Gastric by-pass and paracetamol /codeine (Citodon) and duloxetine (Cymbalta)

Fråga: How should dosing of paracetamol /codeine (Citodon) and duloxetine (Cymbalta) be modified after gastric bypass surgery?

The patient needs high doses of paracetamol/codeine to have sufficent effect.

Sammanfattning: Gastric bypass may reduce drug absorption. Duloxetine comes as an enterocapsule, which could lead to further decreased absorption after gastric bypass. The available studies indicate a decreased bioavailability of duloxetine, and increasing the dosage could therefore be necessary. As a method for blood drug level measurement is not available today the duloxetine effect should be followed clinically.

As there are no indications that the effect of paracetamol is lower in a post gastric bypass patient, there is a high risk that the described patient reaches toxic paracetamol blood concentrations, potentially leading to liver injury. The current, extremely high, dosage of Citodon (paracetamol/codeine) should be reduced immediately (the patient is currently receiving almost double the recommended maximum daily dose). Blood drug concentrations of paracetamol and codeine should be measured and liver function tests taken. Changing to analgetic treatment without codeine would avoid the drug interaction with duloxetine, and is also in line with guidelines for treatment of headache. We strongly recommend that the patient in this case gets help to change his analgetic treatment.

Svar: Roux-en- Y is a common type of gastric bypass surgery where the upper part of the stomach is separated from the main part of the stomach and connected to the distal part of the small bowel. Because most of the stomach is bypassed, food is transported straight to the small intestine. The disconnected, main part of the stomach is left in place to form gastric juice which, along with bile and pancreatic juice, helps digest the food below the lower bowel connection (1). Gastric bypass surgery results in decreased absorption partly due to reduced absorption surface, reduced "gastric mixing" (important for drug disintegration and absorption), increased pH in the remaining stomach part, and decreased gastric emptying (2). After gastric bypass most drug absorption happens in the small intestine (1).

Drugs with the highest potential for malabsorption after gastric bypass are those that dissolve slowly (e.g. modified release capsules), those that are poorly absorbed and undergo enterohepatic recirculation, and drugs with a narrow therapeutic interval (2). Water-soluble drugs are absorbed faster than lipophilic ones. Lipophilic drugs and those with enterohepatic recirculation are probably absorbed to a lesser extent because of their dependence on bile. The increased pH in the stomach remnant can increase the solubility of drugs that are basic and reduce the solubility of the acidic drugs (2).

Cymbalta (duloxetine) is a combined serotonin and noradrenaline reuptake inhibitor (SNRIs) used as an enterocapsule, and is usually well absorbed after oral administration. In a study of 12 patients on antidepressants drug bioavailability was found to be reduced one month after gastric bypass surgery (Roux-en-Y). This, however, had returned to baseline levels at 6 and 12 months. Six of the study patients were on SNRIs preparations (including one patient on duloxetine) and none of them showed reduction in bioavailability (3). Another clinical trial comparing duloxetine exposure in 10 gastric bypass patients 1 year after surgery (Roux-en-Y) to 10 matched controls, found a 57.7% decreased duloxetine AUC among the operated patients (4).

We found one study that measured the absorption of liquid paracetamol before gastric bypass (Roux-en-Y) and on several occasions up to 1 year after (5). The absorption of paracetamol was twice as rapid after surgery, and did not change over time (5). We have not found any studies or case reports about codeine absorption after gastric bypass. As the drug is basic, there is a theoretical possibility of higher absorption because of increased pH in the stomach remnant (see above).

The studies performed regarding drug absorption after gastric bypass surgery are small and the theories mentioned should therefore be considered theories rather than evidence. Where possible, blood drug concentrations should be measured to determine to which extent the patient is exposed to drugs. Methods for measuring blood drug levels of codeine and paracetamol is available. In the current case an assessment of liver function should also be performed to exclude liver injury.

Note that there is an increased risk of abuse of analgesics after gastric bypass surgery. Several case reports have described patients consuming excessive amounts of paracetamol containing analgesics after gastric bypass, resulting in liver or kidney damage (6,7).

Please observe that there is a possible interaction between duloxetine and codeine (duloxetine inhibits CYP2D6, the enzyme catalyzing codeine to morphine), potentially decreasing the analgetic effect of codeine (8). We therefore recommend selecting an analgetic treatment that is not metabolized through CYP2D6. Furthermore, codeine is not recommended for long-term treatment of headaches. Brocks DR, Ben-Eltriki M, Gabr RQ, Padwal RS. The effects of gastric bypass surgery on drug absorption and pharmacokinetics. Expert Opin Drug Metab Toxicol 2012 Dec;8(12):1505-19 Padwall R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev 2010;11:41-50 Hamad GG, Helsel JC, Perel JM, Kozak GM, McShea MC, Hughes C, Confer AL, Sit DK, McCloskey CA, Wisner KL. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am J Psychiatry 2012 Mar;169(3):256-63 Roerig JL, Steffen KJ, Zimmerman C, Mitchell JE, Crosby RD, Cao L. A comparison of duloxetine plasma levels in postbariatric surgery patients versus matched nonsurgical control subjects. J Clin Psychopharmacol 2013 Aug;33(4):479-84 Falkén Y, Hellström PM, Holst JJ, Näslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 2011 Jul;96(7):2227-35 Wendling A, Wudyka A. Narcotic addiction following gastric bypass surgery a case study. Obes Surg 2011 May;21(5):680-3 Mazer M, Perrone J. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol 2008 Mar;4(1):2-6 SFINX