Endoscopic evaluation of the gastrotolerance of short-term antalgic treatment with low dose k-diclofenac
Nonsteroidal anti-inflammatory drugs (NSAIDS) are widely used at a low dosage as an analgesic treatment. They are very efficient analgesic and anti-inflammatory drugs but may cause gastrointestinal damage by two independent mechanisms: a systemic effect (mediated by cyclo-oxygenase 2 inhibition) and a local effect that is pH and pKa related.
Low dose ibuprofen is the reference treatment in analgesic indications, thanks to its analgesic effect without anti-inflammatory activity and the lowest gastrotoxicity.
Diclofenac-K (Cataflam®) is a new pharmaceutical formulation of diclofenac that is not enteric-coated, unlike Voltarene® (diclofenac-Na). Cataflam® looks very attractive in analgesic indications because of its bioequivalence in terms of AUC to diclofenac-Na and a more rapid onset of the analgesic action related to a shorter t max (0.7 ± 0.5 h vs. 2.3 ± 0.9 h). Before generalising its use however, gastric tolerance must be evaluated. Upper fibroscopy is the validated method for visualising and scoring the gastric lesions.
The aim of the present study is to compare short-term gastro-duodenal tolerance of diclofenac-K 12.5 mg (simple analgesic dose) with acetylsalicylic acid 500 mg and ibuprofen 200 mg; all three at the maximal dose recommended in pain indications.
The study was a monocenter single-blind and evaluator blind three way cross-over randomised trial. Thirteen healthy volunteers (10 females and 3 males; mean age 25 years) were enrolled. They did not take any medication, other than oral contraceptives for females, during the study.
At the selection visit, all subjects provided written informed consent. The treatment was allocated in a random order: diclofenac-K 12.5 mg, ibuprofen 200 mg or aspirin 500 mg (acetyl salicylic acid), two tablets of each tid for 48 h. Each treatment period was separated by a wash-out period of at least 14 days. Each volunteer had four endoscopies: the first at inclusion and then one at the end of each period treatment. The endoscopy was carried out 2 h after the last intake of the study medication. Endoscopic findings were graded from 0 to 4 using Lanza scales. The study protocol received the approval of the Ethics Committee of St Louis-Lariboisière.
The primary evaluation criteria was the gastric Lanza score assessed through gastro-intestinal endoscopic examinations. They were performed by a single gastro-enterologist (JFB) at inclusion and 2 h after the last intake of each study medication. The Lanza score is described elsewhere. In summary: 0, normal mucosa; 1, mucosal erythema; 2, 2–10 erosions; 3, 6–10 erosions; 4, > 10 erosions or an ulcer.
Statistical analysis was performed by analysis of variance of the gastric Lanza scores, taking account of subject effect, treatment effect and period–treatment interaction (two-sided test, alpha=5%).
The results for the gastric Lanza score are presented. The analysis was performed with 12 subjects. Subject 11 prematurely discontinued the study at visit 4 (day 42) further to a cutaneous rash that appeared 12 days after the last intake of diclofenac-K. He was replaced by another subject, keeping the same sequence of treatment.
The mean gastric Lanza scores of diclofenac-K and ibuprofen were not significantly different (0.33 ± 0; 49 vs. 0.42 ± 0.67; P=0.66), whereas the gastric Lanza score of aspirin was significantly higher (2.67 ± 0.89; P=0.0029 and P=0.002 for the comparison of aspirin with diclofenac-K and ibuprofen, respectively). Treatment effect was significant (P=0.0001). There was no period effect (P=0.25). Four volunteers out of 12 experienced mild adverse events: 2 pyrosis (aspirin); 1 buccal aphtae and 1 epigastric pains (diclofenac-K).
Filed under: Clinical Pharmacology