Acetaminophen updates

Recently, the FDA approved an IV formulation of acetaminophen (OFIRMEV) for the management of postoperative pain.
The argument for the IV route was to avoid the slow onset of the analgesic effects after oral delivery.

Since the introduction of the injectable formulation, there have been a large number of robust clinical trials on the efficacy of IV acetaminophen (Jones, 2011). Meta-analyses provide a strong indication of the efficacy of the IV formulation in single-dose, randomized, controlled clinical trials, for acute postoperative pain in adults or children.

In one series, 37% of patients receiving i.v. acetaminophen experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo, with larger effects when baseline pain was greater; fewer patients receiving acetaminophen required rescue medications than those receiving placebo (McNicol et al., 2011). Other analyses demonstrate a significant reduction in postoperative morphine consumption in patients receiving IV acetaminophen (Maund et al., 2011). The analgesic effects of IV acetaminophen display a plateau at doses well above those recommended in the US (e.g., 5 mg/kg; Hahn et al., 2003).

The recommended dose of OFIRMEV in adults is 1000 mg every 6 hrs, delivered as a 15 min infusion.
The maximum dose is 4000 mg in 24 hrs.
Contraindications are the same as those of oral acetaminophen formulations and include conditions of hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment.

MECHANISMS OF ACTION

In fact acetaminophen displayed only modest anti-inflammatory effects.
Some  studies have demonstrated measurable but marginal inhibitory effects of acetaminophen on the COX1, 2, and 3 isoforms (Ouelle and Percival, 2001; Graham and Scott, 2005) suggesting that acetaminophen might act on central pain processing initiated by peripheral tissue injury and inflammation.

Acetaminophen is deacetylated to p-aminophenol in the liver.
In the brain and spinal chord, p-aminophenol can be conjugated with arachidonic acid by fatty acid amide hydrolase (FAAH) to form N-arachidonoylphenolamine (AM404; Högestätt et al., 2005).
This particular product is an agonist at both TRPV₁ (vanilloid or capsaicin) and CB₁ (cannabinoid receptors), both of which are expressed heavily in neurons of the spinal and supraspinal pain pathways. While agonists of TRPV₁ are thought to activate small primary afferent and produce pain, CB₁ agonists are known to reduce nociceptive processing. Indeed, the effects of acetaminophen were reduced by CB₁ antagonists (Ottani, et al., 2006).

We conclude that the mechanism of action of acetaminophen has yet to be fully elucidated