The Disutility of Acetaminophen for Influenza

Wait … what?

This headline: “Acetaminophen Appears To Be Ineffective Against Flu.”

Hopefully, when you saw that either in the ACEP member daily news e-mail, or on the Reuters distribution, you had the same befuddled reaction as me.  Even better, the coverage includes this fascinating fearmongering from one of the authors:

“What this study does is raise some very serious questions about the real evidence base for using acetaminophen routinely for anyone that has the flu.”

Actually, it doesn’t.

This is a randomized, double-blind, placebo-controlled study of patients with suspected influenza, treating with five days of either scheduled acetaminophen or placebo.  The primary outcome was the area under the cure for quantitative PCR influenza log(10) viral load from baseline to day 5.  Patients were admitted to a clinical trials unit for the first 48 hours, then followed up in clinic at day 5 and day 14.  Secondary outcomes included symptom scores for health and temperatures of each patient.  The authors based their power calculation on the standard deviation for PCR viral load, and estimated to have 80% power to detect a difference greater than that standard deviation, they would need 80 patients with influenza.

Over the course of two influenza seasons, 2011 and 2012, they were able to enroll: 46

More specifically, they enrolled 46 patients with PCR-confirmed influenza.  The other 34 patients had false-positives on the rapid assay used for enrollment, and could not be included in their primary outcome analysis.  Because of their inadequate sample size, it is therefore mostly nonsensical to comment on their failure to find statistical differences in their outcomes.  However, there do not appear to be any potentially clinically important clues hiding in plain sight.

Bafflingly, one of their discussion points notes “These findings raise questions about the anti-pyretic efficacy of paracetamol in influenza and other respiratory infections.”  The mean temperature in the 80 patients randomized to placebo never even exceeded a 38°C “fever” threshold.  Then, the mean temperature was actually normal on day 2-5.  To suggest acetaminophen fails to normalize fever in respiratory infection compared with placebo, fever ought be relatively ubiquitous in the study population.  Otherwise, there simply isn’t any clinical feasibility of detecting a difference.

Finally, what makes the questions about the use of acetaminophen most bizarre, the study was actually undertaken to confirm the safety of acetaminophen.  Their clinical trial registration states:

“Paracetamol is recommended for the routine treatment of fever and systemic symptoms in influenza. However, this recommendation is contrary to evidence which suggests that the presence of fever is protective in infections. This study aims to investigate whether the regular use of an antipyretic (paracetamol) during acute infection with influenza may prolong viral shedding and clinical symptoms.”

Setting aside the inability of their sample size to actually address their outcomes – their conclusions are based on a failure to detect a difference.  Therefore, their original concerns over potential harms from the anti-pyretic nature of acetaminophen ought to have been allayed!

Quite a long way from the headline at the top of this post.

“Randomized controlled trial of the effect of regular paracetamol on influenza infection”
http://www.ncbi.nlm.nih.gov/pubmed/26638130