**2. NSAIDs and acetaminophen**

Nonselective NSAIDs act inhibiting both the COX‐1 and the COX‐2 enzymes, leading this mechanism of action to both the therapeutic and toxic effects associated with their use. They are extensively prescribed to treat acute and chronically painful conditions. Complications with the use of these agents range from minor gastric complaints (nausea, abdominal pain, etc) to serious complications (gastric ulcers, bleeding, etc). These drugs inhibit platelet aggre‐ gation and increase bleeding time. The introduction of COX‐2 selective NSAIDs in the mar‐ ket did not lead to a more effective and safer therapy, and cardiovascular complications associated with these agents culminated in the withdrawal of rofecoxib and valdecoxib from the market in 2004 [3, 4].

Both COX‐2 selective and nonselective NSAIDs can also cause adverse renal outcomes in chronic use [3, 5]. So, risks associated with prolonged NSAIDs use must be addressed, as well as the benefits, on a patient‐by‐patient basis.

A weak acid drugs NSAIDs are, a plasma‐gastrointestinal tract recirculation process through pancreatic/intestinal juices must be expected, although a systematic overview of the literature made no mention of this phenomenon. Due to the high concentration of sodium bicarbonate, pancreatic juice pH is above 8. This fact makes the transfer of an acidic drug from blood to the pancreatic lumen possible. Once in the duodenum, the accumulated drug in the pancreatic juice is available for reabsorption, resulting in a perceptible multiple peak plasma concentra‐ tion‐time profile. This phenomenon was evidenced by our group in a study carried out in healthy volunteers after ketoprofen administration [6]. In this work, no evidence of secondary peaks was obtained, probably because of the small amount of drug in blood, but once the reab‐ sorption of ketoprofen took place, after the ingestion of food, significant R‐ to S‐isomers con‐ version could be detected. This reveals the importance of drug recirculation at the duodenum level, contributing in some way to the duodenum irritation that arylacetic and arylpropionic acids produce.

Acetaminophen has antipyretic activity and peripheral anti‐inflammatory effects but lacks antiplatelet effect. Although it is a weaker analgesic in comparison with NSAIDs, it can be considered as first‐line option among nonopioids due to a more favorable safety profile [3]. The main concern is that of hepatic impairment at high doses. For chronic pain that is responsive to acetaminophen, daily doses should not exceed 4 g [3, 7]. Acetaminophen blood intestine recirculation was also observed in a study carried out by our group [8]. In this case, it was detected by simultaneous drug monitoring in saliva and plasma. The mechanism of this cycling was through biliary secretion of acetaminophen and its glucuro‐ nide metabolite.
