At what stage of Chronic Kidney Disease (CKD) is morphine contraindicated?

Morphine Use in Chronic Kidney Disease

Morphine should be avoided in CKD stages 4 and 5 (GFR <30 mL/min) due to accumulation of neurotoxic metabolites that can cause opioid-induced neurotoxicity, respiratory depression, and prolonged sedation. 1

Specific CKD Stage Recommendations

CKD Stages 4-5 (GFR <30 mL/min)

• Morphine is contraindicated or should be avoided entirely in patients with significant renal impairment defined as stages 4 and 5 chronic kidney disease (estimated GFR <30 mL/min). 1
• If morphine must be used in this population, it should only be with extreme caution, reduced dosing, extended intervals, and close monitoring for toxicity. 1
• The European Association for Palliative Care specifically states morphine "should be avoided, used with caution, and/or switched to another opioid not having active metabolites with renal excretion" in stages 4-5 CKD. 1

End-Stage Renal Disease (ESRD) and Hemodialysis

• Morphine and codeine are not recommended in ESRD patients due to accumulation of neurotoxic metabolites including morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). 2, 3
• M3G and M6G accumulate to much higher plasma levels in renal failure compared to patients with normal renal function, as these metabolites are primarily cleared renally. 4, 5
• M6G has analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity and may possess opiate antagonist properties. 4, 5
• Morphine is difficult to process in hemodialysis patients due to possible "rebound" of metabolites between dialysis sessions. 6

Mechanism of Toxicity

• Approximately 50% of morphine is converted to M3G and 15% to M6G through hepatic glucuronidation. 4
• Most morphine (about 90%) is excreted in urine as M3G and M6G, with elimination occurring primarily as renal excretion. 4
• In renal failure, the AUC of morphine increases, clearance decreases, and metabolites accumulate to toxic levels. 4
• Accumulation of these metabolites can cause neurotoxic symptoms, excessive sedation, respiratory depression, and prolonged narcosis. 2, 7, 3

Safer Alternatives for CKD Stages 4-5

First-line opioid choices when morphine is contraindicated include:

• Fentanyl (IV or transdermal) is the safest option as it undergoes primarily hepatic metabolism with no active metabolites and minimal renal clearance. 1, 2
• Buprenorphine (transdermal or IV) is also considered first-line as it is mainly excreted through the liver and requires no dose adjustment in renal dysfunction or hemodialysis. 1, 6
• Both agents are specifically recommended by ESMO guidelines as the safest opioids in CKD stages 4-5. 1

Second-line options with caution:

• Hydromorphone and oxycodone can be used with careful dose reduction and extended intervals, but require close monitoring as their metabolites can accumulate. 2, 8, 3
• Methadone is primarily metabolized hepatically and excreted fecally, making it safer in renal failure, but should only be used by experienced clinicians due to complex pharmacokinetics. 2, 8

Clinical Pitfalls to Avoid

• Never use standard morphine dosing protocols in patients with GFR <30 mL/min without significant dose reduction and extended intervals. 1
• Avoid combining morphine with other CNS depressants (benzodiazepines) in renal impairment, as this increases risk of respiratory depression. 1
• Do not assume that reducing morphine dose alone is sufficient—the metabolites will still accumulate over time in stages 4-5 CKD. 4, 3
• Meperidine (pethidine) and codeine should also be strictly avoided in renal failure due to toxic metabolite accumulation (normeperidine and norcodeine). 2, 7, 5