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Dosing Acetaminophen For Inpatient Pain Management

Many years ago, the FDA set the recommended maximum daily dose of acetaminophen (“Tylenol”) at 4,000 mg. During my training, I’ve seen two common ways to write for scheduled acetaminophen around-the-clock: 650 mg every 4 hours (total of 3900 mg per day) and 1000 mg every 6 hours (total of 4000 mg per day). But does it actually make a difference?

Searching through the literature, there is clinical evidence to suggest that 1000 mg scheduled every 6 hours (q6h) provides statistically significant decreases in pain intensity compared to 650 mg scheduled every 4 hours (q4h). But why?

Acetaminophen is absorbed, like most drugs, through the small bowel; however, its diffusion into the central nervous system (CNS) is not based on carrier proteins. Instead, it relies on a concentration gradient. By administering the larger 1,000 mg dose, a higher peak serum concentration is achieved. This creates a much larger diffusion gradient between the plasma and cerebrospinal fluid (CSF) and favors more transfer of acetaminophen into the CNS.

By increasing the CSF concentration to a greater degree, we also “hide” more acetaminophen from hepatic metabolism, so the clinical effects are sustained. Once plasma levels begin to fall, the concentration gradient will be reversed and favor transfer of acetaminophen back into circulation and ultimately metabolism/excretion.

Whenever I have a suitable candidate for pre-operative oral pain medications, I almost always give them 1,000 mg of oral acetaminophen. Pharmacokinetics owns. 🙂


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