Intrasphincteric injection of botulinum toxin was effective for achalasia
ACP J Club. 1995 Sept-Oct;123:38. doi:10.7326/ACPJC-1995-123-2-038
Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med. 1995 Mar 23;322:774-8.
To evaluate the efficacy and safety of botulinum toxin for achalasia.
6-month randomized, double-blind, placebo-controlled trial.
U.S. tertiary care center.
21 patients ≥ 18 years of age (mean age 50.5 y, 52% women) who had clinical, radiographic, and manometric features of achalasia. Exclusion criteria were pregnancy; history of esophageal myotomy or perforation; or a coexisting condition such as esophageal ulcers, Barrett's esophagus, esophageal varices, or esophageal or stomach carcinoma. Follow-up was 95%.
Patients were allocated to an intrasphincteric injection of botulinum toxin, 80 units (n = 11) or to a placebo injection of normal saline (n = 10). One week after the initial injection, the assignment code was broken and those patients in the placebo group who had not gone into remission were given an injection of botulinum toxin. Patients who did not have remission after the initial injection of botulinum toxin were given a second injection within 6 weeks of the code breaking.
Main outcome measures
Change in symptom score for 3 symptoms of achalasia: dysphagia, regurgitation, and chest pain. Each symptom was graded from 0 to 3 (0 = none; 3 = with each meal) for a maximum of 9 points. Clinical remission was equal to a score of ≤ 3. Secondary measures were lower esophageal sphincter (LES) pressure and esophageal retention.
At 1 week, the mean symptom score in the botulinum toxin group had decreased from 7.1 (SD 1.2) to 1.6 (SD 2.2) (P = 0.002); in the placebo group, it had decreased from 5.9 (SD 1.6) to 5.4 (SD 2.0) (P = 0.50). 9 patients in the botulinum toxin group showed clinical improvement and became clinically asymptomatic. The mean symptom score of patients in the placebo group who later received botulinum toxin (n = 10) decreased from 5.9 (SD 1.6) to 0.7 (SD 0.8) (P < 0.001). At 1 week, the mean LES pressure and the mean esophageal retention at 5 minutes in the botulinum toxin group had decreased by 18 mm Hg and 27%, respectively, from baseline (P for both ≤ 0.02) with no appreciable changes in the placebo group. At 6 months, 14 of 21 patients were still in remission, 11 after a single injection. The mean symptom score for 10 patients available for evaluation was 1.3. No serious side effects occurred.
The intrasphincteric injection of botulinum toxin resulted in substantial clinical improvement in patients with achalasia.
Sources of funding: American College of Gastroenterology; American Society of Gastrointestinal Endoscopy; Johns Hopkins General Clinical Research Center.
For article reprint: Dr. P.J. Pasricha, University of Texas Medical Branch, Department of Internal Medicine, Galveston, TX 77555-0764, USA. FAX 409-772-4789.
Achalasia is an esophageal motility disorder with peak onset occurring in the third to fourth decade of life. Classic treatments for achalasia include smooth-muscle relaxants, pneumatic dilations, and surgical myotomy. Only the latter 2 procedures give lasting relief by alleviating LES obstruction and allowing the esophagus to freely drain by gravity, thereby relieving symptoms and returning the esophageal diameter to normal. Pneumatic dilation, however, is complicated by esophageal perforation (5% of patients), and esophageal myotomy requires prolonged hospitalization and can be complicated by gastroesophageal reflux.
The study by Pasricha and colleagues suggests that botulinum toxin may be an effective, minimally invasive new therapy for achalasia. Botulinum toxin inhibits the release of acetylcholine from nerve endings, thereby counterbalancing the loss of inhibitory influences and returning the LES pressure to a normal resting tone. Although this is a placebo-controlled study, its results must be considered preliminary. Achalasia is a lifelong disease, whereas botulinum toxin improves symptoms for only 6 to 12 months. Long-term effectiveness and safety need to be established with monitoring for possible antibody formation and neurotoxicity, particularly after repeated injections.
Further, this study shows a perplexing paradox between symptom relief and improvement of esophageal function. Although dysphagia and regurgitation greatly improved, LES pressure and esophageal emptying decreased only modestly and never approached the values (LES pressure < 10 mm Hg) reported to occur with effective pneumatic dilation or surgery. Thus, functional obstruction persists and the esophagus may continue to dilate.
What is the role for botulinum toxin today? I will use it in patients in whom pneumatic dilation or surgery are contraindicated by age or comorbid illnesses. Should the drug be used as an alternative to more definitive therapies in otherwise healthy patients? My answer is no. Direct comparison studies now show that pneumatic dilation, compared with botulinum toxin, leads to symptomatic improvement and increased esophageal function in patients with achalasia at 1 year (1).
Joel E. Richter, MD
The Cleveland Clinic FoundationCleveland, Ohio, USA