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
- Author Affiliations: Department of Medicine, University of North Carolina, Chapel Hill (Dr Watkins); Keck School of Medicine, Department of Medicine, University of Southern California, Los Angeles (Dr Kaplowitz); Departments of Pharmacology and Medicine, University of Washington, Seattle (Dr Slattery); Boehringer-Ingelheim Pharmaceuticals, Inc, Ridgefield, Conn (Ms Colonese); Department of Clinical Pharmacology and Clinical Pharmacokinetics, Purdue Pharma L.P., Stamford, Conn (Mr Colucci and Dr Harris); Deparment of Biostatistics, University of North Carolina, Chapel Hill (Dr Stewart).
- Corresponding Author: Paul B. Watkins, MD, General Clinical Research Center, Campus Box 7600, Rm 3005 APCF, Chapel Hill, NC 27599-7600 (pbwatkins{at}med.unc.edu).
Abstract
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.
