Current issues of ACP Journal Club are published in Annals of Internal Medicine


A morning dose of ketoprofen was better than evening doses for pain reduction in osteoarthritis

ACP J Club. 1993 Nov-Dec;119:75. doi:10.7326/ACPJC-1993-119-3-075

Source Citation

Vinje O, Fagertun HE, Laerum E, et al. Ketoprofen controlled release (CR) in the treatment of osteoarthritis; a double blind, randomized multicentre study of single morning versus evening dose. Scand J Prim Health Care. 1993 Jun;11:91-7.



To compare the efficacy and gastrointestinal tolerability of single dose morning and evening controlled-release ketoprofen for adults with osteoarthritis (OA).


Randomized, multicenter, placebo-controlled, double-blind, crossover trial.


Primary care clinics in Norway.


194 patients with OA of the hips or knees (diagnosis based on at least 3 of reduced joint space, degenerative changes of the head of the femur or tibial condyles, bone cyst formation, subchondral sclerosis, or ostephytes) were enrolled. Exclusion criteria were chronic inflammatory rheumatic disease, severe hepatic or renal disease, serious gastrointestinal disease within the previous year, severe infection within the previous month, known intolerance to nonsteroidal anti-inflammatory agents, salicylate-sensitive asthma, or previous joint surgery. Data from 163 patients (mean age 64 y) were analyzed.


Anti-inflammatory therapy was withdrawn during a 1-week run-in period, and patients were then randomized to receive controlled-release ketoprofen, 200 mg, either morning or evening, with matching placebo for 4 weeks. After a 1-week wash-out period, the alternate regimen was given for 4 weeks. 73 patients completed the morning-first treatment plan, and 90 patients completed the evening-first treatment plan.

Main outcome measures

Morning stiffness, knee or hip flexion, intermalleolar distance, degree of pain (visual analog scale), walking capacity, and gastrointestinal side effects (heartburn, nausea, gastric pain, constipation, diarrhea) were assessed at the beginning and end of each treatment period. The most affected joint was evaluated.

Main results

Evening medication compliance was better (mean number of missed pills per 4-wk period was 0.6 for evening vs 1.2 for morning for each treatment period, P = 0.05). Both morning and evening doses reduced pain compared with baseline periods ( P< 0.01). The morning dose resulted in more pain reduction than the evening dose for afternoon and evening pain. Increased frequency and degree of gastrointestinal side effects (gastric pain and constipation) were recorded during both treatment periods ( P< 0.01) compared with baseline periods. No differences in tolerability were noted for the 2 regimens.


Controlled-release ketoprofen given to patients with osteoarthritis once in the morning, compared with once in the evening, had increased efficacy without increasing side effects.

Source of funding: Not stated.

For article reprint: Dr. O. Vinje, Oslo Sanitetsforening Rheumatism Hospital, Akersbakken 25, 0172 Oslo, Norway. FAX 47-2-211-4969.


Vinje and colleagues concluded that 1 morning dose of controlled-release ketoprofen decreased the pain of OA more effectively than did the same medication given in the evening, without increasing gastrointestinal intolerability. The study was methodologically sound but several points should be considered by the physician who attempts to translate the results into clinical practice.

As the authors note, the study period was short; effects were compared during only 4 weeks of treatment. It might be expected that after longer exposure, gastrointestinal side effects might increase, and differences between morning and evening dosing could emerge.

The clinician who reads this article might be considering prescribing controlled-release ketoprofen for patients with rheumatoid arthritis (RA), but that extrapolation might not be valid. Persons with RA, as opposed to OA, typically have severe stiffness on arising and thus might find evening dosing more effective than morning dosing. Persons with RA are also frequently taking concurrent medication with major gastrointestinal toxicity, the timing of which might alter the tolerability of a nonsteroidal anti-inflammatory drug.

Finally, there is the crucial issue of compliance, which the authors did not address directly. Their conclusions are based on the assumption of equal compliance with morning and evening dosing, an assumption that their own data belie. Just as patients take a once-daily medication more faithfully than a multiple-dose medication because daily activities have less chance to interfere, patients who are overwhelmed with family or business concerns in the morning may take medication more faithfully at night when extraneous concerns are less intrusive.

In addition to considering the results of this short-term study, when physicians prescribe controlled-dose ketoprofen for patients with arthritic pain, they should also take into account the nature of each patient's symptoms, concurrent medications, and lifestyle.

Mary E. Moore, PhD, MD
Albert Einstein Medical CenterPhiladelphia, Pennsylvania, USA