Medical Policy

Policy Num:      05.001.004
Policy Name:    Botulinum Toxin
Policy ID:          [05.001.004]  [Ac / B / M + / P+]  [5.01.05]

Last Review:      November 04, 2024
Next Review:      November 20, 2025
 

Related Policies:

08.001.044 - Treatment of Hyperhidrosis

Botulinum Toxin

SUMMARY

Botulinum is a family of toxins produced by the anaerobic organism Clostridia botulinum. Four formulations have been approved by the U.S. Food and Drug Administration (FDA). Labeled indications of these agents differ; however, all are FDA-approved for treating cervical dystonia in adults. Botulinum toxin products are also used for a range of off-label indications.

For individuals who have dystonia or spasticity resulting in functional impairment and/or pain (eg, interference with joint function, mobility, communication, nutritional intake) who receive botulinum toxin injections, the evidence includes multiple randomized controlled trials (RCTs) and meta-analyses. Relevant outcomes are symptoms, functional outcomes, medication use, and treatment-related morbidity. The data support the efficacy of botulinum toxin for improving dystonia or spasticity in patients with various conditions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have strabismus who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs evaluating botulinum toxin have reported mixed findings; treatment with botulinum toxin is a noninvasive alternative to surgery and is associated with fewer harms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have blepharospasm or facial nerve (cranial nerve VII) disorders who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs and a systematic review have found symptom improvements in patients treated with botulinum toxin compared with alternative interventions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic migraine headache who receive botulinum toxin injections, the evidence includes several RCTs and meta-analyses. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. RCTs have reported mixed findings; a meta-analysis found that botulinum toxin reduced the frequency of headaches per month compared with placebo or medication. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have esophageal achalasia who receive botulinum toxin injections, the evidence includes a number of RCTs and a systematic review of RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. The systematic review found similar efficacy and less harm with botulinum toxin than with pneumatic dilation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have sialorrhea (drooling) associated with Parkinson disease who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs have consistently found that botulinum toxin provides benefit. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have sialorrhea (drooling) not associated with Parkinson disease who receive botulinum toxin injections, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. Available individual RCTs are small and have not consistently found a clinically meaningful improvement with botulinum toxin therapy. In several trials, rates of adverse events were notably high, making the risk-benefit ratio of botulinum toxin therapy uncertain. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have internal anal sphincter achalasia who receive botulinum toxin injections, the evidence includes 2 RCTs and multiple nonrandomized studies, which have been summarized in a systematic reviews and meta-analysis. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. In a systematic review of nonrandomized studies comparing botulinum toxin injection with myectomy, outcomes were more favorable after surgery. Though the 2 RCTs reported temporary improvement in symptoms after botulinum toxin injections, methodologic limitations, including small sample sizes, lack of blinded assessments, and lack of use of validated outcome measures, limit the interpretation of these RCTs. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic anal fissure who receive botulinum toxin injections, the evidence includes a number of RCTs and a systematic review. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. Studies have found similar efficacy with botulinum toxin or surgery, and less potential harm with toxin injections. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have urinary incontinence due to detrusor overactivity associated with overactive bladder or with neurogenic causes who receive botulinum toxin injections, the evidence includes numerous RCTs. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. Studies have shown that botulinum toxin is effective at reducing symptoms in patients unresponsive to anticholinergic medications. There are adverse events associated with botulinum toxin (eg, urinary retention, urinary tract infection), but patients may find that benefits outweigh harms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with urologic issues other than detrusor overactivity or overactive bladder (eg, detrusor sphincter dyssynergia, benign prostatic hyperplasia, interstitial cystitis) who receive botulinum toxin injections, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. Available RCTs for these conditions are small and have reported mixed findings on the benefit of botulinum toxin. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have other indications (eg, tremors such as benign essential tremor [upper extremity], chronic low back pain, lateral epicondylitis, joint pain, myofascial pain syndrome, temporomandibular joint disorders, trigeminal neuralgia, pain after hemorrhoidectomy, facial wound healing, pelvic and genital pain in women, neuropathic pain, tinnitus, pain associated with breast reconstruction after mastectomy, Hirschsprung disease, gastroparesis, and depression) who receive botulinum toxin injections, evidence includes case series or a few small, flawed RCTs. Relevant outcomes are symptoms, functional outcomes, medication use, and treatment-related morbidity. Evidence of benefit from large, well-conducted RCTs is lacking for these indications. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with Hirschsprung disease who develop obstructive symptoms after a pull-through operation who receive botulinum toxin injections, the evidence includes 3 case series. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. The 3 case series included a total of 73 patients with median follow-up of more than 7 years. In 2 out of the 3 published case series consistent short-term responses were reported in more than 75% of patients. Long- term follow-up is suggestive of durability of response. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

OBJECTIVE

The objective of this evidence review is to assess whether the use of botulinum toxin in a wide variety of neuromuscular conditions and pain syndromes improves the net health outcome.

POLICY STATEMENTS

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.^a (See additional details in Policy Guidelines section.)

•         Upper-limb spasticity^a

•         Dystonia/spasticity resulting in functional impairment (interference with joint function, mobility, communication, nutritional intake) and/or pain in patients with any of the following:

o    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

o    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

•         Strabismus^a

•         Blepharospasm or facial nerve (VII) disorders (including hemifacial spasm)^a

•         Prevention (treatment) of chronic migraine headache in the following situations^a:

o    Initial 6-month trial: Adults who:

§  meet International Classification of Headache Disorders diagnostic criteria for chronic migraine headache (see Policy Guidelines) and

§  have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications used in the treatment of chronic migraine headaches (eg, antidepressants, antihypertensives, antiepileptics). Patients who have contraindications to preventive medications are not required to undergo a trial of these agents.

o    Continuing treatment beyond 6 months:

§  Migraine headache frequency reduced by at least 7 days per month compared with pretreatment level, or

§  Migraine headache duration reduced at least 100 hours per month compared with pretreatment level.

•         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^a

•         Overactive bladder in adults unresponsive to or intolerant of anticholinergics.^a

^a Food and Drug Administration-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

•         sialorrhea (drooling) except that associated with Parkinson disease

•         internal anal sphincter achalasia

•         benign prostatic hyperplasia

•         interstitial cystitis

•         detrusor sphincteric dyssynergia (after spinal cord injury)

•         chronic low back pain

•         joint pain

•         mechanical neck disorders

•         neuropathic pain

•         myofascial pain syndrome

•         temporomandibular joint disorders

•         trigeminal neuralgia

•         pain after hemorrhoidectomy or lumpectomy

•         tremors such as benign essential tremor (upper extremity)

•         tinnitus

•         chronic motor tic disorder and tics associated with Tourette syndrome (motor tics)

•         lateral epicondylitis

•         prevention of pain associated with breast reconstruction after mastectomy

•         Hirschsprung disease

•         gastroparesis

•         facial wound healing

•         depression.

The use of botulinum toxin may be considered investigational as a treatment of wrinkles or other cosmetic indications.

The use of assays to detect antibodies to botulinum toxin is considered investigational.

POLICY GUIDELINES

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 contractions can cause sustained abnormal positions or posturing. Sideways or lateral rotation of the head and twisting of the neck are the most common findings in cervical dystonia. Muscle hypertrophy occurs in most patients. When using botulinum toxin to treat cervical dystonia, postural disturbance and pain must be of such severity as 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 (eg, cervicogenic headaches) must have been considered and excluded.

International Classification of Headache Disorders (ICHD-3) diagnostic criteria for chronic migraine headache include the following:

Headaches at least 15 days per month for more than 3 months; have features of migraine headache on at least 8 days.

Features of migraine headache:

•         Lasts 4 to 72 hours;

•         Has at least 2 of the following 4 characteristics:

o    Unilateral

o    Pulsating

o    Moderate or severe pain intensity

o    Aggravates or causes avoidance of routine physical activity

•         Associated with:

o    Nausea and/or vomiting

o    Photophobia and phonophobia.

(In ICHD-2, absence of medication overuse was one of the diagnostic criteria for chronic migraine. In the ICHD-3, this criterion was removed from the chronic migraine diagnosis and "medication overuse headache" is now a separate diagnostic category.)

Continuing treatment with botulinum toxin beyond 6 months for chronic migraine includes the following.

The policy includes the requirement that migraine headache frequency be reduced by at least 7 days per month compared with pretreatment level, or that migraine headache duration be reduced by at least 100 hours per month compared with pretreatment level in order to continue treatment beyond 6 months. The 7 days per month represents a 50% reduction in migraine days for patients who have the lowest possible number of migraine days (ie, 15) that would allow them to meet the ICHD-3 diagnostic criteria fewest chronic migraine. A 50% reduction in frequency is a common outcome measure for assessing the efficacy of headache treatments and was one of the end points of the PREEMPT study.

CODING

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Electromyographic guidance may be used to direct the injection of the botulinum toxin, particularly for treatment of the larynx or esophagus. Since 2006, there has been a CPT code for needle electromyographic 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.

Preferred drugs

Triple-S Salud will consider Dysport and Botox as preferred agents for covered conditions. In the cases where both toxins share the same indication, the preffred agent will be Dysport.  For this shared indications, Dysport treatmet should be tried first, if treatment fails then Botox could be covered.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Botulinum Toxins

This policy refers to the following botulinum toxin types A and B drug products: abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox) and rimabotulinumtoxinB (Myobloc). PrabotulinumtoxinA-xvfs (Jeuveau) was approved by the U.S. Food and Drug Administration (FDA) on February 1, 2019 for cosmetic use and is considered out of scope of the review.

REGULATORY STATUS

On December 9, 1989, onabotulinumtoxinA (Botox) was approved by the FDA for treatment of ocular dystonias. Since then, its use has been expanded for multiple indications.

On December 8, 2000, rimabotulinumtoxinB (Myobloc) was approved by the FDA for treatment of cervical dystonias. Since then, its use has also been expanded for multiple indications.

On April 29, 2009, abobotulinumtoxinA (Dysport) was approved by the FDA for treatment of cervical dystonias. Since then, its use has been expanded for multiple indications.

On July 30, 2010, incobotulinumtoxinA (Xeomin) was approved by the FDA for treatment of cervical dystonias and blepharospasm. Since then, its use has been expanded for multiple indications.

The FDA-approved indications for the various botulinum toxin products are summarized in Table 1. The evidence for the FDA approved indication for botulinum toxin is not reviewed.

Table 1. FDA Indications of Botulinum Toxin Products^a

FDA: U.S. Food and Drug Administration.a All botulinum toxin products carry black box warnings of the potential for a distant spread of the toxin effect. The warning notes that the risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms.

RATIONALE

This evidence review was created in July 1997 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 15 , 2024. In this section, evidence was only reviewed for clinical indications for which none of the 4 commercially available botulinum toxin products are approved in the U.S.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Study Selection Criteria

Methodologically credible studies were selected for all indications using the following principles:

•         To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

•         In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

•         To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

•         Studies with duplicative or overlapping populations were excluded.

POPULATION REFERENCE NO. 1 

Dystonia OR Spasticity

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients who have dystonia or spasticity resulting in functional impairment and/or pain is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with dystonia or spasticity resulting in functional impairment and/or pain?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with dystonia or spasticity resulting in functional impairment and/or pain.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat dystonia or spasticity: conservative measures and medications (eg, levodopa, anticholinergic drugs, tetrabenazine, clonazepam, baclofen, zolpidem, dopamine receptor blockers).

Outcomes

The general outcomes of interest are symptoms, functional outcomes, medication use, and treatment-related morbidity.

Timing

Follow-up ranges from 8 to 12 weeks to assess outcomes.

Setting

Patients with dystonia or spasticity may be managed by neurologists; botulinum toxin is administered via intramuscular injection in an outpatient setting.

Systematic Reviews

A Cochrane review by Castelão et al (2017), which was an update of a Cochrane Review first published in 2005, identified 8 double-blind RCTs (total N=1010 patients) with moderate overall risk of bias that compared the efficacy and safety of botulinum toxin type A with placebo in cervical dystonia.^15, The primary efficacy outcome was reductions in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. All RCTs evaluated the effect of a single botulinum toxin type A treatment session, using doses from 150 to 236 U of onabotulinumtoxinA (Botox), 120 to 240 U of incobotulinumtoxinA (Xeomin), or 250 to 1000 U of abobotulinumtoxinA (Dysport). Treatment resulted in reduction of 8.06 points (95% confidence interval [CI], 6.08 to 10.05; I²=0%) on the Toronto Western Spasmodic Torticollis Rating Scale at week 4 after injection compared with placebo. While there were no differences in withdrawals due to adverse events between the active and placebo treatment groups, botulinum toxin type A was associated with an increased risk of an adverse event (relative risk [RR], 1.19; 95% CI, 1.03 to 1.36; I²=16%) with dysphagia (9%) and diffuse weakness/tiredness (10%) the most common treatment-related adverse events.

A systematic review and meta-analysis by Dong et al (2017) identified 22 RCTs (total N=1804 participants) that evaluated the efficacy of botulinum toxin type A for upper-limb spasticity after stroke or traumatic brain injury.^16, Compared with placebo, botulinum toxin type A treatment resulted in decrease of muscle tone after week 4 (standardized mean difference [SMD], -0.98; 95% CI, -1.28 to -0.68; I²=66%, p=0.004), week 6 (SMD = -0.85; 95% CI, -1.11 to -0.59; I²=1.2%; p=0.409),week 8 (SMD = -0.87; 95% CI, -1.15 to -0.6; I²=0%, p=0.713), week 12 (SMD = -0.67; 95% CI, -0.88 to -0.46;I²=0%; p=0.896), and week 12 (SMD = -0.73; 95% CI, -1.21 to -0.24; I²=63.5%; p=0.065).A systematic review and meta-analysis by Baker and Pereira (2016) identified 25 RCTs that evaluated the efficacy of botulinum toxin type A for limb spasticity on reducing activity restriction and improving quality of life (QOL) outcomes.^17, Reviewers reported pooled analysis for 6 RCTs that included upper- and lower-limb trials but were unable to pool studies for QOL measures. Evidence quality for the upper-limb was low/very low. Pooled results showed a significant increase in active function with botulinum toxin type A at 4 to 12 weeks for the upper-limb (SMD=0.32; 95% CI, 0.01 to 0.62; p=0.04) and these effects were maintained for up to 6 months (mean difference [MD], 1.87; 95% CI, 0.53 to 3.21; p=0.006). Reviewers reported no conclusion for efficacy in lower-limb or for QOL measures in either limb.

A Cochrane review of 4 RCTs (total N=441 participants) by Marques et al (2016) compared botulinum toxin type B with placebo in cervical dystonia.^18, The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. All trials evaluated the effect of a single treatment session using doses between 2500 U and 10,000 U. Compared with placebo, botulinum toxin type B was associated with an improvement of 14.7% (95% CI, 9.8% to 19.5%) in patients' baseline clinical status with a placebo-corrected reduction of 2.2 points (95% CI, 1.25 to 3.15 points) in the Toronto Western Spasmodic Torticollis Rating Scale at week 4 after injection.

Another Cochrane review of 3 RCTs by Duarte et al (2016) compared botulinum toxin type A with botulinum toxin type B in cervical dystonia.^19, The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. All trials evaluated the effect of a single treatment session using multiple dosing regimens. Reviewers reported no difference between the 2 types of botulinum toxin in terms of overall efficacy or safety.

A systematic review by Dashtipour et al (2015) identified 16 RCTs and noncomparative controlled studies evaluating abobotulinumtoxinA in adults with upper-limb spasticity due to stroke.^20, Total botulinum toxin dose ranged from 500 to 1500 U. Reviewers did not pool study findings, but did report that most studies found a statistically significant benefit of botulinum toxin for functioning (as measured by the Modified Ashworth Scale).

A systematic review and meta-analysis by Marsh et al (2014) identified 18 studies evaluating botulinum toxin type A for treatment of cervical dystonia; five were RCTs, and the remainder were observational studies.^21, A pooled analysis found the mean duration of effect of botulinum toxin to be 93.2 days (95% CI, 91.8 to 94.6 days) using the fixed-effects model, and 95.2 days (95% CI, 88.9 to 101.4 days) using the random-effects model. Most studies included did not have control groups.

In a systematic review, Foley et al (2013) identified 16 RCTs comparing injection of botulinum toxin with placebo injections or a nonpharmacologic treatment of moderate-to-severe upper-extremity spasticity following stroke.^22, Studies evaluated the impact of treatment on activity limitations. Ten trials (total N=1000 patients) had data suitable for pooling. In a pooled analysis of effect size, botulinum toxin was associated with a moderate treatment effect compared with other interventions (SMD=0.54; 95% CI, 0.35 to 0.71; p<0.001). In another systematic review, Baker et al (2013) pooled RCT data and found a statistically significant benefit of botulinum toxin type A for treating limb spasticity.^23, Evidence was limited on botulinum toxin for spasticity-related pain.

This evidence review section is based on a TEC Assessment (1996, updated 2004) that focused on the use of botulinum toxin for the treatment of focal dystonia or spasticity, the American Academy of Neurology (AAN) 2008 assessment of movement disorders and spasticity,^24,25,26,27, and additional controlled trials and systematic reviews identified by MEDLINE literature searches.

The AAN assessment concluded that the evidence was AAN level A (established as effective, should be done) for equinus varus deformity in children with cerebral palsy and AAN level B (probably effective, should be considered) for upper extremity, for adductor spasticity, and for pain control in conjunction with adductor-lengthening surgery in children with cerebral palsy. The evidence was rated level B for treatment of adult spasticity in the upper- and lower-limb for reducing muscle tone and improving passive function, but insufficient evidence to recommend an optimum technique for muscle localization at the time of injection. The evidence was rated level B for upper-limb focal dystonia but insufficient for lower-limb focal dystonia, and was rated level B for adductor laryngeal dystonia but insufficient for abductor laryngeal dystonia.^27,

Randomized Controlled Trials

Poststroke-Related Spasticity

Wein et al (2018) reported on the results of a double-blind RCT that evaluated the efficacy and safety of onabotulinumtoxinA in adults (n=468) with poststroke lower-limb spasticity.^28, The primary end point was change in Modified Ashworth Scale score from baseline between onabotulinumtoxinA and placebo arm at approximately 12-week intervals. Injections were into the ankle plantarflexors (onabotulinumtoxinA 300 U into ankle plantarflexors; ≤100 U, optional lower-limb muscles). Of 468 enrolled, 413 (88%) completed the trial. At the end of blinded phase at 4 to 6 weeks, there were small but statistically significant improvements with onabotulinumtoxinA during for the primary end point (onabotulinumtoxinA, -0.8; placebo, -0.6, p=0.01)

Wissel et al (2016) assigned 273 poststroke adults to a 22- to 34-week treatment with onabotulinumtoxinA or placebo and subsequently open-label onabotulinumtoxinA up to 52 weeks.^29,End points included change in pain and responder analysis (defined as proportion of patients with baseline pain ≥4 achieving a ≥30% improvement in pain and a ≥50% improvement in pain interference with work at week 12). Mean pain reduction from baseline at week 12 was -0.77 (95% CI, -1.14 to -0.40) with onabotulinumtoxinA compared with -0.13 (95% CI, -0.51 to 0.24; p<0.05) with placebo. Respective proportion of responders was 53.7% and 37.0%.

A double-blind RCT published by Gracies et al (2015) assigned 243 adults with a stroke or brain trauma in the last 5 months to a single injection of abobotulinumtoxinA 500 U (n=81) or 1000 U (n=81) or placebo (n=81).^30, The primary end point was the change in muscle tone in the primary target muscle group from baseline to 4 weeks as measured by Modified Ashworth Scale (MAS). At both doses, abobotulinumtoxinA resulted in greater tone reduction as evidenced by statistically significant reduction in placebo-corrected MAS scores from baseline to week 4 (abobotulinumtoxinA 500 U group, -0.9; 95% CI -1.2 to -0.6; p<0.001; abobotulinumtoxinA 1000 U group, -1.1; 95% CI, -1.4 to -0.8; p<0.001 vs placebo).

Shaw et al (2011) randomized 333 patients with poststroke upper-limb spasticity to physical therapy plus Dysport (n=170) or to physical therapy alone (n=163).^31, The primary outcome, improved function at 1 month according to the Action Research Arm Test, did not differ significantly among groups. Improved function using Action Research Arm Test scores also did not differ significantly between groups at 3 or 12 months. Change in muscle tone, based on mean change in the Motor Assessment Scale score significantly favored the Dysport group (-0.6) over the placebo group (-0.1) at 1 month (p<0.001), but not at 3 and 12 months.

Other RCTs have shown that botulinum toxin injection improves outcomes in patients with poststroke upper-limb spasticity.^32,

Cerebral Palsy

Most trials that established the efficacy of abobotulinumtoxinA in treating focal spasticity in patients with cerebral palsy have been small. Delgado et al (2016) reported on a relatively larger RCT in which 249 cerebral palsy children with dynamic equinus foot deformity were randomized to abobotulinumtoxinA 10 or 15 U/kg per leg, or placebo.^34, The primary outcome measure was change in MAS score from baseline to week 4. Of the 246 patients randomized, 226 completed the trial and analysis included 235 (98%) patients. Results showed that both doses of abobotulinumtoxinA resulted in greater improvement in placebo-corrected MAS scores (-0.49; 95% CI, -0.75 to -0.23; p<0.001; -0.38; (95% CI, -0.64 to -0.13; p=0.003 respectively).

Section Summary: Dystonia and Spasticity

Multiple RCTs and systematic reviews with meta-analyses have supported the efficacy of botulinum toxin for treating dystonia and spasticity.

For individuals who have dystonia or spasticity resulting in functional impairment and/or pain (eg, interference with joint function, mobility, communication, nutritional intake) who receive botulinum toxin injections, the evidence includes multiple RCTs and meta-analyses. Relevant outcomes are symptoms, functional outcomes, medication use, and treatment-related morbidity. The data support the efficacy of botulinum toxin for improving dystonia or spasticity in patients with various conditions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

POPULATION REFERENCE NO. 2 

Strabismus

Strabismus is a condition in which the eyes are not in proper alignment.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with strabismus is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with strabismus?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with strabismus.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat strabismus: initial conservative management of strabismus addresses vision impairment caused by amblyopia and therapy may include the refractive error correction with prescription of glasses or contact lenses and/or occlusion therapy or pharmacologic or optical penalization of the preferred eye. In addition, surgical procedures may be necessary to correct conditions that obstruct the visual axis (eg, cataract, ptosis, hemangioma).

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and treatment-related morbidity.

Timing

Follow-up ranges from 6 months to 1 year to monitor outcomes.

Setting

Patients with strabismus may be managed by neurologists; botulinum toxin is injected into selected extraocular muscles to reduce the misalignment of the eyes in an outpatient setting.

Systematic Reviews

A Cochrane review by Rowe and Noonan (2012) evaluated the literature on botulinum toxin for strabismus.^35, Reviewers identified 4 RCTs, all of which were published in the 1990s. Three trials compared botulinum toxin injection with surgery, and one compared botulinum toxin injection with a noninvasive treatment control group. Among the trials that used surgery as a comparator, two found no statistically significant differences in outcomes between groups, and one found a higher rate of a satisfactory outcome in the surgery group (defined as <8 prism diopters). The trial comparing botulinum toxin with no intervention did not find a significant difference in outcomes in the 2 groups. Complications after botulinum toxin included transient ptosis and vertical deviation; combined complication rates ranged from 24% to 56% in the studies.

Randomized Controlled Trials

For patients who failed prior surgery, Tejedor and Rodriguez (1999) conducted a trial that included 55 children with strabismus who remained symptomatic after surgical alignment.^36, Patients were randomized to a second surgery (28 patients) or botulinum toxin injection (n=27). Motor and sensory outcomes did not differ significantly in the 2 groups. For instance, at 3 years, 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). Lee et al (1994) randomized 47 patients with acute unilateral sixth nerve palsy to botulinum toxin treatment or a no treatment control group.^37, The final recovery rate was 20 (80%) of 25 in the botulinum toxin group and 19 (86%) of 22 in the control group.

Section Summary: Strabismus

Several RCTs from the 1990s have reported mixed results on the efficacy of botulinum toxin for strabismus. This evidence has not established that botulinum toxin improves outcomes for patients with strabismus. However, treatment for strabismus is a noninvasive alternative to surgery.

For individuals who have strabismus who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs evaluating botulinum toxin have reported mixed findings; treatment with botulinum toxin is a noninvasive alternative to surgery and is associated with fewer harms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

POPULATION REFERENCE NO. 3 

Blepharospasm

Blepharospasm is a progressive neurologic disorder characterized by involuntary contractions of the eyelid muscles; it is classified as a focal dystonia.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with blepharospasm is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with blepharospasm?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with blepharospasm.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat blepharospasm: medication (ie, zolpidem) or surgery.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and treatment-related morbidity.

Timing

Follow-up ranges from 4 to 8 weeks to monitor outcomes.

Setting

Patients with blepharospasm may be managed by neurologists; botulinum toxin is injected into select eyelid muscles in an outpatient setting.

Systematic Reviews

Dashtipour et al (2015) reported on the results of a systematic review that evaluated 5 RCTs (374 patients with blepharospasm, 172 patients with hemifacial spasm) of abobotulinumtoxinA.^38, All trials showed statistically significant benefits for the treatment of blepharospasm and hemifacial spasm.

Randomized Controlled Trials

RCTs have evaluated Botox, Dysport, and Xeomin for the treatment of blepharospasm and found these agents to be effective at improving symptoms.^39,40,41, No RCTs evaluating Myobloc for treating blepharospasm were identified in literature searches.

Section Summary: Blepharospasm

Multiple RCTs and a systematic review have found that botulinum toxin injection is an effective treatment of blepharospasm.

For individuals who have blepharospasm or facial nerve (cranial nerve VII) disorders who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs and a systematic review have found symptom improvements in patients treated with botulinum toxin compared with alternative interventions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

POPULATION REFERENCE NO. 4 

Headache

Botulinum toxin for treatment of pain from migraine and from chronic tension-type headaches was addressed in a TEC Assessment (2004).^25, The Assessment concluded that the evidence was insufficient for either indication. Because the placebo response rate is typically high in patients with headache, assessment of evidence focuses on randomized, placebo-controlled trials. More recent literature is discussed below, organized by type of headache. Recent studies have focused on frequency of headache as an outcome measure in addition to pain and headache severity.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with chronic migraine headache is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with chronic migraine headache?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with chronic migraine headache.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat chronic migraine headache: Pain-relieving medications taken during migraine attacks and are designed to stop symptoms and include aspirin, ibuprofen, acetaminophen, sumatriptan, rizatriptan, almotriptan, naratriptan, zolmitriptan, frovatriptan, eletriptan, ergotamine, caffeine combination drugs and anti-nausea medications. Preventive medications are drugs taken regularly to reduce the severity or the frequency of migraines and include b-blockers, antidepressants, pain killers, and erenumab-aooe. Complementary treatment (eg, acupuncture) may also be considered.

Outcomes

The general outcomes of interest are symptoms, medication use, and treatment-related morbidity.

Timing

Follow-up ranges from 4 to 8 weeks to monitor outcomes.

Setting

Patients with chronic migraine headache may be managed by general physicians or pain specialists; botulinum toxin is injected into the skin of selected areas in head and neck in an outpatient setting.

Migraine Headache

Migraines can be categorized by headache frequency. According to the Third Edition of the International Headache Classification (ICHD-3), migraine without aura (previously known as common migraine) is defined as at least 5 attacks per month meeting other diagnostic criteria.^42, Chronic migraine is defined as attacks on at least 15 days per month for more than 3 months, with features of migraine on at least 8 days per month.

Systematic Reviews

The Agency for Healthcare Research and Quality published a comparative effectiveness review, conducted by Shamliyan et al (2013), on preventive pharmacologic treatments for migraine in adults.^43, The investigators identified 15 double-blind RCTs evaluating botulinum toxin for migraine prevention: 13 used onabotulinumtoxinA and two used abobotulinumtoxinA. In a meta-analysis of 3 RCTs, onabotulinumtoxinA was more effective than placebo in reducing the number of chronic migraine episodes per month by at least 50% (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 events than placebo (RR=3.2; 95% CI, 1.4 to 7.10). Five RCTs compared the efficacy of onabotulinumtoxinA with another medication (topiramate or divalproex sodium). Findings were not pooled, but, for the most part, there were no statistically significant differences in outcomes between the 2 drugs.

Jackson et al (2012) conducted a meta-analysis of RCTs on botulinum toxin type A for the prophylactic treatment of headache in adults; the analysis addressed migraines and other types of headache.^44, Reviewers 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. Reviewers categorized eligibility criteria as addressing episodic (<15 headaches per month) or chronic headache (≥15 days per month). Ten trials on episodic migraine and 7 trials on chronic migraine were identified. All trials on episodic migraine and 5 of 7 trials on chronic migraine were placebo-controlled; the other 2 trials compared botulinum toxin injections with oral medication. A pooled analysis for chronic migraine (5 trials) found a statistically significantly greater reduction in the frequency of headaches per month with botulinum toxin than with a control intervention (absolute difference, -2.30; 95% CI, -3.66 to -0.94). In contrast, in a pooled analysis of episodic migraine (9 trials), there was no statistically significant difference between groups in the change in monthly headache frequency (absolute difference, -0.05; 95% CI, -0.25 to 0.36).

Previously, Shuhendler et al (2009) conducted a meta-analysis of trials on botulinum toxin for treating episodic migraines.^45, Reviewers identified 8 randomized, double-blind, placebo-controlled trials evaluating the efficacy of botulinum toxin type A injections. A pooled analysis of the main study findings found no significant differences between the botulinum toxin type 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 examining trials using low-dose botulinum toxin type A (<100 U) compared with trials using high-dose botulinum toxin type A (≥100 U) did not find a statistically significant effect of botulinum toxin type A compared with placebo in either stratum.

Randomized Controlled Trials

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) trials 1 and 2.^46,47, Trial designs were similar. Both 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, patients had 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 had to be definite or probable migraine. The investigators did not require that the frequent attacks occur for more than 3 months or exclude patients who overused pain medication, two of the ICHD-2 criteria for chronic migraine. Eligible patients were randomized to 2 cycles of Botox injections 155 U or placebo, with 12 weeks between cycles. Randomization was stratified by frequency of acute headache pain medication used during baseline and whether 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 end point in PREEMPT 1 was mean change from baseline in frequency of headache episodes for 28 days ending with week 24. A headache episode was defined as a headache lasting 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 lasting at least 4 hours). Based on availability of data from PREEMPT 1 and other factors, the protocol of the PREEMPT 2 trial was amended (after study initiation but before unmasking) to make frequency of headache days the primary end point. The trialists noted that, to control for potential type I error related to changes to the outcome measures, a more conservative p value (0.01) was used. Several QOL measures were also used in the trials, including the 6-item Headache Impact Test-6 (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ v.2). Key findings of both trials are described below.

PREEMPT 1 randomized 679 patients.^46, Mean number of migraine days during baseline was 19.1 in each group. The mean number of headache episodes during the 28-day baseline period was 12.3 in the Botox group and 13.4 in the placebo group. Approximately 60% of patients had previously used at least 1 prophylactic medication and approximately 68% overused headache pain medication during baseline. A total of 296 (87%) of 341 patients in the Botox group and 295 (87%) of 338 patients in the placebo group completed the 24-week double-blind phase. The primary outcome (change from baseline in frequency of headache episodes over a 28-day period) did not differ significantly between groups. The number of headache episodes decreased by a mean of 5.2 in the Botox group and 5.3 in the placebo group (p=0.344). Similarly, the number of migraine episodes did not differ significantly. There was a decrease of 4.8 migraine episodes in the Botox group and of 4.9 in the placebo group (p=0.206). In contrast, there was a significantly greater decrease in the number of headache days and the number of migraine days in the Botox group than in the placebo group. The decrease in frequency of headache days was 7.8 in the Botox group and 6.4 in the placebo group, a difference of 1.4 headache days per 28 days (p=0.006). Corresponding numbers for migraine days were 7.6 and 6.1, respectively (p=0.002). There was significantly greater improvement in QOL in the Botox group vs the placebo group. The proportion of patients with severe impact of headaches (ie, HIT-6 score, ³60) in the Botox group decreased from 94% at baseline to 69% at 24 weeks; in the placebo group, it decreased from 95% at baseline to 80%, a between-group difference of 11% (p=0.001). The authors did not report MSQ scores, but stated that there was statistically significant greater improvement in the 3 MSQ role function domains at week 24 (restrictive, p<0.01; preventive, p=0.05; emotional, p<0.002). Adverse events were experienced by 203 (60%) patients in the Botox group and 156 (47%) patients in the placebo group. Eighteen (5%) patients in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. Treatment-related adverse events were consistent with the known safety profile of Botox.

PREEMPT 2 randomized 705 patients.^47, Mean number of migraine days during baseline period was 19.2 in the Botox group and 18.7 in the placebo group. Mean number of headache episodes during the 28-day baseline period was 12.0 in the Botox group and 12.7 in the placebo group. Approximately 65% of patients had previously used at least 1 prophylactic medication and approximately 63% overused headache pain medication during baseline. A total of 311 (90%) of 347 patients in the Botox group and 334 (93%) of 358 patients in the placebo group completed the 24-week, double-blind phase. The primary outcome, change from baseline frequency of headache days over a 28-day period (a different primary outcome from PREEMPT 1), differed significantly between groups and favored Botox treatment. The number of headache days decreased by a mean of 9.0 in the Botox group and 6.7 in the placebo group, an absolute difference of 2.3 days per 28 days (p<0.001). Mean number of migraine days also decreased significantly, more in the Botox group (8.7) than in the placebo group (6.3; p<0.001). Unlike PREEMPT 1, there was a significantly greater decrease in headache episodes in PREEMPT 2 in the Botox group (5.3) than in the placebo group (4.6; p=0.003). Change in frequency of migraine episodes was not reported.

Similar to PREEMPT 1, QOL measures significantly improved in the Botox group. The proportion of patients reporting that their headaches had a severe impact (score of at least 60 on the HIT-6) decreased in the Botox group from 93% at baseline to 66% at 24 weeks; in the placebo group, it decreased from 91% at baseline to 77%. There was a between-group difference of 10% (p=0.003). The trialists reported statistically significantly greater improvement in the 3 MSQ role function domains at week 24 (restrictive, preventive, emotional, p<0.001 for each domain). Adverse events were experienced by 226 (65%) patients in the Botox group and 202 (56%) patients in the placebo group. Fifteen (4%) patients in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. As in PREEMPT 1, treatment-related adverse events in PREEMPT 2 were consistent with the known safety profile of Botox.

Also published was a pooled analysis of findings from the PREEMPT 1 and 2 trials; this analysis by Dodick et al (2010) was also industry-sponsored.^48, 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 group than in the placebo group. For example, the pooled change in mean frequency of headache days was 8.4 in the Botox group and 6.6 in the placebo group (p<0.001). 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 might not be clinically meaningful. In the pooled analysis, the trialists 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 published report 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 as assessed using the HIT-6 and change in MSQ domains. Pooled results of PREEMPT studies at 56 week also reported that repeated treatment (≤5 cycles) of onabotulinumtoxinA was effective, safe, and well-tolerated in adults with chronic migraine.^49,50,

Several issues are worth noting about the methods 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 trialists 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 as secondary efficacy outcomes.

Most patients in both trials fulfilled criteria for medication overuse headache, and therefore many might have been experiencing secondary headaches rather than chronic migraines. If patients had secondary headaches, detoxification alone might have been sufficient to change their headache pattern to an episodic one. The clinical relevance of less than a 2-day difference in reduction in number of headache days is uncertain, though consistent with reductions previously reported in several medication trials.

Another RCT that assessed use of botulinum toxin for treating chronic migraine was published by Cady et al (2011).^51, The trial included patients who met ICHD-2 criteria for chronic migraine. Patients were randomized to treatment with Botox (n=29) or topiramate (n=30). At the 12-week follow-up, the end of the double-blind phase of the trial, treatment effectiveness did not differ significantly between groups. For the primary end point (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.

Section Summary: Migraine Headache

For chronic migraine, a meta-analysis of RCTs found that onabotulinumtoxinA was more effective than placebo in reducing the number of chronic migraine episodes per month, although it was also associated with a significantly higher rate of treatment discontinuation due to adverse events than placebo.

For individuals who have chronic migraine headache who receive botulinum toxin injections, the evidence includes several RCTs and meta-analyses. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. RCTs have reported mixed findings; a meta-analysis found that botulinum toxin reduced the frequency of headaches per month compared with placebo or medication. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Non-Migraine Headache

Medication Overuse Headache

According to the ICHD-2 (and ICHD-3), the diagnostic classification of medication overuse headache differs from chronic migraine.^52, Silberstein et al (2013) published a subanalysis of pooled PREEMPT data limited to patients with headache medication overuse at baseline.^53, A total of 904 patients who indicated they had medication overuse headache were included; 445 were randomized to the botulinum toxin group and 459 to the placebo group. At the end of week 24, there was a significantly greater reduction in outcomes, including headache days, headache episodes, and moderate-to-severe headache days, in the botulinum toxin group than in the placebo group. For example, the number of headache days per month decreased by a mean of 8.2 in the botulinum toxin group and 6.2 in the placebo group (p<0.001). This is a single analysis of RCT data and provides insufficient evidence that botulinum toxin is effective for patients with the diagnosis of medication overuse headache.

Tension Headache

The meta-analysis by Jackson et al (2012), discussed above, identified 7 RCTs evaluating botulinum toxin for treating chronic tension-type headaches; all were placebo-controlled.^44, A pooled analysis of these 7 studies did not find a statistically significant difference in change in the monthly number of headache days in the botulinum toxin group vs the placebo group (difference, -1.43; 95% CI, -3.13 to 0.27). The largest trial (Silberstein et al [2006]^54,) included 300 patients randomized to 1 of 4 doses of botulinum toxin or placebo. Overall, there was no statistically significant difference between the botulinum toxin groups and the placebo group in mean change from baseline to 90 days in number of headache days per month.

Chronic Daily Headache

Although chronic daily headache is not recognized in the ICHD, it is commonly defined to include different kinds of chronic headache (eg, chronic or transformed migraine, daily persistent headache). It may also include chronic tension-type headache (addressed above). The meta-analysis by Jackson (2012) identified 3 RCTs comparing botulinum toxin type A with placebo in patients having at least 15 headaches per month.^44, A pooled analysis of data from these 3 trials found a significantly greater reduction in the number of headaches per month with botulinum toxin than with placebo (absolute difference, -2.06; 95% CI, -3.56 to -0.56). Individually, only one (Ondo et al [2004]^55,) of the 3 trials found a statistically significant benefit with botulinum toxin treatment. Ondo included 60 patients, some with chronic migraines and chronic tension-type headache. The Ondo trial found significantly greater reduction in the number of headache-free days over weeks 8 to 12 with botulinum toxin than with placebo (p<0.05), but there was no statistically significant between-group difference in reduction in headache-free days over the entire 12-week study period (p=0.07). The other 2 trials evaluated more patients: 355 in Mathew et al (2005)^56, and 702 in Silberstein et al (2005).^57, Neither found a statistically significant difference in the reduction in the number of headache days per month with botulinum toxin. The available evidence from RCTs is conflicting and insufficient for conclusions.

Cluster Headache

No controlled trials were identified for cluster headache.

Cervicogenic Headache

Systematic Reviews

A Cochrane review of treatment of mechanical neck disorders, conducted by Peloso et al (2007), included 6 RCTs (total N=273 patients) assessing botulinum toxin and placebo for chronic neck disorders with or without radicular findings or headache.^58, A meta-analysis of 4 studies (n=139 patients) for pain outcomes found no statistically significant results. Reviewers concluded that a range of doses did not show significant differences compared with placebo or other comparators.

Randomized Controlled Trials

Linde et al (2011) published a double-blind, placebo-controlled crossover study that included 28 patients with treatment-resistant cervicogenic headache.^59, Patients were randomized to botulinum toxin type A or placebo; there was at least an 8-week period between treatments. The trial did not find significant differences between active and placebo treatment in the primary outcome, reduction in the number of days with moderate-to-severe headache. Three other RCTs, published between 2000 and 2008, randomized patients with chronic, whiplash-related headache to botulinum toxin type A treatment or placebo.^60,61,62, One trial reported trends toward improvement with treatment for various outcomes; most were not statistically significant.^60, Another reported no significant differences for several pain-related outcomes.^62, The other reported a significant improvement in pain with treatment, but trial design was flawed because the placebo group reported less pain at baseline.^61,

Section Summary: Non-Migraine Headache

For patients with an episodic pattern of migraine (ie, <15 episodes per month), the published evidence does not suggest that botulinum toxin improves net health outcome for patients. For tension headache, RCTs and systematic reviews do not indicate that botulinum toxin improves outcomes. For other headache types, the evidence is inconclusive to confirm efficacy.

POPULATION REFERENCE NO. 5

Esophageal Achalasia

Esophageal achalasia results from progressive degeneration of ganglion cells in the myenteric plexus in the esophageal wall, leading to failure of relaxation of the lower esophageal sphincter (LES), accompanied by a loss of peristalsis in the distal esophagus. Treatment is aimed at decreasing the resting pressure in the LES to a level at which the sphincter no longer impedes the passage of ingested material. This can be achieved by 2 ways: 1) mechanical disruption of the muscle fibers of the LES through pneumatic dilation (PD), surgical myotomy, or peroral endoscopic myotomy (POEM) and 2) pharmacological reduction in LES pressure (eg, injection of botulinum toxin or use of oral nitrates).

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with esophageal achalasia is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with esophageal achalasia who are not candidates for PD, surgical myotomy, or POEM.

Interventions

The therapy being considered is commercially available botulinum toxin products. These are injected directly using endoscopic ultrasound techniques to facilitate localization in the LES region.

Comparators

The following therapies are currently being used to treat esophageal achalasia: medications (ie, zolpidem), PD, surgical myotomy, or POEM.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and treatment-related morbidity. Follow-up ranges from 6 months to a year to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A Cochrane review by Leyden et al (2014) identified 7 RCTs (N=178 participants) that compared onabotulinumtoxinA with endoscopic PD.^1,The outcome reported was symptom remission rate at 1, 6, and 12 months. Study characteristics and results are summarized in Tables 2 and 3, respectively. The meta-analysis of RCTs showed no difference in relative risk (RR) of symptom remission at 1 month between PD versus onabotulinumtoxinA. (RR=1.11, 95% confidence interval [CI]: 0.97 to 1.27). However, at 6 and 12 months, PD resulted in higher symptom remission rates and the difference was statistically significant (RR=1.57, p<.005; RR=1.88, p= <.005, respectively). No serious adverse events were reported after onabotulinumtoxinA injection; however, there were 3 cases of perforation after PD. The authors concluded that PD resulted in superior long-term efficacy compared with onabotulinumtoxinA (at 6 and 12 months). While the overall methodological quality of the individual RCTs was reported to be good, the risk of bias was high. In particular, only 1 RCT was double blind. Five RCTs were potentially at a risk of selection, performance, or detection bias due to inappropriate allocation of concealment, blinding of participants and personnel, and outcome assessment.

Wang et al (2009) conducted a meta-analysis of RCTs that compared the efficacy of different treatments for primary achalasia.^2, Five RCTs compared botulinum toxin A injection with PD in patients with untreated achalasia, and also examined both subjective and objective parameters of esophageal improvement in all patients over 12 months. The authors reported that symptom remission rate was significantly higher in patients treated with PD versus botulinum toxin A injection (65.8% vs. 36%). The proportion of patients who relapsed within a year was 16.7% with PD versus 50% with botulinum toxin injection. Moreover, the relapse time for botulinum toxin injection was shorter than that of PD after first therapy. Two RCTs compared the efficacy of laparoscopic myotomy with botulinum toxin A injection in patients with untreated achalasia. The authors reported that the symptom remission rate of botulinum toxin injection rapidly decreased and nearly 50% of patients were symptomatic again after 1 year of treatment. Laparoscopic myotomy had superior efficacy to botulinum toxin injection (laparoscopic myotomy 83.3% vs. botulinum toxin injection 64.9%, RR 1.28; 95% CI 1.02 to 1.59; p=.03). Patients treated with onabotulinumtoxinA had more frequent relapse and a shorter time to relapse than those treated with laparoscopic myotomy. Some limitations of this meta-analysis include a small number of cohorts in each trial, poor randomization techniques, and inadequate follow-up.

While the evidence is suggestive that PD and surgical myotomy are definitive therapies for esophageal achalasia and associated with superior long-term outcomes compared with botulinum toxin A, in patients who are not good candidates for PD and/or surgical myotomy, botulinum toxin A may be a reasonable option. Further, botulinum toxin injection has the advantage of being less invasive as compared with surgery, it can be easily performed during routine endoscopy. Initial success rates with botulinum toxin are comparable to PD and surgical myotomy.^2, However, patients treated with botulinum toxin have more frequent relapses and a shorter time to relapse.^2, Greater than 50% of patients with achalasia treated with botulinum toxin A require retreatment within 6 to 12 months. Repeated botulinum toxin injections may also make a subsequent Heller myotomy more challenging.^3,

Table 2. Systematic Review/Meta-Analysis Characteristics

NR: not reported; PD: pneumatic dilation; RCT: randomized controlled trial.

Table 3. Systematic Review/Meta-Analysis Results

CI: confidence interval; NR: not reported; PD: pneumatic dilation; RCT: randomized controlled trial; RR: relative risk.

Section Summary: Esophageal Achalasia

For the treatment of esophageal achalasia, 2 meta-analysis that included RCTs compared endoscopic PD or laparoscopic myotomy with botulinum toxin. Results showed that PD, as well as laparoscopic myotomy, afforded higher and statistically significant symptom remission rates. OnabotulinumtoxinA was not associated with any serious adverse events while PD resulted in perforation in a few cases. While the evidence is suggestive that PD and surgical myotomy are definitive therapies for esophageal achalasia and associated with superior long-term outcomes compared with botulinum toxin A, in patients who are not good candidates for PD and/or surgical myotomy, botulinum toxin A may be a reasonable option. Further, botulinum toxin injection has the advantage of being less invasive as compared with surgery and can be easily performed during routine endoscopy. Initial success rates with botulinum toxin are comparable to PD and surgical myotomy.

Population Reference No. 6

Sialorrhea (Drooling)

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with sialorrhea is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with sialorrhea?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with sialorrhea.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat sialorrhea: nonmedication treatments such as chewing gum or hard candy, which encourage swallowing, may reduce drooling in social situations. For patients with more severe symptoms, glycopyrrolate, other anticholinergic medications (eg, oral hyoscyamine and amitriptyline; sublingual ipratropium bromide and sublingual atropine) may also be used.

Outcomes

The general outcomes of interest are symptoms, functional outcomes and treatment-related morbidity.

Timing

The timing of interest ranges from 4 to 8 weeks to evaluate changes in symptoms, functional outcomes, use and treatment-related morbidity.

Setting

Patients with sialorrhea may be managed by neurologists; botulinum toxin is injected into thesalivary glands in an outpatient setting.

Sialorrhea Associated With Parkinson Disease

Several RCTs have evaluated botulinum toxin injections in patients with Parkinson disease. For example, Lagalla et al (2006) randomized 32 patients with Parkinson disease to placebo or botulinum toxin type A; evaluation at 1 month postinjection resulted in significant improvements compared with placebo in drooling frequency, saliva output, and familial and social embarrassment.^64, Dysphagia scores were not significantly improved. Moreover, Ondo et al (2004) randomized 16 patients with Parkinson disease to botulinum toxin type B or placebo.^65, The botulinum toxin group had significantly better outcomes than the placebo group at 1 month on 4 drooling outcomes. Groups did not differ on salivary gland imaging or on a dysphagia scale. Mancini et al (2003) assigned 20 patients with Parkinson disease to injections of either a saline placebo or botulinum toxin type A.^66, The treatment group had significantly better outcomes than the placebo group on a drooling scale at 1 week; the effect disappeared by 3 months.

Section Summary: Sialorrhea Associated With Parkinson Disease

RCTs have consistently found benefit of botulinum toxin injection on sialorrhea in patients with Parkinson disease.

For individuals who have sialorrhea (drooling) associated with Parkinson disease who receive botulinum toxin injections, the evidence includes several RCTs. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. RCTs have consistently found that botulinum toxin provides benefit. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7 

Sialorrhea Not Associated With Parkinson Disease

Systematic Reviews

Several systematic reviews have evaluated botulinum toxin for treating sialorrhea in people with conditions other than Parkinson disease. Squires et al (2014) reviewed the research on botulinum toxin injections for drooling in patients with amyotrophic lateral sclerosis/motor neuron disease.^67, Reviewers included RCTs and controlled and uncontrolled observational studies. They identified 12 studies, of which 8 had no control groups. There were 2 small RCTs, each with fewer than 20 patients. Sample sizes in the non-RCTs ranged from 5 to 26 patients. Due to heterogeneity, study findings were not pooled. Only one of the 2 RCTs reported drooling outcomes; it found a significantly greater reduction in saliva volume with botulinum toxin than with placebo at 2 weeks.

Rodwell et al (2012) published a systematic review evaluating botulinum toxin injections in the salivary gland to treat sialorrhea in children with cerebral palsy and neurodevelopment disability.^68, Reviewers identified 5 RCTs; trial sample sizes ranged from 6 to 48 participants. One of the RCTs (N=6) was terminated due to adverse events. In a pooled analysis of data 4 weeks postintervention in 3 RCTs, the mean score on the Drooling Frequency and Severity Scale was significantly lower in children who received botulinum toxin injections than a control intervention (MD = -2.71 points; 95% CI, -4.82 to -0.60; p<0.001). The clinical significance of this difference in Drooling Frequency and Severity Scale scores is unclear. Data were not pooled for other outcomes. The systematic review also identified 11 prospective case series. The rate of adverse events associated with botulinum toxin injection in the RCTs and case series ranged from 2% to 41%. Dysphagia occurred in 2 (33%) of the 6 participants in an RCT terminated early and in 2 (2%) of 126 patients in a case series. There was 1 reported chest infection, 1 case of aspiration pneumonia, and, in 1 case series, 6 (5%) of 126 patients experienced an increased frequency of pulmonary infections. In 7 studies, there were reports of patients with difficulty swallowing and/or chewing following botulinum toxin treatment.

Randomized Controlled Trials

Gonzalez et al (2017) reported the results of an RCT in which 40 adults with cerebral palsy were randomized to onabotulinumtoxinA or observation.^69, The trial had greater than 80% power to detect a 39% difference in the proportion of patients who achieved at least a 50% reduction in drooling quotient. The primary efficacy outcome was drooling quotient. This quotient, measured as a proportion, is a semi-quantitative method that assesses the presence of newly formed saliva on the lips every 15 seconds with 40 observations in 10 minutes, expressed as a percentage based on the ratio between the number of observed drooling episodes and the total number of observations. The proportion of patients who achieved at least a 50% reduction in drooling quotient in the treated group vs control after 8 weeks and 80 weeks was 45% vs 0.0% (p=0.001) and 20% vs 0% (p=0.106). While the treatment effect was large, the trial did not use a placebo group and was unblinded.

A large RCT on botulinum toxin for treating sialorrhea in children with cerebral palsy was published by Reid et al (2008).^70, Forty-eight children with cerebral palsy (n=31) and other neurologic disorders (n=17) were randomized to a single injection of botulinum toxin type A 25 U compared with no treatment. Drooling was assessed by using the Drooling Impact Scale. Scores differed significantly between groups at 1 month, and a beneficial effect of botulinum toxin injection remained at 6 months.

Retrospective Studies

A retrospective review by Chan et al (2013) focused on the long-term safety of botulinum toxin type A injection for treating sialorrhea in children.^71, Reviewers included 69 children; 47 (68%) had cerebral palsy. Children received their first injection of botulinum toxin type A at a mean age of 9.9 years; mean follow-up was 3.1 years. During the study period, the children received a total of 120 botulinum toxin injections. Complications occurred in 19 (28%) of 69 children and in 23 (19%) of 120 injections. Fifteen of 23 complications were minor, including 6 cases of dysphagia. There were 8 major complications: 3 cases of aspiration pneumonia, 2 cases of severe dysphagia, and 3 cases of loss of motor control of the head. Complications were associated with 5 hospitalizations and 2 cases of nasogastric tube placement.

Section Summary: Sialorrhea Not Associated With Parkinson Disease

Although there is evidence of improvement as measured on 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 amyotrophic lateral sclerosis/motor neuron disease is inconclusive due to the paucity of controlled studies, small sample sizes of available studies, and limited reporting of drooling outcomes.

For individuals who have sialorrhea (drooling) not associated with Parkinson disease who receive botulinum toxin injections, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, functional outcomes, and treatment-related morbidity. Available individual RCTs are small and have not consistently found a clinically meaningful improvement with botulinum toxin therapy. In several trials, rates of adverse events were notably high, making the risk-benefit ratio of botulinum toxin therapy uncertain. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 8 

Anal Applications

Internal anal sphincter (IAS) achalasia is a defecation disorder in which the internal anal sphincter is unable to relax. Symptoms include severe constipation and soiling.

Chronic anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the IAS and is treated surgically with an internal sphincterotomy. Because the anal sphincter contraction could be characterized as a dystonia, botulinum toxin is a logical medical approach.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with IAS achalasia and chronic anal fissure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with IAS achalasia and chronic anal fissure?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant populations of interest are individuals with IAS achalasia or with chronic anal fissure.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat IAS achalasia: surgical management (posterior IAS myectomy).

The following therapies are currently being used for individuals with chronic anal fissure: medication (ie, nitroglycerin, topical anesthetic creams, eg, lidocaine hydrochloride, oral nifedipine, or diltiazem).

Outcomes

The general outcomes of interest are symptoms, health status measures, and treatment-related morbidity.

Timing

Follow-up ranges from 6 months to a year to monitor outcomes.

Setting

Patients with IAS achalasia and chronic anal fissure may be managed by general physicians, surgeons, and gastroenterologist; botulinum toxin is injected intrasphincteric in an outpatient setting.

Internal Anal Sphincter Achalasia

A meta-analysis of studies on treatment of IAS achalasia was published by Friedmacher and Puri (2012).^72, Reviewers only identified 2 prospective case series and 14 retrospective case series (total N=395 patients) of IAS achalasia. Most patients (229/395 [58%]) in the series were treated with posterior IAS myectomy and 166 (42%) were treated with intrasphincteric botulinum toxin injection. A meta-analysis of data from the observational studies found that regular bowel movements were more frequent after myectomy (odds ratio [OR], 0.53; 95% CI, 0.29 to 0.99; p=0.04). Moreover, the rate of transient fecal incontinence was significantly higher after botulinum toxin injection (OR=0.07; 95% CI, 0.01 to 0.54; p<0.01) and the rate of subsequent surgical intervention was higher after botulinum toxin injection (OR=0.18; 95% CI, 0.07 to 0.44; p<0.001). Other outcomes, including continued use of laxatives or rectal enemas and overall complication rates, did not differ between treatments.

Emile et al (2016) reported on the results of a systematic review that assessed 7 studies comprising 189 patients with a follow-up period greater than 6 months in each study.^73, Of the 7 studies, 2 were RCTs and the others comparative and observational studies. Both RCTs were single site from the same author group and conducted in Egypt, enrolling 15 and 24 patients, respectively.^74,75,Improvement was defined as patients returning to their normal habits. The first RCT used biofeedback and the other used surgery as the comparator. In the first RCT, 50% of individuals in the biofeedback group reported improvement initially at 1 month but it dropped down to 25% by the end of year. The respective proportions of patients in the botulinum toxin arm were 70.8% and 33.3%. In the second RCT, surgery improved outcomes in all patients at 1 month but that percentage dropped to 66.6% at 1 year. The respective proportions of patients in the botulinum toxin arm were 87% and 40%, respectively. While these results would suggest temporary improvement, methodologic limitations, including small sample size and lack of blinded assessment, limit the interpretation of these RCTs.

Section Summary: Internal Anal Sphincter Achalasia

There is a lack of high-quality RCTs evaluating botulinum toxin injection as a treatment of IASachalasia. A meta-analysis of observational data and a systematic review suggested that posterior IAS myectomy results in greater improvements in health outcomes than botulinum toxin injections.

For individuals who have IAS achalasia who receive botulinum toxin injections, the evidence includes 2 RCTs and multiple nonrandomized studies, which have been summarized in a systematic reviews and meta-analysis. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. In a systematic review of nonrandomized studies comparing botulinum toxin injection with myectomy, outcomes were more favorable after surgery. Though the 2 RCTs reported temporary improvement in symptoms after botulinum toxin injections, methodologic limitations, including small sample sizes, lack of blinded assessments, and lack of use of validated outcome measures, limit the interpretation of these RCTs. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 9 

Chronic anal fissure

An anal fissure is a tear or ulceration in the lining of the anal canal below the mucocutaneous junction. Chronic anal fissure is typically associated with anal spasm or high anal pressure. The initial treatment is medical management (combination of supportive measures such as high fiber diet, sitz bath, topical analgesic and 1 of the topical vasodilators such as nifedipine or nitroglycerin for 1 month). Patients who fail medical therapy are candidates for surgical therapy that includes lateral internal sphincterotomy or botulinum toxin injection. Patients who are at a high-risk for fecal incontinence such as women who have had multiple vaginal deliveries and older patients with may have a weak anal sphincter complex are advised to undergo surgical procedures that do not require division of the anal sphincter muscle (eg, botulinum toxin injection, fissurectomy, or anal advancement flap). Patients who are not at risk for developing fecal incontinence may undergo lateral internal sphincterotomy, which is considered the most effective treatment for anal fissure.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with chronic anal fissure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with chronic anal fissure who fail medical management and are at a high-risk of incontinence.

Interventions

The therapy being considered is commercially available botulinum toxin products and is generally prescribed by general physicians, surgeons, and gastroenterologist. It is injected intrasphincteric in an outpatient setting.

Comparators

The following therapies are currently being used for individuals with chronic anal fissure who failed medical management: fissurectomy, anal advancement flap and lateral internal sphincterotomy.

Outcomes

The general outcomes of interest are symptoms, health status measures, and treatment-related morbidity. Follow-up ranges from 6 months to a year to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Chen et al (2014) compared outcomes of onabotulinumtoxinA injection with lateral internal sphincterotomy based on 7 RCTs.^4, The study characteristics and results are summarized in Table 4 and 5. Treatment with botulinum toxin injection was associated with lower healing rate and a higher recurrence rate compared with lateral internal sphincterotomy. Sphincterotomy also resulted in higher complication rates but the difference was not statistically significant (p-value=0.35). The meta-analysis suggests that internal sphincterotomy is more effective to treat anal fissure but onabotulinumtoxinA injection was associated with lower rates of incontinence. Authors reported multiple limitations in the evidence pooled for the meta-analysis including various dose of onabotulinumtoxinA used in different trials, inconsistent definition of chronic anal fissure used in the RCTs and none of the included RCTs were blinded. In addition, results of included studies were not consistent. The total complication rate varied from 0 to 64 % among the trials, while the incontinence rate varied from 0 to 48%. Nelson et al (2012) published a Cochrane review that compared multiple treatment options for chronic anal fissure.^5, Reported results for comparison of botulinum toxin injection with sphincterotomy are consistent with those reported by Chen et al (2014). Botulinum toxin A injection is therefore preferably used for patients who are at a high-risk of developing fecal incontinence (eg, multiparous women or older patients).

Table 4. Systematic Review/Meta-Analysis Characteristics

NR: not reported; RCT: randomized controlled trial.

Table 5. Systematic Review/Meta-Analysis Results

a Comparison indicates that sphincterotomy was 7.2 times more likely to heal than botulinum toxin injectionNR = Not reported; CI: Confidence interval; OR: odds ratio; RCT: randomized controlled trial.

Section Summary: Anal Fissure

Two meta-analysis suggests that sphincterotomy is a more effective treatment option for chronic anal fissure compared with botulinum toxin A and results in significantly higher healing rate as well lower recurrence rate. However, these meta-analysis report higher incontinence rate with surgical procedures. Since botulinum toxin A injections are less invasive and do not require the internal sphincter muscle to be divided and thereby reduce the risk of fecal incontinence, they are preferred for patients who are not good surgical candidates or who want to minimize the likelihood of incontinence.

Population Reference No. 10 

Urologic Applications

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with urologic conditions including urinary incontinence due to detrusor overactivity associated with overactive bladder (OAB) or neurogenic causes or urologic issues other than detrusor overactivity or OAB is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with urologic conditions?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant populations of interest are individuals with urinary incontinence due to detrusor overactivity associated with OAB or neurogenic causes or urologic issues other than detrusor overactivity or OAB.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat urinary incontinence: conservative measures and pharmacotherapy (antimuscarinic agents, b-adrenergic therapy).

Outcomes

The general outcomes of interest are symptoms, medication use, and treatment-related morbidity.

Timing

Follow-up ranges from 6 months to a year to monitor outcomes.

Setting

Patients with urinary incontinence may be managed by general physicians, urologists, and/or gynecologists; botulinum toxin is injected intradetrusor in an outpatient setting.

OAB and Neurogenic Detrusor Overactivity

Systematic Reviews

Drake et al (2017) reported on the results of a network meta-analysis of 56 RCTs that compared the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic OAB.^86, While all treatments were more efficacious than placebo after 12 weeks, patients who received onabotulinumtoxinA (100 U) reported the greatest reductions in urinary incontinence episodes, urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and 50% or greater from baseline in urinary incontinence episodes per day. The exclusion of studies with a high risk of bias had little impact on the conclusions. Freemantle et al (2016) also reported on the results of a network meta-analysis of 19 RCTs comparing onabotulinumtoxinA, mirabegron, anticholinergic drugs, or placebo.^87, Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination, and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 mg and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency, and urination.

A network meta-analysis by Cheng et al (2016) assessed 1915 patients with neurogenic detrusor overactivity from 6 RCTs.^88, Using the mean number of urinary incontinence episodes per week as the primary outcome measure, reviewers reported that treatment with onabotulinumtoxinA 200 U and 300 U compared with placebo reduced the mean number of urinary incontinence episodes at week 6 by 10.72 (95% CI, -13.4 to -8.04; p<0.001) and -11.42 (95% CI, -13.91 to -8.93; p<0.001), respectively. Treatment with onabotulinumtoxinA was associated greater frequency of urinary tract infections (RR=1.47; 95% CI, 1.29 to 1.67; p<0.001), urinary retention (RR=5.58, 95% CI, 3.53 to 8.83; p<0.001), hematuria (RR=1.70; 95% CI, 1.01 to 2.85; p=0.05), and muscle weakness (RR=2.59; 95% CI, 1.36 to 4.91; p=0.004).

Cui et al (2015) identified 6 double-blind RCTs comparing botulinum toxin type A with placebo for treating patients with idiopathic OAB.^89, 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). Cui et al (2013) also published another systematic review evaluating botulinum toxin type for OAB.^90, Previously, Duthie et al (2011) published a Cochrane review of RCTs evaluating botulinum toxin injections for patients with idiopathic or neurogenic OAB.^91, Reviewers identified 19 trials that compared treatment using botulinum toxin with placebo or another intervention. Two studies included botulinum toxin type B; the remainder included botulinum toxin type A. Outcomes varied, which made it difficult to pool findings. A pooled analysis of 3 trials found change in urinary frequency episodes at 4 to 6 weeks a significantly better outcome with botulinum toxin injection than with placebo (MD = -6.50; 95% CI, -8.92 to -4.07). A pooled analysis of 3 trials on change in incontinence episodes at 4 to 6 weeks also found a significantly greater improvement with botulinum toxin (MD = -1.58; 95% CI, -2.16 to -1.01).

Other systematic reviews have included both controlled and uncontrolled studies. A systematic review by Soljanik (2013) identified 28 studies evaluating onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity or neurogenic OAB; 6 studies were RCTs.^92, The reviewer reported that studies with comparative data found superior outcomes with onabotulinumtoxinA compared with 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 (UTI; 16.7%). Also, Mehta et al (2013) identified 14 studies evaluating botulinum toxin type A for treating neurogenic detrusor overactivity after spinal cord injury; only one was an RCT.^93, Studies tended to have large effect sizes (>0.8) for outcomes including bladder capacity and reflex detrusor volume. Rates of incontinence episodes decreased after treatment with botulinum toxin type A from 23% to 1.3% per day. Previously, Karsenty et al (2008) identified 18 studies evaluating botulinum toxin type A to treat patients who were refractory to anticholinergics.^94, Most studies reported statistically significant improvements in clinical and urodynamic outcomes, without major adverse events.

Randomized Controlled Trials

Representative large, double-blind RCTs are described below. Herschorn et al (2017) reported on the results of a double-blind RCT that compared the efficacy and safety of onabotulinumtoxinA or solifenacin vs placebo in patients with OAB, urinary incontinence, and an inadequate response to or were intolerant of an anticholinergic.^95, The primary end point included change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a 100% reduction (dry) in the number of incontinence episodes per day. While both onabotulinumtoxinA and solifenacin fared better than placebo in terms of change from baseline in incontinence episodes per day (-3.19 or -2.56 vs -1.33; both p<0.001), the incontinence reduction was significantly greater for onabotulinumtoxinA vs solifenacin (p=0.022). At week 12, 33.8% (vs placebo p<0.001), 24.5% (vs placebo p=0.028), and 11.7% of patients receiving onabotulinumtoxinA, solifenacin, and placebo, respectively, were dry.

Nitti et al (2017) reported on the results of open-label RCT in which 557 patients with OAB, 3 or more urgency urinary incontinence episodes in 3 days, and 8 or more micturitions per day inadequately managed with anticholinergics were randomized to onabotulinumtoxinA 100 U or placebo.^96, Coprimary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the Treatment Benefit Scale at posttreatment week 12. OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p<0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo-treated patients reported a positive response on the Treatment Benefit Scale (60.8% vs 29.2%, p<0.001). Uncomplicated UTI was the most common adverse event.

Amundsen et al (2016) reported on the findings of a multicenter open-label RCT that assigned 381 women with refractory urgency urinary incontinence to cystoscopic intradetrusor injection of onabotulinumtoxinA (n=192) or sacral neuromodulation (n=189).^97, The primary outcome measure was change in the mean number of daily urgency urinary incontinence episodes from baseline to 6 months as measured with monthly 3-day diaries. Per protocol, analysis of data from 364 women showed that onabotulinumtoxinA group had statistically significant greater reduction in the primary outcome compared with sacral neuromodulation group (-3.9 vs -3.3 episodes per day, p=0.01). However, the mean difference of 0.63 (95% CI, 0.13 to 1.14) was of uncertain clinical importance. Additionally, UTIs (35% vs 11%, respectively; risk difference, -23%; 95% CI, -33% to -13%; p<0.001) and need for transient self-catheterization (8% and 2% at 1 and 6 months in the onabotulinumtoxinA group) were higher in the onabotulinumtoxinA group than in the sacral neuromodulation group. Outcomes at 2 years of the open-label extension follow-up reported that no difference between the 2 therapies in reducing urgency urinary incontinence symptoms.^98,

Nitti et al (2013) published data from an industry-supported study that included 557 patients with OAB and urinary incontinence inadequately controlled by anticholinergics.^99, Patients were randomized to an intradetrusor injection of onabotulinumtoxinA 100 U or placebo. At the 12-week follow-up, there was a statistically significantly greater reductions in the daily frequency of urinary incontinence episodes in the group that received botulinum toxin (-2.65) than in the placebo group (0.87; p<0.001). The other primary end point was the proportion of patients with a positive response at week 12 using the Treatment Benefit Scale. A significantly larger proportion of patients in the botulinum toxin group than in 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, UTIs 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 (5.4%) patients in the botulinum toxin group and 1 (0.4%) patient in the placebo group. Between-group p values were not reported for adverse events.

In a prespecified subgroup analysis of data from this RCT and another placebo-controlled trial (Chapple et al [2013]^100,), Sievert et al (2014) evaluated the efficacy of onabotulinumtoxinA by number of anticholinergic therapies used.^101, Patients had used a mean of 2.4 anticholinergic therapies before enrolling in the study. At week 12, reduction in the daily number of urinary incontinence episodes was significantly greater in the onabotulinumtoxinA group than in the control group, whether or not 1, 2, 3, or more prior anticholinergics had been used. Mean reduction in daily incontinence episodes for patients with 1 prior anticholinergic was 2.82 in the onabotulinumtoxinA group and 1.52 in the placebo group (p<0.001); with 3 or more prior anticholinergics, it was 2.92 and 0.73, respectively (p<0.001). Results with a follow-up of 3.5 years (extension phase) reported durable and consistent mean reductions in urinary incontinence episodes ranging from -3.1 to -3.8.^102,

An industry-supported RCT by Ginsberg et al (2012) included 416 patients with neurogenic detrusor activity associated with multiple sclerosis or spinal cord injury.^103, Patients were randomized to injections with onabotulinumtoxinA 200 U, onabotulinumtoxinA 300 U, 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-U group, -23 in the 300-U 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% were in the 200-U group, 42% were in the 300-U group, and 10% were on placebo-initiated catheterization. A total of 329 (79%) of 416 patients completed the 52-week study; however, outcomes like the number of weekly incontinence episodes were not reported at 52 weeks.

Section Summary: OAB and Neurogenic Detrusor Overactivity

Numerous RCTs and observational data studies have reported improvements in outcomes following botulinum toxin treatment in patients with neurogenic detrusor overactivity or OAB unresponsive to anticholinergic medication. Despite the risk of adverse events, including urinary retention and UTI, evidence would suggest that botulinum toxin improves the net health outcome.

For individuals who have urinary incontinence due to detrusor overactivity associated with OAB or with neurogenic causes who receive botulinum toxin injections, the evidence includes numerous RCTs. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. Studies have shown that botulinum toxin is effective at reducing symptoms in patients unresponsive to anticholinergic medications. There are adverse events associated with botulinum toxin (eg, urinary retention, urinary tract infection), but patients may find that benefits outweigh harms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 11 

Other Urologic Issues

Detrusor Sphincter Dyssynergia

Systematic Reviews

Systematic reviews have addressed treating detrusor sphincter dyssynergia with botulinum toxin injection. Mehta et al (2012) conducted a meta-analysis on botulinum toxin injection as a treatment of detrusor external sphincter dysfunction and incomplete voiding after spinal cord injury.^104, Reviewers identified 2 RCTs and multiple uncontrolled studies. The RCTs included the de Seze study (discussed below) and a second study of 5 patients.

A systematic review by Karsenty et al (2006) reviewed trials of botulinum toxin type A injected into the urethral sphincter to treat different types of lower urinary tract dysfunction, grouped into neurogenic detrusor sphincter dyssynergia and non-neurogenic obstructive sphincter dysfunction.^105, In the former group, reviewers cited 10 small studies (N range, 3-53 patients; 3 studies included patients in both categories). Most patients were quadriplegic men unable to self-catheterize or patients (of both sexes) with multiple sclerosis. All studies except two were case reports or case series; both exceptions were controlled studies and included in the Mehta meta-analysis. The authors of both reviews noted that, while most of the available studies have reported improvements with botulinum toxin injections, there are few published studies, and those published have small sample sizes.

Randomized Controlled Trials

De Seze et al (2002) studied 13 patients with chronic urinary retention due to detrusor sphincter dyssynergia from spinal cord disease (traumatic injury, multiple sclerosis, congenital malformations) who were randomized to perineal botulinum toxin type A or lidocaine injections into the external urethral sphincter.^106, In the botulinum group, there was a significant decrease in the primary outcome of postvoid residual volume compared with no change in the control group (lidocaine injection). Improvements were also seen in satisfaction scores and other urodynamic outcomes.

Section Summary: Detrusor Sphincter Dyssynergia

There is lack of adequately powered, scientifically rigorous RCTs to establish the efficacy of botulinum toxin in patients with detrusor sphincter dyssynergia

Benign Prostatic Hyperplasia

There is lack of adequately powered, scientifically rigorous RCTs to establish the efficacy of botulinum toxin in patients with detrusor sphincter dyssynergia

The use of botulinum toxin to treat symptoms of benign prostatic hyperplasia (BPH) is premised in part on a static component related to prostate size and a dynamic component related to the contraction of smooth muscle within the gland. Botulinum therapy treats this latter component. Marchal et al (2012) published a systematic review on use of botulinum toxin to treat BPH.^107, Reviewers identified 25 studies, including controlled and uncontrolled studies and abstracts in journal supplements. There were 6 RCTs, three published as full articles and three published as abstracts (2 RCTs were included in a meta-analysis). Reviewers reported that the mean postvoiding residue, both in pre- and posttreatment, did not differ significantly; pooled results were not reported for between-group outcomes. One of the RCTs, by Maria et al (2003), reported on 30 patients with BPH randomized to intraprostatic botulinum toxin type A or saline injection.^108, Inclusion criteria were moderate-to-severe symptoms of BPH based on the American Urological Association score and a mean peak urinary flow rate of no more than 15 mL per second with a void volume of 150 mL or less. After 2 months, the American Urological Association symptom score decreased by 65% among those receiving botulinum toxin compared with no significant change in the control group. Mean peak urinary flow rate was significantly increased in the treatment group.

Section Summary: Benign Prostatic Hyperplasia

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.

Interstitial Cystitis

Interstitial cystitis (IC) is a chronic condition characterized by pain, urgency, and frequent urination of small volumes.

Systematic Reviews

Wang et al (2016) reported the findings of meta-analysis that included 7 RCTs and a retrospective study.^109, Reviewers rated only one of the 7 RCTs as high quality (ie, low risk of bias) while five were rated as moderate, and the other was rated as a high risk of bias. Moreover, reviewers reported a statistically significant effect on multiple outcome measures. However, the trials that generated these data suffered from multiple sources of bias, leading reviewers to conclude that "further well-designed, large-scale RCTs are required to confirm the findings of this analysis."

The systematic review by Tirumuru et al (2010) identified 3 RCTs and 7 prospective cohort studies evaluating intravesical botulinum toxin type A injections for IC/painful bladder syndrome.^110,Sample sizes of all studies were relatively small (range, 10-67 patients; total N=260 patients). Treatment protocols varied (eg, dose of botulinum toxin, number of injection sites, location of injection sites). Meta-analyses were not performed due to heterogeneity among studies. All 3 RCTs were conducted outside of the United States. Two studies reported response rates as an outcome measure (both used a 7-point Global Response Assessment scale). One study found a significantly higher response rate with botulinum toxin plus hydrodistension than with hydrodistension-only, and the other found a significantly higher response rate with bacillus Calmette-Guérin therapy than with botulinum toxin. Some adverse events, in particular dysuria and voiding difficulty, were reported and 19 (7%) of 260 patients self-catheterized at some time after treatment.

Randomized Controlled Trials

Three RCTs evaluating botulinum toxin for treatment of IC and/or bladder pain syndrome have been published. One, by Akiyama et al (2015), lacked blinding and reported only 1 month of comparative data.^111, The 2 recent double-blind, placebo-controlled trials are described next.

The RCT by Kuo et al (2016) included 60 Taiwanese patients (52 women, 8 men) with IC/painful bladder syndrome who had failed at least 6 months of conventional therapy.^112, To be eligible, patients had to fail at least 2 types of treatment modalities (ie, oral medications, intravesical treatment with heparin or hyaluronic acid). Individuals with a variety of comorbid conditions were excluded, including those with urinary retention. Participants received intravesical injection of botulinum toxin type A (Botox 100 U) or normal saline (placebo), followed by hydrodistention under general anesthesia. The primary end point was the reduction in pain on a 10-point visual analog scale (VAS) score 8 weeks after treatment. There was a significantly greater reduction in the mean VAS score in the botulinum toxin group (-2.6) than in the placebo group (-0.9; p=0.021). Secondary outcomes, including overall subjective success (assessed by a Global Response Assessment), Interstitial Cystitis Symptom Index, urinary frequency, and nocturia did not differ significantly between groups. The incidence of adverse events was significantly higher in the botulinum toxin group than in the placebo group at 8 weeks (p=0.033). For example, 16 (40%) patients in the botulinum group and 1 (5%) in the placebo group reported dysuria at 8 weeks.

The RCT by Manning et al (2014) included 54 women with IC or BPS refractory to at least 2 recognized treatments.^113, Patients with voiding difficulty, bladder malignancy, and recurrent UTI were excluded. The primary outcome was the O'Leary-Sant (OLS) Questionnaire score, which assesses on daytime frequency, nocturia, urgency, and bladder pain. Patients received hydrodistention under general anesthesia, with either an injection of botulinum toxin type A (Dysport 500 U) or normal saline (placebo). The OLS score at 3 months did not differ significantly between groups. Scores were 20.4 (95% CI, 17.1 to 23.7) in the botulinum toxin group, and 25.3 (95% CI, 21.9 to 28.8) in the placebo group (MD=3.7; 95% CI, -0.34 to 7.6; p=0.12). However, in the subgroups of 42 patients without UTIs, the OLS score was significantly improved with botulinum toxin than with placebo (MD=6.1; 95% CI, 2.5 to 9.6; p=0.02). Adverse events were not reported.

Section Summary: Interstitial Cystitis

There is insufficient evidence that botulinum toxin improves the net health outcome in patients with IC. RCTs have had mixed findings on efficacy outcomes, and botulinum toxin has been associated with adverse events (eg, dysuria). Moreover, there is insufficient evidence comparing botulinum toxin injection with alternative treatments.

For individuals with urologic issues other than detrusor overactivity or OAB (eg, detrusor sphincter dyssynergia, BPH, IC) who receive botulinum toxin injections, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, medication use, and treatment-related morbidity. Available RCTs for these conditions are small and have reported mixed findings on the benefit of botulinum toxin. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 12 

Other Indications

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with other conditions including tremors, musculoskeletal pain, neuropathic pain, and postsurgical pain is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of botulinum toxin improve the net health outcome in patients with conditions such as tremors, musculoskeletal pain, neuropathic pain, and postsurgical pain?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with conditions such as tremors such as benign essential tremor [upper extremity], chronic low back pain, lateral epicondylitis, joint pain, myofascial pain syndrome, temporomandibular joint disorders, trigeminal neuralgia, pain after hemorrhoidectomy, facial wound healing, pelvic and genital pain in women, neuropathic pain after neck dissection, tinnitus, pain associated with breast reconstruction after mastectomy, Hirschsprung disease, gastroparesis, and depression.

Interventions

The therapy being considered is botulinum toxin.

Comparators

The following therapies are currently being used to treat tremors: conservative measures and pharmacotherapy (including b-blockers, anticonvulsants).

The following therapies are currently being used to treatmusculoskeletal pain, neuropathic pain, and postsurgical pain: conservative measures and pharmacotherapy including non-steroidal anti-inflammatory drugs, anticonvulsants, antidepressants, and opioids.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, medication use, and treatment-related morbidity.

Timing

Follow-up ranges from 4 to 12 weeks to monitor outcomes.

Setting

Patients with tremors, musculoskeletal pain, neuropathic pain, and postsurgical painmay be managed by general physicians, pain specialists, neurologists, and/or endocrinologists; botulinum toxin is injected in an appropriate muscle in an outpatient setting.

Tremor

A tremor can 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 can reduce tremors.

Three randomized, placebo-controlled studies have addressed essential hand tremors; the trial by Brin et al (2001) enrolled 133 patients, and the trial by Jankovic et al (1996) enrolled 25 patients.^114,115, These RCTs reported inconsistent findings using tremor symptom scales and neither reported functional outcomes. The third trial, by Mittal et al (2017), randomized 30 patients with essential tremor and Parkinson disease tremor to incobotulinumtoxinA in a crossover design.^116, Treatment efficacy was evaluated by the tremor subsets of the Unified Parkinson's Disease Rating Scale, the Patient Global Impression of Change 4, and an evaluation set for 8 weeks after each of the 2 sets of treatments. There were statistically significant improvements in clinical rating scores of rest tremor and tremor severity at 4 and 8 weeks after the incobotulinumtoxinA injection and of action/postural tremor at 8 weeks; however, there was no statistically significant difference in grip strength at 4 weeks between the 2 groups. Other studies have shown that 30% to 70% patients who receive onabotulinumtoxinA for tremor develop moderate-to-severe hand weakness.

Botulinum toxin has been investigated in patients with tremors unrelated to dystonias in case reports and case series.

Section Summary: Tremor

The clinical significance of contradictory findings from 2 RCTs in patients with tremor are unclear. While a third small crossover trial has reported a statistically significant reduction in tremors in patients with Parkinson disease, a larger trial with longer term follow-up is required to replicate these findings and provide long-term follow-up to mitigate the risk of developing hand weakness over the course of time.

Musculoskeletal, Neuropathic, and Postsurgical Pain

Chronic Low Back Pain

Only 1 RCT of botulinum toxin type A treatment in patients with low back pain has been published.^117, The trial, by Foster et al (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 Botox 40 U at 5 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 8 weeks, 60% of treated patients and 12.5% of placebo patients showed reductions 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).

Section Summary: Chronic Low Back Pain

The population with chronic low back pain is heterogeneous. Results of a 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 repeated courses of botulinum toxin to determine the durability of repeated treatments.

Lateral Epicondylitis

Lin et al (2017) published a systematic review and meta-analysis that included 6 RCTs (total N=321 participants) comparing botulinum toxin with placebo or corticosteroid injections.^118, Reviewers assessed SMDs in pain relief and grip strength at 3 time points: 2 to 4, 8 to 12, and 16 weeks or more after injection. Compared with placebo, botulinum toxin injection significantly reduced pain at all 3 time points (SMD = -0.73; 95% CI, -1.29 to -0.17; SMD = -0.45; 95% CI, -0.74 to -0.15; SMD = -0.54; 95% CI, -0.99 to -0.11, respectively). Botulinum toxin was less effective than corticosteroid at 2 to 4 weeks (SMD=1.15; 95% CI, 0.59 to 1.78), and both treatments appeared similar in efficacy after 8 weeks.

Krogh et al (2013) published a systematic review and meta-analysis on the comparative effectiveness of injection therapies for lateral epicondylitis.^119, Seventeen trials, four of which evaluated botulinum toxin, were identified. In a meta-analysis, botulinum toxin showed marginal benefit (SMD = -0.50; 95% CI, -0.81 to -0.08). All trials were at high risk of bias, and the treatment was associated with temporary paresis of finger extension.

Another relevant systematic review was conducted by Sims et al (2014).^120, The systematic review addressed nonsurgical treatment of lateral epicondylitis. Reviewers identified 58 RCTs. Four addressed treatment with botulinum toxin, and the remainder addressed other treatments (eg, corticosteroid injection, iontophoresis, prolotherapy). All trials were placebo-controlled. Three of the trials did not report significant differences in pain scores or grip strength over 18 weeks. The other 3 RCTs found significant improvements in pain scores, but not in grip strength. All studies had patients in treatment groups who reported transient weakness in finger extension.

Section Summary: Lateral Epicondylitis

Several systematic reviews have identified a small number of RCTs evaluating botulinum toxin for treating epicondylitis. The RCTs were generally considered to be at high risk of bias, had mixed findings, and all reported transient adverse events for patients treated with botulinum toxin. The RCTs evaluating botulinum toxin were all placebo-controlled, and potential alternative treatments are available for this condition that could have been compared with botulinum toxin. A systematic review that included trials comparing botulinum toxin with corticosteroid injections reported that botulinum toxin was less effective than corticosteroid at 2 to 4 weeks and both treatments appeared similar in efficacy after 8 weeks.

Other Joint Pain

Two case series of patients with chronic joint pain refractory to conservative management studied the effect of botulinum toxin type A injections into several joints of patients with arthritis and into the knee joint of patients with chronic knee pain (1 case series specified that Dysport was to be used).^121,122, Both patient groups reported significant reductions in joint pain and improvements 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 favored treatment, some did not.

Section Summary: Other Joint Pain

Due to the lack of consistent findings from well-designed studies, the evidence is insufficient that botulinum toxin for treatment of other joint pain improves the net health outcome.

Myofascial Pain Syndrome

Myofascial pain syndrome is characterized by muscle pain with increased tone and stiffness associated using myofascial trigger points. Patients are often treated with trigger point injections with saline, dilute anesthetics, or dry needling. These injections, while 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 design to evaluate the efficacy of botulinum toxin injection for treating myofascial pain syndrome would be a double-blind RCT to minimize the placebo effect and would compare botulinum toxin injections with dry needling and/or with anesthetic injection.

Systematic Reviews

Several systematic reviews of RCTs have evaluated botulinum toxin injection for myofascial pain syndrome. More recently, a Cochrane review by Soares et al (2014) identified 4 RCTs (total N=233 patients).^123, All RCTs were placebo-controlled and double-blind. Three were prospective, and one 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, reviewers did not pool analyses. The primary outcomes were change in pain as assessed by validated instruments. Three of the 4 studies found that botulinum toxin did not significantly reduce pain intensity. Another 2014 systematic review had similar findings.^124,

A systematic review that included a meta-analysis was published by Langevin et al (2011).^125, A pooled analysis 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).

Randomized Controlled Trials

An industry-sponsored RCT by Nicol et al (2014), not included in the systematic reviews, focused on patients with myofascial pain who had responded to an initial injection of botulinum toxin type A.^126, A total of 114 patients received an initial injection and 54 responders were subsequently randomized to a second injection of botulinum toxin or saline placebo 14 weeks after the initial injection. At week 26 after the initial injection, but not at week 20, there was a significantly greater improvement in the mean visual numeric scores for pain in the botulinum toxin group than in the placebo group (p=0.019). There was no significant difference between groups at week 26, compared with baseline, in QOL using the 36-Item Short-Form Health Survey. Thus, this trial had mixed outcomes and restricted study participation to a responder group. As a result, this inclusion criterion could have biased the proportion of patients who initially experienced a placebo response, thereby making blinding more difficult for those familiar with side effects of the active treatment.

Section Summary: Myofascial Pain

Several RCTs have evaluated botulinum toxin for treatment of myofascial pain syndrome. Studies were double-blind, but compared botulinum toxin with placebo, rather than common alternative treatments. Most trials, as well as a pooled analysis of study findings, did not report improved health outcomes with botulinum toxin.

Temporomandibular Joint Disorders

A systematic review by Chen et al (2015) evaluated the literature on botulinum toxin for treatment of temporomandibular joint disorders.^127, Eligibility included RCTs comparing any dose or type of botulinum toxin with any alternative intervention or placebo. Five RCTs met the inclusion criteria; two were parallel- group studies, and two were crossover studies. Study sizes tended to be small; all but one included 30 or more participants. Three of the 5 studies were judged to be at high risk of bias. All studies administered a single injection of botulinum toxin and followed patients up at least 1 month later. Four studies used a placebo (normal saline) control group and the fifth used botulinum toxin to fascial manipulation. The primary outcome was a validated pain scale. Data were not pooled due to heterogeneity among trials. In a qualitative review of the studies, only 2 of the 5 trials found a significant short-term (1-to-2 months) benefit of botulinum toxin compared with control on pain reduction.

Section Summary: Temporomandibular Joint Disorders

A systematic review of RCTs found insufficient evidence that botulinum toxin improves the net health outcome in patients with temporomandibular joint disorders. Studies have tended to be small, have a high risk of bias, and only 2 of 5 RCTs found that botulinum toxin reduced pain more than a comparator.

Trigeminal Neuralgia

Systematic Reviews

Morra et al (2016) published a systematic review that included 4 RCTs (total N=178 patients).^128, Pooled results showed that patients receiving botulinum toxin type A were 2.87 (95 % CI, 1.76 to 4.69; p<0.001) times more likely to be responder (defined as patients with >50% reduction in mean pain score from baseline to end point) than the controls, with no significant detected heterogeneity (p=0.31; I²=4 %). Further, there was reduction in the paroxysms frequency per day (MD = -29.79; 95 % CI, -38.50 to -21.08; p<0.001).

Randomized Controlled Trials

Three RCTs using botulinum toxin to treat trigeminal neuralgia were identified; all were double-blind, placebo-controlled, conducted in China, and appear to have been done by the same research group. No industry funding was reported. Sample sizes in the trials were relatively small, with fewer than 30 in any one. More recently, an RCT by Zhang et al (2014) included 84 patients with trigeminal neuralgia for at least 4 months who had failed other treatments (most commonly carbamazepine, gabapentin, or opioids), had a mean pain intensity score of at least 4, and had a mean attack frequency of at least 4 per day.^129, Medication treatment remained unchanged during the trial. Patients were randomized to 1 of 3 groups: a single injection of normal saline (placebo) (n=28), botulinum toxin 25 U/l (n=27), or botulinum toxin 75 U/l (n=29). The primary efficacy outcome was the proportion of responders, defined as at least a 50% reduction in the mean pain score from baseline to 8 weeks. Pain severity was measured on an 11-point VAS (0-10 points). Mean baseline VAS scores were similar across the 3 groups (range, 6.24-7.18). At week 8, the proportion of responders was 32.1% in the placebo group, 70.4% in the 25-U group, and 86.2% in the 75-U group (p<0.002). No severe adverse events were reported, and no patients discontinued study participation due to adverse events. No severe or long-lasting adverse events were reported.

An RCT by Shehata et al (2013) in Egypt included 20 women diagnosed with intractable idiopathic trigeminal neuralgia, defined as insufficient response to medication treatments for 3 months prior to study participation.^130, Patients were randomized to a single injection of botulinum toxin type 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 postinjection, the VAS score decreased by 6.5 points in the botulinum toxin group and by 0.3 points in the placebo group (p<0.001). Paroxysm frequency was a secondary outcome. 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 per day and 36.1 per day, respectively (p<0.001).

The third trial, published by Wu et al (2012), included 42 patients with trigeminal neuralgia.^131, To be eligible for participation, patients had to have a mean pain intensity of at least 4 and a mean attack frequency of at least 4 per day despite medication therapy. Most patients were taking medication at baseline (eg, opioids, carbamazepine, gabapentin); medications remained unchanged during the trial. Patients were randomized to botulinum toxin type A 75 U or saline (placebo). They were followed for 12 weeks. The primary end points were pain severity and pain attack frequency. Symptoms were recorded by patients each morning, for the previous 24-hour period using a VAS. Both of the primary end points were statistically significantly better in the treatment group than in the control group. The proportion of patients with at least a 50% reduction in the mean pain score from baseline to 12 weeks (a secondary end point) was 15 (68%) of 22 in the botulinum toxin group and 3 (15%) of 20 in the placebo group (p<0.01). No severe or long-lasting adverse events were reported.

Section Summary: Trigeminal Neuralgia

Three small RCTs from China and one from Egypt have assessed patients who had failed medication treatment; the RCTs found a statistically significant benefit for botulinum toxin type added to their medication regimen vs placebo on pain intensity and attack frequency. Limitations of the evidence base included studies from only a single research group, the small overall number of patients evaluated, relatively short follow-up (8-12 weeks), and lack of reported statistical power analysis. In the absence of power analysis, there is a higher chance of spurious statistically significant findings.

Pain Control After Hemorrhoidectomy

Several small RCTs of botulinum toxin intrasphincter injection for controlling pain after hemorrhoidectomy have been published. A trial by Patti et al (2005) randomized 30 patients to botulinum toxin 20 U or saline injection and reported a significantly shorter duration of postoperative pain at rest and during defecation in the treated group.^132, A trial by Patti et al (2006), which also included 30 patients, found significant differences in postoperative maximum resting pressure change from baseline with botulinum toxin vs topical glyceryl trinitrate (p<0.001).^133, 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.

Section Summary: Pain Control After Hemorrhoidectomy

RCTs evaluating botulinum toxin injection after hemorrhoidectomy have suggested improvement in pain control; however, findings need confirmation in larger trials.

Facial Wound Healing

Ziade et al (2013) reported on a trial including 30 adults presenting to the emergency department with facial wounds without tissue loss.^134, 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 VAS. The PSAS is 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 PSAS scores might have been a more subjective outcome, whereas it is likely that OSAS, VSS, and VAS scores were 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 scores. For example, median OSAS score was 8 in the botulinum toxin group and 9 in the control group. However, a significant between-group difference was found for the VAS score, favoring the botulinum toxin group. Median VAS score was 8.25 for the botulinum group and 6.35 for the control group (p<0.001). These results demonstrated a lack of consistency in finding a benefit across outcomes-there was no significant difference in the patient-reported or clinically accessed outcomes, only in the outcome based on photographic analysis.

Previously, Gassner et al (2006) conducted a small RCT of botulinum toxin-induced immobilization of facial lacerations to improve wound healing compared with placebo (n=31).^135, The outcome was determined by blinded assessment of photographs of wound healing at intervals using a VAS. The trialists reported enhanced wound healing in the treatment arm (8.9) compared with the placebo arm (7.2; p=0.003).

Section Summary: Facial Wound Healing

There are few RCTs evaluating botulinum toxin for facial wound healing, and the available trials offer inconsistent evidence of benefit.

Pelvic and Genital Pain in Women

Randomized Controlled Trials

One double-blind, randomized, placebo-controlled trial by Abbott et al (2006) evaluated 60 women with chronic pelvic pain and pelvic floor spasm.^136, Patients received injections of botulinum toxin type 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.

Nonrandomized Studies

Other studies include a small, open-label trial by Dykstra et al (2006) that tested botulinum toxin type A injections in painful vulvar tissue to alleviate provoked vestibulodynia (n=19).^137, Patients receiving up to 2 doses had significantly reduced pain compared with baseline for 8 (lower dose) to 14 weeks (higher dose). A prospective cohort study by Jarvis et al (2004) tested different doses of botulinum toxin in 12 women with pelvic floor muscle hypertonicity and history of chronic pelvic pain.^138, Compared with baseline, there were nonsignificant reductions in pelvic pain and nonsignificant improvements in QOL.

Section Summary: Pelvic and Genital Pain in Women

A single inadequately powered RCT that evaluated botulinum toxin to treat pelvic or genital pain in women failed to demonstrate statistically significant reduction in pain scores compared with placebo.

Neuropathic Pain

Two open-label trials of 16 and 23 patients, respectively, who had failed conservative therapy investigated various doses of botulinum toxin type A injected into the area of complaint.^139,140, For both studies, which were conducted by the same group, results indicated significant reductions in pain compared with baseline and trends toward improved QOL.

Section Summary: Neuropathic Pain

Lack of a randomized, placebo-controlled trial, controlling for strong placebo effects in pain therapy, render the results of 2 open-label trials inconclusive for the use of botulinum toxin to treat neuropathic pain.

Tinnitus

Systematic Reviews

Slengerik-Hansen et al (2016) reported the findings of a systematic review of 22 studies, which mainly included case reports and case series with a total of 51 treated patients.^141, Reviewers acknowledged that selected studies suffered from an extremely low evidence level with several sources of bias.

Randomized Controlled Trials

Stidham et al (2005) explored the use of botulinum toxin type A injections for tinnitus treatment under the theory that blocking the autonomic pathways would reduce the perception of tinnitus.^142, In this trial, 30 patients were randomized in a double-blind study to 3 subcutaneous injections of botulinum toxin type A around the ear followed by placebo injections 4 months later, or placebo injections first, followed by botulinum toxin type A. The trialists reported that 7 patients had reduced tinnitus after the botulinum toxin type A injections, which was statistically significant compared with the placebo groups in which only 2 patients reported reduced tinnitus (p<0.005). Tinnitus Handicap Inventory scores were also significantly lower between pretreatment and 4 months after botulinum toxin type A injections. However, no other significant differences were noted between both treatments at 1 and 4 months postinjection. Trial limitations included sample size and lack of intention-to-treat analysis.

Section Summary: Tinnitus

The evidence for botulinum toxin in patients with tinnitus consists mostly of case reports and case series. Well-conducted RCTs with sufficiently large sample sizes are needed to demonstrate that botulinum toxin improves the net health outcomes in patients with tinnitus.

Pain Associated With Breast Reconstruction After Mastectomy

There are no published RCTs evaluating botulinum toxin for pain associated with breast reconstruction after mastectomy. A systematic review by Winocour et al (2014) identified 7 studies on perioperative injection of botulinum toxin type A following breast reconstruction surgery.^143, They consisted of 2 prospective controlled cohort studies, 3 retrospective controlled cohort studies, and 2 case series. Most studies were small; only 1 (N=293) had more than 50 participants. Three studies assessed postoperative pain and all three found that at least some outcomes were significantly better in the botulinum toxin group than in the comparison group.

Section Summary: Pain Associated With Breast Reconstruction After Mastectomy

The evidence for botulinum toxin in patients with pain associated with breast reconstruction after mastectomy mostly consists of observational studies. Well-conducted RCTs with sufficiently large sample sizes are needed to demonstrate that botulinum toxin improves the net health outcomes in these patients.

Hirschsprung Disease

The published literature on use of botulinum toxin injection to treat Hirschsprung disease consists of small case series.^144,145,146, The largest prospective case series, published by Minkes and Langer (2000), included 18 children (median age, 4 years) with persistent obstructive symptoms after surgery for Hirschsprung disease.^145, 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 U. Twelve (67%) of 18 patients improved 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 series by Patruset al (2011) retrospectively reviewed outcomes in 22 patients with Hirschsprung disease treated over 10 years; subject had received a median of 2 (range, 1-23) botulinum toxin injections for postsurgical obstructive symptoms.^146, 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 chart review, 2 (9%) of 22 patients had persistent symptoms. Eighteen (80%) children had a "good response" to the initial treatment (not defined), and 15 (68%) 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 patients received other treatments during the follow-up period in either case series.

Section Summary: Hirschsprung Disease

The evidence for botulinum toxin in patients with Hirschsprung disease mostly consists of observational studies. Well-conducted RCTs with sufficiently large sample sizes are needed to demonstrate that botulinum toxin improves the net health outcome in such patients.

Gastroparesis

Systematic Reviews

A systematic review by Bai et al (2010) identified 15 studies on botulinum toxin injection to treat gastroparesis.^147, Two studies were RCTs; the remainder was case series or open-label observational studies. Reviewers stated that, while the nonrandomized studies generally found improvements in subjective symptoms and gastric emptying after botulinum toxin injections, the RCTs did not confirm the efficacy of botulinum toxin for treating gastroparesis. Reviewers concluded that there was insufficient evidence to recommend botulinum toxin for gastroparesis. Brief summaries of the 2 RCTs follow.

Randomized Controlled Trials

Arts et al (2007) published a randomized crossover study with 23 patients.^148, The trial 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. 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 after Botox injection and 22.5 minutes after saline injection (p>0.05). In addition, in pooled analyses, mean total GCSI score did not differ significantly after Botox (6.1) compared with saline treatment (3.8; p>0.05).

The other RCT, by Friedenberg et al (2008), was a single-center, double-blind trial with 32 patients.^149, Patients had delayed gastric emptying and GCSI scores of 27 or higher. They received an injection of Botox (n=16) or saline placebo (n=16). All patients completed the trial. 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 GCSI score 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 end point) also did not differ significantly between groups.

Section Summary: Gastroparesis

Two small inadequately powered RCTs failed to show a benefit of botulinum toxin for treatment of gastroparesis. Additional adequately powered RCTs are needed.

Depression

Magid et al (2015) published a meta-analysis of 3 placebo-controlled randomized trials evaluating botulinum toxin type A for treating unipolar major depressive disorder.^150, Sample sizes were small; a total of 59 patients were treated with botulinum toxin and 75 with placebo. In a pooled analysis of individual patient data, there was a significantly higher response rate in the botulinum toxin group (54.2%) than in the placebo group (10.7%; OR=7.3; 95% CI, 2.4 to 22.5). Other outcomes also favored the botulinum toxin group. No RCTs compared botulinum toxin with antidepressant treatment, which is standard of care.

Section Summary: Depression

A pooled analysis of 3 small RCTs showed a statistically significant benefit of botulinum toxin compared with placebo. Studies were small and did not compare botulinum toxin with antidepressants.

For individuals who have other indications (eg, tremors such as benign essential tremor [upper extremity], chronic low back pain, lateral epicondylitis, joint pain, myofascial pain syndrome, temporomandibular joint disorders, trigeminal neuralgia, pain after hemorrhoidectomy, facial wound healing, pelvic and genital pain in women, neuropathic pain, tinnitus, pain associated with breast reconstruction after mastectomy, Hirschsprung disease, gastroparesis, and depression) who receive botulinum toxin injections, evidence includes case series or a few small, flawed RCTs. Relevant outcomes are symptoms, functional outcomes, medication use, and treatment-related morbidity. Evidence of benefit from large, well-conducted RCTs is lacking for these indications. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 13 

Hirschsprung Disease

Hirschsprung disease is a rare genetic birth defect that results in a motor disorder of the gut due to failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during intestinal development during fetal life. The resulting aganglionic segment of the colon fails to relax, causing a functional obstruction.

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with Hirschsprung disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Hirschsprung disease who develop obstructive symptoms after a pull-through operation.

Interventions

The therapy being considered is commercially available botulinum toxin products. These are injected intrasphincterically.

Comparators

The mainstay of treatment is surgery. The goals are to resect the affected segment of the colon, bring the normal ganglionic bowel down close to the anus, and preserve internal anal sphincter function. Many surgical techniques have been developed. The choice among them usually is based upon surgeon preference since the overall complication rates and long-term results are similar.

Outcomes

The general outcomes of interest are symptoms, health status measures, and treatment-related morbidity. Follow-up ranges from 6 months to 5 years to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Roorda et al (2019) conducted a meta-analysis of 14 studies (N=278 patients) published through December 2018 on the efficacy of botulinum toxin injections in patients with Hirschsprung disease.^10,The primary outcome assessed was proportion of patients with improvement of obstructive symptoms. Secondary outcomes included type of botulinum toxin, average dose, average age at first injections and proportion of patients with associated syndromes. Botulinum toxin injections were effective in treating obstructive symptoms in 66% of patients [event rate (ER)=0.66, p=0.004, I²=49.5]. Secondary outcomes were not predictive for this effect. There was a significantly higher response rate within one month after botulinum toxin injections compared to greater than one month (p<0.001). Botulinum toxin injections were not effective in treating enterocolitis (p=0.65). Adverse effects were observed on average in 17% of patients (p<0.001), varying from temporary incontinence to mild anal pain.

Cohort Studies

A retrospective cohort study by Svetanoff et al (2021) included 40 patients admitted for Hirschsprung-associated enterocolitis (HAEC) from January 2010 to December 2019.^11, The aim of the study was to determine if botulinum toxin injection during HAEC episodes decreased the number of recurrent HAEC episodes and/or increased the interval between readmissions. In the 40 patients analyzed, a total of 120 episodes of HAEC occurred. Patients who received botulinum toxin during their inpatient HAEC episode had a longer median time between readmissions (p=.04) and trended toward an association with fewer readmissions prior to a follow-up clinic visit (p=.08). This study provides additional evidence that the use of botulinum injections for Hirschsprung disease among patients hospitalized for HAEC is associated with an increased time between recurrent HAEC episodes and trend toward decreasing recurrent enterocolitis incidence.

A retrospective cohort study by Roorda et al (2021) of 41 patients consecutively treated for Hirschsprung disease from 2003 and 2017in 2 academic hospitals in Amsterdam with a follow-up duration of ≥1 year after corrective surgery were analyzed.^12, All patients had obstructive defecation problems non-responsive to high-dose laxatives or rectal irrigation, 2 patients also had an episode of HAEC. Twenty-five (61%) of 41 patients had clinical improvement after a first injection. In 29 (71%) of the 41 patients, spontaneous defecation or treatment with laxatives only was achieved. These cohort studies are summarized in Tables 6 and 7.

Table 6. Summary of Cohort Study Characteristics

NR: not reported.

Table 7. Summary of Cohort Study Results

CI: confidence interval; HAEC: Hirschsprung-associated enterocolitis; IQR: interquartile range; NR: not reported; SD: standard deviation.

Section Summary: Hirschsprung Disease

Hirschsprung disease is a rare disease where the mainstay of treatment is surgery. However, patients may develop obstructive symptoms after surgery. The published literature on use of onabotulinumtoxinA to treat Hirschsprung disease consists of case series with a total of 73 patients with median follow-up of more than 7 years in 2 out of 3 published case series. All case series report consistent short-term responses in more than 75% of patients in 2 of the 3, case series. Long-term follow-up is suggestive of durability of response.

For individuals with Hirschsprung disease who develop obstructive symptoms after a pull-through operation who receive botulinum toxin injections, the evidence includes 3 case series. Relevant outcomes are symptoms, health status measures, and treatment-related morbidity. The 3 case series included a total of 73 patients with median follow-up of more than 7 years. In 2 out of the 3 published case series consistent short-term responses were reported in more than 75% of patients. Long- term follow-up is suggestive of durability of response. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Miscellaneous Conditions

Clinical Context and Therapy Purpose

The purpose of botulinum toxin in patients with the miscellaneous conditions listed below is to provide a treatment option that is an alternative to or an improvement on existing therapies. In general, many treatment options are available for treatment of these indications. Commercially available botulinum toxin products have been evaluated in these settings when patients have failed the standard of care or in whom standard of care interventions are contraindicated.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with the miscellaneous conditions listed above who have failed standard of care or in whom standard of care interventions are contraindicated.

Interventions

The therapy being considered is commercially available botulinum toxin products.

Comparators

The therapies listed in Table 9 are currently being used to treat the miscellaneous conditions listed above.

Table 9. Current Treatment Options for Miscellaneous Indications

Outcomes

The general outcomes of interest are symptoms, functional outcomes, medication use, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Neurological indications

Tension and Cervicogenic Headache

Dhanasekara et al (2023) conducted a meta-analysis of 11 RCTs (n=390 botulinum toxin A, n=297 controls) published through May 2020 on the effectiveness of botulinum toxin for chronic tension-type headache prophylaxis.^17,Headache intensity (mean, -0.50; standard deviations: -0.94, −0.06), frequency (-2.83 days/month; -4.08, -1.58), daily headache duration (-0.96; -1.86, -0.07), and the frequency of acute pain medication use (-2.2 days/month; -3.48, -0.91]) were improved with botulinum toxin A. These improvements exceeded minimal clinically important differences for headache intensity, frequency, and acute pain medication use. A 79% (28%, 150%) greater response rate was observed for botulinum toxin vs controls in improving chronic tension-type headache. This review however had some notable limitations, including the low-quality evidence and a small number of patients across studies. There is a need to establish the effects of botulinum toxin A for this indication in adequately-powered high-quality RCTs. An earlier meta-analysis by Jackson et al (2012) of 8 placebo-controlled RCTs evaluating botulinum toxin A for chronic tension-type headaches did not find a statistically significant difference in change in the monthly number of headache days in the botulinum toxin group versus the placebo group (difference, -1.43; 95% CI, -3.13 to 0.27; p=.02).^18,

Essential Tremor

Marques et al (2024) conducted a multicenter, double-blind, RCT in adult patients with essential or isolated head tremor receiving botulinum toxin type A or placebo.^19,The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change scale at week 6 after the second injection (week 18 after randomization). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. One-hundred and seventeen (of 120) patients were randomly assigned to receive botulinum toxin (n=62) or placebo (n=55) and included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and two patients in the placebo group did not receive injections during week 12. The primary outcome was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% CI, 1.35 to 8.42; p=0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. The study had some limitations, such as loss to-follow-up of patients, potential unmasking of the trial-group assignments, and lack of control for external factors affecting tremor.

An earlier systematic review by Liao et al (2022) of 5 RCTs published before December 2021 concluded that botulinum toxin significantly reduced essential tremor severity, including hands tremor and head tremor within 6 weeks of treatment (standardized mean difference (SMD), -0.58, 95% CI, -0.28 to -0.88, p=0.002, I²=0%).^20, The main side effect was weakness, but it did not affect the grip strength of the patients. This review had limitations, such as small sample sizes, and use of diverse assessment methods across trials.

Tinnitus

Slengerik-Hansen et al (2016) reported the findings of a systematic review that included 22 studies, mainly case reports and case series, with a total of 51 patients treated with onabotulinumtoxinA for the treatment of tinnitus.^21, A small (N=30) cross-over prospective study by Stidham et al (2005) reported a statistically significant decrease in tinnitus handicap inventory scores between pretreatment and 4 months post botulinum toxin A injection.^22, Multiple other outcome studies showed no difference. Well-conducted RCTs with sufficiently large sample sizes are needed.

Tourette syndrome

A Cochrane review was conducted by Pandey et al (2018) to assess the efficacy and safety of botulinum toxin for treating motor and phonic tics in people with Tourette's syndrome, and to examine its impact on premonitory urge and sensory tics.^23, Only one RCT (N=20 patients) met the study selection criteria. The results of botulinum toxin injections on tic frequency, measured by video or self-report, and on premonitory urge, are unclear based on low-quality of evidence. The evidence for side effects of botulinum toxin was also very low. Nine individuals had muscle weakness following the injection, which could have led to unblinding of treatment group assignment. No data were available to evaluate whether botulinum injections led to immuno-resistance to botulinum toxin.

Urological Indications

Benign Prostatic Hyperplasia

Shim et al (2016) reported the results of a systematic review of 3 studies (N=522) on use of botulinum toxin A to treat benign prostatic hyperplasia.^24,Study duration ranged from 8 to 24 weeks. The pooled overall SMD in the mean change in International Prostate Symptom Score for the botulinum toxin group versus the placebo group was -1.02 (95% CI, -1.97, -0.07). The other outcomes (peak flow rate (Qmax), prostate volume, and post-voided residual volume) were not statistically different between the two groups. This review showed no overall differences in efficacy and procedure-related adverse events of botulinum toxin compared with placebo for this indication.

Interstitial Cystitis

The mechanism of the effect of intradetrusor botulinum toxin therapy for interstitial cystitis is likely the ability of botulinum toxin to modulate sensory neurotransmission. While botulinum toxin has been shown to alleviate symptoms in multiple studies,^25,26,27, mostly conducted outside of the U.S., there is a risk of urinary retention,^26, which may be particularly devastating for a patient with a painful bladder. Therefore, any patient considering this treatment must be willing and able to perform intermittent self-catheterization.

The American Urological Association published guidelines for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome in 2011 based on a systematic review that included published evidence from January 1, 1983 to July 22, 2009.^28, The guideline is updated periodically by conducting incremental systematic reviews to maintain guideline currency with newly published relevant literature. Most recently, an updated literature review in 2022 (search dates, June 2013 to January 2021) was published.^29, In addition, multiple systematic reviews have been published.^30,31,32,33, There is large variability in the botulinum toxin type, dosage, frequency and site of injection and comparators among the RCTs included in the systematic reviews. Further, several studies appear to include overlapping patient groups. These limitations make it challenging to interpret the results of these meta-analysis.

Detrusor Sphincteric Dyssynergia

Goel et al (2020) conducted a systematic review of 11 studies (N=353 patients) that evaluated the use of botulinum toxin A as the first-line treatment for detrusor external sphincter dyssynergia.^34, Botulinum toxin improved urinary retention, bladder and urethral pressure, and leakage rate in 60%-78% of patients after one month. Most patients needed another injection after 4-9 months. A previous Cochrane review by Utomo et al (2014), because of the limited availability of eligible trials (4 RCTs), was unable to provide robust evidence in favor of botulinum toxin injections for detrusor external sphincter dyssynergia.^35, Results were from small studies with a high risk of bias.

Pain Due to Multiple Etiologies

Lateral Epicondylitis

Although the mechanism of action for botulinum toxin in epicondylitis is not clearly understood, it is thought to be "proinflammatory". Botulinum toxin has been evaluated as a treatment for epicondylitis in a number of RCTs as summarized in a number of systematic reviews.^36,37,38,

In the systematic review and meta-analysis published by Lin et al (2018 ), the authors included 6 RCTs (N=321) that compared onabotulinumtoxinA or abobotulinumtoxinA with placebo or corticosteroid injections in patients with lateral epicondylitis.^36, Four of the 6 trials enrolled less than 30 participants per treatment arm and allocation concealment was unclear in 4 out of 6 trials. Results were reported as a standardized mean differences and a negative number implied a favorable effect of botulinum toxin on pain reduction. Compared with placebo, botulinum toxin injection significantly reduced pain at all 3 time points (2 to 4 weeks, 8 to 12 weeks, and at 16 weeks or more; standardized mean difference, -0.73 (95% CI, -1.29 to -0.17), -0.45 (95% CI, -0.74 to -0.15), and -0.54 (95% CI, -0.99 to -0.11), respectively). In contrast, botulinum toxin was significantly less effective than a corticosteroid 2 to 4 weeks following injection; standardized mean difference, 1.15 (95% CI, 0.57 to 1.34) with no difference at the 8 to 12 weeks or 16 weeks or more time points. While the systematic reviews generally report pain relief in individual trials of botulinum toxin versus the comparator, treatment with botulinum toxin was associated with temporary paresis of finger extension. Similar results were reported by Tavassoli (2022) in a systematic review and meta-analysis of 31 RCTs (N=1948 patients) comparing local injection therapies for lateral epicondylitis: the efficacy of corticosteroids was greater than botulinum toxin within 4 weeks of treatment, with no significant therapeutic effects observed between groups in any study outcomes after 12 weeks of follow-up.^39,

Myofascial Pain Syndrome

Several systematic reviews of RCTs have evaluated onabotulinumtoxinA and abobotulinumtoxinA for myofascial pain syndrome. The Cochrane systematic review by Soares et al (2014) identified 4 placebo-controlled, double-blind RCTs that included 233 participants with myofascial pain syndrome excluding neck and head muscles.^40, Due to heterogeneity among studies, reviewers did not pool analyses. The primary outcome was change in pain as assessed by validated instruments. Three of the 4 studies found that botulinum toxin did not significantly reduce pain intensity. Major limitations included a high-risk of bias due to study size in 3 of the 4 studies and selective reporting in 1 study.

Two other systematic reviews that focused on myofascial pain syndrome involving head and neck muscles reported similar findings. Leonardi et al (2024) conducted a systematic review of 10 RCTs (N=651 patients) to assess the efficacy and safety of botulinum toxin injections for upper back myofascial pain syndrome.^41, Botulinum toxin was compared with placebo, anesthetic plus dry needling, or anaesthetic injections. The methodological quality of the trials was moderate and no serious adverse events or major complications were reported. However, the results did not show that botulinum toxin had a clear advantage over the other treatment modalities. Most included studies had small sample sizes, low power, varied outcome measures, and inconsistent follow-up periods. A previous systematic review by Desai et al (2014) included 7 trials that evaluated the efficacy of botulinum toxin type A in cervico-thoracic myofascial pain syndrome.^42, The majority of studies found negative results and 6 identified trials had significant failings due to deficiencies in 1 or more major quality criteria.

Low Back Pain

Foster et al (2001) reported the findings of a RCT in which 31 consecutive patients with chronic low back pain of at least 6 months in duration were randomized to onabotulinumtoxinA or saline.^43,Botulinum toxin A was superior to placebo injection for pain relief and improved function at 3 and 8 weeks (50% pain relief at 3 weeks: 73.3% vs. 25%; at 8 weeks: 60% vs. 16%, respectively). However, in most patients, benefits were no longer present after 3 to 4 months. Findings from a more recent small RCT by Cogne et al (2017) (N=19 patients) did not find botulinum toxin injections to be effective in relieving low back pain.^44, Results from these two trials should be considered preliminary, and further data from randomized trials are needed to confirm findings in a larger number of patients over a longer duration and to evaluate benefits and harms of repeated injections before this treatment can be recommended.

Temporomandibular Joint Disorders

Saini et al (2024) conducted a systematic review and meta-analysis of 14 RCTs (N=395 patients) to assess the effectiveness of botulinum toxin in the treatment of temporomandibular joint disorders.^45, The overall risk of bias showed a low to moderate quality of evidence. Results from 6 studies were reported only narratively; four studies were used for meta-analysis on pain reduction, and five were used for meta-analysis on adverse events. The control used in the meta-analysis was placebo injections. Results of the meta-analysis (n=84, 4 RCTs) for pain reduction were statistically insignificant for the botulinum toxin group with mean differences (MD) at -1.71 (95% CI, −2.87 to −0.5) at one month, -1.53 (95% CI, −2.80 to −0.27) at three months, and -1.33 (95% CI, −2.74 to 0.77) at six months. Regarding safety, the placebo group showed a relative risk of 1.34 (95% CI, 0.48 to 6.78) and 1.17 (95% CI, 0.54 to 3.88) at 1 and 3 months respectively. Botulinum toxin was also not associated with better outcomes in terms of adverse events, maximum mouth opening, bruxism events, and maximum occlusal force. More high-quality RCTs are needed to assess the efficacy and safety of botulinum toxin for this indication.

Chen et al (2015) summarized the evidence assessing the efficacy of botulinum toxin A for treatment of temporomandibular joint disorders in a systematic review that included 5 RCTs.^46, Sample size in all trials was 30 or less except for 1 study. Three of the 5 studies were judged to be at high-risk of bias. All studies administered a single injection of onabotulinumtoxinA or abobotulinumtoxinA and followed patients up at least 1 month later. Four studies used a placebo (normal saline) control group and the fifth compared abobotulinumtoxinA to fascial manipulation. Data were not pooled due to heterogeneity among trials. In a qualitative review of the studies, 2 of the 5 trials found a significant short-term (1 to 2 months) benefit of onabotulinumtoxinA compared with control on pain reduction.

Post Hemorrhoidectomy Pain

Lie et al (2023) conducted a systematic review and meta-analysis of 5 clinical trials (N=260 patients) published through March 2022 assessing the utility of botulinum toxin injection for post-operative pain management after conventional hemorrhoidectomy.^47, The pooled analysis revealed that botulinum toxin injection after hemorrhoidectomy was associated with lower visual analog scale (VAS) at 24 hours post-operative [MD, -1.35 (95% CI -1.90 to -0.80), p<0.00001, I²=0%] and shorter time to return work [MD, -8.94 days (95% CI, -12.57 to -5.30), p<0.00001, I²=0%]. However, botulinum toxin injection did not differ significantly from placebo in terms of time to first defecation (p=0.22), fecal incontinence (p=0.91) and urinary retention incidence (p=0.18). Further RCTs with larger sample sizes are needed to confirm the results of this meta-analysis.

Pelvic and Genital Pain in Women

Parenti et al (2023) conducted a systematic review of 22 studies to assess the efficacy and safety of botulinum toxin use in the treatment of vaginal, vulvar and pelvic pain disorders.^48, Botulinum toxin injection was found to be effective in improving vulvar and vaginal dyspareunia, vaginismus, and chronic pelvic pain. No irreversible side effects were detected. Major side effects reported were transient urinary or fecal incontinence, constipation and rectal pain. A meta-analysis was not performed given the use of different definitions, methods, and timing of botulinum toxin injection across studies.

Neuropathic Pain

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain published a systematic review and meta-analysis in 2015 which included 6 RCTs that assessed the efficacy of a single administration of botulinum toxin A (50 to 200 units subcutaneously in the region of pain) in patients with peripheral neuropathic pain.^49, The number needed to treat for 50% pain relief was a primary measure. Within the pool of included studies, those with smaller sample sizes had a positive primary outcome (number needed to treat, 1.9; 95% CI, 1.5 to 2.4 for 4 studies) with a low placebo effect, but one large, unpublished study was negative. Overall, the published meta-analysis assigned weak GRADE recommendations for use in neuropathic pain mainly because of the weak quality of evidence.

Datta Gupta et al (2022) published the results of a meta-analysis of RCTs evaluating the use of botulinum toxin A in neuropathic pain.^50, Of the 17 RCTs that were included (N=703), 6 reported the proportion of patients with at least a 50% reduction in VAS between baseline and final time periods in the botulinum toxin A and placebo groups. The mean RR was 4.90 (95% CI, 2.00 to 6.13; I²=44.9%).

Trigeminal Neuralgia

Evidence for the efficacy and safety of botulinum toxin A for trigeminal neuralgia is limited to 4 RCTs (N=178 patients) summarized in at least two meta-analyses by Morra et al, 2016 and Hu et al, 2024).^51,52,While these results reported a significant reductions in mean pain scores and attack frequency in the botulinum toxin compared with the placebo group, there are concerns about small patient numbers, limited durability, and quality of evidence. More high-quality studies are needed to further confirm its efficacy for patients with refractory trigeminal neuralgia or those not responding to medical or surgical management,.

Prevention of Pain associated with Breast Reconstruction after Mastectomy

Li et al (2018) conducted a systematic review and meta-analysis of 10 studies (N=682 patients) published through March 2018 on the use of botulinum toxin A in breast surgery using implants deep within the pectoralis major muscle.^53, The studies considered for inclusion consisted of six prospective controlled trials (2 RCTs and 4 other trials), three retrospective cohort studies, and one case series. The study time ranged from 4 months to 13 years, and 15 patients (3%) received botulinum toxin injection more than two times. No complications associated with botulinum toxin were mentioned, almost all the studies reported efficacy for pain control. The included studies were primarily retrospective, nonrandomized trials.

Gastrointestinal Disorders

Internal Anal Sphincter Achalasia

Friedmacher and Puri (2012) reported the results of a meta-analysis that included 395 patients from 2 prospective and 14 retrospective case series that compared internal anal sphincter myectomy (n=229) with botulinum A injection (n=166).^54, Regular bowel movements (odds ratio [OR] , 0.53; 95% CI, 0.29 to 0.99 ; p=.04), short-term improvements (OR , 0.56; 95% CI, 0.32 to 0.97 ; p=.04) and long-term improvement (OR , 0.25; 95% CI, 0.15 to 0.41 ; p<.0001) favored myectomy compared with botulinum toxin A injection. Further, the rate of transient fecal incontinence (OR , 0.07 ; 95% CI, 0.01 to 0.54; p<.01), rate of non-response (OR, 0.52 ;95% CI, 0.27 to 0.99 ; p=.04) and subsequent surgical treatment (OR, 0.18 ;95% CI, 0.07 to 0.44 ; p<.0001) was significantly higher with botulinum A injection compared with myectomy. There was no significant difference in continued use of laxatives or rectal enemas, overall complication rates, constipation and soiling between the 2 procedures. The authors concluded that myectomy was a more effective treatment option compared with intrasphincteric botulinum toxin A injection.

Anismus

Emile et al (2016) reported on the results of a systematic review that assessed 7 studies comprising 189 patients with a follow-up period greater than 6 months in each study.^55, Of the 7 studies, 2 were RCTs and the others were comparative and observational studies. Both RCTs were from the same author group and were conducted at a single site in Egypt, enrolling 15 and 24 patients, respectively.^56,57, Improvement was defined as patients returning to their normal habits. The first RCT used biofeedback and the other used surgery as the comparator. In the first RCT, 50% of individuals in the biofeedback group reported improvement initially at 1 month, but this decreased to 25% at 1year. The respective proportions of patients in the botulinum toxin arm were 70.8% and 33.3%. In the second RCT, surgery improved outcomes in all patients at 1 month, but that percentage dropped to 66.6% at 1 year. The respective proportions of patients in the botulinum toxin arm were 87% and 40%, respectively. While these results would suggest temporary improvement, methodologic limitations, including a small sample size and lack of blinded assessment, limit the interpretation of these RCTs.

Gastroparesis

Gonzalez et al (2024) conducted a French multi-center RCT (N=40 patients) comparing the clinical efficacy of gastric POEM versus pyloric botulinum toxin injection for refractory gastroparesis.^58, Patients were medically managed for >6 months and confirmed by gastric emptying scintigraphy (GES), with follow-up of 1 year. The primary end point was the 3-month clinical efficacy, defined as a >1-point decrease in the mean Gastroparesis Cardinal Symptom Index (GCSI) score. Secondary end points were: 1-year efficacy, GES evolution, adverse events, and quality of life. POEM showed a trend towards higher 3-month clinical success than botulinum toxin (65% vs. 40%, respectively; p=0.10), along with non-significantly higher 1-year clinical success (60% vs. 40%, respectively) on intention-to-treat analysis. The GCSI decreased in both groups at 3 months and 1 year. Only three minor adverse events occurred in the POEM group. The GES improvement rate was 72% in the POEM group versus 50% in the botulinum toxin group (non-significant).

A systematic review by Bai et al (2010) identified 15 studies on onabotulinumtoxinA to treat gastroparesis.^59, Two studies were RCTs; the remainder were case series or open-label observational studies. Reviewers stated that, while the nonrandomized studies generally found improvements in subjective symptoms and gastric emptying after onabotulinumtoxinA injections, the RCTs^60,61, did not report treatment benefit with onabotulinumtoxinA for treating gastroparesis. The 2 RCTs were inadequately powered; 1 included 23 patients and the other included 32 patients. Additional adequately powered RCTs are needed.

Other Populations

Depression

Brin et al (2020) performed a double-blind placebo-controlled multicenter RCT (N=255 patients) evaluating the efficacy and safety of onabotulinumtoxinA compared to placebo for major depressive disorder.[^62, This was a 24-week, two-dose cohort parallel-group study of 30 units (U) and 50 U botulinum toxin in outpatient female patients. The primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS); secondary endpoints were Clinical Global Impressions-Severity and 17-item Hamilton Depression Rating Scale (HDRS) at week 6. Following a single-treatment session, neither 30 U nor 50 U botulinum toxin injections demonstrated statistically significant superiority over placebo at the primary endpoint, but 30 U injection showed consistent numerical improvement in depressive symptoms compared to placebo up to week 15 with statistical separation from placebo for MADRS changes at weeks 3 and 9. Botulinum toxin was generally well-tolerated: the only treatment-emergent adverse events reported in ≥5% in either botulinum toxin group, and more than matching placebo were headache, upper respiratory infection, and eyelid ptosis. Limitations of this study included a relatively small sample size in each treatment group, lack of generalizability to male patients, and the study design, which effectively created two parallel studies with different treatment sites and different investigators.

Magid et al (2015) published a pooled analysis^63, of individual patient data from 3 previous RCTs (2012, 2014a, 2014b) ^64,65,66, evaluating injections of onabotulinumtoxinA in the glabellar region (forehead) for treating unipolar major depressive disorder as an adjunctive treatment. The response rate (defined as ≥50% improvement from baseline in the depression score) was higher in the onabotulinumtoxinA group compared with placebo (54.2% vs. 10.7%; OR , 11.1; 95% CI, 4.3 to 28.8). The respective remission rate (defined as a score ≤7 for the HDRS , ≤10 for the MADRS ) was 30.5% vs. 6.7% (OR , 7.3; 95% CI, 2.4 to 22.5). While the effect size of the treatment observed in the pooled analysis and individual RCTs is clinically meaningful and large, there are multiple limitations that preclude drawing meaningful conclusions about the net health benefit. Limitations in study design and conduct include the potential of unblinding due to changes in cosmetic appearance, small sample size, lack of power analysis,^65, short duration of follow-up in 2 out of 3 RCTs,^65,64, lack of clarity on allocation concealment,^64,65,66, and lack of an intention-to-treat analysis. More importantly, patients with a history of major depressive disorder, presenting with an acute depressive episode prior to enrollment in the trial, were evaluated. It is unclear if botulinum toxin A treatment is intended to be used as a short-term treatment of a depressive episode or as a maintenance treatment for depression.

Facial Wound Healing

Fu et al (2022) conducted a meta-analysis of 16 RCTs (N=510 patients) to evaluate the efficacy and safety of botulinum toxin A for preventing scarring.^67, The outcomes were primarily quantified by measures including the Vancouver Scar Scale (VSS), VAS, Stony Brook Scar Evaluation Scales (SBSES), modified SBSES (mSBSES), and scar width. Patients' satisfaction and adverse events were also reported. Results showed significant superiority of botulinum toxin compared to placebo in VSS (MD, -1.32; 95% CI, -2.00 to -0.65, p=0.0001), VAS (1.29; 95% CI, 1.05 to 1.52, p<0.00001), SBSES or mSBSES (-0.18; 95% CI, -0.27 to -0.10, p<0.0001), scar width (-0.18; 95% CI, -0.27 to -0.10, p<0.0001), and patients' satisfaction (risk ratio [RR], 1.25; 95% CI, 1.06 to 1.49, p=0.01). No significant difference of adverse events incidence was observed (p=0.36). Despite these results, the review has several study limitations including small sample size hindering detailed subgroup analyses, publication bias, and lack of a standardized treatment algorithm. Further large-scale and well-designed RCTs are needed to assess the long-term efficacy and safety of botulinum toxin for facial post-operative scar prevention and wound healing improvements.

Section Summary: Miscellaneous conditions

Botulinum toxin has been evaluated as a treatment option for multiple neurological, urological, pain, gastrointestinal disorders , and miscellaneous clinical indications. Generally botulinum toxin has been evaluated in clinical settings where patients have failed the standard of care or in whom standard of care interventions are contraindicated. However, in multiple indications with high prevalence rates (eg, benign prostatic hyperplasia, low back pain, depression, tinnitus), where multiple effective treatments supported by an adequate quality evidence base are available, studies using a placebo comparator that lack scientific rigor do not permit conclusions about the net health benefit of botulinum toxin. Future studies in these clinical indications should use appropriate comparators in adequately powered prospective studies with a standardized treatment dose and adequate follow-up.

Populations

The relevant population of interest is individuals with the miscellaneous conditions listed above who have failed standard of care or in whom standard of care interventions are contraindicated.

Interventions

The therapy being considered is commercially available botulinum toxin products.

Comparators

The therapies listed in Table 9 are currently being used to treat the miscellaneous conditions listed above.

Table 9. Current Treatment Options for Miscellaneous Indications

Outcomes

The general outcomes of interest are symptoms, functional outcomes, medication use, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Neurological indications

Tension and Cervicogenic Headache

Dhanasekara et al (2023) conducted a meta-analysis of 11 RCTs (n=390 botulinum toxin A, n=297 controls) published through May 2020 on the effectiveness of botulinum toxin for chronic tension-type headache prophylaxis.^17,Headache intensity (mean, -0.50; standard deviations: -0.94, −0.06), frequency (-2.83 days/month; -4.08, -1.58), daily headache duration (-0.96; -1.86, -0.07), and the frequency of acute pain medication use (-2.2 days/month; -3.48, -0.91]) were improved with botulinum toxin A. These improvements exceeded minimal clinically important differences for headache intensity, frequency, and acute pain medication use. A 79% (28%, 150%) greater response rate was observed for botulinum toxin vs controls in improving chronic tension-type headache. This review however had some notable limitations, including the low-quality evidence and a small number of patients across studies. There is a need to establish the effects of botulinum toxin A for this indication in adequately-powered high-quality RCTs. An earlier meta-analysis by Jackson et al (2012) of 8 placebo-controlled RCTs evaluating botulinum toxin A for chronic tension-type headaches did not find a statistically significant difference in change in the monthly number of headache days in the botulinum toxin group versus the placebo group (difference, -1.43; 95% CI, -3.13 to 0.27; p=.02).^18,

Essential Tremor

Marques et al (2024) conducted a multicenter, double-blind, RCT in adult patients with essential or isolated head tremor receiving botulinum toxin type A or placebo.^19,The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change scale at week 6 after the second injection (week 18 after randomization). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. One-hundred and seventeen (of 120) patients were randomly assigned to receive botulinum toxin (n=62) or placebo (n=55) and included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and two patients in the placebo group did not receive injections during week 12. The primary outcome was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% CI, 1.35 to 8.42; p=0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. The study had some limitations, such as loss to-follow-up of patients, potential unmasking of the trial-group assignments, and lack of control for external factors affecting tremor.

An earlier systematic review by Liao et al (2022) of 5 RCTs published before December 2021 concluded that botulinum toxin significantly reduced essential tremor severity, including hands tremor and head tremor within 6 weeks of treatment (standardized mean difference (SMD), -0.58, 95% CI, -0.28 to -0.88, p=0.002, I²=0%).^20, The main side effect was weakness, but it did not affect the grip strength of the patients. This review had limitations, such as small sample sizes, and use of diverse assessment methods across trials.

Tinnitus

Slengerik-Hansen et al (2016) reported the findings of a systematic review that included 22 studies, mainly case reports and case series, with a total of 51 patients treated with onabotulinumtoxinA for the treatment of tinnitus.^21, A small (N=30) cross-over prospective study by Stidham et al (2005) reported a statistically significant decrease in tinnitus handicap inventory scores between pretreatment and 4 months post botulinum toxin A injection.^22, Multiple other outcome studies showed no difference. Well-conducted RCTs with sufficiently large sample sizes are needed.

Tourette syndrome

A Cochrane review was conducted by Pandey et al (2018) to assess the efficacy and safety of botulinum toxin for treating motor and phonic tics in people with Tourette's syndrome, and to examine its impact on premonitory urge and sensory tics.^23, Only one RCT (N=20 patients) met the study selection criteria. The results of botulinum toxin injections on tic frequency, measured by video or self-report, and on premonitory urge, are unclear based on low-quality of evidence. The evidence for side effects of botulinum toxin was also very low. Nine individuals had muscle weakness following the injection, which could have led to unblinding of treatment group assignment. No data were available to evaluate whether botulinum injections led to immuno-resistance to botulinum toxin.

Urological Indications

Benign Prostatic Hyperplasia

Shim et al (2016) reported the results of a systematic review of 3 studies (N=522) on use of botulinum toxin A to treat benign prostatic hyperplasia.^24,Study duration ranged from 8 to 24 weeks. The pooled overall SMD in the mean change in International Prostate Symptom Score for the botulinum toxin group versus the placebo group was -1.02 (95% CI, -1.97, -0.07). The other outcomes (peak flow rate (Qmax), prostate volume, and post-voided residual volume) were not statistically different between the two groups. This review showed no overall differences in efficacy and procedure-related adverse events of botulinum toxin compared with placebo for this indication.

Interstitial Cystitis

The mechanism of the effect of intradetrusor botulinum toxin therapy for interstitial cystitis is likely the ability of botulinum toxin to modulate sensory neurotransmission. While botulinum toxin has been shown to alleviate symptoms in multiple studies,^25,26,27, mostly conducted outside of the U.S., there is a risk of urinary retention,^26, which may be particularly devastating for a patient with a painful bladder. Therefore, any patient considering this treatment must be willing and able to perform intermittent self-catheterization.

The American Urological Association published guidelines for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome in 2011 based on a systematic review that included published evidence from January 1, 1983 to July 22, 2009.^28, The guideline is updated periodically by conducting incremental systematic reviews to maintain guideline currency with newly published relevant literature. Most recently, an updated literature review in 2022 (search dates, June 2013 to January 2021) was published.^29, In addition, multiple systematic reviews have been published.^30,31,32,33, There is large variability in the botulinum toxin type, dosage, frequency and site of injection and comparators among the RCTs included in the systematic reviews. Further, several studies appear to include overlapping patient groups. These limitations make it challenging to interpret the results of these meta-analysis.

Detrusor Sphincteric Dyssynergia

Goel et al (2020) conducted a systematic review of 11 studies (N=353 patients) that evaluated the use of botulinum toxin A as the first-line treatment for detrusor external sphincter dyssynergia.^34, Botulinum toxin improved urinary retention, bladder and urethral pressure, and leakage rate in 60%-78% of patients after one month. Most patients needed another injection after 4-9 months. A previous Cochrane review by Utomo et al (2014), because of the limited availability of eligible trials (4 RCTs), was unable to provide robust evidence in favor of botulinum toxin injections for detrusor external sphincter dyssynergia.^35, Results were from small studies with a high risk of bias.

Pain Due to Multiple Etiologies

Lateral Epicondylitis

Although the mechanism of action for botulinum toxin in epicondylitis is not clearly understood, it is thought to be "proinflammatory". Botulinum toxin has been evaluated as a treatment for epicondylitis in a number of RCTs as summarized in a number of systematic reviews.^36,37,38,

In the systematic review and meta-analysis published by Lin et al (2018 ), the authors included 6 RCTs (N=321) that compared onabotulinumtoxinA or abobotulinumtoxinA with placebo or corticosteroid injections in patients with lateral epicondylitis.^36, Four of the 6 trials enrolled less than 30 participants per treatment arm and allocation concealment was unclear in 4 out of 6 trials. Results were reported as a standardized mean differences and a negative number implied a favorable effect of botulinum toxin on pain reduction. Compared with placebo, botulinum toxin injection significantly reduced pain at all 3 time points (2 to 4 weeks, 8 to 12 weeks, and at 16 weeks or more; standardized mean difference, -0.73 (95% CI, -1.29 to -0.17), -0.45 (95% CI, -0.74 to -0.15), and -0.54 (95% CI, -0.99 to -0.11), respectively). In contrast, botulinum toxin was significantly less effective than a corticosteroid 2 to 4 weeks following injection; standardized mean difference, 1.15 (95% CI, 0.57 to 1.34) with no difference at the 8 to 12 weeks or 16 weeks or more time points. While the systematic reviews generally report pain relief in individual trials of botulinum toxin versus the comparator, treatment with botulinum toxin was associated with temporary paresis of finger extension. Similar results were reported by Tavassoli (2022) in a systematic review and meta-analysis of 31 RCTs (N=1948 patients) comparing local injection therapies for lateral epicondylitis: the efficacy of corticosteroids was greater than botulinum toxin within 4 weeks of treatment, with no significant therapeutic effects observed between groups in any study outcomes after 12 weeks of follow-up.^39,

Myofascial Pain Syndrome

Several systematic reviews of RCTs have evaluated onabotulinumtoxinA and abobotulinumtoxinA for myofascial pain syndrome. The Cochrane systematic review by Soares et al (2014) identified 4 placebo-controlled, double-blind RCTs that included 233 participants with myofascial pain syndrome excluding neck and head muscles.^40, Due to heterogeneity among studies, reviewers did not pool analyses. The primary outcome was change in pain as assessed by validated instruments. Three of the 4 studies found that botulinum toxin did not significantly reduce pain intensity. Major limitations included a high-risk of bias due to study size in 3 of the 4 studies and selective reporting in 1 study.

Two other systematic reviews that focused on myofascial pain syndrome involving head and neck muscles reported similar findings. Leonardi et al (2024) conducted a systematic review of 10 RCTs (N=651 patients) to assess the efficacy and safety of botulinum toxin injections for upper back myofascial pain syndrome.^41, Botulinum toxin was compared with placebo, anesthetic plus dry needling, or anaesthetic injections. The methodological quality of the trials was moderate and no serious adverse events or major complications were reported. However, the results did not show that botulinum toxin had a clear advantage over the other treatment modalities. Most included studies had small sample sizes, low power, varied outcome measures, and inconsistent follow-up periods. A previous systematic review by Desai et al (2014) included 7 trials that evaluated the efficacy of botulinum toxin type A in cervico-thoracic myofascial pain syndrome.^42, The majority of studies found negative results and 6 identified trials had significant failings due to deficiencies in 1 or more major quality criteria.

Low Back Pain

Foster et al (2001) reported the findings of a RCT in which 31 consecutive patients with chronic low back pain of at least 6 months in duration were randomized to onabotulinumtoxinA or saline.^43,Botulinum toxin A was superior to placebo injection for pain relief and improved function at 3 and 8 weeks (50% pain relief at 3 weeks: 73.3% vs. 25%; at 8 weeks: 60% vs. 16%, respectively). However, in most patients, benefits were no longer present after 3 to 4 months. Findings from a more recent small RCT by Cogne et al (2017) (N=19 patients) did not find botulinum toxin injections to be effective in relieving low back pain.^44, Results from these two trials should be considered preliminary, and further data from randomized trials are needed to confirm findings in a larger number of patients over a longer duration and to evaluate benefits and harms of repeated injections before this treatment can be recommended.

Temporomandibular Joint Disorders

Saini et al (2024) conducted a systematic review and meta-analysis of 14 RCTs (N=395 patients) to assess the effectiveness of botulinum toxin in the treatment of temporomandibular joint disorders.^45, The overall risk of bias showed a low to moderate quality of evidence. Results from 6 studies were reported only narratively; four studies were used for meta-analysis on pain reduction, and five were used for meta-analysis on adverse events. The control used in the meta-analysis was placebo injections. Results of the meta-analysis (n=84, 4 RCTs) for pain reduction were statistically insignificant for the botulinum toxin group with mean differences (MD) at -1.71 (95% CI, −2.87 to −0.5) at one month, -1.53 (95% CI, −2.80 to −0.27) at three months, and -1.33 (95% CI, −2.74 to 0.77) at six months. Regarding safety, the placebo group showed a relative risk of 1.34 (95% CI, 0.48 to 6.78) and 1.17 (95% CI, 0.54 to 3.88) at 1 and 3 months respectively. Botulinum toxin was also not associated with better outcomes in terms of adverse events, maximum mouth opening, bruxism events, and maximum occlusal force. More high-quality RCTs are needed to assess the efficacy and safety of botulinum toxin for this indication.

Chen et al (2015) summarized the evidence assessing the efficacy of botulinum toxin A for treatment of temporomandibular joint disorders in a systematic review that included 5 RCTs.^46, Sample size in all trials was 30 or less except for 1 study. Three of the 5 studies were judged to be at high-risk of bias. All studies administered a single injection of onabotulinumtoxinA or abobotulinumtoxinA and followed patients up at least 1 month later. Four studies used a placebo (normal saline) control group and the fifth compared abobotulinumtoxinA to fascial manipulation. Data were not pooled due to heterogeneity among trials. In a qualitative review of the studies, 2 of the 5 trials found a significant short-term (1 to 2 months) benefit of onabotulinumtoxinA compared with control on pain reduction.

Post Hemorrhoidectomy Pain

Lie et al (2023) conducted a systematic review and meta-analysis of 5 clinical trials (N=260 patients) published through March 2022 assessing the utility of botulinum toxin injection for post-operative pain management after conventional hemorrhoidectomy.^47, The pooled analysis revealed that botulinum toxin injection after hemorrhoidectomy was associated with lower visual analog scale (VAS) at 24 hours post-operative [MD, -1.35 (95% CI -1.90 to -0.80), p<0.00001, I²=0%] and shorter time to return work [MD, -8.94 days (95% CI, -12.57 to -5.30), p<0.00001, I²=0%]. However, botulinum toxin injection did not differ significantly from placebo in terms of time to first defecation (p=0.22), fecal incontinence (p=0.91) and urinary retention incidence (p=0.18). Further RCTs with larger sample sizes are needed to confirm the results of this meta-analysis.

Pelvic and Genital Pain in Women

Parenti et al (2023) conducted a systematic review of 22 studies to assess the efficacy and safety of botulinum toxin use in the treatment of vaginal, vulvar and pelvic pain disorders.^48, Botulinum toxin injection was found to be effective in improving vulvar and vaginal dyspareunia, vaginismus, and chronic pelvic pain. No irreversible side effects were detected. Major side effects reported were transient urinary or fecal incontinence, constipation and rectal pain. A meta-analysis was not performed given the use of different definitions, methods, and timing of botulinum toxin injection across studies.

Neuropathic Pain

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain published a systematic review and meta-analysis in 2015 which included 6 RCTs that assessed the efficacy of a single administration of botulinum toxin A (50 to 200 units subcutaneously in the region of pain) in patients with peripheral neuropathic pain.^49, The number needed to treat for 50% pain relief was a primary measure. Within the pool of included studies, those with smaller sample sizes had a positive primary outcome (number needed to treat, 1.9; 95% CI, 1.5 to 2.4 for 4 studies) with a low placebo effect, but one large, unpublished study was negative. Overall, the published meta-analysis assigned weak GRADE recommendations for use in neuropathic pain mainly because of the weak quality of evidence.

Datta Gupta et al (2022) published the results of a meta-analysis of RCTs evaluating the use of botulinum toxin A in neuropathic pain.^50, Of the 17 RCTs that were included (N=703), 6 reported the proportion of patients with at least a 50% reduction in VAS between baseline and final time periods in the botulinum toxin A and placebo groups. The mean RR was 4.90 (95% CI, 2.00 to 6.13; I²=44.9%).

Trigeminal Neuralgia

Evidence for the efficacy and safety of botulinum toxin A for trigeminal neuralgia is limited to 4 RCTs (N=178 patients) summarized in at least two meta-analyses by Morra et al, 2016 and Hu et al, 2024).^51,52,While these results reported a significant reductions in mean pain scores and attack frequency in the botulinum toxin compared with the placebo group, there are concerns about small patient numbers, limited durability, and quality of evidence. More high-quality studies are needed to further confirm its efficacy for patients with refractory trigeminal neuralgia or those not responding to medical or surgical management,.

Prevention of Pain associated with Breast Reconstruction after Mastectomy

Li et al (2018) conducted a systematic review and meta-analysis of 10 studies (N=682 patients) published through March 2018 on the use of botulinum toxin A in breast surgery using implants deep within the pectoralis major muscle.^53, The studies considered for inclusion consisted of six prospective controlled trials (2 RCTs and 4 other trials), three retrospective cohort studies, and one case series. The study time ranged from 4 months to 13 years, and 15 patients (3%) received botulinum toxin injection more than two times. No complications associated with botulinum toxin were mentioned, almost all the studies reported efficacy for pain control. The included studies were primarily retrospective, nonrandomized trials.

Gastrointestinal Disorders

Internal Anal Sphincter Achalasia

Friedmacher and Puri (2012) reported the results of a meta-analysis that included 395 patients from 2 prospective and 14 retrospective case series that compared internal anal sphincter myectomy (n=229) with botulinum A injection (n=166).^54, Regular bowel movements (odds ratio [OR] , 0.53; 95% CI, 0.29 to 0.99 ; p=.04), short-term improvements (OR , 0.56; 95% CI, 0.32 to 0.97 ; p=.04) and long-term improvement (OR , 0.25; 95% CI, 0.15 to 0.41 ; p<.0001) favored myectomy compared with botulinum toxin A injection. Further, the rate of transient fecal incontinence (OR , 0.07 ; 95% CI, 0.01 to 0.54; p<.01), rate of non-response (OR, 0.52 ;95% CI, 0.27 to 0.99 ; p=.04) and subsequent surgical treatment (OR, 0.18 ;95% CI, 0.07 to 0.44 ; p<.0001) was significantly higher with botulinum A injection compared with myectomy. There was no significant difference in continued use of laxatives or rectal enemas, overall complication rates, constipation and soiling between the 2 procedures. The authors concluded that myectomy was a more effective treatment option compared with intrasphincteric botulinum toxin A injection.

Anismus

Emile et al (2016) reported on the results of a systematic review that assessed 7 studies comprising 189 patients with a follow-up period greater than 6 months in each study.^55, Of the 7 studies, 2 were RCTs and the others were comparative and observational studies. Both RCTs were from the same author group and were conducted at a single site in Egypt, enrolling 15 and 24 patients, respectively.^56,57, Improvement was defined as patients returning to their normal habits. The first RCT used biofeedback and the other used surgery as the comparator. In the first RCT, 50% of individuals in the biofeedback group reported improvement initially at 1 month, but this decreased to 25% at 1year. The respective proportions of patients in the botulinum toxin arm were 70.8% and 33.3%. In the second RCT, surgery improved outcomes in all patients at 1 month, but that percentage dropped to 66.6% at 1 year. The respective proportions of patients in the botulinum toxin arm were 87% and 40%, respectively. While these results would suggest temporary improvement, methodologic limitations, including a small sample size and lack of blinded assessment, limit the interpretation of these RCTs.

Gastroparesis

Gonzalez et al (2024) conducted a French multi-center RCT (N=40 patients) comparing the clinical efficacy of gastric POEM versus pyloric botulinum toxin injection for refractory gastroparesis.^58, Patients were medically managed for >6 months and confirmed by gastric emptying scintigraphy (GES), with follow-up of 1 year. The primary end point was the 3-month clinical efficacy, defined as a >1-point decrease in the mean Gastroparesis Cardinal Symptom Index (GCSI) score. Secondary end points were: 1-year efficacy, GES evolution, adverse events, and quality of life. POEM showed a trend towards higher 3-month clinical success than botulinum toxin (65% vs. 40%, respectively; p=0.10), along with non-significantly higher 1-year clinical success (60% vs. 40%, respectively) on intention-to-treat analysis. The GCSI decreased in both groups at 3 months and 1 year. Only three minor adverse events occurred in the POEM group. The GES improvement rate was 72% in the POEM group versus 50% in the botulinum toxin group (non-significant).

A systematic review by Bai et al (2010) identified 15 studies on onabotulinumtoxinA to treat gastroparesis.^59, Two studies were RCTs; the remainder were case series or open-label observational studies. Reviewers stated that, while the nonrandomized studies generally found improvements in subjective symptoms and gastric emptying after onabotulinumtoxinA injections, the RCTs^60,61, did not report treatment benefit with onabotulinumtoxinA for treating gastroparesis. The 2 RCTs were inadequately powered; 1 included 23 patients and the other included 32 patients. Additional adequately powered RCTs are needed.

Other Populations

Depression

Brin et al (2020) performed a double-blind placebo-controlled multicenter RCT (N=255 patients) evaluating the efficacy and safety of onabotulinumtoxinA compared to placebo for major depressive disorder.[^62, This was a 24-week, two-dose cohort parallel-group study of 30 units (U) and 50 U botulinum toxin in outpatient female patients. The primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS); secondary endpoints were Clinical Global Impressions-Severity and 17-item Hamilton Depression Rating Scale (HDRS) at week 6. Following a single-treatment session, neither 30 U nor 50 U botulinum toxin injections demonstrated statistically significant superiority over placebo at the primary endpoint, but 30 U injection showed consistent numerical improvement in depressive symptoms compared to placebo up to week 15 with statistical separation from placebo for MADRS changes at weeks 3 and 9. Botulinum toxin was generally well-tolerated: the only treatment-emergent adverse events reported in ≥5% in either botulinum toxin group, and more than matching placebo were headache, upper respiratory infection, and eyelid ptosis. Limitations of this study included a relatively small sample size in each treatment group, lack of generalizability to male patients, and the study design, which effectively created two parallel studies with different treatment sites and different investigators.

Magid et al (2015) published a pooled analysis^63, of individual patient data from 3 previous RCTs (2012, 2014a, 2014b) ^64,65,66, evaluating injections of onabotulinumtoxinA in the glabellar region (forehead) for treating unipolar major depressive disorder as an adjunctive treatment. The response rate (defined as ≥50% improvement from baseline in the depression score) was higher in the onabotulinumtoxinA group compared with placebo (54.2% vs. 10.7%; OR , 11.1; 95% CI, 4.3 to 28.8). The respective remission rate (defined as a score ≤7 for the HDRS , ≤10 for the MADRS ) was 30.5% vs. 6.7% (OR , 7.3; 95% CI, 2.4 to 22.5). While the effect size of the treatment observed in the pooled analysis and individual RCTs is clinically meaningful and large, there are multiple limitations that preclude drawing meaningful conclusions about the net health benefit. Limitations in study design and conduct include the potential of unblinding due to changes in cosmetic appearance, small sample size, lack of power analysis,^65, short duration of follow-up in 2 out of 3 RCTs,^65,64, lack of clarity on allocation concealment,^64,65,66, and lack of an intention-to-treat analysis. More importantly, patients with a history of major depressive disorder, presenting with an acute depressive episode prior to enrollment in the trial, were evaluated. It is unclear if botulinum toxin A treatment is intended to be used as a short-term treatment of a depressive episode or as a maintenance treatment for depression.

Facial Wound Healing

Fu et al (2022) conducted a meta-analysis of 16 RCTs (N=510 patients) to evaluate the efficacy and safety of botulinum toxin A for preventing scarring.^67, The outcomes were primarily quantified by measures including the Vancouver Scar Scale (VSS), VAS, Stony Brook Scar Evaluation Scales (SBSES), modified SBSES (mSBSES), and scar width. Patients' satisfaction and adverse events were also reported. Results showed significant superiority of botulinum toxin compared to placebo in VSS (MD, -1.32; 95% CI, -2.00 to -0.65, p=0.0001), VAS (1.29; 95% CI, 1.05 to 1.52, p<0.00001), SBSES or mSBSES (-0.18; 95% CI, -0.27 to -0.10, p<0.0001), scar width (-0.18; 95% CI, -0.27 to -0.10, p<0.0001), and patients' satisfaction (risk ratio [RR], 1.25; 95% CI, 1.06 to 1.49, p=0.01). No significant difference of adverse events incidence was observed (p=0.36). Despite these results, the review has several study limitations including small sample size hindering detailed subgroup analyses, publication bias, and lack of a standardized treatment algorithm. Further large-scale and well-designed RCTs are needed to assess the long-term efficacy and safety of botulinum toxin for facial post-operative scar prevention and wound healing improvements.

Section Summary: Miscellaneous conditions

Botulinum toxin has been evaluated as a treatment option for multiple neurological, urological, pain, gastrointestinal disorders , and miscellaneous clinical indications. Generally botulinum toxin has been evaluated in clinical settings where patients have failed the standard of care or in whom standard of care interventions are contraindicated. However, in multiple indications with high prevalence rates (eg, benign prostatic hyperplasia, low back pain, depression, tinnitus), where multiple effective treatments supported by an adequate quality evidence base are available, studies using a placebo comparator that lack scientific rigor do not permit conclusions about the net health benefit of botulinum toxin. Future studies in these clinical indications should use appropriate comparators in adequately powered prospective studies with a standardized treatment dose and adequate follow-up.

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.

SUPPLENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

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.

2011 Input

Input was received only on botulinum toxin for migraine from 4 academic medical centers and 4 physician specialty societies (7 reviews) while this policy was under review in 2011. Most reviewers agreed with the investigational indication for episodic migraine. Several reviewers indicated that botulinum toxin was medically necessary in patients with disabling and/or frequent episodic migraines refractory to other treatments. Input was more divergent on the use of botulinum toxin for chronic migraine; some agreed that use was investigational and others did not. Reviewers who considered botulinum toxin medically necessary for patients with chronic migraines generally thought its use should be limited to patients unresponsive to other treatments.

2008 Input

Input was received on a number of indications from 3 academic medical centers and 5 physician specialty societies while this policy was under review in 2008. Nearly all reviewers 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.

PRACTICE GUIDELINES AND POSITION STATEMENT

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society for Gastrointestinal Endoscopy

In 2020, the American Society for Gastrointestinal Endoscopy (ASGE) guideline on the management of achalasia recommended against the use of botulinum toxin injection as definitive therapy for achalasia patients. Botulinum toxin injection may be reserved for patients who are not candidates for other definitive therapies (Grade of Recommendation: moderate quality evidence).^68,

American Urological Association

In 2019, the American Urological Association guideline on non-neurogenic overactive bladder stated, “clinicians may offer intradetrusor onabotulinumtoxinA (100U) as a third-line treatment in the carefully-selected and thoroughly-counseled patient who has been refractory to first- and second-line overactive bladder treatments. The patient must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary. Standard (Evidence Strength Grade B).”^69,

In 2022, the American Urological Association guideline on diagnosis and treatment of interstitial cystitis/bladder pain syndrome stated, “intradetrusor botulinum toxin A may be administered if other treatments have not provided adequate symptom control and quality of life or if the clinician and patient agree that symptoms require this approach. Patients must be willing to accept the possibility that post-treatment intermittent self-catheterization may be necessary. Option (Evidence Strength C)”.^29, Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; options may be supported by Grade A (high certainty), B (moderate certainty), or C (low certainty) evidence.

American Academy of Neurology

The American Academy of Neurology updated their practice guideline on use of botulinum toxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and chronic headache in 2016 (reaffirmed April 30, 2022).^70, Recommendations are summarized in Table 10.

Table 10. Recommendations for Use of Botulinum Toxin to Treat Various Disorders

LOR: level of recommendation.

In 2011 (reaffirmed April 30, 2022), the American Academy of Neurology updated its evidence-based guidelines that conclude botulinum toxin A is “possibly effective (Level C)” for treatment of essential tremor.^71,

American Society of Colon and Rectal Surgeons

The revision of a practice parameter on the treatment of anal fissures by the American Society of Colon and Rectal Surgeons (ASCRS, 2023) states, “Botulinum toxin has similar results compared with topical therapies as first-line therapy for chronic anal fissures, and modest improvement in healing rates as second-line therapy following treatment with topical therapies. Grade of Recommendation: Strong recommendation based on moderate-quality evidence, 1B.” ^72,According to the 2023 survey conducted by the ASCRS, dose above 50 U of botulinum toxin appeared to correlate with higher success rate and healing rate.^73,

American Pediatric Surgical Association

In 2017, the American Pediatric Surgical Association published guidelines based on group discussions, literature review, and expert consensus for the management of postoperative obstructive symptoms in children with Hirschsprung disease. These guidelines recommend that if there is no mechanical obstruction and rectal biopsy is normal, botulinum toxin injection into the internal anal sphincter should be tried. If a patient shows significant improvement, the patient can receive botulinum toxin injection every 3 to 6 months as many times as necessary depending on symptoms. In most cases, the symptoms will gradually improve with age.^74,

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for botulinum toxin have been identified.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials for Off Label Use of Botulinum Toxins

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

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