SUMMARY

Nausea and vomiting are common symptoms with many possible causes, including the adverse effects of drugs. If a drug is indicated, the cause guides the choice of antiemetic drug.

The main antiemetic classes include antagonists of the serotonin, dopamine, histamine, muscarinic and neurokinin systems, corticosteroids and benzodiazepines. Some antiemetics appear more effective for specific indications.

Serotonin and neurokinin antagonists, such as ondansetron and aprepitant, are highly effective in treating chemotherapy-induced nausea and vomiting. Metoclopramide and antihistamines are first-line options for nausea and vomiting in pregnancy.

Serotonin antagonists and some dopamine antagonists, such as metoclopramide, can prolong the QT interval on the ECG. Dopamine antagonists can cause extrapyramidal adverse effects, particularly in children.

What are antiemetic drugs?

Antiemetic drugs are medications used to treat nausea and vomiting. These two symptoms are very common and can be caused by many different conditions, therapies, procedures, and medications (such as opioids). Though vomiting is considered to be a protective reflex of the body to expel toxic substances in the stomach and gut, antiemetic drugs are often necessary to suppress vomiting, especially if there’s severe dehydration.

What does antiemetic mean?

Antiemetic literally means ‘against emesis’, otherwise known as against vomiting.

Introduction

Nausea and vomiting are commonly encountered symptoms with multiple causes. These include infections, cancer, pregnancy and the adverse effects of many drugs.

Physiology

Multiple neurohumoural pathways can induce nausea and vomiting. Key foci include the chemoreceptor trigger zone in the floor of the fourth ventricle and the vomiting centre in the medulla with inputs from the nucleus tractus solitarius and vagus nerve. The emetic response is mediated through multiple neurotransmitters including histamine, dopamine, serotonin, acetylcholine and neurokinin. With the exception of neurokinin, cannabinoids modulate the activity of these neurotransmitters to influence the emetic response.

Classes of antiemetics

The various classes of antiemetics target different pro-emetic pathways to alleviate nausea and vomiting. Some target more than one pathway. The classes of antiemetics include antagonists of dopamine, serotonin, neurokinin, histamine and acetylcholine. The cannabinoid agonists, corticosteroids and benzodiazepines also have antiemetic actions.

How do antiemetics work?

Antiemetics work on the neural pathways involved with vomiting by blocking specific receptors that respond to neurotransmitter molecules, such as serotonin, dopamine, and histamine. Most of these are central receptors found in the vomiting center of the brainstem, while peripheral receptors are found in the vagus nerve. When the gastrointestinal tract senses a threat, it sends information to the peripheral receptors, which in turn convey the information to the central receptors in the vomiting center. In response, the vomiting center triggers nausea and vomiting by stimulating the gastrointestinal tract, abdominal muscles, and the diaphragm.

What are the side effects of antiemetic drugs?

Antiemetics are generally well-tolerated, but can have potential side effects, such as constipation or diarrhea, headache, fatigue, malaise, dizziness, light-headedness, blurred vision, dry mouth, or photosensitivity. Consulting the family physician before taking over the counter antiemetics or prescription drugs is vital, especially if taking any other medications at the same time due to potential additive effects. 

How do antiemetic medicines work?

Bismuth subsalicylate works by protecting the stomach lining.

Antihistamines appear to dull the inner ear’s ability to sense motion. They block messages to the part of the brain that controls nausea and vomiting. This is why they work best if you take them before you start feeling motion sickness.

How do I safely take OTC antiemetic medicines?

Before you take an OTC antiemetic medicine, read the directions on the drug facts label. This will tell you how much medicine to take and how often to take it. If you have any questions, call your family doctor. Keep a record of which OTC medicines you’re using and when you take them. If you need to go to the doctor, take this list with you.

If you are pregnant, do not take any OTC antiemetic medicines without first contacting your doctor.

Follow these tips to make sure you are taking the right amount of medicine:

• Take only the amount recommended on the medicine’s label. Don’t assume that more medicine will work better or quicker. Taking more than the recommended amount can be dangerous.
• If you’re taking a prescription medicine, ask your doctor if it’s okay to also take an OTC antiemetic medicine.
• Don’t use more than 1 kind of OTC antiemetic medicine at a time unless your doctor says it’s okay. They may have similar active ingredients. These could add up to be too much medicine.

How can I safely store OTC antiemetic medicines?

Store all medicines up and away, out of reach and sight of young children. Keep medicines in a cool, dry place. This will help prevent them from becoming less effective. Don’t store medicines in bathrooms or bathroom cabinets. These locations are often hot and humid.

Things to consider

Healthy adults usually don’t experience side effects from antiemetic medicines. Side effects can be a concern for older adults or people who have health problems.

What are antiemetic drugs used for?

Antiemetic drugs are taken to treat nausea and vomiting, and can be administered as tablets, sublinguals, oral solutions, suppositories, transdermal patches or intravenous injections. Nausea and vomiting can be symptoms of various conditions, such as motion sickness, upper abdominal irritation, food poisoning, and gastroenteritis. Nausea and vomiting are also common side effects of many drugs including opioid analgesics, anaesthetics (postoperative nausea), and chemotherapy directed against cancer. Finally, nausea and vomiting are often experienced in pregnancy-related morning sickness or hyperemesis gravidarum, which is extreme morning sickness including severe vomiting, during pregnancy. However, antiemetic medications should not be taken during pregnancy without first consulting with your family physician, who might prescribe them only after weighing the risks and benefits. 

What are some examples of antiemetics?

There are a few classes of antiemetic medications, which are categorized based on the predominant receptor they act on. Choosing the most appropriate one is key in order to optimize effectiveness and minimize side effects. 

5-HT3 receptor antagonists, such as ondansetron (Zofran), granisetron, and palonosetron (2nd generation) are medications that work on central serotonin receptors in the vomiting center, as well as the peripheral serotonin receptors in the vagus nerve. 5-HT3 receptor antagonists are indicated for use against vomiting caused by acute gastroenteritis or postoperative nausea. It’s also the first go-to antiemetic class for radiotherapy- and chemotherapy-induced nausea and vomiting, which are common side effects. 

Dopamine antagonists, such as metoclopramide (Reglan), domperidone (Motilium), and chlorpromazine, are amongst the most commonly used antiemetics, and they’re also indicated for postoperative nausea and motion sickness. 

Antihistamines, such as cyclizine, promethazine, and diphenhydramine, or antimuscarinics (anticholinergics) like scopolamine (Hyoscine) are often used to treat and prevent nausea and vomiting induced by vestibular disturbances like vertigo or motion. Scopolamine is predominantly used to prevent motion sickness, and can come in a transdermal patch, making it easier to administer, especially for people with swallowing problems. The transdermal patch is also useful for maintaining a steady release of the medication and lowering the risk of side effects. As a downside, antihistamines generally lead to drowsiness.

Glucocorticoids are also indicated as antiemetics against chemotherapy-induced emesis. They are effective and generally well-tolerated, but insomnia, increased energy, and mood changes are common side effects.Neurokinin 1 (NK-1) receptor antagonists, like aprepitant (Emend) and rolapitant (Varubi), are a relatively new medication class that can be used as antiemetics, especially for suppressing radiotherapy- and chemotherapy-induced nausea and vomiting, as well as to prevent nausea and vomiting after surgery. NK-1 receptor antagonists should not be taken while pregnant or breastfeeding.

What is the most effective antiemetic?

Out of all medications indicated for vomiting, it’s difficult to choose the most effective one. The medication should be appropriately chosen by a healthcare professional according to the situation and the person in need of it, as well as taking into consideration the underlying cause, the severity of the case, and the possible side effects.

Which antiemetic is indicated for use with vertigo?

Vertigo is an illusion of motion often accompanied by headaches, nausea, and vomiting. Most often, H1 receptor antagonists from the antihistamines class, like loratadine, can be prescribed. In any case, the appropriate medication for each person is chosen after careful assessment by a healthcare professional.

What are the most important facts to know about antiemetics?

Antiemetics are medications aimed at preventing or treating nausea and vomiting, which are common symptoms that may be tied to numerous different causes. For instance, motion sickness, gastroenteritis, and as a side effect of other treatments can all commonly lead to nausea. There are many classes of antiemetic medications, so they should be appropriately prescribed or recommended by a healthcare professional, taking into consideration the person in need of it, the underlying cause, the severity of the case, and the possible side effects. Possible side effects of antiemetic medications include headache, fatigue, dizziness, dry mouth, and abnormal defecation. Choosing the appropriate antiemetic medication should be carefully done by the family physician, taking into consideration the severity and cause of the symptoms, as well as any underlying diseases or medications taken by the person.

The most common side effects of bismuth subsalicylate are:

• Darkened stools or tongue
• Constipation
• Ringing sound in the ears (tinnitus)

These are short-term side effects.

Antihistamines may make you feel sleepy. This can affect your ability to drive or operate machines. It may be hard for you to think clearly. Alcohol can increase the drowsiness caused by antihistamines. They may also cause your mouth and eyes to feel dry.

Who shouldn’t take OTC antiemetic medicines?

Some people are allergic to aspirin or other salicylate medicines. They shouldn’t take bismuth subsalicylate. Don’t give bismuth subsalicylate to children 12 years of age or younger. Don’t give it to children or teenagers who may have the flu or chickenpox. This increases their risk for Reye syndrome. This is a serious illness that can lead to death.

Before taking an antihistamine, talk to your doctor if you have any of the following problems:

• Glaucoma
• Trouble urinating (from an enlarged prostate gland)
• Breathing problems, such as asthma, emphysema, or chronic bronchitis
• Thyroid disease
• Heart disease
• High blood pressure

Can OTC antiemetic medicines cause problems with any other medicines I take?

Bismuth subsalicylate may affect how well some medicines work. It also may cause side effects if combined with other medicines. Ask your doctor before taking bismuth subsalicylate if you also take:

• Blood-thinning medicines
• Medicines for gout
• Medicines for arthritis
• Medicines for diabetes

Ask your doctor before taking bismuth subsalicylate if you take pain relievers or cold medicines. These medicines may contain aspirin, which is a salicylate. You may get too much salicylate if you take more than 1 of these medicines at a time.

Talk to your doctor before taking an antihistamine if you take sleeping pills, sedatives, or muscle relaxants. Many OTC cold and allergy medicines contain antihistamines. If you use more than 1 of these medicines, you may get more antihistamine than you intend.

Some prescription medicines have side effects similar to the side effects of antihistamines. These could include dry mouth and drowsiness. Talk with your doctor before taking these medicines at the same time.

Questions to ask your doctor

• What kind of antiemetic medicine is best for me?
• How does the medicine help my nausea?
• How often can I take it?
• Is there a limit on how many days I can take it?
• What kinds of side effects should I look for?

Gastroenteritis

Acute gastroenteritis is caused by viral, bacterial or protozoal infections. Therapeutic options available for adults with vomiting secondary to gastroenteritis include dopamine antagonists such as metoclopramide or prochlorperazine and serotonin antagonists such as ondansetron.

Nausea and vomiting resulting from acute gastroenteritis is particularly challenging in children. Until the early 2000s, antiemetics including promethazine, metoclopramide and prochlorperazine were widely used in children, however their use is now controversial due to reports of adverse events including sedation and extrapyramidal reactions.

When an antiemetic drug is indicated, serotonin antagonists such as ondansetron are now recommended in guidelines, such as those published by the Royal Children’s Hospital Melbourne. These guidelines recommend a single weight-based dose of oral ondansetron. Children weighing 8–15 kg should receive 2 mg, children weighing 15–30 kg should receive 4 mg and children weighing more than 30 kg should receive 8 mg. Ondansetron is not recommended in children under six months of age or less than 8 kg in weight.

A systematic review reported that oral ondansetron reduced vomiting, hospitalisation and the need for intravenous rehydration in children with acute gastroenteritis. Intravenous ondansetron or metoclopramide also reduced vomiting and hospitalisation. A single study in the review reported that rectal dimenhydrinate was effective at reducing vomiting.

Opioid-induced

The role of antiemetics to manage opioid-induced nausea and vomiting is poorly defined. Evidence is lacking and confounded by studies focused on postoperative nausea and vomiting (where patients were given opioids and anaesthetic drugs). As a result, the choice of antiemetic for opioid-induced nausea and vomiting will depend on factors such as medical comorbidities, the adverse effects of the drug, its cost and the clinician’s familiarity with it.

A systematic review reported that low-dose droperidol (less than 4 mg per day) was effective at reducing opioid-induced nausea and vomiting. Ondansetron at doses of 8 mg or 16 mg per day was effective, but metoclopramide is not superior to placebo. The role of serotonin antagonists may be limited because opioid-induced nausea and vomiting is not an indication which is currently subsidised by the Pharmaceutical Benefits Scheme (PBS).

Migraine-related

Migraines are commonly associated with nausea, vomiting and reduced gastrointestinal motility.¹ Due to this impaired motility and delayed drug absorption, parenteral routes of antiemetic administration may be required.

Metoclopramide, a prokinetic antiemetic, reduces the absorption lag time of oral aspirin and non-steroidal anti-inflammatory drugs in patients with migraine. In one study it reduced the time for aspirin to reach a maximum plasma concentration, from 24.6 to 18 minutes and reduced the time for tolfenamic acid (not available in Australia) from 2 hours 51 minutes to 2 hours 19 minutes. Additionally in healthy volunteers, administration of metoclopramide with paracetamol resulted in both a higher peak plasma concentration of paracetamol and a shorter time to peak plasma concentration. The average time taken to reach the peak plasma concentration of paracetamol was reduced from 120 minutes to 48 minutes. Consequently, metoclopramide has been incorporated into numerous guidelines as it may be beneficial in reducing nausea while enhancing the efficacy of concurrent analgesics.

Dopamine antagonists such as prochlorperazine or chlorpromazine are effective in controlling nausea and vomiting. Data are lacking on the efficacy of serotonin antagonists in migraine.

Pregnancy

Nausea and vomiting are common during the first trimester of pregnancy, affecting up to 90% of women. If drug treatment is needed, antihistamines including doxylamine and diphenhydramine are efficacious, without an increased risk of congenital malformations. Metoclopramide is also effective with no increased risk of congenital malformation, spontaneous abortion or reduced birthweight. Other dopamine antagonists are not recommended due to conflicting evidence of safety during pregnancy.

The use of serotonin antagonists, such as ondansetron, in pregnancy has been increasing. However, ondansetron has limited safety data. A 2018 study reported no increased risk of cardiac malformation, but a slightly increased risk of oral clefts/ Ondansetron is therefore not recommended as a first-line treatment.

Vestibular disorders including motion sickness

Nausea and vomiting from conditions such as benign paroxysmal positional vertigo and motion sickness are due to stimulation of the vomiting centre via the vestibular nuclei. The primary neurotransmitters involved in this pathway are histamine receptors and acetylcholine muscarinic receptors. The main treatments are therefore antihistamines such as promethazine, anticholinergics such as hyoscine, and dopamine antagonists such as prochlorperazine.

Palliative care

The causes of nausea and vomiting in palliative care can broadly be divided into:

• disease state-related (e.g. cancer burden, ileus, uraemia in kidney disease or gastrointestinal oedema in heart failure)
• treatment-related (e.g. chemotherapy-induced or opioid-induced)
• biochemical (e.g. hypercalcaemia)
• toxin-mediated (secondary to anorexia-cachexia syndrome).

Evidence to guide the choice of antiemetics in palliative care is lacking. Metoclopramide 10 mg three times daily is effective in up to 40% of cases. Haloperidol 1.5–5 mg daily is effective in up to 47% of cases, while chlorpromazine 25 mg four times daily is effective in up to 70% of cases. Olanzapine 2.5–7.5 mg daily is also considered effective, but the precise response rate is unknown. Adverse reactions such as sedation and anticholinergic effects, particularly with olanzapine and chlorpromazine, may limit the usefulness of dopamine antagonists.

There are conflicting data on the use of serotonin antagonists in refractory nausea and vomiting in palliative care. In a single randomised trial, tropisetron was more effective than metoclopramide or chlorpromazine, even when they were combined with dexamethasone. The combination of tropisetron, dexamethasone and chlorpromazine was most effective. However, another trial examining opioid-induced nausea and vomiting in palliative care reported that ondansetron was not more effective than metoclopramide or placebo. There are no randomised trials examining the efficacy of antihistamines, however an uncontrolled study based on patient reports suggested cyclizine had efficacy.

Anticholinergics such as hyoscine are used in palliative care, but not primarily for nausea. They are often prescribed for excessive gastric secretions and in terminal bowel obstruction.

Corticosteroids such as dexamethasone (4–8 mg daily) are effective at managing chemotherapy-induced nausea and vomiting, bowel obstruction and raised intracranial pressure. Dexamethasone, at doses as low as 2 mg daily, enhances the control of nausea and vomiting when added to combination treatment with tropisetron and either metoclopramide or chlorpromazine.

Chemotherapy-induced

The emetogenic potential of chemotherapy drugs varies. For example, nausea and vomiting resulting from low emetogenic chemotherapy, such as paclitaxel, can be treated with a serotonin antagonist, while highly emetogenic chemotherapy, such as cisplatin, will require a combination of a serotonin antagonist, neurokinin antagonist and dexamethasone.

Haloperidol and olanzapine are effective for chemotherapy-induced nausea and vomiting. Olanzapine is now recommended as part of first-line management of highly emetogenic chemotherapy.

Antihistamines, metoclopramide and prochlorperazine are less effective in chemotherapy-induced nausea and vomiting. Benzodiazepines such as lorazepam may be used as adjunctive therapy. They function to reduce anxiety and anticipatory nausea and vomiting. There is a lack of data regarding the use of anticholinergics.

While not registered in Australia, cannabinoid products have been tried for chemotherapy-induced nausea and vomiting. A systematic review concluded that cannabinoids were superior to placebo but not prochlorperazine. The data were inadequate to determine efficacy compared to metoclopramide, domperidone or chlorpromazine. Cannabinoids have not been compared to newer antiemetics such as serotonin or neurokinin antagonists. They may have a role for patients with chemotherapy-induced nausea and vomiting that fails to respond to first-line treatment. However, cannabinoids are only available through the Special Access Scheme.

Radiation-induced

The severity of radiation-induced nausea and vomiting depends on the irradiated body area. For example, total body irradiation has a high risk of nausea and vomiting and requires combination treatment with a serotonin antagonist and dexamethasone. Radiation to the head and neck has a lower risk and can be managed with a serotonin antagonist alone.

Serotonin antagonists are more effective than dopamine antagonists alone or in combination with dexamethasone. Adding dexamethasone to a serotonin antagonist further reduces radiation-induced nausea and vomiting.

Postoperative

A systematic review found that serotonin antagonists (ondansetron, granisetron and tropisetron), dexamethasone, droperidol and cyclizine were all more effective than placebo for the treatment of postoperative nausea and vomiting. Depending on the clinical situation, certain antiemetics may need to be avoided. For example, given the constipating effect of serotonin antagonists, they should either be avoided or used with caution in patients at high risk of intestinal obstruction, as they may worsen or mask a progressive ileus.

Metoclopramide, at the standard 10 mg dose, is less effective than serotonin antagonists and no more effective than placebo. Although doses of metoclopramide greater than 25 mg may be more effective the increased risk of adverse events such as dystonia limit its use.

A recent study demonstrated that benzodiazepines such as lorazepam may be beneficial at reducing postoperative nausea and vomiting. Compared with placebo, 1 mg of orally administered lorazepam 60 minutes before general anaesthesia significantly reduced both postoperative nausea and vomiting and the requirement for antiemetic treatment during the postoperative period.

Studies have also demonstrated that neurokinin antagonists such as aprepitant are effective at reducing postoperative nausea and vomiting. However, they are not currently PBS subsidised for this indication.