New Management Approaches for Gastroparesis

Christopher K Rayner; Michael Horowitz

Disclosures

Nat Clin Pract Gastroenterol Hepatol. 2005;2(10):454-462. 

In This Article

Medical Therapy

The main goals of treatment for gastroparesis are alleviation of symptoms, correction of malnutrition, and resumption of adequate oral intake of liquids and solids.[8] Patients with severe nausea and vomiting might require hospitalization for intravenous fluid and electrolyte replacement, and prokinetic and/or antiemetic drugs might initially need to be administered intravenously. Glycemic control must be optimized in patients with diabetes, given the potential for acute hyperglycemia to impair gastric motor function, as well as to inhibit the action of prokinetic drugs such as erythromycin.[26] In patients with type 1 diabetes, gastroparesis can be an indication for insulin-pump therapy.[8]

A diet low in fat and fiber, taken in small, frequent meals, has been advocated, although different diets have not been rigorously compared in patients with gastroparesis. Nutrient liquids might be better tolerated than solids as their emptying from the stomach is less likely to be grossly impaired, whereas indigestible solids should be avoided to lessen the risk of bezoar formation.[7] When oral intake cannot be tolerated, nasojejunal feeding can be successful provided small-intestinal motility is not severely disturbed, and it is preferable to parenteral nutrition.

Prokinetic Drugs

Most patients with gastroparesis require drug therapy, and for most this needs to continue long term. Drugs that increase the rate of gastric emptying -- prokinetics ( Table 1 ) -- are generally prescribed in order to relieve symptoms, although as discussed, the presence of symptoms often correlates poorly with the rate of gastric emptying. Most of the available prokinetic drugs have multiple actions, targeting both sensory and motor pathways, and the agents providing greatest symptom relief are not necessarily the most potent in terms of their capacity to accelerate emptying.[3] Patients with upper-gastrointestinal symptoms but normal gastric emptying might therefore respond to prokinetic therapy, and furthermore, these medications are likely to have a placebo effect in a proportion of patients. The prokinetics metoclopramide, domperidone, and cisapride are all reported to improve disturbances of the gastric electrical rhythm, and might provide greater symptomatic relief than the more potent prokinetic erythromycin, which can increase gastric dysrhythmias.[27]

Rather than simply stimulating an increased frequency or amplitude of gastric contractions, such as with bethanechol or acetylcholinesterase inhibitors, effective prokinetic drugs, such as cisapride, stimulate coordinated sequences of pressure waves in the antrum, pylorus and duodenum.[7,28] Some prokinetic agents, including cisapride, also relax the fundus, which might improve symptoms in a subgroup of patients, independent of their effects on gastric emptying;[3] conversely, erythromycin increases fundic tone.

In addition to treating symptoms, prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin,[29] but evidence to support this strategy is limited. In type 2 diabetes, which is characterized by diminished and delayed endogenous insulin release, slower gastric emptying might actually improve glycemic control because nutrients are absorbed more slowly, so there might be no reason to use prokinetic drugs in the absence of symptoms.

The choice of prokinetic drug is determined by local availability, the side-effect profile, and the clinician's personal experience with the drug, and there are few data comparing the drugs directly. Combinations of prokinetic drugs could be more effective than a single agent,[30] but this issue has not been sufficiently evaluated. Most reports of drug efficacy relate to short-term usage, and there is some concern that longer term use of metoclopramide, domperidone, and erythromycin might result in tachyphylaxis.[8]

Erythromycin. Erythromycin is the most potent prokinetic drug when given intravenously in the acute setting[31] and is therefore useful in the initial management of hospitalized patients with severe gastroparesis. Administration of erythromycin in the acute setting can improve bloating, but not other meal-related symptoms,[32] although there is some evidence that a low dose (50-100 mg four times daily) of oral erythromycin suspension might be associated with long-term symptomatic benefit.[33] Drawbacks of treatment with erythromycin include its potential to induce abdominal cramps and nausea, and to slow small-intestinal transit,[34] as well as its antibiotic effects. Synthetic erythromycin analogues (motilides) devoid of antibiotic properties have been developed, but have so far been disappointing; ABT229 increases the rate of gastric emptying, but with poor symptom relief,[35,36] while KC11458 fails to accelerate gastric emptying in diabetic gastroparesis.[37]

Cisapride. Cisapride has been a useful drug in treating gastroparesis, with evidence for long-term symptomatic benefit.[38] Furthermore, it can accelerate small-bowel and large-bowel transit.[39] Cisapride has recently been withdrawn from many markets owing to its potential to induce cardiac arrhythmias, which is probably related to its class III antiarrhythmic properties rather than serotonin-receptor-4 (5-HT4) stimulation,[40] but its manufacturer makes it available for carefully selected patients. A long QT interval (>450 msec), electrolyte disturbances, and concurrent use of drugs that inhibit cytochrome P450 3A4 or prolong the QT interval, are contraindications to the use of cisapride, and the dose should remain as low as possible (ideally less than 40 mg daily).

Metoclopramide. Metoclopramide might be a less potent prokinetic drug than cisapride,[41] particularly with prolonged use, but its antiemetic properties can provide prolonged symptom relief in gastroparesis.[42] It has the advantage of either parenteral (including subcutaneous) or oral dosing, but side effects including extrapyramidal reactions are not uncommon.[43] Tardive dyskinesia represents a potentially irreversible side effect.[44]

Domperidone. Like metoclopramide, domperidone has antiemetic and prokinetic effects, although central nervous system reactions are uncommon owing to its relative lack of penetration of the blood-brain barrier. This property makes it suitable for use in Parkinson's disease.[45] The drug can still influence the vomiting center in the area postrema of the medulla, which is outside the blood-brain barrier. The prokinetic effects of domperidone seem to be comparable in magnitude to those of metoclopramide. Domperidone improves quality of life in patients with diabetic gastroparesis, in at least the short term.[46] This drug is available in Europe, Canada, South America, and Australia; though not approved by the FDA, it is now available in the US under the Investigative New Drug program.

Other Prokinetic Drugs. The dopamine D2 receptor antagonist levosulpiride has been reported to improve gastric emptying and symptoms in diabetic gastroparesis during 6 months of treatment,[47] but is not widely available outside Europe. Tegaserod, a partial 5-HT4 agonist, is marketed for constipation-predominant irritable bowel syndrome, but there are conflicting data regarding its effect on gastric emptying.[7] A recent report indicates acceleration of gastric emptying by intravenous ghrelin in symptomatic patients with diabetes.[48]

Antiemetic Agents

Additional nausea relief to that provided by the prokinetic drugs might be required. The phenothiazine derivatives, promethazine and prochlorperazine, are dopamine antagonists, and can be given orally, rectally, or parenterally. As with metoclopramide, sedation and extrapyramidal reactions are relatively frequent.[49] The serotonin-receptor-3 (5-HT3)antagonists ondansetron, granisetron, and tropisetron, are effective treatments for nausea associated with chemotherapy, but their role in gastroparesis has not been established.

Other Medical Therapies

There has been recent interest in drugs that promote relaxation of the fundus for the treatment of patients with functional dyspepsia who have impaired meal-induced gastric accommodation. These agents can relieve symptoms such as fullness and include the serotonin-receptor-1 (5-HT1) agonists sumatriptan (which is not suitable for oral administration) and buspirone,[4] which have the potential disadvantage of slowing gastric emptying. The α-2-adrenergic agonist clonidine also relaxes the fundus and diminishes the perception of gastric distension:[50] reports relating to its effects on gastric emptying are inconsistent. The selective phosphodiesterase-type-5 inhibitor, sildenafil, has been reported to relax the pylorus in rodent models of diabetic gastroparesis, but it did not improve the rate of emptying of solids in patients with end-stage renal failure, including some with diabetes,[51] possibly because of its capacity to relax the fundus concurrently.

Antinociceptive agents include the κ-opioid agonist fedotozine, which has been disappointing in the treatment of symptoms in diabetic gastroparesis,[52] and low-dose antidepressants,[53] although there are few data on the use of the latter in gastroparesis, and they could exacerbate the delay in gastric emptying.

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