Which opioids should be avoided in patients with elevated liver enzymes (liver impairment)?

From the Guidelines

In patients with elevated liver enzymes or liver impairment, opioids that should be avoided include codeine, tramadol, methadone, propoxyphene, and meperidine, as well as oxycodone, due to their extensive hepatic metabolism and potential to accumulate to toxic levels. These medications can cause increased side effects or complications in patients with compromised liver function 1. Morphine should also be used with caution as its active metabolite, morphine-6-glucuronide, can accumulate in liver disease, though it may still be used with appropriate dose adjustments. Better options for patients with liver impairment include:

• Fentanyl, which is metabolized by cytochromes and does not produce toxic metabolites, making it a safer choice for patients with liver impairment 1
• Hydromorphone, which has a stable half-life even in patients with liver dysfunction and is metabolized and excreted by conjugation 1
• Oxymorphone, which has less hepatic metabolism and fewer active metabolites compared to other opioids

When prescribing opioids to patients with liver impairment, it is recommended to:

• Start with lower doses (typically 25-50% of the standard dose) 1
• Extend dosing intervals
• Monitor closely for signs of opioid toxicity such as excessive sedation, confusion, or respiratory depression
• Regularly monitor liver function tests to adjust dosing as needed 1

The severity of liver impairment should guide dosing adjustments, with more significant reductions needed for severe hepatic dysfunction 1. It is essential to consider the individual patient's liver function and adjust opioid doses accordingly to minimize the risk of adverse effects and optimize pain management.

From the FDA Drug Label

8.6 Hepatic Impairment The pharmacokinetics of hydromorphone is affected by hepatic impairment. Due to increased exposure of hydromorphone, patients with hepatic impairment should be started at one-fourth to one-half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration

8.6 Hepatic Impairment Because oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of oxycodone hydrochloride tablets and titrate carefully. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension

Opioids to avoid or use with caution in patients with elevated liver enzymes (liver impairment):

• Hydromorphone: should be started at one-fourth to one-half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration 2
• Oxycodone: initiate therapy with a lower than usual dosage and titrate carefully, monitoring closely for adverse events such as respiratory depression, sedation, and hypotension 3

From the Research

Opioids to Avoid in Elevated Liver Enzymes

• Certain opioids should be avoided in patients with elevated liver enzymes due to the risk of increased toxicity and adverse effects 4.
• Opioids such as codeine, tramadol, and pethidine (meperidine) rely on hepatic biotransformation to active metabolites, and their use may lead to reduced analgesic effect or increased risk of toxicity in patients with liver disease 4.
• Pethidine (meperidine) has toxic metabolites, and its slower elimination can result in an increased risk of toxicity in patients with liver disease, making it an opioid to avoid in this population 4.
• Other opioids, such as morphine, oxycodone, and hydromorphone, may require lower doses and/or longer administration intervals in patients with liver disease to avoid the risk of accumulation and potential increase of adverse effects 4.

Alternative Opioids for Patients with Elevated Liver Enzymes

• Phenylpiperidine opioids such as fentanyl, sufentanil, and remifentanil appear to be unaffected in hepatic disease, making them potential alternatives for patients with elevated liver enzymes 4.
• However, all opioid drugs can precipitate or aggravate hepatic encephalopathy in patients with severe liver disease, requiring cautious use and careful monitoring 4.

Considerations for Opioid Use in Patients with Elevated Liver Enzymes

• The pharmacokinetics of opioids can be altered in patients with liver disease, leading to increased concentrations and reduced plasma clearance of drugs 4.
• Patients with liver disease may require individualized opioid dosing and monitoring to minimize the risk of adverse effects 5, 4.
• The selection of suitable opioids for patients with liver disease should be based on the patient's specific condition, the opioid's pharmacokinetic profile, and the potential for drug interactions 5, 4.