Nausea and vomiting in palliative careBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h6249 (Published 03 December 2015) Cite this as: BMJ 2015;351:h6249
- Emily Collis, consultant in palliative medicine1,
- Harriet Mather, specialty trainee in palliative medicine2
- 1Camden, Islington ELiPSe and UCLH & HCA Palliative Care Service, Central and North West London NHS Foundation Trust, London, UK
- 2Department of Palliative Medicine, Mount Vernon Hospital, Northwood, UK
- Correspondence to: E Collis
What you need to know
Nausea and vomiting in advanced disease is often multifactorial. Common causes include gastric stasis, chemical disturbances, intestinal obstruction, and raised intracranial pressure
It can cause serious physical complications, including nutritional deficiency, electrolyte disturbance, dehydration, and aspiration pneumonia
Knowledge of the emetogenic pathway and antiemetic actions can help select an antiemetic that targets the underlying cause
Check renal function, electrolytes, and calcium level when appropriate
Give antiemetics orally unless the patient is vomiting or has suspected malabsorption or gastric stasis
When symptoms persist, prescribe a regular antiemetic with another antiemetic to be taken as required
Consider parenteral fluid replacement after an individual assessment of benefits and risk
What is the likely cause?
It is important to determine the cause of nausea and vomiting to identify potentially reversible causes and to inform antiemetic strategy. In advanced cancer, six broad causes of nausea and vomiting have been identified (table 1⇓). Gastric stasis and chemical disturbance are the most common.1 2 However, the aetiology is often multifactorial, and in many cases a cause cannot be confidently established.1
Sources and selection criteria
We searched Medline and Embase combining the terms “nausea,” “vomiting,” “palliative care,” “anti-emetics,” and “emesis” and conducted a narrative review of relevant articles. We included studies in adults receiving palliative care treated with an antiemetic for nausea or vomiting, or both. We excluded studies of chemotherapy or radiotherapy induced nausea and vomiting and studies of postoperative nausea and vomiting. We prioritised systematic reviews and controlled trials. We also used professional guidelines to develop our recommendations. The evidence comes largely from studies in patients with advanced cancer.
Specific management of chemotherapy and radiotherapy induced nausea and vomiting is outside the scope of this article and has been recently covered in a comprehensive review.42
How to identify the cause?
Table 1⇑ contains includes the symptoms that might point to the underlying cause of the nausea and vomiting. The abdomen should be examined for signs of intestinal obstruction and also for hepatomegaly and ascites, which may suggest gastric stasis. The presence of a “succession splash” (heard through auscultation of upper abdomen while patient is rocked from side to side at the hips) is indicative of gastric outlet obstruction. Rectal examination should be performed if faecal impaction is suspected; however, in patients with possible neutropenia this should be avoided. A thorough neurological examination should be conducted to elicit signs of raised intracranial pressure or focal neurology suggestive of meningeal metastases or a base of skull tumour.
What investigations are appropriate?
Investigations depend on the overall goals of care and the burden of tests and treatment to the patient. It is important to communicate openly and honestly with the patient to understand their goals and to reach a shared consensus. All patients should have blood sugar measured and urine analysis to exclude infection. Specific blood tests and imaging are recommended in some cases to rule out underlying treatable causes (see table 1⇑). Available treatments for reversible causes are listed in table 2⇓.
Parenteral hydration in nausea and vomiting
The GMC recommends that clinically assisted hydration should be offered intravenously or subcutaneously if there is overall benefit.4 Patients requiring parenteral hydration should be admitted, and clinicians should be vigilant to the signs of fluid overload as terminally ill patients require lower volumes for hydration.5
How strong is the evidence base for antiemetics in palliative care?
The evidence base underpinning most antiemetics in palliative care is limited, and much is derived from studies involving patients with cancer. More high quality, randomised controlled trials—including participants with diagnoses other than cancer, in a variety of settings, and using consistent and validated outcome measures—are required.
Which antiemetic should I prescribe?
Figure 1⇓ shows the emetogenic pathway, including the receptors activated at different points, the underlying causes, and the antiemetics most effective in different circumstances. Details of the antiemetics used as first line and second line treatment on this basis are outlined in table 3⇓, together with the common routes of administration and doses. The evidence base and side effect profiles of commonly used antiemetics can are outlined in table 4⇓.
Box 1: Recent guidance on the use of metoclopramide and domperidone from the British National Formulary
A recent review by the European Medicines Agency and Medicines and Healthcare products Regulatory Agency concluded that the risks of neurological effects with metoclopramide such as extrapyramidal disorders and tardive dyskinesia outweigh the benefits in long term or high dose treatment. Recommended used for short period (5 days) at maximum dose of 30 mg/24 hours. In practice sometimes used for longer durations and higher doses in palliative care but only if benefit outweighs risk.
Additionally, domperidone, due to small increased risk of serious cardiac side effects, should be used at the lowest effective dose for the shortest possible duration. The maximum treatment duration for domperidone is one week. Recommended dose 30 mg/24 hours. Domperidone is contra-indicated in conditions where cardiac conduction is, or could be, impaired, underlying cardiac disease, concomitant prescription of drugs that prolong the QTc interval, potent CYP3A4 inhibitors, or severe hepatic impairment
Which route of administration?
Antiemetics should be prescribed orally if there is no vomiting, malabsorption, or severe gastric stasis. For persistent symptoms, an antiemetic should be prescribed regularly with a second line antiemetic prescribed on an “as required” basis.
Parenteral administration of antiemetics is recommended if there is vomiting, malabsorption, or severe gastric stasis. If intravenous access is already established, this route can be used to provide a continuous infusion, with additional doses given by direct intravenous injection. If intravenous access is not in situ, the subcutaneous route is favoured as it is least invasive. Syringe drivers can provide a continuous subcutaneous infusion over 24 hours. Up to three drugs are commonly combined within a syringe driver, including opioids for pain. Syringe drivers should not be reserved for end of life care and can also be used to manage mucositis and bowel obstruction. The appropriate diluent (water or normal saline) and compatibility of agents within the infusion should be checked before administration—specialist help should be sought if there is any uncertainty. Syringe driver prescriptions should be reviewed daily, and sites of infusion on the skin inspected closely for evidence of erythema or tenderness, which should prompt relocation. Extra doses can be given by direct subcutaenous injection or via a second indwelling subcutaneous line. Intramuscular administration should be avoided as this is painful and can cause haematomas in patients with bleeding tendencies. Box 2 lists alternatives to parenteral or oral administration.
Box 2: Alternatives to oral, intravenous, or subcutaneous administration of antiemetics
Ondansetron suppositories—16 mg per suppository, £14.39 per dose
Granisetron transdermal patch—31 mg for 24 hours, £56.00 per patch
Hyoscine hydrobromide transdermal post-auricular patch (Scopaderm)—1.5 mg for 72 hours, £2 per patch
How to titrate antiemetics
Figure 2⇓ provides a guide to titrating antiemetics. Using a similar approach, in a before-after uncontrolled study of patients in a hospice, resolution of nausea occurred in 82% of patients and resolution of vomiting in 84% of patients.2 The median time to complete resolution of symptoms was two days. In a second similarly designed study, vomiting was controlled in 89% and nausea only in 56% of patients at one week, although almost all patients reported an improvement in nausea.1
During titration, antiemetics with similar receptor profiles (such as metoclopramide and domperidone) should not be combined. Combinations with competing mechanisms of action (for example, prokinetics such as metoclopramide and anticholinergics such as cyclizine) should also be avoided. Agents with activity at multiple receptors, such as levomepromazine or olanzapine, have a broader side effect profile, but they can be effective as second line agents when more selective first line agents have failed.33
What is the role of dexamethasone?
Dexamethasone is used when there is evidence of raised intracranial pressure.6 It can also be used in malignant bowel obstruction. Clinicians and patients should be vigilant to the development of side effects, including myopathy, hyperglycaemia, mood changes, and changes in body image. To minimise side effects, the lowest effective dose should be used for the shortest time.
Managing nausea and vomiting in malignant bowel obstruction
Malignant bowel obstruction not amenable to surgical intervention is managed with the use of opioids and antiemetics, and sometimes also antisecretory agents, via a continuous subcutaneous infusion.
Metoclopramide can be used in early stage, partial obstruction because of its prokinetic effect. However, it should be avoided if there is complete obstruction or colic,34 when cyclizine with or without haloperidol or levomepromazine is used.
If large volume vomiting occurs despite the above measures, antisecretory drugs such as hyoscine butylbromide (an anticholinergic) or octreotide (a somatostatin analogue) or a combination can be used. Both have antispasmodic action if colic is problematic, with hysocine butylbromide more commonly used for this effect. A recent randomised trial failed to show benefit of octreotide given first line in addition to standard therapy (which included dexamethasone) on the primary outcome of vomit-free days.35 However, there was a reduction in the number of vomiting episodes in patients receiving octreotide. The role of octreotide as second line therapy in patients who continue to vomit despite standard first line therapy requires further research.
Dexamethasone can be used in addition to antiemetics and antisecretory agents in malignant bowel obstruction. A systematic review of its use in malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer failed to show a significant benefit, but its use in malignant bowel obstruction remains widespread.36 A typical dose is 4-16 mg (subcutaneous or intravenous) daily. Response to treatment should be reviewed after five days.
Other interventions for refractory symptoms
About 10% of patients with malignant bowel obstruction continue to vomit despite palliative pharmacological management.37 Some patients may therefore benefit from a wide bore ‘Ryles’ nasogastric tube to decompress the stomach and for ongoing drainage of gastric contents and any oral intake ingested for pleasure.38 If a nasogastric tube is effective in helping relieve symptoms, venting gastrostomy insertion can provide a longer term option to allow for discharge home. The procedure is similar to percutaneous endoscopic gastrostomy and radiologically inserted gastrostomy. Risks of the procedure include over-sedation, aspiration pneumonia, haemorrhage, perforation, and, more commonly, peristomal cellulitis. However, a small retrospective case notes review showed that in six out of seven cases, venting gastrostomy relieved nausea and vomiting with only minor complications, with the same proportion achieving discharge home.39
What newer agents are available?
Aprepitant is a NK1 antagonist used for the prevention of delayed chemotherapy induced nausea and vomiting. This has been reported to be effective in a case of refractory nausea associated with leptomeningeal disease40 and is available in oral and intravenous preparations.
Serotonin 5-HT3 receptor antagonists are currently used in the management of chemotherapy and radiotherapy induced and postoperative nausea and vomiting. These agents can be constipating, which limits their use in palliative care, and they should be used with caution in patients succeptible to QTc prolongation. Evidence from case reports supports 5-HT3 antagonists as effective agents in refractory nausea and vomiting in advanced cancer,27 29 AIDS,29 and advanced multiple sclerosis.28 Palonosetron is a new long acting 5-HT3 antagonist (a single dose effective for up to five days) that is less constipating than conventional 5-HT3 antagonists. Granisetron, now available as a transdermal preparation, may offer a useful alternative to continuous subcutaneous infusions of antiemetics for patients in the community. Evidence for both to date is limited to chemotherapy induced nausea.41 A more cost effective alternative may be ondansetron administered in the form of rectal suppositories.
Targeted prokinetics are currently in development, including selective 5-HT4 agonists, ghrelin agonists, and motilin agonists.9 Cannabinoids (such as nabilone) mediate an antiemetic effect through the CB1 receptor and anecdotally can be used with good effect in selected patients with refractory nausea, although evidence to date is limited to a role in chemotherapy related nausea when standard agents have failed.10
A patient’s perspective
Nausea has been one of the most disabling symptoms from diagnosis [leukaemia]. Originally this was from the chemotherapy. I was lucky to be treated in a unit where they used aprepitant and palonosetron with the chemotherapy, as these worked well for me.
As I’ve become less well with recurrent disease, I’ve had to have a lot of antifungals and antibiotics. These have made the nausea much worse. Cyclizine doesn’t work for me and makes me feel spaced out. I’ve got a scopoderm patch on, which works OK, and omeprazole helps a bit with the reflux. I use levomepromazine as a top-up, and it works but gives me a horrible hangover feeling the next day. Complementary therapy helps [reiki and reflexology] for a few hours and makes me feel better overall. It’s really important to me.
Recently I’ve had bowel obstruction; they don’t really know why, there isn’t a blockage. I know I can’t have steroids, and I had such bad crampy pain on the metoclopramide when it first happened that I’m scared to try it again. I had to stop my palonosetron to try and help my bowel start working again. I didn’t want a syringe driver as it’s just another pump attached to me. I did have a [nasogastric] tube, which made me feel a bit better. Thankfully it’s out now, and I seem to be doing a bit better again. Bowel obstruction is really horrible.
Priorities for future research
Randomised controlled trials of antiemetics are needed that include patients with life limiting illness who are receiving palliative care. These should include patients with non-malignant and malignant disease. Stratification on the basis of likely aetiology should also be undertaken. In order to accrue sufficient participants to achieve adequate power, multicentre collaboration should be encouraged.
Future preclinical studies should examine similarities in pathways and receptors between nausea and vomiting in advanced disease and other clinical contexts to establish whether advances in control of nausea and vomiting in other fields can be translated to patients with advanced disease.
Pathways encoding the sensation of nausea (as distinct from vomiting) require further elucidation.
Additional educational resources
Resources for professionals
Palliative Care Adult Network guidelines—http://book.pallcare.info/
Detailed electronic resource for symptom control in palliative care. Includes a syringe driver drug compatibility resource and opioid dose calculator. iPhone app available. (Free resource, no registration)
e-Learning for Healthcare modules on end of life care—www.e-lfh.org.uk/projects/end-of-life-care/
Over 150 modules on end of life care, including symptom management, patient assessment, communication skills, and advance care planning. (Free resource for healthcare professionals, individual registration required but straightforward)
Map of Medicine updated guide on end of life care in adults—http://mapofmedicine.com/end-life-care-pathway-includes-five-new-priorities-care/
Contains useful, well referenced, flow diagrams around care of dying patients. (Free resource for healthcare professionals, registration required by trust/CCG)
Palliative Care Formulary—Available through www.palliativedrugs.com
Resources for patients
Palliative Care Adult Network guidelines— http://book.pallcare.info/
Electronic resource for accessible to patients for those who wish to read in detail about their symptoms and medications. iPhone app available. (Free resource, no registration)
St Christopher’s information leaflet for patients and carers: symptom control medications— www.stchristophers.org.uk/wp-content/uploads/2015/10/StChris_Additional_info_on_medicines_used_in_symptom_control.pdf
(Free resource, no registration)
Macmillan Cancer Support information leaflets—http://be.macmillan.org.uk/be/s-614-side-effects-and-symptoms.aspx?pagenum=1
Includes leaflet Controlling the Symptoms of Cancer. Free resource, no registration
How patients were involved in the creation of this article
A patient perspective is included in this review.
Cite this as: BMJ 2015;351:h6249
Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
Patient consent: Patient consent obtained.
Provenance and peer review: Commissioned; externally peer reviewed.