William T. Beaver

A model to evaluate mild analgesics in oral surgery outpatients

A model was developed to evaluate mild analgesics in an oral surgery outpatient clinic population. On a reportform, 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 reliel 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 < 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.

Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain

Two randomized, double‐blind, parallel‐group single‐dose 2 × 2 factorial analgesic studies compared a single‐dose or a 2‐tablet dose of a combination of 7.5 mg hydrocodone bitartrate with 200 mg ibuprofen with each constituent alone and with a placebo in women with moderate or severe postoperative pain from abdominal or gynecologic surgery. A nurse‐observer recorded patient reports of pain intensity and pain relief periodically for 8 hours. In both studies, the combination was significantly superior to placebo for sum of the pain intensity differences (SPID), total pain relief (TOTPAR), peak pain intensity difference (PID) and pain relief, global evaluation, and time to remedication. The combination was likewise significantly superior to both hydrocodone and ibuprofen for most of these summary measures of analgesia. In a factorial analysis, both the hydrocodone and ibuprofen effects were significant for most summary measures of analgesia, whereas results of the interaction contrast were consistent with the concept that the analgesic effect of the combination represents the additive analgesia of its 2 constituents.

Evaluation of ketorolac, ibuprofen, acetaminophen, and an acetaminophen-codeine combination in postoperative oral surgery pain.

Two‐hundred six outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned on a double‐blind basis to receive oral doses of ketorolac tromethamine 10 and 20 mg, ibuprofen 400 mg, acetaminophen 600 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. Analgesia was similar for ketorolac 10 and 20 mg and ibuprofen 400 mg; however, these treatments were superior to acetaminophen alone and the acetaminophen‐codeine combination. The analgesic effect of each active medication was significant by hour 1 and persisted for 5–6 hours. The data suggest a plateau in ketorolacs analgesic efficacy at the 10‐mg level. Repeat‐dose data indicated that on the day of surgery ketorolac 10 and 20 mg and ibuprofen 400 mg were superior to acetaminophen 600 mg; ketorolac 20 mg was also superior to acetaminophen‐codeine. Differences among active medications were not significant when data for the entire postoperative period (days 0–6) were evaluated. The frequency of adverse effects was similar for the active medications.

Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain

Recent studies have demonstrated that caffeine acts as an analgesic adjuvant when combined with acetaminophen, aspirin, or their mixture. Our objective was to determine whether similar enhancement of analgesia could be demonstrated when caffeine is combined with ibuprofen. On a double‐blind basis, a single oral dose of ibuprofen (50, 100, or 200 mg), a combination of ibuprofen, 100 mg, with caffeine, 100 mg, a combination of ibuprofen, 200 mg, with caffeine, 100 mg, or placebo was randomly assigned to 298 outpatients with postoperative pain after the surgical removal of impacted third molars. With a self‐rating record, subjects rated their pain and its relief hourly for 8 hours. All active treatments were significantly superior to placebo, and the caffeine effect was significant for every measure of analgesia. Relative potency estimates indicated that the combination was 2.4 to 2.8 times as potent as ibuprofen alone. The combination also had a more rapid onset and longer duration of analgesic action. The analgesic adjuvancy of caffeine clearly extends to combinations with nonsteroidal anti‐inflammatory drugs other than acetaminophen or aspirin.

Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain.

One‐hundred twenty‐eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double‐blind basis, to receive oral doses of ketorolac tromethamine 10 mg, aspirin 650 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. The acetaminophen‐codeine combination was significantly superior to aspirin for peak analgesia. Ketorolac was significantly superior to aspirin for every measure of total and peak analgesia, and significantly superior to acetaminophen‐codeine for measures of total effect. The analgesic effect of ketorolac was significant by hour 1 and persisted for 6 hours. Repeat‐dose data also suggested that ketorolac 10 mg was superior to aspirin 650 mg and acetaminophen‐codeine on the day of surgery. Differences among the active medications were trivial for the postoperative days 1–6 analyses. The frequency of adverse effects was over 4 times greater for acetaminophen‐codeine than for ketorolac or aspirin.

The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia: A double-blind, randomized, placebo-controlled, parallel study

Twenty severely retarded institutionalized epileptic adults with phenytoin-induced gingival hyperplasia were divided into two groups and received a daily 3 mg capsule of either folic acid or lactose for 16 weeks in a randomized, double-blind, parallel study. Serum folate and phenytoin levels were recorded at baseline and on completion of the study. Twelve areas of the gingiva on each patient were graded at 4-week intervals for 16 weeks with respect to the three indexes: hyperplasia, gingival health, and plaque index. There were no significant differences between treatment groups for any of the three indexes over time. The poststudy serum folate levels were three times baseline levels for the active drug group (p less than 0.001) but unchanged in the placebo group. Phenytoin blood levels that began within the therapeutic window (10 to 20 micrograms/ml) tended to remain within the therapeutic window for both groups, with no reported seizure activity. A single daily oral 3 mg capsule of folic acid did not show efficacy as the sole therapeutic agent in the reduction of phenytoin-induced gingival hyperplasia.

Analgesic efficacy of bromfenac, ibuprofen, and aspirin in postoperative oral surgery pain

We recently demonstrated that 25 mg of bromfenac, a new nonsteroidal anti‐inflammatory analgesic, is at least as effective as 400 mg of ibuprofen in relieving postoperative oral surgery pain. Our objective in this study was to determine whether higher doses were significantly more effective. Two hundred eighty (280) outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double‐blind basis, a single oral dose of 10, 25, 50, or 100 mg bromfenac; 650 mg aspirin; 400 mg ibuprofen; or placebo. Subjects rated their pain and its relief for 8 hours. All active treatments were significantly superior to placebo, and bromfenac and ibuprofen were significantly superior to aspirin. The slope of the dose‐response curve of bromfenac was significant. The 100 mg bromfenac dose was significantly more effective than the 400 mg ibuprofen dose and had a significantly longer duration of analgesic action.

A Comparison of the Analgesic Effect of Oxymorphone by Rectal Suppository and Intramuscular Injection in Patients with Postoperative Pain

The relative analgesic potency of oxymorphone by rectal suppository and intramuscular injection was evaluated in a double-blind, twin-crossover comparison of graded single doses in 136 patients with postoperative pain. The time-effect curves of the two routes of administration differed substantially; rectal resulted in lower and more delayed peak analgesia and a longer duration of action than intramuscular administration. When both duration and intensity of analgesia are considered (total effect), rectal oxymorphone was 1/10 as potent as the intramuscular form; in peak effect, it was only 1/16 to 1/20 as potent. However, because intramuscular oxymorphone is nine to ten times as potent as intramuscular morphine, 5 to 10 mg oxymorphone by suppository provides analgesia comparable to that provided by the usually used doses of parenteral narcotics. Rectal oxymorphone produced no more, and perhaps somewhat fewer, side effects than doses of intramuscular oxymorphone producing equivalent total analgesic effect. None of the patients objected to the rectal route of analgesic administration. This study demonstrates the feasibility of well-controlled analgesic assays employing the double-dummy technique to compare suppositoreis with oral or parenteral analgesic dosage forms. Our observations also suggest that the rectal route is an acceptable and practical way of administering potent analgesics and is probably being underutilized by physicians in the control of moderate to severe pain.

Evaluation of aspirin, caffeine, and their combination in postoperative oral surgery pain.

Three hundred fifty 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 aspirin 650 or 1000 mg, caffeine 65 mg, a combination of aspirin 650 mg with caffeine 65 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. Estimates of summed pain intensity difference, peak pain intensity difference, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. All active treatments except caffeine were significantly superior to placebo. Pairwise comparisons indicated the aspirin‐caffeine combination was statistically superior to aspirin 650 mg alone for hours of 50% relief among patients who had severe baseline pain. Adverse effects were transitory and none were serious.

Evaluation of Bromfenac, Aspirin, and Ibuprofen in Postoperative Oral Surgery Pain

Two hundred forty‐one 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 bromfenac 5, 10, or 25 mg, aspirin 650 mg, ibuprofen 400 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief for 8 hours after medicating. Estimates of summed pain intensity difference, peak pain intensity difference, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. All active treatments were significantly superior to placebo, and the slope of the dose‐response curve for bromfenac was significant. Bromfenac 5 mg and aspirin 650 mg were equianalgesic; bromfenac 25 mg was slightly more efficacious than ibuprofen 400 mg. Bromfenac 25 mg and ibuprofen 400 mg were significantly superior to the other active treatments. Adverse effects were transient and consistent with the pharmacologic profiles of the medications evaluated.