STUDY OBJECTIVE: To evaluate the effects of acetaminophen, naproxen, and acetylsalicylic acid on the pharmacokinetics of the centrally acting analgesic tapentadol in healthy subjects. DESIGN: Two randomized, open-label, crossover, drug-drug interaction studies. SETTING: Clinical research facilities in the United States and Belgium. PARTICIPANTS: Twenty-four healthy adults (2-way crossover study) and 38 healthy adults (3-way crossover study). INTERVENTIONS: In both studies, tapentadol immediate release (IR) 80 mg was administered as a single oral dose alone. In the 2-way crossover study, tapentadol IR was also given with the fifth of seven doses of acetaminophen 1000 mg; in the 3-way crossover study, tapentadol IR was also given with the third of four doses of naproxen 500 mg and the second of two doses of acetylsalicylic acid 325 mg. All treatments were separated by a washout period of 7-14 days. MEASUREMENTS AND MAIN RESULTS: Overall, mean serum concentrations were similar after administration of tapentadol IR alone and after coadministration with acetaminophen or acetylsalicylic acid, and the 90% confidence intervals (CIs) for the ratios of the mean area under the serum concentration-time curve (AUC) from time zero to time of the last measurable concentration (AUC(0-t)) and from time zero extrapolated to infinity (AUC(0-infinity)) and the maximum serum concentration (C(max)) of the combined treatments to those parameters of tapentadol alone were well within 80-125%, representing the accepted range for bioequivalence. Coadministration of naproxen did not significantly alter the C(max) of tapentadol, although a slightly higher serum tapentadol exposure relative to tapentadol alone was observed. Coadministration of naproxen resulted in a mean increase of 17% in AUCs, and the upper limits of the 90% CIs for the ratios of the mean AUC(0-t) and AUC(0-infinity) were slightly outside the upper limit of bioequivalence range of 80-125%(126.47%AUC(0-t) and 126.14%AUC(0-infinity)). CONCLUSION: No clinically relevant changes were noted in the serum concentrations of tapentadol, and accordingly, no dosage adjustments with respect to the investigated pharmacokinetic mechanism of interaction are warranted for the administration of tapentadol given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid

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BACKGROUND: As part of ongoing studies to evaluate the analgesic efficacy and pharmacokinetic properties of combination oxycodone plus ibuprofen in the treatment of moderate to severe acute pain, 2 pharmacokinetic studies were conducted. OBJECTIVES: The goals of these studies were to compare the pharmacokinetic properties of monotherapy with oxycodone or ibuprofen with those of a tablet formulation of these 2 agents combined (study A), and to determine whether the absorption of the individual agents when given in the combination tablet was affected by the concomitant ingestion of food (study B). METHODS: Study A was a single-center, open-label, randomized, single-dose, 3-period, 3-way, crossover study. Healthy male subjects received oxycodone 5 mg, ibuprofen 400 mg, or a combination tablet containing both, after an overnight fast of > or =8 hours, on study days 1, 8, and 15. Study B was a single-center, open-label, randomized, single-dose, single-crossover study. Healthy volunteers received a tablet containing a combination of oxycodone 5 mg plus ibuprofen 400 mg after either an overnight fast of > or =8 hours or a standardized high-fat breakfast. Both studies included a washout period of > or =7 days between treatments. In both studies, the pharmacokinetic properties (C(max), T(max), t(1/2), AUC(0-4), AUC(0-1), and AUC(0-infinity)) of oxycodone and ibuprofen were derived from plasma drug concentrations. Analysis of variance was used to determine and compare pharmacokinetic properties. RESULTS: Twenty-four healthy, white, male subjects were included in study A (mean age, 26.0 years; mean body weight, 71.3 kg; mean height, 170.0 cm). Study B involved 12 subjects (11 men, 1 woman; mean age, 24.8 years; mean body weight, 77.2 kg; mean height, 181.4 cm). The pharmacokinetic properties of ibuprofen and oxycodone were not statistically different when administered alone or combined. Food intake did not affect the rate of oxycodone absorption (90% Cl of C(max) of fasted state vs fed state, 103-130), or the rate (90% Cl of C(max) of fasted state vs fed state, 72-95) or extent (90% Cl of AUC(0-infinity) of fasted state vs fed state, 88-102) of ibuprofen absorption. The extent of oxycodone absorption was slightly increased when the combination was given with food (90% Cl of AUC(0-infinity) of fasted state vs fed state, 115-127). CONCLUSIONS: The single-dose pharmacokinetic profiles of oxycodone and ibuprofen in these healthy volunteers were similar when these 2 drugs were given as monotherapy or in combination, suggesting bioequivalence. Food intake before administration of a single dose of the combination did not affect ibuprofen absorption but marginally increased the extent, but not the rate, of oxycodone absorption

Nonsteroidal antiinflammatory drugs (NSAIDs) decrease the postoperative requirements for opioid analgesic medication. To determine whether NSAIDs potentiate the respiratory effects of opioids, we studied the effects of ketoprofen (K), an NSAID, on respiratory depression induced by morphine (M) in volunteers. After ethics committee approval, 12 healthy male volunteers received infusions of K (1.5 mg/kg), M (0.1 mg/ kg), and KM (1.5 mg/kg + 0.1 mg/kg) in a double-blind, randomized, three-treatment, three-period cross-over trial. During the three sessions, CO2 rebreathing challenges for ventilatory and occlusion pressure responses to CO2 were performed immediately before and 10, 70, 130, 190, and 250 min after drug infusion over 10 min. Venous blood samples for plasma drug concentrations were withdrawn at the same times. Comparisons were made on slopes of ventilatory and occlusion pressure responses to CO2. Venous blood samples confirmed that morphine plasma concentrations were similar when subjects had received morphine alone and when they had received the combination of drugs. Morphine alone induced a respiratory depression with a decrease in both ventilatory and occlusion pressure responses to CO2. Ketoprofen alone did not produce any respiratory effects. The combination of drugs induced a decrease in ventilatory responses to CO2, but intergroup comparisons showed that this was significantly less marked than the decrease induced by morphine alone. In conclusion, for similar morphine plasma concentrations, respiratory depression was less marked with the combination of drugs than with morphine alone. Therefore, ketoprofen may reduce the respiratory depression induced by morphine