Botulinum Neurotoxins in the Management of Smooth Muscle Disorders of the Gastrointestinal Tract

Advisory Editor
P. Jay Pasricha, MD
Chief, Division of Gastroenterology and Hepatology
Professor of Medicine, Anatomy & Neurosciences and Biomedical Engineering
University of Texas Medical Branch
Galveston, Texas

Introduction

Most research regarding the use of botulinum neurotoxins (BoNTs) in smooth muscle disorders has focused on gastrointestinal and urological applications. Gastrointestinal uses of BoNT therapy include treatment of achalasia cardia, chronic anal fissure, sphincter of Oddi dysfunction, and a variety of other disorders. BoNT therapy for urological disorders has been assessed in the management of detrusor-sphincter dyssynergia and refractory overactive bladder with urge incontinence. The common premise for the application of BoNT in all of these disorders is that it blocks cholinergic neurotransmission to smooth muscle tissue. Based on historical accounts of botulism and in vitro evidence that BoNT interferes with cholinergic signaling in the myenteric nervous system, Pasricha et al investigated the effect of BoNT on gastrointestinal smooth muscle in a live animal model (Pasricha et al, 1993). This study showed that BoNT is a potent inhibitor of resting lower esophageal sphincter tone and provided the basis for the first clinical trials of BoNT for spastic disorders of the gastrointestinal tract (Pasricha et al, 1994; Pasricha et al, 1995) as well as subsequent applications for other smooth muscle targets, particularly those in the urological tract such as overactive bladder and related disorders.

The use of BoNT to relax overactive smooth muscle sphincters has been applied to the therapeutic management of achalasia, chronic anal fissure, gastroparesis, and postcholecystectomy pain syndromes, among others. These uses of BoNT represent a novel approach to the management of spastic gastrointestinal motility.

Achalasia

Achalasia is one of the most well characterized primary esophageal motility disorders, associated with abnormal relaxation of the lower esophageal sphincter (LES) and with swallowing and dysfunctional or absent peristalsis in the body of the esophagus (Garofalo and Pofahl, 2002; St. Peter and Swain, 2003). The etiology of the disorder remains unknown but is believed to involve a selective loss of postganglionic inhibitory neurons of the myenteric plexus of the esophagus and LES and the persistence of excitatory postganglionic cholinergic neurons (Garofalo and Pofahl, 2002; Mikaeli et al, 2004). This pathophysiologic imbalance in neurotransmitter release accounts for the high LES pressures and failure of the LES to relax. Common symptoms of achalasia include dysphagia (82% to 100%), regurgitation (56% to 97%), weight loss (30% to 91%), chest pain, and heartburn. Symptoms may also include vomiting, reflux, choking, and cough (Garofalo and Pofahl, 2002; St. Peter and Swain, 2003; Kaufman and Oelschlager, 2005). The disorder is diagnosed by radiographic, histologic, and manometric findings combined with clinical signs and symptoms (St. Peter and Swain, 2003). Radiographic barium swallow typically shows smooth tapering stenosis of the distal esophagus and proximal dilatation (Figure).

Figure. Contrast swallow study demonstrating a dilated esophageal body to 5.3 mm and a tight gastroesophageal junction of 4 mm. These are classic findings in a patient with achalasia. Reproduced with permission from St. Peter SD, Swain JM. Achalasia: a comprehensive review. Surg Laparosc Endosc Percutan Tech. 2003;13:227-240.

Esophageal manometry studies show absent peristalsis in the esophageal body and incomplete or absent relaxation of the LES. When surgical specimens have been available for examination, a loss of enteric neurons in the esophagus has been characteristically noted, disproportionately affecting the inhibitory myenteric plexus ganglionic cells (St. Peter and Swain, 2003; Mikaeli et al, 2004).

Current Treatment Options

None of the currently available therapies for achalasia reverses the underlying neuropathology and aperistalsis associated with impaired LES relaxation. The goal of current treatments is reducing LES pressure, resulting in symptom relief via facilitated esophageal emptying by gravity. Current treatment options include pharmacologic agents, pneumatic balloon dilatation, intersphincteric botulinum toxin injection, open surgical myotomy, and minimally invasive surgical approaches (Hoogerwerf and Pasricha, 2001; Garofalo and Pofahl, 2002; Martínek and Špičák, 2003; Mikaeli et al, 2004; Kaufman and Oelschlager, 2005). Pharmacological management of achalasia is aimed at lowering LES tone or resting pressure, thereby alleviating functional obstruction. The most commonly used systemic pharmacologic agents are calcium channel blockers and long-acting nitrates. Anticholinergics (atropine, dicyclomine, cimetropium bromide), beta-adrenergic agonists (terbutaline), and theophylline are used less commonly. Calcium channel blockers (nifedipine, isosorbide dinitrate) inhibit smooth muscle contraction and have been shown to provide symptomatic relief in 53% to 87% of achalasia patients. The use of these agents, however, has been limited by persistent dysphagia, poor long-term efficacy, and side effects such as headache, hypotension, and pedal edema (Hoogerwerf and Pasricha, 2001; Garofalo and Pofahl, 2002). Long-lasting nitrates relax gastrointestinal smooth muscle by increasing nitric oxide and relaxing the normally contracted LES. These agents are more potent LES relaxants than calcium channel blockers but are not as well tolerated (Kaufman and Oelschlager, 2005).

Endoscopic pneumatic balloon dilation is the most widely used non-surgical treatment for achalasia (Garofalo and Pofahl, 2002; Kaufman and Oelschlager, 2005). The procedure does not improve LES relaxation but reduces resting LES pressure. Therapy can be very effective in the short term (one prospective study of 16 patients showed a remission rate of 94% at 8 months [Johnston et al, 1992]), but remission rates drop noticeably in the long term. In one study, therapy was effective in 80% of patients after 1 to 4 dilations, with a remission rate at 5 years of 51% (Ponce et al, 1996). Another prospective trial of a single dilatation in 40 patients and 2 or 3 dilatations in 10 other patients recorded a short-term (<1 year) remission rate of 83% and 2- to 7-year rate of 67% (Boztas et al, 2005). A recent prospective study of 54 patients treated by a single pneumatic dilation showed a 5-year remission rate of 40%; repeated dilations only mildly improved the clinical response (Eckardt et al, 2004). A recent long-term study reported a 74% and 62% success rate at 5 years and 19 years, respectively, but 14 patients (20%) underwent a second procedure within a median of 7 months, and 13 of them further dilations within the first 2 years; 5 patients (7.5%) required further surgical and endoscopic therapy. There were 3 perforations (4.5%), with no mortality (Chan et al, 2004). Esophageal perforation, a major complication of this procedure, has been reported to occur overall in 2.0% to 6.4% of patients (Garofalo and Pofahl, 2002).

The most permanent method of palliation for achalasia is a myotomy of the LES, which can be performed as an open procedure or laparoscopically. The open abdominal and open thoracic procedures have shown long-term efficacy in over 80% of patients (Garofalo and Pofahl, 2002). Laparoscopic myotomy is now the preferred approach, with comparable efficacy and lower morbidity. Although the short-term results of myotomy are impressive, patients need to be followed carefully for the development of gastroesophageal reflux (GER), which is not uncommon even with the use of a partial anti-reflux wrap. In a recent study, pathologic GER occurred in 48% of patients with achalasia who had undergone myotomy, and in 9% after myotomy plus Dor fundaplication, a common anti-reflux procedure (Richards et al, 2004).

Botulinum Neurotoxins in the Treatment of Achalasia

BoNT-induced inhibition of acetylcholine release ameliorates the unopposed cholinergic stimulation responsible for maintaining LES pressure and preventing LES relaxation. Over the last decade, numerous studies have evaluated the efficacy of BoNT injections in the treatment of achalasia. BoNT is regarded as a palliative, short-term treatment, as the effect of the toxin is reversible. Accordingly, treatment of achalasia with BoNT requires repeated injections.

Clinical Studies of Botulinum Neurotoxin in the Treatment of Achalasia

Evidence-Based Reviews

A number of systematic evidence-based reviews of all available treatments for achalasia were published in the 1990s. These reviews concluded that nitrates, nifedipine, and botulinum toxin were the best studied and most effective pharmacologic treatment options. A single BoNT treatment was clinically effective in approximately 85% of achalasia patients in the short-term period, but effects were transient, with 30% to 60% efficacy after 1 year, and repeated treatments often necessary. No differences in efficacy were noted between the two BoNT type A (BoNT-A) preparations that were commercially available when used in comparable doses. Of the non-pharmacologic treatments reviewed, pneumatic dilation was found to be associated with a 3% risk of perforation, and morbidity from thoracotomy was considered the major limitation of myotomy; however, surgical morbidity was reduced by performing the procedure laparoscopically (Bassotti and Annese, 1999; Spiess and Kahrilas, 1998).

Clinical Studies

Clinical studies of BoNT therapy for achalasia include open-label trials, randomized placebo-controlled trials, and comparisons with other therapies, such as pneumatic dilation. A number of trials were conducted in the 1990s. In one randomized, double-blind, placebo-controlled trial of 21 patients, those receiving 80 units (U) of BoNT had a significant decrease in mean symptom score vs baseline (P=0.002), while those receiving placebo did not. All 21 patients were eventually given BoNT, and at 6 months, 14 patients (74%) were still in remission, 11 after a single injection (Pasricha et al, 1995). In another prospective study of 55 patients, initial response to BoNT was 75%. At month 6, 60% showed clinical improvement, 27 out of these 33 patients with but 1 injection (Cuillière et al, 1997). In general, studies that examined long-term (12 months or longer) efficacy showed greater recurrence of clinical symptoms in patients who received BoNT compared with those who underwent pneumatic dilation (Muehldorfer et al, 1999; Vaezi et al, 1999). However, some BoNT studies achieved very good results in certain subgroups. In a prospective study of 20 patients aged 60 years or more with tortuous mesaesophagus or epiphrenic diverticulum, which would make endoscopy more risky, clinical response was found in 80% at 6 weeks, and after multiple injections, continued in 70% after median follow-up of 2 years (range, 5-48 months) (Wehrmann et al, 1999). All studies noted the generally favorable side effect profile of BoNT. (A minor side effect attributable to the injection volume itself is transient chest pain [Gui et al, 2003].)

More recent clinical trials, using different dosages, multiple injections, and varying placement of injections, have produced a wide range of results. In general, response is very good in the short term, but efficacy diminishes over time without repeat injections (Table 1).

Table 1. Recent Clinical Studies of BoNT Therapy for Achalasia.

OL = open-label; DB = double-blind; RT = randomized trial; N = number of patients.

These studies demonstrated that BoNT treatment may provide short-term relief of the symptoms of achalasia in the majority (65% to 100%) of patients (Gui, et al 2003; Brisinda et al, 2004). The long-term efficacy of BoNT in achalasia is the subject of ongoing investigation. While several studies suggest that long-term efficacy of BoNT is inferior to both pneumatic dilatation and surgery (Ghoshal et al, 2001; Mikaeli et al, 2001; Bansal et al, 2003; Zaninotto et al, 2004a), others report that optimal BoNT efficacy may require repeated injections (Annese et al, 2000; D’Onofrio et al, 2000), and still others indicate that a single BoNT treatment can provide long-lasting efficacy (Martínek and Špičák, 2003; Friedenberg et al, 2004). The results of some studies suggest that certain patient groups might be better candidates for BoNT than others. One study found the presence of vigorous achalasia to be an independent predictor of response (Annese et al, 2000).Another found BoNT unsuccessful in patients with normal LES pressure, but recommended it as an alternative treatment choice in high-risk patients due to the lack of any serious side effects after 28 injections (D’Onofrio et al, 2000). Echoing the results of Wehrmann et al’s 1999 study, another suggests BoNT may be a useful therapy in patients with megaesophagus and/or epiphrenic diverticulum, and complicated or failed attempts at pneumatic dilatation, particularly in patients in whom surgery presents a risk (Ghoshal et al, 2001).Other studies recommend BoNT for patients unfit for surgery or as a bridge to endoscopic or surgical therapies (Bansal et al, 2003; Zaninotto et al, 2004a). All of the studies of BoNT therapy for achalasia note that BoNT was generally safe and produced minimal side effects. In summary, BoNT therapy provides an important treatment alternative for those patients with achalasia who are unable or unwilling to undergo more invasive procedures.

Dr. Pasricha discusses clinical studies of botulinum neurotoxin in achalasia. Among the noteworthy features of BoNT treatment of achalasia is the duration of the therapeutic effect. Dr. Pasricha also discusses the safety of BoNT and its role as a palliative treatment for a chronic condition.

Chronic Anal Fissure

Chronic idiopathic anal fissure 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 (Maria et al, 1998a; Maria et al,1998b). Chronic anal fissure (CAF) results from contraction of the internal anal sphincter and is consistently associated with pain from spasm of the sphincter. In addition to pain, fissures typically present with small amounts of bright red rectal bleeding but are accompanied by constipation in only approximately 20% of patients (McCallion and Gardiner, 2001).

Current Treatment Options

Therapies that reduce the internal sphincter pressure and increase blood flow have been used to treat anal fissures (Arroyo et al, 2005). Relief of the spasm has been associated with relief of pain and healing of the fissure without recurrence (Nelson, 2004). The most common approach for relieving the spasm has been surgical therapy using a variety of procedures, including stretch, open lateral sphincterotomy, closed lateral sphincterotomy, posterior midline sphincterotomy, and, to a lesser extent, dermal flap coverage of the fissure (Nelson, 2004). Sphincterotomy permanently weakens the internal sphincter and has a success rate of >90%, but is associated with high rates of incontinence, prompting the search for alternative medical treatments (Nelson, 1999; Arroyo et al, 2005). Nonsurgical options for treatment of CAF include topical nitroglycerin ointment to promote healing of fissures by increasing local blood flow and BoNT injection. However, a common side effect of topical nitroglycerin is headache. In one study, 60% of patients given topical nitroglycerin were healed, but 49% developed headaches (Jonas et al, 2002a).

Clinical Studies of Botulinum Neurotoxin Therapy for Chronic Anal Fissure

Evidence-Based Reviews

An evidence-based systematic review of available treatments for CAF found improved healing with BoNT versus placebo or versus topical nitroglycerin (Jonas and Scholefield, 2002b). Another review, highlighting the results of a study by Brisinda et al in 1999, similarly concluded that BoNT more effectively heals CAF than topical nitroglycerin does and that the advantages of BoNT therapy over surgical treatment include fewer long-term complications and avoidance of hospitalization (Brisinda, 1999; McCallion and Gardiner, 2001).

Clinical Studies of Botulinum Neurotoxin Therapy for Chronic Anal Fissure

Numerous studies have evaluated the efficacy of BoNT in the treatment of CAF; these studies range from open-label trials to randomized, placebo- and active-controlled studies. Studies conducted in the 1990s assessed the safety and efficacy of BoNT in the treatment of CAF, with success rates ranging from 44% to 100% (Maria et al, 1998a; Maria et al, 1998b; Jost, 1997; Brisinda et al, 1999; Minguez et al, 1999, Madalinski et al, 1999). BoNT-A showed greater efficacy than either placebo or nitroglycerin. Furthermore, no adverse effects were noted in BoNT-treated patients compared with those treated with nitroglycerin, many of whom experienced moderate to severe headaches (Brisinda et al, 1999).

More recent studies have reported greater therapeutic efficacy of BoNT followed by three-times-daily application of topical isosorbide dinitrate compared with BoNT injection alone at 6 weeks (Lysy et al, 2001), and greater efficacy of BoNT compared with lidocaine pomade in treating patients with CAF (Colak et al, 2002). Another randomized, double-blind trial of patients with CAF reported earlier and greater success rates with higher doses of BoNT without increased complications or side effects (Brisinda et al, 2002) (Table 2).

Table 2. Recent Clinical Studies of BoNT Therapy for Chronic Anal Fissure.

OL = open-label; DB = double-blind; DBPC = double-blind, placebo-controlled; RT = randomized trial; N = number of patients.

*All other studies were conducted using BOTOX®.

Another recent study found that repeated injections of BoNT were necessary for long-term efficacy (Godevenos et al, 2004). In this study, 45 patients received injections of BoNT (20 U) in the anal sphincter. Two months after the first injection, post-defecatory pain had disappeared with complete healing in 8 patients and was reduced in the remaining 37, who then received a second injection (25 U). Two months later, anal fissures had completely healed in 27 of these patients. These authors suggest that long-term follow-up is needed to assess the recurrence rate of fissure.

In contrast to studies supporting the efficacy of BoNT in the treatment of CAF, one recent study of patients who received 100 U of the Dysport formulation of BoNT-A reported no differences in efficacy, adverse effects, or recurrence between a single injection of BoNT and placebo at any time of follow-up (Siproudhis et al, 2003).

Several studies have examined the long-term efficacy of BoNT in the treatment of CAF. Long-term follow-up studies of patients treated with BoNT found successful outcomes for as long as 42 months, although some patients required repeat injections (Jost, 2002; Minguez et al, 2002; Arroyo et al, 2005). Increased risk of recurrence of anal fissures was associated with anterior location of the fissure, longer duration of the disease, the need for reinjection, a higher total dose needed to achieve definite healing, and a lower reduction in maximum squeeze pressure after injection (Minguez et al, 2002). More recently, Arroyo et al analyzed the effectiveness and morbidity of BoNT in the treatment of chronic anal fissure in 100 patients over a 3-year follow-up. These authors identified a subgroup of patients with clinical (symptoms lasting longer than 12 months) and manometric (persistently elevated mean resting pressure) factors associated with a higher recurrence of fissures. They suggest BoNT be considered as the first therapeutic approach for patients with CAF and risk factors for incontinence, with repeated injection of BoNT in those patients having risk factors for recurrence.

Dysfunction of Sphincter of Oddi

Sphincter of Oddi dysfunction is an uncommon disorder characterized by recurrent upper abdominal pain that is usually biliary or pancreatic in nature (Mandal and Robinson, 2001). Sphincter of Oddi dysfunction typically affects 10% to 20% of postcholecystectomy patients (Brisinda et al, 2004; Gui et al, 2003; Linder et al, 2002; Mandal and Robinson, 2001; Sherman and Lehman, 2001). The disorder is typically diagnosed by elevated basal sphincter pressure ( ≥40 mm Hg) and can lead to pancreatitis, chronic right upper quadrant pain, and elevated liver function tests (Friedenberg et al, 2004). Endoscopic sphincterotomy has been the standard treatment for sphincter of Oddi dysfunction (Wehrmann et al, 1998). However, recent studies have demonstrated that endoscopic BoNT injection into the papilla of Vater is a safe procedure that reduces lower sphincter of Oddi pressure and provides short-term relief in approximately 80% of patients with pancreatic sphincter of Oddi dysfunction (Wehrmann et al, 2000).

Wehrmann et al found that the therapeutic response to BoNT was predictive of successful outcome of endoscopic sphincterotomy in patients with sphincter of Oddi dysfunction and would therefore be a useful diagnostic tool for selection of patients most likely to benefit from sphincterotomy. If a reduction in sphincter pressure fails to relieve the patient’s pain, sphincter of Oddi dysfunction may not be the cause of the symptoms and it is unlikely that sphincterotomy would have a positive therapeutic outcome (Wehrmann et al, 1998; Wehrmann et al, 2000).

A recent study examined the possibility that BoNT injection could be used to reduce pancreatic sphincter hypertension following biliary sphincterotomy, thereby reducing the incidence of procedure-induced pancreatitis (Gorelick et al, 2004). Following sphincterotomy, patients were randomly assigned to receive either BoNT injections into the pancreatic sphincter or sham (saline) injections into the duodenal lumen. In the sham group, 43% of the patients developed pancreatitis compared with 25% of patients in the BoNT group, although the results were not statistically significant. Further studies will be needed to determine the validity of these findings.

Future and Emerging Gastrointestinal Uses of BoNT Therapy

The results of several small, open-label trials suggest that BoNT may improve symptoms of gastroparesis, a disorder of gastric motility that results in delayed gastric emptying (Lacy et al, 2002; Miller et al, 2002a; Ezzedine et al, 2002). The rationale for BoNT use in this disorder is based on the hypothesis that injection of BoNT into the pyloric sphincter would result in decreased pyloric resistance and improvement of symptoms. Other studies suggest that BoNT may have utility in nonachalasic spastic esophageal dysmotility syndromes based on its ability to reduce muscle tone in the targeted areas. Studies in this area have been small and uncontrolled, however (Zhao and Pasricha, 2003). A number of case studies have evaluated BoNT in the treatment of cricopharyngeal dysphagia, a condition characterized by incomplete or poorly coordinated opening of the upper esophageal sphincter during the pharyngeal phase of swallowing (Zhao and Pasricha, 2003). Although preliminary results of case studies appear promising, controlled trials are lacking.

Several other potential uses of BoNT therapy for gastrointestinal disorders warrant further investigation. Among these are oropharyngeal dysphagia (Schonweiler and Rapp, 2005; Zaninotto et al, 2004b); noncardiac chest pain (Wong and Fass, 2004; Miller et al, 2002b); postoperative pyloric spasm (Wiesel et al, 1997); obstructive constipation (Maria et al, 2001; Ron et al, 2001); Hirschsprung’s constipation (Langer and Birnbaum, 1997; Minkes and Langer, 2000); and irritable bowel syndrome and proctalgia fugax (Hansen, 2003; Katsinelos et al, 2001). Recent animal experiments suggest that BoNT may also be useful in the treatment of obesity by inhibiting voluntary and involuntary smooth muscle: In one study of rats who lost weight after botulinum injections, slow gastric emptying was posited to lead to early satiety and thus reduce food intake (Gui et al, 2000). In a later placebo-controlled study in rats, reduced weight gain after BoNT injection was thought to be related to impaired digestive ability, mediated by the inhibition of gastric acid secretion and other mechanisms (Runfola et al, 2003). As the spectrum of gastrointestinal indications for BoNT continues to expand, further controlled clinical trials will be needed to establish its safety and efficacy in a variety of disorders.

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