The original definitive study which established the value of 5-aminosalicyclic acid in preventing relapse was published by Misiewicz and colleagues in 1965.1 In this first placebo-controlled maintenance trial, patients were randomised to receive sulfasalazine or placebo for one year. Seventy-three per cent of patients taking the placebo relapsed during that time, compared to 21% taking the active drug.
The benefit from sulfasalazine was subsequently shown to persist regardless of how long a patient had already been taking it.
The Oxford group demonstrated a dose–response relationship, in that higher doses of sulfasalazine appeared to be more protective, although the differences that were demonstrated between 2 and 4 g/day were not significant.2
The Oxford group also showed that the active moiety in sulfasalazine was the 5-aminosalicyclic acid, rather than the sulphur component,3 which was also found to be responsible for many of the side-effects of sulfasalazine, such as headaches, rash, gastrointestinal effects (especially nausea), and male infertility. Side-effects were experienced by about 20% of patients taking this drug. This led to the development of a new generation of 5-aminosalicylic acid drugs which did not contain sulphur.
Because 5-aminosalicylic acid is readily absorbed from the upper gastrointestinal tract, and because it works via a luminal mechanism, it needed to be formulated in a preparation allowing it to be delivered intact to the large bowel. Subsequent formulations included coating the 5-ASA with a pH sensitive coating (Eudragit) that would allow mesalazine (5-aminosalicyclic acid) to be liberated in the mid and distal small bowel at a pH of 6 or more (Claversal or Salofalk) or in the terminal ileum at a pH 7 or more (Asacol). An alternative approach involved substituting the sulphonamide part of the sulfasalazine molecule with either an inert carrier molecule (balsalazide, Colazide) or another 5-ASA molecule (olsalazine, Dipentum), with the azo bond still broken to release the active drug by bacteria in the proximal colon. A third approach involved formulating the 5-ASA in ethylcellulose microgranules which are liberated progressively through the small bowel and colon (mesalazine, Pentasa). Each of these drugs has a different profile with regard to release, potential side-effects, and concentration in different parts of the intestine.
Numerous subsequent studies have demonstrated a similar therapeutic efficacy in maintaining remission in ulcerative colitis for sulphasalzine and the range of newer 5-ASA preparations. Sutherland et al. have recently undertaken a systematic review of all the double-blind randomised controlled studies of the 5-ASA containing drugs, conducted between 1981 and 1998, for this indication.4 5-aminosalycylic acid was superior to placebo in reducing the chance of relapse. There appeared to be a marginal superiority of sulfasalazine over newer 5-SASA drugs.
Although each of the mesalazine preparations is superior to placebo in maintaining remission, there may be differences in efficacy between these preparations.
For patient convenience and compliance, twice daily dosing is probably optimal to maintain remission. It may be that once daily dosing would also be effective, but there are too few data to be certain about this. A dose of 1 g twice per day appears to be an effective compromise which decreases relapse rate while not producing too many side-effects. Higher doses can be employed if a patient still experiences frequent relapses.
Rectal preparations of mesalazine have been shown to be effective in acute episodes of colitis, and in maintaining remission. Marshall & Irvine undertook a meta-analysis of five controlled trials comparing rectal mesalazine with placebo in maintaining remission for distal colitis.5 There was a clear superiority of mesalazine over placebo.
Maintenance of remission has usually involved the daily use of medication. However, given the unpleasantness and inconvenience of using rectal preparations each day or night, it may be possible to maintain remission using less frequent administration. Slow release 1 g mesalazine suppositories used three times per week were compared with placebo in maintaining remission in patients with proctitis.6 Patients were treated for 1 year. If they experienced a flare up they used their suppositories each night, and then reverted to three times per week when the condition had settled. The relapse rate was lower in the mesalazine group for the first three quarters of the year, but not at 1 year. However, 61% of patients on mesalazine, and 28% of patients on placebo remained in the protocol and were in remission at 1 year.