Treatment of pain has always been a major goal in the clinic, as it is related to several pathological conditions of inflammatory origin and surgical procedures, which are associated with inflammatory mediators. Understanding the molecular mechanisms underlying the association between inflammatory mediators and pain perception, from peripheral to central sensitization, can provide the basis for the development of new pharmacological treatments. Despite safety concerns, till date, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to be efficacious, safe, and well tolerated by patients. Thus, choosing the appropriate administration route, developing new formulations and lowering the efficacious dose represent, currently, effective means of treating inflammation and relieving the pain, without inducing significant side effects.