Nausea and Vomiting in Palliative Care

Nausea and vomiting are common and distressing symptoms in patients receiving palliative care for advanced cancer and the effective management of these symptoms can make a major contribution to improving quality of life in these patients. An understanding of the likely causes of these symptoms is required for accurate assessment and treatment, resulting in better symptom control.

• The prevalence of nausea is 20-30% in all patients with advanced cancer,¹ and this rises to 70% in the last week of life.²
• 20% of all cancer patients develop vomiting.¹
• Nausea and vomiting is highest in advanced gynaecological cancers (42%) and advanced stomach cancer (36%).³
• About 30% of patients who receive morphine feel nauseous during the first week of treatment.⁴

A greater understanding of the physiological mechanisms causing nausea and vomiting in the palliative care patient will help to select the most appropriate treatment. There are four main sites of activity:⁵

• The vomiting centre (VC) - this is situated in the brainstem and has histamine (H1), acetylcholine (ACh) and 5-hydroxytryptamine 2 (5-HT2) receptors.
• The chemoreceptor trigger zone (CTZ) - located in an area of the brain that has no blood-brain barrier, which enables various drugs, toxins and metabolites to access the site. It has dopamine (D2) and 5-HT3 receptors.
• The cerebral cortex - there are multiple receptors which can be triggered by anxiety. Also, mechanoreceptors in the meninges are sensitive to changes in intracranial pressure.
• The vestibular system - changes in movement or diseases of the ear may stimulate the ACh or H1 receptors, triggering nausea or vomiting.
• Gut and serosal surfaces in the viscera - 5-HT3 receptors in the gut 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.

Blocking the receptors at various sites is the mainstay of the drug management of nausea and vomiting.
In cancer patients, it is helpful to group the principle causative pathways into seven syndromes, based on receptor sites, clinical features and treatment. ⁵

An accurate assessment of patients with nausea and vomiting will allow for appropriate management of the patient and better symptom control.
Assessment of the patient may include the following:

History

• Timing of symptoms - after meals (e.g. gastric stasis), on movement (e.g. vestibular disease),when lying flat (e.g. due to meningeal irritation or raised intracranial pressure)
• Food and fluid intake
• Drugs, including over-the-counter ones and alternative therapies.
• Pain
• Bowel habit
• Urinary output
• Affect on daily life

Examination

• Assessment of hydration
• Signs of infection, e.g. fever
• Presence of jaundice
• Neurological examination, including examination of the optic fundi to exclude papilloedema
• Rectal examination
• Abdominal examination - tenderness, distension, ascites, masses, hepatomegaly

Depending on the findings of the history and examination, further investigations may be performed to look for the underlying cause of the symptoms, e.g:

• Urea and electrolytes
• Serum calcium level
• Liver function tests
• FBC and differential
• Urine culture
• Abdominal ultrasound/X-ray
• Endoscopy
• CT/MRI scan

At the end of the assessment it should be possible to categorise the cause into one of the following syndromes:⁵

• The effective management of nausea and vomiting in palliative care demands a multi-disciplinary approach with good communication between all members of the team and the patient and their family. Support for the patient should be available at all times and they should be aware of whom to contact in order to help with queries and concerns .
• Simple advice such as the size and type of meal, advice on fluid intake and the timing of medication, may all be helpful.
• Attention to the patient's environment is also very important. Bowls, tissues and fresh drinking water should always be within reach.
• For patients unable to drink, attention to oral hygiene and regular mouth washes are important.
• If nausea and vomiting are preventing other medication such as analgesia from being effective, then it may be appropriate to consider other forms of delivery of these medications, such as syringe drivers and patches.
• A review of current medication should be undertaken and drugs likely to be aggravating the situation, e.g. NSAIDs should be changed or stopped.^5,7
• Reversible causes of nausea and vomiting should be corrected first wherever possible:
  • Hypercalcaemia may respond to rehydration and the use of bisphosphonates.
  • Uraemia may be corrected by rehydration using IV fluids in some patients.
  • Gastric ulceration or gastritis may respond to treatment with proton pump inhibitors or H₂antagonists.
  • Infection should be treated with appropriate antibiotics.
  • Constipation may respond to the use of laxatives or enemas.
  • Corticosteroids such as dexamethasone, may reduce the size of the tumour, or reduce oedema surrounding the tumour.
  • Anxiolytics may have a role in some patients in whom anxiety is thought to be playing a part.

Treatment in specific scenarios⁵

First-line treatment should be tailored according to the identified clinical syndrome and likely receptors to be targeted. A non-oral route should be used for the first 48 hours, changing to an oral preparation once the symptoms have improved.
Irritation or stretching of the meninges

• If the patient has raised intracranial pressure, refer for consideration of radiotherapy.
• High-dose dexamethasone (16 mg daily for 4-5 days, subsequently reducing to 4-6 mg daily), may help. ⁸
• Add cyclizine 25-50 mg three times a day or levomepromazine⁹ once at bedtime (2.5-5 mg subcutaneously or 12.5 mg oral dose). Higher doses of levomepromazine can cause significant adverse effects (postural hypertension, dry mouth, sedation).

• Cyclizine is helpful as it blocks ACh and histamine H1 receptors in the vomiting centre that are triggered by the mechanoreceptors in the abdominal and pelvic viscera.
• Try 25-50 mg oral tablets or subcutaneous injection first-line, including when vomiting is aggravated by movement.
• Add dexamethasone if vomiting persists.

• Functional or partial bowel obstruction:
  • Preserving bowel motility needs to be balanced with the prevention of colic.
  • Stop osmotic and stimulant laxatives.
  • Docusate is minimally stimulated and should be titrated to produce a comfortable stool without colic. Avoid high-fibre foods and advise taking food and fluids at regular intervals and in small amounts.
  • A prokinetic anti-emetic such as metoclopramide or domperidone should be given if the patient continues to pass flatus and does not have colic.
  • Prokinetics block dopamine D2-receptor activity in the gut.
  • Metoclopramide has a direct excitatory activity and may be better than domperidone for patients in this situation.⁵ It may be given as a 10 mg oral dose four times a day or as a 40-60 mg/24 hours continuous subcutaneous infusion.
  • Domperidone has a long plasma half-life; a starting oral dose of 20 mg twice a day may be increased if necessary to a 30 mg oral dose, or a 90 mg rectal dose every 8 hours.
  • Prokinetic drugs should not be given with antimuscarinic drugs (e.g. cyclizine, hyoscine) as they are competitively blocked by the latter. If colic develops, stop the prokinetic immediately and treat as obstruction.
  • Haloperidol is another option for the management of persistent vomiting or nausea in the absence of colic. It is a specific dopamine D2-receptor antagonist that has a profoundly inhibitory effect on the CTZ. Small doses, e.g. 2.5 mg haloperidol once at bedtime by subcutaneous injection, are normally effective.¹⁰
• Complete bowel obstruction:
  • The first-line treatment is cyclizine as it blocks the stimulation of the vomiting centre via the vagal afferents, which happens in complete obstruction. If this fails, change to levomepromazine.
  • Large-volume vomiting should be treated with an antisecretory drug.
  • A nasogastric tube should be inserted to drain intestinal secretions if there is gastric outflow obstruction with rapid dehydration. This may be removed as soon as control is achieved with medication.
  • Intravenous hydration should be commenced, or if the patient is at home, 1000-1500 ml of saline can be given subcutaneously. Ranitidine should be used to reduce volume of gastric secretions.
  • Complete distal obstruction may require hyoscine butylbromide or octreotide. Hyoscine is preferred if there is colic but it is slower in reducing secretions than octreotide. ¹¹
  • Consider referring for venting gastrostomy if there is an ongoing need for a nasogastric tube.
  • If vomiting persists, consider referring for stent emplacement to overcome obstruction, or consider starting corticosteroids.
  • Consider parenteral hydration of fluid to reduce the intensity of nausea in a dehydrated patient. This can be given subcutaneously at home.

• Prokinetics such as metoclopramide or domperidone are first-line drugs.
• See above for details of dosage.
• If prokinetics fail, consider adding therapies which reduce gastric secretions, such as ranitidine or octreotide.⁵

• Haloperidol is the first-line drug for opioid-induced nausea, renal failure and hypercalcaemia.¹⁰ Hypercalcaemia should also be treated with a biphosphonate.¹²
• A prokinetic may be useful prophylactically when initiating and titrating morphine.
• If nausea develops secondary to cytotoxic therapy or radiotherapy haloperidol should be used first-line, keeping levomepromazine in reserve should this fail.
• Another option is a specific 5-HT3 antagonist, such as dolasetron, granisetron or ondansetron, which block 5-HT3 receptors in the gastro-intestinal tract and in the CNS.¹³ Palonosetron is licensed for the prevention of nausea and vomiting induced by moderately and severely emetogenic chemotherapy.
• Aprepitant, a neurokinin 1 receptor antagonist, is licensed for the prevention of acute and delayed nausea and vomiting associated with cisplatin-cytotoxic chemotherapy. It is often used with dexamethasone and a 5-HT3 antagonist and this combination is being increasingly used as standard therapy in many patients receiving moderately or highly emetogenic chemotherapeutic agents.¹⁴
• A further option occasionally used under specialist care is nabilone, a synthetic cannabinoid with anti-emetic properties although its use is limited by side-effects such as dizziness and drowsiness. It is particularly useful in children.¹⁵

• Anxiety is often generated by lack of information or failure of communication and may be easily resolved with simple explanation and reassurance. More deep-seated anxiety may require the support of other members of the multidisciplinary team such as psychologists, Macmillan nurses, or spiritual advisers.
• Ensure that all other physical causes of nausea and vomiting have been excluded before attributing the symptoms to anxiety.
• Avoid diazepam, which has a long plasma half-life and may cause excessive sedation when given to palliative care patients who may be old, debilitated, have hepatic impairment, or be on other therapy such as strong opioids.⁵