Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Watkins
Paul B
PB
Department of Medicine, University of North Carolina, Chapel Hill, USA. pbwatkins@med.unc.edu
Kaplowitz
Neil
N
Slattery
John T
JT
Colonese
Connie R
CR
Colucci
Salvatore V
SV
Stewart
Paul W
PW
Harris
Stephen C
SC
D000082:Acetaminophen / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016037:Single-Blind Method
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000082:Acetaminophen; D000410:Alanine Transaminase