Scientific and Clinical Modules

In order to receive a certificate for this activity

1. Read the CME information on this page.

2. Review information on the contributor biographies.

3. Go to the module and review the material.

4. Complete the CME Post-Test.

5. Complete the evaluation and registration forms.

A link to your certificate will be e-mailed to you within 24 hours of satisfactory completion of these documents.

I. CME Information for Gastroenterological Disorders

Abstract

The injection of botulinum neurotoxin (BoNT) into smooth muscle targets in the gastrointestinal tract has emerged as an acceptable treatment option for disorders characterized by spasticity, including achalasia, esophageal spasm, gastroparesis, chronic anal fissure, and sphincter of Oddi dysfunction. In addition to its established utility in gastrointestinal spastic disorders, there is ongoing exploration of a potential role for BoNT in the treatment of obesity by achieving selective blockade of non-hyperkinetic normal muscle of the gastric wall. An expanding literature encompassing case reports, small series, and prospective studies supports the use of BoNT in carefully selected patients, with cumulative experience demonstrating that BoNT is a relatively simple and effective therapy for these often intractable, chronic conditions, achieving clinically meaningful short-term benefits with remarkable safety. Investigations directed to more fully defining the mechanism of action by which BoNT achieves its therapeutic effect in gastrointestinal disease suggest that in addition to impeding local neuromuscular transmission, BoNT may elicit clinically relevant changes at distant sites, such as altering molecular signaling within the central nervous system. Long-term outcome studies are required to fully characterize the indications and benefits of BoNT. This chapter reviews current clinical utilization of BoNT in the management of gastrointestinal disorders in adults.

Educational Objectives

Upon completion of this activity, participants should be able to:

Discuss the range of gastroenterologic disorders for which the injection of botulinum neurotoxin (BoNT) into hyperkinetic anatomic sphincters has been evaluated
Evaluate clinical trials experience assessing the potential role of BoNT for management of obesity, in which the anatomic target for injection is not hypertonic muscle tissue
Identify an appropriate role for BoNT in the diagnosis and treatment of achalasia in comparison with established surgical approaches and newly-described endoscopic techniques such as the per oral endoscopic myotomy (POEM) procedure
Review patient characteristics most highly associated with a favorable response to BoNT injection for management of chronic anal fissure

Target Audience

This activity is directed to gastroenterologists, internists, neurologists, and other healthcare providers involved in the treatment of gastrointestinal disorders using neurotoxin therapy.

Method of Participation

To receive a maximum of 1.0 AMA PRA Category 1 Credit(s)™ you should:

View the presentations in this CME activity and evaluate the content presented
Complete and submit the posttest, CME registration, and activity evaluation forms

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Beth Israel Medical Center and Scientiae, LLC. The provider is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement

Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals designate this online educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Term of Approval

October 2013 through October 2015. Original Release Date: October 2013.

Program Director

Pankaj (Jay) Pasricha, MD

Director, Division of Gastroenterology, Johns Hopkins Bayview Medical Center
Director, Johns Hopkins Center for Neurogastroenterology
Professor of Medicine and Neurosciences, Johns Hopkins School of Medicine
Professor of Innovation Management, Johns Hopkins Carey School of Business
Baltimore, Maryland

CME Program Reviewer

Susan Bressman, MD

Chairman of the Department of Neurology
Beth Israel Medical Center
New York, New York
Professor of Neurology
Albert Einstein College of Medicine

Disclosure Statement

It is the policy of Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals that faculty and providers disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals have established policies that will identify and resolve all conflicts of interest prior to this educational activity.

This CME activity discusses the off-label use of botulinum neurotoxin.

Susan Bressman, MD, Program Reviewer

Dr. Bressman has indicated no conflict of interest.

Pankaj (Jay) Pasricha, MD:

Dr. Pasricha has indicated no conflict of interest.

Acknowledgement of Support

This activity is jointly sponsored by Beth Israel Medical Center Scientiae, LLC.

It is supported by an unrestricted educational grant from Allergan, Inc.

Educational Objectives

Upon completion of this activity, participants should be able to:

Discuss the range of gastroenterologic disorders for which the injection of botulinum neurotoxin (BoNT) into hyperkinetic anatomic sphincters has been evaluated
Evaluate clinical trials experience assessing the potential role of BoNT for management of obesity, in which the anatomic target for injection is not hypertonic muscle tissue
Identify an appropriate role for BoNT in the diagnosis and treatment of achalasia in comparison with established surgical approaches and newly-described endoscopic techniques such as the per oral endoscopic myotomy (POEM) procedure
Review patient characteristics most highly associated with a favorable response to BoNT injection for management of chronic anal fissure

Target Audience

This activity is directed to gastroenterologists, internists, neurologists, and other healthcare providers involved in the treatment of gastrointestinal disorders using neurotoxin therapy.

Method of Participation

To receive a maximum of 1.0 AMA PRA Category 1 Credit(s)™ you should:

View the presentations in this CME activity and evaluate the content presented
Complete and submit the posttest, CME registration, and activity evaluation forms

Accreditation Statement

Credit Designation Statement

Term of Approval

October 2013 through October 2015. Original Release Date: October 2013.

Program Director

Pankaj (Jay) Pasricha, MD

CME Program Reviewer

Susan Bressman, MD

Chairman of the Department of Neurology
Beth Israel Medical Center
New York, New York
Professor of Neurology
Albert Einstein College of Medicine

Disclosure Statement

This CME activity discusses the off-label use of botulinum neurotoxin.

Susan Bressman, MD, Program Reviewer

Dr. Bressman has indicated no conflict of interest.

Pankaj (Jay) Pasricha, MD:

Dr. Pasricha has indicated no conflict of interest.

Acknowledgement of Support

This activity is jointly sponsored by Beth Israel Medical Center Scientiae, LLC.

It is supported by an unrestricted educational grant from Allergan, Inc.

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Gastroenterological Disorders

II. ABSTRACT

III. INTRODUCTION

Naturally occurring botulinum neurotoxin (BoNT) is one of the most lethal poisons known, with a fearsome reputation arising over centuries of human affliction. Yet the contemporary medical use of pharmaceutical BoNT offers an array of benefit to millions of patients worldwide, through the purposeful and expert re-creation of BoNT's hallmark effect: profound blockade of acetylcholine-mediated neuromuscular transmission.

Following intramuscular injection, all available BoNT preparations achieve multi-step inhibition of acetylcholine release from cholinergic nerve terminals of motor neurons, preganglionic sympathetic and parasympathetic neurons, and post-ganglionic parasympathetic nerves.^1,2 Apart from these actions across the synaptic cleft, data suggest that BoNT exerts additional effects distant from the site of local injection, accomplished through retrograde axonal transport to neuronal sites within the spinal cord and central nervous system.^3,4 The extent to which distant translocation of BoNT to second-order neurons in higher cortical centers contributes to meaningful improvements in symptoms is incompletely defined and warrants further study. Relevant to clinical gastroenterology practice, however, the desired effect following BoNT injection is entirely due to motor inhibition of the muscle target, which is potent but temporary; consequently, BoNT therapy requires periodic re-injection at variable intervals.

The spectrum of gastrointestinal disorders for which BoNT has been investigated for use continues to expand, with an emphasis on conditions characterized by excessive muscle tone at specific smooth muscle sphincters within the digestive tract. Judicious application of BoNT is associated with weakening of hyperkinetic anatomic structures implicated in the pathophysiology of a range of conditions, including achalasia, chronic anal fissure, gastroparesis, and post-cholecystectomy pain syndromes, and, as will be discussed in following sections, likely contributes to clinical improvement. In addition, there is widening experience with the use of BoNT for the management of obesity, in which the anatomic target is not hyperkinetic muscle but, rather, normally functioning gastric musculature that is intentionally made paretic by BoNT injection, thus increasing gastric transit time, delaying gastric emptying, and leading to early satiety.⁵

IV. ACHALASIA

Achalasia (Latin: "without loosening") is a primary esophageal motility disorder associated with impaired relaxation of the lower esophageal sphincter (LES) and ineffective or completely absent peristalsis in the body of the esophagus.^6-8 Achalasia is an uncommon condition that appears to have a stable incidence but a rising prevalence; in a recent population-based survey, the incidence and prevalence of treated achalasia was 1.63/100,000 and 10.82/100,000, respectively.⁹ It may affect patients at any age, from childhood to advanced older age, but its peak incidence is in early middle age, with both sexes equally affected.⁹

The etiology of achalasia involves a selective loss of post-ganglionic inhibitory neurons within the myenteric plexus of the body of the esophagus and LES, occurring in conjunction with the persistence of excitatory cholinergic input.^6,¹⁰ This signaling imbalance results in sustained elevation of LES tone in association with failure of relaxation, which in turn leads to functional obstruction.

Common symptoms of achalasia include dysphagia to solids and liquids, weight loss, chest pain, and heartburn and may also include vomiting, reflux, choking, and cough.^6,^7,¹¹ Because many of these symptoms are non-specific and common to other disorders, the diagnosis of achalasia requires a high index of suspicion and sophisticated esophageal testing that includes manometry.^6,7

Achalasia is associated with considerable morbidity. Whether achalasia is associated with an increased risk of mortality is unclear. Recent work suggests that survival of achalasia patients may be significantly less than age-matched controls, but factors contributing to this finding are not clearly defined and require further study.⁹ Common primary complications of achalasia are predictably related to functional obstruction and include postprandial or nocturnal aspiration, reflux esophagitis, megaesophagus, and progressive malnutrition. Aspiration pneumonia is a potentially lethal complication. Achalasia appears to be a risk factor for esophageal malignancy.^9,¹²

Achalasia: Current Treatment Options

There is at present no definitive therapy to correct the underlying neuropathology and aperistalsis associated with impaired LES relaxation; medical and surgical treatments are therefore palliative and are directed toward reducing LES pressure. Options include pharmacologic agents such as nitrates and calcium channel and phosphodiesterase inhibitors, intersphincteric BoNT injection, pneumatic balloon dilation, open surgical myotomy, and minimally invasive surgical approaches.^6,^10-14 Medical therapy for achalasia is only modestly effective, is associated with side effects, and is reserved for patients who are unable to tolerate more invasive treatment modalities.¹²

a) Endoscopic and Surgical Techniques

In contrast to the generally unsatisfactory responses achieved with medical therapy, endoscopic and surgical techniques provide significantly more effective and durable improvement. The mainstays of contemporary treatment are endoscopic (pneumatic) dilation, surgical division of the LES (e.g., Heller myotomy), and pharmacologic paralysis of the LES with BoNT.¹⁵ Dilation has good short-term efficacy but frequently requires a repeat procedures. Myotomy, which may be performed laparoscopically with a concurrent anti-reflux procedure, is associated with the greatest probability of sustained relief, whereas BoNT injections require repeat treatments at intervals that are usually in the range of several months.^6,¹⁶

Among surgical alternatives, per-oral endoscopic myotomy (POEM) has emerged as an important new technique. This highly selective approach targets only diseased circular and sling muscles of the LES while avoiding any disruption of the suspensory muscles of the hiatus. POEM was shown in a recent prospective study to achieve safe and effective relief of dysphagia in all patients (n = 18) undergoing the procedure. Dysphagia relief was durable, with all patients reporting sustained relief at mean follow-up of 11.4 months. Notably, 46% of subjects exhibited objective evidence of mild gastroesophageal reflux post-operatively, confirmed in a 6-month pH study. Reflux symptoms were generally mild and were easily managed with medical therapy.¹⁶ A current review indicates that POEM and the more invasive laparoscopic Heller myotomy have similar perioperative outcomes; further investigation is required regarding the comparative long-term results achieved with either strategy.¹⁷

b) BoNT for Achalasia

While myotomy in possible conjunction with an anti-reflux procedure should be considered the treatment of choice in younger patients or those without contraindications to surgical treatment,¹⁵ there remains an important role for BoNT in the management of achalasia.

The safety, efficacy, and reasonably durable symptom improvement characteristic of BoNT injection for the management of achalasia has been well supported by nearly 20 years of clinical study. The majority of reports describe the efficacy of BoNT administered as the sole therapeutic modality, with more recent publications exploring the role of BoNT plus another intervention.

BoNT was initially introduced for therapy of achalasia in 1995 in a randomized, placebo-controlled trial in which symptomatic improvement following injection was obtained in 82% of patients compared with 10% of those who received placebo. All patients receiving 80 units of BoNT-A (onabotulinumtoxinA; Botox^®) demonstrated a significant decrease in mean symptom score from baseline at 1 week (P = .002), vs none receiving placebo. Improvement was sustained at 6 months in 14 of 21 (66%) treatment responders. Among responders, mean LES pressure decreased by one-third, and mean opening width of the LES increased by more than 200%. No serious adverse effects of BoNT emerged over the course of the study.¹⁸ Participants from this trial as well as those from an earlier, pilot study were subsequently enrolled in a prospective long-term follow-up study, results of which indicated that the median duration of improvement after a single treatment was 16 months (range, 5-28 months). A positive response to BoNT conferred a 68% probability that remission would be maintained at 1 year.¹⁹

The prompt onset and durability of symptom relief was again demonstrated in a multicenter study enrolling 55 patients, with 75% reporting clinical improvement at 2 weeks. Improvement was maintained at 6 months in 33 patients, 27 of whom had received a single injection. Apart from transient non-cardiac chest pain or epigastric pain (noted in 22% of subjects), no serious adverse effects were reported. ²⁰

Available information indicates that a good short-term response to BoNT may be reliably anticipated in 64% to as many as 100% of patients.²¹ Consistent with its mechanism of action, a single BoNT injection would be unlikely to achieve permanent relief ^22-24 and optimal patient management may require repeated injections.^25,26 With scrupulous attention to injection site technique and infiltration, a variable proportion of patients may remain asymptomatic for more than a year following a course of injection, but randomized, controlled data on longer term outcomes are limited.^14,²⁷

Long-term studies extending for 12 months or more document a higher rate of symptom recurrence in patients treated with BoNT in comparison with those undergoing pneumatic dilation.^8,²⁸ Per a structured Cochrane meta-analysis, pneumatic dilation is more effective for long-term improvement of achalasia but is associated with more complications than BoNT, most notably, esophageal perforation; among patients receiving BoNT, no serious adverse outcomes were reported.²⁹ In a prospective study of 20 patients with achalasia aged 60 years or more with tortuous megaesophagus or epiphrenic diverticulum (contraindications to first-line use of pneumatic dilation), clinical response to BoNT occurred in 80% at 6 weeks and, after multiple injections, continued in 70% after median follow-up of 2 years (range, 5-48 months).³⁰

Certain factors associated with a favorable response have been identified, such as older age and the presence of vigorous achalasia.¹⁹ ^,25 Of note, treatment of 33 octogenarians and nonagenarians (range, 81-94 years) with botulinum toxin was safe and effective, yielding good quality of life (including weight gain) in a majority of these subjects. Seventy-eight percent of patients were considered responders at 1 year, and 54% were considered responders at 2 years. The weight gain at the end of the follow-up period was 2kg (range, 0-3 kg). No major complications of botulinum toxin therapy were reported.³¹

c) BoNT as an Adjunct to Dilation

There is limited study data exploring an adjunctive role of BoNT plus endoscopic dilation. BoNT (abobotulinumtoxinA) followed 8 days later by pneumatic dilation was effective for long-term symptomatic improvement in a cohort of 51 patients followed prospectively, with a cumulative 5-year remission rate that was approximately 19% higher than historic controls, but combined therapy was not statistically superior to pneumatic dilation alone.³² In a study that enrolled patients with multiple prior pneumatic dilation failures, BoNT plus dilation within 4 weeks achieved better decreases in mean symptom score and clinical remission vs pneumatic dilation alone by the end of the first year following intervention, but the difference failed to achieve statistical significance.³³ In contrast to these results, a prospective study enrolling 90 patients who were randomly assigned to BoNT alone, dilation alone, or BoNT plus small balloon dilation 15 days after injection demonstrated that the combination was superior to either modality alone in terms of LES pressure and symptom score at any point in a 24-month follow-up period.³⁴

A recent Clinical Outcomes Research Initiative audit of contemporary endoscopic practice patterns across diverse clinical settings concluded that BoNT injection has emerged as the primary choice of initial endoscopic therapy in achalasia, representing 41% of interventions; balloon dilation was the next most common initial strategy, selected in 21%. One-quarter of achalasia patients treated with any endoscopic intervention required a repeat therapy approximately every 14 months.³⁵

Structured review has also confirmed that BoNT has an excellent safety profile and can be performed as a same-day procedure.³⁶ In experienced hands, the injection of an approved formulation of BoNT in the appropriate dose should not unduly extend the time required for an endoscopic procedure in most clinical settings.

In summary, current literature indicates that BoNT should be considered for older patients, in patients for whom an operation or pneumatic dilation entails a higher risk, or as a bridge when these more effective modalities are not immediately available.³⁶ BoNT injection is nearly universally regarded as a useful temporizing or emergency measure, is appropriate for those with contraindications to dilation or myotomy, and is appropriate for proof-of-concept confirmation of achalasia in patients who are difficult to diagnose.^15,16 ^,37

V. CHRONIC ANAL FISSURE

Chronic idiopathic anal fissure (CAF) is a common and painful disorder characterized by the presence of a well-circumscribed ulcer in the distal anal canal with persistent symptoms for more than 2 months.^38,39 CAF results from contraction of the internal anal sphincter, and pain is consistently associated with sphincter spasm. In addition to the marked pain associated with defecation, fissures typically present with small amounts of rectal bleeding, and constipation may be reported in approximately 20% of patients.⁴⁰

Current Treatment Options

Relief of sphincter spasm leads to pain relief and healing of the fissure without recurrence.⁴¹ A number of surgical procedures may be considered, including stretch, open or closed sphincterotomy, dermal flap, and others.41 Sphincterotomy permanently weakens the internal sphincter and has a success rate of more than 90% but is associated with high rates of incontinence to flatus.^42,43 Non-surgical options include topical agents such as nifedipine and nitroglycerin ointment. These medications promote healing by reducing internal sphincter pressure and increasing local blood flow. Both medications are effective and generally safe, although a common adverse effect of nitroglycerin therapy is headache.^44,45 BoNT injection is another non-surgical alternative for management of CAF, for which good evidence from randomized clinical studies supports its consideration. Table 1 summarizes some recent clinical studies of BoNT therapy for CAF.^45-65

Table 1. Recent Clinical Studies of BoNT-A Therapy for Chronic Anal Fissure

Author	Study Design	N	Total Dose (Units)	Outcome
Lysy (2001)⁵⁸	Randomized trial	30	20(OnabotulinumtoxinA)	At 6 wks, BoNT plus topical isosorbide dinitrate was more effective than BoNT alone (66% vs 20%)
Brisinda (2002)⁵³	Double-blind, randomized trial	150	20-30(OnabotulinumtoxinA)	Earlier and greater success with higher doses of BoNT
Colak (2002)⁵⁴	Randomized trial	62	25(OnabotulinumtoxinA)	BoNT was more effective than lidocaine pomade (71% vs 21% complete epithelialization, respectively)
Siproudhis (2003)⁶³	Double-blind, placebo-controlled trial	45	100(AbobotulinumtoxinA)	No differences between BoNT and placebo
Godevenos (2004)⁵⁶	Open-label case series	45	20(OnabotulinumtoxinA)	Repeated BoNT injections gave greater complete healing
Lindsey (2004)⁵⁷	Prospective pilot case series	30	25(OnabotulinumtoxinA)	Combination treatment with fissurectomy + BoNT injection was effective in 93% of patients with CAF who had not responded to nitroglycerin or BoNT therapy alone
Simms (2004)⁶²	Retrospective chart review and follow-up	47	30(OnabotulinumtoxinA)	37 of 47 patients healed after BoNT injection; authors concluded that BoNT treatment is as effective in clinical practice as in trials
Arroyo (2005)⁴⁷	Prospective controlled clinical trial	100	25(OnabotulinumtoxinA)	BoNT injection was effective at 3-y follow-up; authors recommend BoNT as first-line treatment in patients at risk for incontinence
Arroyo (2005)⁴⁸	Randomized controlled trial	80	25(OnabotulinumtoxinA)	Surgical treatment achieved a higher rate of successful healing than BoNT at 3-y follow-up; authors recommend BoNT as first-line treatment in patients at risk for incontinence
Thornton (2005)⁶⁴	Open-label case series	56	20(OnabotulinumtoxinA)	BoNT injection reduced anal resting pressure by 17% (0%-71%), but this was not correlated with clinical outcome
De Nardi (2006)⁵⁵	Open-label case series	30	20(OnabotulinumtoxinA)	Nitroglycerin and BoNT injection were both efficacious through 36 months and are both appropriate first-line non-surgical treatments
Tranqui (2006)⁴⁵	Retrospective chart review and follow-up	88	30-100(OnabotulinumtoxinA)	Treatment with topical nifedipine and BoNT was more effective than topical nitroglycerin with pneumatic dilation
Brisinda (2007)⁵¹	Randomized, prospective comparative study	100	30 units of OnabotulinumtoxinA or 90 units of AbobotulinumtoxinA	Treatment with BoNT was more effective
Witte (2007)⁶⁵	Prospective series	100	40-100 units of AbobotulinumtoxinA	BoNT effective in a majority of cases of isosorbide dinitrate-resistant chronic anal fissure
Arthur (2008)⁴⁹	Comparative study	51	40 units of OnabotulinumtoxinA	Fissurectomy followed by a short course of twice-daily topical 2% diltiazem as efficacious as fissurectomy combined with BoNT
Baraza (2008)⁵⁰	Prospective study	46	25-100 units of OnabotulinumtoxinA	Fissurectomy plus BoNT an effective medium-term alternative to more invasive surgery in females, although there was a high rate of late recurrence; a minority of patients proceeded to more invasive surgical intervention.
Brisinda (2008)⁵²	Prospective, uncontrolled, non-comparative study	80	30 units of OnabotulinumtoxinA, or 90 units of AbobotulinumtoxinA	In this series of patients with recurrent anal fissure following previous lateral internal sphincterotomy, BoNT achieved complete healing in 54 patients (68%) with no relapses during extended follow-up (mean, 57.9 months)
Aivaz (2009)⁴⁶	Retrospective study	59	80 units of botulinum toxin A	BoNT plus fissurectomy a viable alternative to lateral internal sphincterotomy; non-significant difference in recurrence rate observed over 19-month (mean duration) follow-up period
Nasr (2010)⁵⁹	Randomized, controlled trial	80	20 units of OnabotulinumtoxinA	Surgical internal sphincterotomy was associated with a higher healing rate and lower rate or recurrence; BoNT was associated with a lower risk of incontinence
Patti (2010)⁶⁰	Prospective, uncontrolled, non-comparative study	10	30 units of OnabotulinumtoxinA	Fissurectomy plus advancement flap plus intrasphincteric BoNT achieved complete healing and full symptom relief
Samim (2012)⁶¹	Double-blind, randomized trial	134	20 units of OnabotulinumtoxinA	No statistically significant advantage of BoNT over diltiazem regarding healing, pain, and recurrence; mean pain scores were marginally lower in the BoNT group

a) Botulinum Neurotoxin Therapy for CAF

Clinical studies assessing the safety and efficacy of onabotulinumtoxinA in the treatment of CAF record success rates of 44% to 100%,³⁸ with excellent safety and fewer side effects compared with subjects treated with nitroglycerin.^38,39,^66-68 In addition, numerous evidence-based systematic reviews of available CAF treatments confirm improved healing with BoNT vs placebo and vs topical nitroglycerin, with fewer long-term complications than surgical treatment and the obvious avoidance of hospitalization and associated expense.^40,^66,^69,⁷⁰ A recent surgical systematic review recommends either nitroglycerin, diltiazem, or BoNT as appropriate for first-line pharmacologic therapy for CAF, or BoNT as second line in cases of pharmacologic failure with nitroglycerin or diltiazem.⁷¹ Another structured review notes that trials comparing BoNT with nitroglycerin are characterized by statistically significant heterogeneity, but results from well-designed trials included in the meta-analysis suggest that BoNT is at least as effective as nitroglycerin, with significantly fewer side effects.⁷²

BoNT was considered superior to nitroglycerin ointment in a study that randomly assigned 100 adults to abobotulinumtoxinA, onabotulinumtoxinA, or nitroglycerin. After 2 months, fissures were healed in 46 of 50 patients receiving BoNT versus 35 of 50 randomly assigned to nitroglycerin.⁵¹ In another report, BoNT injection was shown to be effective in 100 patients with isosorbide dinitrate ointment-resistant CAF, achieving an early response rate of 77% and an overall success rate of 66% at median follow-up of 10 months.⁶⁵ BoNT was compared directly with diltiazem in a double-blind, randomized clinical trial with median follow-up of 39 months. The authors reported that treatment with BoNT yielded higher healing rates in the short term, although healing rates at 3 months were comparable, and by study end, there were no significant differences overall regarding healing rates, pain, or rates of recurrence.⁶¹

Other studies have reported greater efficacy of BoNT-A followed by 3-times-daily application of topical isosorbide dinitrate compared with BoNT-A injection alone at 6 weeks,⁵⁸ greater efficacy of BoNT-A compared with lidocaine pomade in treating patients with CAF,⁵⁴and greater efficacy of combined treatment with nifedipine and BoNT compared with nitroglycerin with pneumatic dilation with respect to healing and recurrence.⁴⁵ Another randomized, double-blind trial of patients with CAF reported earlier and greater success rates with higher doses of onabotulinumtoxinA without increased complications or side effects.⁵³

Repeat injections may be required to maintain relaxation for optimal healing; similarly, patients in whom anal fistula recurs achieve benefit from repeat injection. In a retrospective study of 47 patients,⁶² 37(78.7%) were healed following onabotulinumtoxinA injection; of these 37,¹⁰ (27.0%) developed a recurrent CAF after a median of 16.0 months (interquartile range, 3.8-20 months), and repeat onabotulinumtoxinA injection was successful in 7 of the 8 patients (87.5%) who opted for the second treatment. No adverse effects were reported. A study in which 45 patients received intrasphincteric injections of onabotulinumtoxinA (20 units) found that most subjects required a second treatment for long-term efficacy.⁵⁶ Two months after the first injection, post-defecatory pain had disappeared, with complete healing in 8 patients. The remaining 37 patients then received a second injection (25 units). Two months later, anal fissures had completely healed in 27 of these patients. In contrast, some investigators have reported that a single injection provides only negligible benefits. A study of 44 patients randomized to placebo or BoNT (100 units of abobotulinumtoxinA) reported no differences in efficacy, adverse effects, or recurrence between BoNT treatment and placebo at any time during follow-up.⁶³

Long-term studies with BoNT have demonstrated successful outcomes to 42 months, although some patients will require repeat injections.⁴⁷ ^,73 ^,74 Investigators compared non-surgical treatments for CAF in 30 patients treated with either 0.2% nitroglycerin ointment 3 times daily for 8 weeks or 2 injections of 10 units of onabotulinumtoxinA and followed patients for 36 months.⁵⁵ Both groups showed improvement, with a non-significant, slightly higher percentage of patients in the nitroglycerin group showing improvement at long term follow-up. The healing rate at 3 years was 40% in the nitroglycerin group and 33% in the BoNT group. There were no adverse events observed in the BoNT group; 3 patients in the nitroglycerin group reported mild headache but did not discontinue treatment. The authors concluded that although surgical sphincterotomy remains the most effective treatment for CAF, some patients may prefer non-surgical treatments and, particularly in patients at risk for incontinence, these 2 treatments may be considered first-line non-surgical treatments.⁵⁵

Recurrence is not unusual with non-surgical interventions. Certain clinical characteristics are considered to be associated with an increased risk of recurrence. These include anterior location of the fissure, longer disease duration, the need for reinjection, requirement of a higher total dosage needed to achieve definite healing, and a lower reduction in maximum squeeze pressure after injection.⁷⁴ Botulinum toxin is an effective treatment in patients with recurrent anal fissure who previously underwent lateral internal sphincterotomy, with no relapses reported during a mean value of nearly 5 years follow-up.⁵²

b) BoNT in Comparison With or as an Adjunct to Surgical Correction

A 2005 investigation ⁴⁸ compared injection of 25 units of onabotulinumtoxinA with open lateral internal sphincterotomy in 80 CAF patients. Patients were followed for 3 years and at 1-year review, overall healing was observed in 92.5% of surgical patients and 45% of the BoNT patients. There were no recurrences at the second- and third-year follow-up evaluations. The authors recommended surgical treatment as the first-line approach in patients with risk factors for recurrence. Noting that in contrast to 5% of patients treated with surgery, no BoNT patient reported permanent incontinence (P = NS) over the 1- to 3-year follow-up period, the authors recommended BoNT treatment as a first-line approach in patients >50 years of age or with risk factors for incontinence. In a prospective controlled clinical trial of 100 CAF patients with 3-year follow-up, the authors identified a subgroup in whom clinical findings (symptoms lasting longer than 12 months and manometric factors [persistently elevated mean resting pressure]) were associated with a higher recurrence of fissures.⁴⁷ The authors confirmed that BoNT treatment was effective, but observed a greater tendency to progressive recurrence over time. Noting that treatment with BoNT avoids the greater risk of incontinence associated with surgical treatment, the authors again recommended BoNT as first-line therapy in patients with risk factors for incontinence, with repeated injections administered to those having risk factors for recurrence.

In a study examining combination therapy in CAF patients who had not responded to treatment with nitroglycerin or BoNT injection alone,⁵⁷ 30 patients underwent fissurectomy and injection with 25 units of onabotulinumtoxinA. At 16-week follow-up, 28 (93%) had healed completely and the other 2 patients had improved to such a degree that no further treatment was required.

In a randomized, consecutive study enrolling 80 patients receiving either BoNT or lateral sphincterotomy, surgery was associated with a higher healing rate and lower recurrence rate than BoNT injection, but a higher rate of incontinence. Considering incontinence as the most unsatisfactory outcome, the incidence of which they consider negligible following BoNT injection, the authors suggested that BoNT is a simple, non-invasive technique that may be considered a viable first therapeutic approach in selected patients who are not at high risk for recurrence.⁵⁹

Fissurectomy combined with advancement flap and intrasphincter injection of botulinum toxin achieved complete healing, significant changes in maximum resting pressure on manometry, and complete relief of symptoms in 10 consecutively enrolled patients.⁶⁰ Similarly, BoNT injection with simple local fissurectomy proved a viable first-line alternative to more extensive lateral internal sphincterotomy for chronic anal fissure in a study enrolling 59 patients, with choice of operation based on patient preference. The primary healing rate was 90% in the extensive surgery group, with a 10% complication rate, versus a healing rate of 74% and a complication rate of 0% among those selecting BoNT.⁴⁶Note should be made, however, of a study comparing local fissurectomy followed by 8 weeks of twice-daily topical diltiazem cream (DTC) with fissurectomy followed by BoNT injection, in which topical DTC appeared to be equivalent to BoNT.⁴⁹ Fissurectomy plus BoNT was effective for CAF in a cohort of 44 females with CAF, a population for whom incontinence poses particular challenges, with only a minority of patients proceeding to more invasive surgical intervention.⁵⁰

VI. SPHINCTER OF ODDI DYSFUNCTION

Sphincter of Oddi dysfunction typically affects 10% to 20% of postcholecystectomy patients. It is characterized by recurrent upper abdominal pain,⁷⁵ usually biliary or pancreatic in nature.^21,^76-78 The disorder is usually diagnosed by elevated basal sphincter pressure (≥40 mm Hg) and can lead to chronic right upper quadrant pain, pancreatitis, and hepatic abnormalities.²⁷ While endoscopic sphincterotomy has been the standard treatment, studies have demonstrated that endoscopic BoNT injection safely reduces sphincter of Oddi pressure,⁷⁹ providing short-term relief in approximately 80% of patients.⁸⁰

The therapeutic response to BoNT may be predictive of successful outcome of endoscopic sphincterotomy in patients with sphincter of Oddi dysfunction. If, following injection, a reduction in sphincter pressure fails to improve clinical symptoms, then it must be considered that sphincter of Oddi dysfunction is not the cause of the discomfort, and it would therefore be unlikely that sphincterotomy would achieve a positive symptom response.^80,81

Patients with acalculous biliary pain represent a diagnostic dilemma, since the symptoms may be due to intrinsic gallbladder disease or sphincter of Oddi hyperkinesis. In a small series of 25 patients with acalculous pain receiving BoNT injection, those with a positive symptom response were offered endoscopic biliary sphincterotomy, while those patients remaining in pain after BoNT were assessed for laparoscopic cholecystectomy. The authors propose that BoNT injection may be useful to direct appropriate therapy for patients with acalculous biliary pain based on symptom response, but these results are speculative and await confirmation through randomized clinical study.⁸² A recent study examined the possibility that onabotulinumtoxinA injection could be used to reduce pancreatic sphincter hypertension following biliary sphincterotomy, thereby reducing the incidence of procedure-induced pancreatitis.⁸³ After sphincterotomy, patients were randomly assigned to receive either BoNT injections into the pancreatic sphincter or saline injections into the duodenal lumen. In the saline group, 43% of patients developed pancreatitis compared with 25% in the BoNT group, a trend that was not statistically significant.

VII. FUTURE AND EMERGING GASTROINTESTINAL USES OF BoNT THERAPY

Gastroparesis

Gastroparesis is a disorder of diverse etiology, characterized by delayed gastric emptying that is not attributable to mechanical obstruction and is often associated with nausea, repetitive vomiting, and postprandial discomfort.⁸⁴ Any potential role for BoNT in the management of mild-to-moderate gastroparesis is predicated on the finding that injection of BoNT into the pyloric sphincter results in decreased pyloric resistance.^85-88A retrospective analysis of 179 pyloric BoNT injections for gastroparesis undertaken from 2001 to 2007 reported an overall decrease in symptoms at 1 to 4 months post-injection in 51.4% of patients, which was maintained in a majority of those who continued with follow-up injections.⁸⁹ Treatment efficacy was dose-dependent. Additional factors contributing to improved treatment response were female sex, age <50 years, and non-diabetic non-postsurgical etiology (all P < .005). Prospective confirmation of these results is warranted.⁸⁹

Clinical investigation of the potential role of BoNT injection for improvement of gastroparesis is notable for predominantly open-label, uncontrolled trials. Quality data have been lacking, and a systematic review of available evidence concludes that none of the individual, predominantly non-randomized trials to date demonstrate any statistically significant subjective or objective improvement in patients receiving BoNT compared with patients receiving placebo.^84,^90,91 Note should be made of a small, randomized, controlled crossover study of patients with primarily idiopathic gastroparesis who were randomly assigned to either intrapyloric saline or BoNT injection, in which outcomes were essentially indistinguishable. Significant improvement in emptying and symptom score was seen after initial injection of saline or BoNT, with no further improvement with a second injection after 4 weeks. Overall, there were no significant differences between groups in terms of solid or liquid emptying and meal-related symptoms.⁹² In another randomized trial enrolling 32 patients with moderate-to-severe gastroparesis symptom scores, intrapyloric BoNT improved gastric emptying on scintigraphy at 1 month, but this improvement was not superior to that achieved by placebo (saline), nor did symptoms improve significantly.⁹³

Esophageal and Oropharyngeal Dysmotility

There is speculation that BoNT may have utility in treating nonachalasic spastic esophageal dysmotility syndromes⁹⁴ and in cricopharyngeal achalasia and related forms of oropharyngeal dysphagia, a condition characterized by incomplete or poorly coordinated opening of the upper esophageal sphincter during the pharyngeal phase of swallowing.^94,95 Other areas of interest include a role in improving gastroesophageal reflux-related non-cardiac chest pain,^96,97 post-operative pyloric spasm,⁹⁸ obstructive constipation,^99,100 Hirschsprung's constipation,^101-103 and post-fundoplication esophageal clearance in patients with gastroesophageal reflux.¹⁰⁴

Obesity

Intragastric BoNT appears to hold promise for non-surgical management of obesity, although the treatment is experimental at present and numerous issues await resolution, including the optimal site or sites for injection, dosage, and retreatment interval.^105,106 By interfering with normal gastric propulsive movements, BoNT delays gastric emptying, which presumably engenders a prolonged satiety sensation resulting in diminished intake and consequent weight loss over time.

A small number of clinical studies evaluating onabotulinumtoxinA in the treatment of obesity have been published, with most demonstrating that BoNT has no significant effect on weight loss despite promoting sensations of satiety.¹⁰⁶ However, a double-blind controlled investigation that enrolled 24 morbidly obese subjects randomly assigned to BoNT or placebo administered to antral and fundus sites had positive results. Eight weeks after treatment, onabotulinumtoxinA patients had significantly higher weight loss (11 ± 1.09 vs 5.7 ± 1.1 kg; P < .001) and body mass index (BMI) reduction (4 ± 0.36 vs 2 ± 0.58 kg/m², P< .001) and reported higher satiety vs controls. Among patients available for further follow-up, all but one failed to lose any additional weight at 3 months, suggesting a very limited effect of one-time administration.¹⁰⁷ A major difference between this study and others was the addition of muscle targets in the fundus, although an association between fundal BoNT injection and weight loss was not elucidated.¹⁰⁶

In a randomized trial enrolling 20 obese subjects, a single endoscopic session entailing multiple injections of BoNT into the gastric fundus, gastric antrum, and gastric body was associated with significant decreases in body weight and body mass index, decreased triglyceride levels, and prolonged gastric emptying times. In addition, a significant decrease in levels of fasting ghrelin (an appetite-inducing hormone) was documented at 1 month in 19 of 20 subjects who completed follow-up. Levels of hormone PYY, a known mediator of satiety when elevated, also decreased in all 19 subjects; the reason for diminishment was unclear. The authors propose that injection of BoNT into fundal sites is crucial for achieving a weight loss response relative to investigations restricting injection to the antrum alone or to only the antrum and gastric body.¹⁰⁸

Gastric antral injection alone delayed gastric emptying but had no effect on sensations of early satiety, eating behavior, or weight loss in a 24-week, double-blind, placebo-controlled trial that enrolled 60 obese subjects. Patients received 1 session of endoscopic BoNT injection into antral muscularis propria under ultrasound guidance. The authors employed a range of BoNT dosages in this study, with the most statistically significant delay in gastric emptying mean half-life (24 minutes) achieved with the intermediate dose. The authors conclude that higher doses of BoNT are unlikely to achieve better results than those obtained in this study.¹⁰⁹

VIII. Conclusion

The use of BoNT in hyperkinetic muscle disorders of the gastrointestinal tract continues to expand. Ease of application, predictability of response, excellent safety, and a voluminous literature in which dosages and protocols undergo continual refinement and validation support the use of BoNT for the management of appropriate patients with gastrointestinal disorders such as achalasia, gastroparesis, chronic anal fissure, and sphincter of Oddi dysfunction. BoNT represents an effective and safe therapy for these challenging conditions, achieving meaningful symptom relief through endoscopic techniques that are easily implemented in outpatient settings, thus reducing the need for invasive surgery.

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