What are the effects of opioids in patients with liver failure?

From the Guidelines

Opioids should be used cautiously in patients with liver failure, with dose reductions and careful monitoring required, and fentanyl is a preferred option due to its lack of active metabolites requiring hepatic clearance. When administering opioids to patients with liver failure, it is essential to consider the altered pharmacokinetics, which stem from decreased drug metabolism, reduced protein binding, and impaired clearance of medications and their metabolites, increasing the risk of toxicity even at standard doses 1.

Key Considerations for Opioid Use in Liver Failure

• Morphine, hydromorphone, and oxycodone should be avoided or significantly dose-reduced (by 50% or more) as they accumulate in liver failure, potentially causing excessive sedation and respiratory depression 1.
• Fentanyl and methadone are safer options as they don't produce active metabolites requiring hepatic clearance, with fentanyl being a preferred choice due to its pharmacokinetic profile 1.
• Start fentanyl at 25-50% of normal dosing (e.g., 25-50 mcg IV q1-2h PRN initially) and titrate slowly, and methadone can be initiated at 2.5-5mg orally q8-12h with careful monitoring 1.
• Avoid codeine and tramadol completely as they require hepatic activation to be effective and can accumulate toxically 1.
• When administering any opioid in liver failure, use lower starting doses, extend dosing intervals, monitor closely for side effects (sedation, confusion, respiratory depression), and consider consulting pain management or hepatology specialists 1.

Monitoring and Dose Adjustment

• Monitor patients with liver failure closely for signs of opioid toxicity, including sedation, confusion, and respiratory depression 1.
• Adjust opioid doses and intervals according to liver function and the patient's response to treatment, taking into account the potential for altered pharmacokinetics in liver failure 1.
• Consider consulting pain management or hepatology specialists for guidance on opioid use in patients with liver failure, especially in complex cases or when patients require high doses or prolonged treatment 1.

From the FDA Drug Label

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)]. Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life The M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity.

Key Considerations:

• Dosing: Start with a lower than usual dosage of morphine sulfate in patients with liver failure.
• Titration: Titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.
• Monitoring: Monitor patients closely for adverse effects due to altered morphine pharmacokinetics in liver failure.
• Pharmacokinetics: Morphine clearance decreases and half-life increases in patients with cirrhosis, indicating diminished metabolic activity 2, 2.

From the Research

Opioids in Liver Failure

• The liver plays a crucial role in the metabolism of opioids, and liver disease can affect the disposition of these drugs 3, 4, 5, 6.
• In patients with liver disease, the administration of opioid analgesics should be observed accurately, with lower doses administered at regular intervals based on signs of drug accumulation 3.
• The interactions of opioid drugs with different levels of substrates of the P450 cytochrome enzyme should be considered, and the risk of accumulation and adverse effects should be taken into account 3, 4, 5, 6.

Pharmacokinetics of Opioids in Liver Disease

• The major metabolic pathway for most opioids is oxidation, with exceptions including morphine and buprenorphine, which primarily undergo glucuronidation 4, 5.
• Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in decreased drug clearance and increased oral bioavailability due to reduced first-pass metabolism 4, 5.
• The clearance of morphine was found to be decreased and its oral bioavailability increased in patients with liver cirrhosis 4, 5, 7.

Clinical Implications

• Pain management in patients with liver disease is challenging due to the risk of adverse reactions, especially with opioids 3, 6.
• Certain opioids, such as codeine or tramadol, rely on hepatic biotransformation to active metabolites, and their analgesic effect may be reduced in patients with liver disease 6.
• Some opioids, such as pethidine (meperidine), have toxic metabolites, and their use should be avoided in patients with liver disease due to the risk of accumulation and toxicity 4, 5, 6.
• The pharmacokinetics of phenylpiperidine opioids, such as fentanyl, sufentanil, and remifentanil, appear to be unaffected in liver disease 4, 5, 6.