Does morphine undergo hepatic metabolism?

From the Guidelines

Morphine undergoes hepatic metabolism, with over 90% being metabolized by conjugation in the liver. This process is crucial in determining the drug's analgesic effects and potential side effects, particularly in patients with liver impairment 1. The liver's role in metabolizing morphine is significant, as it converts the drug into two major metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), with M6G being more potent than morphine itself and contributing to the analgesic effects 1.

Key points to consider:

• Morphine's hepatic metabolism affects its bioavailability, with oral administration having lower bioavailability compared to other routes like intravenous injection 1
• Patients with liver cirrhosis may experience increased side effects from morphine due to decreased metabolism, potentially requiring dose adjustments 1
• The half-life of morphine is increased by about two-fold in patients with liver cirrhosis, and its bioavailability is four-fold in patients with HCC compared to healthy individuals 1
• Recent guidelines recommend careful consideration of opioid use in patients with renal or hepatic impairment, with morphine being one of the opioids that should be avoided in patients with renal impairment unless there are no alternatives 1

In clinical practice, it is essential to consider the liver's role in metabolizing morphine when prescribing the drug, especially in patients with liver impairment, to minimize potential side effects and optimize analgesic effects 1.

From the FDA Drug Label

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).

• Hepatic Metabolism: Morphine undergoes hepatic metabolism, with the major pathway being conjugation to produce glucuronides.
• Metabolites: The main metabolites of morphine are M3G and M6G, which are produced through hepatic metabolism. Morphine undergoes hepatic metabolism to produce its metabolites, primarily M3G and M6G 2.

From the Research

Hepatic Metabolism of Morphine

• Morphine undergoes hepatic metabolism, primarily through glucuronidation, as stated in 3, 4, 5, 6, 7.
• The liver is the major site of biotransformation for most opioids, including morphine, which is metabolized to 3-glucuronide and 6-glucuronide, mainly by UGT2B7 5.
• Morphine-6-glucuronide (M6G) is a pharmacologically active metabolite of morphine, formed in the liver, and excreted by the kidneys 7.
• The clearance of morphine was found to be decreased and its oral bioavailability increased in patients with hepatic cirrhosis, although glucuronidation is thought to be less affected in liver cirrhosis 3, 4.

Metabolic Pathways

• The major metabolic pathway for most opioids is oxidation, but morphine and buprenorphine primarily undergo glucuronidation 3, 4.
• Morphine is metabolized to M3G and M6G, which have different effects on opioid receptors and analgesic activity 6.
• M6G binds to opioid receptors and may be a more potent analgesic than morphine, while M3G has no analgesic activity and may antagonize the analgesic effect of morphine and M6G 6.

Clinical Implications

• The disposition of morphine may be affected in patients with liver insufficiency, resulting in decreased drug clearance and increased oral bioavailability 3, 4.
• The risk of accumulation of morphine and its metabolites in the body, especially with repeated administration, should be considered in patients with liver disease 3, 4.
• Special risks are known for morphine in patients with renal failure, as M6G can accumulate in the blood and lead to severe intoxication 7.