From the Guidelines
Morphine use in patients with Impaired Renal Function (IRF) leads to increased somnolence due to the accumulation of neurotoxic metabolites, such as morphine-3-glucuronide and normorphine 1.
Mechanism of Increased Somnolence
- The accumulation of these metabolites occurs because morphine is primarily eliminated in the urine, and in patients with IRF, the kidneys are unable to effectively clear these metabolites, leading to their buildup in the body 1.
- Morphine-6-glucuronide, an active metabolite of morphine, also contributes to analgesia but may worsen adverse effects, such as somnolence, as it accumulates in patients with renal insufficiency 1.
Clinical Implications
- Clinicians should avoid using morphine in patients with IRF, unless there are no alternatives, and instead consider rotating to methadone, which is excreted fecally, or using other opioids like hydromorphone or fentanyl that are less likely to result in accumulation of active metabolites in renal failure 1.
- Patients with IRF who receive opioids should be closely monitored for signs of opioid-induced neurotoxicity and have their doses frequently adjusted to minimize the risk of adverse effects 1.
From the FDA Drug Label
Morphine pharmacokinetics are altered in patients with renal failure The AUC is increased, and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
The mechanism for increased somnolence in patients with Impaired Renal Function (IRF) prescribed Morphine is likely due to the accumulation of morphine metabolites, such as M3G and M6G, which can occur when renal clearance is decreased. This can lead to increased plasma levels of these metabolites, potentially causing increased sedation and somnolence 2 2.
- Key points:
- Morphine pharmacokinetics are altered in patients with renal failure
- Accumulation of morphine metabolites can occur due to decreased renal clearance
- Increased plasma levels of morphine metabolites can cause increased sedation and somnolence
From the Research
Mechanism of Increased Somnolence in Patients with Impaired Renal Function (IRF) Prescribed Morphine
- The mechanism of increased somnolence in patients with IRF prescribed morphine is attributed to the accumulation of morphine-6-glucuronide (M6G), a pharmacologically active metabolite of morphine 3, 4, 5, 6.
- M6G is formed from morphine in the liver and is excreted by the kidney 4, 5.
- In patients with renal failure, the clearance of M6G is reduced, leading to its accumulation in the blood and penetration of the blood-brain barrier, resulting in increased somnolence and respiratory depression 4, 5, 6.
- The accumulation of M6G is thought to be responsible for the prolonged effect of morphine in patients with IRF, rather than the accumulation of morphine itself 7, 5, 6.
- Studies have shown that the peak concentrations of M6G are greater in patients with renal failure, and the area under the curve (AUC) of M6G is increased, contributing to the prolonged effect of morphine 5.
- The use of morphine in patients with IRF should be carefully controlled due to the increased risk of morphine toxicity and somnolence 3, 4.