Is pregabalin (lyrica) hepatotoxic in patients with pre-existing liver disease?

Is Pregabalin Hepatotoxic?

Pregabalin is not inherently hepatotoxic and is actually recommended as a preferred antiepileptic drug in patients with liver disease due to its minimal hepatic metabolism, though rare idiosyncratic hepatotoxicity has been documented in isolated case reports. 1, 2

Pharmacokinetic Profile Supporting Hepatic Safety

• Pregabalin undergoes less than 2% hepatic metabolism and is excreted virtually unchanged by the kidneys 1
• It does not bind to plasma proteins and does not induce or inhibit liver enzymes such as the cytochrome P450 system 1
• The drug is not subject to hepatic metabolism, making pharmacokinetic drug-drug interactions unlikely 1
• Dose adjustment is only necessary in patients with renal insufficiency, not hepatic impairment 1

Clinical Guideline Recommendations for Liver Disease

Pregabalin is specifically recommended as first-line therapy for seizures in patients with advanced liver disease because of its favorable metabolic profile 2

• Newer antiepileptic drugs without or with minimal hepatic metabolism, including pregabalin, gabapentin, levetiracetam, lacosamide, and topiramate, should be used as first-line therapy in patients with liver disease 2
• Medications undergoing extensive hepatic metabolism (valproic acid, phenytoin, felbamate) should be used as drugs of last resort 2
• Pregabalin has been mentioned as a potential alternative for alcohol withdrawal syndrome in patients with advanced liver disease, where benzodiazepines carry significant side effects 3

Rare Idiosyncratic Hepatotoxicity: Case Reports

While pregabalin is generally safe, isolated case reports document rare idiosyncratic hepatotoxic reactions:

• A 59-year-old man developed acute liver enzyme elevation (AST 907 U/L, ALT 1582 U/L, GGT 510 U/L) 14 days after starting pregabalin 25 mg daily, with gradual normalization over 4 months after discontinuation 4
• A 76-year-old woman developed jaundice and elevated liver enzymes (ALT 246 U/L, AST 86 U/L, GGT 2068 U/L, bilirubin 6 mg/dl) 15 days after initiating pregabalin, with resolution after drug discontinuation 5
• The low dosages and short time to enzyme elevation in these cases suggest idiosyncratic reactions rather than dose-dependent toxicity 4
• A MEDLINE search through 2010 revealed only 2 reports of acute liver injury with pregabalin initiation 4

Clinical Implications for Patients with Pre-existing Liver Disease

Pregabalin remains a safe choice even in patients with pre-existing liver disease:

• The drug's renal elimination pathway bypasses hepatic metabolism entirely 1
• No dose adjustment is required for hepatic impairment, only for renal insufficiency 1
• The idiosyncratic nature of reported hepatotoxicity (occurring in patients without pre-existing liver disease) does not contraindicate use in liver disease patients 4, 5

Monitoring Recommendations

While routine hepatic monitoring is not required based on pregabalin's pharmacokinetic profile, clinicians should maintain awareness of rare idiosyncratic reactions:

• Consider baseline liver function tests if clinically indicated by patient history 4
• Monitor for clinical signs of hepatotoxicity (jaundice, nausea, right upper quadrant pain) during the first few weeks of therapy 5
• If unexplained liver enzyme elevation occurs, discontinue pregabalin and evaluate for alternative causes 4, 5
• Liver enzymes typically normalize gradually over weeks to months after discontinuation in idiosyncratic cases 4, 5