M01: Antiinflammatory and antirheumatic products
M01 holds the anti-inflammatory and antirheumatic products. M01A holds the non-steroidal anti-inflammatory drugs (NSAIDs), and M01C a few specific antirheumatic agents, such as gold preparations and penicillamine. The disease-modifying drugs listed in the rheumatoid arthritis primer all carry ATC codes outside M01 [1].
How do NSAIDs work?
NSAIDs are inhibitors of the cyclooxygenase (COX) enzymes. There are two isoforms: COX-1 is critical to normal platelet function, and COX-2 mediates the inflammatory response. Conventional NSAIDs inhibit both. Celecoxib (M01AH01), from the coxib subgroup, inhibits COX-2 but spares COX-1 at therapeutic doses [2].
Efficacy
The endpoint is pain, and the pain relief NSAIDs give varies markedly, partly because human pain is quantified imprecisely [3].
In a postoperative pain trial of intramuscular ketorolac (M01AB15) in 522 patients, pain relief was recorded on a five-category ordinal scale. The population model characterized the distribution of these scores. Models for such scores are covered under ordinal data. Pain relief depended on ketorolac concentration through an Emax model, on time through a waxing and waning placebo effect, and on an individual random effect. The effect lagged behind plasma concentration, with an equilibration (ke0) half-life of 24 minutes. Patients with insufficient relief could take rescue medication, and 288 of the 522 did so within the 6 hours of observation. The probability of remedication depended on the observed pain relief and increased with time [4].
In a simulation study of informative dropout, which depended on the efficacy variable as remedication does here, leaving the dropout out of the model biased fixed-effect estimates by up to 21% with FOCE-I, although the effect on predictions was small, and a dropout model was needed to simulate realistic trial outcomes [5].
In osteoarthritis trials, pain can be scored with the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which also has subscales for stiffness and function. In a model-based meta-analysis of 130 placebo-controlled trials of oral treatments, the placebo response reached 90% of its maximum between 5 and 7 weeks. The size of the placebo response was associated with the baseline score [6].
Safety
NSAIDs are associated with gastrointestinal and cardiovascular complications [3]. In a meta-analysis of three case-control studies, the risk of serious upper gastrointestinal bleeding varied twenty-fold between individual NSAIDs, and three- to seven-fold with the dose chosen. Ibuprofen (M01AE01) carried the lowest risk of the drugs studied. The risk was highest in the first week of use [7].
In a trial in 24 healthy adults, the conventional NSAID naproxen (M01AE02) reduced platelet aggregation and prolonged bleeding time, while celecoxib did not, even at a supratherapeutic dose, consistent with its sparing of COX-1 [2].
Patients with reduced renal blood flow depend on prostaglandin synthesis to maintain renal function, and in them NSAIDs can cause renal abnormalities. Fluid retention is the most common renal complication, while high blood potassium (hyperkalemia) and acute deterioration of renal function occur in patients at risk [8].