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Oral metronidazole use and risk of acute pancreatitis: a population-based case-control study

Authors Barbulescu A, Oskarsson V, Lindblad M, Ljung R, Brooke HL

Received 13 December 2017

Accepted for publication 11 May 2018

Published 25 October 2018 Volume 2018:10 Pages 1573—1581


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Irene Petersen

Andrei Barbulescu,1 Viktor Oskarsson,2 Mats Lindblad,3,4 Rickard Ljung,1 Hannah L Brooke1

1Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 3Division of Surgery, Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 4Centre for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden

Objective: Oral metronidazole used in combined regimens for Helicobacter pylori eradication has been associated with an increased risk of acute pancreatitis; however, it is less clear whether a similar association exists for single-regimen metronidazole. We, therefore, examined the association of single and combined regimens of oral metronidazole with risk of acute pancreatitis.
Methods: In this population-based case-control study, all individuals in Sweden (aged 40–84 years) hospitalized with acute pancreatitis between January 2006 and December 2008 were identified from a national hospital register (n=5,996). Controls, matched for calendar year, age, and sex, were randomly sampled from a national population register (n=60,681). Data on oral metronidazole and covariates were extracted from national health and prescription registers. Odds ratios (ORs) of acute pancreatitis, according to timing of the latest metronidazole prescription before hospitalization, were estimated using logistic regression models. Confounding by indication was examined by contrasting the main results with the association when amoxicillin was used as exposure. The robustness of results was examined by calculating incidence rate ratios using a self-controlled case series approach.
Results: After adjustment for potential confounders, there was a substantially increased risk of acute pancreatitis within 30 days of oral metronidazole exposure, both for single (OR: 4.06; 95% confidence interval [CI]: 1.90–8.64) and combined (OR: 11.80; 95% CI: 6.86–20.28) regimens, compared to nonexposure. In contrast, the adjusted OR was 1.79 (95% CI: 1.25–2.54) for current use of amoxicillin compared to nonexposure. These results were supported by the self-controlled cases series analysis (incidence rate ratio: 3.30; 95% CI: 2.69–4.06, for single and combined regimens of oral metronidazole pooled). There was no strong association between oral metronidazole and acute pancreatitis more than 30 days after exposure.
Conclusion: There was an increased risk of acute pancreatitis within 30 days of exposure to single and combined regimens of oral metronidazole. While reverse causality and confounding by indication cannot be entirely excluded, they are unlikely to fully explain the association. These results warrant an increased awareness among physicians.

Keywords: case–control studies, Helicobacter infections, drug therapy, metronidazole, adverse effects, pancreatitis, epidemiology, Sweden

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