Palliation of Nausea and Vomiting in Malignancy

CME Palliative care

Palliation of nausea Nausea and vomiting are common Mechanisms of nausea and symptoms that can cause enormous vomiting misery for cancer patients, undermining and vomiting in quality of life and contributing to weak- Emesis is a protective reflex triggered by ness, anorexia and nutritional problems.1 physical stimuli that include poisoning malignancy Evidence-based recommendations for and overdistension of hollow viscera, the management of treatment-induced psychological stimuli or vestibular emesis are available, but the manage- stimulation (including motion sickness). Kathryn Mannix MB BS FRCP, Consultant in ment of nausea arising as a consequence The various nerve pathways activated by Palliative Medicine, Royal Victoria Infirmary of the disease itself is less well researched. 4 and Marie Curie Hospice, Newcastle upon these stimuli are summarised in Fig 1. Tyne This article summarises palliative care Chemical triggers to nausea are guidelines derived from animal models detected at the chemoreceptor trigger and validated in a range of human Clin Med 2006;6:144–7 zone (CTZ) in the floor of the 4th studies.2,3 ventricle. Here, there is effectively no

Higher centres: D receptors ¥ pain 2 ¥ haloperidol Chemicals in ¥ fear 5HT receptors blood: ¥ memory 3 ¥ ‘–setrons’ ¥ drugs ¥ metabolites ¥ toxins D2 5HT3 CTZ

H receptors 1 Ach ¥ cyclizine m Achm receptors ¥ hyoscine hydrobromide Achm 5HT2 receptors VIII ¥ levomepromazine nucleus VC H1

5HT2 Autonomic afferents

Stretch receptors in serosae and viscera: ¥ head and neck ¥ thorax Emesis: ¥ abdomen and pelvis ¥ nausea ¥ retching ¥ vomiting

Fig 1. Pathways and neurotransmitters involved in nausea and vomiting. Achm = muscarinic acetylcholine receptors; CTZ = chemoreceptor trigger zone; D2 = dopamine type 2; H1 = histamine type 1; 5HT2 and 3 = serotonin receptor subtypes 2 and 3; po = oral; pr = per rectum; sc = subcutaneous; sl = sublingual; TD = transdermal; VC = vomiting centre. Copyright retained by K Mannix.

144 Clinical Medicine Vol 6 No 2 March/April 2006 CME Palliative care blood-brain barrier so water-soluble more selective the binding of a drug, the 6 Give the drug regularly and titrate the chemicals in blood can diffuse into the fewer its side effects. Relative binding dose carefully, with frequent review cerebrospinal fluid and stimulate the affinities are summarised in Table 1. of the patient. chemoreceptors there. 7If symptoms persist, review all the The vomiting centre (VC) in the brain- steps: The eight key steps to stem integrates all the components of the Is another cause also present, reflex, resulting in nausea, salivation, successful management of • nausea requiring an additional pallor, sweating, retching, protective anti-emetic? closure of the glottis and vomiting. The 1 Identify the likely cause(s) of nausea Is a different cause more likely VC receives sensory input from auto- • and/or vomiting: to make an accurate now that there has been more nomic nerves; stretch receptors on these diagnosis of cause(s) requires a time to assess the patient? nerve terminals detect distortion such as thorough assessment including 8Consider whether the trigger can be liver capsule stretch by metastatic disease, history, examination and diagnostic removed: for example, treat peritoneal distortion by para-aortic tests, including biochemistry, hypercalcaemia, reverse intestinal lymphadenopathy or bowel dilatation due infection screen, imaging etc. to obstruction or constipation. Afferents obstruction and reduce raised 2 Identify the pathway by which each include the vagus, sympathetic trunk and intracranial pressure. Maintain cause triggers the vomiting reflex glossopharyngeal nerve. The VC also anti-emetics until the trigger is (Fig 1). receives input from higher centres, for reversed: if reversal is not possible, 3 Identify the neurotransmitter receptor example, fear, pain and memory. long-term anti-emetic therapy may involved in each pathway identified. be necessary to maintain palliation. 4 Prescribe the most potent antagonist Choosing an anti-emetic to each receptor identified (Table 1). Other anti-emetic drugs With knowledge both of the central path- It is usually sufficient to block one ways that mediate nausea and vomiting receptor at the VC. • Corticosteroids are known to have and of the neuroreceptors involved, it is 5Choose a route of administration that intrinsic anti-emetic action which is possible to select specific receptor antago- ensures the drug will reach its not well understood. In addition, nist drugs as anti-emetics.5 The efficacy of receptors: gastric stasis is usually their mass-reducing effects may a drug as an anti-emetic is proportional to present in nausea, often precluding reduce stimulus to nausea in its binding affinity for its receptor.6 The the oral route. advanced cancer.

Table 1. Receptor binding affinities of commonly used receptor-specific anti-emetic drugs.

Receptor binding

Achm H1 5HT3 αAd (antagonists Drug Recommended D2 5HT2 (VC and VIII (VC and VIII (vagal afferent cause dose (CTZ) (VC) nucleus) nucleus) endings) hypotension)

Haloperidol 1.5–3 mg daily po or sc +++ – – – – – Metoclopramide 10–20 mg tds po or sc ++ – – – (+) – Cyclizine 50 mg tds po or sc – – (+) +++ – – Levomepromazine 6.25–12.5 mg daily po or sc + +++ + + – – Domperidone (does 10–20 mg tds po + – – – – – not cross blood- 30–60 mg tds pr brain barrier) Prochlorperazine + – + + – + (not recommended) Hyoscine 400 µg qds sl or sc – – +++ – – – hydrobromide 500–1,500 µg/72 h TD patch Granisetron, – – – – +++ – ondansetron, etc (not recommended)

αAd = α-adrenergic; Achm = muscarinic acetylcholine receptors; CTZ = chemoreceptor trigger zone; D2 = dopamine type 2; H1 = histamine type 1; 5HT2 and 5HT3 = serotonin receptor subtypes 2 and 3; po = oral; pr = per rectum; sc = subcutaneous; sl = sublingual; TD = transdermal; VC = vomiting centre.

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Serotonin-3 (5HT ) receptor Clinical examples • 3 antagonists are widely overprescribed. 1 Bowel obstruction below jejunum They are effective for early emesis Triggers to nausea: stretch behind obstruction stimulates VC induced by chemotherapy or during pain (bowel inflammation and colic) stimulates VC radiotherapy across the absorption of bacterial toxins stimulates CTZ gastrointestinal tract (eg low thoracic Management: Establish whether or not surgery or stenting is appropriate: many spine, total body irradiation) but patients with advanced disease or peritoneal metastases are not candidates for surgery7 and require medical palliation. probably have no role in other types of nausea caused by cancer. Cyclizine 50 mg tds sc or per rectum to block VC activity. Constipation is a major side effect of Haloperidol 1.5–3 mg sc daily in addition, if nausea persists. Once nausea is controlled, oral dosing is effective. this class of drugs. Consider: Anticholinergic agents (hyoscine butylbromide 40–120 mg/day or • Neurokinin-1 (NK1) receptor glycopyrrolate 0.1–0.2 mg tds sc) or octreotide 200–1,000 µg/day8 blockers are effective anti-emetics. can be used as antisecretory agents and will also relax smooth NK1 receptors are widely distributed muscle, thus reducing colic. in the brain. An oral NK1-receptor High-dose corticosteroids may help to reduce pressure and restore patency in malignant bowel obstruction, at least temporarily antagonist is licensed for use in (eg dexamethasone 12–16 mg daily).9 chemotherapy-induced nausea; its Correction of dehydration may reduce symptoms.8 role in palliative care has yet to be The use of nasogastric tubes and prolonged intravenous fluids is unnecessary; nasogastric explored. tubes may aggravate nausea by glossopharyngeal stimulation and vigorous rehydration will enhance intraluminal secretion of fluid, increasing pressure, colic and nausea. Non-pharmacological measures Patients can eat and drink for pleasure; they should be warned to expect intermittent mechanical vomits, although it should be possible to control nausea. Attention should be paid to mood and 2 Ureteric obstruction morale, reducing exposure to strong Triggers to nausea: ureteric stretch stimulates VC cooking smells and providing small, uraemia stimulates CTZ palatable meals. Carbohydrate meals are toxic drug accumulation due stimulates CTZ often better tolerated; sour flavours may to reduced renal clearance be preferred by some patients (eg citrus Management: Ureteric stenting will palliate both stretch and chemical stimulation of sorbets, lemon drinks). nausea, but is not always possible. Psychological techniques to palliate Cyclizine 50 mg tds sc or per rectum to block VC activity. Haloperidol 1.5–3 mg sc daily in addition, if there is renal insufficiency. nausea due to advanced disease have not Doses of renally-excreted drugs will also need to be modified. been systematically studied, but studies of relaxation using progressive muscle 3 Gastric stasis relaxation and guided mental imagery in Gastric emptying may be delayed by anticholinergic drugs, increased intra-abdominal pressure or compression of the gastric outlet. chemotherapy patients have shown that the stress of treatment-related nausea Symptoms: Stretching of the stomach by ingested food, drink and air, and by gastric secretions causes distortion of the oesophageal sphincter. This can be reduced by these methods. permits acid reflux causing heartburn, whilst the distending stomach Acupuncture and acupressure have irritates the diaphragm causing hiccups. demonstrated useful anti-emetic effects Eating or drinking, even small volumes, when the stomach is already for chemotherapy-related and post- full induces early satiation accompanied by a sensation of bloating. operative nausea and vomiting; the effect The stomach has great capacity for stretch, and so nausea is not a feature until overstretching occurs; there is often a short period of of acupuncture can be prolonged by premonitory nausea, followed by large-volume vomiting which acupressure; transcutaneous nerve completely relieves all the other symptoms. stimulation at acupuncture points is also Management: Treatment is most effective when directed at the cause (eg stopping effective.9,10 There are no studies of any anticholinergic drugs or tapping ascites). acupuncture in a palliative care setting, Prokinetic agents (metoclopramide, domperidone) can restore although individual case reports suggest peristalsis and reduce reflux. Proton-pump inhibitors reduce the volume and acidity of gastric it can be a successful strategy. secretions. Patients should be encouraged to eat little and often. End-of-life care In duodenal or high jejunal obstruction, prokinetic drugs may cause colic. The volume of pancreatic and mucosal secretion can be reduced using anticholinergic drugs and/or As the end of life approaches, taking oral octreotide (see above); if frequency of vomiting remains intolerable, the use of a venting medications can be a burden. All the PEG should be considered for palliation. anti-emetics recommended in Table 1 can CTZ = chemoreceptor trigger zone; PEG = percutaneous endoscopic gastroscopy; sc = subcutaneously; be given by the sc route. Redness and VC = vomiting centre. swelling at the injection site can be a

146 Clinical Medicine Vol 6 No 2 March/April 2006 CME Palliative care problem with cyclizine which can be given References the resolution of malignant bowel obstruc- as a suppository instead. Anticipating the tion in advanced gynaecological and 1Vainio A, Auvinen A. Prevalence of terminal phase and making appropriate gastrointestinal cancer. Cochrane Database symptoms among patients with advanced of Syst Rev. Chichester: John Wiley and Sons adjustments in route of administration of cancer: an international collaborative study. Ltd, 2000. those drugs essential to maintaining Symptom Prevalence Group. J Pain 10 Vickers AJ. Can acupuncture have specific comfort are important parts of the cancer Symptom Manage 1996;12:3–10. effects on health? A systematic review of team’s work. The Liverpool Care Path- 2Twycross R, Back I. Nausea and vomiting in acupuncture antiemesis trials. Review. J R advanced cancer. Eur J Palliative Care Soc Med 1996;89:303–11. way for the dying patient is a national 1998;5:39–44. framework for excellent end-of-life care 3Mannix K. Palliation of nausea and (more information is available from vomiting. In: Doyle D, Hanks G, Cherny N, www.lcp-mariecurie.org.uk). Calman K (eds). Oxford textbook of palliative medicine, 3rd edn. Oxford: Oxford University Press, 2004. Conclusions 4Borison HL, Wang SC. Physiology and pharmacology of vomiting. Pharmacol Rev Cancer-related nausea and vomiting may 1953;5:193–230. be a presenting symptom of curable 5Peroutka SJ, Snyder SH. Antiemetics: disease or a burden of advanced disease. neurotransmitter receptor binding predicts In either case, it is possible to palliate the therapeutic actions. Lancet 1982;i:658–9. 6Ison PJ, Peroutka SJ. Neurotransmitter symptoms by applying a knowledge of receptor binding studies predict antiemetic the pathways that mediate emesis and efficacy and side effects. Cancer Treat Rep selecting anti-emetic drugs on the basis 1986;70:637–41. of their site of action. Other disease- 7Blair SL, Chu DZ, Schwarz RE. Outcome of modifying treatments, if available, can palliative operations for malignant bowel obstruction in patients with peritoneal proceed in parallel with palliation of carcinomatosis from nongynecological nausea and vomiting. Good palliation of cancer. Ann Surg Oncol 2001;8:632–7. these distressing symptoms can be 8Ripamonti C, Mercadante S, Groff L, Zecca achieved and should be the aim of care E et al. Role of octreotide, scopolamine for nauseated patients. butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a Conflicts of interest prospective randomized trial. J Pain Symptom Manage 2000;19:23–34. None. 9Feuer DJ, Broadley KE. Corticosteroids for

Key Points

Nausea and vomiting are common symptoms that can cause enormous misery for cancer patients

It is possible to palliate the symptoms by selecting anti-emetic drugs on the basis of their site of action in the emesis pathway

The efficacy of a drug as an anti-emetic is proportional to its binding affinity for its receptor

The more selective the binding of an anti-emetic drug, the fewer its side effects

The aim of therapy is control of nausea

Choose a non-oral route for anti-emetics until nausea has been absent for 24 hours

5HT3 receptors have no identified role in palliative care Medical management of bowel obstruction does not usually include permanent nasogastric intubation or intravenous fluids

Nausea at introduction of opioids occurs in about 30% of patients, but tolerance to nausea arises within two weeks so that anti-emetics can then be withdrawn

KEY WORDS: anti-emetic, bowel obstruction, nausea, palliative treatment, vomiting

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