Population-based Case-control Study

Chemoprotection of Colorectal Cancer With Non-aspirin Nonsteroidal Anti-inflammatory Drugs and Other Drugs for Pain Control

Antonio Rodriguez-Miguel; Luis A. Garcia-Rodríguez; Miguel Gil; Diana Barreira-Hernández; Sara Rodriguez-Martín; Francisco J. de Abajo


Aliment Pharmacol Ther. 2019;50(3):295-305. 

In This Article

Abstract and Introduction


Background: Inflammation and overexpression of cyclooxygenase-2 (COX-2) have been described to play a key role in the progression from nonpathologic intestinal mucosa to colorectal cancer (CRC).

Aims: To assess the chemoprotective effect of non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) under different patterns of use in a Mediterranean population and to explore the potential effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs; chondroitin sulfate and glucosamine) and metamizole (or dipyrone), also reported to influence COX-2 activity.

Methods: We performed a case-control study nested in a cohort extracted from the primary care database, BIFAP. From 2001 to 2014, we included 15 491 incident cases and 60 000 random controls. To estimate the association between the drugs of interest and CRC, we built logistic regression models to compute the adjusted-odds ratios (AOR) and 95% confidence intervals (CI).

Results: NA-NSAIDs use was associated with a reduced risk of CRC (AOR = 0.67; 95% CI: 0.63-0.71) and increased linearly with duration of treatment (p for trend <0.001). The effect diminished upon discontinuation but persisted statistically significant up to 1 year. All individual NA-NSAIDs examined showed a decreased risk. The concomitant use of proton-pump inhibitors (PPI) had no impact on the protective effect of NA-NSAIDs; AORPPI + NSAID = 0.64; 0.58-0.71. SYSADOA use was associated with a reduced risk (0.79; 0.69-0.90) but disappeared after the exclusion of NSAID users during the previous 1 or 3 years (0.85; 0.70-1.04 and 1.00; 0.76-1.31 respectively). Metamizole did not show a chemoprotective effect.

Conclusions: NA-NSAID use is associated with a duration-dependent risk reduction of CRC not shared by SYSADOAs or metamizole.


Colorectal cancer (CRC) is the most prevalent type among men and women in western lifestyle countries.[1,2] Although overall 5-year survival has reached up to 65% in these countries, in part associated to efficient strategies of prevention and treatment, their effectiveness can vary drastically depending on the stage at diagnosis.[1,3] About 70%-80% of all CRC diagnosed are sporadic forms.[4,5] Apart from sex, age or family history of CRC, other risk factors are known to be involved in the tumourigenesis of CRC, as inflammatory status[3,4] to which some metabolic disorders like diabetes or visceral obesity could contribute to.[6] To this day, several drugs have been reported to show a protective effect against CRC,[7] placing chemoprotection as another factor to be considered in prevention strategies. In fact, in 2016, the US Preventive Services Task Force (USPSTF) endorsed the use of low-dose aspirin for primary prevention of cardiovascular diseases and CRC in a specific group of population.[8] Recently, new results from three randomised clinical trials assessing the efficacy of low-dose aspirin in primary prevention of cardiovascular diseases, have been published concluding that the risks may outweigh the benefits.[9–11] Although non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) have shown a remarkable reduction in the incidence of colonic adenomas and CRC in a large number of observational studies and randomised clinical trials,[12–14] their use for that indication, at present, is not supported due to cardiovascular and gastrointestinal (GI) harms.[12] Thus, it would be necessary to gather updated evidence on the chemoprotective effect of NA-NSAIDs under different patterns of use (daily dose, duration, treatment persistence, concomitant use with proton-pump inhibitors (PPI) or the influence of sex and age) in order to gauge how to optimise the benefit-risk ratio and perhaps, reconsider them as suitable chemoprotective agents for the prevention of CRC. On the other hand, the evidence at individual drug level is still scarce, mostly due to the limited number of users included in previous studies;[14] hence, we need more data to assess whether all individual NA-NSAIDs share the same effect or not. Other agents with allegedly anti-inflammatory actions, like systemic slow-acting drug for osteoarthritis (SYSADOAs),[15,16] have also been reported to reduce the risk of CRC,[17–21] but these data need to be replicated in other studies and populations. Finally, metamizole (or dipyrone), an analgesic, anti-pyretic and spasmolytic drug widely used in Spain and other countries, has been reported to inhibit peripheral cyclooxygenase (COX) enzymes[22] and then could also be potentially useful as a chemopreventive agent.