NOTE: On August 1, 2009, the U.S. Food and Drug Administration (FDA) established new names for the botulinum toxin products; these products are not interchangeable:
IncobotulinumtoxinA (FDA-approved 2010)
OnabotulinumtoxinA (Botox®) may be considered medically necessary for the following U.S. Food and Drug Administration (FDA)-labeled indications:
- Upper limb spasticity in adults, to decrease the severity of increased muscle tone in elbow flexors (i.e., biceps), wrist flexors (i.e., flexor carpi radialis and flexor carpi ulnaris), finger flexors (i.e., flexor digitorum profundus and flexor digitorum sublimis);
- 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, e.g., sternocleidomastoid, splenius, trapezius, or posterior cervical muscles. (* See additional details in Description section);
- Prophylaxis of headaches in adult patients with chronic migraine when the following criteria are met:
- Patient has been diagnosed with chronic migraine for at least 3 months; AND
- Migraine headaches last 4 hours a day or longer for ≥15 days per month; AND
- Migraine is refractory to at least two migraine prophylactic medications from different classes (e.g., tricyclic antidepressants, anticonvulsants, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers, or calcium channel blockers);
- Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication; and
- Treatment of urinary incontinence due to detrusor overactivity, either idiopathic or associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in patients who have an inadequate response to or are intolerant of an anticholinergic medication.
NOTE: For coverage of FDA-labeled indication Hyperhidrosis, see medical policy titled MED201.014 Treatment of Hyperhidrosis.
OnabotulinumtoxinA (Botox®) is considered cosmetic for the FDA-labeled indication of treatment of wrinkles. NOTE: Special comment regarding cosmetic services: Check member’s contract for benefit coverage. Determination of benefit coverage for procedures considered to be cosmetic is based on how a member's benefit contract defines cosmetic services and their eligibility for benefit coverage.
OnabotulinumtoxinA (Botox®) may be considered medically necessary for the following off-label indications:
- Achalasia in patients who have not responded to dilation therapy or who are considered poor surgical candidates;
- Treatment of chronic anal fissure;
- Multiple sclerosis;
- Spinal cord or traumatic brain injury;
- Sialorrhea (drooling) that is associated with advanced Parkinson’s disease;
- Facial nerve (7th cranial nerve) disorders; OR
- Treatment of dystonia that is associated with one of the following hereditary, degenerative, or demyelinating diseases of the central nervous system, and that results in functional impairment (e.g., interference with joint function, limitation of mobility) and/or pain:
- Idiopathic (primary or genetic) torsion dystonia;
- Symptomatic (acquired) torsion dystonia;
- Oromandibular dyskinesia (e.g., orofacial dyskinesia, Meige syndrome);
- Organic writer's cramp;
- Hereditary spastic paraplegia;
- Neuromyelitis optica;
- Schilder's disease;
- Spastic hemiplegia;
- Spasticity related to stroke;
- Infantile cerebral palsy; or
- Spasmodic dysphonia, for initial treatment when diagnosis is affirmed by laryngoscopy, or video stroboscopy; OR maintenance or continuing treatment (which does not require reaffirmation of a previously established diagnosis).
OnabotulinumtoxinA (Botox®) is considered experimental, investigational and unproven for all other indications, including but not limited to:
- Benign prostatic hyperplasia;
- Chronic low back pain;
- Chronic motor tic disorder;
- Detrusor sphincteric dyssynergia;
- Interstitial cystitis;
- Joint pain;
- Lateral epicondylitis;
- Mechanical neck disorders;
- Myofascial pain syndrome;
- Neuropathic pain after neck dissection;
- Pain after hemorrhoidectomy or lumpectomy;
- Pelvic and genital pain;
- Prophylaxis of episodic migraine (which does not meet the coverage criteria outlined above), or other types of headaches, including but not limited to tension headache, cluster headache, chronic daily headache, and cervicogenic headache;
- Sialorrhea (drooling) except that associated with Parkinson’s disease;
- Tics associated with Tourette syndrome;
- Tremors such as benign essential tremor;
- Treatment to improve upper extremity functional abilities or range of motion at a joint affected by a fixed contracture;
- Wound healing and pain control; or
AbobotulinumtoxinA (Dysport™) may be considered medically necessary for the FDA-labeled indication of treatment of adults with 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, e.g., sternocleidomastoid, splenius, trapezius, or posterior cervical muscles. (* See additional details in Description section).
AbobotulinumtoxinA (Dysport™) is considered cosmetic for the FDA-labeled indication of treatment of wrinkles. NOTE: Special comment regarding cosmetic services: Check member’s contract for benefit coverage. Determination of benefit coverage for procedures considered to be cosmetic is based on how a member's benefit contract defines cosmetic services and their eligibility for benefit coverage.
AbobotulinumtoxinA (Dysport™) may be considered medically necessary for the following off-label indications:
- Achalasia in patients who have not responded to dilation therapy or who are considered poor surgical candidates;
- Facial nerve (7th cranial nerve) disorders; or
- Spasticity related to cerebral palsy or stroke.
AbobotulinumtoxinA (Dysport™) is considered experimental, investigational and unproven for any other indication not listed above.
IncobotulinumtoxinA (Xeomin®) may be considered medically necessary for the following FDA-labeled indications:
- Blepharospasm in adults previously treated with onabotulinumtoxinA (Botox®).; or
- 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, e.g., sternocleidomastoid, splenius, trapezius, or posterior cervical muscles. (* See additional details in Description section).
IncobotulinumtoxinA (Xeomin®) is considered experimental, investigational and unproven for any other indication.
NOTE: AbobotulinumtoxinA (e.g., Dysport™), onabotulinumtoxinA (e.g., Botox™), and incobotulinumtoxinA (Xeomin) are NOT interchangeable.
RimabotulinumtoxinB (Myobloc®) may be considered medically necessary for the FDA-labeled indication of 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, e.g., sternocleidomastoid, splenius, trapezius, or posterior cervical muscles. (* See additional details in Description section).
RimabotulinumtoxinB (Myobloc®) may be considered medically necessary for the off-label indication of sialorrhea associated with advanced Parkinson’s disease.
RimabotulinumtoxinB (Myobloc®) is considered experimental, investigational and unproven for any other indication.
NOTE: On August 1, 2009, the FDA established new names for the botulinum toxin products:
IncobotulinumtoxinA (FDA-approved 2010)
This policy section was originally based on a 1996 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment 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, (1-3) and additional controlled trials identified by MEDLINE literature searches.
At the time of the 1996 TEC Assessment, only onabotulinumtoxinA (Botox) was commercially available. Based on the evidence, the TEC Assessment concluded that Botox therapy for the following indications met the BCBSA TEC Criteria:
- Children with cerebral palsy in whom dynamic joint deformity secondary to spasticity or athetosis produces pain and/or interferes with function; and
- Ambulatory and nonambulatory patients with chronic limb spasticity, in whom dynamic joint deformity produces pain and/or interferes significantly with supportive care and quality of life (sitting, balance, hygiene, pain control). (Note: evidence for this indication was derived from trials that enrolled patients with chronic spasticity due to stroke, multiple sclerosis, trauma, familial spastic paresis, Friedrich’s ataxia, hypoxic brain damage, motor neuron disease, and hemorrhage from aneurysm.)
In addition, the AAN assessments summarized the evidence and concluded the following:
- BoNT (botulinum toxin) is established as effective and should be offered (Level A) for equinus varus deformity in children with cerebral palsy.
- BoNTB is probably effective and should be considered (Level B) for treatment of adductor spasticity and/or pain control in conjunction with adductor-lengthening surgery in children with cerebral palsy.
- BoNTB is probably effective and should be considered (Level B) for treatment of upper extremity spasticity.
- BoNT (botulinum toxin) is established as effective and should be offered to reduce muscle tone and improve passive function in adults with spasticity (Level A), and should be considered to improve active function (Level B); however, there is insufficient evidence to recommend an optimum technique for muscle localization at the time of injection). (1-3)
The bulk of the reviewed literature is based on trials using onabotulinumtoxinA (i.e., Botox).
A 1990 National Institutes of Health (NIH) Consensus Development Conference concluded that botulinum toxin therapy is safe and effective for the currently FDA-approved indications, as well as for adductor spasmodic dysphonia and jaw-closing oromandibular dystonia. (4) According to information provided by the NIH National Institute on Deafness and Other Communication Disorders (NIDCD), the only available treatments for all types of spasmodic dysphonia is surgery (improvement often temporary), or botulinum toxin therapy. (5)
Two recent trials evaluated botulinum toxin A for treating mobility limitations in patients with spastic cerebral palsy. In 2010, van der Houwen et al. in the Netherlands randomized 22 children who walked with flexion of the knee in midstance to standard rehabilitation with and without multilevel Botox injections. (6) Botox injection did not result in general improvement in lower limb muscle activation during gait 6 weeks after the intervention. A 2011 study, conducted in Norway, randomized 66 patients who had decreased walking ability to Botox or placebo injections. (7) No significant differences were found between groups in the primary outcomes, which included kinematics (joint angles) and the Norwegian version of the short form 36 (SF-36) quality-of-life scale. However, among the secondary outcomes, the Botox group had significantly more reduction in muscle stiffness/spasticity and significantly greater improvement in the global improvement scale than the placebo group at week 8; these effects were not sustained at week 16.
Randomized controlled trials (RCTs) were identified that evaluated Botox, Dysport, and Xeomin used to treat spasticity after stroke. In 2010, Kaji and colleagues reported the findings of a trial conducted in Japan with 120 patients who had post-stroke lower limb spasticity randomly assigned to receive a single injection of Botox or placebo. (8) The primary outcome, change from baseline in modified Ashworth scale (MAS) of muscle spasticity, indicated significantly greater improvement in the Botox group compared to the placebo group over 8 weeks. Bakheit and colleagues randomly assigned 83 patients with upper limb spasticity after stroke to receive 1 of 3 doses of Dysport or placebo. (9) All 3 doses of Dysport resulted in a statistically significantly greater reduction in the MAS score than placebo.
In 2011, Shaw and colleagues reported on results of a study randomizing 333 patients with post-stroke upper limb spasticity to physical therapy plus Dysport (n=170) or physical therapy alone (n=163). (10) 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 MAS 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 post-stroke upper limb spasticity. Kanovsky and colleagues randomized 148 patients with post-stroke upper limb spasticity to treatment with either Xeomin or placebo. (11) 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. (12) Patients received up to 5 additional sets of Xeomin injections, with 12-week intervals between injections. A total of 111 (77%) patients 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 post-treatment visit. None of the patients developed neutralizing antibodies in either the double-blind or extension phases of the study.
A multicenter study by Barnes and colleagues randomly assigned patients with upper limb spasticity (88% post-stroke) to receive either 50 U/mL or 20 U/mL Xeomin and did not find a substantial difference in outcomes with the 2 doses. (13)
A 2010 Cochrane systematic review identified 5 double-blind RCTs comparing a single injection of botulinum toxin A to a placebo injection for the treatment of shoulder spasticity after stroke or hemiplegia. (14) A pooled analysis of data from 4 studies (3 using Dysport and 1 using Botox) found a significantly greater reduction in pain severity in the botulinum toxin group compared to the placebo group at a follow-up visit between 12 and 24 weeks (mean difference= -1.2, 95% confidence interval [CI]: -2.37 to -0.07). At 12 to 24 weeks, shoulder range-of-motion outcomes did not differ significantly between groups. Most of the studies included in the review were small, and the investigators rated the overall evidence as low to mediocre.
A 2007 systematic review identified 70 studies that examined two botulinum toxin agents used to treat cervical dystonia. (15) There were 30 studies on Botox, 24 on Dysport, 11 on Myobloc, and five combining two agents. Xeomin for treating cervical dystonia has been evaluated in an RCT that found it to be non-inferior to Botox. (16) There is evidence from multiple RCTs that botulinum toxin is an effective treatment for cervical dystonia; therefore, this is considered medically necessary.
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 and colleagues evaluating the literature on botulinum toxin for strabismus. (17) 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 non-invasive 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. (18) 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 and colleagues randomized 47 patients with acute unilateral sixth nerve palsy to botulinum toxin treatment or a no treatment control group. (19) The final recovery rate was 20 of 25 (80%) in the botulinum toxin group and 19 of 22 (80%) in the control group.
Conclusions: 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 non-invasive 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. Randomized controlled trials have evaluated Botox, Dysport, and Xeomin for the treatment of blepharospasm and found these agents to be effective at improving symptoms. (20-22) No RCTs evaluating either Myobloc or Xeomin for treating blepharospasm were identified in literature searches
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 achalasia. In 1999, Vaezi and colleagues (23) reported a trial that randomly assigned 42 patients with achalasia to receive either 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 conclude 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. (24)
A RCT by Annese and colleagues in Italy with 78 patients found 100 U of Botox and 250 U of Dysport to have comparable efficacy for treating esophageal achalasia. (25) Due to evidence indicating that at least one botulinum toxin agent is an effective treatment of achalasia, botulinum toxin is considered medically necessary for this indication.
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. Since the anal sphincter contraction could be characterized as a dystonia, botulinum toxin is a logical medical approach. In 1998, Maria and colleagues randomly assigned 30 patients with chronic anal fissure to receive either two injections of 20 units of botulinum toxin, on either side of the fissure, or two injections of saline. (26) After two months, 11 patients in the treatment group reported healing, compared to only two in the control group. The four patients who still had fissures after two months underwent retreatment with botulinum toxin; two of these four patients reported healing scars and symptomatic relief. These results are consistent with earlier case series that reported a healing rate of 80%. (27) Nitroglycerin ointment has also been used to successfully treat anal fissure. In 1999, Brisinda and colleagues in Italy compared the results of nitroglycerin ointment and botulinum toxin in a randomized trial of 50 patients. (28) After two months, 96% of the fissures were healed in the botulinum group compared with 60% in the nitroglycerin group. Brisinda and colleagues 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). (29) Another trial by Brisinda and colleagues found that Botox and Dysport used to treat anal fissures were similar in terms of efficacy and tolerability. (30)
Others have reported both supportive (31) and contradictory (32) data from randomized trials comparing the same treatments. Randomized controlled trials of botulinum toxin versus sphincterotomy have reported significantly better results 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. (33-34) 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. (35) 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.
Conclusions: Due to evidence of effectiveness in numerous small RCTs, combined with being a less invasive option than the gold standard of surgery, botulinum toxin may be considered medically necessary for treatment of anal fissure.
In 2011, Duthie and colleagues published a Cochrane review of RCTs evaluating botulinum toxin injections for treating adults with overactive bladder syndrome. (36) The authors identified 19 trials that compare treatment with botulinum toxin to placebo or another intervention in patients with idiopathic or neurogenic overactive bladder. 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 4-6 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). The findings were similar when 2 studies that reported outcomes at 12 weeks were pooled. It was noted by the authors that additional data are needed on long-term outcomes and optimal dose of botulinum toxin. This review suggests that botulinum toxin injections are an effective treatment for refractory overactive bladder symptoms.
Previously in 2008, Karsenty et al. conducted a systematic review of studies of Botulinum toxin A intradetrusor injections in adults with neurogenic detrusor overactivity and urinary incontinence or overactive bladder symptoms of neurogenic origin. (37) The authors identified 18 studies evaluating Botulinum toxin A to treat patients who were refractory to anticholinergics. Most of the studies reported statistically significant improvement in clinical and urodynamic outcomes, without major adverse events. The authors concluded that botulinum toxin treatment results in a clinically significant improvement in outcomes in this group of patients.
As an example, in 2005 Ghei and colleagues conducted a double-blind placebo-controlled crossover trial with 20 patients who had detrusor overactivity unresponsive to oral antimuscarinic agents. (38) Patients received botulinum toxin B or placebo in random order, with 6 weeks between treatments. There was significantly greater reduction in incontinence episodes and improvement in quality of life with active botulinum toxin injection. In addition, in 2011, Hershorn and colleagues published a double-blind trial that included 57 patients with neurogenic detrusor inactivity. (39) Botulinum toxin A injections were compared to placebo. At weeks 6, 24 and 36, the mean daily frequency of incontinence episodes was significantly lower in the botulinum toxin group than the placebo group. At 6 weeks, there were an average of 1.31 incontinence episodes in the botulinum toxin group compared to 4.75 with placebo, p<0.001.
The FDA revised label for 2013 (125) cites two double-blind, placebo-controlled, randomized, multi-center, 24-week clinical studies were conducted in patients with OAB with symptoms of urge urinary incontinence, urgency, and frequency (Studies OAB-1 and OAB-2). Patients needed to have at least 3 urinary urgency incontinence episodes and at least 24 micturitions in 3 days to enter the studies. A total of 1105 patients, whose symptoms had not been adequately managed with anticholinergic therapy (inadequate response or intolerable side effects), were randomized to receive either 100 Units of Botox (n=557), or placebo (n=548). Patients received 20 injections of study drug (5 units of Botox or placebo) spaced approximately 1 cm apart into the detrusor muscle. In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of urinary incontinence episodes were observed for Botox 100 Units at the primary time point of week 12. Significant improvements compared to placebo were also observed for the secondary efficacy variables of daily frequency of micturition episodes and volume voided per micturition. The median duration of response in Study OAB-1 and OAB-2, based on patient qualification for re-treatment, was 19-24 weeks for the Botox 100 Unit dose group compared to 13 weeks for placebo. To qualify for re-treatment, at least 12 weeks must have passed since the prior treatment, post-void residual urine volume must have been less than 200 mL and patients must have reported at least 2 urinary incontinence episodes over 3 days.
In addition, the revised FDA label (125) cites two double-blind, placebo-controlled, randomized, multi-center clinical studies that were conducted in patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition, who were either spontaneously voiding or using catheterization (Studies NDO-1 and NDO-2). A total of 691 spinal cord injury (T1 or below) or multiple sclerosis patients, who had an inadequate response to or were intolerant of at least one anticholinergic medication, were enrolled. These patients were randomized to receive either 200 Units of Botox (n=227), 300 Units of Botox (n=223), or placebo (n=241). In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in weekly frequency of incontinence episodes were observed for Botox (200 Units) at the primary efficacy time point at week 6. Increases in maximum cystometric capacity and reductions in maximum detrusor pressure during the first involuntary detrusor contraction were also observed. No additional benefit of Botox 300 Units over 200 Units was demonstrated. The median duration of response in study NDO-1 and NDO-2, based on patient qualification for re-treatment was 295-337 days (42-48 weeks) for the 200 Units dose group compared to 96-127 days (13-18 weeks) for placebo. Re-treatment was based on loss of effect on incontinence episode frequency (50% of effect in Study NDO-1; 70% of effect in Study NDO-2). The FDA states that treatment with Botox can be repeated when the benefits from the previous treatment have decreased, but there should be at least 12 weeks between treatments.
Detrusor sphincter dyssynergia
In 2002, deSeze and colleagues studied 13 patients with chronic urinary retention due to detrusor sphincter dyssynergia from spinal cord disease (traumatic injury, multiple sclerosis, congenital malformations), 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 post-void 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 and colleagues 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 and colleagues 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 nonneurogenic obstructive sphincter dysfunction. (42) In the former group, the authors cite 10 small studies (n ranged from 3 to 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.
Benign prostatic hyperplasia
The rationale for botulinum treatment is based on the theory that symptoms of benign prostatic hyperplasia (BPH) 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 and colleagues 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 post-treatment 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 and colleagues in 2003. (44) The investigators reported on 30 patients with 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 (n = 10-19) of botulinum toxin treatment of patients with interstitial cystitis for alleviation of chronic pain and improving bladder capacity have been published. (e.g., 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. The results suggest efficacy but need confirmation in a larger population and preferably in controlled clinical trials.
Conclusion: There is evidence from multiple RCTs that botulinum toxin is an effective treatment for detrusor overactivity; therefore this is considered medically necessary. There is insufficient evidence on other urologic applications; thus botulinum toxin is considered experimental, investigational and unproven.
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. Thus, the clinical significance of these findings is unclear.
A number of RCTs have evaluated botulinum toxin injection compared with placebo injection to control sialorrhea in patients with neurologic diseases (e.g., Parkinson, cerebral palsy, amyotrophic lateral sclerosis [ALS]). The largest amount of evidence is available on botulinum toxin for treating Parkinson disease. For example, in 2006, Lagalla et al. randomly assigned 32 patients with Parkinson disease to placebo or 50 U botulinum toxin A; evaluation at 1 month post-injection 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 and colleagues randomly assigned 16 patients with Parkinson disease to receive placebo or 2,500 U 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 and a dysphagia scale. Mancini and colleagues (52) assigned 20 patients with Parkinson disease to injections of either a saline placebo or 450 U of Dysport. The treatment group was significantly better than placebo on a drooling scale at 1 week; the effect disappeared by 3 months.
Less evidence is available on botulinum toxin to reduce drooling in children with cerebral palsy. In 2008, Reid and colleagues randomly assigned 48 children with cerebral palsy (n=31) and other neurologic disorders to a single injection of 25 U botulinum toxin A compared to no treatment. (53) 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.
While some questions remain, studies on those with Parkinson disease provide consistent findings related to impact on sialorrhea. Thus, for this specific disease indication, this use of botulinum toxin is considered medically necessary. For sialorrhea associated with other disorders, there is little evidence and additional studies are needed.
Chronic Low Back Pain
Only one RCT of botulinum toxin A treatment in patients with low back pain has been published. (54) The trial, published in 2001, enrolled 31 consecutive patients with chronic low back pain of at least six months' duration and more predominant pain on one side. Patients were injected with 40 units of Botox (Allergan, Inc.) at five lumbosacral locations for a total of 200 U (treated group) or saline placebo (placebo group). Injections were made on one side of the back only, depending on predominance of pain. At eight weeks, 60% of treated patients and 12.5% of placebo patients showed improvement in VAS pain scores (p=0.009). Perceived functional status (Oswestry scale) at eight 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 a heterogeneous population, and results in this small 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 experimental, investigational and unproven 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 BCBSA TEC Assessment that was completed in 2002 and updated in 2004. (2) 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. (55) 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 2012, Jackson and colleagues 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. (56) 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 per month) or chronic headache (at least 15 days per 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 not a 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 and colleagues published a systematic review and meta-analysis of trials on botulinum toxin for treating episodic migraines. (57) 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 standardized mean difference (SMD) was -0.06 (95% confidence interval [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 (less than 100 units) separately from trials using high-dose botulinum toxin A (100 units or more) did not find a statistically significant effect of botulinum toxin A compared to placebo in either strata.
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 II Research Evaluating Migraine Prophylaxis Therapy) studies 1 and 2. (58, 59) 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, two of the ICHD-2 criteria for chronic migraine. Eligible patients were randomly assigned to receive two cycles of injections of Botox 155 U or placebo, with 12 weeks between cycles. Randomization was stratified based on the frequency of acute headache pain medication during baseline and whether or not they 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 two 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-1 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 includes the 6-item Headache Impact Test (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ v.2). Key findings of the two studies are described below.
PREEMPT 1 randomly assigned a total of 679 patients. (58) 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 one prophylactic medication and approximately 68% overused headache pain medication during baseline. A total of 296/341 (87%) in the Botox group and 295/338 (87%) 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 to 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 (i.e., 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. Treatment-related adverse events were consistent with the known safety profile of Botox.
PREEMPT 2 randomly assigned a total of 705 patients. (59) 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 one prophylactic medication, and approximately 63% overused headache pain medication during baseline. A total of 311/347 (90%) in the Botox group and 334/358 (93%) in the placebo group completed the 24-week double-blind phase. The primary outcome, change from baseline in 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 three 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. (60) 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 four 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 had statistically significant findings 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, 1 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, e.g., 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 discusses 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. (61) 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. (62) 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 and colleagues. (63) 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 of 24 (79%) in the Botox group and 17 of 24 (71%) in the topiramate group; 9 patients (15%) were not available for this analysis.
The 2012 meta-analysis by Jackson and colleagues, discussed above, (56) 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 and colleagues in 2006. (64) 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 and colleagues (56) 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 and colleagues in 2004, found a statistically significant benefit with botulinum toxin treatment. (65) This study included 60 patients and included patients with chronic migraines, as well as chronic tension-type 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 and colleagues (66) and 702 patients in a study by Silberstein and colleagues. (67) 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 experimental, investigational and unproven indication.
No controlled trials have been reported on cluster headache.
In 2011, Linde and colleagues published a double-blind placebo-controlled crossover study that included 28 patients with treatment-resistant cervicogenic headache. (68) 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. (69-71) One trial reported trends toward improvement with treatment for various outcomes; most were not statistically significant. (69) Another reported no significant differences in any of several pain-related outcomes. (71) 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. (70) A Cochrane review of treatment of mechanical neck disorders, published in 2007, (72) 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.
Conclusions: For patients with migraine headache, the published evidence does not suggest that botulinum toxin improves net health outcome for patients with an episodic pattern (i.e., fewer than 15 episodes per month); thus, it is considered experimental, investigational and unproven. 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 were 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, i.e., 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 scant and insufficient to form conclusions about efficacy.
Myofascial Pain Syndrome
Painful muscles with increased tone and stiffness containing trigger points characterize myofascial pain syndrome. 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, since it is unclear whether any treatment effect is due to the injection, dry needling of the trigger point, or a placebo effect. Seven randomized, blinded, placebo-controlled clinical trials of botulinum toxin versus placebo for cervicothoracic myofascial pain syndrome have been reported. All trials injected botulinum toxin or placebo into trigger points in the upper back, shoulder, and/or cervical muscles. Total botulinum toxin doses varied considerably across trials as did numbers of patients enrolled (n=20-132) and methods of pain assessment. Five trials reported no significant differences in response between treatment and placebo. (73-77) The majority of trials specified that botulinum toxin A was used. One trial, administering high-dose botulinum toxin versus placebo, reported significant differences in pain relief at marginal p values. (78) The last trial reported significant differences in only a few of several outcome measures. (79)
Two RCTs compared botulinum toxin to dry needling and to lidocaine or bupivacaine injection. In one trial published in 2005, lidocaine trigger point injection was significantly more effective than dry needling but significantly less effective than botulinum toxin. (80) In the other, both bupivacaine and botulinum toxin A were similarly effective and not significantly different. (81)
Three studies addressed another form of myofascial pain, piriformis syndrome, characterized by buttock tenderness and sciatica. One study of nine patients compared botulinum toxin with placebo, finding that postinjection pain scores were significantly improved in the treatment group for only 1 of 4 pain domains, while none improved in the placebo group. (82) Another study of 36 patients had a high loss to follow-up (23%) and found that the botulinum toxin group had a significantly higher proportion, with 50% or greater reduction in pain on each of the last 2 follow-up visits, compared with placebo. (83) These small and flawed studies, both published in 2002, do not establish that the effects of botulinum toxin exceed those of placebo. A third study from 2000, comparing botulinum toxin with methylprednisolone, found better results for the former, but placebo effects were not considered. (84) The evidence for piriformis myofascial pain syndrome does not support conclusions about the effects of botulinum toxin.
One RCT enrolled patients with myofascial pain related to bruxism; while subjective and objective improvements in several outcomes measures were reported favoring treatment versus placebo, none was significant. (85)
A 2007 systematic review (86) selected RCTs of trigger-point injection; use of the Oxford Pain Validity Scale was also a selection criterion. Five trials were included; 1 trial resulted in a significant effect, whereas the other 4 did not. The data were described as “limited and clinically heterogeneous,” and the authors concluded that the evidence did not support the use of botulinum toxin A injections in trigger points for myofascial pain. A 2011 meta-analysis by Langevin and colleagues of four trials comparing botulinum toxin to placebo for chronic myofascial neck pain did not find a statistically significant short-term difference between groups. (87) The pooled standard mean difference (SMD) was -0.21 (95% CI=-0.50 to 0.70). These four trials were considered to have high validity; that is they scored at least 6 on a 12-point risk of bias instrument used by the Cochrane collaboration. All of the four trials were cited previously in this policy (73, 75, 78, 79).
Conclusions. Numerous RCTs have been performed for treatment of myofascial pain syndrome. The majority of these trials do not report benefit for botulinum toxin. Due to the lack of consistent evidence of benefit, botulinum toxin is considered experimental, investigational and unproven for treatment of myofascial pain syndrome.
Wound Healing and Pain Control
Three small RCTs of botulinum toxin intra-sphincter injection for controlling pain after hemorrhoidectomy have been published. Davies and colleagues evaluated 50 patients and showed marginal improvement in pain control at days 6 and 7 by patient visual analogy scale (p<0.05) with Botox injections; there was no significant difference in morphine or analgesic use. (88) A 2005 article describes a study by Patti and colleagues (n=30) who randomly assigned patients to 20 U botulinum toxin or saline injection and reported significantly decreased duration of postoperative pain at rest and during defecation in the treated group. (89) A 2006 study by Patti and colleagues, which also included 30 patients, found significant differences in postoperative maximum resting pressure change from baseline comparing botulinum toxin treatment to topical glyceryl nitrate (p<0.001; resting pressure is increased after surgery and may be responsible for pain). (90) In addition, there was a significant reduction in postoperative pain at rest (p=0.01) but not during defecation. There was no difference in time of healing. These small studies suggest improvement in pain control; however, differences may be small and need confirmation in larger trials.
In 2006, Gassner and colleagues conducted a small, RCT of botulinum toxin-induced immobilization of facial lacerations to improve wound healing compared to placebo (n=31). (91) The outcome was determined by blinded assessment of photographs of wound healing at intervals using a VAS. The authors report enhanced wound healing in the treatment arm (8.9 vs. 7.2, p=0.003). These results conflict with the wound-healing outcome after hemorrhoidectomy, as reported by Patti and colleagues that same year. Additional studies are necessary to identify indications and confirm improved outcomes; thus, botulinum toxin is considered experimental, investigational and unproven for wound healing.`
Pelvic and Genital Pain in Women
One double-blind, randomized, placebo-controlled trial evaluated 60 patients with chronic pelvic pain and pelvic floor spasm. (92) 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). (93) 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. (94) Compared to baseline, there were nonsignificant reductions in pelvic pain and nonsignificant improvements in quality of life. The evidence is insufficient for this indication.
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. (95, 96) 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. However, lack of a randomized, placebo-controlled study design to control for strong placebo effects in pain therapy render these studies inconclusive.
Lateral Epicondylitis and Other Joint Pain
In 2005, Wong and colleagues reported on the results of a double-blind, placebo-controlled trial that randomly assigned 60 patients with lateral epicondylitis of at least three months’ duration to receive either a single intramuscular injection of botulinum toxin or placebo, targeted at the tender spot in the elbow. (97) In the botulinum group, the mean VAS improved from 65.5 mm to 25.3 mm at four 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 four patients in the botulinum group. In a similarly designed study of 40 patients, published in 2005, Hayton and colleagues reported no treatment effect at three months. (98) 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. (99) 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 to placebo.
Two case series of patients with chronic joint pain refractory to conservative management studied the effect of botulinum toxin A injections (one series specified that Dysport was used) into several joints of patients with arthritis and into the knee joint of patients with chronic knee pain. (100, 101) Both reported significant improvement in joint pain and function compared to baseline, lasting for 3–12 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 experimental, investigational and unproven.
In 2005, Stidham and colleagues 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. (102) In this study, 30 patients were randomly assigned in a double-blind study to receive either three subcutaneous injections of botulinum toxin A around the ear followed by placebo injections four 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 post-botulinum toxin A injections. However, no other significant differences were noted when comparing the two treatments at one and four 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 experimental, investigational and unproven.
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. (103) In approximately 3–10% of adult patients, true secondary resistance arises due to the development of antibodies that specifically neutralize the activity of botulinum toxin. e.g., (104, 105) That neutralizing antibodies directly causes 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. (106) Non-neutralizing 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. (107) In 2 studies of pediatric patients treated for spasticity, neutralizing antibodies were detected in 28–32% of patients. (108, 109) Recommendations for avoiding eventual resistance are to use the lowest dose possible to obtain a clinical response, and schedule intervals of 10–12 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 re-develop quickly. (110) 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. (107, 111)
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 serum (112) or with an in vitro toxin-neutralizing assay based on a mouse diaphragm nerve-muscle preparation. (113) 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 (ELISA). However, unless only the protein sequences that specifically react with neutralizing antibodies are employed, these formats detect both neutralizing and non-neutralizing antibodies (108, 114, 115) and would therefore result in significant numbers of false-positive results. Thus, the currently available testing approach is considered experimental, investigational and unproven. An option for some patients might be to inject toxin into the frontal muscle above one eyebrow; a toxin-responsive patient would have asymmetry of the forehead on attempted frowning, whereas, a nonresponsive patient would not. (115)
Chronic Pain after Lumpectomy
There are no relevant publications on the use of botulinum toxin for pain following mastectomy or lumpectomy.
Pain Associated With Breast Reconstruction After Mastectomy
No randomized controlled trials were identified evaluating botulinum toxin for pain control after mastectomy and expander reconstruction. One published study was identified, an observational study published by Layeeque and colleagues in 2004. (116) The study included 48 patients who were undergoing mastectomy with tissue expander placement. Treatment selection was based on physician preference; 22 (46%) patients had Botox injections to prevent postoperative pain and 26 (54%) patients were treated without Botox. Botulinum toxin was injected into the pectoralis major, serratus anterior and rectus abdominis insertion. Pain was scored using a VAS of 0 to 10.
Pain-related outcomes tended to be better among patients who received Botox injections. Mean immediate postoperative pain was 3.09 (standard deviation [SD] = 0.92) in the botulinum toxin group and 6.80 (SD=1.98) in the standard treatment group, p<0.0001. The mean dose of morphine used during the first 24 hours was 3.27 mg (SD=3.18) in the Botox group and 17.15 (SD=10.40) in the standard treatment group, p<0.0001. Among the other outcomes, mean length of hospital stay was 26 hours (SD=8) in the Botox group and 37 hours (SD=19) in the standard treatment group; this difference was statistically significant, p=0.015. A limitation of the study was that it was not randomized, and there may have been differences between groups that affected outcomes. Findings have not been replicated in large observational studies or RCTs using any of the FDA-approved formulations of botulinum toxin. Thus, botulinum toxin injection to prevent pain associated with breast reconstruction after mastectomy is considered experimental, investigational and unproven.
The published literature consists of small case series. (117-119) 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’s disease. (118) 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 U to 60 U. Twelve of 18 (67%) 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 1-5 additional injections due to either treatment failure or recurrence of symptoms; re-treatment was not based on a standardized protocol.
A 2011 series by Patrus and colleagues retrospectively reviewed outcomes in 22 patients with Hirschsprung’s disease treated over 10 years who had received a median of 2 (range 1-23) botulinum toxin injections for post-surgical obstructive symptoms. (119) 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 to 10 years). At the time of chart review, 2 of 22 patients (9%) 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 to pre-injection (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 experimental, investigational and unproven.
A systematic review of the literature, published in 2010, identified a total of 15 studies on botulinum toxin injection to treat gastroparesis. (120) Two of the studies were RCTs; the remainders were case series or open-label observational studies. The authors stated that, while the non-randomized 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 and colleagues published a randomized cross-over study with 23 patients. (121) 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 (SD=13.7) minutes after Botox injection and 22.5 (SD=7.7) minutes 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=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. (122) 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 (GES) prior to treatment and at a 1-month follow-up. The proportion of patients with at least a 9-point reduction in the GES at 1 month, the primary endpoint, was 6 of 16 (37.5%) in the Botox group and 9 of 16 (56.3%) 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.
Conclusions: Two small RCTs have failed to show a benefit for treatment of gastroparesis. This evidence is insufficient to form conclusions about the efficacy of botulinum toxin for this indication.
Practice Guidelines and Position Statements
In 2011, the Academy of Neurology, Quality Standards Subcommittee, published an update of evidence-based recommendations for treating essential tremor. (123) The report reaffirms their 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 (124) states: “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.”
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