Effect of metoclopramide and domperidone

Clinical question 2a:

What is the effect of metoclopramide and domperidone in the treatment of nausea and/or vomiting in patients in the palliative phase of cancer, heart failure, COPD, MS, ALS or renal failure and is there a difference in effectiveness between metoclopramide and domperidone?

Recommendation

Metoclopramide is recommended as first chance antiemetic in the treatment of nausea and vomiting in patients in the palliative phase, unless caused by chemotherapy, ileus, brain metastases or vestibular causes. In case of (a high risk of) central side effects that bother the patient, treatment with domperidone is preferred.

Introduction

Metoclopramide promotes gastric emptying by increasiing peristalsis of the proximal section of the gastrointestinal tract, increasing the tone of the bottom sphincter muscle of the oesophagus and relaxing the pylorus. The antiemetic effect is also the result of antagonism of D2 receptors in the chemoreceptor trigger zone and in the vomiting centre and of antagonism of 5-HT3 receptors. The drug is administered orally (as tablet or drink), rectally or parenterally.

Domperidone is a dopamine antagonist that increases peristalsis of the stomach and duodenum, increases the pressure of the gastro-oesophageal sphincter and also relaxes the sphincter of the pylorus. It also affects the dopamine receptors in the chemoreceptor trigger zone. In contrast to metoclopramide, the drug barely passes the blood-brain barrier., As a result, there are no central side effects (drowsiness, akathisia, dystonia). The drug is administered as tablet, suspension or suppository.
Both drugs are registered for the treatment of nausea and vomiting, independent of the cause.

In the following text, the role of metoclopramide and domperidone in the prevention and treatment of nausea and vomiting as a result of chemotherapy will not be discussed.

Literature discussion

No studies have been found that compare the effectiveness of metoclopramide and domperidone

One review was found in which the effectiveness of domperidone was described for various causes of nausea and/or vomiting [Reddymasu 2007], showing domperidone to be an effective antiemetic. However, the drug has not been studied in patients in the palliative phase. The fact that domperidone is not officially registered in the United States also plays a role in this.

Four articles have been found in which the effect of metoclopramide on nausea and vomiting has been studied in patients in the palliative phase [Bruera 1996 and 2000; Ljutic 2002; Wilson 2002] as well as three reviews [Benze 2012; Davis 2010; Glare 2008] and a protocol of the Cleveland Clinic [Gupta 2012].

In 1996, Bruera conducted a retrospective study on the effect of metoclopramide on nausea and vomiting in 100 patients with cancer in an advanced stage, who were admitted to a palliative care unit [Bruera 1996]. All patients were offered the same medication schedule if they suffered from nausea; first metoclopramide orally or s.c. six times daily; if that did not help, dexamethasone 10 mg twice daily was added; step 3 was continuous subcutaneous infusion of metoclopramide 60-120 mg/24 hours per day plus dexamethasone. If nausea persisted, patients were switched to a different antiemetic. The visual analogue scale (VAS) scores for nausea were significantly lower than that of other symptoms (anorexia, pain, dyspnoea, unwell). The conclusion was that this schedule with metoclopramide is effective. Other medication was used for 25 patients, especially for patients with intestinal obstruction (n=17) or patients with extrapyramidal side effects (n=3).

Bruera conducted a double-blind cross-over study in 2000 in patients with a cancer-associated dyspepsia syndrome [Bruera 2000]. All patients used an opioid. They were treated with metoclopramide with delayed release 40 mg twice daily or placebo for a duration of 4 days. On day 5, the treatment group was switched for another 4 days. Adjustments in dose and addition of other antiemetics were accepted. The VAS scores for nausea at the end of the treatment period were lower for metoclopramide than placebo (12 vs 17); the VAS scores for vomiting showed a trend for a difference (9 vs 14). There were no differences in side effects.

In 2002, Wilson published a multicentre study on the effectiveness of metoclopramide with controlled release in patients with a cancer-associated dyspepsia syndrome [Wilson 2002]. Forty-eight patients with nausea and vomiting received metoclopramide with controlled release 20-80 mg twice daily for a duration of at least two weeks in an open label group. There was a 40-60% reduction in nausea complaints after two weeks of treatment. There was a 50% reduction in vomiting after 4 weeks.
In a double-blind crossover study [Ljutic 2002], Ljutic compared a single dose of metoclopramide (10 mg i.v.) with ondansetron (8 mg i.v.) in 10 patients with complaints of nausea and vomiting with terminal renal failure. The effect of vomiting was scored on a scale of 1-3 by both the patient and the researcher. Nausea was scored by the patients on a scale of 1-5. High scores indicated a better effect. Ondansetron was more effective than metoclopramide against nausea (average score 4.10 vs 2.10) and vomiting (average score 2.80 vs 1.40).

Reviews state that the evidence for effectiveness of all antiemetics researched (including metoclopramide and domperidone) is of moderate quality [Benze 2012; Davis 2010; Glare 2008]. Benze and Davis recommended using metoclopramide as first line treatment. According to Glare, metoclopramide has the advantage that it can be administered parenterally and domperidone has the advantage that it does not show side effects due to the inability to pass the blood-brain barrier [Glare 2008 34]. He advises against the use of metoclopramide if there is an ileus. In the Cleveland protocol, metoclopramide is the treatment of first choice (except if there is an ileus or brain metastasis) [Gupta 2012].

There are indications that metoclopramide is an effective antiemetic in patients with an advanced stage of cancer.
[Bruera 1996 and 2000; Wilson 2002]

There are indications that metoclopramide is a less effective antiemetic than ondansetron in patients with terminal renal failure.[Ljutic 2002]

No statement can be made about the effectiveness of metoclopramide in patients with other diseases than cancer and terminal renal failure.

No statement can be made about the effectiveness of domperidone in patients in the palliative phase.

No statement can be made about the difference in effectiveness between metoclopramide and domperidone.

Despite the lack of evidence, domperidone is used regularly in daily practice for the treatment of nausea and vomiting in patients in the palliative phase. (A high risk of) side effects such as akathisia and drowsiness with metoclopramide may result in a preference for domperidone [Glare 2008; Bruera 1996]. On the other hand, the use of more than 30 mg daily domperidone is associated with an increased risk of acute cardiac death due to prolongation of the QT-time [Van Roeden 2013]. However, the risk of acute cardiac death is probably very low [Otten 2013].

Metoclopramide can also be administered parenterally, which can be a benefit in some situations.
Metoclopramide has not been studied in patients with other diseases than cancer and terminal renal failure. However, there is no reason to assume that it would be less effective in other diseases in the palliative phase.