Metoclopramide in the treatment of diabetic gastroparesis

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.     

Metoclopramide for the treatment of diabetic gastroparesis

ABSTRACT

Introduction: Gastroparesis is a chronic disorder of the stomach characterized by delayed gastric emptying without mechanical obstruction. Diabetes is the most commonly known cause of gastroparesis. Management of diabetic gastroparesis involves lifestyle modifications, glycemic control, pharmacological drugs, and for refractory cases surgical treatments. Metoclopramide remains the only drug approved by the Food and Drug Administration for diabetic gastroparesis. The aim of this article is to provide a concise review of the pharmacology, clinical efficacy and tolerability of metoclopramide.

Areas covered: We searched PubMed using the key words ‘metoclopramide’, ‘diabetic gastroparesis’, and ‘gastric emptying’. The relevant articles and their bibliography were reviewed. Metoclopramide acts on several different receptors; primarily as a dopamine receptor antagonist, both peripherally improving gastric emptying, and centrally resulting in an anti-emetic effect. Metoclopramide side effects, mostly related to its ability to cross the blood-brain barrier, include drowsiness, restlessness, hyperprolactinemia, and tardive dyskinesia (TD), a movement disorder that may be irreversible.

Expert opinion: Metoclopramide carries a black box warning for use >12 weeks due to the risk of TD. However, gastroparesis patients experience chronic symptoms often requiring prolonged treatments. Physicians and patients look forward to FDA approval of new agents for gastroparesis with better efficacy and safety profile.     

糖尿病胃轻瘫的治疗进展

糖尿病胃轻瘫(DGP)是糖尿病常见的并发症,发生率达50%～76%,主要表现为胃排空延缓,临床可见厌食、恶心、早饱、呕吐、腹胀等症状,严重影响患者的生活质量和血糖的控制.目前DGP的发病机制尚未明确,可能与自主神经病变、精神心理因素等有关.DGP的治疗方法较多,包括基础治疗、血糖控制、药物治疗、营养支持、胃电起搏、手术及心理治疗等.本文就上述治疗方法在DGP治疗中的最新研究进展作一综述.     

糖尿病胃轻瘫的诊断及治疗进展

糖尿病胃轻瘫可影响患者的营养状况和血糖的控制,增加患者的死亡率.核素显像技术、胃排空呼气试验(GEBT)、胶囊内镜、MRI等,可用于胃轻瘫的诊断.在治疗方面,尽管仍以胃肠动力药物治疗为主,但多种新型药物均表现出良好的效果.同时,传统中医中药的应用也具有一定前景,而诸如干细胞移植等新技术则有望成为治疗胃轻瘫的最有效手段.     

Gastric electrical stimulation for the treatment of diabetic gastroparesis

Diabetic gastroparesis is a component of autonomic neuropathy, and is the most common manifestation of gastrointestinal neuropathy. Diabetes is responsible for about one quarter of gastroparesis. The upper gastrointestinal symptoms are often non-specific and dominated by nausea, vomiting, early satiety, fullness, bloating. We also have to look for diabetic gastroparesis in case of metabolic instability, such as postprandial hypoglycaemia. The pathophysiology of diabetic gastroparesis is complex, partly due to a vagus nerve damage, but also to changes in secretion of hormones such as motilin and ghrelin. A decrease in the stem cell factor (SCF), growth factor for cells of Cajal (gastric pacemaker), was found in subjects with diabetic gastroparesis. These abnormalities lead to an excessive relaxation in the corpus, a hypomotility of antrum, a desynchronization antrum-duodenum-pylorus, and finally an abnormal duodenal motility. The treatment of diabetic gastroparesis is based on diabetes control, and split meals by reducing the fiber content and fat from the diet. The antiemetic and prokinetic agents should be tested primarily in people with nausea and vomiting. Finally, after failure of conventional measures, the use of gastric neuromodulation is an effective alternative, with well-defined indications. Introduced in the 1970s, this technology works by applying electrical stimulation continues at the gastric antrum, particularly in patients whose gastric symptoms are refractory to other therapies. Its efficacy has been recently reported in different causes of gastroparesis, especially in diabetes. Gastric emptying based on gastric scintigraphy, gastrointestinal symptoms, biological markers of glycaemic control and quality of life are partly improved, but not normalized. Finally, a heavy nutritional care is sometimes necessary in the most severe forms. The enteral route should be preferred (nasojejunal and jejunostomy if possible efficiency). However, in case of failure especially in patients with small bowel neuropathy, the long-term parenteral nutrition is sometimes required.     

Advances in diabetic gastroparesis

This review addresses the advances in our understanding of the epidemiology and mechanisms in diabetic gastroparesis and dyspepsia. The mechanisms discussed include: blood glucose levels at the time of presentation, "autovagotomy," and the intrinsic innervation (particularly the interstitial cells of Cajal and nitrergic nerves). In animal models of diabetic gastroparesis, there is evidence that homeostatic mechanisms are activated in the enteric nervous system to compensate for the loss of extrinsic innervation. Understanding these advances is key to the development of novel therapeutic strategies and for making rational choices in the management of diabetic gastroparesis and dyspepsia.     

Novel surgical treatment and gastric pathology in diabetic gastroparesis.

AIMS: Observations are made on four Type 1 diabetic patients with the rare syndrome of intractable vomiting from confirmed gastroparesis, to determine whether radical surgery would alleviate their symptoms and subsequently to examine in detail the gastric histopathology. METHODS: The surgical approach consisted of an approximate 70% resection of the stomach, including the antrum and pylorus, with closure of the duodenum and restoration of gastrointestinal continuity with a 60-cm Roux-en-Y jejunal loop. Four longstanding Type 1 diabetic patients were examined and treated as described. They were all women in the age range 2741 years with grossly abnormal autonomic function tests in whom other causes for gastric paresis had been excluded. RESULTS: Vomiting episodes leading to multiple hospital admissions (6-8) in the year preceding surgery were eliminated in three of the four patients, while in the fourth initial success was followed by the need for dialysis for renal failure. Gastric histopathology showed evidence of smooth muscle degeneration and fibrosis, with eosinophilic inclusion bodies (M-bodies) which appear to be unique to this condition. The findings suggest the presence of a gastromyopathy. CONCLUSIONS: Satisfactory relief of intractable vomiting from diabetic gastroparesis was achieved by a novel radical surgical procedure. Histopathological findings suggest that gastromyopathy may contribute to the production of this syndrome.     

莫沙比利联合胃肠起搏治疗糖尿病胃轻瘫疗效观察

目的评价莫沙比利联合胃肠起搏治疗糖尿病胃轻瘫（DGP）的疗效。方法将60例糖尿病胃轻瘫患者随机分为两组,治疗组采用莫沙比利联合胃肠起搏治疗,对照组单用莫沙比利治疗,疗程均为2周。治疗前后进行消化道症状评分。结果治疗组消化道症状积分下降显著高于对照组。治疗组总有效率90.0%,对照总有效率63.3%,两组比较差异有统计学意义（P〈0.05）。结论使用莫沙比利联合胃肠起搏治疗能有效缓解糖尿病胃轻瘫（DGP）的症状。     

Pyloric injection of botulinum toxin for treatment of diabetic gastroparesis

BACKGROUND: Diabetic gastroparesis is a common clinical problem. The pathophysiology includes prolonged pyloric contractions that may cause functional resistance to gastric outflow. Botulinum toxin was injected into the pyloric sphincter in an attempt to decrease pyloric resistance and improve gastric emptying. METHODS: Six patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study underwent upper endoscopy during which 100 units of botulinum toxin were injected into the pyloric sphincter. Gastric emptying studies were obtained at 48 hours and 6 weeks after injection. Patients were questioned about symptoms of gastroparesis, and a symptom score was obtained at baseline and at 2 weeks and 6 weeks after injection. OBSERVATIONS: There was a mean improvement in the subjective symptom score at 2 weeks of 55% (range 14% to 80%). This improvement was maintained at 6 weeks. There was a 52% improvement in gastric emptying at 2 and 6 weeks. CONCLUSION: Pyloric injection of botulinum toxin can improve symptoms and gastric emptying in patients with diabetic gastroparesis. Further evaluation of pyloric injection of botulinum toxin as a treatment for diabetic gastroparesis is warranted.     

Idiopathic and diabetic gastroparesis

Opinion statement The management of both diabetic and idiopathic gastroparesis often represents a substantial clinical challenge. In formulating recommendations for therapy, it should be recognized that these are based on less than optimal evidence; in particular, there are substantial deficiencies in current knowledge relating to the pathophysiology of gastroparesis, as well as the natural history of gastrointestinal symptoms, and the majority of pharmacologic trials have been short term and associated with methodologic limitations. Although the etiologic factors differ, the overall management principles are similar in the two conditions. Maintenance of adequate nutrition is pivotal, and parenteral nutrition may be required in severe cases associated with malnutrition. In patients with diabetes, rigorous attempts should be made to optimize glycemic control —hyperglycemia slows gastric emptying and may exacerbate symptoms and attenuate the effects of prokinetic drugs. Despite the relatively poor predictive value of symptoms, it is reasonable to suggest a trial of prokinetic therapy for about 4 weeks, rather than initially establishing the diagnosis by measurement of gastric emptying. However, it should be recognized that there is a substantial placebo response, a lack of evidence to support the cost effectiveness of such an approach, and that most patients will require prolonged therapy. In type 1 diabetic patients, prokinetic therapy may potentially benefit glycemic control, and this forms an additional rationale (albeit not established) for therapy. Some patients with diabetes and idiopathic gastroparesis with severe vomiting are unable to tolerate oral medication; in such cases subcutaneous metoclopramide may prove useful. Patients with intractable symptoms should be hospitalized and given intravenous erythromycin. The repertoire of prokinetic agents available in the United States is limited and includes metoclopramide, erythromycin, and cisapride (available by special program from its manufacturer); all of these drugs are associated with side effects. The use of metoclopramide may represent the first choice for chronic oral therapy, although it has been studied less comprehensively than cisapride. Combination therapy may be potentially more efficacious than the use of single agents. Dehydration and metabolic derangements should be corrected. The choice of chronic medical therapy should be individualized, taking factors such as age, presence of diabetes, concurrent medications, and comorbidities into account. In a small number of patients in whom medical treatment fails, surgery should be considered, and, if performed, done in a specialized center. A number of novel therapies, including gastric electrical stimulation, are currently being evaluated.     

Effect of metoclopramide in diabetic gastroparesis

The aims of our study were to: determine the effect of metoclopramide parenterally and orally on delayed gastric emptying of a radionuclide test meal in symptomatic patients with diabetic gastroparesis not explained by ulceration or other mechanical problems; and evaluate in a double-blind crossover fashion the efficacy of metoclopramide in relieving the symptoms of diabetic gastroparesis. Thirteen patients with subjective evidence of gastric stasis had delayed gastric emptying of an isotope-labeled semisolid meal which was significantly accelerated (p less than 0.05) after 10 mg of metoclopramide parenterally. Patients then received metoclopramide 10 mg and placebo before meals and prior to retiring for 3 weeks in a randomized double-blind crossover design. During metoclopramide therapy nausea, vomiting, anorexia, fullness, and bloating were significantly (p less than 0.05) ameliorated compared to placebo with an overall mean symptom reduction of 52.6%. Gastric emptying studies after completion of the trial is seven patients, subjectively improved and receiving open-labeled metoclopramide, showed significantly less gastric retention. Individual improvements in gastric emptying after parenteral or oral metoclopramide, however, could not be correlated with symptom change during the treatment trial. We conclude that metoclopramide is an important therapeutic adjunct in the management of diabetic gastroparesis and its therapeutic effects are mediated through its prokinetic properties as well as centrally mediated antiemetic actions.     

Xiangshaliujunzi Decoction for the treatment of diabetic gastroparesis: A systematic review

AIM:To assess the current clinical evidence of the effectiveness of Xiangshaliujunzi Decoction(XSLJZD)for the treatment of diabetic gastroparesis(DGP).METHODS:Randomized controlled trials(RCTs)were retrieved from seven major electronic databases including Medline,the Cochrane Library,Embase,Chinese Biomedical Literature Database(CBM),Chinese National Knowledge Infrastructure,Chinese Scientific Journal Database(VIP),and Wanfang Databases,using search dates from the beginning of the databases to May 2013.No language limitations were applied.We included RCTs that used XSLJZD or a modified XSLJZD compared with a control group for the treatment of DGP.The control groups included conventional treatment(Western medicinal treatment),placebo,and no treatment(blank),but not acupuncture.The main outcome index was clinical effectiveness,which was based on the gastric emptying test and variations in the gastrointestinal(GI)symptoms between the treatment and control groups after intervention.Data extraction,analysis,and quality assessment were conducted according to the Cochrane Handbook for Systematic Review of Interventions,Version 5.1.0.RESULTS:Ten RCTs involving 867 patients(441 in the experimental groups,and 426 in the control groups)were identified,and the overall methodological quality was evaluated as generally low.In the treatment groups,all 10 trials used herbs alone as the treatment,whereas all control groups used prokinetic medicine.The period of intervention ranged from 2 to 8 wk.Three classes were used to evaluate treatment efficacy:significant effective,effective,and ineffective,and all trials used the clinical effective rate(based on the gastric emptying test and changes in GI symptoms)to evaluate efficacy.The data showed that the effects of XSLJZD for the treatment of DGP were superior to the control group(n=867,RR=1.33,95%CI:1.24-1.42,Z=8.11,P<0.00001).Two trials recorded adverse events,and one trial reported follow-up.CONCLUSION:XSLJZD could restore the gastric emptying rate and improve symptoms.However,the evidence remains weak due to the poor methodological quality of the included studies.     

Surgical therapy of diabetic gastroparesis

Diabetic gastroparesis is a complication of diabetes mellitus that usually responds to medical management. We report a patient in whom medical management failed, and a gastrostomy, pyloroplasty, and jejunostomy were done to insure nutrition and to decompress the stomach. We also review the surgical management of this condition.     

Nutrition therapy for diabetic gastroparesis

The management of diabetic gastroparesis often represents a significant clinical challenge in which the maintenance of nutrition is pivotal. Gastric emptying is delayed in 30% to 50% of patients with longstanding type 1 or type 2 diabetes and upper gastrointestinal symptoms also occur frequently. However, there is only a weak association between the presence of symptoms and delayed gastric emptying. Acute changes in blood glucose concentrations affect gastric motility in diabetes; hyperglycemia slows gastric emptying whereas hypoglycemia may accelerate it; blood glucose concentrations may also influence symptoms. It is now recognized that gastric emptying is a major determinant of postprandial glycemia and, therefore, there is considerable interest in the concept of modulating gastric emptying, by dietary or pharmacologic means, to optimize glycemic control in diabetes.     

Metoclopramide in the treatment of gastric bezoars

The effect of metoclopramide as an adjunct to the conventional treatment of gastric bezoars was studied. All patients received conventional endoscopic treatment which consisted of mechanical fragmentation and the instillation of papain solution. Fifteen patients received only endoscopic treatment while nine patients were given, in addition, metoclopramide 10 mg orally before meals and at bedtime. The conventionally treated group required a mean of 1.9 courses of endoscopic treatments, while the metoclopramide treated group required a mean of 1.2 courses to resolve the bezoar. This difference was statistically significant. It was also found that long-term metoclopramide treatment reduced the frequency of bezoar formation in four patients with recurrent gastric bezoars.     

红霉素对糖尿病性胃排空延迟的作用

我们对１４例糖尿病性胃排空延迟患者给予红霉素静脉注射２００ｍｇ，以后口服０．２５ｇ，每日３次，共７天。采用超声法测定胃液体排空时间。将２０例正常人作为对照，二种途径给药均使平均半排空和全排空时间正常，静脉注射和口服后胃排空恢复正常的患者分别是１００％和７１％。结果提示红霉素具有促进糖尿病患者胃排空的作用，作为胃动素激动剂，可能是新型胃肠道动力药。