Symptomatic management: pharmacological

Vastgesteld: 16-06-2014
Regiehouder: IKNL

Introduction

Antiemetics have different methods of action (see Table 1). Some agents have multiple mechanisms of action and interact with various receptors.
The following agents are used as antiemetics (see Table 2):

dopamine antagonists (metoclopramide, domperidone, haloperidol)
prokinetic drugs (metoclopramide, domperidone): promote gastric emptying by inhibiting dopamine receptors in the stomach and (only in the case of metoclopramide) stimulate cholinergic receptors in the stomach
serotonin (5HT3) antagonists (ondansetron, granisetron, tropisetron, palonosetron)
neurokinin-1 antagonists (aprepitant, fosaprepitant)
corticosteroids (in practice especially dexamethasone, method of action unknown)
anticholinergic agents (scopolamine, hysocine butylbromide)
levomepromazine, olanzapine: antidopaminergic as well as antiserotonergic (5HT2), anticholinergic and antihistaminergic mode of action
antisecretory agents: octreotide/lanreotide (somatostatin analogues: a gastrointestinal hormone that inhibits secretion in the gastrointestinal tract)

There is a chance with a number of the abovementioned agents (scopolamine, levomepromazine and olanzapine) of anticholinergic side-effects, such as a delirium. This is especially the case with elderly patients. Metoclopramide and haloperidol have extrapyramidal disorders, akathisia, dystonia and drowsiness as possible side-effects and are contraindicated in patients with Parkinson's disease.
Antiemetics may be administered by oral, rectal, transdermal, or parenteral (subcutaneous or intravenous) routes.

Table 1. The mechanism of action of antiemetics
	Central dopamine- antagonist	5-HT3- antagonist	5-HT2- antagonist	Pro- kinetic agent	Anti-cholinergic agent	Anti-histaminic agent	Neurokinin- 1 antagonist
Metoclopramide	++	+		++
Domperidon	++			++
Haloperidol	++				+
Ondansetron, granisetron, tropisetron, palonosetron		++
Corticosteroids¹
Scopolamine\ Hyoscine butylbromide					++
Levomepromazine, olanzapine	++		++		++	++
Aprepitant, fosaprepitant							++

¹Mechanism of antiemetic action unknown

Tabel 2. Antiemetics
Agent/ method of administration	Mechanism of action	Dose	Dose
Metoclopramide Tablet, drink, suppository, injection	Central dopamine-2 antagonist Prokinetic agent(advances gastric emptying) Weak serotonin(5HT3) antagonist	3 dd 10 mg orally or supp. In case of insufficient effect, high doses (40-100 mg/24 hrs s.c. or i.v.) can be considered	May worsen colic-like abdominal pain if there is ileus Do not combine with anticholinergic agents Central side effects: extrapyramidal side effects, akathisia, dystonia, drowsiness, especially at an elderly age and/or with comedication
Domperidon Tablet, suspension, suppository	Central dopamine-2 antagonist Prokinetic agent	3-4 dd 10-20 mg orally 3-4 dd 60-120 mg supp	May worsen colic-like abdominal pain if there is ileus Do not combine with anticholinergic agents Few or no central side effects. Arrhythmia
Haloperidol Tablet, drops (buccal), injection	Dopamine-2 antagonist (central)	2 dd 1-2 mg orally 2 dd 0.5-1 mg s.c. or i.v., or 1-2 mg/24 hrs s.c. or i.v. Dose orally. : s.c./i.v. = 2 : 1	Side effects: extrapyramidal side effect, akathisia, dystonia, drowsiness, dry mouth, vision abnormalities, urine retention, arrhythmia
Dexamethasone Tablet, drink, injection	Reduction in cerebral oedema and possibly also oedema around the tumour or metastasis Other mechanisms unknown	1 dd 4-8 mg orally, s.c. or i.v. Dose orally = s.c./i.v..	Especially with chemotherapy (acute and delayed nausea and vomiting) or increased intracranial pressure With therapy-resistant nausea and/or vomiting
Ondansetron Tablet, orodispersible tablet, syrup, suppository, injection	Serotonin (5HT3) antagonist (central + peripheral)	1-2 dd 8 mg orally or i.v. 1 dd 16 mg supp. 16mg/24 hrs s.c. or i.v.	Especially with chemotherapy or radiotherapy, postoperative or with nausea and vomiting as a result of renal failure. Constipation as a side effect
Granisetron Tablet, injection, patch	Serotonin (5HT3) antagonist (central + peripheral)	2 dd 1 mg orally 1-3 dd 3 mg i.v. 3.1 mg/24 hr transdermal	Especially with chemotherapy, radiotherapy or postoperative Granisetron transdermal in the case of treatment across multiple days Constipation as side effect
Tropisetron Tablet, injection	Serotonin (5HT3) antagonist (central + peripheral)	1 dd 5 mg orally or i.v.	Especially with chemotherapy or radiotherapy or postoperative Constipation as side effect
Palonosetron	Serotonin (5HT3) antagonist (central + peripheral)	250 µg i.v. (single dose)	With chemotherapy Constipation as side effect
Aprepitant Capsule	Neurokinin-1 (NK1) antagonist	1 dd 125 mg orally on day 1 1 dd 80 mg orally on day 2-3	With nausea and/or vomiting as a result of chemotherapy Increases levels of dexamethasone
Fosaprepitant, injection	Neurokinin-1 (NK1) antagonist	1 dd 150 mg i.v. on day 1
Levomepromazine Tablet, injection	Dopamine-2 antagonist 5-HT2 antagonist Antihistaminic agent Anticholinergic agent	Starting dose 1 dd 6.25-12.5 mg orally a.n. or 3.12 mg s.c. (as bolus or as continuous infusion), increase where necessary to max. 25 mg dd Dose orally : s.c. = 2 : 1	Sedation, dry mouth Can also be administered buccally As monotherapy with therapy-resistant nausea and/or vomiting Is not reimbursed
Olanzapine Tablet, injection	Dopamine-1/4 antagonist Serotonin (5HT2,3,6) antagonist Antihistaminic agent Anticholinergic agent	1-2 dd 5 mg orally	Increased chance of CVA and death reported for use in elderly patients with dementia
Scopolamine	Anticholinergic agent	1-2 patches of 1.5 mg every 3 days	Place behind the ear Side effects: dry mouth, vision disturbances, urine retention, confusion. Do not combine with prokinetic agents
Scololaminebutyl Injection	Anticholinergic agent	40-120 mg/24 hrs s.c. or i.v.	With ileus Dry mouth, impaired vision, urine retention, confusion Do not combine with prokinetic agents. .
Cyclizin Tablet, suppository	Antisecretory agent	50 mg orally 3-4 times daily 100 mg rectally 3 times daily	Do not combine with prokinetic drugs Reimbursement only with prescription for chronic use
Octreotide Injection	Antisecretory agent	3 dd 100-300 microgr or 300-900 microgr/24 h s.c. or i.v.	With ileus
Octreotide LAR Injection	Antisecretory agent	30 mg i.m. once every 4 weeks	With ileus, responding well to octreotide
Lanreotide PR Injection	Antisecretory agent	30 mg i.m. once every 4 weeks	With ileus, responding well to octreotide

Almost all research on the effect of antiemetics has been performed in cancer patients. In making the recommendations given below, no distinction is made between cancer patients and patients with other life-threatening disorders.

For patients in the palliative phase of nausea and vomiting as a result of other causes than chemotherapy, ileus, brain metastases, terminal renal failure or vestibular causes, it is recommended to choose an empirical approach with metoclopramide as first choice. In case of (a high risk of) central side effects that (may) bother the patient, the use of domperidone is preferred (see paragraph effectiveness of antiemetics on the basis of the cause and effect of metoclopramide and domperidone).

Haloperidol is recommended for the treatment of nausea and vomiting in the palliative phase as alternative for metoclopramide or domperidone, especially if there is another indication for this agent (such as hallucinations or (starting) delirium) (see paragraph effect of haloperidol).

The guideline development group is of the opinion that dexamethasone monotherapy may be employed in the treatment of nausea and vomiting in the palliative phase if there is insufficient response to treatment with metoclopramide, domperidone or haloperidol (see paragraph effect of dexamethasone).

Treatment with levomepromazine orally (possibly buccally or s.c.) is recommended for patients in the palliative phase with nausea and/or vomiting that responds insufficiently to other antiemetics. Olanzapine is an alternative (see paragraph effect of levomepromazine and olanzapine).

Treatment with serotonin antagonists is recommended for patients in the palliative phase:

to prevent or treat nausea and vomiting as a result of chemotherapy, radiotherapy or postoperatively
with nausea and/or vomiting that does not respond sufficiently to earlier treatment with metoclopramide, domperidone, haloperidol, dexamethasone and levomepromazine
as a first choice in patients with terminal renal failure with nausea and vomiting
see paragraph effect of serotonine-antagonists).

Due to a lack of research and clinical experience, no recommendations are made about the use of cyclizine in the treatment of nausea and vomiting in patients in the palliative phase (see paragraph effect of cyclizine).

Erythromycin is not recommended for the treatment of nausea or vomiting for patients in the palliative phase, unless there is gastroparesis with diabetes mellitus or after vagotomy (see paragraph effect of erythromycin).

Ginger is not recommended for patients in the palliative phase with nausea and/or vomiting (see paragraph effect of ginger).

In some cases, the choice of agents is dependent on the cause of the nausea and/or vomiting:

prokinetic drugs (metoclopramide or domperidone) with gastroparesis
serotonin (5HT3) antagonists (possibly in combination with dexamethasone and (fos)aprepitant) with nausea and/or vomiting postoperatively or after radiotherapy, to prevent or treat nausea and vomiting as a result of chemotherapy (only during the first 24 hours) or nausea and/or vomiting with terminal renal failure
aprepitant to prevent nausea and/or vomiting after highly emetogenic chemotherapy
dexamethasone if there is nausea due to chemotherapy (in combination with serotonin antagonists), in the case of brain metastases with oedema and possible with ileus
scopolamine patch for vestibular causes of nausea and/or vomiting
octreotide/octreotide LAR/lanreotide and/or hyoscine butylbromide for pharmacological treatment of ileus

In all other cases an empirical approach is chosen, in which metoclopramide or domperidone are started (usually orally or rectally), independent of the cause of the nausea and/or vomiting. A switch is made from metoclopramide to domperidone if there are central side effects. It is also possible to choose haloperidol, especially if there is another indication to do so (hallucinations or (starting) delirium).
The effect of oral or rectal administration of metoclopramide and domperidone can be assessed within 1-2 hours, the effect of oral administration of haloperidol after 2-6 hours.

Given that metoclopramide and haloperidol are both dopamine antagonists, combining these agents for the treatment of nausea is not rational. Moreover, the chance of extrapyramidal side effects when combining these agents increases greatly. If adequately dosed metoclopramide or domperidone does not provide sufficient effect, it is not rational to switch to haloperidol. Metoclopramide and domperidone must not be combined with agents with anticholinergic (side-)effects because they counteract the prokinetic effect.
If metoclopramide, domperidone or haloperidol has insufficient effect, these agents are discontinued and the patient is started on dexamethasone 1 dd 4-8 mg orally. The effect of this can only be assessed after 24-48 hours.

A switch is made to levomepromazine if the effect is insufficient. Olanzapine or serotonin antagonists (ondansetron, granisetron or tropisetron) are possible alternatives. If there is persistent vomiting, rectal administration of metoclopramide or domperidone is chosen, or parenteral administration of:

metoclopramide: 40-100 mg/24 hours s.c. or i.v. as continuous infusion
haloperidol: 1-2 mg s.c. or i.v. twice daily or 2-4 mg/24 hours s.c. or i.v. as continuous infusion
dexamethasone: once daily 4-8 mg s.c. or i.v.
ondansetron: 8 mg twice daily or 16 mg/24 hours s.c. or i.v.
levomepromazine: 3.25-12.5 mg s.c. a.n. or as continuous infusion

With the exception of dexamethasone, the aforementioned agents may be easily combined with other agents (e.g. morphine) in one solution. The disadvantages of this approach, however, are that the dose of each agent can no longer be adjusted individually and a bolus injection is not wellr possible.

In relation to the choice between rectal and parenteral administration of antiemetics, the following recommendation has been made on the basis of the detailing for clinical question 3:

When making a choice between rectal or parenteral administration of antiemetics, it is recommended to be guided primarily by the preference and situation of the patient, within the possibilities of the care setting (see paragraph effect of erythromycin).

If anxiety and/or stress also play a role, all the above mentioned agents may be combined with oxazepam 10 mg orally 3 times daily or lorazepam 1-2 mg three times orally, i.v. or possibly sublingually.