Nausea and Vomiting in Palliative Care
Key points
- Frequency: nausea affects up to 60% of patients with advanced cancer and vomiting around 30%; nausea is usually the more distressing of the two.
- The principle: identify the mechanism, then choose the antiemetic that blocks the receptors involved in that pathway. Prescribing by habit is the commonest reason for failure.
- Four inputs: the chemoreceptor trigger zone (chemical and metabolic), the gut via vagal afferents, the vestibular apparatus, and higher cortical centres.
- Chemical or metabolic cause: haloperidol - a potent D2 antagonist acting at the chemoreceptor trigger zone. Think opioids, hypercalcaemia, uraemia, infection.
- Gastric stasis: metoclopramide, a prokinetic - but it is contraindicated in complete bowel obstruction and where there is colic.
- Raised intracranial pressure: dexamethasone with cyclizine.
- Do not combine metoclopramide with cyclizine: cyclizine's anticholinergic action blocks the prokinetic effect, so the two cancel out.
- Route matters: a vomiting patient cannot absorb an oral antiemetic - use the subcutaneous, buccal or rectal route, or a syringe driver.
Introduction
Nausea and vomiting are among the most common and most miserable symptoms in advanced disease. Nausea affects up to 60% of patients with advanced cancer, and patients consistently rate persistent nausea as worse than intermittent vomiting - vomiting at least brings temporary relief.1
This is a topic where a small amount of applied physiology produces disproportionately better prescribing. There are only four routes by which a stimulus reaches the vomiting centre, each dominated by particular neurotransmitter receptors, and each blocked by a particular class of antiemetic. Work out the pathway, choose the matching drug, and most patients improve. Prescribe cyclizine reflexively for everyone, and many will not.
The other habit that changes outcomes is looking for a reversible cause before reaching for a drug at all. Constipation, hypercalcaemia, oral candidiasis, a urinary tract infection and a recently started drug together account for a large share of nausea in palliative patients, and all are treatable.
Physiology: the four pathways
The vomiting centre in the medullary reticular formation is the final common pathway. It coordinates the reflex and is itself rich in histamine H1, muscarinic acetylcholine and 5-HT2 receptors - which is why broad-spectrum drugs acting at these receptors, such as cyclizine and levomepromazine, work whatever the cause. Four sets of afferents feed into it.
| Pathway | Main receptors | Typical triggers | Drug of choice |
|---|---|---|---|
| Chemoreceptor trigger zone - in the area postrema on the floor of the fourth ventricle, outside the blood-brain barrier so it samples the circulation directly | D2, 5-HT3, NK1 | Opioids and other drugs, chemotherapy, hypercalcaemia, uraemia, hepatic failure, hyponatraemia, infection and toxins | Haloperidol (D2); ondansetron (5-HT3) for chemotherapy; aprepitant (NK1) for highly emetogenic regimens |
| Gastrointestinal tract - vagal and splanchnic afferents | 5-HT3, D2 (and 5-HT4 for prokinesis) | Gastric stasis, gastric outlet or bowel obstruction, constipation, gastric irritation, hepatomegaly, ascites, radiotherapy to the abdomen | Metoclopramide or domperidone if the problem is stasis; cyclizine with hyoscine butylbromide if there is obstruction with colic |
| Vestibular apparatus - via the vestibular nuclei | H1, muscarinic acetylcholine | Motion, opioids acting on the vestibular apparatus, base of skull metastases, middle ear disease | Cyclizine (H1); hyoscine hydrobromide or prochlorperazine |
| Higher cortical centres - cortex and limbic system | GABA, H1 | Anxiety, fear, anticipatory nausea, pain, unpleasant smells or sights, raised intracranial pressure | Benzodiazepine such as lorazepam for anxiety; dexamethasone with cyclizine for raised intracranial pressure; non-drug measures |
Causes
Most patients have more than one contributing cause, which is one reason combination therapy is often needed.
- Drugs - opioids (usually settling within a week of starting), chemotherapy, antibiotics, NSAIDs, SSRIs, digoxin, iron, anticonvulsants and antifungals
- Metabolic and biochemical - hypercalcaemia, uraemia, hyponatraemia, hepatic failure, ketoacidosis. Hypercalcaemia is the one that is missed.
- Gastrointestinal - constipation (extremely common and often the whole answer), gastric stasis from autonomic failure or drugs, gastric outlet or bowel obstruction, gastritis and peptic ulceration, squashed stomach syndrome from hepatomegaly or ascites, oral or oesophageal candidiasis
- Central nervous system - raised intracranial pressure from brain metastases (vomiting on waking, headache, papilloedema), leptomeningeal disease, vestibular disturbance
- Psychological - anxiety, anticipatory nausea before chemotherapy, and the smell or sight of food
- Infection - urinary, chest or gastrointestinal
- Other - severe pain, persistent cough, radiotherapy to the abdomen or brain
Assessment
The pattern of the symptom often reveals the mechanism, so the history is worth taking properly.
| Pattern | Likely mechanism |
|---|---|
| Persistent nausea with little vomiting, worse in the morning, no relation to food | Chemical or metabolic - drugs, hypercalcaemia, uraemia; acting at the chemoreceptor trigger zone |
| Large-volume vomiting with immediate relief of nausea, early satiety, fullness, hiccups, heartburn | Gastric stasis or gastric outlet obstruction |
| Vomiting of undigested food hours after eating, with colic and distension | Bowel obstruction |
| Vomiting on waking, with headache and neurological signs | Raised intracranial pressure |
| Nausea provoked by movement or turning in bed | Vestibular |
| Nausea before an appointment or on entering a hospital | Anticipatory - a conditioned response |
- Drug history - what has been started or increased in the last week, including over-the-counter and complementary medicines
- Bowel history - when did they last open their bowels, and what was it like? Ask explicitly; patients rarely volunteer it.
- Examination - mouth (candidiasis), abdomen (distension, succussion splash, hepatomegaly, ascites, faecal loading, bowel sounds), neurological examination and fundoscopy, and a rectal examination if faecal impaction is suspected
- Investigations proportionate to the situation - U&Es, corrected calcium, LFTs, glucose, CRP, and a plain abdominal film or CT head where these would change management
Antiemetic drugs
| Drug | Receptor action | Best used for | Cautions |
|---|---|---|---|
| Haloperidol 1.5 mg at night, or 1.5 to 5 mg per 24 hours subcutaneously | D2 antagonist at the chemoreceptor trigger zone | Chemical and metabolic causes - opioids, hypercalcaemia, uraemia, infection | Extrapyramidal effects, QT prolongation; avoid in Parkinson's disease and Lewy body dementia |
| Metoclopramide 10 mg three times daily, or 30 to 60 mg per 24 hours subcutaneously | D2 antagonist plus 5-HT4 agonist - a prokinetic | Gastric stasis, functional or partial obstruction, squashed stomach | Contraindicated in complete obstruction and where there is colic. Extrapyramidal reactions, particularly acute dystonia in young women; MHRA restricts non-palliative use to 5 days5 |
| Domperidone 10 mg three times daily orally | Peripheral D2 antagonist, does not cross the blood-brain barrier | Gastric stasis where extrapyramidal effects must be avoided, particularly in Parkinson's disease | QT prolongation; oral route only |
| Cyclizine 50 mg three times daily, or 100 to 150 mg per 24 hours subcutaneously | H1 antagonist with anticholinergic action, at the vomiting centre and vestibular pathway | Bowel obstruction, raised intracranial pressure, vestibular causes, and broad-spectrum use | Anticholinergic effects - dry mouth, blurred vision, urinary retention, drowsiness; can irritate at the subcutaneous site |
| Levomepromazine 6.25 mg at night, or 6.25 to 25 mg per 24 hours subcutaneously | Broad-spectrum - D2, H1, 5-HT2 and muscarinic | Refractory nausea, or where the cause is unclear or multifactorial | Sedation (dose-related), postural hypotension; the low dose is antiemetic, higher doses are sedating |
| Ondansetron 4 to 8 mg twice daily | 5-HT3 antagonist | Chemotherapy and radiotherapy-induced nausea, and bowel-derived nausea | Causes marked constipation - which itself causes nausea; QT prolongation. Of limited value in most other palliative indications. |
| Dexamethasone 4 to 8 mg daily | Reduces peritumoural and peri-obstruction oedema; mechanism in nausea incompletely understood | Raised intracranial pressure, bowel obstruction, and as an adjuvant to other antiemetics | Hyperglycaemia, agitation, insomnia, proximal myopathy; give in the morning |
| Lorazepam 0.5 mg sublingually | GABA - acts on the cortical pathway | Anticipatory and anxiety-related nausea | Sedation, falls, tolerance |
| Olanzapine 2.5 to 5 mg at night | Broad-spectrum antagonist | Refractory nausea, increasingly used as a second-line broad-spectrum agent | Sedation, metabolic effects |
Route
A patient who is vomiting cannot absorb an oral antiemetic, and giving one anyway is a common source of apparent treatment failure. Use the subcutaneous route - either as stat doses or a continuous subcutaneous infusion via a syringe driver - or buccal, sublingual or rectal preparations. Once the vomiting is controlled for 24 to 48 hours, convert back to oral where the patient prefers it.
A practical approach
- Look for and treat reversible causes - constipation, hypercalcaemia, infection, oral candidiasis, gastritis, an offending drug
- Identify the likely mechanism from the history and examination
- Choose the antiemetic that matches that mechanism, at an adequate dose, by a route that will be absorbed, and regularly rather than as required
- Review at 24 to 48 hours. If there is no response, check the dose and route first, then reconsider the mechanism.
- Add a second antiemetic acting at a different receptor rather than swapping randomly, or switch to a broad-spectrum agent such as levomepromazine
- Add dexamethasone as an adjuvant if the response remains inadequate
- Seek specialist palliative care advice for refractory nausea - ketamine, olanzapine and other options exist
Non-drug measures
- Small, frequent, bland meals rather than large plates, which patients find overwhelming - and remove the pressure from families to make them eat
- Avoid strong cooking smells - cold food is often better tolerated than hot for this reason
- Cool fizzy drinks, ginger, and sipping rather than gulping
- A calm environment, away from the sight and smell of other patients' food
- Meticulous mouth care, which relieves the taste disturbance that perpetuates nausea
- Relaxation, distraction and acupressure wristbands, which have modest but real benefit particularly for anticipatory nausea
- Position - sitting upright after meals for gastric stasis, and avoiding sudden movement for vestibular nausea
- Explanation - telling a patient that opioid-induced nausea usually settles within a week substantially improves adherence
Complications
Persistent vomiting causes dehydration, acute kidney injury and a hypokalaemic hypochloraemic metabolic alkalosis, and the renal impairment in turn causes opioid metabolites to accumulate, producing toxicity that worsens the nausea - another self-reinforcing loop worth recognising.
- Inability to take oral medication - including analgesia, so pain control deteriorates in parallel. This is often the trigger for converting everything to a syringe driver.6
- Aspiration pneumonia, particularly in the drowsy or obstructed patient
- Mallory-Weiss tear, oesophagitis and dental erosion from repeated vomiting
- Malnutrition, weight loss and worsening cachexia
- Profound distress for the patient and family, and loss of the ability to eat together, which carries considerable social meaning at the end of life
- Antiemetic adverse effects - extrapyramidal reactions, constipation from ondansetron, sedation from levomepromazine, anticholinergic effects from cyclizine
Red flags
Outcomes
With a mechanism-based approach, nausea and vomiting can be controlled or substantially improved in the great majority of palliative patients - reported response rates are around 80 to 90% within 48 to 72 hours.1,4 The patients who remain difficult are usually those with mechanical bowel obstruction, gastric outlet obstruction, or a strong anticipatory or anxiety component.
When treatment fails, the fault is more often in the prescription than in the patient. The checklist is short and worth running through explicitly: is the mechanism right, is the dose adequate, is it prescribed regularly rather than as required, and is the route one the patient can actually absorb? Reviewing those four questions resolves most apparent treatment failures.
Finally, remember what good control buys. A patient who is not nauseated can take their analgesia, drink, eat a little, sit with their family and be cared for at home. Controlling nausea is therefore one of the interventions that most directly determines whether someone can be where they want to be at the end of life.
References
- Scottish Palliative Care Guidelines. Nausea and vomiting. Available here
- NICE Clinical Knowledge Summaries. Palliative care - nausea and vomiting. Available here
- BNF. Prescribing in palliative care. Available here
- Glare P, Miller J, Nikolova T, Tickoo R. Treating nausea and vomiting in palliative care: a review. Clinical Interventions in Aging. 2011. Available here
- MHRA Drug Safety Update. Metoclopramide: risk of neurological adverse effects. Available here
- NICE NG31. Care of dying adults in the last days of life. 2015. Available here
This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.