The use of nonsteroidal anti-inflammatory drugs and the risk of Barrett's oesophagus

Aliment Pharmacol Ther 2011; 34: 1235–1244

Summary

Background Epidemiological studies have consistently reported inverse associations between nonsteroidal anti‐inflammatory drugs (NSAIDs) and oesophageal adenocarcinoma, but few have investigated associations with the precursor lesion, Barrett’s oesophagus. Aim To investigate the relationship between NSAID use and risk of Barrett’s oesophagus. Methods We conducted a large population‐based case‐control study that collected information on patterns of intake for aspirin and non‐aspirin NSAIDs during the past 5 years and other exposures from 285 patients with nondysplastic Barrett’s oesophagus, 108 patients with dysplastic Barrett’s oesophagus, and two separate control groups: 313 endoscopy patients with acute inflammatory changes (‘inflammation controls’) and 644 population controls. We calculated odds ratios (ORs) and 95% CIs using unconditional logistic regression. Results Use of aspirin was not associated with nondysplastic Barrett’s oesophagus when compared with population (OR = 1.01, 95% CI 0.71–1.43) or inflammation controls (OR = 1.16, 95% CI 0.80–1.68). Whereas we observed significant risk reductions for use of non‐aspirin NSAIDs when nondysplastic Barrett’s oesophagus cases were compared with population controls (OR = 0.69, 95% CI 0.49–0.97), the effect was weaker and nonsignificant when cases were compared with inflammation controls (OR = 0.82, 95% CI 0.57–1.18), and no dose‐response effects were present in either analysis. We found no evidence that aspirin or non‐aspirin NSAID use conferred risk reductions for dysplastic Barrett’s oesophagus, regardless of the control series. We excluded effect modification by known risk factors as an explanation for these null findings. Conclusions We found little support for an inverse association between use of NSAIDs and Barrett’s oesophagus. The question of whether or not these medications prevent the onset of Barrett’s oesophagus remains open.     

非甾体抗炎药物在骨性关节炎中的应用

骨性关节炎是老年人中常见、多发的慢性进行性骨关节疾病,主要临床表现为缓慢发展的可使活动受限的关节疼痛、僵硬和肿胀,严重的能导致关节功能障碍.非甾体抗炎药物是目前治疗骨性关节炎等关节炎性疾病的最常用药物,作用机制为抑制环氧化酶活性、阻断该酶催化花生四烯酸转化为炎性物质前列腺素,从而发挥止痛、消炎作用.非甾体抗炎药物分为非选择性环氧化酶抑制剂和选择性环氧化酶-2抑制剂两类,应用广泛,但也存在多种不良反应,故选择用药时要严格掌握适应证,合理用药.     

非甾体抗炎药物在骨性关节炎中的应用

骨性关节炎是老年人中常见、多发的慢性进行性骨关节疾病,主要临床表现为缓慢发展的可使活动受限的关节疼痛、僵硬和肿胀,严重的能导致关节功能障碍。非甾体抗炎药物是目前治疗骨性关节炎等关节炎性疾病的最常用药物,作用机制为抑制环氧化酶活性、阻断该酶催化花生四烯酸转化为炎性物质前列腺素,从而发挥止痛、消炎作用。非甾体抗炎药物分为非选择性环氧化酶抑制剂和选择性环氧化酶-2抑制剂两类,应用广泛,但也存在多种不良反应,故选择用药时要严格掌握适应证,合理用药。     

Medical decision analysis of endoscopic surveillance of Barrett's oesophagus to prevent oesophageal adenocarcinoma

BACKGROUND: Barrett's oesophagus is associated with an increased risk of the development of oesophageal adenocarcinoma. Endoscopic surveillance every 2-5 years has been recommended to prevent death from adenocarcinoma. AIM: To assess the cost-effectiveness of this strategy. METHODS: The incremental cost-effectiveness of surveillance (as compared to no surveillance) was analysed with a computer model of a Markov process. RESULTS: Compared to no surveillance, the incremental cost-effectiveness of bi-annual endoscopy is 16,695 dollars per life-year saved. Surveillance is less cost-effective if the incidence rate of oesophageal adenocarcinoma is low and the 5-year survival rate is high. For surveillance to be cost-effective, there should be little reduction in health-related quality of life following surgical oesophagectomy to prevent death. Moreover, endoscopic surveillance and oesophagectomy need to be efficacious in reliably diagnosing high-grade dysplasia and preventing deaths from cancer. If such ideal conditions of surveillance are not met, the cost per life-year saved could rise five-fold. CONCLUSIONS: Endoscopic surveillance of patients with Barrett's oesophagus may be a cost-effective means to prevent death from oesophageal adenocarcinoma.     

Biliary elimination of non-steroidal anti-inflammatory drugs in patients.

In view of evidence in animals that enterohepatic recirculation of non-steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.     

Continued use of non-steroidal anti-inflammatory drugs: an index of clinical efficacy.

1 A double-blind entry to a trial of an active non-steroidal anti-inflammatory drug, flurbiprofen against placebo was undertaken until 100 patients with classical rheumatoid arthritis had been allocated to each treatment. 2 Each patient was given a long-term supply of drug and was asked to vary their own dosage within simple limits, according to the severity of their symptoms. They were instructed to return immediately they felt dissatisfied with their medication either on account of side-effect or of lack of effect. 3 The length of time that patients remained satisfied with their drug was used as the sole measure of efficacy of the drug. At 2 weeks there were only 30% remaining on placebo and by 4 months no patients remained satisfied with the inactive drug. Forty-three per cent were satisfied with flurbiprofen at the end of 1 year. 4 Clearly compliance with anti-rheumatic drugs is better if the drugs are effective and there is no long-term placebo response in rheumatoid arthritis.     

Pain control and the use of non-steroidal analgesic anti-inflammatory drugs

Rheumatic complaints, particularly associated with osteoarthritis, are responsible for about one third of all General Practice consultations in people over the age of 65 and non-steroidal anti-inflammatory drugs (NSAIDs) are used on a vast scale for pain relief. Although the individual risk to life is small NSAIDs are the major cause of serious adverse reactions (ADRs) reported to drug regulatory authorities and ADRs are more common and more serious in the elderly. Gastric ulceration, haemorrhage and perforation are the major concern but fluid retention, renal and hepatic failure, asthma, skin reactions, bone marrow suppression and a host of drug interactions can occur. NSAIDs are responsible for a fifth of all admissions to hospital with bleeding or perforated peptic ulcer and thousands of deaths worldwide. Strategies for minimising the risks of ADRs are discussed and emphasis is placed on using minimal analgesic, rather than anti-inflammatory, doses of short-acting NSAIDs and where possible avoiding their use in high risk patients. For the future cytoprotection with prostaglandin analogues may have a role to play.     

Mortality rates in patients with Barrett's oesophagus

Background  Patients with Barrett’s oesophagus are at increased risk of oesophageal adenocarcinoma. Observational studies have suggested increase in overall mortality also but data are conflicting. Aim  To assess the cause of death in patients with Barrett’s oesophagus compared with the general population. Methods  Patients with Barrett’s oesophagus were identified retrospectively in four hospitals in Leicestershire, UK using electronic endoscopy and histopathology records from 1997 to 2003. Data on deaths from this cohort of patients were identified through the Office of National Statistics and compared with age– and gender‐adjusted mortality in the Leicestershire region. Results  In all, 1272 Barrett’s patients were identified with 245 deaths in this cohort. Overall mortality was found to be increased [male standardized mortality ratio (SMR) = 552, 95% CI = 466–638; female SMR 455, 95% CI = 357–552]. The main disease areas that were responsible for this increase were oesophageal adenocarcinoma (n = 25, male SMR = 2171, 95% CI = 991–3351; female SMR = 1300, 95% CI = 26–2574), bronchopneumonia (n = 70, male SMR = 146, 95% CI = 55–236; female SMR = 436, 95% CI = 272–601) and ischaemic heart disease (n = 51, male SMR = 186, 95% CI = 97–2748; female SMR = 205, 95% CI = 105–306). Conclusions  Patients with Barrett’s oesophagus die more commonly of bronchopneumonia and ischaemic heart disease compared with oesophageal adenocarcinoma, and overall mortality in this group may be increased.     

Chronic use of non-steroidal anti-inflammatory drugs does not alter colonic mucosa of patients without diarrhoea

BACKGROUND: Several types of colitis can be NSAID-induced, but whether chronic use of NSAIDs alters colonic mucosa in patients without diarrhoea is not known. PATIENTS AND METHODS: Biopsy specimens of rectal mucosa were taken in six patients with rheumatoid arthritis without diarrhoea receiving NSAIDs (group 1, n=6). Patients with rheumatoid arthritis without diarrhoea not receiving NSAIDs (group 2, n=9), and patients undergoing surveillance colonoscopy (group 3, n=23) served as controls. In all patients from the three study groups, intraepithelial lymphocyte count and apoptotic cell count were assessed, and sub-epithelial collagen band thickness was measured. Leucocyte population of lamina propria was evaluated semi-quantitatively. HLA-DR and CD25 expression of mucosal cells was appreciated by immunohistochemistry. RESULTS: Intraepithelial lymphocyte count was in the normal range in all three group patients, and not statistically different between groups. Apoptotic epithelial cell count was not different between groups. Sub-epithelial collagen band thickness was normal in all the patients. No patient had a marked infiltration of lamina propria by leucocytes, and HLA-DR and CD25 were normally expressed in all patients. CONCLUSION: These results from a small sample of patients suggest that patients without diarrhoea receiving NSAIDs on a long-term basis do not develop microscopic or inflammatory colitis.     

Management of high-risk patients on non-steroidal anti-inflammatory drugs or aspirin

Low-dose aspirin is increasingly used for the primary prevention of cardiovascular events. However, current evidence suggests that the gastrointestinal and other bleeding risks of aspirin probably outweigh its potential benefits in primary prevention. Various strategies have been proposed to reduce the gastrointestinal risk of aspirin, including gastroprotection with a proton pump inhibitor (PPI), eradication of Helicobacter pylori infection and replacing aspirin with other anti-platelet agents. Although co-therapy with a PPI and the eradication of H. pylori substantially reduce the risk of recurrent ulcer bleeding with aspirin, the replacement of aspirin by clopidogrel cannot be recommended to patients with a high gastrointestinal risk. Traditionally, strategies for the prevention of non-steroidal anti-inflammatory drug (NSAID)-induced ulcer complications included co-therapy with a gastroprotective agent and the substitution of cyclooxygenase (COX)-2 inhibitors for non-selective NSAID. Evidence emerged recently that COX-2 inhibitors and some non-selective NSAID increase cardiovascular risk. Before prescribing anti-inflammatory therapy, both gastrointestinal and cardiovascular risk factors of individual patients need to be evaluated. In patients with increased cardiovascular risk requiring anti-inflammatory analgesics, the combination of a non-selective NSAID, low-dose aspirin and a PPI is the preferred treatment.     

外用非甾体抗炎药治疗肌肉骨骼疼痛合理应用多学科指南计划书

外用非甾体抗炎药(NSAIDs)是治疗肌肉骨骼疼痛的主要药物之一,但目前对于这类药物的使用方法、药物相互作用以及特殊人群使用等药学相关的内容尚无指南做出基于循证医学证据的推荐。为解决现有指南临床适用性不足的问题,中国药学会医院药学专业委员会采用多学科协作方式,制定外用NSAIDs治疗肌肉骨骼疼痛合理应用的临床实践指南。本指南将严格采用世界卫生组织指南制订手册的制定步骤,指南2.0标准和国际实践指南报告规范声明来制定及报告指南。指南项目组将采用德尔菲法构建临床问题、指导独立的系统评价小组进行系统检索与证据整合,依据现有最佳证据提示的利弊平衡、证据质量、患者偏好与价值观、成本与成本效果等因素,基于GRADE证据推荐表形成推荐意见,再通过指南制订小组内部讨论和外部评审完善指南内容,最终形成一份基于循证医学证据的指南。同时,该指南将聚焦临床医务人员和肌肉骨骼疼痛患者在使用外用NSAIDs时最关切的问题。因此,该指南将是一部高质量、临床实践指导性强的指南,有助于促进临床合理使用外用NSAIDs。     

Barrett's oesophagus with predominant intestinal metaplasia correlates with superficial cyclo-oxygenase-2 expression, increased proliferation and reduced apoptosis: changes that are partially reversed by non-steroidal anti-inflammatory drugs usage

BACKGROUND: Cyclo-oxygenase-2 expression has been reported to play an important role in the metaplasia-dysplasia-carcinoma sequence in Barrett's oesophagus. However, the existence of cyclo-oxygenase-2 expressing cells in Barrett's epithelium is still uncertain. AIM: To identify the cells that express cyclo-oxygenase-2 protein and to investigate the relationship between cyclo-oxygenase-2 expression and mucin-phenotype of Barrett's epithelium. METHODS: Sections from 466 biopsy samples of Barrett's epithelium from 358 non-medicated patients were immunohistochemically examined for the cyclo-oxygenase-2 expression, mucin-phenotype, cell proliferation and apoptosis. RESULTS: Cyclo-oxygenase-2 expression was detected in 71.0% of Barrett's epithelium biopsy samples. In Barrett's epithelium with the gastric predominant mucin-phenotype, cyclo-oxygenase-2 expression was mainly found in stromal and deep epithelial cells, whereas in intestinal predominant mucin-phenotype, it was mostly in superficial epithelial cell. A significant elevation of proliferating cell nuclear antigen index and suppression of apoptotic index was observed in Barrett's epithelium with superficial epithelial cyclo-oxygenase-2 expression. Neither such elevation of proliferating cell nuclear antigen index nor the suppression of apoptotic index could be found in chronic non-steroidal anti-inflammatory drugs users. CONCLUSIONS: Barrett's epithelium with intestinal mucin and superficial epithelial cyclo-oxygenase-2 expression possess a higher proliferation potential, but this risk may be thwarted by non-steroidal anti-inflammatory drugs administration.     

Lack of predictors of normalization of oesophageal acid exposure in Barrett's oesophagus

BACKGROUND: Barrett's oesophagus patients may continue to have abnormal oesophageal acid exposure on proton pump inhibitor therapy. The effect of factors such as Barrett's oesophagus length, hiatal hernia size and Helicobacter pylori infection on intra-oesophageal pH in Barrett's oesophagus patients has not been adequately studied. AIM: To evaluate oesophageal acid exposure in a large Barrett's oesophagus population on b.d. proton pump inhibitor therapy and determine clinical factors predicting normalization of intra-oesophageal pH on therapy. METHODS: Barrett's oesophagus patients were studied using 24 h pH monitoring to evaluate intra-oesophageal acid suppression on b.d. dosing of rabeprazole. RESULTS: Forty-six Barrett's oesophagus patients completed the study. Median total percentage time pH < 4 was 1.05% (range: 0-29.9%) in the entire group and respective values for upright and supine percentage time pH < 4 were 1.15% and 0%. However, 34 of the Barrett's oesophagus patients (73.9%) had a normal pH study (median total percentage time pH < 4: 0.2%) and 12 patients (26.1%) had an abnormal result (median total percentage time pH < 4: 9.3%). There were no significant differences between patients with a normal and abnormal 24 h pH result with respect to age, Barrett's oesophagus length, hiatal hernia size and presence of H. pylori infection. CONCLUSIONS: Approximately 25% of Barrett's oesophagus patients continue to have abnormal total intra-oesophageal pH profiles despite b.d. proton pump inhibitor therapy. Factors such as age, Barrett's oesophagus length and hiatal hernia size cannot be used to predict persistent abnormal intra-oesophageal pH on proton pump inhibitor.