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Is Acetaminophen Still a Good ALTernative?

Acetaminophen at maximal doses appears to raise liver enzymes.

To further investigate previous observations that combinations of opioids and acetaminophen can elevate liver alanine aminotransferase (ALT) levels, the authors conducted a clinical trial of acetaminophen with and without opioids. Healthy volunteers were recruited to participate in this 14-day study in which they received one of three acetaminophen/opioid combinations, acetaminophen alone, or placebo orally every 6 hours. The total daily dose of acetaminophen was 4 g.

A total of 145 subjects constituted the modified intent-to-treat population. Similar elevations in ALT were observed for all of the active treatment combinations (acetaminophen alone or in combination with oxycodone, morphine, or hydromorphone). Seventy-nine percent of participants receiving the active treatments had ALT levels greater than twice baseline, and 63% had levels greater than three times baseline, compared with 28% and 10%, respectively, of the placebo group. More than 25% of participants in the four active treatment groups had ALT measurements greater than five times the upper limit of normal (ULN). The study population included a high proportion of Hispanics (57%), who were 1.9 times as likely to have a maximum ALT level greater than three times the ULN as were whites or blacks.

Comment: These findings raise concern about the safety of acetaminophen doses at the high end of the recommended range. However, given that there were only 2 weeks of monitoring, the duration and long-term implications of these elevations remain unknown. We are not yet at the point of recommending frequent liver monitoring during acetaminophen use, but we should advise patients to take this medication at the lowest effective dose for the shortest time and without exceeding the recommended dose limits. Clinicians prescribing combination formulations should consider use of products with lower (e.g., 325 mg) rather than higher (e.g., 500 mg) doses of acetaminophen.

— Marian C. Limacher, MD

Published in Journal Watch Women's Health August 10, 2006

Citation(s):

Watkins PB et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. JAMA 2006 Jul 5; 296:87-93.

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