Open Access
Issue
BioMedicine
Volume 7, Number 1, March 2017
Article Number 4
Number of page(s) 5
DOI https://doi.org/10.1051/bmdcn/2017070104
Published online 03 March 2017

© Author(s) 2017. This article is published with open access by China Medical University

Licence Creative Commons
Open Access This article is distributed under terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided original author(s) and source are credited.

1. Introduction

Etodolac is one of the cyclooxygenase-2 inhibitors, which belong to the nonsteroidal anti-inflammatory agents. Etodolac is available in many countries and is commonly prescribed to treat patients with rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis[13]. It also provides relief of pain caused by minor surgery and relief of other types of pain because of its excellent anti-inflammatory and analgesic effects [1, 3]. Etodolac has a favorable safety profile with a low incidence of serious gastrointestinal events, including bleeding, ulceration, and perforation, when compared with other traditional nonsteroidal anti-inflammatory agents [36]. However, the U.S. Food and Drug Administration (FDA) has reported that among the 4290 persons taking etodolac who experienced side effects from 2003 to 2012, 27 persons (0.63%) had pancreatitis [7].

Although there is no formal pharmacoepidemiological study available to focus on the association between etodolac use and acute pancreatitis, based on the aforementioned U.S. FDA report, we think there might be an association between etodolac use and acute pancreatitis. If the association really exists, physicians should alert etodolac users to the risk of acute pancreatitis. It is with this in mind that we conducted this case-control study by analyzing the database of Taiwan’s National Health Insurance Program to explore this issue of etodolac use and acute pancreatitis.

2. Methods

2.1. Study design and data source

Taiwan is an independent country with more than 23 million people. This population-based case-control study was conducted using the database of Taiwan’s National Health Insurance Program. The National Health Insurance Program launched on March 1st, 1995, and it covered about 99% of the entire 23 million people living in Taiwan [8]. Further details of the program can be found in previous studies [920]. This study was approved by the Ethics Review Board of China Medical University and Hospital in Taiwan. (CMUH-104-REC2-115)

2.2. Inclusion criteria

For this study, we selected subjects who were newly diagnosed with acute pancreatitis (International Classification of Diseases 9th Revision-Clinical Modification, ICD-9 code 577.0) during the period of 1998-2011 and aged 20 years or older at the date of their diagnosis. We defined the index date of each case as the date of their being diagnosed with acute pancreatitis. We also randomly selected subjects without acute pancreatitis from the same database as controls who were matched for sex, age (per 5 years), and index year with those subjects who had been diagnosed with acute pancreatitis. We excluded subjects with chronic pancreatitis (ICD-9 code 577.1) or pancreatic cancer (ICD-9 code 157) before the date of their being diagnosed with acute pancreatitis. Comorbidities before the date of subjects being diagnosed with acute pancreatitis that were potentially related to said acute pancreatitis were included as follows: alcohol-related diseases, bililary stone, cardiovascular disease including coronary artery disease, heart failure, cerebrovascular disease, and peripheral atherosclerosis, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatitis B, hepatitis C, as well as hypertriglyceridemia. All comorbidities were diagnosed with ICD-9 codes. The diagnosis accuracy of the ICD-9 codes has been carefully assessed in previous studies [2129]. The history of prescriptions for other cyclooxygenase-2 inhibitors available in Taiwan was also collected.

2.3. Definition of etodolac exposure

The definition of etodolac use was adapted from previous studies [3032]. Never having used etodolac is defined as subjects never receiving a prescription for etodolac. Active use of etodolac is defined as subjects receiving at least 1 prescription for etodolac within 7 days of the date of their being diagnosed with acute pancreatitis. Non-active use of etodolac is defined as subjects not receiving a prescription for etodolac within 7 days but receiving at least 1 prescription for etodolac ≥ 8 days before the date of their being diagnosed with acute pancreatitis.

2.4. Statistical analysis

We demonstrated the differences in demographic factors, medication use, and comorbidities between the acute pancreatitis cases and the controls by using the Chi-square test for categorized variables and the t-test for continuous variables. The significant variables found in the univariable unconditional logistic regression model were further included in the multivariable unconditional logistic regression model. The odds ratio and 95% confidence interval were estimated to explore the association of acute pancreatitis with medication use and comorbidities. All data processing and statistical analyses were performed with the SAS software version 9.2 (SAS Institute, Inc., Cary, North Carolina, USA). A two-tailed P value < 0.05 was considered statistically significant.

3. Results

3.1. Characteristics of the study population

Table 1 compares the demographic factors, medication use and comorbidities between the acute pancreatitis subjects and the control subjects. There were 7577 cases of acute pancreatitis and 27032 controls with an even distribution of sex and age. The acute pancreatitis subjects had higher proportions of etodolac use, use of other cyclooxygenase-2 inhibitors, alcohol-related disease, biliary stone, cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatitis B, hepatitis C, and hypertriglyceridemia than the control subjects to statistical significance (Chi-square test, P < 0.001 for all).

Table 1

Chararacteristics of acute pancreatitis cases and control subjects

3.2. Acute pancreatitis associated with etodolac use

After adjustment for covariates, the adjusted odds ratio of acute pancreatitis was 3.78 for subjects with an active use of etodolac (95% confidence interval 1.11, 12.9), compared with subjects who never used etodolac. The adjusted odds ratio decreased to 1.18 for subjects with a non-active use of etodolac (95% confidence interval 0.38, 3.67), but the 95% confidence interval was lacking statistical significance (Table 2).

Table 2

Crude and adjusted odds ratio and 95% confidence interval of acute pancreatitis associated with etodolac use.

4. Discussion

A growing body of epidemiological research has demonstrated that medication use can correlate with the risk of acute pancreatitis [33, 34]. In this present study, we demonstrated that active use of etodolac was associated with a 3.78-fold increased chance of acute pancreatitis, while non-active use of etodolac was not associated with acute pancreatitis (Table 2). These results indicate that only patients who have used and continue to use etodolac might have a risk of acute pancreatitis. Patients who used etodolac before but stopped using it likely do not have the same risk. In further analysis, we demonstrated that acute pancreatitis cases with non-active use of etodolac had longer durations of etodolac therapy than those with active use of etodolac did (mean ± standard deviation, 78 ± 98 vs. 14 ± 14 days). This result indicates that the therapy duration of etodolac is not associated with acute pancreatitis, but active use of etodolac is potentially associated with acute pancreatitis. Therefore, physicians should alert patients actively using etodolac about the risk of acute pancreatitis.

There are numerous limitations to this study. The first concern is that drug-induced pancreatitis is an important topic, but there have been no actual reports of etodolac-associated acute pancreatitis worldwide. The U.S. Food and Drug Administration (FDA) reported a casual possible occurrence but did not confirm the causal effect [7]. Likewise, this present observational study cannot fully illustrate the causal effect or the possible pharmacological mechanism connecting etodolac use and acute pancreatitis. Second, there is no evidence to support whether patients who were prescribed etodolac actually took it or not. Thus, our best strategy was to use etodolac prescriptions for analysis. Third, despite active use of etodolac being associated with increased odds of acute pancreatitis, the 95% confidence interval appeared too wide (95% confidence interval 1.11, 12.9). It is our opinion that the number of subjects in our study with active use of etodolac might be too small to narrow the confidence interval (only 7 cases and 5 controls). Also, any major confounders that were not well-controlled would have changed the results of this study. Therefore, further well-designed research with more subjects is needed to confirm our results. Fourth, due to their being no record of indications contributing to etodolac being prescribed and used, there is no knowing whether etodolac was used for controlling acute pancreatitis-related pain. Fifth, a potential bias of this study is that patients using etodolac without a prescription (“over-the-counter”) were missed. Sixth, to present the original differences of comorbidities between the acute pancreatitis subjects and the control subjects, we did not control for said comorbidities. That is why the acute pancreatitis subjects had higher proportions of comorbidities than the controls (Table 1). Seventh, according to the reported data from the U.S. Food and Drug Administration (FDA), the incidence of etodolac-related pancreatitis in the U.S. is quite low, accounting for only 0.63% of patients with etodolac-related adverse effects [7]. It may be that etodolac-related acute pancreatitis is not an interesting clinical issue, yet no pharmacological study is presently available to support this correlation. Indeed, to the best of our knowledge this is the first population-based pharmacoepidemiological study to explore the association between etodolac use and acute pancreatitis in Taiwan. This manuscript is well written and organized and provides updated findings about this issue.

In conclusion, this study demonstrates that there could be an association between active use of etodolac and acute pancreatitis. Clinicians, therefore, should take into account the possibility of etodolac-associated acute pancreatitis when patients currently using etodolac present with acute pancreatitis with an unknown cause.

Specific author contributions

Kuan-Fu Liao planned and conducted this study. He participated in the data interpretation and also critically revised the article.

Kao-Chi Cheng, and Cheng-Li Lin conducted the data analysis and critically revised the article.

Shih-Wei Lai planned and conducted this study. He substantially contributed to the conception of the article, initiated the draft of the article, and critically revised the article.

Conflicts of Interest Statement

The authors declare no conflicts of interest.

Acknowledgments

This study was supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (M0HW105-TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), National Research Program for Biopharmaceuticals (NRPB) Stroke Clinical Trial Consortium (MOST 105-2325-B-039 -003), Tseng-Lien Lin Foundation in Taichung in Taiwan, Taiwan Brain Disease Foundation in Taipei in Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds in Japan. These funding agencies did not influence the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  1. Lynch S, Brogden RN. Etodolac: A preliminary review of its pharmacodynamic activity and therapeutic use. Drugs. 1986; 31: 288300. [CrossRef] [Google Scholar]
  2. Karbowski A.. A global safety evaluation of etodolac. Clinical Rheumatology. 1989; 8 Suppl 1: 73–9. [CrossRef] [PubMed] [Google Scholar]
  3. Balfour JA, Buckley MM. Etodolac: A reappraisal of its pharmacology and therapeutic use in rheumatic diseases and pain states. Drugs. 1991; 42: 274–99. [CrossRef] [PubMed] [Google Scholar]
  4. Serni U.. Global safety of etodolac: reports from worldwide postmarketing surveillance studies. Rheumatology International. 1990; 10: Suppl: 23–7. [CrossRef] [PubMed] [Google Scholar]
  5. Jones RA. Etodolac: An overview of a selective COX-2 inhibitor. Inflammopharmacology. 1999; 7: 269. [CrossRef] [PubMed] [Google Scholar]
  6. Jones RA. Etodolac (Lodine[sup®]): Profile of an established selective COX-2 inhibitor. Inflammopharmacology. 2001; 9: 63–70. [CrossRef] [Google Scholar]
  7. eHealthMe study from FDA and social media reports. Review: could etodolac cause pancreatitis? http://www.ehealthme.com/ds/etodolac/pancreatitis/#print [cited in 2016 August 1]. [Google Scholar]
  8. National Health Insurance Research Database, Taiwan. http://nhird.nhri.org.tw/en/index.html [cited in 2016 March 1, English version]. [Google Scholar]
  9. Lai SW, Liao KF, Liao CC, Muo CH, Liu CS, Sung FC. Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study. Medicine (Baltimore). 2010; 89: 295–9. [CrossRef] [PubMed] [Google Scholar]
  10. Lai SW, Muo CH, Liao KF, Sung FC, Chen PC. Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-based cohort study in Taiwan. Am J Gastroenterol. 2011; 106: 1697–704. [CrossRef] [Google Scholar]
  11. Hung SC, Liao KF, Lai SW, Li CI, Chen WC. Risk factors associated with symptomatic cholelithiasis in Taiwan: a population-based study. BMC Gastroenterol. 2011; 11: 11–111. [CrossRef] [PubMed] [Google Scholar]
  12. Liao KF, Lai SW, Li CI, Chen WC. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol. 2012; 27: 709–13. [CrossRef] [PubMed] [Google Scholar]
  13. Chen HY, Lai SW, Muo CH, Chen PC, Wang IJ. Ethambutol-induced optic neuropathy: a nationwide population-based study from Taiwan. Br J Ophthalmol. 2012; 96: 1368–71. [CrossRef] [PubMed] [Google Scholar]
  14. Hung SC, Lai SW, Tsai PY, Chen PC, Wu HC, Lin WH, et al. Synergistic interaction of benign prostatic hyperplasia and prostatitis on prostate cancer risk. Br J Cancer. 2013; 108: 1778–83. [CrossRef] [PubMed] [Google Scholar]
  15. Lai HC, Lin CC, Cheng KS, Kao JT, Chou JW, Peng CY, et al. Increased incidence of gastrointestinal cancers among patients with pyogenic liver abscess: a population-based cohort study. Gastroenterology. 2014; 146: 129–37. [CrossRef] [PubMed] [Google Scholar]
  16. Kuo SC, Lai SW, Hung HC, Muo CH, Hung SC, Liu LL, etal. Association between comorbidities and dementia in diabetes mellitus patients: population-based retrospective cohort study. J Diabetes Complications. 2015; 29: 1071–6. [CrossRef] [PubMed] [Google Scholar]
  17. Yang SP, Muo CH, Wang IK, Chang YJ, Lai SW, Lee CW, et al. Risk of type 2 diabetes mellitus in female breast cancer patients treated with morphine: A retrospective population-based time-dependent cohort study. Diabetes Res Clin Pract. 2015; 110: 285–90. [CrossRef] [PubMed] [Google Scholar]
  18. Cheng KC, Chen YL, Lai SW, Mou CH, Tsai PY, Sung FC. Patients with chronic kidney disease are at an elevated risk of dementia: a population-based cohort study in Taiwan. BMC Nephrol. 2012; 13: 1471–2369. [CrossRef] [Google Scholar]
  19. Cheng KC, Chen YL, Lai SW, Tsai PY, Sung FC. Risk of esophagus cancer in diabetes mellitus: a population-based case-control study in Taiwan. BMC Gastroenterol. 2012; 12: 12–177. [CrossRef] [PubMed] [Google Scholar]
  20. Chen YL, Cheng KC, Lai SW, Tsai IJ, Lin CC, Sung FC, et al. Diabetes and risk of subsequent gastric cancer: a population-based cohort study in Taiwan. Gastric Cancer. 2013; 16: 389–96. [CrossRef] [PubMed] [Google Scholar]
  21. Lai SW, Liao KF, Muo CH, Hsieh DPH. No Association between Statin Use and Pancreatic Cancer Risk in Taiwan. In: KUWAIT MEDICAL JOURNAL. 2013: 251–2. [Google Scholar]
  22. Hung SC, Hung SR, Lin CL, Lai SW, Hung HC. Use of celecoxib correlates with increased relative risk of acute pancreatitis: a case-control study in Taiwan. Am J Gastroenterol. 2015; 110: 1490–6. [CrossRef] [Google Scholar]
  23. Lai SW, Lai HC, Lin CL, Liao KF. Finasteride use and acute pancreatitis in Taiwan. J Clin Pharmacol. 2015; 55: 657–60. [CrossRef] [PubMed] [Google Scholar]
  24. Liao KF, Lin CL, Lai SW, Chen WC. Parkinson’s disease and risk of pancreatic cancer: a population-based case-control study in Taiwan. Neurology Asia. 2015; 20. [Google Scholar]
  25. Lai SW, Lin CL, Liao KF. Association of Meloxicam Use with the Risk of Acute Pancreatitis: A Case-Control Study. Clin Drug Investig. 2015; 35: 653–7. [CrossRef] [Google Scholar]
  26. Liao KF, Lin CL, Lai SW, Chen WC. Sitagliptin use and risk of acute pancreatitis in type 2 diabetes mellitus: A population-based case-control study in Taiwan. Eur J Intern Med. 2016; 27: 76–9. [CrossRef] [PubMed] [Google Scholar]
  27. Lai SW, Lin CL, Liao KF. Rheumatoid Arthritis and Risk of Pyogenic Liver Abscess in Taiwan. International Medical Journal. 2016; 23: 267–8. [Google Scholar]
  28. Lin HF, Lai SW, Lin WY, Liu CS, Lin CC, Chang CM. Prevalence and factors of elevated alanine aminotransferase in central Taiwan - a retrospective study. BioMedicine. 2016; 6: 016–0011. [CrossRef] [Google Scholar]
  29. Cheng KC, Lin WY, Liu CS, Lin CC, Lai HC, Lai SW. Association of different types of liver disease with demographic and clinical factors. BioMedicine. 2016; 6: 016–0016. [CrossRef] [Google Scholar]
  30. Liao KF, Lin CL, Lai SW, Chen WC. Zolpidem Use Associated With Increased Risk of Pyogenic Liver Abscess: A Case-Control Study in Taiwan. Medicine. 2015; 94: 0000000000001302. [CrossRef] [PubMed] [Google Scholar]
  31. Lai SW, Lin CL, Chen WC, Liao KF. Correlation Between Use of Zopiclone and Risk of Hip Fracture in Elderly Adults: A Case-Control Study in Taiwan. J Am Geriatr Soc. 2015; 63: 2534–7. [CrossRef] [PubMed] [Google Scholar]
  32. Lai SW, Lin HF, Lin CL, Liao KF. No association between losartan use and acute pancreatitis in hypertensive patients. Eur J Hosp Pharm. doi:10.1136/ejhpharm-2015-000840. [Google Scholar]
  33. Andersen V, Sonne J, Andersen M. Spontaneous reports on drug-induced pancreatitis in Denmark from 1968 to 1999. Eur J Clin Pharmacol. 2001; 57: 517–21. [CrossRef] [PubMed] [Google Scholar]
  34. Lancashire RJ, Cheng K, Langman MJ. Discrepancies between population-based data and adverse reaction reports in assessing drugs as causes of acute pancreatitis. Aliment Pharmacol Ther. 2003; 17: 887–93. [CrossRef] [PubMed] [Google Scholar]

All Tables

Table 1

Chararacteristics of acute pancreatitis cases and control subjects

Table 2

Crude and adjusted odds ratio and 95% confidence interval of acute pancreatitis associated with etodolac use.

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