies are described below.
PREEMPT 1 randomly assigned a total of 679 patients.(62) The 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 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 compared with 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 quality of life in the Botox versus the placebo group. The proportion of patients with severe impact of headaches (ie, HIT-6 score at least 60) in the Botox group decreased from 94% at baseline to 69% at 24 weeks and in the placebo group decreased from 95% at baseline to 80%. There was a between-group difference of 11% (p=0.001). The authors did not report scores on the Migraine Specific Quality (MSQ) of Life Questionnaire 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), and emotional (p<0.002). Adverse events were experienced by 203 patients (60%) in the Botox group and 156 patients (47%) in the placebo group. Eighteen patients (5%) in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. Treatmentrelated adverse events were consistent with the known safety profile of Botox.
PREEMPT 2 randomly assigned a total of 705 patients.(63) The mean number of migraine days during baseline period was 19.2 in the Botox group and 18.7 in the placebo group. The 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 than 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, a difference of 2.3 days per 28 days (p<0.001). The number of migraine days also decreased significantly, more in the Botox compared to the placebo groups, a mean of 8.7 versus 6.3 (p<0.001). In contrast to PREEMPT 1, there was a significantly greater decrease in headache episodes in the Botox group than the placebo group, 5.3 versus 4.6 (p=0.003). Change in frequency of migraine episodes was not reported.
Similar to PREEMPT 1, quality-of-life measures significantly improved in the Botox versus the placebo group. The proportion of patients with severe impact of headaches in the Botox group decreased from 93% at baseline to 66% at 24 weeks and in the placebo group decreased from 91% at baseline to 77%. There was a between-group difference of 10% (p=0.003). The authors reported statistically significantly greater improvement in the 3 MSQ role function domains at week 24, restrictive, preventive and emotional (p<0.001 for each domain). Adverse events were experienced by 226 patients (65%) in the Botox group and 202 patients (56%) in the placebo group. Fifteen patients (4%) in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. As in PREEMPT 1, treatment-related adverse events were consistent with the known safety profile of Botox.
Also published in 2010 was a pooled analysis of findings from the PREEMPT 1 and PREEMPT 2 studies; this analysis was also industry-sponsored.(64) There were 688 patients in the Botox group and 696 in the placebo group in the pooled analysis of outcomes at week 24. In the combined analyses, there was a significantly greater reduction in change from baseline in frequency of headache days, migraine days, headache episodes, and migraine episodes in the Botox compared to placebo groups. For example, the pooled change in frequency of headache days was a mean of 8.4 in the Botox group and 6.6 in the placebo group (p<0.001). The mean difference in number of headache days over a 28-day data collection period was 1.8 (95% CI, 1.13 to 2.52). The pooled change in frequency of headache episodes was 5.2 in the Botox group and 4.9 in the placebo group, a relative difference of 0.3 episodes (95% CI, 0.17 to 1.17; p=0.009). Between-group differences, though statistically significant, were relatively small and may not be clinically significant. In the pooled analysis, the authors also reported the proportion of patients with at least a 50% decrease from baseline in the frequency of headache days at each time point (every 4 weeks from week 4 to week 24). For example, at week 24, the proportion of participants with at least a 50% reduction in headache days was 47.1% in the Botox group and 35.1% in the placebo group. In contrast, the difference in the proportion of patients experiencing at least a 50% reduction in headache episodes did not differ significantly between groups at 24 weeks or at most other time points, with the exception of week 8. The article did not report the proportion of participants who experienced at least a 50% reduction in migraine days or migraine episodes. The pooled analysis showed statistically significant differences for the change in proportion of patients with severe headache impact according to the HIT-6 and change in MSQ questionnaire domains.
There are several issues worth noting regarding the methodology and findings of the PREEMPT studies. There was a statistically significant difference in headache episodes in PREEMPT 2 but not PREEMPT 1 (for which it was the primary outcome); the primary outcome was changed after initiation of PREEMPT 1. Moreover, one of the main secondary outcomes in PREEMPT 1, change in the number of migraine episodes, was not reported in the second trial; the authors did not discuss this omission. In addition, the individual studies did not include threshold response to treatment, eg, at least a 50% reduction in headache or migraine frequency, as a key outcome. The pooled analysis did report response rates, but these were presented as secondary efficacy outcomes.
An editorial that discussed the findings of the PREEMPT studies commented that the majority of patients in both trials fulfilled criteria for medication overuse headache, and therefore many patients may have been experiencing secondary headaches rather than chronic migraines.(65) If patients did have secondary headaches, detoxification alone may have been a sufficient treatment to change their headache pattern to an episodic one. Another opinion piece, published after the PREEMPT 1 and 2 studies, mentioned that the clinical relevance of less than a 2-day difference in reduction in number of headache days is uncertain.(66) The author of the second article noted, though, that this degree of reduction in headache days is similar to that previously found in several medication trials.
Another example of an RCT on botulinum toxin for treating chronic migraine was published by Cady et al.(67) The study included patients who met ICHD-2 criteria for chronic migraine. Patients were randomized to receive treatment with Botox (n=29) or topiramate (n=30). At the 12-week follow-up, the end of the double-blind phase of the study, treatment effectiveness did not differ significantly between groups. For the primary endpoint, Physician Global Assessment at week 12, physicians noted improvement in 19 (79%) of 24 patients in the Botox group and 17 (71%) of 24 patients in the topiramate group; 9 patients (15%) were not available for this analysis.
Medication Overuse Headache
According to the ICHD-2, medication overuse headache is a different diagnostic classification from chronic migraine.(68) In 2013, Silberstein et al published a sub-analysis of pooled PREEMPT data that was limited to patients with headache medication overuse at baseline.(69) 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 compared to the placebo group. For example, the number of headache days per month decreased by a mean of 8.2 (SE=0.3) in the botulinum toxin group and 6.2 (SE=0.3) 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.
The 2012 meta-analysis by Jackson et al, discussed above,(60) identified 7 RCTs evaluating botulinum toxin for treating chronic tension-type headaches; all were placebo-controlled. 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 versus placebo groups (difference, -1.43; 95% CI, -3.13 to 0.27). The trial with the largest sample size was published by Silberstein et al in 2006.70 This study included 300 patients randomized to 1 of 4 doses of botulinum toxin or placebo. Overall, there was not a statistically significant difference between the botulinum toxin groups and the placebo group in the mean change from baseline to 90 days in number of headache days per month.
Chronic Daily Headache
Although this category is not recognized in the International Classification of Headache Disorders, it is commonly defined to include different kinds of chronic headache such as chronic or transformed migraine and daily persistent headache and may also include chronic tension-type headache, addressed separately here. The 2012 meta-analysis by Jackson et al60 identified 3 RCTs comparing botulinum toxin A to placebo in patients with at least 15 headaches per month. A pooled analysis of data from these 3 trials found a significantly greater reduction in the number of headaches per month in the botulinum toxin versus the placebo group (difference, -2.06; 95% CI, -3.56 to -0.56). Individually, only 1 of the 3 trials, published by Ondo et al in 2004, found a statistically significant benefit with botulinum toxin treatment. (71) This study included 60 patients and included patients with chronic migraines, as well as chronic tensiontype headache. The Ondo study found significantly greater reduction in the number of headache-free days over weeks 8 to 12 in the botulinum toxin versus placebo group (p<0.05), but there was not a 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 had much larger sample sizes; 355 patients in a study by
Mathew et al72 and 702 patients in a study by Silberstein et al.(73) Neither found a statistically significant difference in the reduction in the number of headache days per month with botulinum toxin versus placebo. The available evidence from RCTs is conflicting and insufficient for conclusions; thus chronic daily headache remains an investigational indication.
No controlled trials have been reported on this type of headache. Thus, botulinum toxin is considered investigational for this indication.
In 2011, Linde et al published a double-blind placebo-controlled crossover study that included 28 patients with treatment-resistant cervicogenic headache.(74) Patients were randomized to treatment with botulinum toxin A and placebo, in random order; 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 number of days with moderate to severe headache. Three other RCTs, published between 2000 and 2008, randomly assigned patients with chronic headache related to whiplash injury to botulinum toxin A treatment or placebo.(75-77) One trial reported trends toward improvement with treatment for various outcomes; most were not statistically significant.(75) Another reported no significant differences in any of several pain-related outcomes.(77) One trial reported a significant improvement in pain with treatment while the placebo group reported no improvement, but the study design was flawed in that the placebo group reported less pain at baseline.(76) A Cochrane review of treatment of mechanical neck disorders, published in 2007,(78) included 6 RCTs (total N=273) of botulinum toxin compared to placebo for chronic neck disorders with or without radicular findings or headache. A meta-analysis of 4 studies (total N=139) for pain outcomes gave a nonsignificant result. The authors concluded that a range of doses have not shown significant differences compared to placebo or to each other.
For patients with migraine headache, the published evidence does not suggest that botulinum toxin improves net health outcome for patients with an episodic pattern (ie, <15 episodes per month); thus, it is considered investigational. There are several published RCTs on botulinum toxin for chronic migraine including the PREEMPT 1 and 2 trials, which had a number of statistically significant findings, but the clinical significance of these results was unclear. The 2012 meta-analysis by Jackson et al found that botulinum toxin reduced the frequency of headaches per month compared to placebo or medication. Based on the published data, FDA approval, and clinical input obtained in 2010, botulinum toxin is considered medically necessary for the prevention of chronic migraine in certain situations, ie, patients diagnosed with chronic migraine who failed trials of other medications. For tension headache, RCTs and systematic reviews have been performed. These do not indicate that botulinum toxin improves outcomes. For other headache types, the evidence is insufficient to form conclusions about efficacy.
Myofascial Pain Syndrome
Myofascial pain syndrome is characterized by painful muscles with increased tone and stiffness associated with myofascial trigger points. Patients are often treated with injections of the trigger points with saline, dilute anesthetics, or dry needling. These trigger point injections, while considered established therapy, have been controversial, because it is unclear whether any treatment effect is due to the injection, dry needling of the trigger point, or a placebo effect. The optimal study to evaluate the efficacy of botulinum toxin injection for treating myofascial pain syndrome would be double-blind RCTs to minimize the placebo effect and would compare injections of botulinum toxin to dry needling and/or anesthetic injection.
There are several systematic reviews of RCTs evaluating botulinum toxin injection for treating myofascial pain syndrome. Most recently, a 2014 Cochrane review by Soares et al identified 4 RCTs with a total of 233 patients.(79) Although the authors searched for studies comparing botulinum toxin to an alternative treatment, all of the RCTs were placebo-controlled. The studies were all were double-blind; 3 were prospective and 1 used a crossover design. Follow-up in the prospective studies was 12 weeks in 2 studies and 4 weeks in the third. Due to heterogeneity among studies, the investigators did not conduct pooled analyses of study findings. The primary outcomes of interest were change in pain as assessed by validated instruments. Three of the 4 studies found that botulinum toxin did not significantly improve pain intensity compared to placebo. A 2013 systematic review had similar findings.(80)
A systematic review that included a meta-analysis of study results was published in 2011 by Langevin et al.(81) A pooled analysis of data from 4 placebo-controlled trials did not find a statistically significant benefit of botulinum toxin. The SMD was -0.21 (95% CI, -0.50 to 0.70). These 4 trials were considered by the authors to have high validity; that is they scored at least 6 on a 12-point risk of bias instrument used by the Cochrane collaboration.
A 2014 industry-sponsored RCT, not included in the systematic review, focused on patients with myofascial pain who had responded to an initial injection of botulinum toxin A.(82) A total of 114 patients received an initial injection and 54 responders were subsequently randomized to receive a second injection of botulinum toxin or saline placebo 14 weeks after the initial injection. At week 26 after the initial injection, but not week 20, there was a significantly greater improvement in the mean visual numeric scores for pain in the botulinum toxin group than the placebo group (p=0.019). There was no significant difference between groups at week 26, compared to baseline, in quality of life using the SF-36 scale. Thus, this study had mixed outcomes and some limitations. Restricting study participation to a responder group could introduce bias, eg, it may increase the proportion of patients who initially experienced a placebo response and make blinding more difficult if patients are familiar with side effects of the active treatment.
Several RCTs have evaluated botulinum toxin for treatment of myofascial pain syndrome. Studies were double-blind, but compared botulinum toxin with placebo, rather than with a commonly used alternative treatment. Most of the individual trials, as well as a pooled analysis of study findings, did not find that botulinum toxin improved health outcomes. Therefore, botulinum toxin for treating myofascial pain syndrome is considered investigational.
A 2013 systematic review by Hu et al evaluated the literature on botulinum toxin for treatment of trigeminal neuralgia.(83) The authors searched for RCTs as well as controlled and uncontrolled observational studies. A total of 6 studies were identified; only one of these was an RCT. Sample sizes ranged from 8 to 42, the largest was the RCT. Study findings were not pooled. The primary outcome of interest was the proportion of responders, defined as at least a 50% reduction in the frequency and/or
intensity of pain. In the RCT, the response rate was 68.2% in the botulinum toxin and 15% in the placebo group. The mean proportion of responders in all included studies reporting this outcome was 80%.
An additional small RCT was published in 2013; this study was double-blind and included 20 women.(84) Eligibility included a diagnosis of idiopathic trigeminal neuralgia that was intractable, defined as insufficient response to medication treatments for 3 months prior to study participation. Patients were randomized to receive a single injection of botulinum toxin A or placebo. The primary efficacy outcome was reduction in pain, as measured by a 10-point VAS, and change in frequency of paroxysms. Baseline VAS scores were similar (8.3 in the botulinum toxin group, 8.3 in the placebo group). At 12 weeks after the injection, the VAS decreased 6.5 points in the botulinum toxin group and 0.3 points in the placebo group. The difference between groups was statistically significant (p<0.001). The baseline frequency of
paroxysm was 39.2 in the botulinum toxin group and 36.7 in the placebo group. After 12 weeks, the mean frequency of paroxysms per day was 4.0 and 36.1 per day, respectively (p<0.001).
There is insufficient evidence from 2 small RCTs, neither of which compared botulinum toxin to an alternative intervention and only one of which was double-blind, and several small observational studies that botulinum toxin improves outcomes in patients with trigeminal neuralgia.
Pain Control After Hemorrhoidectomy
Several small RCTs of botulinum toxin intrasphincter injection for controlling pain after hemorrhoidectomy have been published. A 2005 article described a study by Patti et al (n=30) who randomly assigned patients to 20 units of botulinum toxin or saline injection and reported significantly decreased duration of postoperative pain at rest and during defecation in the treated group.(85) A 2006 study by Patti et al, which also included 30 patients, found significant differences in postoperative maximum resting pressure change from baseline comparing botulinum toxin treatment to topical glyceryl trinitrate (p<0.001; resting pressure is increased after surgery and may be responsible for pain).(86) In addition, there was a significant reduction in postoperative pain at rest (p=0.01) but not during defecation. There was no difference in healing.
RCTs evaluating botulinum toxin injection after hemorrhoidectomy suggest improvement in pain control; however, differences may be small and need confirmation in larger trials.
Facial Wound Healing
In 2013, Ziade et al reported on findings of a study including 30 adult patients presenting to the emergency department with facial wounds without tissue loss.(87) Patients were assigned to have an injection of botulinum toxin (n=11) or no injection (n=13) within 72 hours of the suturing of the wounds. The primary outcomes were scores on the following scales at 1 year: Patient Scar Assessment Scale (PSAS), Observer Scar Assessment Scale (OSAS), Vancouver Scar Scale (VSS) and a 1 to 10 visual analog scale (VAS). The PSAS was a patient-reported outcome, the OSAS and VSS were assessed clinically by a blinded independent evaluator, and the VAS was assessed using photograph analysis by a team of 6 medical specialists. Patients were not blinded to treatment group, and thus the PSAS might be a more subjective outcome, whereas it is likely that the OSAS, VSS, and VAS were all reasonably objectively assessed. Twenty-four (80%) of 30 patients were available for the 1-year follow-up. There
were no significant differences between groups in the PSAS, OSAS, and VSS scales. For example, the median OSAS score was 8 in the botulinum toxin group and 9 in the control group. However, a significant between-group difference was found on the fourth outcome, the VAS score, favoring the botulinum toxin group. The median VAS score was 8.25 for the botulinum group and 6.35 for the control group (p<0.001). These results demonstrate a lack of consistency in finding a benefit across outcomes, ie, there was no significant difference in the patient-reported or clinically accessed outcomes, only in the outcome based on photographic analysis. Previously, in 2006, Gassner et al conducted a small RCT of botulinum toxin‒induced immobilization of facial lacerations to improve wound healing compared with placebo (n=31).(88) The outcome was determined by blinded assessment of photographs of wound healing at intervals using a VAS. The authors reported enhanced wound healing in the treatment arm compared with the placebo arm (8.9 vs 7.2, p=0.003).
There are few RCTs evaluating botulinum toxin for facial wound healing, and the available trials did not find consistent evidence of benefit.
Pelvic and Genital Pain in Women
One double-blind, randomized, placebo-controlled trial evaluated 60 patients with chronic pelvic pain and pelvic floor spasm.(89) Patients received injections of either botulinum toxin A or placebo. Pain scores were reduced for both groups, but there were no significant differences between groups. The trial likely was underpowered to detect clinically significant differences in outcomes between groups. Other studies include a small, open-label trial from 2006 that tested botulinum toxin A injections in painful vulvar tissue to alleviate provoked vestibulodynia (n=19).(90) Patients receiving either of 2 doses had significantly reduced pain compared to baseline for 8 (lower dose) to 14 weeks (higher dose). A prospective cohort study tested different doses of botulinum toxin in 12 women with pelvic floor muscle hypertonicity and history of chronic pelvic pain.(91) Compared with baseline, there were nonsignificant reductions in pelvic pain and nonsignificant improvements in quality of life.
Evidence for the use of botulinum toxin to treat pelvic or genital pain in women is insufficient to form conclusions.
Neuropathic Pain After Neck Dissection
Two open-label trials of 16 and 23 patients who had failed conservative therapy investigated various doses of botulinum toxin A injected into the area of complaint.(92,93) For both studies, which were conducted by the same group, results indicated significant reductions in pain compared to baseline and trends toward improved quality of life.
Lack of a randomized, placebo-controlled trial to control for strong placebo effects in pain therapy render results from 2 open-label trials inconclusive for the use of botulinum toxin to treat neuropathic pain after neck dissection.
Lateral Epicondylitis and Other Joint Pain
In 2005, Wong et al reported on the results of a double-blind, placebo-controlled trial that randomly assigned 60 patients with lateral epicondylitis of at least 3 months in duration to receive either a single intramuscular injection of botulinum toxin or placebo, targeted at the tender spot in the elbow.(94) In the botulinum group, the mean VAS improved from 65.5 mm to 25.3 mm at 4 weeks, compared to a change of 66.2 mm to 50.5 mm in the placebo group, a statistically significant difference. Mild paresis was reported in 4 patients in the botulinum group. In a similarly designed study of 40 patients, published in 2005, Hayton et al reported no treatment effect at 3 months.(95) However, the injection site was targeted at 5 cm distal to the most tender spot and a different formulation of botulinum toxin was used. In a randomized, blinded, placebo-controlled trial of 130 patients, a single injection of botulinum toxin A into the painful origin of the forearm extensor muscles was tested versus placebo.(96) Treated patients were significantly improved overall at weeks 2, 6, 12, and 18. Continuous pain was significantly improved in the treated group only at weeks 6 and 18; maximum pain showed no improvement compared with placebo.
Two case series of patients with chronic joint pain refractory to conservative management studied the effect of botulinum toxin A injections (1 series specified that Dysport was used) into several joints of patients with arthritis and into the knee joint of patients with chronic knee pain.(97,98) Both reported significant improvement in joint pain and function compared with baseline, lasting for 3 to 12 months. Although the results of several trials of botulinum toxin injections into joints for chronic pain tend to favor
treatment, some results are contradictory.
Due to the lack of consistent findings from well-designed studies, botulinum toxin for treatment of lateral epicondylitis and other joint pain is considered investigational.
In 2005, Stidham et al explored the use of botulinum toxin A injections for tinnitus treatment under the theory that blocking the autonomic pathways could reduce the perception of tinnitus.(99) In this study, 30 patients were randomly assigned in a double-blind study to receive either 3 subcutaneous injections of botulinum toxin A around the ear followed by placebo injections 4 months later, or placebo injections first, followed by botulinum toxin A. The authors reported that 7 patients had reduced tinnitus after the botulinum toxin A injections, which was statistically significant when compared to the placebo groups in which only 2 patients reported reduced tinnitus (p<0.005). The tinnitus handicap inventory scores were also significantly decreased between pretreatment and 4 months after botulinum toxin A injections. However, no other significant differences were noted when comparing the 2 treatments at 1 and 4 months after injections. The authors noted larger studies are needed. Also, study limitations, including size and lack of intention-to-treat analysis limit interpretation of results.
Due to insufficient evidence from large randomized trials, botulinum toxin for tinnitus is considered investigational.
Antibody Testing for Botulinum Toxin Resistance
Rare patients have no response to initial administration of botulinum toxin (primary resistance) and a small percentage of adult patients 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 interfere with perception of response.(100) In approximately 3% to 10% of adult patients, true secondary resistance arises due to the development of antibodies that
specifically neutralize the activity of botulinum toxin (eg,(101,102)). That neutralizing antibodies directly cause resistance has been shown in a case study in which a patient 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.(103) Nonneutralizing antibodies may also develop in patients but have no effect on outcomes. The predisposing factors are not completely understood but include use of higher doses, shorter intervals between repeat treatments, and younger age.(104) In 2 studies of pediatric patients treated for spasticity, neutralizing antibodies were detected in 28% to 32% of patients.(105,106) Recommendations for avoiding eventual resistance are to use the lowest dose possible to obtain a clinical response and schedule intervals of 10 to 12 weeks between injections, if possible.
Patients who develop secondary resistance to botulinum toxin A may stop treatment for several months and then undergo retreatment with likely success; however, the duration of response is often short, as neutralizing antibodies may redevelop quickly.(107) Alternatively, the patient may be administered botulinum toxin B, with which neutralizing antibodies to toxin A will not interfere. However, the duration of effect is shorter, and adverse effects have occurred at higher frequencies than for botulinum toxin A.(104,108)
Confirmation of neutralizing antibodies to botulinum toxin A in research studies has most often been accomplished with either protection of mice from lethal doses of toxin with injection of patient serum109 or with an in vitro toxin-neutralizing assay based on a mouse diaphragm nerve-muscle preparation.(110) 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(105,111,112) and would therefore result in significant numbers of false-positive results. Thus, the currently available testing approach is considered investigational. An option for some patients might be to inject toxin into the frontal muscle above 1 eyebrow; a toxin-responsive patient would have asymmetry of the forehead on attempted frowning, whereas, a nonresponsive patient would not.(112)
Evidence for the use of assays to detect antibodies to botulinum toxin is insufficient to support its use in a clinical setting.
Chronic Pain After Lumpectomy
There are no relevant publications on the use of botulinum toxin for pain following lumpectomy.
Pain Associated With Breast Reconstruction After Mastectomy
There are no published RCTs evaluating botulinum toxin for pain associated with breast reconstruction after mastectomy. A 2014 systematic review identified 7 studies on perioperative injection of botulinum toxin A following breast reconstruction surgery.(113) These consisted of 2 prospective controlled cohort studies, 3 retrospective controlled cohort studies, and 2 case series. The studies were mainly small; only one, with a sample size of 293, had more than 50 participants. Three of the studies assessed postoperative pain and all of these found that at least some outcomes were significantly better in the botulinum toxin group than the comparison group.
The evidence on botulinum toxin for perioperative management of pain associated with breast reconstruction after mastectomy is insufficient due to a lack of RCTs or large observational studies, and thus, this is an investigational indication.
The published literature consists of small case series.(114-116) The largest prospective case series, published by Minkes and Langer in 2000, included 18 children (median age, 4 years) with persistent obstructive symptoms after surgery for Hirschsprung disease.(115) Patients received injections of botulinum toxin (Botox) into 4 quadrants of the sphincter. The total dose of botulinum toxin during the initial series of injections was 15 to 60 units. Twelve (67%) of 18 patients experienced improvement for more than 1 month and the remaining 6 (33%) either showed no improvement or improved for less than 1 month. Ten children had 1 to 5 additional injections due to either treatment failure or recurrence of symptoms; retreatment was not based on a standardized protocol.
A 2011 series by Patrus et al retrospectively reviewed outcomes in 22 patients with Hirschsprung disease treated over 10 years who had received a median of 2 (range, 1-23) botulinum toxin injections for postsurgical obstructive symptoms.(116) The formulation of botulinum toxin was not specified. Median follow-up (time from first injection to time of chart review) was 5.0 years (range, 0-10 years). At the time of chart review, 2 (9%) of 22 patients had persistent symptoms. Eighty percent of children had a “good
response” to the initial treatment (not defined), and 69% had additional injections. The authors reported that the number of hospitalizations for obstructive symptoms decreased significantly after botulinum toxin injection (median, 0) compared with preinjection (median, 1.5) (p=0.003). The authors did not report whether or not patients received other treatments during the follow-up period in either case series. A limitation of the case series study design is that it lacks a control group. Due to the lack of controlled studies showing benefit, this indication is considered investigational.
There are no controlled trials of botulinum toxin for treatment of Hirschsprung disease; therefore the evidence is insufficient to form conclusions on efficacy.
A systematic review of the literature, published in 2010, identified a total of 15 studies on botulinum toxin injection to treat gastroparesis.(117) Two of the studies were RCTs; the remainders were case series or open-label observational studies. The authors stated that, while the nonrandomized studies generally found improvement in subjective symptoms and gastric emptying after botulinum toxin injections, the RCTs did not confirm the efficacy of botulinum toxin for treating gastroparesis. The authors concluded that there is insufficient evidence to recommend botulinum toxin for gastroparesis. Brief descriptions of the 2 RCTs are as follows.
In 2007, Arts et al published a randomized crossover study with 23 patients.(118) The study included consecutive patients at a single institution who had symptoms suggestive of gastroparesis and established delayed gastric emptying for solids and liquids. Patients received, in random order, injections of Botox or saline during gastrointestinal endoscopies, with a 4-week interval between injections. Symptoms were assessed using the Gastroparesis Cardinal Symptom Index (GCSI), which has a
maximum score of 45. When data from both groups were combined, there were no statistically significant differences in improvement after botulinum toxin injection or saline injection for either solid or liquid emptying times. For example, liquid half-emptying time was 8.2 minutes (SD=13.7) after Botox injection and 22.5 minutes (SD=7.7) after saline injection (p>0.05). In addition, in pooled analyses, the total GCSI score did not differ significantly after Botox compared to saline treatment (mean GCSI score, 6.1 and 3.8, respectively, p>0.05).
The other RCT, published in 2008, was a single center double-blind trial with 32 patients.(119) Patients had symptoms consisting of delayed gastric emptying and had a GCSI score of 27 or higher. They received an injection of either Botox (n=16) or saline placebo (n=16). All patients completed the study. Patients were evaluated with gastric emptying scintigraphy prior to treatment and at a 1-month follow-up. The proportion of patients with at least a 9-point reduction in the GCSI at 1 month, the primary end point, was 6 (37.5%) of 16 in the Botox group and 9 (56.3%) of 16 in the placebo group; the difference between groups was not statistically significant. Improvement in gastric emptying after 1 month, a secondary endpoint, also did not differ significantly between groups.
Two small RCTs have failed to show a benefit for treatment of gastroparesis. This evidence is insufficient to draw conclusions about the efficacy of botulinum toxin for this indication.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
In response to requests, clinical input was received on this policy when it was under review in 2008 and again in 2010. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
Input was received on a number of indications from 5 physician specialty societies and 3 academic medical centers while this policy was under review in 2008. Nearly all reviewers who provided input agreed with the investigational determination for use in headaches and on the investigational role for antibody testing. Among the 4 reviewers who commented on use in sialorrhea, 2 reviewers felt this was medically necessary, and 2 disagreed.
In 2010, input was received only on botulinum toxin for migraine from 4 physician specialty societies (7 reviews) and 4 academic medical centers. The majority of reviewers agreed with the investigational indication for episodic migraine. Several reviewers thought that botulinum toxin was medically necessary in patients with disabling and/or frequent episodic migraines that were refractory to other treatments. Clinical input was more divergent for use of botulinum toxin for chronic migraine; some agreed that use was investigational and others did not. Reviewers who thought that botulinum toxin was medically necessary for patients with chronic migraines generally thought its use should be limited to patients unresponsive to other treatments.
Summary of Evidence
This is a multisection policy and evidence is summarized at the end of each section.
Practice Guidelines and Position Statements
In 2012, the American Urological Association issued a guideline on non-neurogenic overactive bladder in adults.(120) The guideline includes intradetrusor onabotulinumtoxinA injection as a third-line treatment option in “carefully selected and thoroughly-counseled” patients who are refractory to first- and secondline
treatments and are willing to perform self-catheterization if needed for postvoid retention.
In 2011, the American Academy of Neurology, Quality Standards Subcommittee, published an update of evidence-based recommendations for treating essential tremor.(121) The report reaffirms the Academy’s previous position that botulinum toxin is “possibly effective” and may be considered to reduce limb tremor associated with essential tremor.
The 2010 revision of a practice parameter on treatment of anal fissures by the American Society of Colon and Rectal Surgeons states(122):
“Patients who do not respond to topical nitrates should be referred for botulinum toxin injections or surgery…. Botulinum toxin injection has been associated with healing rates superior to placebo. There is inadequate consensus on dosage, precise site of administration, number of injections, or efficacy. Grade of Recommendation: Strong recommendation based on low-quality evidence 1C.”
U.S. Preventive Services Task Force Recommendations
No relevant recommendations were found.
Medicare National Coverage
There is no national coverage determination (NCD) for botulinum toxin. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
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- Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. Jun 2010;50(6):921-936. PMID 20487038
- Schoenen J. Botulinum toxin in headache treatment: finally a promising path? Cephalalgia. Jul 2010;30(7):771-773. PMID 20647167
- Cady RK. OnabotulinumtoxinA (botulinum toxin type-A) in the prevention of migraine. Expert Opin Biol Ther. Feb 2010;10(2):289-298. PMID 20088719
- Cady RK, Schreiber CP, Porter JA, et al. A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache. Jan 2011;51(1):21-32. PMID 21070228
- Silberstein SD, Olesen J, Bousser MG, et al. The International Classification of Headache Disorders, 2nd Edition (ICHD-II)--revision of criteria for 8.2 Medication-overuse headache. Cephalalgia. Jun 2005;25(6):460-465. PMID 15910572
- Silberstein SD, Blumenfeld AM, Cady RK, et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. Aug 15 2013;331(1-2):48-56. PMID 23790235
- Silberstein SD, Gobel H, Jensen R, et al. Botulinum toxin type A in the prophylactic treatment of chronic tensiontype headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. Jul 2006;26(7):790-800. PMID 16776693
- Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia. Jan 2004;24(1):60-65. PMID 14687015
- Mathew NT, Frishberg BM, Gawel M, et al. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. Apr 2005;45(4):293-307. PMID 15836565
- Silberstein SD, Stark SR, Lucas SM, et al. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. Sep 2005;80(9):1126-1137. PMID 16178492
- Linde M, Hagen K, Salvesen O, et al. Onabotulinum toxin A treatment of cervicogenic headache: a randomised, double-blind, placebo-controlled crossover study. Cephalalgia. May 2011;31(7):797-807. PMID 21300635
- Braker C, Yariv S, Adler R, et al. The analgesic effect of botulinum-toxin A on postwhiplash neck pain. Clin J Pain. Jan 2008;24(1):5-10. PMID 18180629
- Freund BJ, Schwartz M. Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot study. Headache. Mar 2000;40(3):231-236. PMID 10759926
- Padberg M, de Bruijn SF, Tavy DL. Neck pain in chronic whiplash syndrome treated with botulinum toxin. A double-blind, placebo-controlled clinical trial. J Neurol. Mar 2007;254(3):290-295. PMID 17345052
- Peloso P, Gross A, Haines T, et al. Medicinal and injection therapies for mechanical neck disorders. Cochrane Database Syst Rev. 2007(3):CD000319. PMID 17636629
- Soares A, Andriolo RB, Atallah AN, et al. Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. 2014;7:CD007533. PMID 25062018
- Desai MJ, Shkolnikova T, Nava A, et al. A Critical Appraisal of the Evidence for Botulinum Toxin Type A in the Treatment for Cervico-Thoracic Myofascial Pain Syndrome. Pain Pract. May 21 2013. PMID 23692187
- Langevin P, Lowcock J, Weber J, et al. Botulinum toxin intramuscular injections for neck pain: a systematic review and metaanalysis. J Rheumatol. Feb 2011;38(2):203-214. PMID 21123322
- Nicol AL, Wu, II, Ferrante FM. Botulinum toxin type a injections for cervical and shoulder girdle myofascial pain using an enriched protocol design. Anesth Analg. Jun 2014;118(6):1326-1335. PMID 24842179
- Hu Y, Guan X, Fan L, et al. Therapeutic efficacy and safety of botulinum toxin type A in trigeminal neuralgia: a systematic review. J Headache Pain. 2013;14(1):72. PMID 23964790
- Shehata HS, El-Tamawy MS, Shalaby NM, et al. Botulinum toxin-type A: could it be an effective treatment option in intractable trigeminal neuralgia? J Headache Pain. 2013;14:92. PMID 24251833
- Patti R, Almasio PL, Muggeo VM, et al. Improvement of wound healing after hemorrhoidectomy: a double-blind, randomized study of botulinum toxin injection. Dis Colon Rectum. Dec 2005;48(12):2173-2179. PMID 16400513
- Patti R, Almasio PL, Arcara M, et al. Botulinum toxin vs. topical glyceryl trinitrate ointment for pain control in patients undergoing hemorrhoidectomy: a randomized trial. Dis Colon Rectum. Nov 2006;49(11):1741-1748. PMID 16990976
- Ziade M, Domergue S, Batifol D, et al. Use of botulinum toxin type A to improve treatment of facial wounds: a prospective randomised study. J Plast Reconstr Aesthet Surg. Feb 2013;66(2):209-214. PMID 23102873
- Gassner HG, Brissett AE, Otley CC, et al. Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc. Aug 2006;81(8):1023-1028. PMID 16901024
- Abbott JA, Jarvis SK, Lyons SD, et al. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. Oct 2006;108(4):915-923. PMID 17012454
- Dykstra DD, Presthus J. Botulinum toxin type A for the treatment of provoked vestibulodynia: an open-label, pilot study. J Reprod Med. Jun 2006;51(6):467-470. PMID 16846084
- Jarvis SK, Abbott JA, Lenart MB, et al. Pilot study of botulinum toxin type A in the treatment of chronic pelvic pain associated with spasm of the levator ani muscles. Aust N Z J Obstet Gynaecol. Feb 2004;44(1):46-50.PMID 15089868
- Vasan CW, Liu WC, Klussmann JP, et al. Botulinum toxin type A for the treatment of chronic neck pain after neck dissection. Head Neck. Jan 2004;26(1):39-45. PMID 14724905
- Wittekindt C, Liu WC, Preuss SF, et al. Botulinum toxin A for neuropathic pain after neck dissection: a dosefinding study. Laryngoscope. Jul 2006;116(7):1168-1171. PMID 16826054
- Wong SM, Hui AC, Tong PY, et al. Treatment of lateral epicondylitis with botulinum toxin: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med. Dec 6 2005;143(11):793-797. PMID 16330790
- Hayton MJ, Santini AJ, Hughes PJ, et al. Botulinum toxin injection in the treatment of tennis elbow. A doubleblind, randomized, controlled, pilot study. J Bone Joint Surg Am. Mar 2005;87(3):503-507. PMID 15741614
- Placzek R, Drescher W, Deuretzbacher G, et al. Treatment of chronic radial epicondylitis with botulinum toxin A. A double-blind, placebo-controlled, randomized multicenter study. J Bone Joint Surg Am. Feb 2007;89(2):255-260. PMID 17272437
- Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res. Apr 2006;9(2-3):179-188. PMID 16785116
- Singer BJ, Silbert PL, Dunne JW, et al. An open label pilot investigation of the efficacy of Botulinum toxin type A [Dysport] injection in the rehabilitation of chronic anterior knee pain. Disabil Rehabil. Jun 15 2006;28(11):707-713. PMID 16809213
- Stidham KR, Solomon PH, Roberson JB. Evaluation of botulinum toxin A in treatment of tinnitus. Otolaryngol Head Neck Surg. Jun 2005;132(6):883-889. PMID 15944559
- Hyman N. Botulinum toxin for focal dystonia. Pract Neurol 2004;4(1):30-35. PMID
- Hsiung GY, Das SK, Ranawaya R, et al. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. Nov 2002;17(6):1288-1293. PMID 12465070
- Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord. May 2005;20(5):592-597. PMID 15645481
- Naumann M, Toyka KV, Mansouri Taleghani B, et al. Depletion of neutralising antibodies resensitises a secondary non-responder to botulinum A neurotoxin. J Neurol Neurosurg Psychiatry. Dec 1998;65(6):924-927. PMID 9854974
- Mahant N, Clouston P, D., Lorentz I, T. The current use of botulinum toxin. J Clin Neurosci 2000;7(5):389-394. PMID
- Herrmann J, Geth K, Mall V, et al. Clinical impact of antibody formation to botulinum toxin A in children. Ann
- Koman LA, Brashear A, Rosenfeld S, et al. Botulinum toxin type a neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial. Pediatrics. Nov 2001;108(5):1062-1071. PMID 11694682
- Sankhla C, Jankovic J, Duane D. Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord. Jan 1998;13(1):150-154. PMID 9452341
- Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg. May-Jun 2006;22(3):173-177. PMID 16714924
- Pearce LB, Borodic GE, First ER, et al. Measurement of botulinum toxin activity: evaluation of the lethality assay. Toxicol Appl Pharmacol. Sep 1994;128(1):69-77. PMID 8079356
- Goschel H, Wohlfarth K, Frevert J, et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies-- therapeutic consequences. Exp Neurol. Sep 1997;147(1):96-102. PMID 9294406
- Cordivari C, Misra VP, Vincent A, et al. Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test. Mov Disord. Oct 2006;21(10):1737-1741. PMID 16874756
- Hanna PA, Jankovic J. Mouse bioassay versus Western blot assay for botulinum toxin antibodies: correlation with clinical response. Neurology. Jun 1998;50(6):1624-1629. PMID 9633703
- Winocour S, Murad MH, Bidgoli-Moghaddam M, et al. A systematic review of the use of Botulinum toxin type A with subpectoral breast implants. J Plast Reconstr Aesthet Surg. Jan 2014;67(1):34-41. PMID 24094619
- Koivusalo AI, Pakarinen MP, Rintala RJ. Botox injection treatment for anal outlet obstruction in patients with internal anal sphincter achalasia and Hirschsprung's disease. Pediatr Surg Int. Oct 2009;25(10):873-876. PMID 19662428
- Minkes RK, Langer JC. A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung's disease. J Pediatr Surg. Dec 2000;35(12):1733-1736. PMID 11101725
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- Bai Y, Xu MJ, Yang X, et al. A systematic review on intrapyloric botulinum toxin injection for gastroparesis. Digestion. 2010;81(1):27-34. PMID 20029206
- Arts J, Holvoet L, Caenepeel P, et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther. Nov 1 2007;26(9):1251-1258. PMID 17944739
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|CPT||31513||Laryngoscopy, indirect, with vocal cord injection|
|31570||Laryngoscopy, direct, with injection into vocal cords, therapeutic|
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 (e.g., for blepharospasm or hemifacial spasm)|
|64613||; neck muscle(s) (e.g. for spasmodic torticollis, spasmodic dysphonia)|
|64614||; extremity(s) and/or trunk muscle(s) (e.g. for dystonia, cerebral palsy, multiple sclerosis)|
|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 (e.g., for cervical dystonia, spasmodic torticollis)|
|64617||; larynx, unilateral, percutaneous (e.g., for spasmodic dysphonia), includes guidance by needle electromyography, when performed|
|64642, 64643, 64644, 64645||Chemodenervation of one extremity code range|
|64646, 64647||Chemodenervation of trunk muscle(s) code range|
|ICD-9 Procedure||99.29||Injection (or infusion) of other therapeutic or prophylactic agent|
|ICD-9 Diagnosis||333.6||Idiopathic torsion dystonia|
|333.7||Symptomatic torsion dystonia|
|333.83||Spasmodic torticollis excludes:
torticollis NOS (723.5)
|333.84||Organic writer's cramp|
|333.89||Fragments of torsion dystonia, other|
|334.1||Hereditary spastic paraplegia|
|341.0-341.9||Other demyelinating diseases of central nervous system|
|343.0-343.9||Cerebral palsy code range|
|346.01-346.93||Migraine code range (intractable migraine codes end with 5th digit of 1 or 3)|
|351.8||Other facial nerve disorders: facial myokymia, Melkersson’s syndrome|
|378.00-378.90||Strabismus and other disorders of binocular eye movements|
|478.75||Laryngeal spasm laryngismus (stridulus)|
|596.54||Neurogenic bladder, NOS|
|723.5||Torticollis, unspecified contracture of neck excludes:
due to birth injury (767.8)
traumatic, current (847.0)
|788.30-788.39||Urinary incontinence 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 (effective 10/1/15)||G11.4||Hereditary spastic paraplegia|
|G24.01 -G24.9||Dystonia code range (includes blepharospasm)|
|G80.0 -G80.9||Cerebral palsy code range|
|G81.10 -G81.14||Spastic hemoplegia 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.b11; G43.b19||Chronic migraine without aura, intractable codes|
|G43.d11; G43.d19||Menstrual migraine, intractable codes|
|G43.811; G43.819||Other migraine, intractable codes|
|G43.911; G43.919||Migraine, unspecified, intractable codes|
|H49.00 -H50.99||Strabismus code range|
|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|
|R25.0 -R25.9||Abnormal involuntary movements code range|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are used for inpatient services only.|
|3E234Z, 3E023GC||Administration, physiological systems and anatomical regions, introduction, muscle, percutaneous, codes for serum, toxoid and vaccine, or other therapeutic substance|
|Type of Service||Prescription Drug|
|Place of Service||Physician`s Office/Inpatient|
|07/31/97||Add to Prescription section||New policy|
|07/16/99||Replace policy||Updated; cross-referenced to new policy No. 8.01.19|
|08/18/00||Replace policy||Policy updated; policy statement suggests that botulinum toxin treatment of anal fissure may be considered medically necessary, treatment for headache may be considered investigational|
|10/15/00||Replace policy||New CPT codes|
|05/31/00||Replace policy||Policy revised to include discussion of MyoBloc and further discussion of headaches; policy statement unchanged|
|12/18/02||Replace policy||Policy updated with focus on botulinum for headache and low back pain; policy statement unchanged regarding headache; still considered investigational. Policy statement added regarding low back pain; also considered investigational|
|11/9/04||Replace policy||Policy updated with October 2004 TEC Assessment. Chronic low back pain and sialorrhea (drooling) added to investigational policy statement|
|12/14/05||Replace policy||Policy updated to address 2 published RCTs of botulinum toxin in non-ICHD-classified headache disorder (“chronic daily headache”); no change to the policy statement. Policy also expanded to include discussion of botulinum toxin as a treatment of lateral epicondylitis, considered investigational. Reference numbers 31, 32, 36, and 37 added. CPT coding updated|
|04/25/06||Replace policy||Policy updated to address urologic indications; policy statement revised to indicate that treatment of incontinence related to detrusor overactivity due to spinal cord injury is medically necessary; treatment of BPH and detrusor sphincteric dyssynergia identified as investigational. Reference numbers 38–41 added|
|12/12/06||Replace policy||Policy updated with literature review focused on headache indications; no changes made in policy statements. Reference numbers 21, 22, and 31 added; other references renumbered|
|12/13/07||Replace policy||Entire policy updated with literature searches; policy statement revised to indicate that treatment of incontinence related to detrusor overreactivity due to either idiopathic causes or neurogenic causes may be considered medically necessary. Treatment of joint pain; mechanical neck disorders; neuropathic pain; pain after hemorrhoidectomy or lumpectomy; or interstitial cystitis identified as investigational. Reference list revised extensively.|
|10/07/08||Replace policy||Policy updated with literature review in July 2008; policy rationale section extensively rewritten/revised. Clinical input reviewed. Information regarding antibody testing added to policy; antibody testing identified as investigational. Minor language changes to other indications; however, intent of policy statements otherwise unchanged. References list revised extensively.|
|10/19/10||Replace policy||Policy updated with literature review through July 2010; literature review focused on evidence on migraine headache and on the new agent Xeomin. References 5-7, 10-14, 17, 22, 55-61 added; other references renumbered/removed. The medically necessary policy statements were combined into a single statement; no changes to the indications considered medically necessary; minor language changes to other policy statements|
|01/13/11||Replace policy||Clinical input added; Regulatory status information updated. Chronic migraine added as medically necessary indication in certain situations; policy statements on indications other than headache unchanged.|
|09/01/11||Replace policy||Entire policy updated with literature review through July 2011. Prevention of pain associated with breast reconstruction after mastectomy, Hirschsprung’s disease and gastroparesis added as investigational indications. References 7, 8, 11-13, 15, 32, 35, 36, 62, 96, 125-131 added; other references renumbered or removed.|
|9/13/12||Replace policy||Policy updated with literature review through July 2012. Policy statements unchanged. References 17-19, 35, 36, 41, 43, 56, 64-68, 123 and 124 added; other references renumbered or removed.|
|11/08/12||Replace policy-coding update only||CPT and ICD coding updated|
|09/12/13||Replace policy||Policy updated with literature review through July 16, 2013. Overactive bladder in adults unresponsive to or intolerant of anticholinergics added to medically necessary statement. Facial wound healing and internal anal sphincter (IAS) achalasia added to investigational statement. Bullet points on headache and on urinary incontinence due to detrusor overactivity edited for clarity. References 4, 19, 31, 32, 34, 35, 49, 51, 54, 72, 80 and 113 added; other references renumbered or removed.|
|10/10/13||replace policy - coding update only||CPT coding updated – new codes for chemodenervation added.|
|10/09/14||Replace policy||Policy updated with literature review through September 1, 2014. Trigeminal neuralgia added to investigational statement. References 6, 30, 33, 53, 68-69, 79, 82-84 and 113 added.|