Antiemetics

Antiemetics are used to treat nausea and vomiting which are common complications of multiple conditions. They give symptomatic relief but should only be used when the cause of these symptoms is known as they can cause delay in diagnosis and treatment of underlying cause, for example, diabetic ketoacidosis, digoxin toxicity.¹
Nausea and vomiting are mediated by three different pathways (key neurotransmitters in brackets):

• By visceral stimulation (dopamine and serotonin)
• By CNS vestibular stimulation (histamine, acetylcholine)
• By activation of the chemoreceptor trigger zone in the floor of the 4th ventricle(dopamine, serotonin).

The pathways converge in the medulla which directly mediates nausea and vomiting.²
The choice of antiemetic should depend on the cause and rational prescribing, based on an understanding of the pathophysiology, should optimise treatment efficacy.
Side-effects can also be predicted based on the drug's mode of action.

Migraine^1,3,4

Migraine headaches are frequently associated with nausea. The underlying mechanism is not well understood. Antiemetics tend to be used combined with standard analgesics or triptans in the treatment of acute attacks and can be given orally or rectally.
Prokinetic anti-emetics are first-line choices.⁵ As well as their anti-emetic effect, they increase gastric emptying (increasing the absorption of oral analgesia) and dopamine is thought to be a primary mediator in migraine so that they may have a role in treating the headache also. Domperidone has less evidence backing its role in migraine but fewer side-effects (especially extrapyramidal) than metoclopramide.
Combination products such as Migramax™ and Paramax™ exist and can be useful for early self-medication in an attack.

Postoperative nausea and vomiting^2,6,7

Postoperative nausea and vomiting is a frequent complication of recovery from surgery. Shorter-acting anaesthetic drugs have reduced the overall incidence to about 30% but in high-risk patient populations (risk factors include: female sex, history of motion sickness or previous postoperative nausea and vomiting, non-smoking status, those undergoing emetogenic procedures and use of postoperative opioid) it can still be as high as 60%. The use of an antiemetic acting on one receptor type typically reduces post-op nausea and vomiting by about 30% and combination of antiemetics acting on different receptor types reduces the incidence further. A 5HT₃ antagonist combined with a phenothiazine or dexamethasone can achieve a 90% response rate.
Antiemetics (including phenothiazines, metoclopramide, 5HT₃ antagonists, antihistamines and dexamethasone) are frequently given prophylactically - some will receive antiemetics that do not require them and others will develop post-op nausea and vomiting despite prophylaxis. A multimodal approach is advocated: preoperatively identify those at high risk, reduce avoidable risk-factors and consider the use of combination antiemetics in resistant postoperative nausea and vomiting.

Chemotherapy-induced nausea and vomiting¹

The nausea and vomiting associated with chemotherapy (and to a lesser extent, radiotherapy) can drastically reduce cancer patients' quality of life and may lead to refusal of further treatment. Symptoms may be acute (<24hours of treatment), delayed (>24hours) or anticipatory (occurring via classical conditioning prior to subsequent doses). Women, patients under 50, anxious patients and those who have had motion sickness in the past are more susceptible.

Palliative care^1,9

Nausea and vomiting is common in patients with advanced cancer prevalence of 20-30% (rising to 70% in the last week of life) but has multiple causes so that appropriate palliation requires careful diagnosis. Nausea and vomiting in cancer may be:

Drug-related

Opioid therapy is often associated with nausea and vomiting and can be prevented by giving an antiemetic such as haloperidol or metoclopramide for the first 4-5 days. Long term anti-emetic treatment is unnecessary (most patients develop tolerance quickly) and should be avoided due to increasing risk of side-effects.

Associated with gastritis, gastric stasis, functional bowel obstruction

Metoclopramide and domperidone are useful prokinetics to treat gastric stasis as well as having central action. Do not give anti-muscarinic drugs in combination with metoclopramide as the prokinetic action will be antagonised. Gastric irritation (often due to NSAID treatment) should be treated with PPIs, antacids and misoprostol.

Mechanical bowel obstruction

If surgery is an option, refer for a surgical opinion. Otherwise treatment is symptomatic: dexamethasone (antiemetic and minimises obstruction), cyclizine/haloperidol or levomepromazine (antiemetics which may not abolish vomiting completely but aim to eliminate nausea) are usually the drugs of choice. Where colic is a problem, stop prokinetics (metoclopramide/domperidone) and start an anti-spasmodic (eg. hyoscine). Ensure adequate pain-relief with opiates (often via a syringe-drive as malabsorption limits the oral route). If vomiting cannot be controlled, consider referral for a venting gastrostomy. Also consider referral to palliative care for consideration of antisecretory agents (eg. octreotide).

Constipation

Treat with laxatives, suppositories and enemas.

Raised intracranial pressure

Dexamethasone, cyclizine and levomepromazine are the drugs most frequently used in this context.

Chemical causes

Examples include hypercalcaemia and renal failure. Haloperidol is used for most chemical causes of vomiting. Alternatives include metoclopramide, cyclizine and levomepromazine.

Anxiety, fear and pain

Benzodiazepines (such as diazepam and midazolam), cyclizine and levomepromazine may help in this situation.

Unknown cause

Sometimes despite best efforts, diagnosis of the cause of nausea and vomiting in end-stage cancer may be possible. In this case, treatment with a broad-spectrum antiemetic such as cyclizine, levomepromazine or metoclopramide may be indicated.

• Do not forget non-drug measures such as avoiding food smells and unpleasant odours, diversion and relaxation. Complementary therapies may also have a role.
• Always review antiemetic treatment regularly. Add in or switch to a second-line therapy if nausea, retching and vomiting persists 24-48 hours after starting a first-line antiemetic. Review and reconsider the diagnosis if symptoms persist with the second-line therapy. Consider seeking specialist help if symptoms remain difficult to control.
• For prophylaxis of nausea and vomiting, use oral medications on a regular basis. For established nausea and vomiting, consider a parenteral route.

Vomiting of pregnancy^1,10

Between 70 and 85% of women have nausea during pregnancy and 1 in 200 develop hyperemesis gravidarum. The underlying mechanism is not well understood.
Antiemetics are generally effective in pregnancy-induced nausea but little information exists regarding fetal outcome. Consequently, they are often avoided until women are dehydrated, have documented weight loss or electrolyte abnormality.

• Simple dietary advice and the use of complementary or alternative therapies are often popular in the treatment of mild and self-limiting vomiting of pregnancy. Oral ginger (1g per day) is more effective than placebo in controlling symptoms and is generally considered safe. Evidence regarding the efficacy of acupressure and acupuncture is inconclusive in this context.
• Where vomiting is severe, short-term treatment with an anti-histamine such as promethazine would then be required. Second-line drugs are prochlorperazine and metoclopramide. There is little information on the safety of 5HT3 antagonists in pregnancy.
• If vomiting fails to settle within 24-48 hours, refer to secondary care as the woman may require IV fluids and electrolyte replacement and sometimes nutritional support. Supplementation with thiamine should also be considered to prevent Wernicke's encephalopathy in severe cases.

Motion sickness¹

Motion sickness is experienced when perceived motion disturbs the organs of balance. Antiemetics need to be given prophylactically in advance of symptoms. Hyoscine is effective but patches which provide prolonged activity need to be applied several hours prior to setting-off. Evidence comparing hyoscine to anti-histamines is equivocal and sedative antihistamines tend to be better tolerated.¹¹ Cyclizine or cinnarizine are less sedating compared to promethazine. The 5HT₃ antagonists are not effective for motion sickness.

Other vestibular disorders^11,12

Vertigo and nausea associated with Meniere's disease and middle-ear surgery can be difficult to treat. Betahistine is licensed for the treatment of the vertigo associated with Meniere's disease. A diuretic alone may also provide some benefit. Antihistamine and phenothiazine antiemetics are suitable for the prophylaxis and treatment of the nausea associated with vestibular disorders.

Gastroenteritis¹³

Infective intestinal irritation (viral or bacterial) is a common cause of nausea and vomiting, particularly in children. There is lack of evidence to support the use of antiemetics for gastroenteritis in primary care. This lack of evidence for added value and risk of significant adverse effects, especially in children, means that treatment concentrates on rehydration rather than relief of vomiting.