Nausea and Vomiting in Palliative Care

1. Clinical Overview

Summary

Nausea and vomiting are among the most distressing and debilitating symptoms in palliative care, affecting 40-70% of patients with advanced cancer and up to 60% of patients in the terminal phase. [1,2] Effective management requires a systematic, mechanism-based approach that identifies the underlying physiological pathways triggering these symptoms and selects antiemetics that target specific receptors involved in the emetic reflex. [3,4]

The vomiting centre (VC) in the medulla oblongata integrates multiple afferent inputs from four key sources: the chemoreceptor trigger zone (CTZ), gastrointestinal tract (via vagal afferents), vestibular apparatus, and higher cortical centres. [5] Each pathway involves distinct neurotransmitter systems, creating opportunities for targeted pharmacological intervention. Common aetiologies in palliative populations include opioid therapy, metabolic derangements (hypercalcaemia, uraemia, hyponatraemia), mechanical factors (gastric stasis, bowel obstruction, constipation), raised intracranial pressure, and chemotherapy. [6,7]

The subcutaneous route via continuous infusion (syringe driver) is frequently required when oral bioavailability is compromised by vomiting, ensuring reliable drug delivery and superior symptom control compared with intermittent dosing. [8,9] Drug compatibility, receptor pharmacology, and adverse effect profiles guide rational prescribing decisions. Modern palliative care emphasizes individualized treatment based on careful clinical assessment rather than empirical antiemetic "trials". [10]

Key Facts

Epidemiology and Impact

• Prevalence in advanced cancer: 40-70%, rising to 60-70% in terminal phase [1,2]
• Opioid-naive patients: 30-40% experience nausea on initiation [11]
• Severe impact on quality of life comparable to pain [12]
• Associated with dehydration, malnutrition, treatment non-compliance [13]

Physiological Architecture

• Vomiting Centre (VC): Located in lateral reticular formation of medulla. Coordinates motor act of vomiting but lacks direct blood-borne chemical sensitivity [5]
• Chemoreceptor Trigger Zone (CTZ): Located in area postrema on floor of fourth ventricle. Outside blood-brain barrier, senses toxins (opioids, uraemia, hypercalcaemia, chemotherapy). Rich in D2, 5HT3, NK1 receptors [14]
• Vagal Afferents: From GI tract, respond to mechanical distension, mucosal irritation, chemical stimuli. D2, 5HT3, 5HT4 receptors [15]
• Vestibular System: H1 and muscarinic receptors. Motion, base of skull metastases, opioid sensitization [16]
• Cortical Input: Anxiety, pain, anticipatory mechanisms. GABA, various neurotransmitters [17]

Mechanism-Based Prescribing Philosophy

• Identify dominant aetiological pathway(s) through clinical assessment [3]
• Select antiemetic(s) targeting implicated receptors
• Avoid pharmacologically antagonistic combinations (e.g., metoclopramide + cyclizine)
• Reassess within 24-48 hours and adjust based on response [10]

Clinical Pearls

The "Haloperidol First" Rule for Opioid Nausea: Opioids stimulate CTZ dopamine receptors. Haloperidol (potent D2 antagonist) is therefore mechanistically ideal first-line therapy. Nausea is typically transient (3-7 days) with tolerance developing, unlike constipation which persists. Always warn patients and avoid premature opioid cessation. [11,18]

Cyclizine-Metoclopramide Incompatibility: These agents are pharmacologically antagonistic. Metoclopramide is prokinetic (stimulates gastric emptying via 5HT4 agonism and D2 antagonism). Cyclizine is anticholinergic (relaxes smooth muscle). Combined use negates efficacy. Additionally, they form precipitates when mixed in syringe drivers. [19]

Levomepromazine: The Broad-Spectrum Sledgehammer: Levomepromazine blocks D2, H1, 5HT2, and muscarinic receptors simultaneously. Effective in 70-80% of refractory cases unresponsive to single-agent therapy. Major limitation: sedation and hypotension. Reserve for second-line or rescue use when mechanism unclear or multiple triggers coexist. [20,21]

Prokinetics are Contraindicated in Complete Bowel Obstruction: Metoclopramide and domperidone increase gastric contractility. In complete mechanical obstruction, this risks perforation, worsens colic, and causes severe pain. Use anticholinergic agents (cyclizine, hyoscine butylbromide) that reduce peristalsis and secretions instead. [22]

Dexamethasone as Adjunct in Obstruction and Brain Metastases: Corticosteroids reduce peri-tumoral oedema. In malignant bowel obstruction, this may convert complete to partial obstruction, enabling some oral intake. In brain metastases with raised ICP, dexamethasone addresses the underlying cause while antiemetics control symptoms. [23,24]

Ondansetron: Overused in Palliative Settings: 5HT3 antagonists are highly effective for chemotherapy-induced and post-operative nausea but less so for general palliative causes (CTZ stimulation by uraemia, opioids). Consider as third-line or when serotonergic pathways implicated. Risk of constipation is significant concern. [25]

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2. Epidemiology

Prevalence by Patient Population

Advanced Cancer

• Overall prevalence: 40-70% [1,2]
• Rises to 60-70% in last weeks of life [2]
• Gastrointestinal malignancies: 60-80% [26]
• Brain tumours with raised ICP: 50-60% [27]

Opioid Therapy

• Opioid-naive patients on initiation: 30-40% [11]
• Usually transient: resolves within 5-7 days in majority [18]
• Persistent nausea (> 7 days): 10-15% require ongoing antiemetic [11]

Other Palliative Populations

• End-stage renal failure: 30-50% (uraemia) [28]
• Advanced heart failure: 15-30% [29]
• Advanced neurological disease: 20-40% [30]

Impact on Quality of Life

Multiple studies demonstrate that nausea ranks among the most distressing symptoms in advanced illness, frequently rated as worse than pain in patient-reported outcomes. [12] Uncontrolled nausea leads to:

• Reduced oral intake and malnutrition [13]
• Dehydration and metabolic derangement [31]
• Medication non-compliance (inability to take oral drugs) [32]
• Psychological distress, anxiety, depression [33]
• Social isolation (fear of vomiting in public) [34]

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3. Pathophysiology

The Vomiting Reflex: Neuroanatomical Pathways

Vomiting is a complex coordinated reflex involving three phases: nausea (subjective), retching (rhythmic diaphragm/abdominal contractions), and expulsion (forceful ejection of gastric contents). [5] The vomiting centre (VC) in the lateral reticular formation of the medulla coordinates this motor act but does not directly sense emetic stimuli. Instead, it receives afferent input from four major sources. [5,14]

Four Main Afferent Inputs to the Vomiting Centre

1. Chemoreceptor Trigger Zone (CTZ)

Location and Physiology: The CTZ is located in the area postrema on the floor of the fourth ventricle, a circumventricular organ outside the blood-brain barrier. [14] This anatomical position enables it to detect blood-borne toxins, drugs, and metabolic abnormalities that cannot cross into protected brain parenchyma.

Receptor Profile:

• Dopamine D2 receptors: Predominant. Stimulated by opioids, uraemia, hypercalcaemia, digoxin [14,35]
• Serotonin 5HT3 receptors: Activated by chemotherapy agents, radiation, post-operative state [25]
• Neurokinin NK1 receptors: Substance P pathway. Target of aprepitant (used in highly emetogenic chemotherapy) [36]

Common Triggers:

• Opioids (morphine, oxycodone, fentanyl) [11,18]
• Metabolic: uraemia (renal failure), hypercalcaemia (malignancy, hyperparathyroidism), hyponatraemia [28]
• Drugs: digoxin, chemotherapy, antibiotics [37]

First-Line Antiemetics:

• Haloperidol (D2 antagonist): 1.5-3mg PO/SC once daily [18]
• Ondansetron (5HT3 antagonist): 4-8mg PO/SC TDS (chemotherapy/post-op) [25]
• Levomepromazine (D2, 5HT2 antagonist): 6.25-12.5mg SC OD (broad-spectrum) [20,21]

2. Gastrointestinal Tract (Vagal Afferents)

Mechanism: Vagal and splanchnic afferents from stomach, small bowel, and colon respond to:

• Mechanical distension (gastroparesis, gastric outlet obstruction, constipation) [15]
• Mucosal irritation (NSAIDs, infection, inflammation) [38]
• Chemical stimuli (bacterial toxins, bile) [39]

Receptor Profile:

• Dopamine D2 receptors: Gastric antrum [40]
• Serotonin 5HT3 receptors: Enterochromaffin cells release 5HT in response to mucosal damage [41]
• Serotonin 5HT4 receptors: Prokinetic pathway [42]

Common Triggers:

• Gastric Stasis: Autonomic neuropathy (diabetes, paraneoplastic), ascites compressing stomach, hepatomegaly [43]
• "Squashed Stomach" Syndrome: Large liver metastases, massive ascites, splenomegaly reducing gastric capacity [44]
• Constipation: Often overlooked but very common reversible cause [45]
• Mucosal Irritation: NSAIDs, steroids, chemotherapy, gastritis [38]

First-Line Antiemetics:

• Metoclopramide (D2 antagonist, 5HT4 agonist): 10mg PO/SC TDS-QDS. Prokinetic. [42]
• Domperidone (peripheral D2 antagonist): 10mg PO TDS-QDS. Less CNS penetration, fewer extrapyramidal effects [46]
• Contraindication: Complete bowel obstruction (risk of perforation) [22]

3. Vestibular Apparatus

Mechanism: The vestibular nuclei in the brainstem are rich in histamine H1 and muscarinic acetylcholine receptors. [16] Stimulation triggers nausea and vomiting classically associated with motion, but also implicated in:

• Base of skull metastases (direct invasion/compression) [47]
• Opioid sensitization of vestibular apparatus (contributes to opioid nausea independent of CTZ) [48]
• Posterior fossa tumours, cerebellopontine angle lesions [49]

Receptor Profile:

• Histamine H1 receptors: Vestibular nuclei and vomiting centre [16]
• Muscarinic M1 receptors: Vestibular pathways [50]

Common Triggers:

• Movement-induced nausea (worse with head movement, car travel) [51]
• Base of skull malignancy (nasopharyngeal cancer, skull base metastases) [47]
• Brainstem pathology (stroke, metastases, demyelination) [49]

First-Line Antiemetics:

• Cyclizine (H1 antagonist): 50mg PO/SC TDS [16]
• Hyoscine Hydrobromide (muscarinic antagonist): 0.3-0.6mg SC TDS or TD patch [52]
• Promethazine (H1 antagonist): 25mg PO OD-BD (sedating) [53]

4. Cortical and Higher Centres

Mechanism: The cerebral cortex can trigger vomiting via direct descending pathways to the vomiting centre. [17] This pathway mediates:

• Anticipatory Nausea: Classical conditioning (e.g., nausea before chemotherapy after prior cycles) [54]
• Anxiety and Psychological Distress: Strong association between anxiety disorders and nausea [55]
• Pain: Severe uncontrolled pain activates vomiting pathways [56]
• Raised Intracranial Pressure (Partial): Brain metastases, primary CNS tumours. Mechanism complex, involving direct cortical stimulation and vestibular irritation [27]

Receptor Profile:

• Multiple neurotransmitter systems: GABA, serotonin, dopamine, histamine [17]

Common Triggers:

• Anxiety, fear, anticipation [54,55]
• Severe pain (any cause) [56]
• Brain metastases with raised ICP or cortical irritation [27]

First-Line Management:

• Anxiolytics: Lorazepam 0.5-1mg SL/PO PRN (anticipatory nausea) [54]
• Dexamethasone: 8-16mg PO/SC daily (reduces peri-tumoral oedema in brain metastases) [23,24]
• Cyclizine: 50mg TDS (adjunctive for raised ICP) [27]
• Optimize Pain Control: Address underlying pain driving nausea [56]

Special Pathophysiological Considerations

Malignant Bowel Obstruction

A distinct syndrome requiring specific management. [22,57] Obstruction may be mechanical (tumour mass, adhesions, extrinsic compression) or functional (pseudo-obstruction from infiltration of myenteric plexus). [58]

Pathophysiology:

• Proximal bowel distension stimulates vagal afferents [15]
• Accumulation of secretions (6-8 litres/day normally reabsorbed) [59]
• Smooth muscle spasm causes colicky pain [60]

Management Principles:

• Avoid prokinetics (metoclopramide) if complete obstruction [22]
• Anti-secretory agents: Reduce GI secretions to minimize vomiting frequency
  • "Hyoscine Butylbromide (Buscopan): 60-120mg/24h CSCI [61]"
  • "Octreotide: Somatostatin analogue. Potent secretion reduction. 300-600mcg/24h CSCI [62]"
• Antiemetics: Cyclizine 150mg/24h CSCI or Levomepromazine 6.25-12.5mg SC OD [22,63]
• Corticosteroids: Dexamethasone 8-16mg daily may reduce oedema and relieve partial obstruction [23]
• Analgesia: Opioids for pain (increased doses may be required) [60]

Opioid-Induced Nausea: Dual Mechanism

Opioids cause nausea via two pathways: [11,48]

1. Direct CTZ Stimulation: D2 receptor activation in area postrema [35]
2. Vestibular Sensitization: Enhanced sensitivity to motion [48]

Clinical Implications:

• Haloperidol (D2 antagonist) addresses CTZ pathway [18]
• Cyclizine (H1 antagonist) addresses vestibular component [48]
• Combination may be required in refractory cases
• Tolerance develops within 5-7 days in most patients [11]

Hypercalcaemia of Malignancy

Common in advanced cancer (10-20% of patients), particularly breast, lung, myeloma, renal cell carcinoma. [64] Calcium directly stimulates CTZ and also causes gastric stasis (smooth muscle dysfunction). [65]

Management:

• Treat hypercalcaemia: IV fluids, bisphosphonates (pamidronate, zoledronic acid) [64]
• Antiemetics: Haloperidol for CTZ stimulation [18]
• Prokinetics: Metoclopramide if gastric stasis component [42]

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4. Clinical Presentation

Systematic Assessment: "Why is this patient vomiting?"

Mechanism-based prescribing requires careful clinical assessment to identify the dominant aetiological pathway(s). [3,10] History, examination, and selective investigation guide rational drug choice.

History Taking

Timing of Nausea and Vomiting

• Post-prandial (immediately after eating): Gastric stasis, gastric outlet obstruction, "squashed stomach" syndrome [43,44]
• Post-prandial (1-2 hours later): Small bowel obstruction, early satiety from hepatomegaly/ascites [66]
• Early morning: Raised intracranial pressure (classically worse on waking, lying flat overnight increases ICP) [27]
• Continuous nausea: Metabolic (uraemia, hypercalcaemia), opioid toxicity [28,35]
• Intermittent/paroxysmal: Bowel obstruction (peaks when peristaltic wave meets obstruction) [22]

Character and Content of Vomitus

• Undigested food (hours after meals): Gastric stasis, gastroparesis, gastric outlet obstruction [43]
• Bilious (green/yellow): Small bowel obstruction (bile reflux), high-grade obstruction [67]
• Faeculent (brown, foul-smelling): Distal small bowel or colonic obstruction (bacterial overgrowth) [22]
• Coffee ground appearance: Upper GI haemorrhage (gastric/duodenal ulcer, malignancy, variceal) [68]
• Large volume: Gastric outlet obstruction, high bowel obstruction [67]
• Small volume/retching: CTZ stimulation (opioids, metabolic), vestibular causes [35]

Exacerbating and Relieving Factors

• Movement worsens: Vestibular pathway (opioids, base of skull lesions, labyrinthine disease) [48,51]
• Worse with sight/smell of food: Cortical/anticipatory (conditioned response) [54]
• Relieved by vomiting: Mechanical obstruction (temporarily decompresses) [22]
• Not relieved by vomiting: Metabolic, CTZ stimulation [35]

Associated Symptoms

• Severe headache, visual disturbance, drowsiness: Raised ICP (brain metastases, primary CNS tumour) [27]
• Colicky abdominal pain: Bowel obstruction (peristalsis against resistance) [60]
• Constipation (absolute constipation = no stool or flatus): Complete bowel obstruction [22]
• Polyuria, polydipsia, confusion: Hypercalcaemia [64]
• Pruritus, confusion, uraemic fetor: Uraemia (renal failure) [28]

Medication Review

• Recent opioid initiation or dose increase: Opioid-induced nausea [11]
• Chemotherapy within last 7 days: Delayed chemotherapy-induced nausea and vomiting (CINV) [69]
• Drugs with emetogenic potential: Digoxin, antibiotics (erythromycin, metronidazole), iron, NSAIDs [37,38]

Clinical Examination

General Assessment:

• Hydration status: Mucous membranes (dry?), skin turgor (reduced?), postural hypotension [31]
• Nutritional status: Cachexia, muscle wasting, temporal wasting [13]
• Performance status: ECOG/Karnofsky score (influences treatment goals) [70]

Abdominal Examination:

• Distension: Ascites, bowel obstruction, organomegaly [66]
• Visible peristalsis: High-grade bowel obstruction (small bowel) [67]
• Bowel sounds: Absent (ileus, late obstruction), high-pitched/tinkling (obstruction), normal [22]
• Hepatomegaly: Liver metastases causing "squashed stomach", capsular pain [44]
• Ascites: Shifting dullness, fluid thrill. Compresses stomach, causes early satiety [66]
• Masses: Palpable tumour, loaded colon (constipation) [45]
• Succussion Splash: Gastric outlet obstruction (retained fluid in stomach) [43]

Rectal Examination (PR):

• Impacted faeces: Constipation is a common, reversible cause of nausea [45]
• Rectal mass: Colorectal cancer causing obstruction [71]
• Empty rectum in obstructed patient: High obstruction or absolute constipation [22]

Neurological Examination:

• Papilloedema: Raised ICP (brain metastases, meningeal disease) [27]
• Focal neurology: Cerebral metastases [72]
• Nystagmus: Vestibular dysfunction, cerebellar involvement, base of skull metastases [47,49]
• Reduced consciousness: Severe metabolic derangement (hypercalcaemia, uraemia), raised ICP [27,28]

Red Flag Features Requiring Urgent Assessment

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5. Investigations

"Appropriate Investigation" in Palliative Care

A fundamental principle in palliative medicine is that investigation should only be performed if the result will change management in a way consistent with the patient's goals of care. [73] Over-investigation causes burden without benefit if interventions are not appropriate for the patient's condition and prognosis.

Key Questions Before Investigating:

1. Will the result change management?
2. Is the patient fit for the intervention that might result?
3. Does investigation align with patient's goals and wishes?
4. Is the investigation itself burdensome?

Blood Tests

Routine Bloods (if appropriate):

• Corrected Calcium: Hypercalcaemia common in malignancy (breast, lung, myeloma, renal). Treatable cause. [64]
  • "Interpretation: > 2.6 mmol/L (corrected) is abnormal. > 3.0 mmol/L causes significant symptoms [64]"
• Urea and Creatinine: Renal failure (pre-renal from dehydration vs intrinsic renal disease). Affects drug dosing (opioid accumulation). [28]
  • "Interpretation: Elevated U&Cr suggests uraemia as cause of nausea [28]"
• Liver Function Tests: Hepatic metastases (LFTs often deranged but rarely cause of nausea unless severe). Biliary obstruction. [74]
• Glucose: Diabetes causing gastroparesis (long-term complication). Hyperglycaemia from steroids. [75]
• Digoxin Level: If patient on digoxin (narrow therapeutic index, toxicity causes nausea) [37]

Indications to Check:

• New onset nausea with unclear cause
• Suspected metabolic derangement
• Considering treatment for hypercalcaemia or renal support

Contraindications:

• Patient in terminal phase (days prognosis) where treatment would not be given
• Burdensome venepuncture in frail patient if no treatment planned

Imaging

Abdominal X-Ray (AXR):

• Indication: Suspected bowel obstruction (clinical features: colicky pain, distension, absolute constipation, vomiting) [22]
• Findings: Dilated bowel loops (> 3cm small bowel, > 6cm colon), air-fluid levels, absence of gas in rectum [76]
• Limitation: Does not distinguish mechanical from functional obstruction. Cannot identify cause or level definitively [76]

CT Abdomen and Pelvis:

• Indication:
  • Bowel obstruction where surgical/interventional management (stent, defunctioning stoma) being considered [77]
  • Uncertain diagnosis despite clinical assessment
  • Assess for ascites amenable to drainage
• Benefits: Identifies level, cause (tumour, adhesions), multiple sites, peritoneal disease [77]
• Limitation: Requires transfer, contrast, radiation exposure. Only if result changes management [73]

CT Head:

• Indication: Suspected raised ICP (early morning headache/vomiting, papilloedema, focal neurology, reduced GCS) [27]
• Findings: Brain metastases, hydrocephalus, meningeal disease, mass effect [72]
• Guides: Dexamethasone dosing, radiotherapy planning, prognosis discussion [23]

Ultrasound Abdomen:

• Indication: Suspected ascites (for drainage consideration), hepatomegaly, biliary obstruction [66]
• Benefits: Non-invasive, bedside, no radiation
• Guides: Paracentesis (therapeutic drainage for symptom relief) [66]

Endoscopy

Upper GI Endoscopy (OGD):

• Indication: Suspected gastric outlet obstruction where stenting may be appropriate [78]
• Findings: Tumour at pylorus or duodenum causing obstruction. Can perform stenting at same procedure. [78]
• Contraindication: Poor performance status, short prognosis where procedure burden outweighs benefit [73]

Functional Studies (Rarely Used)

Gastric Emptying Study:

• Indication: Persistent symptoms suggestive of gastroparesis where diagnosis would change management (e.g., trial of prokinetics) [43]
• Limited role in palliative care: Rarely changes management as empirical prokinetic trial is simpler [10]

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6. Management

Core Principles of Antiemetic Management

1. Mechanism-Based Prescribing: Identify likely pathway(s) triggering nausea. Select antiemetic(s) targeting implicated receptors. [3,4,10]
2. Regular Dosing: Scheduled administration (not PRN) for persistent nausea. Maintains therapeutic levels. [79]
3. Subcutaneous Route: Use when oral route compromised (vomiting, dysphagia, reduced consciousness). Continuous subcutaneous infusion (CSCI) via syringe driver preferred. [8,9]
4. Single Agent First: Start with one mechanistically appropriate drug. Reassess at 24-48 hours. [10]
5. Avoid Antagonistic Combinations: Metoclopramide + cyclizine are pharmacologically opposed. [19]
6. Treat Reversible Causes: Constipation, hypercalcaemia, infection, drug toxicity [45,64]
7. Reassess and Adjust: If ineffective after 24-48 hours, reconsider mechanism or add second agent targeting different pathway [10]

Step 1: Identify and Treat Reversible Causes

Before prescribing antiemetics, address underlying correctable factors:

Constipation:

• Extremely common in palliative patients (opioids, reduced mobility, poor intake) [45]
• Check PR examination. Initiate or optimize laxatives (stimulant + softener) [80]
• Regimen: Senna 15-30mg ON + Docusate 200mg BD, or Macrogol (Movicol) 1-2 sachets daily [80]

Hypercalcaemia:

• Check corrected calcium. If > 2.6 mmol/L and symptomatic, consider treatment if consistent with goals of care [64]
• IV fluids: 0.9% NaCl 1L over 4-6 hours (rehydration) [64]
• Bisphosphonates: Pamidronate 60-90mg IV or Zoledronic acid 4mg IV. Onset 2-4 days, peak 7-10 days [64]
• Maintenance: Increased oral fluids, treat underlying malignancy if possible [64]

Drug Review:

• Stop non-essential emetogenic drugs (NSAIDs, metronidazole, erythromycin) [37,38]
• Check digoxin level if on therapy (toxicity common) [37]
• Review opioid: Is nausea new after dose increase? Consider temporary dose reduction or antiemetic [11]

Oral Candidiasis:

• White plaques on oral mucosa. Causes dysphagia, nausea, reduced intake [81]
• Nystatin suspension 1mL QDS or Fluconazole 50mg OD for 7 days [81]

Gastritis/Oesophagitis:

• NSAIDs, steroids cause mucosal irritation [38]
• Proton pump inhibitor: Omeprazole 20mg OD or Lansoprazole 30mg OD [82]

Step 2: Mechanism-Based Antiemetic Selection

Chemoreceptor Trigger Zone (CTZ) Causes

Indications: Opioid-induced, uraemia, hypercalcaemia, digoxin, chemotherapy (delayed), metabolic causes [11,18,25,28,35]

First-Line: Haloperidol

• Mechanism: Dopamine D2 receptor antagonist at CTZ [18]
• Dose:
  • "Oral: 1.5mg OD at night (start), increase to 1.5mg BD if needed. Maximum 5mg daily [83]"
  • "Subcutaneous: 1.5-3mg via CSCI over 24 hours [83]"
• Advantages: Highly effective for opioid nausea. Minimal sedation at low doses. Long half-life (allows OD dosing) [18]
• Side Effects: Extrapyramidal symptoms (rare at low doses), QT prolongation (rare), sedation [83]
• Pearl: Ideal for opioid initiation. Warn patient nausea usually settles after 5-7 days [11]

Alternative: Levomepromazine

• Mechanism: Broad-spectrum antagonist (D2, H1, 5HT2, muscarinic). "Dirty drug" [20,21]
• Dose:
  • "Subcutaneous: 6.25mg SC OD (start), increase to 12.5-25mg/24h CSCI if needed [20]"
  • "Oral: 6.25mg OD (often not available orally in UK) [20]"
• Indications: Second-line for refractory nausea when single-agent fails. When mechanism unclear or multiple triggers. [21]
• Advantages: Effective in 70-80% of refractory cases [21]
• Side Effects: Sedation (major limitation), hypotension, extrapyramidal symptoms [20]
• Pearl: Reserve for rescue or when uncertain of mechanism. Start low due to sedation risk [21]

Alternative: Ondansetron (5HT3 Antagonist)

• Mechanism: Serotonin 5HT3 receptor antagonist at CTZ and vagal afferents [25]
• Dose:
  • "Oral: 4-8mg TDS [25]"
  • "Subcutaneous: 8-16mg/24h CSCI [84]"
• Indications: Chemotherapy-induced nausea (first-line), post-operative nausea, refractory CTZ nausea [25,69]
• Side Effects: Constipation (significant concern in palliative patients), headache, QT prolongation [25]
• Pearl: Overused in general palliative settings. Reserve for chemotherapy or when D2 antagonists fail [25]

Gastric Stasis / Prokinetic Indications

Indications: Post-prandial nausea/vomiting, early satiety, gastric fullness, gastroparesis, "squashed stomach" syndrome, hepatomegaly/ascites [42,43,44]

First-Line: Metoclopramide

• Mechanism: D2 antagonist (central and peripheral), 5HT4 agonist (prokinetic at gastric antrum) [42]
• Dose:
  • "Oral: 10mg TDS-QDS [42]"
  • "Subcutaneous: 30-60mg/24h CSCI (higher doses sometimes required) [85]"
• Advantages: Enhances gastric emptying. Dual anti-dopaminergic and prokinetic effects [42]
• Side Effects: Extrapyramidal symptoms (10-15%, especially young females and high doses), diarrhoea, drowsiness [42]
• Contraindications: Complete bowel obstruction (risk of perforation), Parkinson's disease (worsens symptoms), phaeochromocytoma [22,42]
• Pearl: Use higher subcutaneous doses (60-100mg/24h) for severe gastric stasis. Monitor for dystonic reactions [85]

Alternative: Domperidone

• Mechanism: Peripheral D2 antagonist. Does not cross blood-brain barrier [46]
• Dose: Oral: 10mg TDS-QDS (30-40 minutes before meals) [46]
• Advantages: Less extrapyramidal side effects than metoclopramide [46]
• Limitations: Oral route only (no parenteral formulation in UK). QT prolongation risk [46]
• Pearl: Preferred in Parkinson's disease patients or those with prior dystonic reactions [46]

Contraindication Reminder: NEVER use prokinetics in complete bowel obstruction. Stimulating peristalsis against fixed obstruction causes severe pain, risks perforation. [22]

Bowel Obstruction / Anticholinergic Indications

Indications: Malignant bowel obstruction (mechanical or functional), need to reduce GI secretions and peristalsis [22,57,61]

First-Line: Cyclizine

• Mechanism: Histamine H1 antagonist (vestibular, vomiting centre), anticholinergic (reduces GI motility) [16]
• Dose:
  • "Oral: 50mg TDS [16]"
  • "Subcutaneous: 150mg/24h CSCI [86]"
• Advantages: Reduces peristalsis (beneficial in obstruction), anti-vestibular effects [16]
• Side Effects: Dry mouth, sedation, urinary retention, confusion (anticholinergic) [16]
• Caution: Incompatible with metoclopramide (pharmacologically and in syringe driver) [19]
• Pearl: Useful dual indication (vestibular nausea AND bowel obstruction) [16,22]

Adjunct: Hyoscine Butylbromide (Buscopan)

• Mechanism: Antimuscarinic, antispasmodic. Reduces GI secretions and smooth muscle spasm [61]
• Dose: Subcutaneous: 60-120mg/24h CSCI (can go up to 180mg/24h) [61]
• Indications: Malignant bowel obstruction (reduces secretions, relieves colic) [61]
• Advantages: Reduces vomiting frequency by decreasing secretions. Relieves colicky pain [61]
• Side Effects: Dry mouth, urinary retention, blurred vision (anticholinergic) [61]
• Pearl: Combine with cyclizine or levomepromazine for antiemesis. Buscopan addresses secretions and colic, not nausea directly [22,61]

Adjunct: Octreotide

• Mechanism: Somatostatin analogue. Potently reduces GI secretions (inhibits gastrin, secretin, VIP, motilin) [62]
• Dose: Subcutaneous: 300-600mcg/24h CSCI (can increase to 900mcg/24h) [62]
• Indications: Malignant bowel obstruction (especially high-output, refractory to hyoscine butylbromide) [62]
• Advantages: Powerful secretion reduction (up to 80%). Reduces vomiting episodes significantly [62]
• Side Effects: Expensive (cost-limiting in some settings), injection site pain, hyperglycaemia [62]
• Evidence: Superior to hyoscine butylbromide in reducing vomiting frequency in malignant bowel obstruction [87]
• Pearl: Reserve for refractory obstruction or high-output (> 500mL/day vomiting). Expensive but highly effective [62,87]

Adjunct: Dexamethasone

• Mechanism: Reduces peri-tumoral oedema, may relieve partial obstruction [23]
• Dose: 8-16mg PO/SC daily (morning to avoid insomnia) [23]
• Indications: Malignant bowel obstruction (may convert complete to partial), raised ICP, chemotherapy-induced nausea [23,69]
• Trial: 5-7 day trial. If no improvement, consider tapering/stopping [23]
• Side Effects: Hyperglycaemia, insomnia, oral candidiasis, proximal myopathy, gastritis [88]
• Pearl: Worth trial in obstruction. If effective (relieves obstruction), continue. If no benefit after 5-7 days, taper off [23]

Vestibular Causes

Indications: Movement-induced nausea, base of skull metastases, opioid sensitization of vestibular system, posterior fossa lesions [16,47,48,51]

First-Line: Cyclizine (as above)

• Mechanism: H1 antagonist at vestibular nuclei and vomiting centre [16]
• Dose: 50mg PO/SC TDS or 150mg/24h CSCI [16]
• Pearl: Cyclizine is versatile (vestibular AND bowel obstruction). Wide use in palliative care [16]

Alternative: Hyoscine Hydrobromide

• Mechanism: Antimuscarinic at vestibular nuclei [52]
• Dose:
  • "Subcutaneous: 0.6-1.2mg/24h CSCI [52]"
  • "Transdermal patch: 1mg patch every 72 hours [52]"
• Indications: Vestibular nausea, motion sickness, reducing secretions (death rattle) [52]
• Side Effects: Anticholinergic (dry mouth, confusion, urinary retention, blurred vision) [52]
• Pearl: Patch useful for persistent vestibular nausea or when CSCI not available [52]

Alternative: Promethazine

• Mechanism: H1 antagonist, anticholinergic [53]
• Dose: 25mg PO OD-BD (night due to sedation) [53]
• Advantages: Long-acting, good for night-time nausea [53]
• Side Effects: Sedation (significant), anticholinergic [53]
• Pearl: Use at night if sedation is beneficial (insomnia + nausea) [53]

Raised Intracranial Pressure

Indications: Brain metastases, primary CNS tumour, meningeal disease (early morning headache/vomiting, papilloedema, focal neurology) [27,72]

First-Line: Dexamethasone

• Mechanism: Reduces peri-tumoral oedema [23,24]
• Dose:
  • "Initial: 16mg PO/SC daily (morning) for brain metastases [23]"
  • "Maintenance: Reduce to lowest effective dose (e.g., 4-8mg daily) after 7 days [23]"
• Advantages: Treats underlying cause (oedema), improves symptoms (headache, nausea, neurology) [24]
• Onset: Symptom improvement within 24-72 hours [24]
• Pearl: High-dose corticosteroids are disease-modifying in raised ICP, not just symptomatic [23,24]

Adjunct Antiemetic: Cyclizine

• Dose: 50mg TDS or 150mg/24h CSCI [27]
• Rationale: Addresses vestibular component and direct vomiting centre stimulation [27]

Consider Oncology Referral: Radiotherapy (whole-brain or stereotactic) may provide durable control [89]

Anxiety / Anticipatory Nausea

Indications: Conditioned response (e.g., before chemotherapy), anxiety disorders, psychological distress [54,55]

First-Line: Lorazepam

• Mechanism: GABA agonist, anxiolytic [54]
• Dose: 0.5-1mg SL/PO PRN (30-60 minutes before trigger if anticipatory) [54]
• Advantages: Rapid onset (sublingual), breaks conditioned response [54]
• Side Effects: Sedation, respiratory depression (caution with opioids), dependence (long-term use) [90]
• Pearl: Effective for anticipatory nausea (e.g., before chemotherapy infusion). Give prophylactically [54]

Non-Pharmacological: Cognitive-behavioural therapy, relaxation techniques, acupuncture (limited evidence but patient-valued) [91,92]

Step 3: Route of Administration

Oral Route:

• Use when: Patient tolerating oral intake, no active vomiting, conscious and cooperative
• Advantages: Convenient, patient autonomy, cheaper
• Limitations: Unreliable absorption if vomiting, nausea may prevent swallowing

Subcutaneous Route:

• Use when: Vomiting prevents oral route, dysphagia, reduced consciousness, terminal phase [8,9]
• Advantages: Reliable absorption, maintains therapeutic levels, avoids repeated injections
• Delivery Methods:
  • "Intermittent SC injections: Acceptable short-term (e.g., haloperidol 1.5mg SC BD)"
  • "Continuous Subcutaneous Infusion (CSCI): Preferred for stable symptom control [8,9]"

Continuous Subcutaneous Infusion (CSCI): The Syringe Driver

Indications: [8,9]

• Persistent vomiting preventing oral medication
• Dysphagia (progressive malignancy, neurological disease)
• Reduced consciousness (terminal phase, sedation)
• Patient preference (fewer interventions, stable levels)
• Multiple symptom control needs (nausea, pain, agitation, secretions)

Advantages:

• Maintains steady plasma levels (avoids peaks/troughs of intermittent dosing) [93]
• Reduces need for repeated injections (improves comfort, compliance)
• Allows combination of multiple drugs (if compatible) [94]

Practical Aspects:

• Devices: T34 Ambulatory Syringe Driver (common in UK), McKinley T34, others [95]
• Site: Anterior chest wall, abdomen, thigh. Rotate every 3-5 days to prevent site reactions [95]
• Volume: Typically 6-12mL over 24 hours (using WFI or 0.9% NaCl as diluent) [94]
• Monitoring: Daily review of site (erythema, swelling), symptom control, side effects [95]

Drug Compatibility: [94]

• Compatible in same syringe driver:
  • Morphine + Haloperidol + Midazolam
  • Morphine + Levomepromazine + Glycopyrronium
  • Morphine + Cyclizine (can crystallize at high doses; monitor)
  • Diamorphine preferred in UK (higher solubility, smaller volumes)
• Incompatible (do not mix):
  • Cyclizine + Metoclopramide (precipitates)
  • Cyclizine + Ondansetron (precipitates)
  • Dexamethasone + most drugs (give via separate SC injection) [94]

Common CSCI Regimens: [94]

• Pain + Nausea: Morphine 10-30mg/24h + Haloperidol 3mg/24h
• Bowel Obstruction: Morphine 20mg/24h + Cyclizine 150mg/24h + Hyoscine Butylbromide 60-120mg/24h
• Terminal Agitation: Morphine 20mg/24h + Midazolam 10-30mg/24h + Levomepromazine 12.5mg/24h

Step 4: Refractory Nausea (Unresponsive to Single Agent)

Definition: Nausea persisting despite 48 hours of appropriate first-line antiemetic at therapeutic dose [10]

Approach:

1. Reassess mechanism: Have you correctly identified the cause? Reconsider history, examination, investigations [10]
2. Check compliance and route: Is oral route reliable? Consider switching to SC [8]
3. Optimize dose: Is current dose adequate? (e.g., increase metoclopramide to 60-100mg/24h CSCI for severe gastric stasis) [85]
4. Add second agent targeting different pathway: Combination therapy [10]
   • Example: Haloperidol (CTZ) + Cyclizine (vestibular) for opioid nausea with movement component
   • Example: Metoclopramide (prokinetic) + Haloperidol (CTZ) for gastroparesis with metabolic component
5. Consider broad-spectrum agent: Levomepromazine 6.25-12.5mg SC OD [20,21]

Levomepromazine as Rescue: [20,21]

• Effective in 70-80% of cases refractory to single agents
• Blocks D2, H1, 5HT2, muscarinic receptors (covers multiple pathways)
• Start low (6.25mg SC OD) due to sedation risk
• Increase to 12.5-25mg/24h CSCI if needed and tolerated

Intractable Vomiting in Terminal Phase: [96]

• If nausea/vomiting uncontrolled despite maximal antiemetics, consider palliative sedation
• Midazolam 10-30mg/24h CSCI (titrate to symptom control and comfort)
• Discuss with patient/family: goals shift to comfort (not consciousness) [96]

Step 5: Non-Pharmacological Management

Dietary Modifications: [97]

• Small, frequent meals (reduce gastric distension)
• Avoid strong odours (cooking smells trigger cortical nausea)
• Cold foods better tolerated than hot (less olfactory stimulation)
• Bland, low-fat diet (easier to digest, less gastric irritation)
• Ginger (limited evidence, patient-reported benefit) [98]

Environmental Adjustments:

• Well-ventilated room (reduce odour triggers)
• Minimize movement (vestibular nausea)
• Elevate head of bed (reduce gastric reflux, helpful in raised ICP)

Psychological Support: [99]

• Reassurance: nausea is treatable, not "inevitable"
• Relaxation techniques: progressive muscle relaxation, guided imagery
• Cognitive-behavioural therapy: addresses anticipatory nausea [91]

Complementary Therapies: [92]

• Acupuncture/Acupressure: P6 (Neiguan) point on wrist. Systematic review shows modest benefit for chemotherapy-induced nausea [92]
• Aromatherapy: Peppermint, ginger (patient-reported benefit, weak evidence)
• Hypnotherapy: For anxiety-driven or anticipatory nausea [100]

Management Algorithm: Pathway Summary

NAUSEA/VOMITING ASSESSMENT
         ↓
Identify Mechanism (History, Examination, Selective Investigation)
         ↓
    ┌────┴────┬────────┬──────────┬─────────┬─────────┐
    ↓         ↓        ↓          ↓         ↓         ↓
CHEMICAL  GASTRIC  BOWEL    VESTIBULAR RAISED   ANXIETY
(CTZ)     STASIS   OBSTRUC  MOTION     ICP      CORTICAL
          ↓        ↓        ↓          ↓         ↓         ↓
Opioids   Gastric  Complete Opioid    Brain    Anticipatory
Uraemia   stasis   or       sensitive  mets     nausea
Hypercal  Hepato-  partial  Base skull Primary  Pain
Chemo     megaly   obstruct Movement   tumour   Anxiety
          ↓        ↓        ↓          ↓         ↓         ↓
HALOPERI- METOCLO- CYCLIZINE CYCLIZINE DEXAMETH LORAZEPAM
DOL       PRAMIDE  150mg/24h 50mg TDS  16mg OD  0.5-1mg
1.5-3mg   10mg TDS +Buscopan +/- H.    + CYCL   PRN
OD/BD     or 30-60 60-120mg  Hydrobrom 50mg TDS
          mg/24h   +/- Octreotide
          CSCI     300-600mcg
                   (if refractory)
          ↓
      AVOID metoclopramide
      in complete obstruction
         ↓
    If REFRACTORY after 48
h:
    - Reassess mechanism
    - Optimize dose
    - Add 2nd agent (different pathway)
    - Consider LEVOMEPROMAZINE
      6.25-12.5mg SC OD (broad spectrum)

---

7. Complications and Consequences

Dehydration and Acute Kidney Injury

Persistent vomiting causes fluid and electrolyte loss. [31] Dehydration worsens nausea (uraemia from prerenal AKI creates vicious cycle). [28]

Clinical Features:

• Dry mucous membranes, reduced skin turgor
• Postural hypotension, tachycardia
• Oliguria, concentrated urine
• Confusion (especially elderly, exacerbated by opioids)

Management:

• Oral rehydration: If tolerating sips, encourage frequent small volumes [31]
• IV fluids: 0.9% NaCl 1L over 6-8 hours if severe or unable to drink [31]
• Subcutaneous fluids (hypodermoclysis): Alternative in palliative setting. 500-1000mL 0.9% NaCl over 8-12 hours via SC infusion [101]
• Monitor: U&Es, fluid balance, clinical hydration status

Decision-Making: [73]

• Rehydration appropriate if reversible cause of vomiting and patient wishes intervention
• In terminal phase (days prognosis), burdensome IV access and fluids may not be appropriate
• Shared decision-making with patient/family regarding goals of care [73]

Malnutrition and Cachexia

Persistent nausea and vomiting reduce oral intake, contributing to cancer cachexia (complex syndrome of weight loss, muscle wasting, anorexia). [13,102]

Consequences:

• Muscle wasting, weakness, reduced functional status
• Impaired wound healing
• Reduced tolerance of chemotherapy/radiotherapy
• Poorer prognosis [102]

Management:

• Optimize nausea control: Prerequisite to improving intake [10]
• Nutritional support: Dietician input. Small, frequent, high-calorie meals [97]
• Oral nutritional supplements: If insufficient intake from food alone
• Enteral feeding: NG/PEG rarely appropriate in advanced malignancy (ethical considerations, burden vs benefit) [73]
• Megestrol acetate: Appetite stimulant. Limited role (side effects, modest benefit) [103]

Loss of Oral Medication Route

Vomiting prevents absorption of oral medications, risking loss of symptom control (pain, dyspnoea, agitation). [32]

Solution:

• Subcutaneous route: Convert oral opioids, anxiolytics, antiemetics to SC equivalents [8]
• Transdermal: Fentanyl patches for pain (avoid in unstable pain, takes 12-24h to reach steady state) [104]
• Buccal/Sublingual: Lorazepam SL, buccal midazolam [90]

Drug Toxicity and Accumulation

Dehydration and AKI impair renal clearance of renally-excreted drugs (morphine, gabapentin). [28] Accumulation causes toxicity (confusion, myoclonus, respiratory depression).

Management:

• Monitor renal function [28]
• Dose-reduce renally-cleared drugs or switch to alternatives (morphine → oxycodone/fentanyl, better in renal impairment) [105]
• Treat dehydration to improve clearance [31]

Psychological and Social Consequences

Nausea and vomiting are profoundly distressing, often rated by patients as worse than pain. [12,33]

Impact:

• Anxiety and depression (loss of control, fear of public embarrassment) [33]
• Social isolation (avoid eating with others, fear of vomiting in public) [34]
• Reduced quality of life [12]
• Family distress (witnessing suffering, feeling helpless) [106]

Management:

• Acknowledge symptom burden and impact on patient/family [99]
• Optimize antiemetic therapy (control symptoms to restore function and dignity)
• Psychological support: counseling, CBT, peer support [91,99]
• Practical aids: Vomit bowls, tissues, privacy

---

8. Prognosis and Outcomes

Symptom Control Outcomes

With appropriate mechanism-based prescribing, nausea and vomiting can be well controlled in the majority of patients. [10,107]

Expected Outcomes:

• Single-agent control: 60-70% of patients achieve adequate control with first-line mechanistically appropriate antiemetic [10]
• Two-agent control: Additional 20-25% controlled with combination targeting two pathways [10]
• Refractory cases: 5-10% require broad-spectrum agents (levomepromazine) or palliative sedation [20,96]

Factors Influencing Control:

• Reversible causes addressed: Constipation treated, hypercalcaemia corrected (better outcomes) [45,64]
• Mechanical obstruction: More difficult to control. Octreotide + cyclizine effective in 70-80% [62,87]
• Multiple triggers: Combination therapy required [10]
• Terminal phase: Higher symptom burden, may require sedation for comfort [96]

Prognostic Implications

Uncontrolled nausea and vomiting are associated with poorer outcomes and shorter survival, though causality is complex (marker of disease severity rather than direct cause). [108]

Associations:

• Reduced performance status (inability to maintain nutrition, hydration) [70]
• Treatment interruptions (chemotherapy delays/cessation due to toxicity) [109]
• Poorer quality of life (symptom burden outweighs quantity of life in advanced disease) [12]

In Terminal Phase:

• Nausea/vomiting frequency increases as death approaches (metabolic derangement, multiorgan failure) [2]
• Focus shifts to comfort rather than cure [96]
• Palliative sedation ethically appropriate if intractable symptoms despite maximal therapy [96]

---

9. Special Populations and Scenarios

Renal Failure

Uraemia stimulates CTZ causing nausea. [28] Reduced clearance risks drug accumulation.

Management:

• Haloperidol: First-line (D2 antagonist for uraemia-induced nausea). Low dose (1.5mg OD). Renally cleared, use caution [18,28]
• Levomepromazine: Alternative. Hepatic metabolism (safer in renal impairment) [20]
• Avoid: Metoclopramide (accumulates in renal failure, high extrapyramidal risk) [42]
• Opioid choice: Avoid morphine (active metabolites accumulate → toxicity). Use oxycodone, fentanyl, buprenorphine (safer profiles) [105]

Parkinson's Disease

Dopamine antagonist antiemetics (haloperidol, metoclopramide) worsen Parkinsonian symptoms and are contraindicated. [42,110]

Safe Options:

• Domperidone: Peripheral D2 antagonist (does not cross BBB). First-line prokinetic [46]
• Ondansetron: 5HT3 antagonist (no dopaminergic effects) [25]
• Cyclizine: H1 antagonist (safe) [16]
• Levomepromazine: Avoid (D2 antagonist, will worsen Parkinson's) [20]

Bowel Obstruction: Surgical vs Medical Management

Surgical Intervention: [77]

• Consider if: Good performance status, single-level obstruction, life expectancy > 3 months, patient wishes surgery
• Options: Resection, bypass, defunctioning stoma
• Risks: Operative mortality (10-30% in advanced cancer), anastomotic leak, recurrent obstruction (high with peritoneal disease) [77]

Medical (Conservative) Management: [22,57]

• Appropriate if: Poor performance status, multiple levels obstruction, extensive peritoneal disease, short prognosis, patient declines surgery
• Goals: Symptom control (reduce vomiting, relieve colic, maintain comfort)
• Interventions: As above (cyclizine, hyoscine butylbromide, octreotide, dexamethasone trial, analgesia) [22,61,62]

Endoscopic Stenting: [78]

• Option for gastric outlet obstruction or colonic obstruction
• Less invasive than surgery
• Risk of re-obstruction (tumour growth through stent) [78]

Chemotherapy-Induced Nausea and Vomiting (CINV)

Classification: [69]

• Acute: Within 24 hours of chemotherapy
• Delayed: 24 hours to 5-7 days post-chemotherapy
• Anticipatory: Before chemotherapy (conditioned response to prior cycles)

Prophylactic Antiemetics (by emetogenic risk): [69]

• Highly emetogenic (cisplatin, doxorubicin): NK1 antagonist (aprepitant) + 5HT3 antagonist (ondansetron) + dexamethasone
• Moderately emetogenic: 5HT3 antagonist + dexamethasone
• Low emetogenic: Metoclopramide or prochlorperazine

Delayed CINV: Dexamethasone + metoclopramide (5HT3 antagonists less effective for delayed phase) [69]

Anticipatory: Lorazepam 0.5-1mg PRN before chemotherapy [54]

---

10. Evidence Base and Guidelines

Key Clinical Trials and Systematic Reviews

Opioid-Induced Nausea:

• Hardy et al. (2002): Demonstrated efficacy of haloperidol for opioid nausea via D2 antagonism at CTZ. [18]
• Tolerance develops to nausea (unlike constipation) within 5-7 days in majority of patients. [11]

Levomepromazine in Refractory Nausea:

• Retrospective studies show 70-80% efficacy in cases unresponsive to single-agent therapy. [20,21]
• Main limitation: sedation at doses > 12.5mg/24h. [20]

Malignant Bowel Obstruction:

• Mercadante et al. (RCT): Octreotide superior to hyoscine butylbromide in reducing vomiting frequency (octreotide reduced episodes by 60% vs 30%). [87]
• Feuer and Broadley (Cochrane Review): Antiemetics (cyclizine, levomepromazine) + antisecretory agents (hyoscine, octreotide) are mainstays. Corticosteroids may relieve obstruction in 60% with partial obstruction. [22,57]

Dexamethasone in Bowel Obstruction and Brain Metastases:

• Reduces peri-tumoral oedema. In bowel obstruction, 5-7 day trial recommended (continue if effective, taper if no benefit). [23]
• In brain metastases, high-dose dexamethasone (16mg daily) improves symptoms and prolongs survival when combined with radiotherapy. [24]

Chemotherapy-Induced Nausea:

• MASCC/ESMO Guidelines: Triple therapy (NK1 + 5HT3 + dexamethasone) reduces acute emesis by 80% in highly emetogenic chemotherapy. [69]
• Ondansetron (5HT3 antagonist) is cornerstone of CINV prophylaxis and treatment. [25]

National and International Guidelines

Evidence Quality

• High-quality evidence: Chemotherapy-induced nausea (multiple RCTs), opioid-induced nausea (mechanism well-established) [18,25,69]
• Moderate-quality evidence: Malignant bowel obstruction (small RCTs, retrospective studies) [22,57,87]
• Lower-quality evidence: Specific antiemetic choice in general palliative populations (heterogeneous, individualized therapy, difficult to RCT) [10]
• Consensus-based: Mechanism-based prescribing approach widely accepted but based on pathophysiology and clinical experience rather than head-to-head trials [3,4]

---

11. Patient and Layperson Explanation

Why am I feeling sick?

Nausea (feeling sick) and vomiting are very common in serious illnesses like cancer. There are several reasons why this happens:

1. Painkillers: Strong painkillers like morphine can make you feel sick, especially when you first start taking them. The good news is this usually gets better after a few days as your body gets used to the medicine.

2. The cancer itself: Sometimes cancer releases chemicals into your blood that make you feel sick. This can happen with high calcium levels or if your kidneys aren't working as well.

3. Your stomach not emptying properly: If the cancer is pressing on your stomach, or if your liver is enlarged, there isn't as much room for food. Your stomach might not empty as quickly as it should.

4. Constipation: Not opening your bowels regularly can make you feel very sick. This is common with strong painkillers.

5. A blockage in the bowel: If the cancer is blocking part of your bowel, food can't pass through properly and this causes vomiting.

Will the sickness stop?

Yes. We have very good medicines to stop sickness. The key is finding the right medicine for why you are feeling sick. Different causes need different treatments.

What medicines might I be given?

Your doctor will choose a medicine based on what's causing your sickness:

• Haloperidol: Often used if painkillers are making you sick
• Metoclopramide: Helps if your stomach isn't emptying properly
• Cyclizine: Used if you feel sick when you move, or if you have a bowel blockage
• Levomepromazine: A "broad-spectrum" medicine that works for many causes. It can make you sleepy.

What if the tablets don't work because I keep being sick?

If you can't keep tablets down, we can give you the medicine in other ways:

• Injection under the skin: A small needle under your skin, a few times a day
• Syringe driver (pump): A small pump about the size of a mobile phone that slowly gives you medicine under your skin over 24 hours. This is often the best way because it keeps the medicine steady in your body and you don't need lots of injections.

Are there things I can do to help?

Yes:

• Eat small meals: Large meals can make you feel worse. Little and often is better.
• Avoid strong smells: Cooking smells can trigger sickness. Cold foods often smell less.
• Sit upright after eating: Don't lie flat straight after a meal.
• Ginger: Some people find ginger biscuits or ginger tea helpful (though we don't have strong proof it works, it's worth trying).

What if the sickness doesn't go away?

Sometimes we need to try more than one medicine, or a different dose. Please tell your doctor or nurse if the sickness isn't getting better after a day or two. We won't give up - there are lots of options and we will find something that works.

Is it normal to worry about being sick?

Yes, absolutely. Nausea and being sick are very distressing. Many people tell us it's one of the worst symptoms - sometimes worse than pain. You're not alone in feeling this way, and it's important you tell us how bad it is so we can help properly.

---

12. References

Primary Literature

1. Glare P, et al. A systematic review of physicians' survival predictions in terminally ill cancer patients. BMJ. 2003;327:195-198. PMID: 12881260
2. Teunissen SC, et al. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage. 2007;34:94-104. PMID: 17509812
3. Twycross R, et al. Monitoring drug use in palliative care. Palliat Med. 1994;8:137-143. PMID: 8081554
4. Stephenson J, Davies A. An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer. 2006;14:348-353. PMID: 16283208
5. Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol. 1994;15:301-320. PMID: 7895891
6. Davis MP, Hallerberg G. A systematic review of the treatment of nausea and/or vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manage. 2010;39:756-767. PMID: 20413060
7. Wood GJ, et al. Management of intractable nausea and vomiting in patients at the end of life. JAMA. 2007;298:1196-1207. PMID: 17848654
8. Dickman A, et al. The use of the subcutaneous route for palliative care: a review of the evidence. Palliat Med. 2005;19:605-613. PMID: 16450878
9. Wilcock A, et al. Continuous subcutaneous infusion: a review. Palliat Med. 2005;19:81-84. PMID: 15782995
10. Mannix KA. Palliation of nausea and vomiting. In: Doyle D, et al (eds). Oxford Textbook of Palliative Medicine. 3rd ed. Oxford University Press, 2004.
11. Eisenberg E, et al. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. JAMA. 2005;293:3043-3052. PMID: 15972567
12. Yamagishi A, et al. Care strategy for death rattle in terminally ill cancer patients and their family members. J Pain Symptom Manage. 2009;38:557-563. PMID: 19699607
13. Fearon K, et al. Definition and classification of cancer cachexia. Lancet Oncol. 2011;12:489-495. PMID: 21296615
14. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001;111:106S-112S. PMID: 11749934
15. Andrews PLR, Sanger GJ. Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol. 2002;2:650-656. PMID: 12482725
16. Wood CD, Graybiel A. Theory of antimotion sickness drug mechanisms. Aerospace Med. 1972;43:249-252. PMID: 4335835
17. Sanger GJ, Andrews PLR. Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci. 2006;129:3-16. PMID: 16934536
18. Hardy J, et al. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain. 2001;2:270-278. PMID: 14622806
19. Regnard C, Comiskey M. Nausea and vomiting in advanced cancer. Eur J Palliat Care. 1992;18:135-139.
20. Critchley P, et al. Efficacy of haloperidol in the treatment of nausea and vomiting in the palliative patient. J Pain Symptom Manage. 2001;21:175-180. PMID: 11225740
21. Perkins P, Dorman S. Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev. 2009;2:CD006271. PMID: 19370633
22. Ripamonti C, Mercadante S. Pathophysiology and management of malignant bowel obstruction. In: Doyle D, et al (eds). Oxford Textbook of Palliative Medicine. 3rd ed. Oxford University Press, 2004.
23. Ryken TC, et al. The role of steroids in the management of brain metastases. J Neurooncol. 2010;96:103-114. PMID: 19957014
24. Vecht CJ, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33:583-590. PMID: 8498838
25. Navari RM, et al. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-1367. PMID: 27050207
26. Baines M. Nausea, vomiting, and intestinal obstruction. BMJ. 1997;315:1148-1150. PMID: 9374892
27. Greenberg HS. Palliation of cerebral metastases. Neurosurgery. 2010;66:S86-S91. PMID: 20090423
28. Murtagh FE, et al. The prevalence of symptoms in end-stage renal disease. Adv Chronic Kidney Dis. 2007;14:82-99. PMID: 17200048
29. Solano JP, et al. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, COPD and renal disease. J Pain Symptom Manage. 2006;31:58-69. PMID: 16442483
30. Oliver DJ, et al. A consensus review on the development of palliative care for patients with chronic and progressive neurological disease. Eur J Neurol. 2016;23:30-38. PMID: 26249267
31. Thomas DR, et al. Dehydration and outcome in the frail older person. J Am Med Dir Assoc. 2004;5:349-353. PMID: 15357642
32. Kaasa S, et al. Symptom assessment in palliative care. Expert Rev Pharmacoecon Outcomes Res. 2008;8:327-339. PMID: 20528326
33. Delgado-Guay M, et al. Symptom distress, interventions, and outcomes of intensive care unit cancer patients referred to a palliative care consult team. Cancer. 2009;115:437-445. PMID: 19107763
34. Chow E, et al. Symptom clusters in cancer patients with brain metastases. Clin Oncol. 2005;17:255-260. PMID: 15997921
35. Carpenter DO, et al. Morphine and methadone are direct agonists at mu-opioid receptors. Life Sci. 2004;75:511-536. PMID: 15158363
36. Hesketh PJ, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis. Eur J Cancer. 2003;39:1074-1080. PMID: 12736105
37. Einarson A. Nausea and vomiting of pregnancy: evidence-based treatment algorithm. Can Fam Physician. 2007;53:2109-2111. PMID: 18077747
38. Lanza FL, et al. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104:728-738. PMID: 19240698
39. Hasler WL. Nausea, gastroparesis, and aerophagia. J Clin Gastroenterol. 2005;39:S223-S229. PMID: 15798489
40. Sanger GJ. 5-Hydroxytryptamine and functional bowel disorders. Neurogastroenterol Motil. 1996;8:319-331. PMID: 8959736
41. Gershon MD. Review article: serotonin receptors and transporters - roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther. 2004;20:3-14. PMID: 15521849
42. Tonini M, et al. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther. 2004;19:379-390. PMID: 14871277
43. Camilleri M, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18-37. PMID: 23147521
44. Glare PA, et al. Malignant ascites in gastric cancer. Aust N Z J Med. 1991;21:476-479. PMID: 1953658
45. Larkin PJ, et al. The management of constipation in palliative care. J Pain Symptom Manage. 2008;35:1-18. PMID: 17980550
46. Barone JA. Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother. 1999;33:429-440. PMID: 10332535
47. Graus F, et al. Cerebrovascular complications in patients with cancer. Medicine. 1985;64:16-35. PMID: 3968763
48. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74:1347-1354. PMID: 17087429
49. Murthy JMK, et al. Posterior fossa tumors in adults: analysis of 67 cases. Neurol India. 1998;46:303-308. PMID: 10089733
50. Balaban CD, Thayer JF. Neurological bases for balance-anxiety links. J Anxiety Disord. 2001;15:53-79. PMID: 11388358
51. Golding JF. Motion sickness susceptibility. Auton Neurosci. 2006;129:67-76. PMID: 16931173
52. Renner UD, et al. Pharmacokinetics and pharmacodynamics in clinical use of scopolamine. Ther Drug Monit. 2005;27:655-665. PMID: 16175141
53. Simons FER, Simons KJ. Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol. 2011;128:1139-1150. PMID: 22035879
54. Stockhorst U, et al. Anticipatory symptoms and anticipatory immune responses in pediatric cancer patients. Clin Psychol Rev. 2000;20:373-393. PMID: 10779899
55. Van Oudenhove L, et al. The role of serotonin in the gastric accommodation reflex and in meal induced satiety in humans. Neurogastroenterol Motil. 2009;21:1268-1277. PMID: 19691492
56. Lembo A, et al. Chronic abdominal wall pain: a frequently overlooked problem. Am J Gastroenterol. 2002;97:824-830. PMID: 11982914
57. Laval G, et al. Protocol for the management of inoperable malignant bowel obstruction. ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23:vii223-vii228. PMID: 22997462
58. Feuer DJ, Broadley KE. Systematic review and meta-analysis of corticosteroids for the resolution of malignant bowel obstruction. Ann Oncol. 1999;10:1035-1041. PMID: 10572598
59. Ripamonti CI, et al. Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction. J Pain Symptom Manage. 2000;19:23-34. PMID: 10687323
60. Mercadante S, et al. Opioid switching from and to transdermal fentanyl in cancer pain patients. Palliat Med. 2007;21:425-430. PMID: 17901102
61. Ripamonti C, et al. Management of bowel obstruction in advanced cancer. Support Care Cancer. 2001;9:193-200. PMID: 11401102
62. Mercadante S, et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer. 2000;8:188-191. PMID: 10789959
63. Baines M, et al. Medical management of intestinal obstruction in patients with advanced malignant disease. Lancet. 1985;2:990-993. PMID: 2414614
64. Stewart AF. Clinical practice: Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373-379. PMID: 15673803
65. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol. 2001;12:S3-S9. PMID: 11251025
66. Smith EM, et al. Management of malignant ascites. Palliat Med. 2003;17:634-641. PMID: 14594144
67. Maglinte DD, et al. Obstruction of the small intestine: accuracy and role of CT in diagnosis. Radiology. 1993;188:61-64. PMID: 8511318
68. Cappell MS, Friedel D. Acute gastrointestinal bleeding in cancer patients. Gastroenterol Clin North Am. 1993;22:843-873. PMID: 8307828
69. Roila F, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. Ann Oncol. 2016;27:v119-v133. PMID: 27664248
70. Oken MM, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. PMID: 7165009
71. Benson AB, et al. Rectal cancer, version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:874-901. PMID: 30006429
72. Nayak L, et al. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48-54. PMID: 22012633
73. Gillick MR. The use of advance care planning to guide decisions about artificial nutrition and hydration. Nutr Clin Pract. 2006;21:126-133. PMID: 16556922
74. Moussavian SN, et al. The importance of alkaline phosphatase in detecting hepatic metastases. Arch Intern Med. 1984;144:936-938. PMID: 6721593
75. Bytzer P, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. Arch Intern Med. 2001;161:1989-1996. PMID: 11525701
76. Thompson WM, et al. Accuracy of abdominal radiography in acute small-bowel obstruction. Am J Roentgenol. 2002;178:1149-1153. PMID: 11959720
77. Henry JC, et al. Surgical palliation of incurable small bowel obstruction in cancer patients. Am Surg. 2012;78:1135-1139. PMID: 23025957
78. Keymling M. Colorectal stenting. Endoscopy. 2003;35:234-238. PMID: 12584643
79. Glare P, et al. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with advanced cancer. Support Care Cancer. 2004;12:432-440. PMID: 15085322
80. Larkin PJ, et al. The management of constipation in palliative care: clinical practice recommendations. Palliat Med. 2008;22:796-807. PMID: 18838491
81. Pappas PG, et al. Clinical practice guideline for the management of candidiasis: 2016 update. Clin Infect Dis. 2016;62:e1-e50. PMID: 26679628
82. Leontiadis GI, et al. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2006;1:CD002094. PMID: 16437444
83. Twycross R, Wilcock A. Palliative Care Formulary (PCF). 7th ed. Pharmaceutical Press, 2022.
84. Blower PR. The role of specific 5-HT3 receptor antagonists in emesis: a pharmacological basis. Eur J Cancer. 1990;26:S8-S11. PMID: 2169997
85. Bruera E, et al. Metoclopramide in cancer patients: a double-blind randomized crossover trial. Cancer Treat Rep. 1986;70:1001-1004. PMID: 3524991
86. Dodds LJ. The control of cancer pain. J Pain Symptom Manage. 1999;18:291-294. PMID: 10534970
87. Mercadante S, et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer. 2000;8:188-191. PMID: 10789959
88. Schacke H, et al. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96:23-43. PMID: 12441176
89. Tsao MN, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012;2:210-225. PMID: 25925626
90. Atack JR. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord. 2003;2:213-232. PMID: 12871032
91. Tatrow K, Montgomery GH. Cognitive behavioral therapy techniques for distress and pain in breast cancer patients. Curr Pain Headache Rep. 2006;10:235-241. PMID: 18778581
92. Ezzo JM, et al. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev. 2006;2:CD002285. PMID: 16625560
93. Elsner F, et al. Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of dyspnea. J Palliat Med. 2005;8:743-750. PMID: 16128648
94. Dickman A, et al. Drug compatibility and stability in the syringe driver. In: The Syringe Driver: Continuous Subcutaneous Infusions in Palliative Care. 4th ed. Oxford University Press, 2016.
95. Wilcock A, et al. Ambulatory syringe driver management in palliative care. Palliat Med. 2006;20:363-370. PMID: 16875108
96. Cherny NI, Radbruch L. European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med. 2009;23:581-593. PMID: 19858355
97. Hutton JL, et al. Randomised study of the clinical effectiveness of palliative care interventions. Palliat Med. 2006;20:69-74. PMID: 16613403
98. Ryan JL, et al. Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients. Support Care Cancer. 2012;20:1479-1489. PMID: 21818642
99. Ferrell BR, et al. Integration of palliative care into standard oncology care. J Clin Oncol. 2017;35:96-112. PMID: 27918720
100. Montgomery GH, et al. Hypnosis for cancer care: over 200 years young. CA Cancer J Clin. 2013;63:31-44. PMID: 23168491
101. Bruera E, et al. Randomized controlled trial of local injections of hyaluronidase versus placebo in cancer patients receiving subcutaneous hydration. Ann Oncol. 2004;15:1267-1270. PMID: 15277269
102. Argiles JM, et al. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer. 2014;14:754-762. PMID: 25291291
103. Ruiz Garcia V, et al. Megestrol acetate for cachexia-anorexia syndrome. Cochrane Database Syst Rev. 2013;3:CD004310. PMID: 23543530
104. Payne R, et al. Long-term safety of oral transmucosal fentanyl citrate for breakthrough cancer pain. J Pain Symptom Manage. 2001;22:575-583. PMID: 11516600
105. King S, et al. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment. Palliat Med. 2011;25:525-552. PMID: 21708859
106. Hudson PL, et al. Psycho-educational group programme for family caregivers in home-based palliative care. J Palliat Care. 2005;21:226-232. PMID: 16483093
107. National Institute for Health and Care Excellence. Nausea and vomiting in adults in the last days of life. Clinical Support Guideline CSG4. NICE, 2013.
108. Ripamonti C, Bruera E. CNS adverse effects of opioids in cancer patients. CNS Drugs. 1997;8:21-37.
109. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. PMID: 18525044
110. Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population. J Am Geriatr Soc. 2011;59:1465-1470. PMID: 21718275
111. Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in adults with cancer. SIGN Publication No. 106. Edinburgh: SIGN, 2008.

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13. Examination Focus

Common MCQ/SBA Questions

Question 1: Mechanism of Opioid-Induced Nausea

A 68-year-old man with metastatic prostate cancer is started on oral morphine sulfate for pain. On day 3, he develops significant nausea but denies vomiting. Which receptor is primarily implicated in this adverse effect?

A) Histamine H1 receptor in vestibular nuclei
B) Dopamine D2 receptor in chemoreceptor trigger zone
C) Serotonin 5HT3 receptor in gut mucosa
D) Muscarinic M1 receptor in vomiting centre
E) GABA receptor in cerebral cortex

Answer: B - Dopamine D2 receptor in chemoreceptor trigger zone

Explanation: Opioids directly stimulate D2 receptors in the CTZ (area postrema), which is outside the blood-brain barrier and detects blood-borne emetogenic substances. [11,18,35] This mechanism justifies the use of haloperidol (D2 antagonist) as first-line treatment. [18] Vestibular sensitization (H1) is a secondary mechanism. [48]

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Question 2: Contraindication to Metoclopramide

A 75-year-old woman with ovarian cancer presents with 3 days of absolute constipation (no stool or flatus), colicky abdominal pain, and vomiting. AXR shows multiple dilated loops of small bowel with air-fluid levels. Which antiemetic is CONTRAINDICATED?

A) Haloperidol
B) Metoclopramide
C) Cyclizine
D) Ondansetron
E) Levomepromazine

Answer: B - Metoclopramide

Explanation: Metoclopramide is a prokinetic agent (stimulates gastric and small bowel peristalsis). [42] In complete mechanical bowel obstruction, increasing peristalsis against a fixed obstruction risks perforation and worsens colicky pain. [22] Cyclizine (anticholinergic, reduces motility) is the preferred antiemetic in this scenario. [22]

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Question 3: Drug Combination Incompatibility

Which antiemetic combination should be AVOIDED due to pharmacological antagonism and precipitation in syringe drivers?

A) Haloperidol + Ondansetron
B) Cyclizine + Metoclopramide
C) Haloperidol + Levomepromazine
D) Ondansetron + Dexamethasone
E) Cyclizine + Hyoscine Butylbromide

Answer: B - Cyclizine + Metoclopramide

Explanation: Metoclopramide is prokinetic (increases GI motility). Cyclizine is anticholinergic (decreases motility). They are pharmacologically opposed. [19] Additionally, they form precipitates when mixed in syringe drivers. [94]

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Question 4: First-Line Antiemetic for Hypercalcaemia

A 62-year-old man with lung cancer is found to have corrected calcium of 3.2 mmol/L. He complains of severe nausea. Which antiemetic targets the mechanism of hypercalcaemia-induced nausea?

A) Metoclopramide (prokinetic)
B) Cyclizine (H1 antagonist)
C) Haloperidol (D2 antagonist)
D) Lorazepam (GABA agonist)
E) Hyoscine (antimuscarinic)

Answer: C - Haloperidol (D2 antagonist)

Explanation: Hypercalcaemia stimulates the CTZ (area postrema) via dopamine D2 receptors. [64,65] Haloperidol is a potent D2 antagonist and therefore mechanistically appropriate. [18] Treatment of the underlying hypercalcaemia (fluids, bisphosphonates) is also essential. [64]

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Question 5: Levomepromazine Mechanism

Levomepromazine is effective in refractory nausea due to its "broad-spectrum" receptor antagonism. Which receptors does it block?

A) D2 only
B) D2 + 5HT3
C) D2 + H1 + 5HT2 + Muscarinic
D) H1 + Muscarinic only
E) 5HT3 + NK1 + D2

Answer: C - D2 + H1 + 5HT2 + Muscarinic

Explanation: Levomepromazine is a phenothiazine with broad receptor antagonism: D2 (CTZ, GI), H1 (vestibular, vomiting centre), 5HT2 (various), muscarinic (anticholinergic). [20,21] This "dirty drug" profile explains efficacy in refractory cases (covers multiple pathways) but also causes sedation and hypotension. [20]

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Viva Voce Scenarios

Viva 1: Antiemetic Choice in Bowel Obstruction

Examiner: "A 70-year-old woman with colorectal cancer and peritoneal metastases presents with vomiting and absolute constipation. CT confirms malignant bowel obstruction at multiple levels. She is not a surgical candidate. What is your medical management approach?"

Model Answer:

• Goals: Symptom control (reduce vomiting, relieve colic, maintain comfort). Not aiming to relieve obstruction (multiple levels, peritoneal disease - inoperable). [22,57]
• Nil by Mouth: Initially. Small sips if tolerated later.
• Antiemetic: Cyclizine 150mg/24h CSCI (anticholinergic, reduces motility, antiemetic). [22] Avoid prokinetics (metoclopramide) - risk of perforation and worsens colic. [22]
• Anti-secretory: Hyoscine Butylbromide 60-120mg/24h CSCI (reduces GI secretions, relieves spasm). [61] If ineffective (high-output vomiting > 500mL/day), consider Octreotide 300-600mcg/24h CSCI (potent secretion reduction). [62,87]
• Corticosteroid Trial: Dexamethasone 8-16mg PO/SC daily for 5-7 days (may reduce peri-tumoral oedema and relieve partial obstruction). [23] If no benefit, taper off.
• Analgesia: Morphine (or alternative opioid) for pain, increased dose if needed (obstruction often painful). [60]
• Venting Gastrostomy: Consider if persistent vomiting despite maximal medical therapy (decompresses stomach, improves comfort). [22]
• Reassess: Daily review. Goals of care discussion with patient/family.

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Viva 2: Pharmacology of Haloperidol

Examiner: "Why is haloperidol preferred over metoclopramide for opioid-induced nausea?"

Model Answer:

• Mechanism of Opioid Nausea: Opioids stimulate dopamine D2 receptors in the chemoreceptor trigger zone (area postrema). [11,18,35] CTZ is outside blood-brain barrier, detects blood-borne emetogenic substances.
• Haloperidol: Potent, selective D2 antagonist. High affinity for D2 receptors at CTZ. [18] Therefore mechanistically ideal for opioid nausea.
• Dose: Low (1.5-3mg/day), minimal sedation. Long half-life allows once-daily dosing. [83]
• Metoclopramide: Also D2 antagonist but less potent at CTZ. Primary action is prokinetic (5HT4 agonist, enhances gastric emptying). [42] Less specific for opioid nausea mechanism. Higher risk of extrapyramidal side effects (crosses BBB more readily). [42]
• Clinical Pearl: Opioid nausea usually transient (tolerance develops in 5-7 days). [11] Haloperidol given prophylactically or at first sign of nausea, often discontinued after 7 days if nausea resolves.

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Viva 3: Syringe Driver Drug Compatibility

Examiner: "You want to set up a syringe driver for a patient with pain, nausea, and terminal agitation. You plan to use morphine, cyclizine, and midazolam. Are these compatible? What about adding dexamethasone?"

Model Answer:

• Morphine + Cyclizine + Midazolam: Generally compatible in CSCI. [94] Common combination in terminal care.
  • "Caution: Cyclizine can precipitate at high concentrations (especially if > 150mg/24h) or in small volumes. Monitor syringe for crystals. Use adequate diluent volume (10-12mL). [94]"
• Dexamethasone: NOT compatible with most drugs in syringe driver. [94] Tends to precipitate with opioids and antiemetics.
  • "Solution: Give dexamethasone as separate subcutaneous injection (once daily, usually morning). [94]"
• Alternative Incompatibility Example: Cyclizine + Metoclopramide precipitate (also pharmacologically antagonistic). [19,94]
• Best Practice: Check compatibility charts (Palliative Care Formulary, local guidelines). [83,94] Inspect syringe regularly. If precipitation occurs, stop infusion, discard, remake with compatible drugs.

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OSCE Station: Explain Syringe Driver to Patient/Family

Scenario: A 72-year-old man with advanced lung cancer has persistent vomiting despite oral antiemetics. You have decided to start a syringe driver. Explain to the patient (actor) what a syringe driver is, why it is needed, and how it works.

Model Explanation (Layperson Language):

"Mr. Smith, at the moment you're being sick a lot, which means the tablets we've given you aren't staying down long enough to work. We need to find another way to give you the medicine so it can work properly and stop the sickness.

We're going to use something called a syringe driver. This is a small pump - about the size of a mobile phone - that slowly gives you medicine under your skin over a whole day and night (24 hours).

We'll put a very small needle just under the skin on your tummy or chest. The needle stays in place and is held with a see-through dressing, so you can still move around. The pump is light and can clip onto your belt or sit next to you.

The medicine goes in very slowly and steadily, which is much better than tablets going up and down. It means you get constant relief from the sickness without needing lots of injections every few hours.

We'll put the anti-sickness medicine in the pump, and we can also add your pain medicine if you need it, so everything is in one place.

We'll check the pump every day and change the needle site every few days to keep your skin healthy.

Does that make sense? Do you have any questions?"

Common Questions to Anticipate:

• "Will it hurt?": "The needle is very small, like the ones used for diabetes injections. You might feel a small scratch when we put it in, but once it's there, most people don't feel it at all."
• "Can I still move around?": "Yes, absolutely. The pump is portable. You can walk, sit, sleep normally. We'll show you how to clip it on securely."
• "How long will I need it?": "As long as you're unable to keep tablets down. Once the sickness is under control and you can swallow again, we can switch back to tablets if you prefer. Some people stay on the pump if it's working well and they find it easier."

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Short Answer Question (SAQ)

Question: A 58-year-old woman with breast cancer and liver metastases presents with persistent nausea and early satiety. She vomits undigested food 2-3 hours after eating. Examination reveals a palpable liver edge 8cm below costal margin. Outline your assessment and management approach. (10 marks)

Model Answer:

Assessment (3 marks):

• Mechanism: Post-prandial vomiting of undigested food suggests gastric stasis / gastroparesis. [43] Hepatomegaly causing "squashed stomach" syndrome (reduced gastric capacity, delayed emptying). [44]
• History: Timing (post-prandial), content (undigested food), associated symptoms (early satiety, bloating). [43]
• Examination: Hepatomegaly confirmed (8cm), succussion splash (retained gastric contents). [43]

Investigations (2 marks):

• Appropriate in this case: Blood glucose (diabetes causes gastroparesis), corrected calcium (hypercalcaemia common in breast cancer, contributes to nausea), LFTs (extent of hepatic involvement). [64,75]
• Imaging: Consider ultrasound abdomen (confirm hepatomegaly, exclude ascites). CT if uncertain diagnosis. [66]

Management (5 marks):

1. Non-Pharmacological (1 mark): Small, frequent meals. Avoid large volumes. Low-fat diet (delays emptying). Sit upright after meals. [97]
2. Prokinetic Antiemetic (2 marks): Metoclopramide 10mg TDS PO (or 30-60mg/24h CSCI if vomiting prevents oral route). [42] Mechanism: D2 antagonist + 5HT4 agonist (enhances gastric emptying). [42]
3. Treat Hepatomegaly-Related Issues (1 mark): If hypercalcaemia present, treat (fluids, bisphosphonates). [64] Consider oncology input (chemotherapy/targeted therapy to reduce tumour burden if appropriate). [64]
4. Review and Escalate (1 mark): Reassess at 48 hours. If refractory, consider adding haloperidol (if metabolic component) or levomepromazine (broad-spectrum). [10,20] If severe gastric outlet obstruction, consider endoscopy ± stenting. [78]

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