Opioid toxicity in advanced prostate cancer with renal impairment
A 66-year-old man with metastatic castration-resistant prostate cancer and widespread bone metastases has been taking morphine sulfate modified-release 60 mg twice daily plus oxycodone immediate-release 10 mg as needed (4–5 doses per day) for the last 3 months. He now reports pain 8/10 despite this, and over the past week has become drowsy with myoclonic jerks, intermittent confusion and reduced oral intake. He has bilateral hydronephrosis with a nephrostomy in situ; creatinine is 260 µmol/L (eGFR 22 mL/min/1.73 m²), corrected calcium 2.35 mmol/L, sodium 132 mmol/L. He is afebrile. Neurological examination shows no focal deficit, no sensory level and normal power. He takes no other sedating drugs and has no history of liver disease. The family ask why he is 'so sleepy' and whether the pain can be controlled.
1. What is the likely explanation for the drowsiness and myoclonus, and what do you do about it today?
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Diagnosis: opioid toxicity from accumulation of morphine metabolites in renal impairment. Morphine is glucuronidated to morphine-6-glucuronide (analgesic and neuroexcitatory) and morphine-3-glucuronide, both renally cleared. With an eGFR of 22 mL/min/1.73 m² these accumulate, producing sedation, myoclonus, confusion and - if continued - respiratory depression. The recent deterioration in renal function is the trigger. This is not simply pain requiring more opioid, and increasing the dose would be dangerous.
Immediate steps:
- Stop morphine and oxycodone; withhold further doses while the picture is assessed.
- Exclude other causes: hypercalcaemia (corrected calcium 2.35 mmol/L is normal here), hyponatraemia (Na 132 mmol/L, mild), infection, brain metastases, and spinal cord compression - normal power and no sensory level are reassuring but do not exclude early compression if back pain is new.
- Review all renally cleared drugs, including gabapentin, pregabalin and NSAIDs, and stop any that contribute.
- Rotate to an opioid less dependent on renal clearance: fentanyl (intravenous or transdermal) is preferred. As a rough guide, 120 mg oral morphine per day is approximately 50 µg/h fentanyl, but start lower (25 µg/h) in renal impairment because of accumulation, and titrate.
- Use intravenous fentanyl for breakthrough pain, and monitor sedation score, respiratory rate and pain every few hours.
- Treat the cause of renal impairment: check nephrostomy patency with urology.
2. How do you distinguish opioid toxicity from other causes of his deterioration, and what investigations do you order?
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Work through the reversible causes systematically, because several can coexist.
- Medication review: calculate the total 24-hour morphine dose, including breakthrough doses, and look for sedating co-medications. This is often the single most informative step.
- Hypercalcaemia: corrected calcium is normal today, but recheck if symptoms persist, since bone metastases and immobility predispose to it.
- Spinal cord compression: ask specifically about new back pain, band-like pain, leg weakness, and bladder or bowel dysfunction. Examine tone, power, reflexes, plantar responses and sensation. Normal power does not exclude early compression - if there is any clinical suspicion, arrange urgent MRI of the whole spine within 24 hours and start dexamethasone 16 mg daily.
- Brain metastases: headache, focal deficit, seizures or papilloedema should prompt CT or MRI.
- Infection and uraemia: check CRP, urine culture, temperature, and the trend in creatinine; uraemia itself causes drowsiness and myoclonus.
- Metabolic: sodium 132 mmol/L is mild and unlikely to explain the picture alone; check glucose and thyroid function if unexplained.
Investigations: FBC, U&E, creatinine, corrected calcium, LFT, CRP, glucose, and a drug chart review. If myoclonus persists after opioid rotation, consider clonazepam or midazolam, but only once the opioid dose has been reduced.
3. Once he is more alert, how would you improve his pain control, and when would you involve radiotherapy?
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Optimise analgesia using a multimodal plan, not just higher opioid doses.
- Radiotherapy is the most effective single intervention for painful bone metastases. A single 8 Gy fraction gives pain relief equivalent to 30 Gy in 10 fractions, with a retreatment rate of about 20%. With widespread disease, target the one or two most painful sites rather than all lesions, and consider wide-field hemibody irradiation only in selected cases.
- Adjuvant analgesia: dexamethasone 8 mg daily for 5–7 days can reduce pain from bone metastases and any associated oedema. NSAIDs should be avoided at this eGFR; bisphosphonates require renal dose adjustment and are contraindicated below certain creatinine clearance thresholds; denosumab is an alternative but requires calcium and vitamin D monitoring and carries a hypocalcaemia risk.
- Disease-directed treatment: continue androgen deprivation, and consider abiraterone or enzalutamide if not already used, or radium-223 if disease is bone-predominant with no visceral metastases and blood counts allow.
- Non-pharmacological: physiotherapy, occupational therapy, TENS, and psychological support; involve the palliative care team early, since this improves symptom control and reduces unplanned admissions.
- Set realistic goals: a 30–50% reduction in pain score, better sleep and function. Review every 24–48 hours. If pain remains refractory despite opioid rotation and radiotherapy, consider nerve blocks or specialist palliative input rather than further dose escalation.