A model was developed to evaluate mild analgesics in an oral surgery outpatient clinic population. On a report form, patients recorded starting pain and then pain intensities, relief responses, and side effects hourly for 3 hr after drug administration. The treatments were randomly allocated to patients on a single-dose-only basis, and the double-blind technique was used. The first of two studies compared codeine 30 mg, aspirin 650 mg, codeine 30 mg with aspirin 650 mg, and placebo in 128 subjects. The second study compared codeine 60 mg, acetaminophen 600 mg, and codeine 60 mg with acetaminophen 600 mg and placebo in 160 subjects. Time-effect curves were generated for both pain relief and pain relief and pain intensity difference (PID). First-hour scores, peak scores, and total scores were statistically analyzed by parametric and nonparametric factorial analysis. Both aspirin 650 mg and acetaminophen 600 mg proved superior to placebo (p less than 0.01) for all measures of effect with both parametric or nonparametric analyses, while codeine 30 mg was not significantly superior to placebo in any analysis. Codeine 60 mg proved significantly superior to placebo for certain measures of effect when analyzed with the nonparametric model. There was no significant interaction between either aspirin or acetaminophen and codeine.

Six randomized, double-blind, two-period crossover studies, conducted under similar protocols, compared the efficacy of two analgesic combinations containing caffeine with an acetaminophen 1000 mg control and with a placebo in outpatients with episodic tension-type headaches. In four studies, comprising 1900 patients, the caffeine-containing analgesic consisted of a combination of 500 mg acetaminophen, 500 mg aspirin, and 130 mg caffeine (APAP/ASA/CAF). In two studies, comprising 911 patients, the caffeine-containing analgesic consisted of a combination of 1000 mg acetaminophen and 130 mg caffeine (APAP/CAF). Patients self-medicated for moderate or severe headache pain, and with a self-rating record they rated their pain and its relief hourly for 4 hours. In all six studies, the caffeine-containing analgesics were significantly superior both to placebo and to 1000 mg acetaminophen, and acetaminophen was significantly superior to placebo. The significant analgesic adjuvant effect of caffeine was independent of patients' usual caffeine use or their caffeine consumption in the 4 hours before medication. For each treatment, the pooled analgesic responses for the four studies of APAP/ASA/CAF were virtually superimposable on the responses in the two APAP/CAF studies. The combinations produced more stomach discomfort, nervousness, and dizziness than acetaminophen or placebo.

Eighty-eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, to receive a single, oral dose of flurbiprofen 100 mg, acetaminophen 600 mg, a combination of acetaminophen 600 mg with codeine 60 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medicating. Estimates of sum of pain intensity differences, peak pain intensity differences, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. Flurbiprofen and the acetaminophen-codeine combination were significantly superior to placebo for every measure of total and peak analgesia and significantly superior to acetaminophen alone for most measures of efficacy. Based on the 12-hour data, acetaminophen alone did not differ significantly from placebo; however, it was superior to placebo for measures of total effect based on the 4-hour data. Flurbiprofen was significantly superior to the acetaminophen codeine combination with respect to the number of hours until remedication. All medications had manifested an effect by hour 1; analgesia persisted for 12 hours for flurbiprofen, 6 hours for acetaminophen-codeine, and 3 hours for acetaminophen alone. The frequency of adverse effects was similar for the active medications.