Combined use of NSAIDs and SSRIs increases the risk for gastrointestinal adverse effects

Abstract

Zullino and Khazaal rightly indicate that NSAIDs and SSRIs both cause alterations of thrombocyte aggregation and consequently increase the risk of gastrointestinal adverse effects. However, they question whether the 10 times higher risk for GI adverse effects during combined use of an NSAID with an SSRI is due to a pharmacodynamic interaction, and whether this higher risk is a class effect of the SSRIs rather than of individual SSRIs. The NSAIDs in our study group consisted of diclofenac (46%), ibuprofen (31%), naproxen (14%) and small numbers of indomethacin, aceclofenac, piroxicam, meloxicam, rofecoxib and nabumeton. Apart from one patient taking rofecoxib all other NSAIDs are metabolized by CYP2C9 [1]. Measured by proxy, we found for this group a relative risk of 3.3 (95% CI 1.5, 7.1) [unpublished data]. In their case-control study De Abajo et al. reported a relative risk for GI adverse effects of 3.7 for unspecified NSAIDs [2]. For the SSRIs we found a relative risk of 1.2. The SSRIs in the study group are fluoxetine (24%), citalopram (7%), paroxetine (60%), sertraline (2%) and fluvoxamine (6%). Of these, only fluvoxamine is a strong CYP2C9 blocker. However, the patients who actually reported GI adverse effects in combination with an NSAID, had the relatively weak blockers fluoxetine and paroxetine. Therefore, the 10 times higher risk, reported for the combined use, cannot be explained by a mere additive effect of the increased risks of SSRIs and NSAIDs. Genetic polymorphism of CYP2C9, causing poor metabolism, might be a contributing factor to this increased risk [3]. In conclusion, our data do not support the suggestions of Zullino & Khazaal. We believe that the 10 times higher risk for the combination of NSAIDs and SSRIs as compared with SSRIs alone is not caused by mere pharmacokinetic interaction. Instead, polymorphism of CYP2C9 might be involved. Efforts should be made to avoid the combination.