Placebo Controlled Trial of Botulinum Toxin for Gastroparesis

• symptom response as assessed by the gastroparesis cardinal symptom index. [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  

• gastric emptying changes as assessed by scintigraphy. [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  

Drug: Botulinum toxin type A
200 U given by injection into the pylorus.

Patients with gastroparesis, or delayed gastric emptying, present with early satiety, postprandial bloating, nausea, vomiting, and abdominal pain or discomfort.1 Gastric emptying is a highly regulated process reflecting the integration of propulsive forces generated by proximal fundic tone and distal antral contractions with the resistance of the pyloric sphincter. Antral hypomotility as well as increased gastric outlet resistance due to pyloric dysfunction or pylorospasm appear to be important physiologic disturbances in gastroparesis.2-4 Current treatment for gastroparesis employs prokinetic agents that increase antral contractility and accelerate gastric emptying.5 Unfortunately, prokinetic agents have limited efficacy and trials of these agents have suffered from significant methodological flaws.6 Troublesome side effects such as cardiac arrhythmias in the case of cisapride (Propulsid, Janssen Pharmaceutica) and extrapyramidal symptoms and sedation in the case of metoclopramide (Reglan, A.H. Robins) have limited the usefulness of these agents.7 Domperidone may be effective for treating symptoms of gastroparesis, however it is unavailable in the U.S.8

Botulinum toxin (Botox, Allergan) is an inhibitor of cholinergic neuromuscular transmission and has been used to treat spastic disorders of both striated and smooth muscles by local injection into affected muscles.9 Previous published work from our institution demonstrated that injection of botulinum toxin into the pylorus improved gastric emptying and reduces symptoms in idiopathic gastroparesis.10 In our open label study, patients had a 38% reduction in gastroparesis symptoms when interviewed 4 weeks after injection. Seventy percent of patients had improved gastric emptying. No immediate or short term (within 6 months) untoward events occurred in our study. The beneficial effect of botulinum toxin injection was suggested to be through decreasing pyloric resistance; however, manometric analysis of this region was not performed. Our results are similar to those seen in other studies that have demonstrated accelerated gastric emptying in response to pyloric botulinum toxin injection.11-13 These studies have included groups of patients with both idiopathic and diabetic gastroparesis. Unfortunately, in all studies, the patient groups have been very small and the study design has been open label that might bias results in favor of a positive response. In addition, follow-up has been for only 6 months.

Despite limited data, many gastroenterologists are now using botulinum toxin injection for the treatment of gastroparesis outside the context of clinical research studies. We are concerned that this practice may be increasing nationwide without definitive proof of efficacy. A randomized, placebo-controlled trial is necessary to establish the usefulness of pyloric botulinum toxin injection for gastroparesis. Botulinum toxin therapy is expensive and may not be efficacious. In addition, if efficacious, the mechanism by which botulinum toxin improves gastric emptying needs to be studied. This research protocol will answer several questions concerning this potentially useful therapy for gastroparesis.