William L. Hasler, MD

Disclosures

Medscape J Med. 2008;10(1):16 

In This Article

Therapy of Gastroparesis

Therapies for gastroparesis include nutritional modifications, medications to stimulate gastric emptying, drugs that reduce vomiting, endoscopic and surgical approaches, and psychological interventions. To facilitate treatment selection, a gastroparesis severity classification has been proposed.[1] Grade 1 (mild) gastroparesis is characterized by intermittent, easily controlled symptoms with maintenance of weight and nutritional status, and is treated with dietary modification and avoidance of medications that slow emptying. Grade 2 (compensated) gastroparesis is characterized by moderately severe symptoms with infrequent hospitalizations that are treated with combined prokinetic and antiemetic agents. Grade 3 (gastric failure) gastroparesis patients are medication-unresponsive, cannot maintain nutrition or hydration, and require frequent emergency department or inpatient care. Individuals with grade 3 gastroparesis may need intermittent intravenous fluids and medications, enteral or parenteral nutrition, and endoscopic or surgical therapy.

Dietary recommendations, including ingesting multiple small meals, favoring liquids over solids, avoiding indigestible solids, and consuming low-fat meals, compensate for the gastric motor impairment in gastroparesis.[111] Medications that inhibit gastrointestinal motility should be discontinued if possible. In diabetic gastroparesis, maintaining euglycemia may avoid the inhibitory effects of hyperglycemia on gastric motor function.[31,32]

Prokinetic medications that stimulate gastric emptying, including metoclopramide, erythromycin, and domperidone, are the mainstays of treatment for gastroparesis of moderate severity or worse ( Table 3 ). Other drugs have motor stimulatory effects but their utility is less well defined. There have been few direct comparison trials of prokinetic agents in gastroparesis. One meta-analysis reported that erythromycin is most potent at stimulating gastric emptying while erythromycin and domperidone both are superior to metoclopramide for symptom control.[112] This interpretation does not exclude possible publication bias favoring only positive reported clinical trials.

Metoclopramide. Metoclopramide is a prokinetic agent that acts as a combined serotonin (5-hydroxytryptamine4 [5-HT]) agonist, dopamine D2 antagonist, and direct stimulant of gut smooth muscle contraction. The drug also has antiemetic effects via brainstem D2 receptor antagonism and vagal and brainstem 5-HT3 receptor antagonism. Metoclopramide increases esophageal, antral, and small bowel contractions, accelerates gastric emptying, and facilitates gastroduodenal coordination. The drug is available in pill, liquid suspension, intravenous, and subcutaneous forms.[113]

At least 5 controlled trials and 4 open series have studied the efficacy of metoclopramide in gastroparesis.[94] Symptoms improved in 7 studies, while stimulation of gastric emptying was noted in 5. Patients may develop tolerance to the prokinetic action of this agent over time, but its antiemetic effects are sustained.[51] Side effects limit metoclopramide use in 30% of patients. Fatigue, agitation, sleep disturbances, and hyperprolactinemic effects (galactorrhea, amenorrhea) are common adverse reactions. Dystonias are common, especially in patients younger than 30 years of age.[114] Irreversible tardive dyskinesia is a catastrophic consequence which occurs in 1% to 10% of cases when metoclopramide is taken for more than 3 months.[115] Because this condition is disabling, the risk should be discussed in detail with the patient prior to prescription and the discussion should be documented in the patient record.

Erythromycin. Erythromycin evokes powerful, lumen-occluding antral contractions via action on neural and smooth muscle receptors for motilin, the physiologic regulator of fasting gastroduodenal motility. Unfortunately, this motor response can impair gastric sieving of solids, leading to duodenal delivery of incompletely triturated food particles.[116] Erythromycin is available in pill, liquid suspension, and intravenous forms. When given acutely, erythromycin can facilitate passage of nasoenteric tubes for supplemental nutrition.[117]

At least 3 controlled trials and 6 open-label trials have been published on the use of erythromycin in gastroparesis.[94] Symptom benefits were observed in 6 of these studies. Tolerance to its prokinetic action with long-term oral use is common and likely relates to motilin receptor downregulation.[118,119] Because erythromycin has no additional antiemetic effect, the benefits of chronic therapy may be transient. Side effects with high doses include abdominal pain, nausea, and vomiting that relate to induction of intense, spastic motor activity in the stomach and upper intestine.[120] Erythromycin also increases the risk for sudden cardiac death.[121] In this large Medicaid cohort, the sudden death rate of current erythromycin users was 2.01 times as high as for control populations. The risk for death was further increased in those patients who also were on CYP3A (cytochrome P-450 3A) inhibitors, including selected antipsychotics, cardiac antiarrhythmics, antifungals, calcium antagonists, antidepressants, and antiemetics.

Domperidone. Domperidone is a peripheral dopamine D2 antagonist that does not cross the blood-brain barrier, thus central nervous system side effects are minimal. Domperidone increases lower esophageal sphincter pressure, accelerates gastric emptying, and enhances gastroduodenal coordination. Because brainstem structures regulating vomiting are outside the blood-brain barrier, domperidone is also a potent antiemetic.[122] The oral form is approved in most countries, except for the United States. An intravenous formulation was withdrawn after fatal cardiac arrhythmias were reported.[123]

At least 5 controlled trials and 4 open case series have assessed domperidone in patients with gastroparesis and diabetic gastropathy.[124] Symptoms improved in all studies, but accelerated gastric emptying was not uniformly observed. The drug's benefits on symptoms and quality of life are sustained while its prokinetic effects wane, emphasizing the importance of its antiemetic actions. Because of its action only on peripheral dopamine receptors, domperidone is also an especially useful drug for Parkinson's disease patients who have gastrointestinal dysmotility.[125] Adverse reactions to domperidone are uncommon, but hyperprolactinemic effects may develop due to the porous blood-brain barrier in the anterior pituitary.[122] Domperidone has effects to prolong the QTc interval on electrocardiographic testing; an intravenous form of the drug was withdrawn from overseas markets because of fatal cardiac events.[123] A more recent population-based study does suggest an increased risk for sudden cardiac death for patients on oral domperidone therapy.[126]

The US Food and Drug Administration has not approved domperidone for prescription use, but the drug has been obtainable from foreign pharmacies, the Internet, and compounding pharmacies in the United States.[1] The FDA discourages these practices but has made the drug available in the past under the auspices of a program to academic clinicians who submit an Investigational New Drug application to the FDA and who obtain Institutional Review Board approval.

Other prokinetic drugs. Although other gastrokinetic drugs are used in the treatment of gastroparesis, trials documenting their benefits have not been performed. An unpublished 8-week controlled trial of the 5-HT4 partial agonist tegaserod observed accelerated gastric emptying at daily doses of 18 and 24 mg, although symptom responses were not quantified.[127] However, tegaserod was withdrawn from the US market in 2007 due to a reported increase in the risk for cardiovascular adverse events. The FDA is allowing limited prescription of tegaserod in selected cases under an investigational new drug program.[128]

Cisapride is a 5-HT4 agonist with weak 5-HT3 antagonist properties that once was widely used for gastroparesis. The drug was withdrawn from the US market in 2000 due to numerous sudden cardiac deaths.[129] Although cisapride is still obtainable from overseas Web sites, a recent consensus document discouraged its use.[1]

Bethanechol is an approved smooth muscle muscarinic agonist that increases lower esophageal sphincter pressure and evokes fundoantral contractions but does not induce propulsive contractions or accelerate gastric emptying.[130] Prominent adverse effects include abdominal cramps, nausea, vomiting, diaphoresis, bronchoconstriction, urinary urgency, hypotension, and atrial fibrillation. Likewise, cholinesterase inhibitors have little effect on gastric emptying. However, pyridostigmine has recently been noted to reduce symptoms in a patient with gastroparesis secondary to underlying autoimmune disease.[71]

Other macrolides, including clarithromycin and azithromycin, have similar prokinetic effects as erythromycin, but their use in gastroparesis is uninvestigated. Mitemcinal, a newer oral motilin agonist without antimicrobial action, produced symptom benefits in patients with diabetic gastropathy which were restricted to those with body mass indexes < 35 kg/m2 and with hemoglobin A1c values < 10%.[131] Recent studies demonstrate potent stimulatory effects for parenteral ghrelin, an endogenous neurohumoral mediator involved in food intake.[132]

Antiemetic agents without motor stimulatory activity are used alone or in combination with prokinetic drugs for gastroparesis; however, no trials have been performed to support this practice. Antiemetic medications act on a broad range of distinct receptor subtypes ( Table 4 ). The most common antiemetic drugs are the phenothiazines (eg, prochlorperazine, thiethylperazine), which are brainstem dopamine and muscarinic antagonists. Thiethylperazine reportedly reduced symptoms in a patient with diabetic gastroparesis.[133] Tricyclic antidepressants reduce symptoms in patients with functional vomiting.[134] In a recent publication, 88% of diabetic patients with nausea and vomiting reported benefits with tricyclic antidepressants.[135] One third of patients had delayed gastric emptying, suggesting that these agents may have utility in gastroparesis. The antidepressant mirtazapine also reduced gastroparesis symptoms in a patient with type 1 diabetes.[136] However, formal prospective trials of these antidepressants for the treatment of gastroparesis have not been performed, thus their use is considered off-label. The benefits of other antiemetic drug classes in gastroparesis, including serotonin 5-HT3 antagonists, muscarinic M1 antagonists, histamine H1 antagonists, neurokinin NK1 antagonists, cannabinoids, and benzodiazepines, are unproved. Corticosteroids are employed as antiemetics in the postoperative setting or in the prevention of chemotherapy-induced emesis. One individual with idiopathic myenteric ganglionitis exhibited improvement with corticosteroid therapy, confirming the inflammatory basis of some cases of upper gut dysmotility.[45]

Complementary and alternative therapies are increasingly used to treat nausea and vomiting of diverse etiologies. Ginger, a Chinese remedy with weak 5-HT3 antagonist properties, has antiemetic actions in some settings but its benefit in gastroparesis is unexplored. Acupressure and acustimulation on the P6 point reduce nausea postoperatively, after chemotherapy, and during first-trimester pregnancy. One group observed benefits with acupuncture in diabetic gastroparesis.[137]

Symptoms other than nausea and vomiting may predominate in gastroparesis. Early satiety relates to impaired fundic accommodation in functional dyspepsia.[138] Nitrates, buspirone, sumatriptan, and selective serotonin reuptake inhibitors promote fundic relaxation in this condition.[139,140] Epigastric pain is disabling in some gastroparesis patients. As in functional dyspepsia, pain in gastroparesis may stem from sensory rather than motor dysfunction.[141] The benefits of agents that relax the fundus or reduce visceral sensation have not been studied in gastroparesis. Finally, the ability of prokinetics to stabilize glycemic control has been studied in gastroparetics with poorly controlled diabetes. Some studies report reductions in glucose levels with erythromycin or cisapride but others observe no effect on either short-term or long-term glycemic control, and thus no consensus opinion has formed on this issue.[142]

Therapeutic endoscopy may provide benefit in some patients with gastroparesis. Injection of botulinum toxin into the pylorus reduces phasic contractions and tone by preventing unopposed cholinergic contractile activity.[1,143] Several uncontrolled case series have reported reduced symptoms and acceleration of gastric emptying after botulinum toxin treatment.[144,145] In the largest series, 43% of 63 patients experienced benefits for a mean of 5 months.[146] An unpublished study involving 78 patients observed similar response rates in diabetic (55%), idiopathic (51%), and postsurgical (44%) gastroparesis.[147] In this study, higher doses of botulinum toxin (150-200 units) had greater symptom benefits than lower doses (75-100 units). Recent unpublished, blinded controlled trials have not demonstrated efficacy of botulinum toxin vs placebo, but these studies are small and may not be adequately powered to detect a therapeutic benefit.[148,149] Use of botulinum toxin for gastroparesis is considered off-label. Other endoscopic procedures provide relief in some cases of gastroparesis. Venting gastrostomies intermittently release retained gas and liquid, reducing fullness, discomfort, and distention-related nausea.[150]

Surgical intervention is increasingly employed to treat refractory gastroparesis. The most common operation, gastric electrical stimulator implantation, has been performed in more than 1500 patients over the past decade. Gastric resection and pancreatic transplantation for diabetic patients are performed less often and their benefits are not well documented.

Gastric electrical stimulation. Recent research suggests that some cases of gastroparesis may respond to stimulation with electrical depolarizing stimuli. In a trial of high-energy gastric pacing at a rate slightly above the normal slow-wave frequency in 9 patients with medication-resistant gastroparesis (5 diabetic, 3 idiopathic, 1 postsurgical), slow-wave entrainment was observed, underlying dysrhythmias were abolished, gastric emptying accelerated, and symptoms improved to the point that 8 patients no longer required supplemental jejunal nutrition.[151] However, this method was impractical for long-term use because the current source needed to pace the stomach was too bulky for implantation.

Because of these drawbacks of pacing, researchers investigated the benefits of other lower-energy stimulation parameters. Initial unpublished series employing an implantable gastric neurostimulator that delivered low-energy impulses at 12 cycles per minute reported reduced symptoms in patients with medication-unresponsive gastroparesis. Due to this apparent benefit, the stimulator received FDA approval as a humanitarian use device and was granted a humanitarian device exemption for application in patients with diabetic and idiopathic gastroparesis. For this judgment, the FDA deems the device to have probable benefit with the expectation that controlled clinical trials will ultimately be performed, and restricts its use to centers in which Institutional Review Board approval has been granted.

The gastric stimulator has since shown efficacy in uncontrolled studies in diabetic, idiopathic, and postsurgical gastroparesis. In one uncontrolled multicenter trial, 35 of 38 patients experienced greater than 80% reductions in nausea and vomiting which persisted for 2.9-15.6 months, with an associated 5.5% increase in weight and reduced requirements for supplemental nutrition.[152] Other studies reported similar long-term symptom benefits which may persist for at least 10 years, with associated improvements in body mass index, serum albumin, and glycemic control.[153,154] In the only controlled trial of gastric electrical stimulation, 33 patients with idiopathic or diabetic gastroparesis completed a 2-month double-blind, crossover, sham stimulation-controlled phase followed by a 12-month uncontrolled observation period with the device activated.[155] During the blinded phase, frequency of vomiting was 14% lower when the device was on as opposed to off. Symptom reductions were more impressive during the unblinded phase of the study. Complications including infection, lead dislodgement, and bowel obstruction necessitated device removal in over 10% of patients; up to one fourth of patients have undergone gastrectomy in some series because of a lack of response.[152] The mechanism of action of gastric stimulation does not involve acceleration of gastric emptying or slow-wave stabilization.[152,155] Rather, in animal and human models, gastric stimulation acts via vagal pathways to promote fundic relaxation and reduce afferent hypersensitivity.[156,157,158]

Other operative interventions. Other operations rarely are considered for patients with gastroparesis unresponsive to drug therapy. Surgical pyloroplasty produced benefit in 1 unpublished series of diabetic patients with gastroparesis, but a more recent report observed symptom improvements in only one third of patients.[159,160] Gastroenteric anastomosis reconstruction (ie, conversion of a Billroth I to a Billroth II or vice versa) is rarely effective. Performance of completion gastrectomy with preservation of only a small cuff of gastric tissue provides long-term symptom relief in 43% to 67% of patients with postsurgical gastroparesis.[161,162] The utility of subtotal gastrectomy for diabetic gastroparesis was promoted in a small series of 7 patients.[163] However, extraintestinal complications developed in 3 patients, 2 of whom died; thus, the benefits of surgery were difficult to evaluate. Pancreas transplants prevent progression of preexisting diabetic complications such as neuropathy or retinopathy, although studies report conflicting data on the benefits of this operation in patients with diabetic gastroparesis.[164]

Some patients with refractory gastroparesis benefit from enteral or parenteral nutrition intermittently for symptom flares or for permanent support. The benefits of parenteral nutrition are clinical observations and have not been reported in the literature. In diabetic gastroparesis, jejunostomy placement for enteral feeding improves overall health status with trends towards reduced symptoms and hospitalization rates and enhanced nutrition.[165] Indications for enteral nutrition include significant malnutrition (eg, greater than 10% weight loss over 6 months) unresponsive to dietary modification, essential mineral deficiencies or electrolyte disturbances, and frequent hospitalizations producing profound disability.[1] Short-term total parenteral nutrition (TPN) can reverse rapid weight decline and ensure adequate fluid delivery, but permanent TPN usually is needed only for individuals with superimposed severe intestinal dysmotility who cannot tolerate enteral feeding.

Patients with gastroparesis commonly experience psychological sequelae of their gastrointestinal disease, including anxiety, depression, and somatization.[4] The degree of psychological impairment correlates strongly with symptom severity in patients with diabetic gastroparesis.[166] Despite these observations, the role of the mental health specialist in managing gastroparesis has not been defined. Small studies report benefits with biofeedback or hypnosis.[167]

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