- Top of page
Aims To assess the risk of acute pancreatitis associated with use of acid-suppressing drugs.
Methods We conducted a retrospective cohort study with a nested case-control design within the General Practice Research Database (GPRD) in the United Kingdom. The cohort included 180 178 persons aged 20–74 years, who had received at least one prescription of cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, or omeprazole from January 1992 to September 1997 and who did not have major risk factors for pancreatic diseases. Patients with a computerized medical history compatible with idiopathic acute pancreatitis were validated through review of medical records. For the nested case-control analysis 1000 controls were randomly selected from the study population.
Results We identified 88 potential cases of idiopathic acute pancreatitis. Medical records were available for 86. After review of these records 36 cases of acute pancreatitis were confirmed. Seven cases occurred during nonuse, corresponding to a background incidence rate (IR) of 4.4/100 000 person-years (PY). Six cases occurred during current use of ranitidine (IR 10.5/100 000 PY), five patients were current users of cimetidine (IR 13.9/100 000 PY), and three were current users of omeprazole (IR 7.8/100 000 PY). There were no cases among current users of famotidine, lansoprazole, or nizatidine. Relative risk (RR) compared with nonuse and corrected for age, gender, calendar year and use of medication known to be associated with acute pancreatitis was 1.3 (95% CI: 0.4,4.1) for ranitidine, 2.1 (95% CI: 0.6,7.2) for cimetidine, and 1.1 (95% CI: 0.3,4.6) for omeprazole.
Conclusions The results of this study do not support an association between acute pancreatitis and the use of acid-suppressing drugs, although a substantial increase in risk cannot be excluded with confidence.
- Top of page
Several drugs have been implicated as possible causes of acute pancreatitis [1–3]. Most information on drug-induced acute pancreatitis is derived from anecdotal case-reports, and very little is known about the incidence and mechanisms of drug-induced acute pancreatitis.
Cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, and omeprazole are extensively used in the treatment of peptic ulcer disease, and reflux oesophagitis. Adverse drug reactions affecting the central nervous system, kidneys, haematological system, gastrointestinal tract and the cardiovascular system have been attributed to these acid-suppressing drugs . Cimetidine and ranitidine have been associated with acute pancreatitis in several case-reports [5–9]. Although a relationship was found between cimetidine and acute pancreatitis in rats , others have questioned this . A record-linkage case-control study showed a crude significant association between cimetidine, ranitidine and acute pancreatitis, but this association disappeared after adjustment for potential confounders .
In view of the controversies regarding the association between acid-suppressing drugs and acute pancreatitis, we conducted a retrospective cohort study in the General Practice Research Database (GPRD) in the United Kingdom (UK) to assess the risk of acute pancreatitis associated with the use of cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, and omeprazole. A nested case-control analysis was conducted to examine in more detail the relationship between dose and duration of treatment, and the risk of acute pancreatitis.
- Top of page
The study cohort consisted of 180 178 subjects who received at least one prescription of cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, or omeprazole. Overall 1 545 921 prescriptions of these acid-suppressing drugs were written during the study period. The age and gender distribution of users of individual acid-suppressing drugs is presented in Table 1. There were 88 patients who had a computerized history compatible with an idiopathic episode of acute pancreatitis and for whom medical records were requested from the GPs. No information was received for two patients. Of the remaining 86 patients, 36 (42%) were classified as cases. The remainder were excluded because of alcohol abuse (n = 11), cholelithiasis (n = 10), cancer, other pancreatic disorders and postoperative pancreatitis in 11 patients. The diagnosis of acute pancreatitis was not confirmed in 11 patients. In the remaining seven patients onset of symptoms was before the start of follow-up.
Table 1. Age and gender distribution: all numbers refer to number of acid-suppressing drug prescriptions.
|Overall||1 545 921||52%||48%||51%||49%|
The overall incidence rate of idiopathic acute pancreatitis during current use of acid-suppressing drugs was 9.9 (95% CI: 4.7,15.1) per 100 000 person years (PY), 7.6 (95% CI: 3.8,11.5) per 100 000 PY for past users, and 4.4 (95% CI: 1.1,7.6) per 100 000 PY for nonusers. After adjustment for age, gender and calendar year the RR was 1.6 (95% CI: 0.6,4.2) for current use and 1.6 (95% CI: 0.6,4.0) for past use of an acid-suppressing drug. Incidence rates and RRs for individual acid-suppressing drugs are given in Table 2.
Table 2. Incidence rates of and relative risks of acute pancreatitis for individual acid-suppressing drugs.
| ||Person-years||Cases||IR/105||Crude RR (95% CI)||RR (95% CI)*|
|Current-use‡||141738||14||9.9||2.3 (0.9,5.6)||1.6 (0.6,4.2)|
| cimetidine||35966||5||13.9||3.2 (1.0,10.0)||2.3 (0.7,7.7)|
| lansoprazole||4567||0||–|| |
| omeprazole||38430||3||7.8||1.8 (0.5,6.9)||1.3 (0.3,5.3)|
| ranitidine||56961||6||10.5||2.4 (0.8,7.2)||1.7 (0.6,5.4)|
|Past use§||196356||15||7.6||1.8 (0.7,4.3)||1.6 (0.6,4.0)|
Table 3 shows the results of the nested case-control analysis. Out of the 36 cases, 20 (56%) were male and the mean age was 61 years. Use of acid-suppressing drugs, gender and calendar year were not significantly associated with acute pancreatitis. The RR among current users of medications suspected to be associated with acute pancreatitis was 2.0 (95% CI: 1.0,4.2). Age was the only factor that was significantly associated with the occurrence of acute pancreatitis. Although not significant, the risk of acute pancreatitis was higher in the first month of acid-suppressing therapy: 2.3 (95% CI: 0.5,9.5) vs 1.1 (95% CI: 0.4,3.3) for long-term users. Exclusion of all current users of medications thought to be associated with acute pancreatitis did not change the risk estimates considerably (data not shown). A dose–response relationship was not observed in users of cimetidine or ranitidine (Table 4).
Table 3. Relative risk of acute pancreatitis associated with use of acid-suppressing drugs and other factors.
| ||Cases (n = 36)||Controls (n = 1000)||OR (95% CI)|
|Current use‡||14||263||1.4 (0.5,3.6)|
| cimetidine||5||65||2.1 (0.6,7.2)*|
| omeprazole||3||69||1.1 (0.3,4.6)*|
| ranitidine||6||129||1.3 (0.4,4.1)*|
|Past users§||15||431||1.3 (0.5,3.3)*|
| 20–59 years||12||639|
| 60–74 years||24||361||3.1 (1.5,6.4)|
| Female||16||514||0.6 (0.3,1.2)|
| 1995–97||20||600||0.9 (0.5,1.8)|
| Current use||15||240||2.0 (1.0,4.2)|
Table 4. Influence of duration of acid-suppressing drug therapy on the risk of acute pancreatitis.
| ||Cases (36)||Controls (1000)||OR (95% CI)*|
|Duration of antiulcer therapy†|
| ≤ 30 days||3||47||2.3 (0.5–9.5)|
| > 30 days||11||234||1.1 (0.4–3.3)|
|Daily dose of cimetidine†, ‡|
| < 800 mg||2||22||2.2 (0.4–12.6)|
| ≥ 800 mg||3||41||1.7 (0.4–7.7)|
|Daily dose of ranitidine†, §|
| < 300 mg||2||26||1.9 (0.3–10.3)|
| ≥ 300 mg||4||100||1.1 (0.3–4.2)|
- Top of page
In this large cohort study, we observed no significant increased risk of acute pancreatitis in users of acid-suppressing drugs. Cimetidine was the only individual acid-suppressing drug with a significantly increased risk of acute pancreatitis, but this association was no longer present after adjustment for potential confounders. There was a tendency towards an increased risk in the first month of treatment. The daily dosage of acid-suppressing drugs had no effect on the risk of acute pancreatitis.
The validity of epidemiological studies may suffer from selection bias, information bias or confounding. The presence of selection bias in this study is unlikely as identification of the study population was based on prerecorded prescriptions of acid-suppressing drugs, and therefore unrelated to the outcome of interest. Since drug exposure was recorded before the onset of disease, recall bias is not present. Case histories concerning the relationship between H2-receptor blockers and acute pancreatitis have been published since the late seventies, some of them proven by recurrence of symptoms after restart of treatment [6, 9]. Physicians may therefore diagnose acute pancreatitis more easily in patients using these H2-receptor blockers. This diagnostic bias might therefore explain the nonsignificant increase in RR of cimetidine and ranitidine seen in this study. Patients with gastric acid related diseases will pay more visits to gastroenterological consultants and may therefore have acute pancreatitis more easily detected. However, as none of the acute pancreatitis diagnoses was made during routine check-ups of antiulcer treatment we expect diagnostic bias to play a minor role, if any, in explaining the results. Misclassification of outcome was limited due to review of the medical records of potential cases. Misclassification of exposure, for instance by noncompliance or dispensing of acid-suppressing drugs in hospital was probably nondifferential and would therefore have biased the risk estimates towards null. By restricting the study to people without major risk factors for acute pancreatitis we tried to control for confounding by these factors.
A recent study on the association between H2-receptor antagonists and acute pancreatitis reported a nonsignificant RR of 3.7 for cimetidine and a nonsignificant RR of 3.1 for ranitidine . In patients without risk factors for acute pancreatitis these figures were 2.0 and 2.5, respectively. The authors concluded that the higher RRs might be due to residual confounding. Prescribing of acid-suppressing drugs for prodromal symptoms of acute pancreatitis, sometimes referred to as protopathic bias could be an alternative explanation for the small increased risk seen in the former study and in our study. We tried to reduce the role of protopathic bias by taking the day of onset of symptoms as index date for patients with acute pancreatitis. The risk in the first 30 days of therapy was somewhat higher than the risk thereafter, albeit nonsignificantly. This could indicate either an acute effect or imperfect control of protopathic bias. However, protopathic bias cannot explain the different risk estimates for the different acid-suppressing drugs as this form of selection bias would affect all the acid-suppressing drugs alike.
In conclusion, the results of this study do not support an association between acute pancreatitis and the use of acid-suppressing drugs, although a substantial increase in risk cannot be excluded with confidence.