Abstract and Introduction
Gastroparesis is a chronic disorder that affects a significant subset of the population. Diabetes mellitus is a risk factor for the development of gastroparesis. Currently, metoclopramide is the only US FDA-approved medication for the treatment of gastroparesis. However, the FDA recently placed a black-box warning on metoclopramide because of the risk of related side effects, including tardive dyskinesia, the incidence of which has been cited to be as high as 15% in the literature. This review will investigate the mechanisms by which metoclopramide improves the symptoms of gastroparesis and will focus on the evidence of clinical efficacy supporting metoclopramide use in gastroparesis. Finally, we seek to document the true complication risk from metoclopramide, especially tardive dyskinesia, by reviewing the available evidence in the literature. Potential strategies to mitigate the risk of complications from metoclopramide will also be discussed.
Gastroparesis is a chronic disorder characterized by impaired gastric emptying and altered motility in the upper GI tract in the absence of mechanical obstruction. It is estimated to affect approximately 5 million individuals in the USA and is most often seen in young individuals with a mean age of onset of 34 years. There is a large female-to-male predominance (4:1 ratio), and gastroparesis is frequently seen in diabetics. It generally presents with nonspecific symptoms including early satiation, nausea, emesis, bloating, abdominal pain, heartburn, anorexia and weight loss. Gastroparesis is likely a heterogeneous condition with the most common etiologies having been identified as idiopathic (36%) and diabetes mellitus (30%). Numerous physiological factors may contribute to symptoms such as abnormalities in liquid and solid meal emptying, emptying of indigestible objects (e.g., fiber), and gastric and proximal small bowel contractility.
The pathophysiology behind gastroparesis is varied and depends upon the etiology of disease. Vagal and/or autonomic neuropathy[3,4] play an important role in the development of diabetic gastroparesis and it is estimated to occur in up to 20–40% of patients with diabetes mellitus. Metabolic abnormalities, especially hyperglycemia, may lead to a delay in gastric emptying, even in healthy individuals. Interruption of hormonal and neural feedback mechanisms is also believed to be significant in the pathogenesis of gastroparesis. The main hormones involved include cholecystokinin from the proximal small bowel as well as glucagon-like peptide-1 (GLP-1), peptide YY from the distal small bowel and amylin from the pancreas. In addition, there is a loss of expression of neuronal nitric oxide, a loss of enteric neurons, smooth muscle abnormalities and disruption of the network of the interstitial cells of Cajal. This can lead to impaired meal-induced relaxation of the gastric fundus, altered intragastric distribution, fewer antral contractions, tonic motor defects, increased outflow resistance in the pylorus or small intestines and impaired distal regulatory mechanisms. Other etiologies for gastroparesis, including idiopathic causes, are less-well understood and may involve inflammatory mechanisms.
However, there is poor correlation between the symptoms of gastroparesis and the severity of delayed gastric emptying. Studies have shown that symptomatic improvement in gastroparesis is only variably correlated with objective improvement in gastric emptying.[11–13] This may be because other pathophysiologic mechanisms (e.g., fundic relaxation, small bowel dysmotility and/or central mechanisms) are improving. However, it is harder to objectively test these factors in clinical practice. It is therfore important to note the distinction between physiologic versus symptomatic improvement of gastroparesis.
Metoclopramide is currently the only medication that is US FDA approved for the treatment of gastroparesis. It was first described by Louis Justin-Besaçon and Charles Laville in 1964 and has been available in the USA since 1979. However, its use has been increasing over the last decade and is estimated by the FDA to be used by over 2 million Americans currently. Given the recent black-box warning issued by the FDA, this review seeks to highlight the clinical efficacy as well as the adverse risks associated with metoclopramide use and to educate healthcare professionals regarding potential ways to mitigate those risks.
Expert Rev Endocrinol Metab. 2010;5(5):653-662. © 2010 Expert Reviews Ltd.
Cite this: Metoclopramide in the Treatment of Diabetic Gastroparesis - Medscape - Sep 01, 2010.