Treatment options for patients with severe gastroparesis
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Chronic gastroparesis is a motility dysfunction often associated with severe symptoms, the most common disabling symptoms being nausea and vomiting. The term “gastroparesis” is a Greek word that means “a weakness of movement”. In this article, some basic facts about gastroparesis are briefly mentioned before aspects on therapy are discussed.
Gastroparesis is defined as delayed gastric emptying in the absence of an obstruction to outflow from the stomach. Hence, the diagnostic procedure in patients with symptoms suggestive of gastroparesis should include at least gastroscopy, so as to exclude obstructive lesions. Furthermore, a gastric emptying test is required to verify abnormal emptying of the stomach. Although delayed emptying of both liquids and solids occurs in patients with gastroparesis, the delayed emptying of solids is considered the most relevant disturbance. Thus, a test of solid emptying is usually applied. The scintigraphic method is considered to be the gold standard. Reference values based on large control samples (>100 subjects) are available for the scintigraphic method 1 ,2 and for the radiological method. 3 In addition, the octanoic acid breath test with reference values from 70 subjects 4 is also frequently used. The larger control samples show a gender difference with a slower emptying rate and higher reference values for retention in healthy women compared with men. 2 ,3 Gastric emptying cannot be reliably evaluated by gastroscopy.
In gastrointestinal (GI) practice, gastroparesis is common among patients with diabetes mellitus, and is reported to occur in 30–50% of the patients. 5 Another large group comprises patients with idiopathic gastroparesis in whom no underlying cause of the disorder can be found. However, many patients with idiopathic gastroparesis have developed the disorder after a gastrointestinal infection, most often a virus infection. 6 ,7 Bacterial infections may also cause gastroparesis, but Helicobacter pylori does not seem to be associated with gastroparesis. 8 ,9 Chronic gastroparesis is also seen to be secondary to systemic disorders such as amyloidosis and scleroderma and to neurological disorders such as Parkinson's disease and myotonic dystrophy. Postsurgical gastroparesis occurs in patients who have undergone ulcer surgery—for example, gastric resections and/or vagotomy. The latter type is likely to become rarer as ulcer surgery decreases, but gastroparesis may also occur after oesophageal surgery such as fundoplication, Heller's myotomy and surgery for oesophageal cancer.
The relation between functional dyspepsia and gastroparesis is of special interest. Delayed gastric emptying is found in about 30% of patients with functional dyspepsia. 10 This group of patients with dyspepsia can be regarded as having idiopathic gastroparesis according to the definitions mentioned above.
Symptoms predictive of gastroparesis
A wide range of dyspeptic symptoms are common in patients with gastroparesis—for example, nausea, vomiting, upper abdominal pain, abdominal distension and bloating. The individual symptoms have, in general, a low specificity to predict delayed emptying. Abdominal bloating has been reported to be significantly correlated with delayed emptying in diabetic gastroparesis. 11 In other studies, postprandial fullness was statistically linked to delayed gastric emptying. 12 ,13 When gastroparesis is associated with weight loss and the patient requires nutritional support to maintain body weight, the gastroparesis is considered to be of a more severe form.
Traditional treatment of gastroparesis
Before 1990, the medical treatment of gastroparesis included dietary measures such as eating frequent, small, liquid meals with a low fat content. Psychotropic drugs with antiemetic effects were available, although these drugs have no significant prokinetic effect on gastric emptying. During the 1970s and 1980s, dopamine‐2 receptor antagonists with antiemetic and some prokinetic effects became available (metoclopramide, domperidone). In the 1980s, the 5‐hydroxytryptamine 4 (5‐HT4) agonist cisapride was marketed and was considered to be a first‐line option in drug treatment of gastroparesis. In drug refractory cases, nutritional support via jejunostomy (J)‐tubes is a possible alternative. In the most advanced cases, gastrectomy has been the final resort, although success with this type of large surgery has been limited.
Recent advances in drug treatment
In the last decade, research has been directed towards obtaining new drugs that can improve gastric emptying and decrease symptoms, without too many side effects. However, despite extensive research, no new drug with proven efficacy in gastroparesis has appeared and been approved during this period.
Macrolides are a group of substances, some of which have antibiotic properties and/or motilin receptor stimulation action in the GI tract, and thereby exert prokinetic effects. The first macrolide clinically explored was erythromycin, which, in early experiments, showed motility‐stimulating properties in dogs. In patients with diabetes mellitus and delayed gastric emptying, Janssens et al 14 found that intravenous administration of erythromycin 200 mg before a test meal could normalise the gastric emptying rate of both liquids and solids. After oral administration of erythromycin 250 mg three times a day for 4 weeks, the gastric emptying was improved but not to the same extent as in the initial experiments with intravenous administration. The observations by the Leuven group were confirmed in several studies 15 ,16 on patients with gastroparesis and also reviewed by Sturm et al. 17 After long‐term administration, the prokinetic effect of erythromycin on gastric emptying may decline due to tolerance development. In clinical practice,
treatment with erythromycin in very sick patients is often started at the hospital, with erythromycin given intravenously before the meals. If the patient responds favourably, treatment is then continued with erythromycin suspension given orally in due time, preferably 30–45 min before meals.
Attempts have been made to develop analogues to erythromycin so as to obtain a prokinetic effect without antibiotic effects, and also to overcome the tolerance phenomenon. Although analogues with prokinetic properties have been developed and tested in clinical trials, these drugs have not shown any significant effect on symptoms in patients with delayed gastric emptying. 18 ,19 ,20 To date, the problem with tolerance development has not been solved and may be one reason why the analogues developed so far do not have the required clinical effects.
Ghrelin is an interesting substance that is structurally related to motilin. Ghrelin is derived from gastric mucosa and seems to have an important role in the regulation of appetite and body weight. Ghrelin has prokinetic motility‐stimulating properties in animals, and has also recently been shown to accelerate gastric emptying of a test meal in patients with diabetes with slow gastric emptying. 21 In patients with idiopathic gastroparesis, ghrelin administration was followed by improved gastric emptying and a decrease in meal‐related symptoms. 22 These interesting effects seen in acute experiments need to be further studied to see if ghrelin‐like drugs can be used for treatment of gastroparesis in clinical practice.
The recently developed drugs, mitemcinal and atilmotin, have been proposed as prokinetics, but full papers on their effects in patients with gastroparesis are still lacking.
The dopamine‐2 (D2) antagonist metoclopramide was developed several decades ago and is still a cornerstone for treatment of gastroparesis in many countries. The prokinetic effects of D2 antagonists in patients with gastroparesis have been thoroughly reviewed. 17 Although metoclopramide has extrapyramidal side effects and sedative effects, at least the latter is not of the same magnitude as that of the older antipsychotic drugs such as haloperidol and chlorpromazine. The D2 antagonist domperidone is an improvement compared with metoclopramide, and has fewer side effects on the central nervous system owing to its limited passage across the blood‐brain barrier. Like many other prokinetic drugs, domperidone may show tolerance development on repeated administration, as observed in studies on gastric emptying. 23 Nevertheless, domperidone is an important alternative in patients in whom gastroparesis‐related symptoms respond to dopamine antagonists, but metoclopramide has produced unwanted side effects on the central nervous system.
Sulpiride is a dopamine blocker used for some psychotic and other psychiatric disorders. This drug has prokinetic properties, but a pharmacological profile that is somewhat different from metoclopramide and domperidone, and has been studied in patients with dyspeptic symptoms. The initial studies show that oral levosulpiride 25 mg three times a day is superior to placebo, 24 and may be as effective as cisapride in relieving nausea and vomiting in patients with gastroparesis. 25 ,26 Further studies are needed to see whether sulpiride is superior to metoclopramide and domperidone for these gastrointestinal indications.
Itopride is a new D2 antagonist with anti‐acetylcholinesterase effects. Itopride has prokinetic properties with promising results in functional dyspepsia, but controlled clinical studies showing its effects in patients with gastroparesis are lacking.
As mentioned above, cisapride had for a long time an established place in the treatment of gastroparesis and gastroparesis‐related symptoms. 17 Cisapride is now essentially withdrawn from the market due to cardiac side effects. No other 5‐HT4 agonists have shown sufficient effects to be approved for treatment of gastroparesis. The 5‐HT4 agonist tegaserod accelerates gastric emptying, 27 but controlled studies showing significant effects in patients with gastroparesis are still lacking.
Evaluation of frequently used prokinetics
The use of botulinum toxin (BTX) for treatment of spasm in gastrointestinal sphincters such as the lower oesophageal sphincter (LOS), sphincter of Oddi and the anal sphincter has been followed by attempts to use intrapyloric injections of BTX for the treatment of gastroparesis. The hypothesis was that gastric emptying would be improved if the release of excitatory transmitter substances to the pyloric muscles was inhibited by BTX. This would lead to a decreased resistance to outflow from the stomach in patients with delayed gastric emptying. Injection of BTX at gastroscopy, 100–200 units divided into four portions, has in some small, uncontrolled studies (<10 patients) been reported to improve gastric emptying and to decrease symptoms in patients with either idiopathic or diabetic gastroparesis. In a recent retrospective study of 63 patients with gastroparesis, 43% of the patients experienced symptomatic response to BTX. 28 The duration of the response was approximately 5 months and improvement was statistically linked to the male gender. To date there has been no controlled study with parallel groups on the effect of BTX in patients with gastroparesis. In a crossover randomised study, preliminarily reported from the Leuven group, 29 BTX was found not to be superior to a placebo injection with respect to its effects on symptoms and on gastric emptying in 23 patients with predominantly idiopathic gastroparesis. Thus, further studies are needed before the definite value of BTX for treatment of severe gastroparesis can be confirmed.