What is the role of opioids in drug-induced liver injury (DILI)?

From the Guidelines

Opioids can be used safely in patients with liver disease, but require careful selection and dose adjustment to minimize the risk of adverse effects, as recommended by the most recent guidelines 1. When considering opioids for patients with liver disease, it is essential to choose medications that do not produce hepatotoxic metabolites and to adjust doses according to liver function.

• Fentanyl, for example, is metabolized by cytochromes and does not produce toxic metabolites, making it a suitable option for patients with liver disease 2.
• Morphine, on the other hand, has a longer half-life in patients with liver cirrhosis and its bioavailability is increased, which may lead to increased side effects 2.
• Hydromorphone has an analgesic effect of its own and its half-life is stable even in patients with liver dysfunction, making it a viable option for pain management in this population 2.
• Oxycodone, however, has a longer half-life, lower clearance, and greater potency for respiratory depression in patients with liver disease, which may increase the risk of adverse effects 2. Key considerations when prescribing opioids to patients with liver disease include:
• Starting with lower doses and extending dosing intervals to minimize the risk of accumulation and adverse effects 1.
• Monitoring liver function regularly to adjust doses and prevent hepatotoxicity 1.
• Avoiding acetaminophen-opioid combinations in patients with significant liver impairment, as acetaminophen can cause dose-dependent hepatotoxicity 3. By carefully selecting and dosing opioids, healthcare providers can effectively manage pain in patients with liver disease while minimizing the risk of adverse effects and improving quality of life.

From the Research

Opioids and Liver Injury

• Opioids are metabolized via the liver, and their use in patients with liver disease can lead to adverse reactions, including drug-induced liver injury (DILI) 4.
• The liver plays a crucial role in the metabolism of opioids, and liver dysfunction can affect the clearance of these drugs, leading to accumulation and increased risk of toxicity 5.
• Certain opioids, such as morphine and buprenorphine, undergo glucuronidation, while others, like remifentanil, are cleared by ester hydrolysis 5.

Mechanisms of Opioid-Induced Liver Injury

• Mitochondrial oxidative stress is considered a key mechanism in acetaminophen-induced liver injury, but the role of opioids in this process is not well understood 6.
• Opioids can cause sedation, constipation, and sudden encephalopathy effects, and their use in patients with liver disease requires careful monitoring and dose adjustment 4.
• The pharmacokinetics of opioids in liver disease are complex, and the disposition of these drugs can be affected by the degree of liver insufficiency 5.

Risk Factors and Management

• Patients with liver disease are at increased risk of opioid-induced liver injury, and the use of these drugs should be carefully evaluated and monitored 4, 5.
• The management of opioid-induced liver injury involves supportive care, and in severe cases, liver transplantation may be necessary 7.
• The identification of toxicity signals during clinical trials and the monitoring of liver tests in clinical practice can help mitigate the risk of opioid-induced liver injury 7.

Hepatotoxicity of Opioids

• Certain opioids, such as pethidine and dextropropoxyphene, have been associated with hepatotoxicity, and their use in patients with liver disease should be avoided or carefully monitored 5.
• The hepatotoxicity of opioids can be influenced by individual susceptibility factors, including genetic and environmental factors 7.
• The pathogenesis of opioid-induced liver injury can involve various mechanisms, including apoptosis, necrosis, and adaptive immune responses 7.