Clinical Chronopharmacology with Special Reference to NSAIDs

Abstract

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.