With over 100000 hospital admissions per annum, acute pancreatitis remains the leading gastrointestinal cause of hospitalization in the United States and has far-reaching impact well beyond. It has become increasingly recognized that drug-induced pancreatitis (DIP), despite accounting for less than 3% of all cases, represents an important and growing though often inconspicuous cause of acute pancreatitis. Nevertheless, knowledge of DIP is often curtailed by the limited availability of evidence needed to implicate given agents, especially for non-prescription medications. Indeed, the majority of available data is derived from case reports, case series, or case control studies. Furthermore, the mechanism of injury and causality for many of these drugs remain elusive as a definitive correlation is generally not established (< 10% of cases). Several classification systems have been proposed, but no single system has been widely adopted, and periodic updates are required in light of ongoing pharmacologic expansion. Moreover, infrequently prescribed medications or those available over-the-counter (including herbal and other alternative remedies) are often overlooked as a potential culprit of acute pancreatitis. Herein, we review the ever-increasing diversity of DIP and the potential mechanisms of injury with the goal of raising awareness regarding the nature and magnitude of this entity. We believe this manuscript will aid in increasing both primary and secondary prevention of DIP, thus ultimately facilitating more expedient diagnosis and a decrease in DIP-related morbidity.

Case reports have suggested that the use of newer cyclo-oxygenase-2 selective inhibitors may cause acute pancreatitis, but there has been no formal study of the association.

To assess the relationship between the use of cyclo-oxygenase-2 inhibitors and other non-steroidal anti-inflammatory drugs, and risk of acute pancreatitis.

A population-based case-control study was conducted using hospital discharge and prescription data from Denmark. Using conditional logistic regression with adjustment for multiple covariates, we estimated the relative risk of acute pancreatitis for use of the cyclo-oxygenase-2 inhibitors celecoxib and rofecoxib and for other non-steroidal anti-inflammatory drugs.

A total of 3083 cases of acute pancreatitis and 30 830 population controls were identified. For current use the relative risk estimate for celecoxib was 1.4 (95% CI: 0.8-2.3) and for rofecoxib was 1.3 (95% CI: 0.7-2.3). The overall relative risk for other non-steroidal anti-inflammatory drugs was 2.7 (95% CI: 2.4-3.0) with a substantial variation in risk between the individual drugs. The highest relative risk was for diclofenac (odds ratio 5.0, 95% CI: 4.2-5.9) and the lowest for naproxen (odds ratio 1.1, 95% CI: 0.7-1.7).

Cyclo-oxygenase-2 selective inhibitors are associated with a lower risk of acute pancreatitis than most other non-steroidal anti-inflammatory drugs.

Drugs are considered a rare cause of acute pancreatitis. We conducted a descriptive study to assess which drugs have been associated with acute pancreatitis in spontaneous adverse drug reaction reports in The Netherlands.

Our study is based on reports of drug-associated acute pancreatitis reported to the Netherlands Center for Monitoring of Adverse Reactions to Drugs and The Netherlands Pharmacovigilance Foundation LAREB between 1 January 1977 and 1 January 1998. We used an algorithm to validate the diagnosis and to assess the causal relationship between acute pancreatitis and use of the suspected drug.

A total of 55 cases were available for review. We excluded 11 (20.0%) reports, as we could not confirm the diagnosis of acute pancreatitis. Another 10 (18%) cases were excluded, as the causal relationship with the suspected drug was unlikely. In the remaining 34 reports, acute pancreatitis was labeled as definite in 11 (32%) and as probable in 23 (68%). The age of the patients ranged from 17 to 84 yr with a median of 41; 24 (71%) patients were female. Of the 34 cases, 27 (79%) recovered, five (15%) died, and in two (6%) the outcome is unknown. Azathioprine, cimetidine, interferon-alpha, methyldopa, metronidazole, olsalazine, and oxyphenbutazon all had a definite causal relationship with acute pancreatitis. Doxycycline, enalapril, famotidine, ibuprofen, maprotiline, mesalazine, and sulindac had a probable causal relationship with acute pancreatitis.

A variety of drugs was associated with acute pancreatitis in Dutch adverse drug reaction reports. Quantitative information about drug-induced pancreatitis is scanty. Epidemiological studies to assess the risk of drug-induced acute pancreas, therefore, are needed.

Few data exist about the incidence of drug-induced pancreatitis in the general population. 20 cases of drug-related pancreatitis were reported in Switzerland over a period of 12 years. The proportion of cases of pancreatitis caused by drugs is estimated to be around 2% in the general population, with much higher proportions in specific subpopulations, such as children and patients who are HIV positive. The literature about drug-induced pancreatitis consists mainly of anecdotal case reports. Clear evidence of a definite association with pancreatitis, by means of rechallenge tests, or consistent case reports, supported by animal experiments or data on the incidence of acute pancreatitis in drug trials exists for didanosine, valproic acid (sodium valproate), aminosalicylates, estrogen, calcium, anticholinesterases and sodium stibogluconate. An association with drug-induced pancreatitis is likely but not definitely proven for thiazide diuretics, pentamidine, ACE inhibitors, asparaginase, vinca alkaloids, some nonsteroidal anti-inflammatory drugs and clozapine. Pancreatitis is possibly caused by azathioprine, furosemide (frusemide), tetracycline, metronidazole, isoniazid, rifampicin (rifampin), sulphonamides, cyclosporin and some antineoplastic drugs. Many drugs have been reported to be associated with acute pancreatitis. However, lack of rechallenge evidence, consistent statistical data, or evidence from experimental studies on a possible mechanism prohibit definitive conclusions about most of them. The high incidence of concurrent illnesses known to induce acute pancreatitis, makes a trigger role or co-factor role for the drug seem most likely.

Drugs are a relatively uncommon cause of pancreatitis in adult patients, but should be considered when other reasonable causes of pancreatitis are not present. A wide variety of drugs have been reported to cause pancreatitis. Drug-induced pancreatitis is almost always acute and may be mild to fatal in severity. Definite proof that a drug causes pancreatitis requires that pancreatitis develops during treatment with the drug, that other likely causes of pancreatitis are not present, that pancreatitis resolves upon discontinuing the drug, and that pancreatitis usually recurs upon readministration of the drug. For ethical reasons, rechallenge with the suspect drug can be done only if the drug is necessary to treat a serious condition; thus this highly convincing piece of evidence relating the drug to pancreatitis may not be available. Information about drug-related pancreatitis is often not readily available, particularly for newer drugs. Clinicians should consider obtaining information directly from regulatory agencies and manufacturers as well as the literature.

Recent emphasis on nonsteroidal anti-inflammatory drug (NSAID)-associated hepatic injury blurs differences between NSAIDs. Accordingly, examination of hepatic injury by individual NSAIDs seemed warranted. Sulindac-associated hepatic injury was selected.

From 338 reports submitted to the Food and Drug Administration, 247 were considered inadequate or unconvincing for sulindac toxicity. The remaining 91 cases of reactions to the drug were analyzed. In 15 there was histological material available.

There were four deaths, three attributed to severe hypersensitivity and one to fulminant hepatic failure. Two thirds of the cases had clinical hallmarks of hypersensitivity. The ratio of females to males was 3.5:1; 69% of the patients were over 50 years of age. Jaundice was recorded in 67% of the patients. The pattern was cholestatic in 43%, hepatocellular in 25%, mixed in 12%, and indeterminate in 20% of the patients. Eosinophilia was significantly more frequent in patients with cholestatic injury (40%) than in those with hepatocellular injury (0).

Sulindac injury involves females more than males. It can lead to cholestatic or hepatocellular injury, most often because of immunological idiosyncrasy. In some patients, metabolic idiosyncrasy may be the mechanism. This study illustrates the utility of analysis of adverse reaction reports in characterizing drug-induced injury.

Acute pancreatitis has a high morbidity and significant mortality. Among its many causes ethanol is pre-eminent, but many other drugs have also been incriminated. This article begins with a definition of the mechanisms, pathogenesis and clinical features of acute pancreatitis; it then critically reviews the evidence for drugs, excluding ethanol, as being causative. The drugs which have been implicated are considered under 3 headings: definite associations, probable associations and unlikely associations. A brief outline of possible treatment, strategies and prognosis associated with acute pancreatitis concludes the article.

We reviewed the English-language literature pertaining to drug-induced pancreatitis and attempted to determine whether the reported association between each drug and pancreatitis was valid. The following drugs seem to cause pancreatitis: azathioprine, chlorothiazide and hydrochlorothiazide, oestrogens, frusemide, 6-mercaptopurine, methyldopa, sulphonamides, sulindac, tetracycline and valproic acid. Less convincing but suggestive evidence exists for colaspase, chlorthalidone, combination cancer chemotherapy, cimetidine, cisplatin, corticosteroids, cytosine arabinoside, diphenoxylate, ethacrynic acid, iatrogenic hypercalcaemia, methandienone, metronidazole, nitrofurantoin, pentamidine, phenformin, piroxicam and procainamide. In general, pancreatitis is a very rare complication of treatment with these drugs. The pathogenesis of the pancreatitis is usually obscure, but is probably mediated by an immune response. Certain drugs such as oestrogens cause hypertriglyceridaemia, which in turn may lead to pancreatitis.

The most common adverse effects of nonsteroidal anti-inflammatory drugs are gastritis, peptic ulceration, and depression of renal function, all of which result primarily from prostaglandin inhibition. The types of side effects observed with diclofenac are similar to those of other nonsteroidal anti-inflammatory drugs and are unavoidable given that the drugs are prostaglandin inhibitors. However, the incidences of such side effects may be lower with diclofenac than with some of the other nonsteroidal anti-inflammatory drugs. Worldwide experience with diclofenac exceeds 7.6 million patient-years, which should provide estimates of the frequency of very rare adverse reactions. The latter include blood dyscrasias, erythema multiforme, hepatitis, and others, such as aseptic meningitis, anaphylaxis, and urticaria. Moreover, some nonsteroidal anti-inflammatory drugs appear to have unique side-effect profiles. Examples include a higher incidence of ulceration and erythema multiforme with piroxicam, and acute pancreatitis, in rare instances, with sulindac. From a careful survey of the world's accumulated literature and reports to CIBA-GEIGY, diclofenac does not appear to have any unusual adverse reactions.

A 44 year old female, previously on propranolol, phenytoin and phenobarbital, developed hepatotoxicity while on sulindac and acetaminophen containing analgesic. A limited review of hepatotoxicity and drug interactions of sulindac is presented. The possible mechanism of hepatotoxicity and its treatment is suggested.