Phenobarbital and Liver Injury at Normal Dosing
Phenobarbital at therapeutic doses rarely causes clinically significant liver injury in adults without pre-existing liver disease, though it commonly elevates liver enzymes through enzyme induction rather than true hepatotoxicity. 1, 2
Risk Profile and Incidence
The risk of serious hepatotoxicity from phenobarbital at normal doses is rare, but fatal hepatotoxicity can occur, particularly in young children under 2 years of age. 1 The FDA label specifically warns that "in patients with hepatic damage, barbiturates should be administered with caution" and notes that "barbiturates should not be administered to patients showing the premonitory signs of hepatic coma." 2
Common vs. Rare Effects
Enzyme elevation (GGT, ALT) is common but typically benign: In a study of 128 adults on stable long-term phenobarbital monotherapy, patients had significantly higher serum GGT (79 IU/L vs 24 IU/L, P<0.001) and ALT (27 IU/L vs 23 IU/L, P<0.001) compared to controls, but these elevations were not clinically significant. 3
True hepatotoxicity is rare: While phenobarbital has been "only rarely been linked to hepatotoxicity" in adults, it should be considered a "drug of last resort" in patients with advanced liver disease. 4
Mechanism: Enzyme Induction vs. True Hepatotoxicity
The key distinction is that most liver enzyme elevations with phenobarbital represent enzyme induction rather than hepatocellular injury:
In 63 children on phenobarbital for >12 months, all 56 with therapeutic drug levels had elevated GGT, and 11 had elevated transaminases. 5
Liver biopsies in 6 patients with persistent transaminase elevations showed uniform hepatocyte swelling and smooth endoplasmic reticulum proliferation without necrosis, inflammation, or fibrosis. 5
All transaminase elevations normalized within 8-14 months despite continuing the medication, confirming enzyme induction rather than toxicity. 5
The FDA label confirms that phenobarbital "can induce hepatic microsomal enzymes resulting in increased metabolism" of other drugs. 2
Rare but Serious Hepatotoxicity
While uncommon, severe liver injury can occur:
Two autopsy cases revealed chronic liver damage with portal inflammatory infiltrate (eosinophils and monocytes), multiple necrotic foci with granulomatous tissue, and biliary duct inflammation in patients on long-term phenobarbital. 6
These cases demonstrate that "PB may be associated with chronic liver damage, which may lead to more serious and deleterious consequences." 6
Clinical Implications and Monitoring
For patients without pre-existing liver disease:
Mild transaminase elevations (up to 2-3× baseline) during phenobarbital therapy typically represent enzyme induction and do not require drug discontinuation. 5
Liver biopsies are not warranted for mild enzyme elevations in clinically well patients. 5
The medication can be continued despite mild SGOT/SGPT elevations "without concern for hepatic damage." 5
For patients with pre-existing liver disease:
Phenobarbital should be "administered with caution and initially in reduced doses" in patients with hepatic damage. 2
It is contraindicated in patients showing premonitory signs of hepatic coma. 2
Newer antiepileptic drugs without hepatic metabolism (levetiracetam, lacosamide, gabapentin) should be first-line choices. 4
Important Caveat: Age-Related Risk
The risk profile differs dramatically by age: Fatal hepatotoxicity with valproic acid (not phenobarbital) is well-documented "especially in children younger than 2 years who are also at greatest risk of febrile seizures." 1 While this specific warning applies to valproate, the pediatric guidelines note concerns about barbiturate hepatotoxicity in young children that are not as prominent in adults. 1
Drug Interactions Increasing Hepatotoxicity Risk
Phenobarbital can potentiate hepatotoxicity of other agents through enzyme induction: A case report documented severe CCl4-induced hepato-nephrotoxicity in a patient on chronic phenobarbital, with the severity attributed to microsomal enzyme induction increasing CCl4 activation. 7