Achalasia
Society Guidelines
We found 3 guidelines issued by medical societies and 1 position statement: the American Society of Gastroenterology (ASGE)’s Guideline on the Management of Achalasia 202013, the International Society for Diseases of the Esophagus (ISDE)’s 2018 Achalasia Guidelines2, the American College of Gastroenterology (ACG) Clinical Guidelines for the Diagnosis and Management of Achalasia, 20208, and the European Society of Gastrointestinal Endoscopy (ESGE) Guideline 20201 support BTI into the distal esophageal sphincter as an effective short-term treatment for achalasia, in medically high-risk patients who are not candidates for other invasive therapies.
The ASGE guidelines13 were based on a systematic review and meta-analysis by Khashab et al. (2020). The review included 22 uncontrolled studies (published from inception to October 2017) in 730 achalasia patients who were treated with BTI. Clinical success, defined by an Eckardt score of 3, was achieved in 77% (95% confidence interval [CI], 72%-81%; I 2 value 35; P= 0.04) over a follow-up period ranging from 1 to 6 months. There was a statistically significant decrease in average LES pressure from 38.23 mm Hg (range, 34.40-42.06) before the procedure to 23.30 mm Hg (range, 20.79-25.81) after BTI (P < 0.01). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), for pneumatic dilation (PD) and BTI respectively (Risk ratio, 1.88; 95% CI, 1.35-2.61; P= 0.0002). Serious adverse events were uncommon, with transient chest pain reported after 4.4% of injections. The authors recommended against the use of BTI as definitive therapy for achalasia patients (AMSTAR moderate quality of evidence, or moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different).
The ESGE1 performed a systematic review (discussed below under the systematic review by Weusten et al. (2020)) and Delphi consensus and aligned with previous recommendations. They additionally made specific dosing recommendations of 100 units onabotulinumtoxinA or equivalent of the toxin diluted in preservative-free saline that is injected in aliquots of 0.5–1mL using an injection needle in forward view just above the squamocolumnar junction in at least 4 quadrants. This was a strong recommendation, high quality of evidence, with a level of agreement of 100%. A multicenter randomized trial with injections of 50, 100, and 200 Units of BTI resulted in similar short-term results in LES pressure 1 month after injection11 and in an SR, a dose of 100 units of botulinum toxin was used most frequently77, supporting this dosing recommendation.
The 2018 ISDE achalasia guidelines were based on a systematic review by Zaninotto et al. (2018)2 (discussed below). The strength of recommendation was graded according to Grading of Recommendations Assessment (GRADE). These guidelines recommend BTI for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation (GRADE – moderate).
The ACG (2020)8 performed a literature review and generated consensus-based recommendations using a modified Delphi process. They recommend BTI as first-line therapy for patients with achalasia that are unfit for definitive therapies compared with other less-effective pharmacological therapies.
Systematic Reviews
Recent systematic reviews and meta-analyses comparing the use of BTI with alternative treatments have found that, while BTI may provide short-term symptom relief and are associated with low complication rates, its results are inferior in both medium- and long-term compared to all other non-pharmacological alternatives.
Gong et al. (2023)12 conducted a systematic review comparing the efficacy of 9 interventional treatments (BTI, PD, BTI + PD, Laparoscopic Heller’s myotomy (LHM) + Toupet, LHM + anterior wrap (D), anterior POEM (APOEM), traditional posterior POEM, double-scope POEM, and waterjet assisted JPOEM) for achalasia. The authors included 27 RCTs published from 1990 to December 2020 with 2,278 achalasia patients (BTI [n = 158], BTI + PD [n =72]) in a meta-analysis. Primary outcome was comparisons of the induction of clinical remission after 1-year follow-up. Results indicated that APOEM was the most effective (rank 1, 50%) strategy to significantly relieve achalasia symptoms, while BTI ranked last (rank 9, 99%), although BTI had the highest safety profile. However, the recommendations provided by the authors were not supported by the reported data.
Shiu et al. (2022)78 conducted a systematic review and meta-analysis of RCTs published between January 2000 and June 2021 to compare the efficacy of 8 treatments for achalasia. Twenty-four studies involved a total of 1,987 participants for analysis. LHM + Dor (OR 2.29, 95% CI: 1.50–3.49) all showed significantly greater efficacy and were at least twice as effective as the reference group with only BTI (OR 0.33, 95% CI: 0.17–0.63) showing significantly lower efficacy. The median interquartile ranges (IQRs) for short-term clinical successful rates (%) of Anterior POEM, Posterior POEM, LHM + Toupet, BTI + PD, LHM + Dor, PD, and BTI were 91.1 (IQR, 84.4–95.4), 92.1 (IQR, 87.0–93.0), 93.9 (IQR, 90.2–97.0), 85.4 (IQR, 84.4–86.5), 86.7 (IQR, 79.7–88.7), 66.35 (IQR, 56.0–77.7), and 53.3 (IQR, 37.5–60.0), respectively.
Weusten et al. (2020)1 conducted a systematic review of the technical aspects of the endoscopic management of gastrointestinal motility disorders (including achalasia). Evidence levels and recommendation strengths were assessed using the GRADE system. The total number of studies included were unclear as was the methods for analysis and combination of study results. The authors concluded that BTI can be considered an effective and safe therapy for short-term symptom relief in esophageal achalasia (GRADE recommendation= Moderate). However, the authors’ recommendations for policy and practice were not supported by the reported data.
Andolfi et al. (2019)10 conducted a systematic review of articles published between 2008 and 2018 comparing the effect of different invasive treatments on symptomatic outcomes across achalasia subtypes. Their search strategy included PubMed® and MEDLINE only. They included 20 studies (1,575 participants) reporting clinical outcomes after BTI, PD, LHM and POEM based on manometric subtypes. The authors performed a meta-analysis. Three studies reported data on botulinum toxin (58 patients). BTI was the treatment modality with the worse outcomes (18% for type I, 59% for type II and 21% for type III). About half of patients needed further injections at intervals of 6–24 months. However, the authors did not assess the likelihood of publication bias.
Zaninotto et al. (2018)2 conducted a systematic review with interdisciplinary and international authors to establish best evidence-based principles to the diagnosis and management of achalasia. The authors included 466 articles in their analysis. The authors found that BTI has a high safety profile with mild adverse events (heartburn or chest pain) observed in less than 10% of patients treated. At 2-year follow up, only 34% of BTI patients versus 87.5% of the Heller patients were asymptomatic. Similarly, 4 randomized trials and a Cochrane meta-analysis comparing BTI with PD consistently reported a higher cumulative rate of remission rate at 1 year after treatment after PD. The authors recommended against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for surgery (LHM) or PD GRADE: moderate. Repeated BTI may be successful, if there are contraindications to invasive, but more durable treatments. The authors also found that BTI efficacy may decrease over time. However, it should be noted that the authors did not assess the likelihood of publication bias. Further, the authors’ recommendations for policy and practice were not supported by the reported data.
Leyden et al. (2014)14 conducted a Cochrane systematic review and meta-analysis comparing the efficacy and safety of 2 endoscopic treatments, PD and BTI. They included 7 randomized controlled trials (RCT) with 178 patients published from 1946 through March 2014. The authors examined symptom remission rates within the first month, at 6 months, and at 12 months. Based on the AMSTAR-2 critical appraisal tool, the overall confidence in the result of this meta-analysis was deemed to be “high.” The overall methodological quality of the studies was good although the risk of bias was high. Only 1 of the included studies was double blinded. There was no significant difference between PD and BTI arms in clinical success rates or LES pressures within 4 weeks of the initial intervention (risk ratio of remission, 1.11; 95% CI, 0.97-1.27) with a weighted mean difference for PD of –0.77 (95% CI, –2.44 to 0.91; P = 0.37). Clinical success rates beyond 4 weeks were available for 3 studies at 6 months and 4 studies at 12 months. At 6 months, clinical success was achieved in 80.7% of patients (46/57) who underwent PD as compared with 51.8% of patients (29/56) who underwent BTI (risk ratio, 1.57; 95% CI, 1.19-2.08; P = 0.0015). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), respectively (risk ratio, 1.88; 95% CI, 1.35-2.61; P = 0.0002). There were no adverse events with BTI (total of 151 injection procedures), whereas perforation occurred in 3 cases (total of 188 PD procedures) in the PD arm. These data demonstrate that PD is a more effective long-term (>6 months) endoscopic treatment option compared with BTI for patients with achalasia. However, the authors’ policy and practice recommendations were not supported by the reported data.
Meta-Analyses
N/A
Randomized Controlled Trials
N/A
Anal Fissure
Society Guidelines
We found 1 medical society guideline issued in 2022 by the American Society of Colon and Rectal Surgeons (ASCRS).79 They state that 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 failed treatment with topical therapies.79 Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. The guideline was based on a systematic review (described below).79
Systematic Reviews
ASCRS’ Systematic Review
ASCRS’ systematic review (n = 1577) included 86 studies treated with botulinum toxin for chronic anal fissures. The review found no clear optimal dosing or injection protocol, with doses ranging from 20 to 100 units and injection sites varying in the literature. Pooled analysis showed botulinum toxin has a 33-96% fissure healing rate, with an overall 5% risk of transient fecal incontinence and no evidence of dose-dependent efficacy or complication rates.79 Compared to topical nitroglycerin or calcium channel blockers, botulinum toxin showed comparable efficacy of 67-71% healing but better side effect profile. As first-line therapy, prospective studies found botulinum toxin heals 67% of fissures, similar to 71% with topicals. Second-line after failed topical therapy, small studies show botulinum improves symptoms and healing without needing sphincterotomy surgery. Limitations include significant heterogeneity amongst studies in botulinum toxin protocol and comparisons.79
Other Systematic Reviews
A large systematic analysis by Vitoopinyoparb et al. (2022) provides moderate quality evidence that low dose botulinum toxin injected out of the fissure (OOF) offers the best short-term healing, while low dose both sides of the fissure (BSF) optimizes longer term outcomes.80 It reviewed 27 RCTs (n = 1,880 patients) to determine the optimal botulinum toxin dose and injection site for chronic anal fissures. Treatments were categorized as low dose (≤20 units) or high dose (>20 units) botulinum toxin injected either OOF, on BSF, or at both sites (BS). For short-term healing (n = 1,720), high dose OOF had significantly better outcomes than high dose BSF, with similar efficacy to low dose OOF but higher incontinence risk (n = 1,458). Low dose BSF with added topical agents demonstrated significantly improved healing over low dose BSF alone.80 For recurrence (n = 1,622), OOF sites had higher rates than BSF sites regardless of dosage.
Boland et al. (2020) found sphincterotomy is most effective for fissure healing, while medical therapies have higher risks of recurrence and variable side effect profiles during its systematic review of 9 RCTs (n = 775) comparing treatments for chronic anal fissure.19 Lateral internal sphincterotomy (LIS) had the highest healing rate at 8 weeks at 95.1% (n = 349) but a 10% overall incontinence risk and 2.3% permanent incontinence rate. Botulinum toxin (n = 132) had a 66.7% healing rate at 8 weeks and a 41.7% recurrence rate but a 14.4% temporary incontinence rate. Topical nitrates (n = 206) had 63.6% healing and 11.2% recurrence but fewer side effects. Permanent incontinence is a concern with sphincterotomy.19 Additional data is still needed comparing sphincter-preserving procedures.19
Sahebally et al. (2018) systematically reviewed 6 RCTs (n = 393) comparing BTI to topical nitrates (TN) for chronic anal fissures (n = 194 botox, n = 199 nitrates).81 There was no significant difference in fissure healing or recurrence rates, but BTI had significantly fewer side effects overall (6.4% vs 33.1%) and less headache specifically (4.8% vs 27.9%) than TN. However, BTI was associated with higher transient anal incontinence (10.4% vs 4.4%, P = 0.06). In summary, while equally effective for healing chronic anal fissures, BTI appears to have a better side effect profile than TN, albeit with a non-significantly higher risk of temporary incontinence. Further adequately powered, high quality head-to-head trials with uniform methodology are still needed to definitively compare these 2 modalities.81
Lin et al. (2016) performed a systematic review and meta-analysis of 18 studies (n = 1,158) with (n = 661) using botox to determine the optimal botulinum toxin dose and injection site for chronic anal fissures.82 Meta-regression analysis found that higher doses were associated with slightly lower healing rates (0.34% reduction per unit increase, P = 0.048) and higher risks of incontinence (1.02 times higher per unit, P = 0.048) and recurrence (1.037 times higher per unit, P = 0.0002).82 There was significant heterogeneity amongst studies regarding injection locations, preventing definitive conclusions, but injecting laterally into the internal anal sphincter was most common. In summary, this well-conducted analysis provides evidence that lower botulinum toxin doses (10-20 units) have similar or better efficacy than higher doses for fissure healing, with less side effects, supporting use of the lowest effective dose.82
Meta-Analyses
Bobkiewicz et al. (2016) performed a meta-analysis of 34 studies involving 1,577 patients to determine if there is a dose-dependent efficacy of BTIs for chronic anal fissures.83 This large meta-analysis found no evidence that higher botox doses improve fissure healing, but similarly no increased side effects, providing support for using the minimum effective dose in treatment regimens. Across a wide 5-150-unit dose range, they found no correlation between dose and healing rates (33-96% range, P = 0.0708), complication rates, or incontinence risks (occurring in 5.01%). There was also no difference between injection sites or number of injections per session. The analysis did reveal short follow-up times, generally under 6 months, which could underestimate recurrence rates. Longer-term data is still needed.83
Randomized Controlled Trials (RCTs)
Pilkington et al. (2018) performed a randomized trial that demonstrated equivalent efficacy but some long-term advantages of unilateral over bilateral BTIs for chronic anal fissures.84 Their study comparing bilateral (n = 49) to unilateral (n = 51) injection of 100 units botulinum toxin for chronic anal fissures. There was no difference in injection pain between groups.84 Healing rates were similar at 53.5% (bilateral) and 52.2% (unilateral). While bilateral injection provided better pain relief initially, at 1-year unilateral injection resulted in significantly greater fissure pain improvement (-39.1 mm on VAS vs -22.3 mm) and higher quality of life, with no increased incontinence risk.84
Gandomkar et al. (2015) performed a randomized trial that provides evidence that combined botulinum toxin and diltiazem cream has similar efficacy to sphincterotomy surgery for short duration chronic anal fissures, with fewer risks. It compared combined botulinum toxin A injection and topical diltiazem (n = 49) to partial lateral internal sphincterotomy (PLIS) (n = 50) for chronic anal fissure.85 After 1 year, PLIS had a significantly higher healing rate than the combined treatment (94% vs 65%, P < 0.001).85 However, PLIS was also associated with higher rates of incontinence (16% vs 4%, P = 0.04) and other complications. For patients with shorter duration fissures (≤12 months), there was no difference in 1-year healing between groups (100% in both). PLIS remains more effective for longer duration lesions.85
Berkel et al. (2014) performed a randomized trial comparing botulinum toxin A (n = 27) to topical isosorbide dinitrate (ISDN) (n = 33) for primary treatment of chronic anal fissure.86 The study provides evidence that botulinum toxin A injection is more effective and better tolerated than topical ISDN as initial therapy for chronic anal fissures. After a median 9 weeks, botulinum toxin A had a significantly higher healing rate than ISDN (67% vs 33%, P = 0.01).86 While pain improvement was similar between groups, botulinum toxin A was associated with significantly fewer side effects. However, fissure recurrence at 1 year was still substantial in both groups (28% botulinum toxin A, 50% ISDN, P = 0.29).86
Blepharospasm
Society Guidelines
The American Academy of Neurology (AAN) 5 recommends onabotulinumtoxinA (OnaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) as level B and abobotulinumtoxinA (AboBoNT-A) as level C treatment options. Overall, botulinum toxin A (BtA) should be considered the first line of treatment.
Systematic Reviews
Duarte et al. (2020)87 performed a systematic review on BtA therapy for patients with blepharospasm. Three RCTs were included with a total of 313 patients. Two of the studies included excluded patients with worse responses to BtA. The trials included and evaluated a single treatment session which showed a moderate to large improvement in blepharospasm severity and a reduction of 0.93 on the JRS at 4-6 weeks. A moderate to large improvement was also found in blepharospasm-specific disability and blepharospasm-specific involuntary movements at 4-6 weeks. The mean duration of effects was about 10.6 weeks. There was an increased risk of vision complaints and eyelid ptosis seen throughout the entire study group compared to the placebo.
Meta-Analyses
N/A
Randomized Controlled Trials (RCTs)
N/A
Other Studies
Calace et al. (2003)88 found that patients who had undergone treatments for over 10 years did not vary in the average duration of relief or response to treatment.
Engstrom et al. (1987)89 found that the average response duration for repeat BTIs increased for the first 3 treatment sessions and the average response time found in this study was 6-12 weeks. The longer response time was reversed starting at the fourth session.
Shorr et al. (1985)90 found that patients had an average of 6.1 weeks of relief after the initial injection of BtA and 8.44 weeks of relief after the second injection.
Scott et al. (1985)91 found that the middle of the upper eyelid should be avoided during injection as this showed an increased risk of ptosis. The superior rectus muscle should also be avoided as this could cause hypotropia. This study also found that patients who had injections of BtA into the orbicularis oculi experienced some relief from their symptoms. It was also found that the orbicularis oculi muscle remained weakened after each subsequent injection, but spasms still reoccurred. This effect was prolonged in patients who had been operated on previously.91
Cervical Dystonia
Society Guidelines
We found 3 society guidelines founded on systematic review outcomes. The AAN issued a guideline in 2016 for treating CD, updating their 2008 guidelines.92 They recommend abobotulinumtoxinA (aboBoNT-A) and rimabotulinumtoxinB (rimaBoNT-B) as highly effective (Level A) treatments, with onabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) as also effective options (Level B).92
The European Federation of the Neurological Societies (EFNS) in 2011 advised using BtA, or botulinum toxin B (BtB) in case of resistance to type A, for CD.93 The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) in 2021 declared botulinum toxin as a safe and effective treatment for CD in a position statement.94
Both AAN and EFNS guidelines are based on systematic reviews performed on their behalf by researchers (discussed below).92,93 The AAO-HNS’s stance was supported by a single systematic review published in 2013 found as part of a literature review.94,95
Systematic Reviews
AAN’s Systematic Review
AAN’s systematic review focused on randomized, masked trials (RMTs) and the medical society found 23 that focused on CD.92 Its review found that various botulinum toxin formulations have shown differing levels of efficacy and safety. AboBoNT-A and rimaBoNT-B are established as effective, based on 2 and 3 Class I studies respectively. OnaBoNT-A and incoBoNT-A are probably effective, supported by Class I and II studies. A study on incoBoNT-A showed a significant improvement in the TWSTRS scores at 4 weeks (placebo: 22.2, 120 U: 29.9, 240 U: -10.9, p < 0.001) with dysphagia in 23.4% (240 U) and 10.7% (120 U) of cases. OnaBoNT-A improved the CD Severity Scale by 21.81 points and the Global Assessment Scale by 61.7% compared to 20.31 points and 41.6% for placebo (p = 0.012 and p = 0.022). Comparative studies found no significant efficacy difference between onaBoNT-A, aboBoNT-A, and rimaBoNT-B. Long-term studies show onaBoNT-A’s benefits persisting for up to 2 years.
EFNS’s Systematic Review
Method specifics for EFNS’s guidelines were less specified than AAN’s. Researchers noted that a total of 299 papers were found relevant to dystonia treatments broadly, with 191 being primary diagnostic studies and 108 efficacy studies.96 But it was unclear how many of the studies reviewed were specific to examining the use of botulinum toxins as a treatment for CD. EFNS’ researchers broadly noted that studies reviewed specific to Botox and CD included systematic reviews, long-term observational studies, RCTs (Class I and II), and comparative efficacy studies (Class III and IV).96
Other Systematic Reviews
Rodrigues et al. (2020)97 performed a systematic review on BtA therapy for CD. The analysis included 9 RCTs (n = 1,144) comparing a single BtA treatment to placebo. Seven studies excluded patients with poorer responses to BtA treatment, therefore, the population had a higher probability of benefiting from BtA. BtA doses ranged from 150-1000 units depending on formulation. The RCTs evaluated patients for a single treatment session and a moderate to large improvement from the patient’s baseline clinical status was found. At week 4, BtA resulted in a mean reduction of 8.09 points in the TWSTRS (95% CI 6.22 to 9.96; I2 = 0%), which was an 18.4% improvement compared to placebo. The mean difference in TWSTRS pain sub-score was 2.11 (95% CI 1.38 to 2.83; I2 = 0%). Patients and clinicians both reported improvement of the patients’ subjective clinical status. Three of the studies included in the systematic review examined the impact of BtA on a patient’s quality of life and it was shown that there was improvement when treated with BtA. A single treatment session of BtA has been found to be effective and well tolerated in the treatment of moderately impaired adults with CD. There has been moderate to large improvement in severity, disability, and pain at 4 weeks but the mean duration of effect for BtA has been inconclusive.97 Adverse events are common but are not commonly associated with discontinuing treatment. It is uncertain whether the clinical effectiveness of botulinum toxin decreases with repeated treatments.97 The systematic review could not evaluate long-term duration as all trials included but 2 evaluated a single treatment session. Overall, with moderate certainty, BtA increased the risk of any adverse event (RR 1.23; 95% CI 1.05 to 1.43; I2 = 28%). The most common were neck weakness (14%; RR 3.40), dysphagia (11%; RR 3.19), and diffuse weakness/tiredness (8%; RR 1.80). Similarly, with moderate certainty, BtA resulted in clinically relevant reductions in dystonia impairment and pain compared to placebo. With high certainty, it was well tolerated.97
Marques et al. (2016)98 performed a systematic review evaluating 4 RCTs (n = 441 patients) that compared botulinum toxin type B (BtB) to placebo for CD. These RCTs evaluated patients during a single treatment session. BtB doses ranged from 2,500-10,000 units. At week 4, BtB improved clinical status by 14.7% (95% CI 9.8–19.5%) and reduced TWSTRS total score by 6.8 points (95% CI 4.54-9.01) versus placebo. The mean difference in TWSTRS pain score was 2.20 (95% CI 1.25-3.15). Patients as well as clinicians reported improvement in subjective status. Withdrawal rates due to adverse events were similar between groups, but BtB increased risk of dry mouth (RR 7.65, 95% CI 2.75–21.32) and dysphagia (RR 6.78, 95% CI 2.42–19.05). There was a dose-dependent response for duration of effect and risk of adverse events (the average duration of benefit lasted from 12-16 weeks).98 BtB was more effective in BtA non-responders, with no difference in effect size between responder subgroups. Overall, the authors concluded that BtB significantly reduced CD severity, disability and pain versus placebo, but increased dry mouth and dysphagia risks. However, data were lacking on repeated BtB cycles, optimal doses/intervals, injection techniques, and quality of life impact.98
Boyce et al. (2022) sought to examine satisfaction rates among CD patients using a botulinum toxin product.99 Their systematic review of 8 studies (n = 1,764) found that the top barrier to patient satisfaction with botulinum toxin treatment was perceived ineffectiveness, with up to 66% reporting dissatisfaction.99 Side effects like dysphagia and neck weakness were the next most common issue, affecting 6-34%. Rigid retreatment schedules and early wearing off of effects also reduced satisfaction. Finally, a lack of experienced injectors capable of proper dosing and muscle targeting was a key barrier.99 Conversely, the top driver of patient satisfaction with botulinum toxin treatment is relief from dystonia symptoms, with 63-78% reporting improvement. Patients expressed wanting more flexible, personalized injection schedules matched to their symptoms. Satisfaction is higher when given by specialized experts.99
Meta-Analyses
N/A
Systematic Reviews and Meta-Analyses
Mainka et al. (2019) performed a systematic review and meta-analysis to examine dystonic remission across 31 studies representing 2,551 patients, with over half having CD (n = 1,319).100 Complete remission of symptoms was experienced by 15.4% of CD patients, while another 7.4% experienced partial improvement. Meta-analysis of 5 CD studies showed that patients experiencing remission had significantly earlier disease onset by an average of 7 years compared to non-remitters. However, relapse was common, occurring in 58.7% of CD cases with remission.100 These data suggest that while complete remission occurs in a sizable minority of CD patients, it is more likely in those with earlier onset disease.100 The long-term durability of symptom remission has not been firmly established even among these select CD subgroups.100
A systematic review and meta-analysis conducted by Marsh et al. (2014) focused on determining the duration of clinical effect of onabotulinumtoxinA in treating CD.101 The analysis included a total of 18 studies involving more than n = 1900 patients. The results revealed that the average duration of effect of onabotulinumtoxinA for CD patients was between 93.2 days (95% CI 91.8-94.6 days) in a fixed effects model and 95.2 days (95% CI 88.9-101.4 days) in a random effects model.101 It was also found that the dosage of onabotulinumtoxinA significantly influenced the duration of effect. Specifically, doses of 180 units or more resulted in longer effect durations (between 107-109 days) compared to doses less than 180 units (86-88 days). The study also noted that country of origin had an influence on the duration of effect. The main conclusion from this analysis is that on average, patients with CD treated with onabotulinumtoxinA would require approximately 4 treatments per year, with higher doses associated with longer durations of effect.101
Randomized Controlled Trials (RCTs)
Samotus et al. (2018) found that many CD patients discontinue BtA injections early due to insufficient relief.102 Tailoring injections through kinematic analysis may improve outcomes.102 In a 38-week study, 28 participants were split into groups receiving expert injector-determined doses by either visual assessment ("vb") or kinematic biomechanics ("kb"). Kinematics utilized sensors capturing severity of static/dynamic neck movements while seated. The "kb" group had a 28.8% TWSTRS score reduction at 6 weeks with sustained improvement. The "vb" group reduced scores by 28.5% at 22 weeks.102 The "kb" group trended towards better outcomes. Kinematic guidance enabled faster optimal muscle selection and dose minimizing while achieving comparable or superior relief versus standard visual assessment.102
Wu et al. (2016) conducted an RCT to compare EMG-guided vs palpation-guided BTIs for CD patients (n = 68).103 The primary endpoint was the Tsui score at 16 weeks. At 16 weeks, the EMG-guided group had a significantly lower (better) Tsui score than the palpation-guided group. Both groups had significant reductions in pain scores over time, with no between-group differences.103 There were no significant between-group differences in Hospital Anxiety and Depression Scale scores or patient/clinician global impression scores, though clinician scores were higher than patient scores.103 The EMG-guided group had significantly more injection site pain but less dysphagia than the palpation-guided group. In conclusion, EMG-guided injections resulted in better dystonia control at 16 weeks, less dysphagia, and more injection discomfort compared to palpation-guided injections.103
A randomized, double-blind, crossover study by Yun et al. (2015) of CD (n = 94) patients that received injections of abobotulinumtoxinA and onabotulinumtoxinA using a 2.5:1 unit conversion ratio.104 Efficacy was measured using the Tsui scale, with mean improvement from baseline of 4.0 points (±3.9 points) after 4 weeks for abobotulinumtoxinA compared to 4.8 points (±4.1 points) for onabotulinumtoxinA (95% CI -0.13 to 1.70 points; P = 0.091). No statistically significant differences were detected between groups in magnitude of symptom improvement per Tsui scale changes. Secondary 10-point TWSTRS scores aligned with the primary outcome. These quantitative clinical efficacy metrics indicate that both formulations reduced CD severity to a similar degree following dose conversion, adding evidence for the non-inferiority of abobotulinumtoxinA to onabotulinumtoxinA in managing this condition when utilized at an optimal 2.5:1 dose ratio.104
Chronic Migraine
Society Guidelines
We found 6 clinical guidelines that suggest botulinum toxin as an effective treatment for chronic migraine. These recommendations were issued by the AAN, the American Headache Society (AHS), the AAO-HNS, European Headache Federation (EHF) and National Institute for Health and Care Excellence (NICE). Among the evaluated guidelines, 3 were founded on systematic review outcomes (AAN, EHF, NICE). The other 2 (AHS, AAO-HNS, are position statements drafted to reflect clinician consensus.
The AAN issued guidelines in 2016 for treating headaches and migraines, updating their 2008 guidelines. They recommend botulinum toxin as a treatment choice for patients with chronic migraines to help them have more days without headaches.92
In 2012, NICE recommended botulinum toxin type A as a preventative therapy option for chronic migraine patients who have failed at least 3 other prophylactic medications.7
The EHF issued guidelines in 2018 that states that onabotulinumtoxinA is recommended as an effective and well-tolerated treatment for chronic migraine.105
In 2021, the AAO-HNS stated that botulinum toxin can be injected in different regions for the prophylactic treatment of migraine headaches that have failed to improve with other medical management.94
The AHS specifically recommends onabotulinumtoxinA (Botox) as an effective treatment for chronic migraine, characterized by headaches on 15 or more days per month, by administering a 155-unit dose without gradual escalation, noted for its rapid efficacy, favorable tolerability, and suitability for patients unresponsive to other treatments, with ongoing treatment based on patient response and regular assessment of benefits. They state the statement was based on a review of existing guidelines.42
Additionally, the American Academy of Pain Medicine (AAPM) 2022 systematic review (and practice guideline)106 includes a strong recommendation for BtA (onabotulinumtoxinA, specifically) for chronic migraines (and a weak recommendation against BtA for episodic migraine).106
Systematic Reviews
AAN’s Systematic Review
In the AAN's systematic review, a total of 28 RMTs were identified and analyzed to assess the efficacy of botulinum toxin formulations in the treatment of headaches, including chronic migraine and episodic migraine. The systematic review found that onabotulinumtoxinA (onaBoNT-A) is established as safe and effective for reducing the number of headache days in chronic migraine, based on 2 Class I studies. These studies highlighted the effectiveness of onaBoNT-A for reducing total headache days over 28 days, with 1 study showing a mean intergroup difference of 1.4 days. In contrast, the systematic review found that onaBoNT-A is probably ineffective for the treatment of EM, based on 3 Class I studies, including 2 from the 2008 report. One Class I study published after 2008 demonstrated that onaBoNT-A was ineffective in reducing migraine frequency over 180 days. As a result, onaBoNT-A is recommended for chronic migraine to increase headache-free days (Level A) and may be considered for improving health-related quality of life (Level B), but it should not be offered as a treatment for episodic migraine (Level A).
EHF’s Systematic Review
Researchers for EHF reviewed 27 studies, including RCTs like the PREEMPT studies which included almost 1,400 chronic migraine patients. In the pooled analysis of the PREEMPT trials, onabotulinumtoxinA resulted in a modest but statistically significant additional reduction of 2 headache days per month over placebo. Almost 50% of onabotulinumtoxinA patients were responders based on a 50% or greater headache frequency reduction, compared to 35% for placebo. Based on this and additional evidence of improved disability scores and quality of life measures versus placebo, the panel strongly recommends onabotulinumtoxinA for treatment of chronic migraine. It is considered effective and well-tolerated. They recommend patients try at least 2 to 3 other preventive medications first, with certain exceptions. Treatment response should be evaluated after the first one to three treatment cycles and discontinued if patients do not achieve at least a 30% headache frequency reduction.
NICE’s Systematic Review
NICE based its recommendation on a systematic review by the drug manufacturer Allergan, which conducted a systematic review to evaluate the clinical effectiveness of botulinum toxin type A for the prevention of headaches in adults with chronic migraine.107 The review identified 7 relevant RCTs comparing botulinum toxin type A against placebo. Of these, 4 trials with active comparators were excluded. The remaining 3 placebo-controlled trials focused on people with chronic migraine defined as at least 15 headache days per month, of which at least 8 days met criteria for migraine headaches. The analysis centered on the results from 2 large, identically designed phase III trials (PREEMPT 1 and PREEMPT 2). These enrolled a total of 1,384 participants - 688 in the botulinum toxin type A arms and 696 in the placebo arms.107 Most patients (approximately 64%) had received at least 1 prior migraine preventive medication, with 35% having failed at least 3 preventatives. The 24-week double-blind treatment phase showed statistically significant improvements with botulinum toxin type A over placebo across several headache symptom outcomes including headache days per month.107
Other Systematic Reviews
A systematic review and meta-analysis by Corasaniti et al. (2023) included 9 randomized clinical trials with a total of n = 3,565 patients to assess the safety of onabotulinumtoxin A compared to placebo or active comparators for treatment of chronic migraine.108 The meta-analysis included n = 1,787 patients treated with onabotulinumtoxin A and n = 1,778 patients treated with comparators. The use of onabotulinumtoxin A produced more treatment-related adverse events (TRAEs) than placebo, but fewer than oral topiramate. The most common adverse events were neck pain, musculoskeletal pain, muscular weakness, migraine, eyelid ptosis, blurred vision and injection site pain. However, there was high heterogeneity between studies (I2 = 96%, P < 0.00001). The authors concluded that further adequately powered, randomized clinical trials are needed to assess safety of onabotulinumtoxin A, including in combination with newer treatments for chronic migraine.108
A systematic review and meta-analysis by Giri et al. (2023) included 3 RCTs (n = 1,139) to assess the efficacy of BtA compared to placebo for prevention of chronic migraine with medication overuse headache.109 The studies showed that treatment with BtA resulted in a reduction of 1.92 headache days per month on average compared to placebo (95% CI -2.68 to -1.16). However, the effect on achieving at least 50% response rate (≥50% reduction in headache days) was uncertain, with substantial heterogeneity between studies (I2 = 92%) and an imprecise odds ratio estimate of 1.56 (95% CI 0.42 to 5.76). The dropout rates ranged from 2.9% to 7.4%. No significant differences were found in adverse events between BoNTA and placebo groups. Due to concerns over risk of bias, inconsistency, and imprecision of results, the quality of evidence was very low for response rate and low for change in headache days.109
A systematic review by Shaterian et al. (2022) included 24 studies on the efficacy of onabotulinumtoxinA for treating migraine (BtA).110 The studies included a total of n = 4,431 patients, mostly with chronic migraine. Doses of Botox ranged from 2.5 to 200 units, with most studies using 155 units. BtA was injected at different sites around the head, neck, and shoulders. The review found that BtA treatment decreased the frequency of migraine attacks per month, pain intensity, medication use, emergency visits, and migraine-related disabilities. Botox also improved quality of life. The authors concluded that BtA is an effective and cost-effective option for treating migraine, including chronic, episodic, unilateral, and vestibular types.110
A systematic review and meta-analysis by Herd et al. (2019) included 28 RCTs with a total of n = 4,190 participants to assess the efficacy of BtA compared to placebo for prevention of chronic migraine. The analysis found that treatment with BtA resulted in a reduction of 2.0 migraine days per month on average compared to placebo (95% CI -2.8 to -1.1, n = 1,384) in patients with chronic migraine. This efficacy was obtained after removing RCTs that were at a high risk of bias due to small study sizes. BtA also showed greater improvements in migraine severity scores and headache days per month versus placebo, though the quality of evidence was low.111 The risk of TRAEs was twice as high with BtA compared to placebo, but these events (the most common being blepharoptosis, muscle weakness, injection site pain and neck pain) were non-serious and transient.111
A systematic review and meta-analysis by Bruloy et al. (2019) included 17 RCTs with a total of n = 3,646 patients to assess the efficacy of BtA compared to placebo for prevention of migraine.112 The analysis found that treatment with BtA resulted in a significant reduction of 1.56 migraine days per month on average compared to placebo (95% CI -3.05 to -0.07; P = 0.04) in patients with chronic migraine (n = 1,551). There was also a tendency for reduction in episodic migraine frequency with BtA versus placebo, but this was not statistically significant. The risk of adverse events was higher with BtA compared to placebo, but adverse events were mild. Patient quality of life at 3 months was significantly improved in the botulinum toxin group (P < 0.00001).112
A systematic review and meta-analysis by Herd et al. (2018) included 28 RCTs with a total of n = 4,190 participants to assess the efficacy of BtA compared to placebo for prevention of chronic migraine.113 The analysis found that treatment with BtA resulted in a reduction of 2 migraine days per month on average compared to placebo (95% CI -2.8 to -1.1) in patients with chronic migraine, based on data from 2 large trials (n = 1,384). BtA also showed greater improvements in number of headache days per month and migraine severity versus placebo, though the quality of evidence was low. The risk of TRAEs was twice as high with BtA compared to placebo, but these events were non-serious and transient.113
Meta-Analyses
A meta-analysis by Lanteri-Minet et al. (2022) included 44 observational studies on the real-world effectiveness of onabotulinumtoxinA for preventing chronic migraine. The meta-analysis included 7 studies assessing change from baseline in number of headache days per month at approximately 24 weeks (n = 1,525) and 5 studies at approximately 52 weeks (n = 995).114 onabotulinumtoxinA treatment resulted in a reduction of 10.64 headache days per month (95% CI -12.31, -8.97) at 24 weeks and 10.32 headache days per month (95% CI -14.92, -5.73) at 52 weeks. The meta-analysis also showed reductions in other outcomes like days taking acute headache medications, ≥50% response rates, Headache Impact Test scores, and improvements in Migraine-Specific Quality of Life scores that were consistent with pivotal clinical trials.114
In another meta-analysis, conducted by Shen and Wang (2020), BtA was found to significantly reduce headache episodes per month relative to placebo for chronic migraine.115 Moreover, the therapy improved the impact of chronic migraines after 16 weeks of therapy.
Randomized Controlled Trials (RCTs)
An RCT by Bono et al. (2023) included 139 patients with chronic migraine who had previously not responded to intramuscular BtA injections. Patients were randomized 2:1 to receive subcutaneous injections of BtA (n = 90) or placebo (n = 49) targeted to the area of maximum headache pain origin (trigeminal or occipital regions).116 At 6 months, BtA significantly reduced monthly headache days versus placebo (-13.2 days versus -1.2 days, P < 0.0001). Secondary outcomes like migraine disability scores also improved with BtA. The results support using a follow-the-pain targeted subcutaneous injection paradigm with BtA in chronic migraine patients unresponsive to other botulinum toxin regimens.116
Overall, there are 12 RCTs comparing BtA to placebo,116-125 including the 2 PREEMPT trials.126,127 Additionally, there are 9 RCTs addressing BtA versus an active comparator including, BtA vs. topiramate128-130, BtA vs. fixed (muscle)-site and acupoint-site injections122, BtA vs. facial nerve blockade123, BtA vs. low-level laser therapy131, BtA vs. amitriptyline132, BtA vs. subcutaneous histamine133, and BtA with preserved saline vs. BtA with preserve free saline.134
Focal Hand Dystonia
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Meta-Analyses
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Randomized Controlled Trials (RCTs)
A Class I trial (strong evidence)135 randomized 40 study participants with writer’s cramp in a double-blind design for botulinum toxin or an equal amount of saline placebo. The primary outcome measured was the patient’s indicated request to continue injection therapy. In patients randomized to BTI, 70% requested to maintain treatment in comparison to 32% of those who received a placebo (P = 0.03). Patients injected with BTI also had considerable improvement in comparison to patients who had been given a placebo in secondary clinical outcome measures including a visual analog scale, symptoms severity scale, writer’s cramp rating scale, and assessment of writing speed, but not in the functional status scale. The only adverse effects reported were temporary weakness and pain at the injection site.
Tsui et al. (1993)136 conducted a Class II study (weak to moderate evidence) utilizing a placebo-controlled, double-blind, crossover design for 20 individuals with writer’s cramp. Clinical assessment was utilized in selecting the muscle to be injected and the dose of BtA was founded on investigator experience. Outcome evaluations included assessment of writing speed, accuracy, writing samples, and patients’ subjective report. There was substantial improvement with BTI in the objective measures, but not in patients’ own evaluations. The only adverse effect was focal weakness, although this was severe enough to worsen pen control in 1 participant. This study only evaluated the first active therapy session for study participants; therefore, the therapeutic effects achieved were not optimal.
Cole et al. (1995)137 conducted a Class II trial with a double-blind, placebo-controlled, crossover design with 10 study participants with focal hand dystonia. Muscles and BTI-A (Botox®) doses were selected and optimized during a time of open treatment before the trial. Outcome measures were based on study participant’s subjective rankings and observation of videotapes taken during actions relevant to the individual dystonia. Eight participants had improved subjective ratings and 6 showed improvement via videotape with BTI in comparison with placebo. Weakness was noted in the injected muscles of 80% of study participants with active treatment.
Three Class II studies assessed technical issues of BTI administration. In 1 trial, Chen et al. (1999) used a blinded, randomized, crossover design to contrast continuous muscle activation with immobilization immediately following BTI.138 Blinded assessment of handgrip strength and writing showed a substantial increase in focal weakness with continuous muscle activity, but no subjective or objective improvement in writing.
In a similar study, Geenen et al. (1996)139 randomized the participants to 1 of 2 muscle localization method groups: EMG recording or electrical stimulation. Injections guided by both techniques were similarly effective in producing weakness in the target muscle.
In a third trial, Molloy et al. (2002) assessed the precision of muscle localization with and without EMG.140 In needle placements established on surface anatomy, 37% were localized in the targeted muscle.
Hemifacial Spasm/Facial Dystonia
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Meta-Analyses
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Randomized Controlled Trials (RCTs)
Despite limited data from high-quality clinical trials, BtA is considered the treatment of choice for HFS patients.141,142 Overall, 76% to 100% of patients have at least a 75% improvement with a typical duration of response lasting from 3 to 4 months.143,144 Both primary and secondary HFS patients respond to BtA, and the average efficacy has been reported to be around 20 years, often with the need for a gradual increase in dose.95,145
From the literature, the efficacy of botulinum toxin ranged from 73% to 98.4%. The mean duration of the effect was around 12 weeks. There were 3 RCT studies, of which 2 were conducted to investigate the efficacy and safety of botulinum toxin in HFS.57 The third study compared pretarsal versus preseptal injections of the orbicularis oculi in 31 patients with HFS. The investigators reported that the pretarsal portion of the orbicularis oculi was associated with a significantly high response rate in terms of latency to response, duration of improvement, JRS, self-response scale, and patient satisfaction scale than the preseptal injections.57
Other Studies
A retrospective longitudinal comparative analysis suggested that the duration of relief from symptoms remains unchanged over the long term in patients with HFS.146 In addition, Tunc et al. (2008) assessed BTI efficacy in 69 patients with primary HFS (n = 46) and those with HFS due to definite neurovascular compression (n = 23), reported that primary HFS patients presented more improvement.147
Upper Extremity Spasticity
Society Guidelines
In 2016, the AAN issued guidelines that Botulinum toxin (BoNT) is recommended for the treatment of spasticity in adults in several instances.92 For upper extremity spasticity, abobotulinumtoxin A (aboBoNT-A), incobotulinumtoxin A (incoBoNT-A), and onabotulinumtoxin A (onaBoNT-A) are established as safe and effective for reducing spasticity and improving passive function (Level A recommendation). Rimabotulinumtoxin B (rimaBoNT-B) is probably safe and effective for reducing upper limb spasticity (Level B recommendation).92
Systematic Reviews
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Randomized Controlled Trials (RCTs)
Four new Class I (strong evidence) trials148-151 investigating abotulinumtoxinA (aboBoNT-A) demonstrated significant reductions in upper limb tone as measured by the modified Ashworth scale. These studies also measured functional outcomes.
A recent study by Gracies et al. (2015)151 showed improved response rate (>1 point) on the principal target of treatment of the Disability Assessment Scale (DAS), a measure of self-reported disability, at 4 weeks among participants treated with 1,000 U of aboBoNT-A, but not with 500 U or placebo (62% in 1,000 U, p = 0.0018 vs placebo; 50% in 500 U, p = 0.1279 vs placebo; and 39.2% in placebo). The higher-dose BoNT-A group also demonstrated improved active range of motion in the elbow, wrist, and fingers.
A Class I study conducted by Lam et al. (2012)152 on patients with upper limb spasticity focused on caregiver burden. This study found that 67% of caregivers of patients receiving aboBoNT-A reported a ≥4-point reduction on the caregiver burden scale as compared with 20% of caregivers of patients injected with saline (P = 0.001).
Another study, by Rosales et al. (2012)150, demonstrated no significant change in functional assessment scores.
Shaw et al. (2011)149 observed no significant difference between groups for improved active arm function as measured by the Action Research Arm Test at 1 month (risk difference [RD] favoring the BoNT group 5.7%, 95% CI −3.5% to 14.6%). However, participants treated with aboBoNT-A showed improvement in upper limb muscle function at 3 months as measured by the Motricity Index (mean change in index 3.5, 95% CI 0.1 to 6.8, greater number of points in the intervention group).
In another study, McCrory et al. (2009)148 demonstrated no significant difference in quality of life but observed significantly greater global benefit in patients given BoNT.
Lower Limb Spasticity
Society Guidelines
A practice guideline update published by the AAN concluded that AboBoNT-A and onaBoNT-A are safe and effective for the reduction of adult lower limb spasticity (multiple Class I studies).92
Systematic Reviews
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Randomized Controlled Trials (RCTs)
A placebo-controlled Class I study153 published since the 2008 guideline examined aboBoNT-A use in MS and observed reduced pain in both legs in patients randomized to aboBoNT-A (RD proportion of patients reporting decreased pain at 12 weeks 29.9%, 95% CI 10.9%–46%).
Three Class I studies of onabotulinumtoxinA (onaBoNT-A) in the treatment of adult lower limb spasticity154-156 demonstrated significant reduction in tone but found inconsistent results regarding functional measures.
Hyperhidrosis
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Randomized Controlled Trials (RCTs)
Only 1 RCT was found, in which 20 patients were randomized to receive toxin injections to 1 axilla and suction-curettage to the contralateral axilla. The primary outcome measure was reduction of sweat rate measured by gravimetry, and the secondary measure was quality of life as measured by a patient-directed questionnaire.157 At 3 months posttreatment, BTIs decreased baseline resting sweat production by 72.1% versus 60.4% (P = .29) for suction-curettage, and baseline exercise-induced sweat production by 73.8% versus 58.8% (P = 0.10). When patients were stratified into the categories of light and heavy sweaters, there was a difference among heavy sweaters, with exercise-induced sweat production lower by 10.48 mg/min or 34.3% (P = 0.0025) at toxin-treated sites. Compared with suction-curettage, toxin also resulted in greater improvements in quality of life by 0.80 points (P = 0.0002) and 0.90 points (P = 0.0017) at 3- and 6-months posttreatment, respectively, as measured by the patient questionnaire.157
By objective measures 3 months after treatment, neurotoxin injections are nominally more effective than suction-curettage in all cases, and markedly more effective than patients who sweat heavily. Patients have a very significant preference for neurotoxin injections at three months, and this is maintained at 6 months.157
At base line, the mean (± SD) rate of sweat production was 192 ± 136 mg per minute. Two weeks after the first injections the mean rate of sweat production in the axilla that received botulinum toxin A was 24 ± 27 mg per minute, as compared with 144 ± 113 mg per minute in the axilla that received placebo (P < 0.001). Injection of 100 U into the axilla that had been treated with placebo reduced the mean rate of sweat production in that axilla to 32 ± 39 mg per minute (P < 0.001). Twenty-four weeks after the injection of 100 U, the rates of sweat production (in the 136 patients in whom the rates were measured at that time) were still lower than baseline values, at 67 ± 66 mg per minute in the axilla that received 200 U and 65 ± 64 mg per minute in the axilla that received placebo and 100 U of the toxin. Treatment was well tolerated.158
Overactive Bladder (OAB)/Urinary Incontinence (UI)
Society Guidelines
American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (AUA/SUFU) guideline69,159 recommends intradetrusor BtA injection as third-line therapy in select patients who have received adequate counseling and who have not responded to first- and second-line treatment.159 They report caution must be used in the elderly, the very frail, and those with pre-existing cognitive deficiencies and further research is needed.
Systematic Reviews
Truzzi et al. (2022)160 performed a systematic review on the use of BTIs in the bladder to treat OAB in men to identify clinical trials on efficacy and safety of BtA injections in the detrusor for treatment of OAB. Six studies were conducted exclusively in men. There were only 2 were RCTs. Most were observational studies and case series. Quality-of-life symptom questionnaires and voiding diary parameters were some of the assessment methods. Only 2 studies separately reported urodynamics data for men before and after intravesical BtA injection. For 7 studies, the outcome data could be pooled, with the most common adverse events after BtA injection being UTI (29.8%), urinary retention (20.0%), increased postvoid residual (37.3%), de novo interstitial cystitis (28.3%), and hematuria (12.4%). The authors concluded that information regarding the efficacy and safety of BtA bladder injections for male OAB was limited and derived from relatively low-quality evidence. There is a need for further research to assess the risk-benefit profile of BtA in males. Limitations of the studies include variability in assessment of BtA injections among studies, self-reporting bias, and small sample size.
Abrar et al. (2021)161 conducted a systematic review to evaluate whether poor response/adverse events to BtA for idiopathic OAB are predictable. This review included 17 cohort studies (primarily level 3 evidence). It was found that the potential predictors for non-responders were male gender, frailty, comorbidity, increasing age, smoking, baseline leakage episodes, and various urodynamic parameters including bladder outlet obstruction index (BOOI), high pretreatment maximum detrusor pressure, and poor bladder compliance. The main predictive factors for clean intermittent self-catheterization (CISC) use were male gender, comorbidity, increasing age, number of vaginal deliveries, hysterectomy, and urodynamic parameters (bladder capacity, postvoid residual volume, projected isovolumetric pressure value, bladder contractility index, and BOOI). Female gender, males with their prostates in situ, and CISC were linked to potential increase UTIs after BtA use. The authors concluded that even though various predictive factors based on the patient, medical conditions, previous surgery, and pretreatment investigations were identified, the quality of included studies was generally poor (poor study design being 1 of the reasons), limiting their conclusions.
Gong and associates (Gong, Xu et al. 2019) conducted a meta-analysis of published RCTs to assess the effect of BTX-A using different dosages for the treatment of UI symptoms. Studies that included patients with neurogenic detrusor overactivity (NLUTD) or idiopathic OAB (IOAB) were included and result in 19 studies which were included for analysis. Authors concluded their analysis suggested BTX-A 200 U and 300 U were more effective as compared to placebo in the treatment of NLUTD. While BTX-A 300 U and 200 U may improve detrusor compliance of IOAB. Authors further state the need for more robust studies to help determine the effect of BTX-A in NLUTD and OAB management.
Gu et al. (2017)162 conducted a systematic review to assess the effectiveness and safety of BtA at different dosages for OAB. A total of 11 studies were included. Parameters considered were UI episodes per week as the primary outcomes, urodynamic parameters including maximum cystometric capacity (MCC), and maximum detrusor pressure (MDP) for neurogenic detrusor overactivity (NLUTD) at 6 weeks, and for idiopathic detrusor overactivity (IDO) at 36 weeks as compared to placebo. The authors reported a dose of BtA greater than 50 U is significantly more effective for certain symptoms of OAB compared with placebo, with escalating adverse events with increase dosage. The authors recommend BtA 200 U for management of NLUTD for short-term treatment and stated there was no significant difference from the larger dose of 300 U.
Drake et al. (2017)163 performed a systematic review/meta-analysis of 56 RCTs to compare the efficacy of BtA, mirabegron, and anticholinergics in adults with idiopathic OAB. They reported 100 U of BtA achieved the greatest reduction in urinary incontinence episodes (UIE), urgency episodes, and micturition frequency. The authors conclude that BtA 100 U provides greater relief of OAB symptoms as compared with other licensed doses of other pharmacotherapies in the network at 12 weeks follow up.
Henriet et al. (2015)164 conducted a systematic review for the treatment of refractory idiopathic OAB with botulinum toxin. Of the 37 studies included, 8 were placebo controlled RCTs. Intra-detrusor injections were associated with reduced frequency, urgency, nighttime urination, incontinence episodes and improved bladder capacity and quality of life. When considering efficiency and tolerance, they suggest a dose of 100 to 150 U of BtA is optimal as a second-line treatment for refractory non-NLUTD and the effects persist between 3 to 12 months. They state long-term effectiveness data is lacking.
Cui et al. (2013)165 systematically reviewed the evidence related to the efficacy and safety of BtA in the management of idiopathic OAB. Twelve RCT (n=1020) comparing BtA with placebo, different doses, and injection techniques for management of idiopathic OAB was included. The author concluded that BtA resulted in reduction in urinary frequency, less incontinence episodes, improvement in quality of life, higher post-void residual-related catheterization and higher UTI. They recommended low-dose BtA in effort to balance the benefits with adverse events.
Meta-Analyses
Gong et al. (2019)166 conducted a meta-analysis of published RCTs to assess the effect of BtA using different dosages for the treatment of UI symptoms. Studies that included patients with neurogenic detrusor overactivity (NLUTD) or IOAB were included and result in a total of 19 studies were included for analysis. Authors concluded their analysis suggested BtA 200 U and 300 U were more effective as compared to placebo in the treatment of NLUTD. While BtA 300 U and 200 U may improve detrusor compliance of IOAB. Authors further state the need for more robust studies to help determine the effect of BtA in NLUTD and IOAB management.
Randomized Controlled Trials (RCTs)
Visco et al. (2012)167 performed a double-blind, double-placebo-controlled RCT to compare anticholinergic medications and BtA in the treatment of urgency UI. A total of 249 women with idiopathic urgency UI who had 5 or more episodes of incontinence per a 3-day period were assigned to receive anticholinergic plus 1 intradetrusor injection of saline or placebo plus 1 intradetrusor injection of 100 U of BtA and followed for 6 months. Starting was a baseline of 5 episodes of incontinence/day the anticholinergic group had a mean reduction of 3.5 and BtA group reduced to 3.3 (P = 0.81). Complete resolution of urgency UI was reported by 13% in the anticholinergic group as compared to 27% in the BtA group (P = 0.003). The authors found both treatments effective and different by side effect profiles.
Sherif et al. (2017)168 conducted a RCT to assess the safety and efficacy of posterior tibial nerve stimulation (PTNS) versus an intradetrusor injection of BtA 100 U in the management of 60 patients with refractory IOAB. Initially both groups showed improvements however the effects diminished for the PTNS group by 9 months. They concluded for refractory IOAB, BtA is more effective than PTNS but had more adverse effects.
Nitti et al. (2013)169 conducted a phase III, placebo-controlled trial of BtA in 557 patients with OAB and UI inadequately managed with anticholinergics. Patients were randomized to receive either intradetrusor injection of BtA 100 U or placebo. They reported the BtA group experienced a greater decreased frequency of UIE than placebo (–2.65 vs –0.87, p = 0.001) and 22.9% vs. 6.5% of patients became completely continent. Improvement in treatment benefit scale, all other OAB symptoms, and patient health-related quality of life across multiple measures also improved in the BtA group. Uncomplicated UTI was the most common adverse event and there was a 5.4% rate of urinary retention. They concluded that BtA yielded significant and clinically relevant improvements in all OAB symptoms.
Yokoyama et al. (2020)170 conducted a phase III RCT to evaluate the efficacy and safety of BtA 100 U in patients with OAB and UI who failed medical management. Enrolled patients were randomized 1:1 to receive a single dose of 100 U of BtA (n=124) or placebo (n=124) into detrusor muscle. The primary endpoint was the change in the number of daily UIEs at week 12 from baseline and the treatment group yielded a significant decrease in mean number of daily UI occurrences as compared to placebo group from baseline (2.16; P < 0.001) and improvements were seen in all secondary endpoints. Mild to moderate adverse events were more common among the treatment group which included UTI, dysuria, urinary retention, and increased volume post-void residual urine. The authors concluded that there were statistically significant improvements in symptoms, suggesting BtA as an option for treatment in patient populations where medications have failed.
Multiple prospective studies investigated the role of repeat injections for management of OAB if initial response was positive. These investigations found the effects of BTI to last 4-10 months with a median of 7.6 months. Improvements were reported in quality of life and OAB symptoms. (Nitti, Ginsberg et al. 2016). An RCT concluded that in patients with dysfunctional voiding and detrusor underactivity repeat injections yielded larger therapeutic effects whereas in non-neurogenic voiding dysfunction patients, success rates of BTX-A was not superior to placebo. (Jiang, Wang et al. 2016)
Detrusor Overactivity
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Randomized Controlled Trials (RCTs)
In a prospective, long-term (3 years), multicenter, open-label extension study following a 52-week, phase III trial of onabotulinumtoxinA, patients were treated on an ‘as needed’ basis with intradetrusor onabotulinumtoxinA (200 U or 300 U) for UI due to neurogenic detrusor overactivity. Ninety-four patients received treatment ≥ 12 weeks since the previous treatment and a UIE threshold. The primary efficacy endpoint was the change from study baseline in UIEs/day at week 6 after each treatment. Additional efficacy measurements included: percent change in UIEs, the proportions of patients with ≥ 50% and 100% reductions from baseline in UIEs/day, changes from baseline in volume/void and Incontinence Quality of Life (I-QOL) total summary scores, IQOL responder rates (proportion of patients achieving a ≥ 11-point increase from baseline in I-QOL total score, which is defined as the minimally important difference for I-QOL in neurogenic detrusor overactivity (NDO)), and duration of treatment effect (time to patient request for retreatment). onabotulinumtoxinA 200U consistently reduced UI episodes/day; reductions from baseline ranged from –3.2 to –4.1 across six treatments. Volume/void consistently increased, nearly doubling after treatment. I-QOL improvements were consistently greater than twice the minimally important difference (+11 points). Overall median duration of effect was 9.0 months (200U). Results were similar for onabotulinumtoxinA 300U. Most common AEs were urinary tract infections and urinary retention. De novo CIC rates were 29.5, 3.4, and 6.0% (200U), and 43.0, 15.0, and 4.8% (300U) for treatments 1–3, respectively; de novo CIC rates were 0% for treatments 4–6. The authors concluded that onabotulinumtoxinA treatments consistently improve UI, volume/void, and quality of life in patients with UI due to neurogenic detrusor overactivity in this 4-year study, with no new safety signals.
The use of intradetrusor injection of botulinum toxin for treatment of IC/BPS may be combined with hydrodistention.171-180 While botulinum toxin may alleviate symptoms of IC/BPS, there is a risk of urinary retention, which may be particularly problematic for a patient with a painful bladder. Any patient considering this treatment must be willing and able to perform intermittent self-catheterization. Use of botulinum toxin for this indication is not approved by the FDA, and payment may not be covered by health insurance.
In a trial of 67 patients randomized to receive suburothelial injection of BtA (100 or 200 Units) combined with hydrodistention, or hydrodistention alone, BtA treatment resulted in a higher proportion of patients with moderate or marked improvement in symptoms at 3-month follow-up (71% versus 48%), and this difference was maintained through 24 months.124 Initially, 200 Units of botulinum toxin was used, but adverse reactions occurred in 9 of 15 patients (4 patients had acute or chronic urinary retention, 7 had severe dysuria) and the dose was decreased to 100 Units. With the 100 Units dose, the number of adverse effects decreased but was still more frequent than for hydrodistention alone.
The 100 Units dose was further evaluated in another trial, in which 60 patients were randomized to receive suburothelial injections of BtA 100 Units (n = 40) or normal saline (n = 20). At week 8, a greater reduction of bladder pain was observed in the BtA treatment group, with treatment success rates of 63% in the BtA groups and 15% in the normal saline group.171
Neurogenic Lower Urinary Tract Dysfunction (NLUTD)
Society Guidelines
The AUA/SUFU guideline amendment66 strongly recommends (evidence level – grade A) clinicians to use BtA to improve bladder storage parameters, decrease episodes of incontinence, and improve quality of life measures in NLUTD patients with SCI or MS refractory to oral medications. The guideline further makes a conditional recommendation (evidence level – grade C) that clinicians may offer BtA to improve bladder storage parameters, decrease episodes of incontinence, and improve quality of life measures in NLUTD patients, other than those with SCI and MS, who are refractory to oral medications. Finally, the guideline highlights the clinical principle that clinicians must discuss the specific risks of urinary retention and the potential need for intermittent catheterization prior to selecting BtA for NLUTD patients who spontaneously void.
Additionally, discussions during the Multi-Jurisdiction Contract Advisory Committee (CAC) meeting held on 10/19/23 led to the conclusion that while there is a paucity of high-quality evidence to support the use of BtA as a first-line treatment for neurogenic for overactive bladder (OAB), the use of BtA is supported in patients with severe issues.
Systematic Reviews
Soljanik et al. (2013)181 conducted a systematic review on the efficacy and safety of BtA in adults with NLUTD dysfunction. Superior effects were reported in 28 studies of BtA compared with placebo in achieving continence as well as a reduction in incontinence episodes, improvements in urodynamic parameters and quality of life. Commonly reported adverse events included intermittent catheterization, urinary retention, and asymptomatic urinary infection. Review limitations include the inclusion of 22 studies with low levels of evidence, high heterogenicity and short follow up periods. The authors concluded that BtA is safe and effective for NLUTD dysfunction patients. They further call for the need of high-quality studies to define standards such as optimal dose, injection technique, long-term safety, and timing indications for re-injections.
Systematic Reviews and Meta-Analyses
Cheng et al. (2016)182 conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BtA for NLUTD. A total of six RCTs comprised of 1,915 patients were included. A significantly decreased mean number of UIEs was observed at 6 weeks in the BtA-treated groups compared to placebo. An increase in adverse events was also reported in the BtA-treated groups (the adverse events included UTIs, urinary retention, hematuria, and muscle weakness). The authors concluded that their meta-analysis suggests BtA is a safe and effective treatment option for patients with NLUTD.
Ni et al.183 conducted a systematic review and meta-analysis to investigate the value of repeat botulinum toxin A (BtA) injections in patients with NDO. A total of 18 studies (level of evidence ranging from 3-4) comprised of 1533 patients were considered. Stable quality of life improvements were reported in patients that received ≤4 injections following the first and last injections. However, a significant decrease in quality of life was reported in last injection of patients that received ≥5 injections. Repeat BtA injections intervals yielded no significant differences.
Randomized Controlled Trials (RCTs)
Fu et al. (2015)184 conducted an RCT to evaluate the efficacy of BtA injection in 60 patients with SCI. Mean UI frequencies were reduced from 15.2+/-3.2 episodes/day to 2.9 ± 1.2 in the 200 U group and 16.2 ± 2.9 episodes/day to 2.5 ± 1.4) in the 300 U groups at 4 weeks. There were no significant differences in continence rates between the dose group (63% [19/30] vs 70% [21/30], respectively; P > 0.05). No adverse effects were reported in either group during the follow up period. The authors concluded that BtA injections may serve as a safe and effective treatment in SCI patients.
Cruz et al. (2011)185 conducted a multicenter RCT to evaluate the effects of BtA on UI, urodynamic variables, and quality of life in incontinent patients with neurogenic detrusor overactivity. Enrollment consisted of patients with MS (n = 154) or SCI (n = 121) with UI (≥14 UIEs per week). Patients were randomized to receive intradetrusor injections of BtA 200 U (n = 92), 300 U (n = 91), or placebo (n = 92). At 6 weeks a significantly reduced incontinence episodes were observed in the BtA 200 U and 300 U groups (-21.8 and -19.4, respectively) compared with placebo (-13.2; P < 0.01). Authors concluded both doses of BtA significantly reduced UI while improving urodynamics and quality of life in both MS and SCI patients with NLUTD.
Interstitial Cystitis (IC) / Bladder Pain Syndrome (BPS)
Society Guidelines
The American Urology Association (AUA) produced a systematic review and guideline for the diagnosis and treatment of IC/BPS in 2022.71,72 They give an ‘optional’ recommendation (evidence level – grade C) that patients, who are willing to accept the possibility that post-treatment intermittent self-catheterization may be required, may be subjected to a trial of neuromodulation if other treatments are not able to adequately improve their symptoms and quality of life.
European Association of Urology Guidelines on Chronic Pelvic Pain186 state that BtA may result in urodynamic improvements.
During a Multi-Jurisdictional CAC meeting held on 10/19/23, subject matter experts (SMEs) reported that BtA for IC/BPS is included in algorithms for treatment and particularly at the time of operative intervention to reduce urgency and frequency symptoms.
Systematic Reviews
Vargas et al. (2018)187 conducted a systematic review to assess the efficacy and safety of BtA, compared with other interventions for the treatment of BPS to improve quality of life. A total of 4 studies were included for analysis. The authors concluded that there was a lack of evidence because of which they were unable to determine the efficacy of BtA for the treatment of IC to improve quality of life.
Wang et al. (2016)188 conducted a systematic review including 7 RCTs and 1 retrospective study to evaluate efficacy and safety of BtA injections for IC/PBS. Results showed a significant improvement in daytime frequency of urination (WMD –2.36; 95% CI –4.23 to –0.49; p=0.01) and maximum cystometric capacity (MCC) (WMD 50.49 mL; 95% CI 25.27 to 75.71; p<0.00001). This study was limited by quality of included studies which included small sample sizes, lack of randomization methods reported, lack of standardization in BtA dosage and short duration of follow up.
Tirumuru et al. (2010)189 conducted a systematic review to assess the effectiveness and adverse effects of intravesical BtA in IC. RCTs and prospective cohort studies comprised of 260 adult subjects with a clinical diagnosis of IC/BPS were included. Variations in urodynamic parameters across studies were noted. Adverse events included dysuria (n=35), temporary hematuria (n=4), UTI (n=4), voiding difficulty resulting in clean intermittent self-catheterization (n=19), impaired detrusor contractility (n=18) and decrease in force of urinary stream (n=18). The authors concluded that BtA may be beneficial to patients with refractory BPS but there is a need for further research.
Systematic Reviews and Meta-Analyses
Shim et al. (2016)190 conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BtA injections as compared to placebo in patients with IC/BPS. Five studies comprised of 252 subjects with 8-12week follow-up duration. Dosage administered ranged from 50-200 U of BtA. Pooled mean change of visual analog score for the treatment group versus control group was -0.49 (95 % CI -0.74, -0.23). Improvements were also reported in ICPI, frequency, and the occurrence of dysuria in the treatment group. Authors conclude their study resulted in significant differences in pain control and efficacy of treatment as compared to placebo.
Imamura et al. (2020)191 conducted a Cochrane systematic review and meta-analysis to evaluate the impact of treatments for BPS patients. Articles considered for inclusion were 13 RCTs which evaluated any treatments for adults with BPS. Neuromuscular blockade was achieved by injection of BtA. The authors concluded that while neuromuscular blockade may be helpful to patients with BPS, the lack of evidence makes it difficult to determine if this treatment is superior to other modalities with very low level of certainty.
Randomized Controlled Trials (RCTs)
Li et al. (2020)192 conducted a randomized study to compare the therapeutic effect of intravesical instillation hyaluronic acid with intradetrusor botulinum toxin A (BtA) injection or cystoscopic hydrodistention (HD) for ketamine-associated cystitis in 36 patients. A significantly more favorable outcome was seen in the BtA group when considering IC Symptom Index, maximal capacity, and maximal cystometric capacity as compared to the HD group. The authors concluded that BtA injection may provide long-term effectiveness compared with cystoscopic HD. However, the study was limited by a small sample size, and unclear effect of the addition of hyaluronic acid.
Kuo et al. (2016)172 conducted a prospective, multicenter, double-blind, placebo controlled RCT to assess the benefit of intravesical BtA for treatment of IC/BPS. The treatment group (n=40) received hydrodistention plus suburothelial injections of BtA 100 while the control group (n=20) received an equivalent amount of normal saline. The primary endpoint was considered successful if a decrease of pain was evaluated at 8 weeks following treatment which was assessed by utilization of the visual analog scale (VAS). A significant decrease in pain at the 8-week follow up was reported in the Botox group as compared to the saline group −2.6 ± 2.8 vs. −0.9 ± 2.2, P = 0.021) with an overall rate of 63% (26/40) in the Botox group and 15% (3/20) in the saline group (P = 0.028). Authors concluded that Botox successfully reduced bladder pain in IC/BPS patients. This study was limited by small sample size, short-term follow-up, baseline imbalance and combining procedures.
Kuo and Chancellor (2009)171 conducted a prospective, randomized study comprised of 67 patients with IC/PBS who failed conventional treatments. Patients were randomized to either receive a suburothelial injection with 200 U (15) or 100 U (29) of BtA followed by cystoscopic HD 2 weeks later (BtA groups) (n=44) or to receive HD with no BtA injection (n=23). A significant decrease in IC/PBS symptoms were seen in all 3 patient outcomes with greater improvement in bladder capacity, reduced VAS score in the BtA group, however they also had more adverse effects with gross hematuria (n=2), urination difficulties (n=12), urinary retention (n=12) and UTI (n=3) only in the BtA groups. The authors concluded that injections of BoNT-A and HD yielded significantly favorable results as compared to HD alone.
Other Studies
Kuo (2013)180 conducted a prospective study comprised of 81 patients with IC/BPS who received intravesical BtA 100 U injections every 6 months for up to 4 times or until the symptoms improved. Active controls were comprised of patients who received a single injection (n=20). Other patients received either 2 (n=19), 3 (n=12), or 4 injections (n=30). Significant improvements following repeat injections were reported in symptom scores, VAS, functional bladder capacity, and daytime frequency with markedly improved rates in patients that received 4 repeated injections (P = 0.0242) and 3 injections (P = 0.050), as compared to single injection patients. The authors concluded that repeat injections were safe and effective in decreasing pain and increasing bladder capacity as compared to single injection.
Laryngeal Dystonia (LD)
Society Guidelines
The AAN published a guideline on botulinum toxin in 2008 at which time a “level B” recommendation was made for botulinum toxin use in adductor LD (insufficient evidence was determined for abductor LD).92 This guideline was retired following the publication of an updated version in 2016. This latest version did not include LD.92
In 2013, an international consortium of neurologists based in the U.S. and Europe published an evidence-based assessment of botulinum toxin for movement disorders that included a “level C” recommendation specifically for BtA as a treatment option for adductor LD only. The evidence for abductor LD and other botulinum toxin products was found to be insufficient or inexistent for some products.95
The 2018 AAO-HNS guideline for the treatment of dysphonia63 is the only active medical society practice guideline identified. The working group recommended the use of BTIs in patients with LD without restricting the recommendation to any LD subgroups or botulinum toxin products. Specifically, it stated that clinicians should offer, or refer to someone who can offer, BTIs for the treatment of dysphonia caused by spasmodic dysphonia and other types of LD. These injections offer the benefits of improved voice quality and voice related quality of life. Overall, botulinum toxin is beneficial despite the potential need for repeated treatments given the limited availability of other effective interventions for spasmodic dysphonia.
Systematic Reviews
The 2006 Cochrane systematic review on botulinum toxin for treating LD restricted eligibility to RCTs.193 Only 1 RCT was found.194 Its quality was downgraded 1 level due to unclear concealment. The authors concluded, however, that the trial demonstrated benefits in objective and subjective outcomes, but that there is insufficient data to generalize. The other 2 systematic reviews mostly included prospective single-arm NRSIs. The primary studies consistently reported clinically and statistically significant post-injection improvements in objective and subjective voice quality scores, as well as in quality of life measures.
Faham et al. (2019)195 included 17 nonrandomized studies of interventions (NRSIs) (16 prospective) (n=474 patients) in their systematic review that aimed to evaluate the efficacy of bilateral (most common) or unilateral injections in the thyroarytenoid muscles. The quality of life measures included in this work were voice handicap index (VHI) and voice-related quality of life (V-RQOL). The minimum post-injection assessment interval was 1 week. Meta-analysis revealed statistically and clinically significant post-injection improvements in VHI and V-RQOL (VHI SMD, -0.36 [-0.58, -0.14]; V-RQOL SMD, [-3.27, -1.32]).
van Esch et al. (2017)196 included 2 RCTs and 11 NRSIs in their work that assessed bilateral or unilateral injections of Botox, 1 to 7.5 U per thyroarytenoid muscle under EMG guidance. A total of 927 patients with adductor LD were included. Objective (5 studies) and subjective (13 studies) voice quality scores as well as quality of life measures (VHI, V-RQOL) were evaluated. The time points ranged from 4 days to 5 years. Consistent and significant improvements were observed in the objective outcome, subjective outcome, and quality of life measurements across studies. The duration of effect, reported by 6 studies, ranged between 14.7 and 18.0 weeks.
Watts et al. (2006)193 conducted a Cochrane systematic review that included only 1 RCT evaluating the effect of Botox injections in thyroarytenoid muscle. The RCT included 13 patients with adductor LD. The outcomes measured were fundamental frequencies, phonation time, spectrographic ratios, and perceptual voice quality measures. This single RCT demonstrated a benefit regarding subjective and objective measures of voice (improved fundamental frequency range, perturbation, spectrographic analysis in and perceptual voice quality) in active group. However, due to the small number of available RCTs, generalizations regarding the degree of effectiveness must be withheld at this point.
Randomized Controlled Trials (RCTs)
Only RCTs comparing botulinum toxin to another active control or to placebo were eligible for this review. Two were found. The first one, which is reported above under the Watts 2006 Cochrane SR, was a double blind cross-over, placebo-controlled trial conducted at the University of California Medical Center in 1991.194 The second RCT, also a double-blind placebo controlled study, was recently conducted at the Kyoto University in Japan.197 In the former, the primary endpoint was the change in the number of aberrant morae (phonemes) at 4 weeks after drug injection. The number of aberrant morae at 4 weeks was reduced by 7.0 ± 2.30 in the botulinum toxin adductor group compared to 0.2 ± 0.46 in the adductor placebo group. The improvement persisted for 12 weeks following injections. Adverse events included breathy hoarseness (77.3%) and aspiration when drinking (40.9%) but were mild and resolved in 4 weeks. As 2 patients only presented with abductor LD, no conclusion could be drawn for that group.
Neurogenic Bladder
Society Guidelines
N/A
Systematic Reviews
Soljanik et al. (2013)181 conducted a systematic review to compare and critically discuss the reported efficacy and safety of BtA in adults with neurogenic bladder dysfunction. Studies published between January 1985 and July 2012 were identified. Analysis of the 28 included studies showed that onabotulinumtoxinA had superior efficacy, compared with placebo, in achieving continence, reducing incontinence episodes, improving urodynamic parameters and health-related quality of life. The most frequently reported adverse events were de novo intermittent catheterization, urinary retention and asymptomatic urinary infection. Limitations of this review are the inclusion of studies with level 3 evidence (22/28 studies), the heterogenicity of outcome parameters and time points chosen for follow-up reported in the reviewed studies. The authors concluded that onabotulinumtoxinA therapy is effective, safe and well tolerated in adults with neurogenic bladder dysfunction. However, further high-quality prospective trials are necessary to determine important parameters such as optimal dose, injection technique, favorable timing, indications for re-injections, long-term safety, and the impact of concomitant antimuscarinics on onabotulinumtoxinA therapy.
Meta-Analyses
N/A
Randomized Controlled Trials (RCTs)
N/A
Strabismus
Society Guidelines
N/A
Systematic Reviews
Binenbaum et al. (2021)198 conducted a systematic review that included 2 RCTs, 3 non-randomized comparative studies and 9 case series. It was found that successful motor outcomes were consistent across 4/5 of the comparative studies. In the 5th level 2 study, success was significantly higher with BtA compared to surgery. The level III case series demonstrated higher motor success rates when children were treated in 2 muscles at a time. In comparison, successful alignment was lower in adults treated with a single muscle BtA injection. BtA injections into the extraocular muscle showed a high rate of successful motor alignment compared to that achieved after eye muscle surgery for nonparalytic, nonrestrictive horizontal strabismus. In this systematic review, the limitations included that the studies were restricted to level II and level III studies.
Bort et al. (2023)199 conducted a systematic review that included a total of 242 patients in 4 RCTs. This systematic review found that patients treated with botulinum toxin may need to re-treat with surgery more frequently. Low certainty evidence suggests that surgery may be more likely to improve or correct strabismus versus BtA. The limitations of this systematic review included that there were not enough studies to be confident of the results and the studies were small.
A systematic review conducted by Escuder et al. (2019)200 revealed that BtA can have positive effects on ocular alignment, promote binocularity, and reduce diplopia. The successful treatment of strabismus with BtA is increasing, with the concomitant reduction in length of anesthesia and increase in muscle preservation. Further studies should be conducted so that we can learn more about the long-term outcomes of BtA in strabismus.
Meta-Analyses
N/A
Randomized Controlled Trials (RCTs)
N/A
Other Studies
A pilot study was conducted that compared the effectiveness of a BTI in combination with surgery compared to surgery alone for the correction of large angle horizontal deviations. The sample size for this study was small with 23 patients, 12 in the Botox group and 11 in the control group. It was found that there was significant increase in the percent net change in deviations between 7 and 30 days but this did not last longer than 3 months.201 Limitations for this study included a small sample size of patients. In another study, it was found that there was a trend toward fewer injections and that treatment of strabismus with BtA is practical for patients with poor binocular potential, complicated strabismus, or multiple previous strabismus operations.202
Sialorrhea
Society Guidelines
N/A
Systematic Reviews
Most systematic reviews targeting sialorrhea in Parkinson’s disease concluded that botulinum toxin is an effective therapeutic option with a certainty of evidence generally rated as moderate.
The authors of a 2022 Cochrane review on treatments for sialorrhea in amyotrophic lateral sclerosis (ALS) concluded that there is some low to moderate certainty evidence for the use of the use of Myobloc® in that indication.203
In a recent well-conducted systematic review with meta-analyses, it was found that either Myobloc® or Xeomin® were likely to alleviate drooling frequency and severity in adults with neurological diseases at 4- and 12-week follow-ups without significantly increasing dysphagia. The review included 17 RCTs involving a total of 981 patients. Results were statistically and clinically significant with a certainty of evidence rated as moderate [Drooling Frequency and Severity Scale (DFSS), Xeomin®: MD = −1.20 [−1.89 to −0.51], Myobloc®: MD = −1.62 (−2.07 to −1.17)]. Xeomin®, but not Myobloc®, remained effective after 12 weeks.204
Meta-Analyses
N/A
Randomized Controlled Trials (RCTs)
Note: BtA: incobotulinumtoxinA (Xeomin®); BtB: rimabotulinumtoxinB (Myobloc®/RIMA)
Three RCTs specifically targeting Parkinson’s disease.205-207 These included trials testing BtB 1,500 U vs. BtB 2,500 U vs. BtB 3,500 U vs. placebo205, BtB 4000 vs placebo206, and BtB 100 U vs placebo207.
Two RCTs in ALS, which includes trials testing BoNT-A vs. radiotherapy208, and BtB vs. placebo209.
One trial in neuroleptic-induced sialorrhea testing BtB vs. placebo.210
Four trials targeting varied etiologies, including Parkinson’s disease, atypical Parkinson’s disease, ALS, stroke, or traumatic brain injury (TBI). These include trials testing BtA vs. BtB211, BtA 50 U vs. BtA 100 U vs. BtA 200 U212, BtA 75 U vs. BtA 100 U213,214 (“SIAXI” trial), and BtB 2500 U vs, BtB 3500 U vs placebo215 (RIMA).
The 2 RCTs cited below were the largest and most consequential trials as they supported FDA approvals of Xeomin® (incobotulinumtoxinA) and Myobloc® (rimabotulinumtoxinB) for sialorrhea. Unstimulated salivary flow rate (uSFR) from baseline to 4 weeks was the primary endpoint in both.
The SIAXI trial was a European multicenter double-blind placebo-controlled trial testing Xeomin®) 75 U vs. 100 U vs. placebo in 184 adults with Parkinson’s disease, stroke, atypical Parkinson’s disease, or TBI.213 Mean age was 65.2 years. Compared to placebo, both treatment groups showed reduced uSFR, but only the 100-unit treatment group showed a statistically significant reduction (−0.09 g/min least squares mean difference versus placebo, P = 0.004 ).213 The reduction in uSFR was maintained in both groups in the 64-week follow-up study, which included 173 patients.214 Treatment-related adverse events included dry mouth and dysphagia.
The second large RCT (RIMA) was an international double-blind trial that evaluated Myobloc® (rimabotulinumtoxinB) 2500 U vs. 3500 U vs. placebo in 249 adult patients with a wide range of pathologies, including but not limited to Parkinson’s disease, ALS, stroke, adult cerebral palsy, TBI, oral cancer, and drug-induced sialorrhea. Sixty-three percent were 65 years of age or older. The trial showed a statistically significant reduction in uSFR in both treatment groups compared to placebo (mean uSFR reduction of 0.3 g/min in both, p < 0.001). The most common treatment-related adverse event was dry mouth (38% and 45% of patients in the 2500 U and 3500 U treatment groups respectively).215 There were no overall differences between older and younger patients regarding safety or effectiveness.