ObjectivesTo compare the effi cacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain. Methods A randomised, double-blind, four-arm, parallelgroup, active controlled trial investigating short-term (day 10) and long-term (week 13) benefi ts and sideeffects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fi xeddose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fi xed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg). Results There were 892 participants (mean age 60.6, range 40-84 years); 63% had radiographic knee osteoarthritis and 85% fulfi lled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p<0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, signifi cantly more participants taking one or two combination tablets rated their treatment as excellent/ good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p<0. 001; paracetamol, 20.3%; ibuprofen, 19.

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The effect compartment does not have real measurable concentrations, but concentrations equate approximately to those observed in the cerebrospinal fluid. A time delay exists before drug reaches the effect compartment, and the equilibration half-time between the central and effect compartment is described by a single first-order parameter (Teq or T(1/2)keo), reported to be approximately 1 h for paracetamol. Paediatric analgesic studies are limited because they have only explored postoperative pain after tonsillectomy or day-stay surgery. Other pain types and pain confounders have not been investigated. Adult studies are also similarly limited. Studies investigating antipyresis have not explored the maximum response, limiting the precision of any EC(50) estimate. The influence of the cyclical nature of fever or initial temperature is seldom accounted for in antipyretic studies. Target effect compartment concentrations of 5 mg/l for fever and 10 mg/l for pain do not seem unreasonable on the basis of current literature. Speed of onset may be shortened by giving a larger initial dose or improving absorption characteristics. Consequent plasma concentration achieved, differences in effect compartment equilibration times, and the shape of the effect compartment concentration-response curve help to explain differences between common analgesic/antipyretic drugs.

The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.

Ibuprofen at a dose of 10 mg/kg and paracetamol at a dose of 15 mg/kg have equivalent efficacy and tolerability; parental opinion in favor of ibuprofen could be explained by additional benefits of ibuprofen that were not measured in this trial and helped allay their anxiety over the treatment of their child.

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