Are recommended doses of acetaminophen hepatotoxic for recently abstinent alcoholics? A randomized trial

Although acetaminophen overdose is a leading cause of fulminant hepatic failure, it is controversial whether therapeutic doses of acetaminophen can cause hepatotoxicity in alcoholics, especially those rendered most vulnerable by recent abstinence. We performed a randomized, triple-blind, parallel-group trial comparing sustained-release acetaminophen, 1300mg orally q8h for 11 doses, against placebo. We enrolled chronic alcohol abusers (defined as >= 6 drinks daily for >= 6 weeks) who had discontinued alcohol consumption 12 to 72 hours prior to enrolment. Individuals with self-reported viral hepatitis, HIV or intravenous drug use, baseline AST or ALT > 120 IU/L, or INR 1.5 were excluded. Hepatic function tests were drawn daily for 5 days. The primary outcome was change in serum alpha-GST, a sensitive experimental biomarker of hepatocellular injury; secondary outcomes were changes in serum AST, ALT, INR, and study withdrawal for a doubling of aminotransferases to > 120 IU/L. Of 52 subjects randomized, 40 completed at least four days of intervention. Subjects receiving acetaminophen had 32% [95% CI 7%, 50%] and 29% [6%, 46%] lower serum alpha-GST concentrations on days 2 and 3, respectively, compared to placebo, but these differences disappeared by day 4. No subjects were withdrawn for safety reasons. In conclusion, therapeutic doses of sustained-release acetaminophen cause a measurable decrease in serum -GST during the first days of abstinence from chronic alcohol use. While the mechanism is unclear, these observations do provide some reassurance that short courses of acetaminophen are unlikely to cause subclinical hepatocellular injury in recently abstinent alcoholics (ClinicalTrials.gov NCT00137059).