A 75-year-old man with gastrointestinal stromal tumour and bone metastasis presented with bone pain. He also had a medical history of hypertension and chronic kidney disease (plasma urea: 16.9 mmol/L; plasma creatinine: 315 µmol/L; estimated GFR: 24 ml/minute per 1.73 m²). The pain control was not satisfactory with simple analgesic paracetamol. Opioid analgesic was considered necessary by his family doctor. His initial analgesic regime was paracetamol 500 mg q.i.d, and morphine sulphate (syrup) 5 mg q4h. He was also on imatinib mesylate for the treatment of gastrointestinal stromal tumor.

(a) Discuss the metabolism of codeine and the impact of pharmacokinetics variation of codeine metabolism on pain control and medication safety (4 marks)

(b) Discuss the use of morphine in this patient with chronic kidney disease:

(i) The metabolism and elimination of morphine in human body. (2 marks)

(ii) ONE major morphine toxicity and it’s pharmacological mechanism. (2 marks)

(iii) Recommended morphine dosage adjustment in this patient (1 mark)

(c) The patient complained of constipation after use of morphine.

i) List THREE non-pharmacological measures to prevent constipation. (1.5 marks)

ii) Give ONE drug example for EACH pharmacotherapeutic agent with different mechanism of action: stool softener; osmotic laxative; contact cathartic. (1.5 marks)

iii) Give ONE drug example for bulk-forming agents and explain why it should be avoided in opioid induced constipation (1 mark)

d) The bone pain was adequately controlled with the morphine sulphate 45 mg per day. Fentanyl dermal patch was switched for pain control.

i) Discuss the metabolism and elimination of fentanyl in human body. (2 marks)

ii) What is the appropriate dosage conversion from morphine sulphate to transdermal fentanyl patch in this patient? (1 mark)

iii) List THREE important advices to the patient about safe use of fentanyl patch. (3 marks)

iv) What potential drug-drug interaction may occur in this patient on fentanyl therapy? (1 mark)