Perforated peptic ulcer and short-term mortality among tramadol users

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1 British Journal of Clinical Pharmacology DOI: /j x Perforated peptic ulcer and short-term mortality among tramadol users Marie L. Tørring, 1,2 Anders Riis, 1 Steffen Christensen, 1 Reimar W. Thomsen, 1 Peter Jepsen, 1 Jens Søndergaard 2 & Henrik T. Sørensen 1 1 Department of Clinical Epidemiology, Aarhus University Hospital and 2 Research Unit for General Practice, University of Aarhus, Aarhus, Denmark WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is a strong risk and prognostic factor for peptic ulcer perforation, and alternative analgesics are needed for high-risk patients. Pain management guidelines propose tramadol as a treatment option for mild-to-moderate pain in patients at high risk of gastrointestinal side-effects, including peptic ulcer disease. Tramadol may mask symptoms of peptic ulcer complications, yet tramadol s effect on peptic ulcer prognosis is unknown. WHAT THIS STUDY ADDS In this population-based study of 1271 patients hospitalized with peptic ulcer perforation, tramadol appeared to increase mortality at least as much as NSAIDs. Among users of tramadol, alone or in combination with NSAIDs, adjusted 30-day mortality rate ratios were 2.02 [95% confidence interval (CI) 1.17, 3.48] and 1.32 (95% CI 0.89, 1.95), compared with patients who used neither tramadol nor NSAIDs. Correspondence Marie Louise Tørring, Research Unit for General Practice, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus, Denmark. Tel.: Fax: mlt@alm.au.dk Keywords Peptic ulcer perforation, tramadol, nonsteroidal, anti-inflammatory agents, mortality Received 26 February 2007 Accepted 15 August 2007 Published OnlineEarly 8 October 2007 AIM Use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases risk and worsens prognosis for patients with complicated peptic ulcer disease. Therefore, patients who are at high risk of peptic ulcer often use tramadol instead of NSAIDs. Tramadol s effect on peptic ulcer prognosis is unknown. The aim was to examine mortality in the 30 days following hospitalization for perforated peptic ulcer among tramadol and NSAID users compared with non-users. METHODS The study was based on data on reimbursed prescriptions and hospital discharge diagnoses for the period, extracted from population-based healthcare databases. All patients with a first-time diagnosis of perforated peptic ulcer were identified, excluding those with previous ulcer diagnoses or antiulcer drug use. Cox regression was used to estimate 30-day mortality rate ratios for tramadol and NSAID users compared with non-users, adjusting for use of other drugs and comorbidity. RESULTS Of 1271 patients with perforated peptic ulcers included in the study, 2.4% used tramadol only, 38.9% used NSAIDs and 7.9% used both. Thirty-day mortality was 28.7% overall and 48.4% among users of tramadol alone. Compared with the 645 patients who used neither tramadol nor NSAIDs, the adjusted mortality rate in the 30 days following hospitalization was 2.02-fold [95% confidence interval (CI) 1.17, 3.48] higher for the 31 tramadol only users, 1.41-fold (95% CI 1.12, 1.78) higher for the 495 NSAID users and 1.32-fold (95% CI 0.89, 1.95) higher for the 100 patients who used both drugs. CONCLUSION Among patients hospitalized for perforated peptic ulcer, tramadol appears to increase mortality at a level comparable to NSAIDs The Authors Journal compilation 2007 Blackwell Publishing Ltd Br J Clin Pharmacol / 65:4 / / 565

2 M. L. Tørring et al. Introduction Perforation is a severe complication of peptic ulcer disease and is associated with an in-hospital mortality rate of 5 25% [1 4]. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important risk factor for upper gastrointestinal (GI) tract perforation [5, 6], and it has recently been shown that NSAID use is associated with a poor prognosis after hospitalization for perforated peptic ulcer [7]. Thus, use of alternative analgesics by high-risk patients is warranted. Tramadol consumption has increased substantially during the last decade. It is now the most frequently prescribed opioid in Denmark, used by approximately 4% of the population [8]. Pain management guidelines currently propose tramadol as a treatment option for mild-tomoderate pain in patients at high risk of GI side-effects, including peptic ulcer disease [9 13]. In patients with peptic ulcer perforation, it is possible that tramadol use could worsen prognosis. The analgesic effect may mask symptoms of perforation, increasing time to surgical treatment that is one of the most important prognostic factors [2, 3]. Also, the immune suppression caused by opioids may increase the risk of severe infections and sepsis after perforation [14]. However, very little information exists on tramadol use and peptic ulcer disease. We therefore conducted this large population-based cohort study to examine whether preadmission tramadol use was associated with 30-day mortality after perforated peptic ulcer. Methods Setting The study was based on data from population-based medical databases in three Danish counties [15]. The total population of these counties is , approximately 25% of the Danish population. We defined three study periods based on the introduction of tramadol in Denmark in 1993 and on initial availability of prescription data records in the three counties (starting on 1 January 1993 in North Jutland County; 1 January 1996 in Aarhus County; and 1 January 1998 in Viborg County). In all counties, the end-date for data retrieval was 31 December Study population Computerized data from the counties hospital discharge databases were used to identify all patients hospitalized with a first-time diagnosis of perforated peptic ulcer during the study period, as previously described [15, 16]. The International Classification of Diseases (ICD)-8 codes used to identify patients with perforated peptic ulcer were , , , , , and ; ICD-10 codes were K25.1, K25.2, K25.5, K25.6, K26.1, K26.2, K26.5, K26.6, K27.1, K27.2, K27.5, K27.6, K28.1, K28.2, K28.5 and K28.6. Of 1791 incident perforated peptic ulcer patients, 198 previously hospitalized with uncomplicated peptic ulcer disease were excluded (the ICD-8 codes were , , , , , , , , , , , , and ; the ICD-10 codes were K22.1, K25.3, K25.7, K25.9, K26.3, K26.7, K26.9, K27.3, K27.7, K27.9, K28.3, K28.7 and K23.9), as well as 322 patients who had filled a prescription for antiulcer drugs <1 year prior to admission [Anatomical Therapeutic Chemical (ATC) code A02B]. There were no significant differences in 30-day mortality between excluded and included tramadol users. Data on medication use Through prescription databases we retrieved records for all tramadol and NSAID prescriptions filled by study subjects before the date of hospitalization for perforated peptic ulcer [15]. Tramadol was identified by ATC code N02AX02, and NSAIDs by ATC code M01A. In Denmark, a typical package of tramadol contains up to 30 daily doses, whereas a typical package of NSAIDs contains approximately 60 (for package sizes available in Denmark, see Patients were categorized as current tramadol users (prescription filled <31 days before admission) or current non-users (all others), as well as current NSAID users (prescription filled <61 days before admission) or current non-users (all others). We also identified users of other drugs that can cause ulcers [low- or high-dose aspirin (ATC codes B01AC06, N02BA01 and N02BA51) and systemic glucocorticoids (ATC code H02AB)]. Based on standard package sizes, patients were classified as current users (prescription filled <61 days before admission for perforated peptic ulcer) or current non-users. Finally, users of strong opioids (ATC code N02A excluding N02AX02 and N02AC04) and paracetamol (ATC code N02BE01) were identified. Data on coexisting illnesses The patients complete hospital discharge history prior to the date of the first hospitalization for perforated peptic ulcer (see Appendix) was used to obtain information on GI cancer, other cancer, cardiovascular disease, chronic obstructive pulmonary disease (COPD), diabetes Types 1 and 2 and musculoskeletal disorders. Record linkage Records from the registries used in this study were linked by means of the civil registration number, a unique personal identifier assigned at birth to all Danish citizens. Mortality data Deaths were ascertained through linkage of study subjects civil registration numbers with the Danish Civil Registration System. The study outcome was survival time, and all patients were followed from admission to death or censored after 30 days. 566 / 65:4 / Br J Clin Pharmacol

3 Tramadol and mortality after perforated peptic ulcer Statistical analysis Duration of follow-up was calculated as the time from the date of hospitalization for perforated peptic ulcer until death or 30 days following admission. Cumulative 30-day mortality risks were computed based on Kaplan Meier estimates and Cox proportional hazard regression analysis was used to compute 30-day mortality rate ratios (MRRs) and to estimate the adjusted effect of tramadol and/or NSAID use on the mortality rate. The assumption of proportional hazards was assessed graphically and found appropriate. We repeated the Cox regression analyses after sequentially restricting the study population to the following groups of patients: male, female, <70 years old, 70 years old, with perforated duodenal ulcer, with perforated gastric ulcer, with cardiovascular disease, without cardiovascular disease, with COPD, without COPD, with musculoskeletal disorder, without musculoskeletal disorder, and without cancer. In order to evaluate the possibilities of confounding by indication and masking of symptoms, the Cox regression analyses were also repeated after modifying the original study population and/or exposure definitions. First, we restricted the study population to patients who did not use NSAIDs and included an additional exposure level, former tramadol users (prescription filled within days before admission). Second, we substituted tramadol for strong opioids and paracetamol. Third, we substituted patients with perforated ulcer for those with bleeding peptic ulcer. For this analysis, patients with a first-time bleeding peptic ulcer during the study period were identified (ICD-8 codes , , , , and ; ICD-10 codes K25.0, K25.4, K26.0, K26.4, K27.0, K27.4, K28.0 and K28.4). Data on medication use, coexisting illnesses and mortality for patients with bleeding peptic ulcer were obtained as for patients with perforated peptic ulcer. SAS software was used (Version 9.1.3; SAS Institute Inc., Cary, NC, USA) for the analyses. The study was approved by the Danish Data Protection Agency and by the Aarhus University Hospital Registry Board. Results We included 1271 patients with a first-time discharge diagnosis of perforated peptic ulcer, of whom 2.4% used tramadol, 38.9% NSAIDs and 7.9% used both. The median age of patients who used tramadol and/or NSAIDs was almost 10 years higher than that of patients who used neither drug (Table 1). Tramadol users had a higher prevalence of cardiovascular disease, COPD and musculoskeletal disor- Table 1 Characteristics of 1271 patients with a first-time hospitalization for perforated peptic ulcer (PPU) in North Jutland, Aarhus and Viborg counties, Denmark Users of neither tramadol nor NSAIDs* Tramadol users Tramadol and NSAID users NSAID users Number n (%) 645 (50.7) 31 (2.4) 100 (7.9) 495 (38.9) 30-day mortality (%) Age, median (quartiles) 66.7 ( ) 76.2 ( ) 74.6 ( ) 76.5 ( ) Gender, female (%) Current use of other ulcer-associated drugs Yes (%) 112 (17.4) 11 (35.5) 34 (34.0) 147 (29.7) No (%) 533 (82.6) 20 (64.5) 66 (66.0) 348 (70.3) Cancer GI cancer 18 (2.8) 0 (0.0) 1 (1.0) 12 (2.4) Other cancer (%) 65 (10.1) 3 (9.7) 7 (7.0) 63 (12.7) No (%) 562 (87.1) 28 (90.3) 92 (92.0) 420 (84.8) Cardiovascular disease Yes (%) 132 (20.5) 11 (35.5) 23 (23.0) 125 (25.3) No (%) 513 (79.5) 20 (64.5) 77 (77.0) 370 (74.7) Diabetes Yes (%) 40 (6.2) 2 (6.5) 7 (7.0) 39 (7.9) No (%) 605 (93.8) 29 (93.5) 93 (93.0) 456 (92.1) COPD Yes (%) 55 (8.5) 6 (19.4) 13 (13.0) 55 (11.1) No (%) 590 (91.5) 25 (80.6) 87 (87.0) 440 (88.9) Musculoskeletal disorders Yes (%) 88 (13.6) 7 (22.6) 35 (35.0) 146 (29.5) No (%) 557 (86.4) 24 (77.4) 65 (65.0) 349 (70.5) *No filled prescriptions of tramadol within 30 days and no filled prescriptions of NSAIDs within 60 days of PPU admission. Filled tramadol prescription within 30 days of PPU admission. Filled tramadol prescription within 30 days and filled NSAID prescription within 60 days of PPU admission. Filled NSAID prescription within 60 days of PPU admission. Other ulcer-associated drugs are glucocorticoids and aspirin. Current use = filled prescription within 60 days of PPU admission. GI, Gastrointestinal; COPD, chronic obstructive pulmonary disease; NSAID, nonsteroidal anti-inflammatory drug. Br J Clin Pharmacol / 65:4 / 567

4 M. L. Tørring et al. Probability of survival (%) Figure Follow-up (days) Survival curves for users of neither tramadol nor nonsteroidal antiinflammatory drugs (NSAIDs) (n = 645), tramadol users (n = 31), NSAID users (n = 495) and tramadol and NSAID users (n = 100) hospitalized for perforated peptic ulcer. Users of neither tramadol nor NSAIDs ( ), Tramadol users ( ), NSAID users ( ), Tramadol & NSAID users ( ) ders and were more likely to use other ulcer-associated drugs compared with users of neither drug. Conversely, a lower proportion of tramadol users had been diagnosed with cancer prior to admission than non-users of either drug. Users of both tramadol and NSAIDs were considerably more likely to suffer from musculoskeletal disorders than tramadol only users (Table 1). The prognosis was worst for those who used only tramadol and best for those who used neither tramadol nor NSAIDs (Figure 1 and Table 2). Compared with the 645 patients who used neither drug, the adjusted mortality rate in the 30 days following hospitalization was 2.02-fold [95% confidence interval (CI) 1.17, 3.48] higher for the 31 tramadol-only users, 1.41-fold (95% CI 1.12, 1.78) higher for the 495 NSAID users and 1.32-fold (95% CI 0.89, 1.95) higher for the 100 users of both drugs. These associations were consistent across the patient groups we examined (Table 2). When excluding current NSAID users, the 30-day mortality risk was 20.9% among never-users of tramadol (n = 611), 26.5% among former users of tramadol (n = 34) and 48.4% among current users of tramadol (n = 31). The corresponding adjusted MRRs,compared with never-users, were 1.16 (0.57, 2.36) in former users and 1.92 (1.10, 3.35) in current users of tramadol. The adjusted MRR comparing current users of strong opioids only (n = 31) with those who used neither strong opioids nor NSAIDs (n = 645) was 2.99 (1.79, 5.00), and for current users of paracetamol (n = 50) vs. neither paracetamol nor NSAID users (n = 626) the adjusted MRR was 1.79 (1.13, 2.82). Among patients with bleeding peptic ulcer the adjusted MRR of current tramadol users compared with non-users of tramadol was 1.25 (CI 0.84, 1.85). Discussion In this large population-based cohort study, we found that both tramadol users and NSAID users had higher mortality after a perforated peptic ulcer than those who used neither drug. The mortality increase was higher for tramadol users than for NSAID users and remained robust in various subanalyses. The weaker association found among former users of tramadol supports a causal association between current tramadol use and mortality following perforated peptic ulcer. Our findings must be interpreted in the context of the study s methodological strengths and weaknesses. Its strengths include a relatively large sample size, a population-based design permitted by Denmark s uniformly organized healthcare system, and complete follow-up through population-based registries, which limited the risks of selection and information bias. This study also has several limitations. First, hospital discharge diagnoses, with their risk of coding errors, were used to identify patients with perforated peptic ulcers and coexisting illnesses. However, the positive predictive value of GI discharge diagnoses is reportedly high [17, 18], and the validity of diagnoses is unlikely to be related to tramadol or NSAID use.thus, any influence on our results is likely to be minor and lead to conservative MRR estimates. Second, while we had a complete prescription history for all study patients, filling of prescriptions was used as proxy for actual drug use. Since some patients taking tramadol stop early due to adverse events [19], it is possible that we underestimated the effect of tramadol by mixing true tramadol users with some who filled a tramadol prescription but discontinued the medication.third, we had no data on in-hospital drug use. Thus, some patients categorized as noncurrent users of tramadol may have been given tramadol during hospitalization. This would also cause underestimation of the effect of tramadol. Finally, as the prescription registries do not contain information on daily tramadol dosage, we were unable to stratify tramadol use to detect a possible dose-related difference in 30-day mortality. Another important limitation of this observational study is that the choice of tramadol treatment may be related to mortality from perforated peptic ulcer [20], i.e. tramadol might be prescribed for patients at high risk of GI adverse effects for whom NSAIDs are contraindicated. Differences in pre-existing risk profiles between exposure groups were reduced by excluding all patients who had been hospitalized previously with uncomplicated peptic ulcer disease or who used antiulcer drugs, and also by controlling for some possible underlying differences. Nevertheless, residual confounding may have led to an overestimation of mortality associated with tramadol use, compared with NSAID use, since physicians may give tramadol instead of NSAIDs to particularly frail patients with multiple severe comorbidities [9, 12, 13, 21 23]. This may 568 / 65:4 / Br J Clin Pharmacol

5 Tramadol and mortality after perforated peptic ulcer Table 2 Cumulative 30-day mortality and adjusted 30-day MRRs for 1271 patients with perforated peptic ulcer (PPU), according to the use of tramadol and NSAIDs n MR (%) Crude MRR (95% CI) Adj. MRR (95% CI) All patients 1271 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.54, 4.48) 2.02 (1.17, 3.48) Tramadol and NSAID users (1.15, 2.46) 1.32 (0.89, 1.95) NSAID users (1.50, 2.34) 1.41 (1.12, 1.78) Males 542 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.16, 8.72) 2.04 (0.73, 5.69) Tramadol and NSAID users (0.65, 3.10) 1.16 (0.52, 2.58) NSAID users (1.60, 3.22) 1.71 (1.19, 2.46) Females 729 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.19, 4.22) 1.91 (0.99, 3.67) Tramadol and NSAID users (1.03, 2.53) 1.47 (0.93, 2.34) NSAID users (1.18, 2.13) 1.36 (1.01, 1.84) Patients < 70 years 575 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (0.21, 11.04) 2.21 (0.28, 17.33) Tramadol and NSAID users (0.63, 3.51) 1.39 (0.57, 3.42) NSAID users (0.97, 2.61) 1.32 (0.79, 2.21) Patients 70 years 696 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.04, 3.19) 1.99 (1.13, 3.52) Tramadol and NSAID users (0.92, 2.15) 1.36 (0.88, 2.10) NSAID users (1.13, 1.88) 1.42 (1.10, 1.85) Perforated duodenal ulcer 582 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.54, 7.38) 2.49 (1.11, 5.56) Tramadol and NSAID users (0.85, 2.95) 1.21 (0.63, 2.30) NSAID users (1.40, 2.77) 1.43 (1.00, 2.03) Perforated gastric ulcer 606 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (0.93, 4.38) 1.78 (0.80, 3.96) Tramadol and NSAID users (0.98, 2.75) 1.37 (0.80, 2.33) NSAID users (1.27, 2.37) 1.39 (1.00, 1.94) Cardiovascular disease 291 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.35, 6.07) 2.77 (1.27, 6.04) Tramadol and NSAID users (0.79, 2.93) 1.32 (0.66, 2.62) NSAID users (1.06, 2.28) 1.53 ( ) No cardiovascular disease 980 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (0.96, 4.46) 1.61 (0.74, 3.51) Tramadol and NSAID users (1.08, 2.75) 1.33 (0.83, 2.15) NSAID users (1.50, 2.58) 1.40 (1.05, 1.86) COPD 129 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (0.81, 5.48) 1.24 (0.44, 3.52) Tramadol and NSAID users (0.37, 2.19) 0.67 (0.25, 1.76) NSAID users (0.47, 1.43) 0.84 (0.46, 1.53) No COPD 1142 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.24, 4.54) 2.00 (1.04, 3.85) Tramadol and NSAID users (1.19, 2.75) 1.53 (0.99, 2.35) NSAID users (1.65, 2.68) 1.54 (1.19, 1.99) Musculoskeletal disorder 276 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (0.47, 5.08) 1.56 (0.46, 5.34) Tramadol and NSAID users (0.69, 1.80) 1.01 (0.62, 1.63) NSAID users (0.33, 1.61) 0.93 (0.41, 2.09) Br J Clin Pharmacol / 65:4 / 569

6 M. L. Tørring et al. Table 2 Continued n MR (%) Crude MRR (95% CI) Adj. MRR (95% CI) No musculoskeletal disorders 995 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.62, 5.32) 2.14 (1.16, 3.95) Tramadol and NSAID users (1.42, 3.38) 1.49 (0.95, 2.33) NSAID users (1.64, 2.72) 1.58 (1.22, 2.05) No cancer 1102 Users of neither tramadol nor NSAIDs* (reference) 1 (reference) Tramadol users (1.88, 5.77) 2.23 (1.26, 3.96) Tramadol and NSAID users (1.29, 2.95) 1.45 (0.95, 2.21) NSAID users (1.75, 2.91) 1.60 (1.23, 2.08) Adjusted for age, gender, coexistent illnesses (GI cancer, other cancer, cardiovascular disease, diabetes, COPD, musculoskeletal disorders), and use of other ulcer-associated drugs. *No filled tramadol prescriptions within 1 year and no filled NSAID prescriptions within 60 days of PPU admission. Filled tramadol prescription within 30 days of PPU admission. Filled tramadol prescription within 30 days and NSAIDs within 60 days of PPU admission. Filled NSAID prescription within 60 days of PPU admission. MRR, Mortality rate ratio; NSAID, nonsteroidal anti-inflammatory drug; COPD, chronic obstructive pulmonary disease. be reflected in the 70% higher MRR among tramadol only users compared with users of both tramadol and NSAIDs. It appears that users of both NSAIDs and tramadol are prone to suffer from painful, but probably less fatal conditions, such as musculoskeletal disorders (Table 1). However, when our analyses were restricted to patients without musculoskeletal disorders or without cancer, we still found tramadol only users to have the highest risk of dying compared with the other exposure groups.this, and the lack of association between former tramadol use and 30-day mortality, suggest that tramadol in itself is responsible for increased short-term mortality. Based on this observational study, we can only speculate on the exact mechanism leading to increased mortality among tramadol users. Opioids induce immune suppression by increasing susceptibility to both bacterial and viral infections, especially following surgery and trauma [14]. However, the immunomodulating effects differ between various opioid analgesics, and tramadol has been shown not to induce postoperative immune suppression in gynaecological cancer patients [24]. Opioids are known to cause respiratory depression. However, respiratory depression is considered a rare adverse effect of tramadol ( %), and no evidence indicates that tramadol given prior to admission should aggravate respiratory depression after admission, i.e. during surgery or treatment for perforated peptic ulcer. The time interval between perforation and treatment is recognized to be one of the most important prognostic factors for perforated peptic ulcer [2, 3]. NSAID users and their doctors may be more aware of symptoms of perforated peptic ulcer, leading to earlier treatment of these patients. Use of tramadol may contribute to increased surgical delay by masking symptoms of perforation (e.g. pain symptoms) and/or by enhancing the probability of misinterpreting/overlooking weaker, initial symptoms of perforated peptic ulcer such as epigastric tenderness, nausea and vomiting, which are common (1 10%) GI sideeffects of tramadol. This masking of symptoms explanation was supported by our finding that use of another analgesic (paracetamol) also increased mortality, whereas use of stronger analgesics (opioids) than tramadol had an even stronger association with mortality after perforated peptic ulcer. It was also supported by the absence of an association between tramadol and mortality after bleeding peptic ulcer, the symptoms of which are less likely to be masked. In conclusion, among patients with perforated peptic ulcer, tramadol appears to increase mortality at least as much as NSAIDs. Appendix A Classification of coexisting illnesses was partly based on illness categories used in the comorbidity index developed by Charlson et al. [25].This index has been adapted for use with hospital discharge data [26]. Patients were thus identified by the following codes: GI Cancer: ICD-8 codes: ; ICD-10 codes: C15-C26. Other cancer: ICD-8 codes: , , , , , , 199; ICD-10 codes: C00-C14, C27-C85, C88, C Cardiovascular disease: ICD-8 codes: 410, ; ; ; , , , , ; ICD-10 codes: I11.0; I13.0, I13.2, I21-23, I50, I60-I69, I70-74, I77, G Chronic Obstructive Pulmonary Disease: ICD-8 codes: ; ICD-10 codes: J40-J / 65:4 / Br J Clin Pharmacol

7 Tramadol and mortality after perforated peptic ulcer B Diabetes was considered present if: i. at least one prescription for insulin or an oral antidiabetic drug was recorded and/or ii. there was a hospital discharge diagnosis of Type 1 or Type 2 diabetes (ICD-8 codes: ; ICD-10 codes E10-E11). C Patients with musculoskeletal disorders were identified by: ICD-8 codes: , ; 725, 726, 728, 734, 44; ICD-10 codes: M05-06; M08-09; M15-M19, M30-36, M40-M54, and D86. Competing interests J.S. has received a fee on one occasion for giving a lecture at an AstraZeneca symposium. AstraZeneca funded an observational cohort study of effects on prescribing patterns in which J.S. participated. Funding was provided as a grant to the Research Unit for General Practice in Odense. This study was supported by grants from the County of Aarhus and from the Western Danish Research Forum for Health Sciences. REFERENCES 1 Irvin TT. Mortality and perforated peptic ulcer: a case for risk stratification in elderly patients. Br J Surg 1989; 76: Wakayama T, Ishizaki Y, Mitsusada M, Takahashi S, Wada T, Fukushima Y, Hattori H, Okuyama T, Funatsu H. Risk factors influencing the short-term results of gastroduodenal perforation. Surg Today 1994; 24: Svanes C. Trends in perforated peptic ulcer: incidence, etiology, treatment, and prognosis. World J Surg 2000; 24: Testini M, Portincasa P, Piccinni G, Lissidini G, Pellegrini F, Greco L. Significant factors associated with fatal outcome in emergency open surgery for perforated peptic ulcer. World J Gastroenterol 2003; 9: Henry D, Lim LL, Garcia Rodriguez LA, Perez GS, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115: Thomsen RW, Riis A, Munk EM, Nørgaard M, Christensen S, Sørensen HT. 30-day mortality after peptic ulcer perforation among users of newer selective Cox-2 inhibitors and traditional NSAIDs: a population-based study. Am J Gastroenterol 2006; 101: Danish Medicines Agency. Report [Consumption of strong analgesic drugs (opioids) in primary care- Denmark ]. Available at dk/publikationer/netpub/forbrugsanalyser/opioid/ (last accessed: 18 September 2007). 9 Wilcox J. Gastrointestinal considerations in patients with cardiovascular disease using nonopioid analgesics for mild-to-moderate pain or cardioprotection. Am J Cardiol 2006; 97 (9 Suppl. 1): Recommendations for the appropriate use of opioids in persistent non-cancer pain. A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners and the Royal College of Psychiatrists. London: The Pain Society, March Available at (last accessed: 18 September 2007). 11 Kalso E, Allan L, Dellemijn PL, Faura CC, Ilias WK, Jensen TS, Perrot S, Plaghki LH, Zenz M. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain 2003; 7: Goodwin JL, Kraemer JJ, Bajwa ZH. The use of opioids in the treatment of osteoarthritis: when, why, and how? Curr Pain Headache Rep 2005; 9: American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000; 43: Budd K. Pain management: is opioid immunosuppression a clinical problem? Biomed Pharmacother 2006; 60: Christensen S, Riis A, Nørgaard M, Thomsen RW, Tønnesen EM, Larsson A, Sørensen HT. Perforated peptic ulcer: use of pre-admission oral glucocorticoids and 30-day mortality. Aliment Pharmacol Ther 2006; 23: Thomsen RW, Riis A, Christensen S, Nørgaard M, Sørensen HT. Diabetes and 30-day mortality from peptic ulcer bleeding and perforation: a Danish population-based cohort study. Diabetes Care 2006; 29: Nickelsen TN. [Data validity and coverage in the Danish National Health Registry. A literature review]. Ugeskr Laeger 2002; 164: Lassen A, Hallas J, Schaffalitzky de Muckadell OB. Complicated and uncomplicated peptic ulcers in a Danish county : a population-based cohort study. Am J Gastroenterol 2006; 101: Jarernsiripornkul N, Krska J, Richards RM, Capps PA. Patient reporting of adverse drug reactions: useful information for pain management? Eur J Pain 2003; 7: Signorello LB, McLaughlin JK, Lipworth L, Friis S, Sørensen HT, Blot WJ. Confounding by indication in epidemiologic studies of commonly used analgesics. Am J Ther 2002; 9: Dubois RW, Melmed GY, Henning JM, Laine L. Guidelines for the appropriate use of non-steroidal anti-inflammatory Br J Clin Pharmacol / 65:4 / 571

8 M. L. Tørring et al. drugs, cyclo-oxygenase-2-specific inhibitors and proton pump inhibitors in patients requiring chronic anti-inflammatory therapy. Aliment Pharmacol Ther 2004; 19: Fendrick A, Garabedian-Ruffalo S. A clinician s guide to the selection of NSAID therapy. Pharm Ther 2002; 27: , Schnitzer TJ. Non-NSAID pharmacologic treatment options for the management of chronic pain. Am J Med 1998; 105: 45S 52S. 24 Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Pancrai AE. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 2000; 90: Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45: / 65:4 / Br J Clin Pharmacol