Pharmaceuticals 2010, 3, 558-571; doi:10.

3390/ph3030558
OPEN ACCESS

pharmaceuticals
ISSN 1424-8247
www.mdpi.com/journal/pharmaceuticals
Review

NSAIDs and Acute Pancreatitis: A Systematic Review
Raffaele Pezzilli *, Antonio Maria Morselli-Labate and Roberto Corinaldesi
Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Via
Massarenti 9, 40138 Bologna, Italy; E-Mails: antonio.morselli@unibo.it (A.M.M.-L.);
roberto.corinaldesi@unibo.it (R.C.)
* Author to whom correspondence should be addressed; E-Mail: raffaele.pezzilli@aosp.bo.it;
Tel.: +39-051-636-4148; Fax: +39-051-636-4148.
Received: 2 January 2010; in revised form: 11 February 2010 / Accepted: 9 March 2010 /
Published: 10 March 2010

Abstract: The resulting pain is the main symptom of acute pancreatitis and it should be
alleviated as soon as possible. NSAIDs are the first line therapy for pain and they
are generally administered to acute pancreatitis patients upon admission to the
hospital. In addition, these drugs have also been used to prevent post-endoscopic
cholangiopancreatography (ERCP) acute pancreatitis. On the other hand, there are several
reports indicating that NSAIDs may be the actual cause of acute pancreatitis. We carried
out a literature search on PubMed/MEDLINE; all full text papers published in from
January 1966 to November 2009 on the use of NSAIDs in acute pancreatitis were
collected; the literature search was also supplemented by a review of the bibliographies of
the papers evaluated. Thus, in this article, we will systematically review the current
literature in order to better illustrate the role of NSAIDs in acute pancreatitis, in particular:
i) NSAIDs as a cause of acute pancreatitis; ii) their use to prevent post-retrograde ERCP
pancreatitis and iii) their efficacy for pain relief in the acute illness of the pancreas.
Keywords: acute pancreatitis; cytokines; inflammation; arachidonic acid; prostaglandins;
leukotrienes; phospholipase A2

ketoprofen. comments and review articles not containing data which met the aims of the study or were duplicate publications. Introduction Pain is the main feature of acute pancreatitis (AP) and the majority of patients are admitted to the hospital for this reason. 2. in particular i) NSAIDs as a cause of acute pancreatitis. rofecoxib and celecoxib with acute pancreatitis.S. in this article. On the other hand. For studies with multiple re-analyses. only the most recent article with the largest population was chosen. Thus. they were four studies [92–95] regarding the incidence of acute pancreatitis in NSAID consumers. A total of 92 citations were found [1. National Library of Medicine National Institutes of Health PubMed/MEDLINE database in order to select the data existing in the literature on NSAIDs and acute pancreatitis covering the period from January 1966 to November 2009. five randomized studies [18. Literature Search A search was made using the U. naproxen. 3 559 1. 79 were excluded [5–17.19–84] because they contained data regarding diseases other than acute pancreatitis and used drugs other than NSAIDs. review articles and key journals. There are no extensive studies on the pharmacological control of pain in acute pancreatitis patients [1–4]. ii) their use in preventing post-ERCP pancreatitis and iii) their efficacy for pain relief in the acute illness of the pancreas. Even if these reports are of importance in pointing out the possible risks of this class of drugs. A study was carried out in . Management of AP is limited to supportive care and the treatment of complications when they develop.86] and two studies regarding the efficacy of NSAIDs in the pain control in acute pancreatitis patients [1. there are several reports concerning the possibility that non-steroidal anti-inflammatory drugs (NSAIDs) may actually induce acute pancreatitis [5–17]. which is quite surprising given the importance of this symptom during the course of the disease. These patients require regular hospital admission. fluid administration.87–90] regarding the prophylactic use of NSAIDs in preventing post-ERCP pancreatitis together two meta-analytic studies on this topic [85. and through contacts with experts in the field.5–95].91]. NSAIDs as Inducers of Acute Pancreatitis There are numerous case reports on the association of the use of indomethacin. we will systematically review the current literature in order to better illustrate the role of NSAIDs in acute pancreatitis. There is also a lack of evidence regarding the degree of efficacy of the various pharmacological substances used to treat the different forms of acute pancreatitis. NSAIDs have also been used to prevent retrograde endoscopic cholangiopancreatography (ERCP)-induced acute pancreatitis [18]. The investigators independently screened all articles for those that met broad inclusion criteria. bowel rest and pain management. piroxicam. Acute Necrotizing” (outcome variables). The Medical Subject Headings (MESH) terms used were “Anti-inflammatory Agents. Of these 92 papers. we should stress the fact that NSAIDs are widely used in the general population of developed countries.Pharmaceuticals 2010. or were case reports or letters. Thus. Non-Steroidal” (explanatory variable) and “Pancreatitis” or “Pancreatitis. 3. 13 papers were considered for the present study. We identified additional studies through a physical search of bibliographies from primary studies.

3 560 Italy between March and September 2002 evaluating the use of generic drugs in a free-living population demonstrated that 20% of the NSAID users were over 65 years of age and 18% were chronic users (daily or frequent use for more than six months). and the remaining one to chlortalidone.1%) were diagnosed as experiencing an adverse drug reaction. it was found that 0. naproxen or piroxicam. one to oral contraceptives. unspecified pain (15%) and osteoarthrosis (9%). in clinical practice. two studies exploring the frequency of acute pancreatitis during the course of NSAID assumption found that this phenomenon is negligible: Ibanez et al.Pharmaceuticals 2010. These data were confirmed by a population-based study carried out in 1993 [93].7 (95% CI: 2.4% of controls were current users (within 90 days before admission into the study) of celecoxib and 0. only one case were considered by the authors related to NSAIDs use. finally.4% of controls were former users (within 91 to 365 days before admission into the study) of this drug. the authors found that only one case and three controls had taken indomethacin. biliary lithiasis was identified in two of the patients with diclofenac-related pancreatitis and in the clomifene-related case.4) for the use of NSAIDs between cases and controls. among 2.7% of the cases and 0.2–3.4% of controls were current users of NSAIDs and 11. the frequency of post-ERCP pancreatitis ranges from 1 to 14%. both for overall and for chronic use.9% of cases and 9. Six cases of drug-induced pancreatitis were found: three related to diclofenac. the highest risk was for diclofenac (OR 5.9) and the lowest for naproxen (OR 1. NSAID use was significantly higher in women. After excluding upper gastrointestinal bleeding (226 cases) and certain bone marrow blood dyscrasias (42 cases). the adjusted OR for other non-steroidal anti-inflammatory drugs was 2.6% of the cases and 0.0) with a substantial variation in risk between the individual drugs. osteoarticular pain (19%). [95] studied a total of 48.8% of cases and 0.4% of controls were former users of rofecoxib. Furthermore. 4.453 acute pancreatitis patients and 2. injury to the gland occurs in an extremely rapid time interval. there is a risk for acute pancreatitis patients taking NSAIDs and. The older age groups showed an increasing risk of chronic NSAID use because the presence of headache (25%). 286 patients with drug-induced events leading to hospital admission were identified in two years. 95% CI: 4. in a case-control study carried out in Sweden in 2002 [94]. 18. in a multivariate analysis. and although the stones were not located in the common bile duct. relative. 95% CI: 0.7). friend. this finding could also explain the biliary etiology of pancreatitis.678 hospitalized patients using the medical records and 554 (1.830 population controls [92].245 controls. On the contrary. The Prophylactic Use of NSAIDs for Preventing Post-ERCP Acute Pancreatitis In various prospective studies.0.1 (95% CI: 1.2% of the cases and 7. in a population-based case-control study including 3.1.2–5. Thus. In conclusion. one related to clomifene.4–3. In conclusion. In this latter study the authors found that a causal relationship of pancreatitis attributed to piroxicam was found in only one case out of 100. 0.000 users of diclofenac.8% of controls were former users of NSAIDs. the adjusted odds ratio (OR) was 2. etc. After exposure to trigger events. In addition. Thus. In .083 cases of acute pancreatitis and 30. More than 50% of all the NSAIDs were prescribed by physicians whereas about 44% were taken as self-treatment or following the advice of a pharmacist.6% of cases and 0. but 25 cases and 36 controls had taken diclofenac and.4% of controls were current users of rofecoxib and 0. it seems that naproxen should be the preferred analgesic for limiting the risk of development of acute pancreatitis.7–1.

there is a co-localization of digestive enzymes and lysosomal hydrolases within large cytoplasm vacuoles. CAPAN-1 cells had a concentration-dependent production of IL-6 and IL-8 in response to both endotoxins and TNF-alpha. CAPAN-1 and CAPAN-2 cells were incubated with endotoxins or TNFalpha and the supernatant was assayed for production of IL-1. The trigger events which may determine the final effect of acute pancreatitis during ERCP is still unknown. the hypothesis of the activation of chemokines by endoscopic maneuvers as a cause of acute pancreatitis cannot be ruled out [97]. making them an attractive option in the pharmacological prevention of post-procedural pancreatitis [86]. in two studies.87] and. they examined the response of welldifferentiated pancreatic ductal adenocarcinoma cell lines to stimuli known to stimulate cytokine production in other cells. such as ERCP and passage of a gallstone. They had low level expression of IL-8 which was unaffected by any concentration of lipopolysaccharide (LPS) and no detectable production of IL-6 in response to LPS. diclofenac was administered in the form of a suppository at a dosage of 100 mg immediately after ERCP [18. in the early stages of acute pancreatitis induced by secretagogues or by diet. The cells were assayed for activation of the transcription factor NF-kappa B by electrophoretic mobility shift assay. chemical. easily administered and have a favorable risk profile when given as a one-time dose.86] on this topic concluded that the widespread prophylactic . and microbiological factors may be involved as well as factors related to the patient and the physician [97]. Another two studies utilized indomethacin [88.Pharmaceuticals 2010. In their study. this co-localization mechanism might result in activation of the digestive enzyme.90]. in the third study.87–90]. [102] hypothesized that cytokines may be produced primarily by pancreatic parenchymal cells. CAPAN-2 cells had a concentration-dependent production of IL-6 and IL-8 in response to TNF-alpha. enzymatic. given as suppositories at a dosage of 100 mg before ERCP examination. phospholipase A2 and neutrophil-endothelial interaction. Blanchard et al. acute phase response determined by serum C-reactive protein levels was rare and did not parallel the serum amylase or lipase levels. mechanical. diclofenac was given by mouth at a dosage of 50 mg 30–90 min before the ERCP and 4–6 h after the procedure. [99] found that. NSAIDs are potent inhibitors of prostaglandins. Recent studies [98–101] have indicated the usefulness of ERCP as a model for studying the early inflammatory response in acute pancreatitis. Five studies have been published in the last decade on the efficacy of NSAIDs in preventing pancreatitis induced by ERCP [18. thus confirming the data of Blanchard et al. Three studies utilized diclofenac. Reasoning that the ductal epithelium is the cell type most likely to be exposed to noxious stimuli in common causes of pancreatitis. Two subsequent meta-analyses [85. However. all of these are believed to play an important role in the pathogenesis of acute pancreatitis [106–108]. NSAIDs are also inexpensive. the authors concluded that pancreatic duct cells may play an active part in the pathogenesis of acute pancreatitis through the production of cytokines. we also found [103] that ERCP maneuvers significantly increase the serum levels of C-reactive protein. More recently. Kiviniemi et al. All the studies except one [87] demonstrated that NSAIDs prevented post-procedural acute pancreatitis in a significant manner. in uncomplicated cases. Finally. On the basis of these findings. However. it has been suggested that digestive enzyme activation might occur within the acinar cells and it has been shown that. the administration of IL-10 in reducing the incidence of pancreatitis after therapeutic ERCP in humans is still under debate [104. 3 561 experimental models of acute pancreatitis. These authors found no detectable production of IL-1 by either cell line.105]. amyloid A and IL-6 in patients who did not develop acute pancreatitis. IL-6 and IL-8 by ELISA. [102].

There were 14 patients in the active treatment group and 16 in the placebo group. acidosis and acute respiratory distress syndrome. In the first controlled double-blind study. The first paper was published in 1985 [1] and the other one in 2008 [91]. NSAIDs for Treating Pain in Acute Pancreatitis The pathological activation of sensory neurons and inflammatory sequelae constitute what is known as neurogenic inflammation which appears to be important in many organ systems. The destruction of the pancreatic parenchyma during acute pancreatitis quickly induces an inflammatory reaction at the site of injury. macrophages and lymphocytes accumulate and phagocyte-derived oxygen radicals participate in a primary injury to the pancreatic capillary endothelial cells. bradykinins and proteases. metamizole was compared to morphine. arachidonic acid metabolites. timing of administration). most importantly. In the second study.Pharmaceuticals 2010. As expected. The increased microvascular permeability facilitates margination and extravascular migration of additional neutrophils and monocytes.113]. Within a few hours.g. choice of drug. fever. was compared to identical-looking placebo suppositories. hypotension. Pain in acute pancreatitis is also due to the release of tachykinin substance P and calcitonin-gene-related peptide. all these differences render the studies heterogeneous and suggest the need to plan more rigorous studies on this topic. The initial cellular response involves the infiltration of polymorphonuclear leukocytes into the perivascular regions of the pancreas. 3 562 administration of NSAIDs may significantly reduce the risk of acute pancreatitis after ERCP. whether a sphincterotomy was performed) as well as in pharmacological manipulation (e. Only two studies exist in the literature on pain control with NSAIDs in patients with acute pancreatitis. but have not been completely proven. leukotrienes. include intracellular inhibition of phosphodiesterase.g. such as trypsin [110]. inhibition of bradykinin levels. amplifying the inflammatory process [109] and leads to many metabolic consequences including pain. Factors which stimulate primary sensory neurons include hydrogen ions. and the uncoupling of G-protein-membrane protein interactions [112. Pain scores were recorded every 4 h during the first 48 h after admission using a visual analogical scale.5% in the morphine group within 24 h of hospitalization. we should point out that even if the studies considered were randomized controlled trials. the number of days with pain and the number of opiate injections were significantly less in patients treated with indomethacin. they had different modalities of ERCP procedures (e. Seventy-five percent of the patients achieved pain relief in the metamizole group versus 37. route of delivery. indomethacin. 5. Other NSAID mechanisms which have recently been proposed. The mechanisms of action of NSAIDs come from their ability to inhibit cyclooxygenase-dependent prostanoid formation [111]. resulting in major clinical and economic benefits.. number of cannulations. number of pancreatic duct injections. in the form of suppositories at a dosage of 50 mg twice daily for seven consecutive days. bleeding from the gastrointestinal tract was not seen in the indomethacin-treated group. Pethidine was also additionally administered as a rescue therapy. but this . However. heat. Other studies have suggested that the major analgesic mechanism for NSAIDs is through a central mechanism while the major anti-inflammatory mechanism occurs at a peripheral site of action [114]. 8 patients with acute pancreatitis were randomized to receive 10 mg of morphine subcutaneously every 4 h and 8 patients received 2 g every 8 h of metamizole intravenously.. including the pancreas.

two out of three achieved pain control in the metamizole group vs. Currently. NSAIDs were administered in 459 patients (54. From the data of this study. the mean time for achieving pain relief was shorter in the metamizole group even if in a non-significant manner. In fact. patients with mild acute pancreatitis received mainly NSAIDs and tramadol whereas patients with severe pancreatitis received a high percentage of opioids or an association of analgesics comprising NSAIDs. tramadol in 216 (25. most importantly. . Data on analgesic administration were available in 840 of the 1. Type of analgesics administered to 700 patients with mild acute pancreatitis and to 140 with severe acute pancreatitis.Pharmaceuticals 2010. there is only one study which has evaluated how pain is routinely treated in patients with acute pancreatitis [115].6%) (Figure 1). tramadol: 3.7 days in patients with severe acute pancreatitis (P < 0.0 ± 2.7 ± 10. Figure 1. At the end of the study (48 h after admission).3 days in patients with mild acute pancreatitis and 8.001).001). 3 563 difference was not statistically significant. tramadol and opioids. This study demonstrates that analgesics were graded according to the severity of the pain. intravenous metamizole shows a non-significant association with quicker pain relief than morphine given subcutaneously in acute pancreatitis but.3 days in patients with mild acute pancreatitis and 6.6%). this drug seems to have the same efficacy as opiates in controlling acute pancreatitis pain. NSAIDs: 3. 75% of patients achieved pain relief in the metamizole group versus 50% in the morphine group.8%) patients.7%). The duration of analgesic treatment was significantly longer in patients with severe acute pancreatitis in comparison to those suffering from the mild form. There was a significant difference in the type of analgesics administered between patients with mild and those with severe disease (P < 0. Three patients in each group needed pethidine. NSAIDs and tramadol were used more frequently in patients with mild disease whereas opioids associated with NSAIDs and or tramadol were used more frequently in patients with severe disease.2 ± 2. opioids in 32 (3. none of the three in the morphine group.001).8%) and a combination of the various drugs in the remaining 133 (13.1 days in patients with severe acute pancreatitis (P < 0.173 patients (71.0 ± 11.

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