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see related article on page 2183
Drug-Induced Acute Pancreatitis:
Uncommon or Commonplace?
James H. Grendell, MD1,2
Abstract: Many drugs have been implicated as
causing acute pancreatitis (AP), mainly based on
the recurrence of pancreatitis following rechallenge
with a drug that the patient had been taking at the
time of an initial episode of AP. However, estimates
of the relative frequency with which drugs cause
AP vary widely. This is largely because many
patients may be taking a number of drugs, may
have co-morbidities such as gallstone disease or
hypertriglyceridemia, or may be consuming large
amounts of alcohol, making it difficult to determine
what actually is the primary cause of an episode
of AP. Large, rigorously designed epidemdiological
studies are needed to better define the frequency
with which the drugs in general cause AP and the
specific risk of pancreatitis associated with any
individual drug.
Am J Gastroenterol 2011; 106:21892191; doi:10.1038/ajg.2011.307
Drugs have generally been considered to be a relatively uncom-
mon cause of acute pancreatitis (AP), with an estimated incidence
of 0.12% (1,2). However, a recent report of 170 cases of pancrea-
titis cared for at a single academic medical center in the Czech
Republic concluded that drugs were the most likely cause in 5.3%
of cases, making drugs the third most frequent cause of AP after
gallstones and alcohol (3). Another report, involving a retrospec-
tive review of 138 patients diagnosed with AP from a single center
in France, attributed the etiology to drugs in 6.5% of cases. How-
ever, the authors of this report qualified this estimate by writing
This higher ratemust be examined with precaution due to the
difficulty in attributing causality. (4).
Indeed, it has not been easy to determine whether a specific
drug is a cause of AP. More than 500 medications have been impli-
1
Division of Gastroenterology, Hepatology, and Nutrition, Winthrop University Hospital, Mineola, New York, USA; 2State University of New York, Stony Brook School
of Medicine, Stony Brook, New York, USA. Correspondence: James H. Grendell, MD, Division of Gastroenterology, Hepatology, and Nutrition, Winthrop University
Hospital, 222 Station Plaza North, Suite 429, Mineola, New York 11501, USA. E-mail: jgrendel@winthrop.org
Received 17 May 2011; accepted 9 August 2011
2011 by the American College of Gastroenterology
EDITORIAL 2189
PANCREAS AND BILIARY TRACT
cated, but most of the evidence comes from random case reports,
with little in the way of sound epidemiological studies (5). When a
case report describes a single exposure to a drug, no reliable con-
clusions can be made because case reports are often incomplete.
Reports frequently do not even fully document a reliable diagno-
sis of AP and often have inadequate data regarding the drug dose
and duration of treatment before the episode of AP and the extent
of efforts to exclude other common causes of AP. In addition, pre-
vious case reports and drug warnings from regulatory agencies
may stimulate additional reporting because of heightened aware-
ness of even the possibility a drug may cause AP. Also drugs that
are widely used are more likely to be on the medication list of a
patient with AP, regardless of the true cause; and new drugs are
monitored much more closely for possible adverse effects than
are medications which have been used for decades. As well stated
in a recent review of drug-induced AP, The incidence rates and
relative risk of single drugs cannot be determined with the help of
case reports alone (2).
However, one specific type of case report has been regarded as
decisive in determining whether a drug is a likely cause of AP; i.e.,
a description of a well-documented episode of recurrent AP after
a rechallenge with a drug which was implicated in an initial attack
of AP (positive rechallenge). The criteria employed for evaluat-
ing proposed rechallenge cases of AP are generally those first pro-
posed by Mallory and Kern (6) more than 30 years ago:
(1) Pancreatitis develops during treatment with a drug,
resolves upon discontinuing the drug, and returns upon
readministration of the drug.
(2) Adequate criteria for the diagnosis of AP are present both
for the initial episode of AP and the episode following the
rechallenge.
(3) Other likely causes of pancreatitis are not present.
Although a strong case could be made that more than one posi-
tive-rechallenge case report should be required before a drug is
considered to be a likely cause of AP, this has not been the prevail-
ing viewpoint in several recent reviews (2,7) in which the drugs
The American Journal of GASTROENTEROLOGY
2190 Grendell
currently considered to cause AP could be categorized as such on
the basis of a single positive-rechallenge case. In one such review
by Badalov et al. (7), drugs were considered to be Class I drugs
PANCREAS AND BILIARY TRACT
(strongest evidence for a causal role in AP) if there was at least one
published positive-rechallenge case report. Class I drugs were fur-
ther subdivided into Ia reports for which all other causes such small, and patients were only followed for a range of 1750 months.
as alcohol, hypertriglyceridemia, gallstones, and other drugs were
excluded (24 drugs) and Ib reports for which other causes were
not ruled out (18 drugs). Three other classes (II, III, IV) were also
defined. However, assignment into one of these three classes did
not require even a single well-documented positive-rechallenge
case, making the relationship of these additional 78 drugs to AP
highly uncertain.
In the current issue Spanier et al. (8), evaluated 168 patients
with confirmed or recurrent AP, who were part of an observational
prospective cohort study involving 2 academic and 16 community
hospitals in Northern Holland. The investigators determined an
etiology for AP after reviewing hospital and outpatient medical
records as well as annual questionnaires which included items
regarding alcohol consumption and medication use. Based on the
classification system in the review of Badalov et al. (7), all drugs
used at the time of hospital admission for AP were classified as
pancreatitis associated or not and, if associated, placed in one of
the four classes used in the review. Episodes of AP were defined as
possibly drug-induced if no other etiological factors were present
besides use of a pancreatitis-associated drug on admission. If
these drugs were discontinued with no subsequent recurrence of
AP, it was assumed that the treating physician had identified the
episodes of AP as drug-induced.
Considering only the patients taking Class I drugs, for which
the potential to cause AP is supported by at least one positive-
rechallenge case, 26% of the entire study population and 9.5% of
the patients considered to have pancreatitis of unknown etiology
but possibly drug-induced were taking one or more of these drugs.
In fact, 15 of the 44 patients were taking two Class I drugs, and
6 patients were taking three or four drugs. Not surprisingly, the
most frequently used Class I drugs taken alone or in combination
with other Class I drugs were simvastatin (13/44 patients), enal-
april (10/44 patients), and omeprazole (9/44) patients.
The treating physician discontinued the Class I drug for 8 of the
16 patients with pancreatitis of unknown cause, possibly drug-
induced; and no recurrence of AP later developed. The investi-
gators concluded that the treating physician had identified these
patients as having drug-induced AP for a prevalence of 4.8%
(5.4% if all four classes of pancreatitis-associated drugs are con-
sidered). Conversely, the other eight patients taking Class I drugs
were continued on those medications, leading the investigators
to suggest that the diagnosis of drug-induced AP may have been
missed for 4.8% of the patients in the study population, possibly
to their detriment.
This report raises several important questions for which there
are no easy or clear answers. Is drug-induced AP more com-
mon than had been previously suspected? Is this diagnosis fre-
quently missed, possibly resulting in recurrent AP? In addition,
as proposed by these investigators, can drugs act as a co-factor
The American Journal of GASTROENTEROLOGY
or disease modifier for patients with other known risk factors for
AP (e.g., alcohol, gallstone disease), lowering their threshold for
developing pancreatitis?
These important questions cannot be answered by this report
because of the limitations of the study. The study population is
Also the drugs most commonly incriminated as causes of AP in
this study are widely prescribed to the general population, with
2 of them (simvastatin and omeprazole) among the 10 most pre-
scribed drugs in the Netherlands (8). For that reason, a coincidental
relationship between use of these drugs and any disease is a likely
possibility. Indeed, in this report, 23% of patients with a diagno-
sis of AP attributed to gallstone or alcohol etiologies were taking a
Class I drug. Although this could mean, as the investigators suggest,
that these drugs may predispose patients to develop pancreatitis in
response to other factors, it is at least as likely that the use of these
drugs in the general population is so common that these relation-
ships are only coincidental in such a small patient sample. For the
current study, it would be valuable to know what percentage of a
matched cohort of patients admitted to the study hospitals with an
unrelated diagnosis (e.g., pneumonia) during the same time period
were taking a Class I pancreatitis-associated drug.
However, the biggest limitation of this study and of the evalu-
ation of drug-induced AP in general is the reliance on positive-
rechallenge cases, often only one (7), as the primary criterion to
determine whether a drug is a likely cause of AP. What are needed
are well-performed, population-based casecontrol studies eval-
uating whether use of a specific drug significantly increases the
risk of AP. Some reports of attempts to perform such studies are
considered in a recent review (2). However, these studies have
not been easy to perform validly. For any given drug suggested
to cause pancreatitis, drug-induced AP is a rare event. Therefore,
very large databases are required such as hospital discharge reg-
istries (9) or medical and pharmacy insurance claims data (10).
Because these databases largely rely on diagnostic codes to iden-
tify patients with AP, the accuracy of the diagnosis is critical but
difficult to verify. In one recent study (11), medical records were
reviewed by a panel of gastroenterologists for a sample of patients
in a health insurance claims database to assess the accuracy of
coding for AP. The panel concluded that the coded diagnosis was
accurate for only about 50% of the patients. An additional chal-
lenge is selecting the appropriate control cases, because patients
are frequently taking multiple medications and the diseases for
which patients are receiving these medications may themselves be
associated with an increased risk of AP, independent of the drugs
being used for treatment. This appears to be an issue for studies
evaluating possible drug-induced AP for patients being treated
for type 2 diabetes mellitus (10,12), inflammatory bowel disease
(13), and human immunodeficiency virus infection (14).
As the potential methodological issues become better under-
stood and more studies are performed, increasingly reliable infor-
mation should become available concerning the actual risk of AP
for various drugs. However, until then, what is a physician to do
when caring for a patient with possible drug-induced AP? For those
patients taking a drug for which at least one well-documented
VOLUME 106 | DECEMBER 2011 www.amjgastro.com

positive-rechallenge case has been reported and who do not have
a more likely cause of AP, the prudent course remains to stop the
drug and not reinstitute treatment with that drug (and, in some
cases, drugs within the same class) unless there are no alternative
medications available and/or the potential benefits outweigh the
risk. In such instances the patient should be brought into the deci-
sion-making process and informed consent obtained (1). That is
an easier question to answer than whether drug-induced AP is
uncommon or commonplace, a question requiring much more
study leading to more and better data.
CONFLICT OF INTEREST
Guarantor of the article: James H. Grendell, MD.
Financial support: None.
Potential competing interests: The author has served as an expert
witness in litigations related to alleged incidents of drug-induced
pancreatitis.
REFERENCES
1. Balani AR, Grendell JH. Drug-induced pancreatitis. Incidence, manage-
ment and prevention. Drug Safety 2008;31:82337.
2. Nitsche CJ, Jamieson N, Lerch MM et al. Drug induced pancreatitis. Best
Prac Res Clin Gastroenterol 2010;24:14355.
3. Vinklerova I, Prochazka M, Prochazka V et al. Incidence, severity, and
etiology of drug-induced acute pancreatitis. Dig Dis Sci 2010;55:297781.
2011 by the American College of Gastroenterology
Editorial 2191
4. Mennecier D, Pons F, Arvers P et al. Incidence and severity of non alcoholic
and non biliary pancreatitis in a gastroenterology department. Gastroen-
terol Clin Biol 2007;31:6647.
5. Lancashire RJ, Cheng K, Langman MJ. Discrepancies between popula-
PANCREAS AND BILIARY TRACT
tion-based data and adverse reaction reports in assessing drugs as causes of
acute pancreatitis. Aliment Pharmacol Ther 2003;17:88793.
6. Mallory A, Kern F. Drug induced pancreatitis: a critical review. Gastroen-
terology 1980;78:81320.
7. Badalov N, Baradarian R, Iswara K et al. Drug-induced acute
pancreatitis: an evidence based review. Clin Gastroenterol Hepatol
2007;5:64861.
8. Spanier BWM, Tuynman ARE, venderHulst RWM et al. Acute pancreatitis
and concomitant use of pancreatitis-associated drugs. Am J Gastroenterol
2011;106:21838 (this issue).
9. Norgaard M, Jacobsen J, Ratanajamit C et al. Valproic acid and risk of
acute pancreatitis: a population-based case-control study. Am J Ther
2006;13:1137.
10. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes
treated with exenatide or sitagliptin: a retrospective observational
pharmacy claims analysis. Diabetes Care 2010;33:234954.
11. Dore DD, Bloomgren GL, Wenten M et al. A cohort study of acute pancrea-
titis in relation to exenatide use. Diabetes Obes Metab 2011;13:55966.
12. Girman CJ, Kou TD, Cai B et al. Patients with type 2 diabetes mellitus have
higher risk for acute pancreatitis compared with those without diabetes.
Diabetes Obes Metab 2010;12:76671.
13. Weersma RK, Peters FT, Oostenbrug LE et al. Increased incidence of
azathioprine-induced pancreatitis in Crohns disease compared with other
diseases. Aliment Pharmacol Ther 2004;20:84350.
14. Smith CJ, Olsen CH, Mocroft A et al. The role of antiretroviral therapy in
the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA
study. AIDS 2008;22:4756.
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