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Nausea, an unpleasant feeling of wanting to vomit, and vomiting, the expulsion of gastric contents, are symptoms that can overlap but are individual. There are many causes of nausea and vomiting (see Panel 1)1 but this article focuses on nausea and vomiting in palliative care.
Moreover, palliative care encompasses a number of conditions that can cause nausea and vomiting, including cancer, cardiac failure, chronic obstructive pulmonary disease, end-stage renal failure and dementia. This article will consider nausea and vomiting in patients with advanced cancer — it is estimated that between 20 and 70 per cent of these patients experience these symptoms.2,3,4
Panel 1: Causes of nausea and vomiting
- Motion (e.g., travel sickness)
- Pregnancy (nausea occurs in 50 to 90 per cent of all pregnancies, vomiting in 25 to 55 per cent)
- Medication (e.g., opioids can induce vomiting)
- Intense pain
- Emotional stress or fear
- Gall bladder disease
- Food poisoning
- Infections (e.g., “stomach flu”)
- Overeating
- Certain smells
- Heart attack
- Concussion or brain injury
- Ulcers
- Some cancers (e.g., brain tumour)
- Bulimia or other psychological illnesses
- Gastroparesis (delayed gastric emptying; a condition often found in people with diabetes)
Nausea and vomiting can have serious effects on quality of life, including reducing mental well-being. Vomiting can lead to metabolic derangements and oesophageal tears. Some patients may experience retching (also known as dry heaving), where the convulsion of vomiting occurs but there is no expulsion of gastric contents, and this can also be distressing.
In practice, it is worth asking patients who are not vomiting whether they are experiencing any nausea so that support is given where needed.
Main mechanisms
Nausea and vomiting are controlled by different central nervous system mechanisms.5 The afferent and efferent reflexes involved in nausea and vomiting are thought to be integrated by two distinct centres at brainstem level. These are the vomiting centre, located in the medulla, and the chemoreceptor trigger zone (CTZ).4
The vomiting centre receives afferent stimulation via the CTZ, the cerebral cortex, and the vestibular system, and peripheral stimulation via the vagal and sympathetic nerves which, in turn, leads to emesis. Panel 2 outlines some of the neurotransmitters, other stimuli, receptors and different locations involved.2
Panel 2: Mechanisms
- The vomiting centre contains histamine (H1), acetylcholine (ACh) and 5-hydroxytryptamine-2 (5HT2) receptors.6
- The chemoreceptor trigger zone is located in an area of the brain that has no blood-brain barrier so various drugs, toxins and metabolites can access it. It has dopamine (D2) and 5HT3 receptors.
- The cerebral cortex contains receptors that are triggered by anxiety.
- The vestibular system is sensitive to changes in movement or diseases of the ear, which can stimulate the ACh or H1 receptors.
- The gut mucosa contains 5HT3 receptors, which are stimulated by drugs, radiotherapy and bacterial exotoxins. H1 and ACh receptors in the gut and the serosal surfaces of other viscera are stimulated by mechanical distortion.
- In addition to the pathways already described, when there is raised intracranial pressure cerebral histamine receptors may be stimulated and meningeal mechanoreceptors stimulate the vomiting centre.
Assessment
A thorough history, examination and investigation are required to identify the cause of nausea and vomiting.3,6 In terms of history, a number of details need to be determined. For nausea, these include onset, frequency, intensity and relieving and exacerbating factors. For example, persistent nausea with little relief from vomiting indicates a chemical cause.
For vomiting, details include onset, frequency, quantity, force, colour, timing and pattern. For example, intermittent vomiting of small amounts of fluid that relieves nausea and that is associated with feelings of early satiety indicates impaired gastric emptying, and “coffee ground vomit” indicates gastrointestinal bleeding.
The patient should also be asked about symptoms such as indigestion, heartburn, a feeling of fullness, constipation, diarrhoea, flatus, cough, headache and confusion.
It is also important to ascertain whether any treatment has been tried already (and what worked well), what other medicines the patient is taking, and when his or her last chemotherapy or radiotherapy was. A thorough review of current medication is also needed to ensure that drugs causing nausea or vomiting are removed where possible.2
Examination of the abdomen is required to assess for organomegaly, other masses and bowel sounds (which may suggest ileus or mechanical obstruction).3,6,7 A rectal examination may be performed. Examination should also look for signs of sepsis, metabolic abnormalities (eg, liver failure, renal failure, hypercalcaemia) and neurological signs, such as drowsiness and confusion.3,6,7
Appropriate investigations include radiology (eg, abdominal X-ray, computed tomography scan, magnetic resonance imaging)3,6 and laboratory tests (to rule out sepsis, renal failure, hypercalcaemia, etc).3,6
Treatment
Treatment of nausea and vomiting in palliative care cancer patients largely depends on the cause and patient preference. In these patients, for whom overall prognosis poor, it is especially important to consider the individual’s wishes, the severity of the nausea and vomiting, and the urgency of the treatment.6
Several classes of drugs are used as antiemetics in palliative care. These include:
- Dopamine antagonists
- Histamine antagonists
- Muscarinic antagonists
- Serotonin antagonists (off-label use)
- Prokinetics
Other antiemetics sometimes used to manage nausea and vomiting include levomepromazine, corticosteroids, olanzapine, benzodiazepines, cannabinoids and aprepitant.
Dopamine antagonists
Haloperidol is an example of a dopamine antagonist. It is a centrally acting and very potent D2 antagonist7 widely used in palliative care (eg, starting at 1.5 od or bd, orally, and increasing to 5–10mg daily in divided doses), predominantly for drug-induced nausea and vomiting.4
Because it antagonises dopamine it can cause extrapyramidal effects, postural hypotension, urinary retention and constipation.8 Use is contraindicated in patients with Parkinson’s disease, central nervous system depression and those with a recent history of cardiac disorder.8
Histamine antagonists
An example of a histamine antagonist used in palliative care is cyclizine (eg, 50mg up to tds orally). Cyclizine is an H1-antihistaminic anticholinergic antiemetic. Its principal mode of action is to decrease excitability of the inner ear labyrinth, blocking conduction in vestibular-cerebellar pathways, as well as acting directly at the vomiting centre.4 It is mainly used when there is raised intracranial pressure, motion sickness or mechanical bowel obstruction.4 Side effects include dizziness, urinary retention, headache, and constipation. It can also lower seizure threshold.8 Use of histamine antagonists requires caution in patients with narrow-angle glaucoma, prostatic hyperplasia, cardiovascular disease, severe hypertension, respiratory compromise, impaired hepatic function or epilepsy.8
Muscarinic antagonists
An example of a muscarinic antagonist is hyoscine butylbromide (usually by injection). The mechanism of action is to block acetylcholine receptors in the gut (relaxing smooth muscle), vestibular system and vomiting centre.4,7
Serotonin antagonists
Serotonin antagonists work in nausea and vomiting by blocking peripheral and central 5HT3 receptors. Examples are ondansetron and granisetron but their licensed use is predominantly in chemotherapy-induced nausea and vomiting. The main side effect that precludes the use of these drugs as first-line agents is constipation, which can already be problematic in palliative care.
Prokinetics
Prokinetics are a group of drugs that increase gastrointestinal motility. They do this via four possible mechanisms: activating 5HT4 receptors (to release ACh from enteric neurons to stimulate the cholinergic system in the gut wall); blocking 5HT3receptors; activating motilin receptors; and releasing the dopaminergic “brake” on gastric emptying. Prokinetic agents include metoclopramide and domperidone. Metoclopramide (10–20mg tds before meals) acts by agonism of 5HT4 receptors and antagonism of peripheral D2 receptors.4 It requires ACh to mediate its effect on the 5HT4 receptors. As a result, its prokinetic effects may be antagonised by anticholinergics such as cyclizine.4,7 At high doses, metoclopramide is also a central D2 antagonist.7
Domperidone works on peripheral dopamine receptors and does not cross the blood-brain barrier so extrapyramidal side effects are less likely.4,7 A typical dose is 10–20mg qds.
Prokinetics are contraindicated in complete bowel obstruction and epilepsy. Side effects include extrapyramidal effects, drowsiness and dizziness.
For first-line treatment it is best to prescribe a single agent based on the underlying cause, often starting at a low dose and titrating to maximal dose for nausea and vomiting. If this is ineffective, switch to another drug. However, if there is partial response to the first agent then consider adding another agent. Drugs with similar modes of action, such as metoclopramide and haloperidol, should be avoided.
Choice of antiemetic will also depend on the route of administration (eg, the oral route may be unavailable and subcutaneous or rectal routes may be used). Panel 3 summarises the various features that can help determine the cause of nausea and vomiting and, in turn, support the most appropriate treatment selection. However, pharmacists should refer to their local palliative care guidelines for recommended agents and doses.
| Features | Likely cause and mechanism | Treatment |
| Large volume of vomit, symptom relief after vomiting | Gastric stasis. Gastric receptors stimulate the vagal nerve which stimulates the vomiting centre | Prokinetic drugs (eg, metoclopramide, domperidone) |
| Intermittent nausea, worsening feculent vomiting, abdominal pain, sometimes colicky | Bowel obstruction. Stretching of mechanorecepetors which stimulates the vomiting centre | In partial bowel obstruction, a prokinetic should be given if the patient continues to pass flatus and does not have colic. Haloperidol is an option for persistent vomiting or nausea in the absence of colic. In complete bowel obstruction, cyclizine or levomepromazine are options. Prokinetics should not be used. Octreotide may be used for high output vomiting not responding to other drugs for complete distal obstruction |
| Effortless vomiting sometimes associated with headache | Raised intracranial pressure. Cerebral histamine receptors that can be stimulated by mechanoreceptors stimulate the vomiting centre | Dexamethasone. Add cyclizine or levomepromazine if corticosteroids do not work |
| Nausea or vomiting on movement | Motion-associated emesis | Anticholinergic drugs such as cyclizine are useful |
| Nausea triggered by a stimulus (eg, anxiety) and alleviated by removal of that stimulus | Anxiety — the cerebral cortex is stimulated, which stimulates the vomiting centre | Benzodiazepines such as lorazepam are useful for anticipatory nausea and vomiting |
| Constant nausea | Chemically induced nausea. For example, drugs stimulate receptors in the CTZ which leads to stimulation of the vomiting centre by the vagal nerve | Dopamine antagonists such as haloperidol are the drugs of choice for opioid induced nausea and vomiting. 5HT3 antagonists are preferred for chemotherapy-induced nausea and vomiting |
Other important considerations
Management of nausea and vomiting should have a multidisciplinary approach. The length of treatment will depend on the underlying cause of the nausea and vomiting. For example, according to the BNF, antiemetics for nausea and vomiting that occurs with opioid therapy are usually only needed for the first four or five days. Pharmacists should check that patients know whether an antiemetic is to be taken regularly or just when required.
Prescribing should be reviewed daily and the patient should be assessed for response to treatment. Antiemetics should be stopped if the underlying cause of nausea or vomiting is resolved. The effects of vomiting on concomitant drug therapy should also be reviewed — alternatives to oral administration may be needed.
Good mouth care (eg, keeping the mouth clean with foam sticks and saline) is needed for those who are unable to drink. 2,6
Pharmacists could also advise on non-drug measures for managing nausea and vomiting. These include removal of stimuli (eg, sights, smells and certain fatty, spicy or salted foods), relaxation, distraction and massage.
Acupuncture and ginger have been shown to be effective for chemotherapy-induced emesis and anticipatory nausea but there is still a lack of evidence base in advanced cancer.5,7
References
- What causes nausea and vomiting. WebMD. http://www.webmd.com/digestive-disorders/digestive-diseases-nausea-vomiting (accessed 12 August 2013)
- Nausea and Vomiting in Palliative care: professional reference. Patient.co.uk http://www.patient.co.uk/doctor/Nausea-and-Vomiting-in-Palliative-Care.htm (accessed 12 August 2013)
- Mannix, K. (2006) Palliation of nausea and vomiting in malignancy. Clinical Medicine 6(2), 144-147.
- Harris, D. Nausea and vomiting in advanced cancer. Br Med Bull (2010) 96 (1): 175-185.
- National Cancer Institute. Nausea and vomiting PDQ. February 2013 http://www.cancer.gov/cancertopics/pdq/supportivecare/nausea/HealthProfessional/page2 (accessed 12 August 2013)
- Palliative cancer care – nausea & vomiting; NICE CKS, September 2012
- Glare P, Miller J, Nikolova T, et al; Treating nausea and vomiting in palliative care: a review. Clin Interv Aging. 2011; 6:243-59.
- Datapharm Communications Limited. Electronic Medicines Compendium. 2013 http://www.medicines.org.uk/emc/ (accessed 13 August 2013)
