JAMA article:

Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily

A Randomized Controlled Trial

Paul B. Watkins, MD; Neil Kaplowitz, MD; John T. Slattery, PhD; Connie R. Colonese, MS; Salvatore V. Colucci, MS; Paul W. Stewart, PhD; Stephen C. Harris, MD

JAMA. 2006;296:87-93.

Context  During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed.

Objective  To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo.

Design, Setting, and Participants  A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units.

Intervention  Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days.

Main Outcomes  Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter.

Results  None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved.

Conclusions  Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.

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Med Clin North Am. 2005 Nov;89(6):1145-59.  Updates on acetaminophen toxicity.APAP is likely to remain a common toxic exposure and continue to cause significant morbidity and mortality. To minimize the harm to patients, it is necessary for the clinician to be aware of the current diagnostic and therapeutic management of APAP poisoning. Despite the bulk of literature on APAP, management strategies are likely to continue to change as more studies are conducted to improve our understanding of nonacute ingestions and the role of prognostic markers in defining those most at risk for life-threatening hepatotoxicity.