Approach
Not all patients with gastroparesis are hospitalised; however the majority of patients are admitted to hospital at least once in their lifetime with an acute episode of severe nausea and vomiting. One of the major goals of management is to optimise the outpatient therapeutic regimen in order to prevent hospitalisation. The general approach to treatment can be considered as two stages:[1]
Correction of fluid, electrolyte, and nutritional deficiencies if required
Reduction of symptoms.
Correction of biochemical abnormalities
Dehydration and electrolyte abnormalities can be corrected by intravenous administration of fluid and the appropriate electrolyte: for example, potassium. Acute hyperglycaemia delays gastric emptying; correcting hyperglycaemia in patients with diabetes is recommended.[1][57] Continuous glucose monitoring and/or an insulin pump may help with dosing and timing of insulin administration in patients with type 1 diabetes or insulin-requiring type 2 diabetes.[57] Correcting nutritional deficiencies is a long-term treatment goal.
Symptom control
Dietary interventions
All patients should be offered dietary advice. Patients may be intolerant of certain types of foods such as dairy products and red meat, which can be avoided. Other dietary interventions that could help are:
Consuming small, frequent (4-6/day) meals
Consuming a diet low in insoluble fibre; a diet high in insoluble fibre slows down gastric emptying and promotes the formation of bezoars
Consuming a low-fat diet
Consuming a small-particle-size diet, which could improve symptoms of nausea/vomiting, postprandial fullness, bloating, and regurgitation
Changing the diet to a high-calorie liquid diet or liquidised/blended meals.[35][60][80][81]
Prokinetic agents
A prokinetic agent should be commenced in patients who continue to have symptoms of gastroparesis despite dietary modification. This may need to be continued as ongoing prophylactic treatment. Some patients may require anti-emetics or analgesia in addition.
Prokinetics increase antral contractility, correct gastric dysrhythmias, and improve antro-duodenal co-ordination. The main classes of prokinetics used are dopamine receptor antagonists (e.g., metoclopramide, domperidone) or motilin receptor agonists (e.g., erythromycin).
Metoclopramide is both a dopamine receptor antagonist and a serotonin receptor agonist/antagonist. It is the only approved drug for the treatment of diabetic gastroparesis in the US, and is the first-line pharmacological therapy.[1] It may be administered orally, parenterally, or intranasally. It is known to improve gastrointestinal symptoms and gastric emptying. It also has anti-emetic properties.[82][83] There is a risk of parkinsonism and tardive dyskinesia, especially with high doses and prolonged use. Therefore, the European Medicines Agency recommends that oral and parenteral formulations should be used for up to 5 days only in order to minimise the risk of neurological and other adverse effects, and its use in the long-term treatment of gastroparesis is no longer recommended.[84] The US Food and Drug Administration (FDA) has placed a warning on metoclopramide because of the risk of extrapyramidal adverse effects and potentially irreversible tardive dyskinesia (which has been reported in a small percentage of cases), but recommends that it can be used for up to 12 weeks.[1][60][68] It is also recommended that 10-day interruptions every 12 weeks (drug holidays) should be instigated. During these drug holidays, patients should be advised to stick to a liquid diet. Rescue anti-emetics or short-term treatment with erythromycin can be used for symptom control if needed.[85] Other adverse effects of metoclopramide may include drowsiness and fatigue. Up to 30% of patients may not be able to tolerate metoclopramide due to its adverse effects, which are generally more common in women, older people, and people with diabetes or renal failure.[86][87] Metoclopramide should be discontinued if the patient does not achieve the desired therapeutic response, or if they develop intolerable or serious adverse effects. One meta-analysis suggested that continuous infusion of metoclopramide, as opposed to bolus administration, reduces the risk of development of extrapyramidal adverse effects.[88] However, the dose for continuous infusion has not been studied in patients with gastroparesis.
Domperidone is an alternative to metoclopramide in patients with gastroparesis. It is a dopamine antagonist with an affinity for the D2 receptor in the brain and peripheral gastrointestinal system. In the US, it can only be prescribed to patients through an FDA expanded access to investigational new drugs programme. Use of domperidone is, therefore, reserved for patients whose symptoms fail to respond to, or who experience adverse effects with, metoclopramide.[1] It does not cross the blood-brain barrier, so does not cause the neurological adverse effects associated with metoclopramide, so may be preferred. However, following a European review, the Medicines and Healthcare products Regulatory Agency and European Medicines Agency have issued recommendations concerning the use of domperidone. The review found that the drug was associated with a small increased risk of potentially life-threatening cardiac effects. As a consequence, the agencies recommend that domperidone should only be used for the treatment of symptoms of nausea and vomiting and is no longer recommended for the treatment of conditions such as heartburn, bloating, or stomach discomfort. The risks and benefits should be weighed carefully before using this drug for this off-label indication. It should be used at the lowest effective dose for the shortest possible duration and the maximum treatment duration should not usually exceed 1 week. The new maximum dose recommended in adults is 30 mg/day. Domperidone is contraindicated in patients with severe hepatic impairment or underlying cardiac disease. It should not be administered with other drugs that prolong the QT interval or inhibit CYP3A4.[89]
A number of macrolide antibiotics act as motilin receptor agonists to promote upper gut transit. Intravenous erythromycin is a potent stimulant of gastric emptying through its action on the motilin receptor, and is often used in the acute care setting if the patient is admitted to hospital. Although erythromycin is often used for this indication, the evidence supporting its use is limited to diabetic gastroparesis.[47] Long-term administration is limited by tachyphylaxis due to down-regulation of motilin receptors that starts within a few days of initiating treatment; usage is generally limited to 4 weeks and should be restricted to patients who have not tolerated or responded to other prokinetics.[1][60]
Anti-emetics
Anti-emetics are used for symptomatic relief in patients with persistent nausea and vomiting despite use of prokinetic agents; however, they do not improve gastric emptying.[1] Anti-emetics have not been studied in the management of patients with gastroparesis; their use in gastroparesis is based on their efficacy in controlling non-specific nausea and vomiting and in patients undergoing chemotherapy. Classes of anti-emetics in use for gastroparesis are as follows:
Histamine H1-receptor antagonists (e.g., diphenhydramine): can have a mild inhibitory effect on gastric emptying.[90]
5-HT3 antagonists (e.g., ondansetron): can be used in patients with persistent symptoms. They are effective in the treatment of chemotherapy-induced vomiting, radiotherapy-induced vomiting, and postoperative vomiting, but controlled studies in gastroparesis are lacking.[68] They reduce nausea from stomach distension without affecting gastric compliance, volume, or accommodation. Routine use of these drugs is limited due to the risk of QTc prolongation and, rarely, torsades de pointes, a life-threatening arrhythmia. Baseline and regular electrocardiogram monitoring is recommended.[85]
Phenothiazines (e.g., prochlorperazine): reduce nausea and vomiting via inhibition of dopamine receptors in the brain.[2] Their use is limited by the risk of central adverse effects (cognitive, psychomotor, and affective disturbances) and QTc prolongation.
Neuromodulators: have some anti-emetic properties and may have a role in refractory gastroparesis. Amitriptyline and nortriptyline are the most commonly used drugs in this class, although evidence for their benefit is limited.[91][92] In one prospective, open-label study, mirtazapine was shown to improve nausea, vomiting, and appetite after 2 and 4 weeks of treatment in patients with gastroparesis. However, 46.7% of patients experienced adverse events, and adverse effects led to treatment self-cessation in one-fifth of patients.[93]
Anticholinergics (e.g., hyoscine): used off-label in gastroparesis despite lack of evidence from clinical trials.[2]
Neurokinin (NK-1) receptor antagonists (e.g., aprepitant): block substance P in critical areas involved in nausea and vomiting, including the nucleus tractus solitarius and the area postrema. Results from randomised controlled trials have been mixed, but the American Gastroenterological Society suggests that up to one-third of patients with refractory nausea may benefit from these drugs.[2]
Current data do not support the use of haloperidol for the treatment of gastroparesis.[1]
Analgesics
Pain can be a prominent symptom in some patients with gastroparesis, leading to significant morbidity and utilisation of healthcare resources. There is a lack of clinical trials addressing the treatment of pain in gastroparesis, meaning that treatment options are limited.[1]
Opioids are associated with increased severity and duration of symptoms of gastroparesis.[94] Pain associated with gastroparesis should therefore not be treated with opioids.[1][2] This includes tramadol, which slows oro-caecal transit, and tapentadol, which slows gastric emptying.[1]
Neuromodulators, including tricyclic antidepressants (TCAs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), can reduce perception of pain at different levels of the brain-gut axis via multiple mechanisms.[2] The only gastroparesis-focused study, a randomised placebo-controlled trial of 130 patients, found that nortriptyline was no better than placebo in relieving global symptoms of idiopathic gastroparesis, although some improvement in abdominal pain was observed.[92] Guidelines differ in their recommendations regarding neuromodulators. The American Gastroenterological Association lists TCAs, SNRIs (specifically duloxetine), anticonvulsants (gabapentin and pregabalin), and mirtazapine as treatment options for visceral pain in refractory gastroparesis, but concedes that there is a lack of high-quality evidence for any of these drugs for this indication.[2] The American College of Gastroenterology advises against the routine use of central neuromodulators.[1]
Acupuncture for diabetic gastroparesis
Very low-quality evidence suggests that acupuncture alone, or in combination with a prokinetic agent, may provide short‐term symptomatic relief from diabetic gastroparesis. Acupuncture cannot be recommended as beneficial for other aetiologies of gastroparesis.[1][95] Reported benefit may be attributable to poor methodological quality of the included studies and, potentially, reporting bias. Further trials, with rigorous methodology, are required.
Treatment-resistant patients
Nutritional support and continued medical therapy
Patients with gastroparesis who do not respond appropriately to dietary and medical management tend to develop dehydration, electrolyte abnormalities, nutritional deficiencies, and malnutrition. Their diet should be evaluated. In patients who cannot maintain their caloric or nutritional needs, a jejunal feeding tube should be placed for this purpose. Doses of prokinetics and anti-emetics can then be optimised and enteral nutrition can be provided. There is rarely a role for parenteral nutrition, as long-term use is usually fraught with complications such as infections.[81] Therapy should be tried for at least 2-3 months before trying other treatments.
Gastric electrical stimulation
This is available for clinical use for patients with refractory nausea and vomiting who have failed standard therapy, who are not on opioids, and who do not have pain as a predominant symptom.[2] The precise mechanism of action is unknown, but gastric electrical stimulation does not accelerate gastric emptying. It has been postulated that its beneficial effects may occur via modulation of the gastric pacemaker, interstitial cells of Cajal, sensory afferents, other myoneural pathways, or the release of peptides.[2] The gastric electrical stimulator was granted the humanitarian device exemption by the FDA for diabetic and idiopathic gastroparesis.[1] It has been shown to improve nutritional status and glycaemic control in people with diabetes, while at the same time reducing the need for prokinetic drugs and healthcare costs.[96][97][98] Patients who need this device should be referred to centres with expertise in its implantation. The UK National Institute for Health and Care Excellence has made similar recommendations regarding use of gastric electrical stimulation for gastroparesis.[99]
Surgical and endoscopic interventions
Surgical management is indicated for patients who have refractory and disabling symptoms of gastroparesis, despite maximal medical management and a gastric electrical stimulator. Available surgical options are pyloroplasty, pyloromyotomy, and partial or total gastric resection.[100] Partial or total gastrectomy is rarely required, carries a risk of dumping syndrome, and should only be considered after all available therapies have been considered.[2] The decision for surgical management should be made after consultation with a gastroenterologist with expertise in management of gastroparesis.
Gastric per oral endoscopic pyloromyotomy (G-POEM) has shown similar symptom control, with fewer post-procedural complications and shorter length of hospital stay, compared with surgical myotomy.[1] The American Gastroenterological Association recommends G-POEM in adult patients with refractory gastroparesis who do not have mechanical gastric outlet obstruction on oesophagogastroduodenoscopy, who have had a solid-phase gastric emptying scan to confirm delayed gastric emptying (retention of >20% at 4 hours), and who have moderate to severe symptoms (with nausea and vomiting as the dominant symptoms).[101] G-POEM is also recommended in patients who have not responded to gastric electrical stimulator therapy, pyloric stenting, and botulinum toxin injection. Nevertheless, failure of these therapies is not a prerequisite to G-POEM.[101]
Endoluminal functional lumen imaging probe (Endo-FLIP) evaluation may have a role in characterising pyloric function and predicting treatment outcomes after pyloromyotomy, with patients who have low pyloric distensibility more likely to have improvement in their symptoms and increased pyloric distensibility following surgical intervention.[1][102]
Endoscopic pyloric injection of botulinum toxin type A
Endoscopic injection of botulinum toxin type A has previously been used as a treatment for gastroparesis based on the results of open-label trials, particularly in patients with post-vagotomy gastroparesis.[103] However, it is not recommended in guidelines as randomised controlled trials have failed to demonstrate its superiority compared to placebo.[1][2][104][105]
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