Acetaminophen has been known as an analgesic for more than a century, and its oral (PO) and rectal (PR) formulations have been used for pain relief in the United States (U.S.) for decades. Acetaminophen is thought to act via central mechanisms1 and therefore must cross into the central nervous system (CNS) to have an effect. As there is no active transport mechanism across the blood–brain barrier, passive diffusion of acetaminophen into the CNS is highly dependent on a concentration gradient with the Cmax being of primary importance.2 There is a direct correlation between the analgesic (and antipyretic) activity of acetaminophen and its concentration-time curve in the cerebrospinal fluid (CSF), which is consistent with its predominantly central site of action.3