Gastroenterology & Hepatology

April 2023 - Volume 19, Issue 4

Botulinum Toxin A Use in the Gastrointestinal Tract: A Reappraisal After Three Decades

Wasay A. Mohajir, DO
Department of Gastroenterology, Texas A&M College of Medicine and Baylor Scott & White Medical Center, Round Rock, Texas 
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas

Shruti Khurana, MD
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas

Khushboo Singh, MD
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas

Reubyn William Chong, MD
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas

Manoop S. Bhutani, MD
Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas

Corresponding author:
Dr Manoop S. Bhutani
Department of Gastroenterology, Hepatology and Nutrition–Unit 1466
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd
Houston, TX 77030-4009
Tel: (713) 794-5073 
Fax: (713) 563-4408

Abstract: The discovery of botulinum toxin A (BTX)’s therapeutic properties has led to studies evaluating its usefulness in multiple medical disorders. Its use in the gastrointestinal (GI) tract has been studied for 30 years. Multiple databases, including PubMed, AccessMedicine, ClinicalKey, Cochrane Library, Embase, and Medline, were used to review research from case series to randomized controlled trials on BTX use in the GI tract. This article reviews the current literature on the efficacy of BTX and the strength of recommendations for or against its use in various disorders, including cricopharyngeal dysphagia, achalasia, nonachalasia motility disorders, gastroparesis, obesity, sphincter of Oddi disorders, chronic anal fissure, chronic idiopathic anal pain, and anismus. The appeal of BTX comes from its simplicity of administration, good safety profile, and reliability in decreasing muscular tone. However, there are several drawbacks that limit its use, including the lack of long-term efficacy and/or limited data in many GI disorders.


Botulinum toxin A (BTX) is produced by Clostridium botulinum and is a neurotoxin that causes flaccid paralysis by inhibiting the release of acetylcholine from axonal endings at the neuromuscular junction.1 Since its first clinical use in 1973, the discovery of BTX as a therapeutic option has led to several advances in treating a multitude of neuromuscular, urologic, gastrointestinal (GI), and dermatologic disorders, among others.2 The goal of injection is to relax the targeted muscles, and experimentation in the GI tract has been underway since at least 1988 in the treatment of anismus for idiopathic constipation.3 Over the past 30 years, research on BTX use in the GI tract for a variety of disorders has continued to grow, particularly in areas of motility and spastic disorders such as achalasia, diffuse esophageal spasm (DES), gastroparesis, sphincter of Oddi disorders, chronic anal fissures (CAFs), and pelvic floor dysfunctions. It has also garnered much interest in disorders such as obesity. This article reviews the current literature on the use of BTX in different regions of the GI tract. 

Cricopharyngeal Dysphagia

Many neurologic disorders can cause dysfunction of the upper esophageal sphincter (UES) by impairing cricopharyngeal muscle relaxation during swallowing, which can lead to dysphagia and possible aspiration. BTX has been shown to have efficacy in treating cricopharyngeal dysphagia in several small case series; however, large randomized controlled trials (RCTs) are still lacking.1,4-8 The endoscopic technique uses a standard adult flexible upper endoscope with a 5-mm sclerotherapy needle to deliver 3 to 4 injections of BTX 25 units (U)/mL or more into the cricopharyngeus.9 However, a variety of other techniques have been used, including rigid endoscopy with electromyography (EMG) as well as an open technique with differing doses (onabotulinumtoxinA [Botox, Allergan] 10-50 U).10,11 Some researchers believe that reflux must be well controlled before injection to rule out mimicry of a primary disorder and to avoid postinjection laryngeal complications caused by a weakening of the UES.10,12-14

Using BTX in cricopharyngeal dysphagia was intended to be an alternative to myotomy, as BTX appears to have a lower risk of complications and decent success. Table 1 summarizes multiple small-scale studies involving a variety of techniques.1,4,6,7,9,15-18 Although BTX appears to be successful in this setting, variation in selected patients and techniques, small sample sizes, and lack of controls make it difficult to compare these studies. Thus, more research is needed. 

A comprehensive systematic review published in 2016 examined more than 500 studies on the use of myotomy, BTX, and dilation in cricopharyngeal dysphagia. Logistic regression analysis of patient-weighted averages found that the success rate of BTX injection was 69%, but the success rate of myotomy was higher (78%; P=.042). The success rate of dilation was not statistically different from that of myotomy or BTX (P values of .37 and .42, respectively).19

Ultimately, BTX injections can be considered as an alternative to surgical myotomy in patients who are not optimal surgical candidates or who seek only temporary relief of symptoms. BTX can also be used as a potential diagnostic test to predict response to surgical myotomy.1,16,20,21  Alberty and colleagues believed that if patients had good clinical response and significant improvement on video fluoroscopic swallow study, they would likely benefit from repeat BTX injections or cricopharyngeal myotomy.1 However, if there was no radiographic or clinical improvement, a stricture would be suspected and surgery considered.1,10 Patients with multilevel dysphagia in whom surgical myotomy may be more detrimental may also be good candidates for BTX injection for treatment of cricopharyngeal dysphagia.1,16,20,21


Achalasia is a motility disorder of the esophagus in which there is a lack of relaxation at the esophagogastric junction and a lack of distal esophageal peristalsis. These consequences occur because of progressive degeneration of inhibitory neurons in the myenteric plexus in the esophagus, which leads to unopposed cholinergic muscle excitation. BTX works by blocking the release of acetylcholine from nerve endings to attenuate muscle excitation and reduce spasticity. Treatments for achalasia include surgical myotomy, peroral endoscopic myotomy (POEM), endoscopic pneumatic dilation (PD), and BTX injection.22 

Although surgical myotomy is a durable option, it is associated with a higher likelihood of complications in patients who are high-risk surgical candidates. POEM is also durable but can be associated with iatrogenic gastroesophageal reflux disease.23 PD has shown to be cost-effective, although it is less durable than POEM or Heller myotomy (HM), and has a small risk of causing esophageal perforation.11,24,25 In patients with achalasia who are not ideal candidates for invasive procedures, BTX injections can be a viable option, particularly for type 2 achalasia. It was less effective in types 1 and 3 achalasia.25,26 

Some of the earliest studies of BTX in achalasia were performed in the 1990s after preliminary testing on piglets.27,28 The initial evaluation compared BTX injections with placebo injections of saline with a protocol to inject 80 U into 4 quadrants above the Z-line. Since then, a variety of techniques have been used for BTX injection in achalasia, including injections into 4 quadrants at 2 different levels in the lower esophageal sphincter (LES) region and below the gastroesophageal junction, endoscopic ultrasound–guided injections, and manometry-guided injections.29-32 Injections are aimed into the muscular layer, but even patients who received injections in the submucosa showed significant symptomatic improvement, particularly in Chagas disease and achalasia over a period of 6 months.33 

Optimal dosage of BTX with the lowest amount of relapse was found to be 100 U, according to a large multicenter randomized trial.30 Multiple trials have looked at BTX injections in relation with placebo and alternative therapies, such as PD, HM, or a combination (see eTable 1 at www.gastroenterology­,30,32-42 Many of these studies showed that, in the short term, BTX can have equitable outcomes in comparison with other modalities with a lower incidence of complications; however, BTX has a higher rate of relapse in symptoms, and PD, HM, and POEM have more long-lasting efficacy. 

Although BTX is safe and minimally invasive, it has several drawbacks. Although initial response can be excellent (~75%), only two-thirds of patients have sustained response at 6 months, with 60% of patients having recurrent dysphagia at 1 year and 80% at 2 years.34,43,44 Another drawback is that BTX injection can cause submucosal fibrosis, which may make subsequent definitive therapy more difficult.45 However, statistically, this did not affect overall outcomes in patients who received injections prior to HM or POEM.40 BTX pretreatment prior to PD showed some benefit vs PD alone in 1 trial (69% vs 50%), but was not statistically significant (P=.07).41 

Patients older than 50 years have higher response rates to BTX injections compared with younger patients for unclear reasons (82% vs 43%, respectively).11 In a study of 33 elderly patients with achalasia (ages 81-94 years), BTX 100 U was injected into the LES; 78% were responders at 1 year, and 54% were considered responders at 2 years. Thus, in this age range, BTX can be a safe and effective alternative that yields a good quality of life in a large portion of patients without risks of major complications.46 In patients who failed prior PD or HM, BTX injections resulted in improvement in 75% of patients. Although the duration of symptom relief was shorter, repeat injections of 100 U into the LES increased remission time.42 

Overall, in achalasia, BTX is recommended for patients who are poor medical candidates for definitive treatment (eg, patients who are elderly, with multiple comorbidities, previous therapeutic failure) or as a transient treatment for very acute cases (eg, total outlet obstruction).25 BTX can help predict who may respond well to alternative treatments such as PD or HM, but when used synergistically with other therapies, it does not increase remission time significantly.39 It is also not effective in type 3 achalasia.36

Nonachalasia Motility Disorders

The use of BTX has been explored in nonachalasia motility disorders such as DES, hypertensive peristalsis (previously known as nutcracker esophagus), and isolated hypertensive LES, as the pathophysiology of these disorders is thought to develop secondary to an imbalance in tissue levels of acetylcholine and nitric oxide. Although some patients with DES and hypertensive peristalsis have symptomatic improvement with BTX injection, this is not always associated with changes on high-resolution manometry. In 2013, a prospective controlled trial of 22 patients with DES or hypertensive peristalsis compared BTX injection (100 U) vs placebo for improvements in dysphagia and noncardiac chest pain. The BTX group had significant improvement with sustained results in 50% of patients at 1-year follow-up, compared with the placebo group.47 

In other studies, BTX injections showed improvement in dysphagia but not in heartburn or chest pain. There has been variable response with esophagogastric junction outlet obstruction and noncardiac chest pain in small retrospective studies.48 Overall, there appears to be a discordance between manometric findings and symptom improvement, in which improvement in both does not always coincide. This raises the question whether manometric findings can be used as a diagnostic or outcome measure in studying response to these therapies.49 

Some case reports describe the benefits of BTX injections in the management of hypertensive LES.44,50 An open-label trial of 29 patients showed a 50% reduction in noncardiac and nonreflux chest pain in 75% of patients for an average of 7.3 months.51 In a clinical trial evaluating the use of BTX in patients with DES (n= 9), BTX 100 U was injected into multiple sites along the esophagus, including contraction rings. At 1 month, 8 of 9 patients had significant improvement in symptoms. At 2 years, 4 patients required subsequent injections.52 These findings are promising; however, they need to be substantiated with larger RCTs.

Use of BTX in esophageal strictures is limited in the literature. However, a 2016 RCT of 67 patients evaluated BTX injections as a prophylactic way of preventing esophageal strictures after endoscopic submucosal dissection (ESD) of esophageal squamous cell carcinoma. BTX significantly reduced the development of strictures compared with ESD alone (6.1% vs 32.4%, respectively; P<.05). Thus, BTX injections may be effective in preventing post-ESD esophageal strictures.53 


Gastroparesis is characterized by impaired gastric emptying into the duodenum in the absence of gastric outlet obstruction. Classifications include idiopathic gastroparesis (IG), diabetic gastroparesis (DG), and postsurgical states. Multiple mechanisms have been theorized, including muscular, neural, or humoral dysfunctions causing gastric pacemaker abnormalities; excessive inhibitory feedback from the small bowel; decreased fundal tone; antrum hypomobility; loss of interstitial cells of Cajal; myenteric plexus degeneration; and pylorospasm.54-56 Injection of BTX into the pylorus was hypothesized as a way to improve gastric emptying. 

Early open-label trials showed a significant reduction in symptoms in patients with DG and improvements in gastric emptying at varying intervals from 4 to 12 weeks. However, these trials tended to be low-powered and lacked randomization or control groups.57-63 In 2007 and 2008, 2 randomized, double-blinded, placebo-controlled trials compared BTX injections with placebo saline injections and showed no statistical significance in the difference between the 2 groups in symptom improvement or solid-phase gastric emptying time. Improvements in gastric emptying time did not always correlate with symptom response.64,65 Criticism of these trials includes having a small sample size (54 total patients) and heterogeneity in the gastroparesis population (mixture of IG and DG patients). Table 2 shows different trials evaluating BTX in gastroparesis.58-67

Studies have attempted to identify which subgroups of gastroparesis patients may be more responsive to intrapyloric BTX injections. A large retrospective analysis by Coleski and colleagues consisted of 179 patients who received intrapyloric BTX injections for gastroparesis over a 7-year period (DG, n=81; IG, n=76; BTX dose, 100-200 U).66 More than half (51.4%) had symptom relief and weight improvement, whereas 32% had no benefit. Factors for better response included higher doses of injection, female sex, age less than 50 years, and etiologies not involving diabetes or surgery (P<.05). Response to repeat injections (87 total) was similar between patients who responded to the first injection and those who did not.66 In 2017, Wellington and colleagues evaluated 33 gastroparesis patients with a suspected etiology of pylorospasms with normal gastric myoelectric activity.68 BTX 100 U was injected intrapylorically, and symptomatic improvement was seen in 78% of patients (P<.04).68 This could suggest that there is a subset of gastroparesis patients that may respond well to BTX injections, but further studies are needed. 

Based on the 2 randomized trials available, the current American College of Gastroenterology guidelines recommend against the use of BTX injections for gastroparesis.69 In practice, BTX injections may still be attempted at some facilities for refractory gastroparesis owing to a good safety profile.70 


It is hypothesized that BTX injection into the gastric antrum can relax gastric smooth muscle, thereby delaying propulsion of food into the duodenum, which leads to early satiety and thus reduces dietary intake and causes weight loss. Initial animal research showed significant weight loss (P<.001) and reduced food intake (P<.05) in rats who received BTX injection vs saline injection or no intervention over 7 weeks.71 

One of the first pilot studies, in 2005, was a small, open-label, prospective trial of 8 patients (median body mass index [BMI] 47) who received gastric antral BTX injections (total 500 U) for weight loss. At 1-month follow-up, all patients lost weight, with a median weight loss of 2.6 kg and 3 patients continuing to lose weight 4 months after injection.72 However, in the same year, a study on endoscopy-guided gastric antral BTX injections in 12 obese patients found no significant changes in body weight or gastric emptying time in comparison with baseline values.73 Two small, open-label, prospective studies of 10 to 12 obese patients found that those who received BTX injections had early satiety, but there was no significant reduction in weight loss or gastric emptying at 12 to 16 weeks.74,75 

Since then, multiple RCTs have had mixed results. Studies have evaluated injection of BTX in varying locations of the stomach (ie, gastric angulus, antrum, or a combination of antrum and fundus) at differing doses (100-500 U) vs placebo. Many RCTs evaluating injection into the antrum or angulus found weight loss to be comparable between the BTX and placebo groups.72-78 RCTs that have shown statistically significant weight loss have injected both the antrum and fundus. A double-blinded placebo RCT that showed the most statistically significant weight loss in obese patients was one that injected both the antrum and fundus. The trial included 24 morbidly obese patients and injected BTX 200 U or placebo into the antrum and fundus of the stomach. At 8 weeks, all patients in the BTX group had a statistically significant amount of weight loss (11 kg vs 5.7 kg; P<.0006) and a decrease in BMI (4 vs 2; P<.001) compared with the placebo group.79 A randomized trial in 2012 evaluated BTX injection (200 U vs 300 U) into the antrum and fundus of 20 obese patients and found statistically significant weight loss, decreased triglyceride levels, and fasting ghrelin levels with longer gastric emptying times in both treatment groups at 12 weeks.80 

In summary, the limited number of studies investigating the effects of BTX on weight loss in obese patients have at best shown equivocal results. The variability may be owing to small sample sizes and differences in location of injection, dosing, or operator skill. A meta-analysis of 6 studies concluded that BTX interventions had no benefit in terms of reduction in weight or BMI in obese patients; however, the meta-analysis did not consider the injection site as an important variable.81 Many physicians have advocated for trials investigating BTX injections into the fundus because the studies reporting weight loss included it as a target site. Injection into the fundus could reduce gastric emptying and gastric accommodation, thereby increasing early satiety and decreasing oral intake. A higher-powered, randomized, double-blind, controlled trial is needed to evaluate this possibility.82 With no apparent serious adverse effects related to its use, BTX still appears to be an attractive option to some doctors, but currently cannot be routinely recommended.

Sphincter of Oddi Disorders

The sphincter of Oddi is a ring of muscle that surrounds the distal end of the biliary and pancreatic ducts at the convergence prior to its emptying into the duodenum. Sphincter of Oddi dysfunction (SOD) is characterized by chronic biliary pain or pancreatitis owing to functional obstruction at the level of the sphincter of Oddi. According to the Rome IV criteria, there are 2 subtypes: functional biliary sphincter of Oddi disorder and functional pancreatic sphincter of Oddi disorder. In functional biliary sphincter of Oddi disorder, there is biliary pain associated with either elevated liver enzymes or a dilated bile duct (not both) and there are no biliary stones or structural abnormalities. In functional pancreatic sphincter of Oddi disorder, there must be recurrent episodes of pancreatitis, exclusion of other causes of pancreatitis, negative endoscopic ultrasound findings, and abnormal sphincter manometry. Endoscopic sphincterotomy is the standard of treatment but is considered a high-risk procedure that is not consistently effective. Thus, BTX, hypothesized to be a safer alternative, has been evaluated to see whether sustained response can be achieved.83 Additionally, the role of BTX in predicting response to sphincterotomy has been evaluated. 

Currently, there are a few potential uses of BTX in SOD. The first research on BTX in SOD examined whether it could predict which of 2 patients would respond to sphincterotomy.84 Several uncontrolled case series or studies have since demonstrated that BTX injections may have a high positive predictive value in identifying patients who may improve after sphincterotomy.85-87 In 1998, a larger study of 22 patients looked at BTX’s effectiveness in type III SOD (using previous Milwaukee criteria: manometric basal sphincter pressures >40 mm Hg without laboratory or structural abnormalities). A single injection of BTX 100 U was inserted at the sphincter of Oddi, and 55% of patients responded to treatment with 92% remaining asymptomatic at 6 months. Eleven of 12 patients who had a recurrence of symptoms were treated with sphincterotomy and had long-term resolution of symptoms at 15 months. Of the 10 patients who did not respond to initial BTX injections, 5 had normal sphincter pressures and did not respond to sphincterotomy, whereas only 2 of the 5 with sustained sphincter hypertension benefited from subsequent sphincterotomy (P<.01).85 However, patients with SOD who underwent biliary sphincterotomy had a higher risk of developing post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis thought to be secondary to residual pancreatic sphincter hypertension. A study in 2004 looked at BTX injection vs sham injection into the pancreatic sphincter of patients after biliary sphincterotomy and found some reduction in postprocedure pancreatitis; however, it was not statistically significant (P=.34).88 Although these data may support a proof of concept for BTX, type III SOD is no longer a recognized entity for which ERCP is indicated, according to the EPISOD trial.89 

BTX has also been evaluated for SOD with recurrent pancreatitis. A study by Wehrmann and colleagues looked at the efficacy of BTX in preventing recurrent pancreatitis owing to SOD in 15 women with recurrent pancreatitis with manometric evidence of SOD.86 Patients were treated with a single injection of BTX 100 U into the ampulla of Vater, and the effectiveness of treatment was monitored over 3 months. Twelve patients (80%) remained asymptomatic at 3-month follow-up; however, 11 patients developed recurrent symptoms at 8 months and underwent pancreatic or biliopancreatic sphincterotomy with long-term remission at 15 months. Of the 3 patients who did not respond to therapy, 1 showed manometric evidence of elevated pancreatic sphincter pressure and benefited from pancreatic sphincterotomy.86 However, 3 months for follow-up is a short time frame for making substantial conclusions given that recurrent acute pancreatitis may occur as often as every 2 years. Additionally, manometry findings and symptoms do not always correlate. 

In acalculous biliary pain, BTX injections have been used for relaxing the sphincter of Oddi.90 One study found that in 25 patients with acalculous biliary pain, 44% had a positive response to injection of BTX 100 U into the sphincter of Oddi. All of these patients who underwent sphincterotomy had resolution of pain. Of those who did not respond to BTX, only 80% improved with sphincterotomy. BTX injections into the sphincter of Oddi may help direct therapy for patients with acalculous biliary pain.90,91 

In a prospective clinical phase 1/2 trial in 2017, preoperative BTX injection into the sphincter of Oddi was used as a novel approach to reduce the incidence of postoperative pancreatic fistula after distal pancreatectomy. None of the 29 patients injected with BTX had clinically relevant fistulas, compared with 33% of the case-control patients (P<.004).92 A retrospective study attempted to reproduce these results in 19 patients but found no statistical significance.93 Regardless, the data have prompted a government-sponsored, multicenter, pilot RCT in Germany (PREBOT; registration number: DRKS00020401).94

In summary, although existing data are very limited, some studies may suggest proof of principle that BTX could provide short-term benefit and may be predictive of response to sphincterotomy in certain patients with sphincter of Oddi disorders. Most of the literature, however, appears to be of limited value owing to small study sizes, uncontrolled series, unclear gold standard, limited duration of follow-up, and the bulk of the supportive data being for a condition (type III SOD) for which it is now believed that sphincter ablation is of no value. Additional methodologically rigorous research is necessary to understand whether BTX plays any role for this condition.

Chronic Anal Fissures

Anal fissures are tears in the anoderm that start at the anal verge and can extend to the dentate line and typically arise in the mid-posterior position of the anus. They are thought to occur secondary to increased anal sphincter pressure in the setting of ischemia. Symptoms can include painful defecation and rectal bleeding. Most acute fissures heal by themselves within several weeks. If anal fissures last more than 4 to 6 weeks, they are considered to be chronic. For CAFs, therapies are aimed at decreasing sphincter tone to help increase blood flow and promote healing. Treatments can include topical nitroglycerin, oral nifedipine, BTX injections, or lateral internal sphincterotomy (LIS).95

Many studies have looked at the effectiveness of BTX injections vs placebo or alternative noninvasive treatments for CAFs (see eTable 2 at www.gastroenterology­ In several studies, BTX injections were more effective than placebo or nitroglycerin ointment and had fewer side effects.96,97 Whether the injection location impacts the effectiveness of healing has also been studied. One theory is that the internal anal sphincter (IAS) has fibrosis at the site of posterior fissures that may delay healing. Patients who received anterior injections of BTX had lower resting IAS pressures and faster healing compared with patients who received posterior injections (88% vs 60%, respectively; P=.025).98 Increasing the number of injections (bilateral injections vs a single injection) did not significantly affect outcomes.99 The optimal dosage for BTX injections remains unsettled for symptom improvement despite multiple small studies.100 A 2016 meta-analysis analyzed dose-dependent efficiency of BTX (5-150 U) among 1577 patients over 34 prospective studies and found no significant difference in terms of effectiveness, postoperative complications, or healing rates.101 There was no significant correlation between dose and recurrence of symptoms or between dose and long-term efficacy of treatment.102,103 

Although the gold standard for CAFs is LIS, BTX can be a safer alternative with lower risk of side effects (eg, anal incontinence, bleeding, pain, abscess, fistula); however, long-term efficacy is lower. LIS is superior in sustained response, but BTX has fewer complications and faster healing times.104 Meta-analyses in the past 2 decades have included many randomized trials on
different treatment options for CAFs; however, the trials have had poor quality of evidence secondary to heterogeneity of the population, risk of bias, and inadequate clinical follow-up. The strongest quality of evidence was comparing LIS with general medical therapy.105-107 LIS is superior to nonsurgical therapies in terms of sustained treatment and low recurrence, but has an overall higher rate of anal incontinence (3.4%-4.4% in 1 study and up to 16% in another), which is dependent on the surgeon’s skill.104,105 In comparison, complication rates with BTX were close to zero, with some patients having mild transient incontinence. BTX was also superior to other nonsurgical methods such as nitroglycerin and oral nifedipine. Combination therapy with BTX and nitroglycerin or oral nifedipine had moderate improvement in healing.108,109 Results were also statistically better with a combination of BTX and oral nifedipine compared with nitroglycerin and PD. In patients with a history of LIS and recurrent anal fissures, BTX can be used therapeutically and diagnostically to identify those who would not be suitable for further surgical LIS if transient fecal incontinence developed.110 

BTX may be an option in patients who are not optimal candidates for LIS or for those who prefer less-­invasive forms of treatment. BTX is a viable treatment modality for elderly patients, those who have a higher risk of fecal incontinence with surgery, those who prefer to avoid surgical management, and those with a history of prior sphincterotomy. When BTX’s effect wanes, repeat injections can be offered.104,107-109 Its short-term response rate is often greater than 60%, symptoms tend to improve with retreatment, and it can be more cost-effective given the unforeseen costs of treating potential complications of surgery.111 Surgical intervention is best considered in patients with persistence/recurrence, noncompliance, or intolerance to other conservative treatments. Although some reviews suggest that medical management and BTX provide little more than placebo, their evidence is low quality and from smaller studies.112 

Overall, larger high-quality multicenter studies are needed with standardized selections of patients, doses, and injection techniques to make a more definitive conclusion. In the interim, BTX may be a good first option in CAFs, as it is a cost-effective approach that can provide symptomatic relief and healing while avoiding permanent alterations to the anal sphincter and complications of incontinence or other systemic side effects.

Chronic Idiopathic Anal Pain

Anal pain can be attributed to structural or functional causes, often with an inappropriate loop between spasms and pain contributing to a chronic pain syndrome.
Functional causes tend to be difficult to manage conservatively. BTX has been studied in chronic functional anorectal pain. In a study evaluating 113 patients at a tertiary proctology clinic, patients with hypertonia of the anal sphincter received 2 injections of BTX 30 U and patients with hypertonia of the levator ani received 2 injections of 40 U. If hypertonia was present in both areas, patients received both treatments. Of those patients who received both treatments, 47% had complete resolution of pain, 20% had temporary resolution with relapse within 3 months, and 33% had poor or no response to therapy.113


Anismus (also known as pelvic floor dyssynergia) is the inappropriate contraction of the pelvic floor muscles when attempting to defecate. This involves the puborectalis muscle and external anal sphincter (EAS) and can lead to chronic severe constipation via outlet obstruction.114-116 It is hypothesized that this inappropriate contraction is a maladaptive learned behavior. However, some research in patients with Parkinson disease suggests that this dysfunction may also present as a form of focal dystonia.117 As a result, some physicians have used BTX injections to lower puborectalis tone and facilitate defecation. The mainstay of treatment in patients with anismus is typically biofeedback, which leads to improvement in up to 70% of patients. Surgery is not an effective treatment.111 There is some evidence that BTX use in these patients can be effective, although the quality of data is poor because it mainly comes from small uncontrolled, open-label, single-group trials. 

In 1988, the first study evaluated 7 patients with anismus and constipation who received BTX injection of unknown dosage into the EAS. Patient symptom scores showed significant improvement correlating with reduced maximum voluntary anal canal squeeze pressure and improvement in anorectal angle on straining; however, 2 of the 7 patients experienced fecal incontinence.3 In a small study of 4 patients who were injected at 2 sites in the puborectalis muscle with BTX 30 U, 3 patients (75%) showed improvement by 8 weeks (the other was lost to follow-up). There was significant improvement in anal tone (96.2 mm Hg vs 42.5 mm Hg) at 4 weeks (P=.003) and (63.2 mm Hg vs 22 mm Hg) at 8 weeks (P=.009), as well as significant improvement in anorectal angle (94º vs 114º; P=.01). Two of the patients had sustained response for up to 1 year, whereas 1 patient required repeat injections at 16 weeks and 8 months.118 In 2006, 15 patients with anismus received onabotulinumtoxinA 25 U into the EAS; improvement was seen in 87% of patients with an average remission time of 4.8 months.119 Similar results were seen in a prior study evaluating BTX injections into the EAS for nonrelaxing puborectalis syndrome.120 A 2016 systematic review of 189 patients from 7 trials evaluated the response of anismus to BTX injection. Five studies used lateral EAS injections, whereas 2 studies used a combination of lateral and posterior injections. A median injection of 100 U resulted in improvement in 77.4% of patients at 1 month (measured via balloon expulsion test, EMG, and defecography). However, that number rapidly dropped to 46% at 4 months, with 7.4% developing complications after injection.121 Thus, although initial improvement can be seen, there tends to be a rapid deterioration of effect by 4 months; however, it may be possible to combat this with repeat injections. Larger studies are needed. 

The combination of BTX and biofeedback training can be effective. A 2014 study looked at 31 patients with anismus who failed simple biofeedback training and evaluated the effects of BTX injection with biofeedback training. The researchers administered BTX 100 U into the puborectalis muscle and EAS consecutively during needle withdrawal and then provided biofeedback training 2 weeks after injection. Twenty-three of the patients had success and reported satisfaction throughout an 8-month period.122

In patients with Parkinson disease and outlet-type constipation secondary to focal dystonia of the pelvic floor, BTX injections led to improvement in 55% in terms of symptoms, anorectal manometry, and defecography. However, the study’s results were weak in strength owing to its small size (N=18) and lack of a placebo group.117 

Outlet obstruction can also be caused by anterior rectoceles, which, in some cases, are thought to form secondary to failure of the puborectalis muscle to relax. Initial management usually involves a high-residue diet with a combination of laxatives and enemas as needed. Although there can be success with surgical options (transanal, trans­perineal, or transvaginal approaches), they come with the risk of impaired anal sphincter function, particularly with the transanal approach. Thus, the use of BTX injections in this patient population has been examined. In 2001, an open-label study of 14 women with anterior rectoceles treated with ultrasound-guided BTX injections found that 64% had symptomatic improvement, and there was a significant reduction in rectocele depth (4.3 cm to 1.8 cm; P<.05). At 1 year, no patients required digital assistance to defecate and had evidence of rectocele on digital examination, although 28.5% had defecographic evidence of a rectocele.123 

Overall, BTX injections are safe and a reasonable option for patients with chronic functional anal pain with a relatively low risk of complications. Early treatment in patients after 3 to 6 months of pain can be a plausible option to prevent behavioral changes such as paradoxical contractions of the pelvic floor (pelvic dyssynergia), which may require further combination of BTX injections and behavioral modification therapies. Additional treatments for recurrent pain can be beneficial; however, larger RCTs are needed for further evaluation. 

Postsurgical Hemorrhoidectomy Pain

In patients who undergo hemorrhoidectomy, the resting pressure of the anal canal can often be significantly elevated. Thus, postsurgical hemorrhoidectomy pain is thought to be secondary to spasms of the IAS. The purpose of BTX injection in postsurgical hemorrhoidectomy pain is to relax the IAS, thereby relieving pain. In a double-blind RCT of BTX use in postsurgical hemorrhoidectomy pain, 50 patients were randomized into treatment and placebo groups for injection of BTX (20 U) vs saline. On postoperative days 6 and 7, there was a significant improvement in pain compared with the placebo group (P<.05).124 Similarly, a study of 30 patients with third- and fourth-degree hemorrhoids compared BTX (20 U) with normal saline injections at the time of surgery. On day 5 postsurgical hemorrhoidectomy, maximum resting pressures, time to wound healing, and postoperative pain at rest and with defecation were significantly decreased in the BTX group (P<.05). However, maximum resting pressures returned to preoperative levels in both groups at 30 days postoperation.125 In an RCT, 90 patients were split into control vs BTX (30 U) groups. At 12 and 24 hours postoperatively, there was a significant reduction in visual analog pain score (P<.001 and P=.003, respectively).126 

However, an RCT of 32 patients found no significant difference between BTX and placebo in decreasing maximal pressure and squeeze pressure at 5 days postoperation.127 Complications related to BTX injections involved transient incontinence (0%-33%) and typically involved flatus lasting 3 to 12 weeks. Ultimately, more high-powered studies are needed to determine how helpful BTX is in this setting, although it appears that maximal anal pressures were reduced and overall healing time was shortened by at least a week (average healing time 3-5 weeks) in patients who received BTX.125,127 

When compared with topical glyceryl trinitrate (GTN), BTX is superior at 7 days for maximal relief of anal pain at rest and for overall analgesic required. Both are equally efficacious at reducing pain scores on defecation, and there was no significant difference in wound healing time. However, topical GTN had more side effects, including increased headaches.128 

Overall, the use of BTX in postsurgical hemorrhoidectomy pain can be useful for decreasing symptoms up to 1 week after the procedure, including pain at rest and with defecation; however, there is some possibility of transient side effects, including flatus that may persist for up to 3 months. BTX may be a good option in patients with poor compliance to medical therapy postoperatively. 


For 30 years, BTX has been studied as a treatment modality in a variety of GI disorders with varying results. The appeal of BTX comes from its simplicity of administration, good safety profile, reliability in decreasing muscular tone, and effective response rate in patients who have failed conventional therapies. However, there are several drawbacks that limit its use, including the lack of long-term efficacy in many GI disorders, which leads to repeat administrations, additional costs associated with multiple procedures, and unclear effect in certain
disorders such as gastroparesis and obesity. Overall, BTX has well-established efficacy in achalasia, CAFs, and cricopharyngeal dysphagia. In disorders such as achalasia, it can serve as a reliable option for patients at higher risk of adverse events from myotomy (eg, patients who are elderly or have multiple comorbidities) and can be palliative in nature. Additionally, BTX can be an option for patients who favor a more conservative approach when there is fear of potential adverse events from surgery (eg, fecal incontinence after LIS). 

However, data in other areas of the GI tract are limited by the number of low-powered trials, heterogeneity of patients, studies without placebo groups, and lack of blinding in open-label trials. There is a strong need for further investigation of BTX use in larger RCTs in various areas of the GI tract. Also, many studies are difficult to compare owing to differing administrative techniques, injection sites, and dosages, as well as variable small patient populations in areas such as anismus, gastroparesis, and obesity. Establishing larger well-designed randomized trials with less heterogeneity among patients and intervention techniques may allow for stronger support for or against BTX use in these disorders. 

In future studies, methods that could potentially prolong the duration of action of BTX injections or combine them with therapies that could target additional neuronal pathways in the GI tract would be worth investigating. Methodologically rigorous prospective studies are needed to define the exact role of BTX for some indications. Table 3 summarizes the current indications for BTX use in the GI tract in the opinion of the authors, as assessed by the quality of evidence.129


The authors have no relevant conflicts of interest to disclose. 


The authors are grateful to B. Joseph Elmunzer, MD, MSc, from Medical University of South Carolina for critical review and suggestions regarding the section on sphincter of Oddi disorders.


1. Alberty J, Oelerich M, Ludwig K, Hartmann S, Stoll W. Efficacy of botulinum toxin A for treatment of upper esophageal sphincter dysfunction. Laryngoscope. 2000;110(7):1151-1156.

2. Scott AB, Rosenbaum A, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol. 1973;12(12):924-927.

3. Hallan RI, Williams NS, Melling J, Waldron DJ, Womack NR, Morrison JF. Treatment of anismus in intractable constipation with botulinum A toxin. Lancet. 1988;2(8613):714-717.

4. Haapaniemi JJ, Laurikainen EA, Pulkkinen J, Marttila RJ. Botulinum toxin in the treatment of cricopharyngeal dysphagia. Dysphagia. 2001;16(3):171-175.

5. Moerman MB. Cricopharyngeal Botox injection: indications and technique. Curr Opin Otolaryngol Head Neck Surg. 2006;14(6):431-436.

6. Krause E, Schirra J, Gürkov R. Botulinum toxin A treatment of cricopharyngeal dysphagia after subarachnoid hemorrhage. Dysphagia. 2008;23(4):406-410.

7. Alfonsi E, Merlo IM, Ponzio M, et al. An electrophysiological approach to the diagnosis of neurogenic dysphagia: implications for botulinum toxin treatment. J Neurol Neurosurg Psychiatry. 2010;81(1):54-60.

8. Regan J, Murphy A, Chiang M, McMahon BP, Coughlan T, Walshe M. Botulinum toxin for upper oesophageal sphincter dysfunction in neurological swallowing disorders. Cochrane Database Syst Rev. 2014;(5):CD009968.

9. Shaw GY, Searl JP. Botulinum toxin treatment for cricopharyngeal dysfunction. Dysphagia. 2001;16(3):161-167.

10. Zhao X, Pasricha PJ. Botulinum toxin for spastic GI disorders: a systematic review. Gastrointest Endosc. 2003;57(2):219-235.

11. Cariati M, Chiarello MM, Cannistra’ M, Lerose MA, Brisinda G. Gastrointestinal uses of botulinum toxin. Handb Exp Pharmacol. 2021;263:185-226.

12. Restivo DA, Marchese Ragona R, Staffieri A, de Grandis D. Successful botulinum toxin treatment of dysphagia in oculopharyngeal muscular dystrophy. Gastroenterology. 2000;119(5):1416.

13. Blitzer A, Sulica L. Botulinum toxin: basic science and clinical uses in otolaryngology. Laryngoscope. 2001;111(2):218-226.

14. Chiu MJ, Chang YC, Hsiao TY. Prolonged effect of botulinum toxin injection in the treatment of cricopharyngeal dysphagia: case report and literature review. Dysphagia. 2004;19(1):52-57.

15. Jeong SH, Kim YJ, Kim YJ, et al. Endoscopic botulinum toxin injection for treatment of pharyngeal dysphagia in patients with cricopharyngeal dysfunction. Scand J Gastroenterol. 2018;53(10-11):1201-1205.

16. Blitzer A, Brin MF. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngol Head Neck Surg. 1997;116(3):328-330.

17. Schneider I, Thumfart WF, Pototschnig C, Eckel HE. Treatment of dysfunction of the cricopharyngeal muscle with botulinum A toxin: introduction of a new, noninvasive method. Ann Otol Rhinol Laryngol. 1994;103(1):31-35.

18. Liu LW, Tarnopolsky M, Armstrong D. Injection of botulinum toxin A to the upper esophageal sphincter for oropharyngeal dysphagia in two patients with inclusion body myositis. Can J Gastroenterol. 2004;18(6):397-399.

19. Kocdor P, Siegel ER, Tulunay-Ugur OE. Cricopharyngeal dysfunction: a systematic review comparing outcomes of dilatation, botulinum toxin injection, and myotomy. Laryngoscope. 2016;126(1):135-141.

20. Kelly EA, Koszewski IJ, Jaradeh SS, Merati AL, Blumin JH, Bock JM. Botulinum toxin injection for the treatment of upper esophageal sphincter dysfunction. Ann Otol Rhinol Laryngol. 2013;122(2):100-108.

21. Kuhn MA, Belafsky PC. Management of cricopharyngeus muscle dysfunction. Otolaryngol Clin North Am. 2013;46(6):1087-1099.

22. Lacy BE, Weiser K, Kennedy A. Botulinum toxin and gastrointestinal tract disorders: panacea, placebo, or pathway to the future? Gastroenterol Hepatol (N Y). 2008;4(4):283-295.

23. Patel K, Abbassi-Ghadi N, Markar S, Kumar S, Jethwa P, Zaninotto G. Peroral endoscopic myotomy for the treatment of esophageal achalasia: systematic review and pooled analysis. Dis Esophagus. 2016;29(7):807-819.

24. Ghoshal UC, Karyampudi A, Verma A, et al. Perforation following pneumatic dilation of achalasia cardia in a university hospital in northern India: a two-decade experience. Indian J Gastroenterol. 2018;37(4):347-352.

25. Zaninotto G, Bennett C, Boeckxstaens G, et al. The 2018 ISDE achalasia guidelines. Dis Esophagus. 2018;31(9).  

26. Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. 2019;106(4):332-341.

27. Pasricha PJ, Ravich WJ, Kalloo AN. Effects of intrasphincteric botulinum toxin on the lower esophageal sphincter in piglets. Gastroenterology. 1993;105(4):1045-1049.

28. Cohen S, Parkman HP. Treatment of achalasia—from whalebone to botulinum toxin. N Engl J Med. 1995;332(12):815-816.

29. Annese V, Bassotti G, Coccia G, et al; the Gismad Achalasia Study Group. Comparison of two different formulations of botulinum toxin A for the treatment of oesophageal achalasia. Aliment Pharmacol Ther. 1999;13(10):1347-1350.

30. Annese V, Bassotti G, Coccia G, et al; GISMAD Achalasia Study Group. A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia. Gut. 2000;46(5):597-600.

31. Hoffman BJ, Knapple WL, Bhutani MS, Verne GN, Hawes RH. Treatment of achalasia by injection of botulinum toxin under endoscopic ultrasound guidance. Gastrointest Endosc. 1997;45(1):77-79.

32. Wehrmann T, Schmitt T, Dietrich CF, Caspary WF, Seifert H. Manometrically-guided endoscopic injection of botulinum toxin for esophageal achalasia: a pilot trial. Z Gastroenterol. 2000;38(11):899-903.

33. Brant C, Moraes-Filho JP, Siqueira E, et al. Intrasphincteric botulinum toxin injection in the treatment of chagasic achalasia. Dis Esophagus. 2003;16(1):33-38.

34. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Intrasphincteric botulinum toxin for the treatment of achalasia [published correction appears in N Engl J Med. 1995;333(1):75]. N Engl J Med. 1995;332(12):774-778.

35. Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial. Gut. 1999;44(2):231-239.

36. Marjoux S, Brochard C, Roman S, et al. Botulinum toxin injection for hypercontractile or spastic esophageal motility disorders: may high-resolution manometry help to select cases? Dis Esophagus. 2015;28(8):735-741.

37. Annese V, Basciani M, Perri F, et al. Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia. Gastroenterology. 1996;111(6):1418-1424.

38. Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia. Cochrane Database Syst Rev. 2014;(12):CD005046.

39. Zaninotto G, Vergadoro V, Annese V, et al. Botulinum toxin injection versus laparoscopic myotomy for the treatment of esophageal achalasia: economic analysis of a randomized trial. Surg Endosc. 2004;18(4):691-695.

40. Horgan S, Hudda K, Eubanks T, McAllister J, Pellegrini CA. Does botulinum toxin injection make esophagomyotomy a more difficult operation? Surg Endosc. 1999;13(6):576-579.

41. Kroupa R, Hep A, Dolina J, et al. Combined treatment of achalasia—botulinum toxin injection followed by pneumatic dilatation: long-term results. Dis Esophagus. 2010;23(2):100-105.

42. Annese V, Basciani M, Borrelli O, Leandro G, Simone P, Andriulli A. Intrasphincteric injection of botulinum toxin is effective in long-term treatment of esophageal achalasia. Muscle Nerve. 1998;21(11):1540-1542.

43. Pehlivanov N, Pasricha PJ. Medical and endoscopic management of achalasia. GI Motility Online. Published May 16, 2006. doi:10.1038/gimo52.

44. Lacy BE, Zayat EN, Crowell MD. Case report: botulinum toxin in hypertensive lower esophageal sphincter: a manometric case study. Dysphagia. 2002;17(1):75-80.

45. Swanström LL. Achalasia: treatment, current status and future advances. Korean J Intern Med (Korean Assoc Intern Med). 2019;34(6):1173-1180.

46. Bassotti G, D’Onofrio V, Battaglia E, et al. Treatment with botulinum toxin of octo-nonagerians with oesophageal achalasia: a two-year follow-up study. Aliment Pharmacol Ther. 2006;23(11):1615-1619.

47. Vanuytsel T, Bisschops R, Farré R, et al. Botulinum toxin reduces dysphagia in patients with nonachalasia primary esophageal motility disorders. Clin Gastroenterol Hepatol. 2013;11(9):1115-1121.e2.

48. Sterling JL, Schey R, Malik Z. The role of botulinum toxin injections for esophageal motility disorders. Curr Treat Options Gastroenterol. 2018;16(4):528-540.

49. Nayar DS, Khandwala F, Achkar E, et al. Esophageal manometry: assessment of interpreter consistency. Clin Gastroenterol Hepatol. 2005;3(3):218-224.

50. Herzig MJ, Tutuian R. Focal achalasia—case report and review of the literature. Clujul Med. 2018;91(1):120-128.

51. Miller LS, Pullela SV, Parkman HP, et al. Treatment of chest pain in patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using botulinum toxin injection into the gastroesophageal junction. Am J Gastroenterol. 2002;97(7):1640-1646.

52. Storr M, Allescher HD, Rösch T, Born P, Weigert N, Classen M. Treatment of symptomatic diffuse esophageal spasm by endoscopic injections of botulinum toxin: a prospective study with long-term follow-up. Gastrointest Endosc. 2001;54(6):754-759.

53. Wen J, Lu Z, Linghu E, et al. Prevention of esophageal strictures after endoscopic submucosal dissection with the injection of botulinum toxin type A. Gastrointest Endosc. 2016;84(4):606-613.

54. Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic gastroparesis. Clin Gastroenterol Hepatol. 2011;9(1):5-12.

55. Bityutskiy LP, Soykan I, McCallum RW. Viral gastroparesis: a subgroup of idiopathic gastroparesis—clinical characteristics and long-term outcomes. Am J Gastroenterol. 1997;92(9):1501-1504.

56. Zárate N, Mearin F, Wang XY, Hewlett B, Huizinga JD, Malagelada JR. Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management. Gut. 2003;52(7):966-970.

57. Wiesel PH, Schneider R, Dorta G, Blum AL, Gillet M, Michetti P. Botulinum toxin for refractory postoperative pyloric spasm. Endoscopy. 1997;29(2):132.

58. Ezzeddine D, Jit R, Katz N, Gopalswamy N, Bhutani MS. Pyloric injection of botulinum toxin for treatment of diabetic gastroparesis. Gastrointest Endosc. 2002;55(7):920-923.

59. Lacy BE, Crowell MD, Schettler-Duncan A, Mathis C, Pasricha PJ. The treatment of diabetic gastroparesis with botulinum toxin injection of the pylorus. Diabetes Care. 2004;27(10):2341-2347.

60. Bromer MQ, Friedenberg F, Miller LS, Fisher RS, Swartz K, Parkman HP. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest Endosc. 2005;61(7):833-839.

61. Rameshshanker R, Smith L, Southern P, Whitelaw D, Beckett C. Gastroparesis and botulinum toxin. Gut. 2011;60(suppl 1):A105-A106.

62. Miller LS, Szych GA, Kantor SB, et al. Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. Am J Gastroenterol. 2002;97(7):1653-1660.

63. Arts J, van Gool S, Caenepeel P, Verbeke K, Janssens J, Tack J. Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients. Aliment Pharmacol Ther. 2006;24(4):661-667.

64. Arts J, Holvoet L, Caenepeel P, et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther. 2007;26(9):1251-1258.

65. Friedenberg FK, Palit A, Parkman HP, Hanlon A, Nelson DB. Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol. 2008;103(2):416-423.

66. Coleski R, Anderson MA, Hasler WL. Factors associated with symptom response to pyloric injection of botulinum toxin in a large series of gastroparesis patients. Dig Dis Sci. 2009;54(12):2634-2642.

67. Rodriguez L, Rosen R, Manfredi M, Nurko S. Endoscopic intrapyloric injection of botulinum toxin A in the treatment of children with gastroparesis: a retrospective, open-label study. Gastrointest Endosc. 2012;75(2):302-309.

68. Wellington J, Scott B, Kundu S, Stuart P, Koch KL. Effect of endoscopic pyloric therapies for patients with nausea and vomiting and functional obstructive gastroparesis. Auton Neurosci. 2017;202:56-61.

69. Camilleri M, Kuo B, Nguyen L, et al. ACG Clinical Guideline: gastroparesis. Am J Gastroenterol. 2022;117(8):1197-1220.

70. Su A, Conklin JL, Sedarat A. Endoscopic therapies for gastroparesis. Curr Gastroenterol Rep. 2018;20(6):25. 

71. Gui D, De Gaetano A, Spada PL, Viggiano A, Cassetta E, Albanese A. Botulinum toxin injected in the gastric wall reduces body weight and food intake in rats. Aliment Pharmacol Ther. 2000;14(6):829-834.

72. Albani G, Petroni ML, Mauro A, et al. Safety and efficacy of therapy with botulinum toxin in obesity: a pilot study. J Gastroenterol. 2005;40(8):833-835.

73. García-Compean D, Mendoza-Fuerte E, Martínez JA, Villarreal I, Maldonado H. Endoscopic injection of botulinum toxin in the gastric antrum for the treatment of obesity. Results of a pilot study. Gastroenterol Clin Biol. 2005;29(8-9):789-791.

74. Júnior AC, Savassi-Rocha PR, Coelho LG, et al. Botulinum A toxin injected into the gastric wall for the treatment of class III obesity: a pilot study. Obes Surg. 2006;16(3):335-343.

75. Gui D, Mingrone G, Valenza V, et al. Effect of botulinum toxin antral injection on gastric emptying and weight reduction in obese patients: a pilot study. Aliment Pharmacol Ther. 2006;23(5):675-680.

76. Mittermair R, Keller C, Geibel J. Intragastric injection of botulinum toxin A for the treatment of obesity [published correction appears in Obes Surg. 2007;17(7):996]. Obes Surg. 2007;17(6):732-736.

77. Topazian M, Camilleri M, Enders FT, et al. Gastric antral injections of botulinum toxin delay gastric emptying but do not reduce body weight. Clin Gastroenterol Hepatol. 2013;11(2):145-150.e1.

78. de Moura EGH, Ribeiro IB, Frazão MSV, et al. EUS-guided intragastric injection of botulinum toxin A in the preoperative treatment of super-obese patients: a randomized clinical trial. Obes Surg. 2019;29(1):32-39.

79. Foschi D, Corsi F, Lazzaroni M, et al. Treatment of morbid obesity by intraparietogastric administration of botulinum toxin: a randomized, double-blind, controlled study. Int J Obes. 2007;31(4):707-712.

80. Li L, Liu QS, Liu WH, et al. Treatment of obesity by endoscopic gastric intramural injection of botulinum toxin A: a randomized clinical trial. Hepatogastroenterology. 2012;59(118):2003-2007.

81. Bustamante F, Brunaldi VO, Bernardo WM, et al. Obesity treatment with botulinum toxin-A is not effective: a systematic review and meta-analysis. Obes Surg. 2017;27(10):2716-2723.

82. Badurdeen DS, Fayad L, Kalloo AN, Kumbhari V. The forgotten fundus-­response to – obesity treatment with botulinum toxin-A is not effective: a systematic review and meta-analysis. Obes Surg. 2018;28(1):262-263.

83. Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES. Rome IV. Gallbladder and sphincter of Oddi disorders [published online February 19, 2016]. Gastroenterology. doi:10.1053/j.gastro.2016.02.033.

84. Pasricha PJ, Miskovsky EP, Kalloo AN. Intrasphincteric injection of botulinum toxin for suspected sphincter of Oddi dysfunction. Gut. 1994;35(9):1319-1321.

85. Wehrmann T, Seifert H, Seipp M, Lembcke B, Caspary WF. Endoscopic injection of botulinum toxin for biliary sphincter of Oddi dysfunction. Endoscopy. 1998;30(8):702-707.

86. Wehrmann T, Schmitt TH, Arndt A, Lembcke B, Caspary WF, Seifert H. Endoscopic injection of botulinum toxin in patients with recurrent acute pancreatitis due to pancreatic sphincter of Oddi dysfunction. Aliment Pharmacol Ther. 2000;14(11):1469-1477.

87. Banerjee B, Miedema B, Saifuddin T, Marshall JB. Intrasphincteric botulinum toxin type A for the diagnosis of sphincter of Oddi dysfunction: a case report. Surg Laparosc Endosc Percutan Tech. 1999;9(3):194-196.

88. Gorelick A, Barnett J, Chey W, Anderson M, Elta G. Botulinum toxin injection after biliary sphincterotomy. Endoscopy. 2004;36(2):170-173.

89. Cotton PB, Durkalski V, Romagnuolo J, et al. Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial. JAMA. 2014;311(20):2101-2109.

90. Murray WR. Botulinum toxin-induced relaxation of the sphincter of Oddi may select patients with acalculous biliary pain who will benefit from cholecystectomy. Surg Endosc. 2011;25(3):813-816.

91. Murray W, Kong S. Botulinum toxin may predict the outcome of endoscopic sphincterotomy in episodic functional post-cholecystectomy biliary pain. Scand J Gastroenterol. 2010;45(5):623-627.

92. Hackert T, Klaiber U, Hinz U, et al. Sphincter of Oddi botulinum toxin injection to prevent pancreatic fistula after distal pancreatectomy. Surgery. 2017;161(5):1444-1450.

93. Volk A, Distler M, Müssle B, et al. Reproducibility of preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi to prevent postoperative pancreatic fistula. Innov Surg Sci. 2018;3(1):69-75. 

94. Klaiber U, Sauer P, Martin E, et al. Protocol of a randomised controlled phase II clinical trial investigating PREoperative endoscopic injection of BOTulinum toxin into the sphincter of Oddi to reduce postoperative pancreatic fistula after distal pancreatectomy: the PREBOT Pilot trial. BMJ Open. 2020;10(9):e036815. 

95. Madoff RD, Fleshman JW. AGA technical review on the diagnosis and care of patients with anal fissure. Gastroenterology. 2003;124(1):235-245.

96. Maria G, Cassetta E, Gui D, Brisinda G, Bentivoglio AR, Albanese A. A comparison of botulinum toxin and saline for the treatment of chronic anal fissure. N Engl J Med. 1998;338(4):217-220.

97. Brisinda G, Maria G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure [published correction appears in N Engl J Med. 1999;341(8):624]. N Engl J Med. 1999;341(2):65-69.

98. Maria G, Brisinda G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure. Am J Surg. 2000;179(1):46-50.

99. Pilkington SA, Bhome R, Welch RE, et al. Bilateral versus unilateral botulinum toxin injections for chronic anal fissure: a randomised trial. Tech Coloproctol. 2018;22(7):545-551.

100. Brisinda G, Maria G, Sganga G, Bentivoglio AR, Albanese A, Castagneto M. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery. 2002;131(2):179-184.

101. Bobkiewicz A, Francuzik W, Krokowicz L, et al. Botulinum toxin injection for treatment of chronic anal fissure: is there any dose-dependent efficiency? A meta-analysis [published correction appears in World J Surg. 2016;40(12):3063]. World J Surg. 2016;40(12):3064-3072.

102. Dat A, Chin M, Skinner S, et al. Botulinum toxin therapy for chronic anal fissures: where are we at currently? ANZ J Surg. 2017;87(9):E70-E73.

103. Ravindran P, Chan DL, Ciampa C, George R, Punch G, White SI. High-dose versus low-dose botulinum toxin in anal fissure disease. Tech Coloproctol. 2017;21(10):803-808.

104. Menteş BB, Irkörücü O, Akin M, Leventoğlu S, Tatlicioğlu E. Comparison of botulinum toxin injection and lateral internal sphincterotomy for the treatment of chronic anal fissure. Dis Colon Rectum. 2003;46(2):232-237.

105. Chen HL, Woo XB, Wang HS, et al. Botulinum toxin injection versus lateral internal sphincterotomy for chronic anal fissure: a meta-analysis of randomized control trials. Tech Coloproctol. 2014;18(8):693-698.

106. Sajid MS, Hunte S, Hippolyte S, Kiri VA, Maringe C, Baig MK. Comparison of surgical vs chemical sphincterotomy using botulinum toxin for the treatment of chronic anal fissure: a meta-analysis. Colorectal Dis. 2008;10(6):547-552.

107. Nelson RL, Manuel D, Gumienny C, et al. A systematic review and meta-analysis of the treatment of anal fissure. Tech Coloproctol. 2017;21(8):605-625.

108. Asim M, Lowrie N, Stewart J, Lolohea S, Van Dalen R. Botulinum toxin versus botulinum toxin with low-dose glyceryltrinitrate for healing of chronic anal fissure: a prospective, randomised trial. N Z Med J. 2014;127(1393):80-86. 

109. Tranqui P, Trottier DC, Victor C, Freeman JB. Nonsurgical treatment of chronic anal fissure: nitroglycerin and dilatation versus nifedipine and botulinum toxin. Can J Surg. 2006;49(1):41-45.

110. Brisinda G, Cadeddu F, Brandara F, et al. Botulinum toxin for recurrent anal fissure following lateral internal sphincterotomy. Br J Surg. 2008;95(6):774-778.

111. Brisinda G, Bianco G, Silvestrini N, Maria G. Cost considerations in the treatment of anal fissures. Expert Rev Pharmacoecon Outcomes Res. 2014;14(4):511-525.

112. Nelson RL, Thomas K, Morgan J, Jones A. Non surgical therapy for anal fissure. Cochrane Database Syst Rev. 2012;2012(2):CD003431. 

113. Ooijevaar RE, Felt-Bersma RJF, Han-Geurts IJ, van Reijn D, Vollebregt PF, Molenaar CBH. Botox treatment in patients with chronic functional anorectal pain: experiences of a tertiary referral proctology clinic. Tech Coloproctol. 2019;23(3):239-244.

114. Maria G, Sganga G, Civello IM, Brisinda G. Botulinum neurotoxin and other treatments for fissure-in-ano and pelvic floor disorders. Br J Surg. 2002;89(8):950-961.

115. Brisinda G, Civello IM, Albanese A, Maria G. Gastrointestinal smooth muscles and sphincters spasms: treatment with botulinum neurotoxin. Curr Med Chem. 2003;10(7):603-623.

116. Brisinda G, Maria G, Bentivoglio AR, et al. Management of bladder, prostatic and pelvic floor disorders. Neurotox Res. 2006;9(2-3):161-172.

117. Cadeddu F, Bentivoglio AR, Brandara F, Marniga G, Brisinda G, Maria G. Outlet type constipation in Parkinson’s disease: results of botulinum toxin treatment. Aliment Pharmacol Ther. 2005;22(10):997-1003.

118. Maria G, Brisinda G, Bentivoglio AR, Cassetta E, Albanese A. Botulinum toxin in the treatment of outlet obstruction constipation caused by puborectalis syndrome. Dis Colon Rectum. 2000;43(3):376-380.

119. Maria G, Cadeddu F, Brandara F, Marniga G, Brisinda G. Experience with type A botulinum toxin for treatment of outlet-type constipation. Am J Gastroenterol. 2006;101(11):2570-2575.

120. Shafik A, El-Sibai O. Botulin toxin in the treatment of nonrelaxing puborectalis syndrome. Dig Surg. 1998;15(4):347-351.

121. Emile SH, Elfeki HA, Elbanna HG, et al. Efficacy and safety of botulinum toxin in treatment of anismus: a systematic review. World J Gastrointest Pharmacol Ther. 2016;7(3):453-462.

122. Zhang Y, Wang ZN, He L, et al. Botulinum toxin type-A injection to treat patients with intractable anismus unresponsive to simple biofeedback training. World J Gastroenterol. 2014;20(35):12602-12607.

123. Maria G, Brisinda G, Bentivoglio AR, Albanese A, Sganga G, Castagneto M. Anterior rectocele due to obstructed defecation relieved by botulinum toxin. Surgery. 2001;129(5):524-529.

124. Davies J, Duffy D, Boyt N, Aghahoseini A, Alexander D, Leveson S. Botulinum toxin (botox) reduces pain after hemorrhoidectomy: results of a double-blind, randomized study. Dis Colon Rectum. 2003;46(8):1097-1102.

125. Patti R, Almasio PL, Muggeo VM, et al. Improvement of wound healing after hemorrhoidectomy: a double-blind, randomized study of botulinum toxin injection. Dis Colon Rectum. 2005;48(12):2173-2179.

126. Sirikurnpiboon S, Jivapaisarnpong P. Botulinum toxin injection for analgesic effect after hemorrhoidectomy: a randomized control trial. J Anus Rectum Colon. 2020;4(4):186-192. 

127. Singh B, Box B, Lindsey I, George B, Mortensen N, Cunningham C. Botulinum toxin reduces anal spasm but has no effect on pain after haemorrhoidectomy. Colorectal Dis. 2009;11(2):203-207.

128. Patti R, Almasio PL, Arcara M, et al. Botulinum toxin vs. topical glyceryl trinitrate ointment for pain control in patients undergoing hemorrhoidectomy: a randomized trial [published correction appears in Dis Colon Rectum. 2007;50(1):122]. Dis Colon Rectum. 2006;49(11):1741-1748.

129. Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.

Millennium Medical Publishing, Inc