Is morphine primarily excreted by the liver or the kidney?

From the Guidelines

Morphine is primarily excreted by the kidney, not the liver. After administration, morphine undergoes metabolism in the liver where it is converted to morphine-3-glucuronide and morphine-6-glucuronide, but the final elimination of these metabolites occurs through the kidneys 1. Approximately 90% of a morphine dose is eliminated in the urine within 24 hours, with only small amounts excreted in feces via biliary elimination.

This renal excretion pathway is clinically significant because patients with kidney impairment may experience prolonged effects or toxicity from morphine due to decreased clearance of the drug and its active metabolites. Dose adjustments are typically necessary in patients with renal dysfunction, while monitoring for signs of opioid toxicity such as excessive sedation or respiratory depression is important. The morphine-6-glucuronide metabolite is actually more potent than morphine itself and can accumulate to dangerous levels in patients with kidney failure.

Key points to consider:

• Morphine metabolism occurs in the liver, but its excretion is primarily renal 1
• Patients with kidney impairment are at risk of morphine toxicity due to decreased clearance 1
• Dose adjustments and monitoring for opioid toxicity are crucial in patients with renal dysfunction
• Alternative opioids like hydromorphone or fentanyl may be considered in patients with significant renal function impairment 1

From the FDA Drug Label

Elimination: Metabolism: The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6- glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). Excretion: Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling.

Morphine is primarily excreted by the kidney. The liver plays a role in the metabolism of morphine, converting it into metabolites such as M3G and M6G, but the primary route of excretion is through the kidneys, with most of the dose being excreted in the urine as these metabolites 2.

From the Research

Morphine Excretion

• Morphine is metabolized in the liver to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G) 3.
• The liver is the primary site of morphine metabolism, with glucuronidation being the main metabolic pathway 4.
• The metabolites of morphine, including M6G, are excreted by the kidney 4, 5.
• In patients with renal insufficiency, the metabolites of morphine accumulate, as they are not effectively excreted by the kidney 4, 5, 6.
• The kidney plays a crucial role in the excretion of morphine and its metabolites, and renal impairment can lead to accumulation of these compounds 5, 6.

Key Findings

• The study by 3 found that after 36 hours, 92% of M6G and 9% of morphine were excreted in the urine.
• The study by 5 found that the renal clearances of morphine, M3G, and M6G were extremely low in patients undergoing continuous ambulatory peritoneal dialysis.
• The study by 6 highlighted the challenges of opioid treatment in patients with renal impairment and suggested that buprenorphine may be a safer option due to its primary excretion through the liver.