Evaluation of analgesic efficacy, gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective, preferential and selective cyclooxygenase inhibitors with paracetamol in rats.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are combined with paracetamol (PCM) with a view to enhance analgesic efficacy and reduce gastric toxicity. However, there are reports of enhanced nephrotoxicity with nonselective NSAID with PCM combinations. The present study investigated the analgesic efficacy, gastrotoxicity and nephrotoxicity of nonselective, preferential and selective cyclooxygenase inhibitors and their combination with PCM in rats. Graded doses of ibuprofen, meloxicam and celecoxib alone and their combination with fixed dose of PCM were administered to the rats by gavage for 14 days. The results showed that PCM potentiated the analgesic effect of all three classes of NSAIDs significantly as evidenced by increase in tail-flick latency in radiant heat method. Dose-dependent gastromucosal damage was produced by all the drugs, which was augmented significantly with PCM in the form of decreased total carbohydrate/protein ratio of mucin and increased gastric ulcer index. It was further confirmed by histopathology of rat's stomach. The renal histopathology was conducted to evaluate inflammation, tubular damage, papillary necrosis, and interstitial changes. Increased nephrotoxicity was observed with all NSAIDs in dose-dependent manner and in combination with PCM. Our study revealed the augmented analgesia as well as enhanced gastrotoxicity and nephrotoxicity with all three major NSAIDs classes when combined with PCM. These findings highlighted the need for large pharmacoepidemiological studies to evaluate the magnitude of gastrotoxicity and nephrotoxicity in population who are on long-term treatment with NSAID combinations.