Other minor metabolites, each accounting for 4% or less of a therapeutic dose, include sulfate and glucuronide conjugates of 3-methoxy-acetaminophen, 3-hydroxy-acetaminophen, and 3-methyl-thioacetaminophen.^39,41-43 Slight differences have been seen in ethnically distinct populations (eg, Asian, Spanish).^36,44-46

Clinical Studies: Therapeutic Comparisons With Other Drugs Or Treatments

a. Antipyresis

In controlled trials, acetaminophen was shown to be superior to placebo.^53-56 Tepid sponging and acetaminophen have been shown to be approximately equivalent for the initial 30 minutes of treatment, after which acetaminophen is superior. The combination of acetaminophen and sponging may provide additive benefit, but at the expense of additional discomfort to the child.^54,56. There is no significant difference in antipyresis between equivalent doses of aspirin and acetaminophen. ^51,52,57,58 Comparative clinical studies of the antipyretic efficacy of acetaminophen and ibuprofen administered in recommended dosages to pediatric patients suggest that both drugs are effective.^59-62 However, results vary depending on the dosage of each agent administered. Acetaminophen at a dose of 15 mg/kg is equivalent to ibuprofen at a dose of 10 mg/kg.⁶⁰ Acetaminophen 10 mg/kg or 12.5 mg/kg does not produce the same degree of antipyresis as ibuprofen 7.5 mg/kg or 10 mg/kg.^59,61,62 Acetaminophen 12.5 mg/kg is superior to ibuprofen 5 mg/kg.⁶³ In these studies, onset of antipyresis with acetaminophen generally occurred within 30 to 60 minutes following administration and peak antipyresis was noted at 2 to 3 hours.

b. Analgesia

Acetaminophen is effective in the treatment of various disorders associated with pain of mild to moderate intensity. Studies have been performed in a variety of pain models to assess the overall efficacy of acetaminophen. Clinical research has substantiated efficacy in pain associated with the following conditions:

Arthritis Pain

At recommended dosages, acetaminophen is well tolerated and effective for the treatment of minor pain of arthritis. Clinical studies have compared the efficacy of acetaminophen to placebo, ibuprofen, and naproxen in patients with osteoarthritis of the knee.^48-50 In a double-blind, placebo-controlled study, Amadio and Cummings⁴⁸ found that 1000 mg of acetaminophen administered four times daily was significantly more effective than placebo in relieving tenderness, pain at rest, and pain on motion. In a randomized, double-blind study comparing acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400 mg/d) doses of ibuprofen, Bradley and colleagues49 reported that acetaminophen was comparable to both doses of ibuprofen in relieving pain. In a double-blind study lasting up to 2 years that compared the relative safety and efficacy of acetaminophen (2600 mg/d) to naproxen (750 mg/d), Williams and associates⁵⁰ noted that acetaminophen was similar to naproxen in improving pain on motion and in physicians' global assessment of disease activity.

Acetaminophen taken for 1 month to 2 years is beneficial in relieving osteoarthritic pain and causes no significant adverse effects. American College of Rheumatology* Guidelines for the Medical Management of Osteoarthritis, published in 1995, recommend acetaminophen in doses up to 4000 mg daily as the preferred first-line therapy in patients with symptomatic osteoarthritis of the knee.⁶⁴

Headache

Three randomized, multicenter, double-blind, single-dose, placebo-controlled studies have been conducted by McNeil (unpublished), which evaluated the efficacy of acetaminophen in the tension headache model. In the first study, patients were treated with acetaminophen 1000 mg, ibuprofen 200 mg, ibuprofen 400 mg, or placebo. The active treatments were more effective than placebo, and neither strength of ibuprofen was different from acetaminophen; however, ibuprofen 400 mg was significantly more effective than ibuprofen 200 mg in patients' overall evaluation. The second study compared the efficacy of acetaminophen 1000 mg, naproxen 375 mg, and placebo. Acetaminophen and naproxen were rated significantly higher than placebo but were not different from each other. The third study evaluated acetaminophen 1000 mg, naproxen sodium 440 mg, and placebo. Both active treatments were significantly better than placebo. Naproxen sodium was significantly more effective than acetaminophen for patients with baseline pain of moderate severity. However, comparisons of patients with severe baseline pain were not significantly different between the active treatment groups.

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