Clinical chronopharmacology with special reference to NSAIDs

Both drug disposition and effects vary as a function of dosing time. A chronotherapeutic study was therefore undertaken with sustained-release indomethacin (ISR) to quantitate any potential therapeutic gain from an optimal time of administration. Four studies were performed on a total of 517 patients with osteoarthritis of the hip or knee. Each patient took the same dose of ISR at 8:00 am for one week, 12:00 noon for one week and 8:00 pm for one week. In addition to conventional evaluation criteria, patients performed self-rating of pain on visual analogue scales. Overall, there were 44 withdrawals (29 associated with morning ingestion). At group level, time-dependent differences in drug effectiveness were small, although large inter-individual differences were documented. Evening ingestion was most effective in patients with predominant nocturnal or morning pain; conversely, morning or noon ingestion was most effective in patients with maximum afternoon or evening pain. A four-fold improvement in tolerance and a doubling of analgesic effectiveness resulted from varying the ingestion time. Chronotherapeutic studies should therefore include careful longitudinal documentation of pertinent marker rhythms such as self-rating of pain.