For which client would the use of a phenothiazine most likely be contraindicated?

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.15

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.16

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.17 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.17

A systematic review reported that oral ondansetron reduced vomiting, hospitalisation and the need for intravenous rehydration in children with acute gastroenteritis.18 Intravenous ondansetron or metoclopramide also reduced vomiting and hospitalisation. A single study in the review reported that rectal dimenhydrinate was effective at reducing vomiting.18

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.19 Ondansetron at doses of 8 mg or 16 mg per day was effective,20 but metoclopramide is not superior to placebo.21 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).

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.1

Metoclopramide, a prokinetic antiemetic, reduces the absorption lag time of oral aspirin and non-steroidal anti-inflammatory drugs in patients with migraine.22,23 In one study it reduced the time for aspirin to reach a maximum plasma concentration, from 24.6 to 18 minutes22 and reduced the time for tolfenamic acid (not available in Australia) from 2 hours 51 minutes to 2 hours 19 minutes.23 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.24 The average time taken to reach the peak plasma concentration of paracetamol was reduced from 120 minutes to 48 minutes.24 Consequently, metoclopramide has been incorporated into numerous guidelines as it may be beneficial in reducing nausea while enhancing the efficacy of concurrent analgesics.1,25

Dopamine antagonists such as prochlorperazine or chlorpromazine are effective in controlling nausea and vomiting.26 Data are lacking on the efficacy of serotonin antagonists in migraine.

Nausea and vomiting are common during the first trimester of pregnancy, affecting up to 90% of women.27 If drug treatment is needed, antihistamines including doxylamine and diphenhydramine are efficacious, without an increased risk of congenital malformations.27 Metoclopramide is also effective with no increased risk of congenital malformation, spontaneous abortion or reduced birthweight.28 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.29 Ondansetron is therefore not recommended as a first-line treatment.

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.1 The main treatments are therefore antihistamines such as promethazine, anticholinergics such as hyoscine, and dopamine antagonists such as prochlorperazine.1,30

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).13

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.13 Haloperidol 1.5–5 mg daily is effective in up to 47% of cases,31 while chlorpromazine 25 mg four times daily is effective in up to 70% of cases.32 Olanzapine 2.5–7.5 mg daily is also considered effective, but the precise response rate is unknown.33 Adverse reactions such as sedation and anticholinergic effects, particularly with olanzapine and chlorpromazine, may limit the usefulness of dopamine antagonists.13

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.34 However, another trial examining opioid-induced nausea and vomiting in palliative care reported that ondansetron was not more effective than metoclopramide or placebo.35 There are no randomised trials examining the efficacy of antihistamines, however an uncontrolled study based on patient reports suggested cyclizine had efficacy.13,36

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.13

Corticosteroids such as dexamethasone (4–8 mg daily) are effective at managing chemotherapy-induced nausea and vomiting, bowel obstruction and raised intracranial pressure.13 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.34

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.12

Haloperidol and olanzapine are effective for chemotherapy-induced nausea and vomiting.37 Olanzapine is now recommended as part of first-line management of highly emetogenic chemotherapy.9,38

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.39 There is a lack of data regarding the use of anticholinergics.4

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.40 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.40 However, cannabinoids are only available through the Special Access Scheme.

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.41

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.42

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.19 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 antagonists43 and no more effective than placebo.44 Although doses of metoclopramide greater than 25 mg may be more effective,45 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.46

Studies have also demonstrated that neurokinin antagonists such as aprepitant are effective at reducing postoperative nausea and vomiting.47 However, they are not currently PBS subsidised for this indication.

What is the therapeutic action of the phenothiazines in reducing nausea?

What are the most common adverse effects associated with drug therapy?

Which of the following is the drug of choice for children who need an antiemetic?

What medication would the nurse suspect a patient complaining of motion sickness may benefit from?