Importance Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids. Objective To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings. Design, Setting, and Participants Retrospective, population-based, propensity score-matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (≈6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017. Exposures New prescription dispensation of tramadol or codeine (no dispensation in the previous year). Main Outcomes and Measures Outcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models. Results Of the 1 093 064 patients with a tramadol or codeine dispensation during the study period (326 921 for tramadol, 762 492 for codeine, 3651 for both drugs concomitantly), a total of 368 960 patients (184 480 propensity score-matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders. Conclusions and Relevance In this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders. The findings should be interpreted cautiously, given the potential for residual confounding.

中文翻译：

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曲马多与可待因处方分配与死亡率和其他不良临床结果的关联。

重要性 尽管曲马多越来越多地用于治疗慢性非癌性疼痛，但很少有安全性研究将其与其他阿片类药物进行比较。目的 评估曲马多与可待因相比，与门诊环境中使用的死亡率和其他不良临床结果的关系。设计、设置和参与者 回顾性、基于人群、倾向得分匹配的队列研究使用初级保健数据库，常规收集医疗记录和药房分配，覆盖西班牙加泰罗尼亚超过 80% 的人口（约 600 万人）。纳入并随访至 2017 年 12 月 31 日，具有 1 年或以上可用数据和使用曲马多或可待因（2007-2017 年）的 18 岁或以上患者。 ）。主要结果和措施 研究的结果是第一次分配后 1 年内的全因死亡率、心血管事件、骨折、便秘、谵妄、跌倒、阿片类药物滥用/依赖和睡眠障碍。使用特定原因 Cox 模型计算具有 95% 置信区间的绝对率差异 (ARD) 和风险比 (HR)。结果 在研究期间接受曲马多或可待因分配的 1 093 064 名患者中（曲马多 326 921 人，可待因 762 492 人，两种药物同时使用 3651 人），共有 368 960 名患者（184 480 对倾向评分匹配）在研究排除和倾向评分匹配后被纳入（平均年龄，53.1 [SD，16.1] 岁；57.3% 的女性）。与可待因相比，曲马多分配与更高的全因死亡风险显着相关（发病率，13. 每 1000 人年 00 对 5.61；人力资源，2.31 [95% CI，2.08-2.56]；ARD，7.37 [95% CI，6.09-8.78]/1000 人年），心血管事件（发生率，10.03 vs 8.67/1000 人年；HR，1.15 [95% CI，1.05-1.27]；ARD，1.36 [ 95% CI，0.45-2.36]/1000 人年）和骨折（发生率，12.26 对 8.13/1000 人年；HR，1.50 [95% CI，1.37-1.65]；ARD，4.10 [95% CI， 3.02-5.29] 每 1000 人年）。跌倒、谵妄、便秘、阿片类药物滥用/依赖或睡眠障碍的风险没有观察到显着差异。结论和相关性 在这项基于人群的队列研究中，与可待因相比，曲马多的新处方配药与随后的全因死亡率、心血管事件和骨折风险显着相关，但便秘、谵妄、跌倒、阿片类药物滥用/依赖或睡眠障碍的风险没有显着差异。考虑到残留混杂的可能性，应谨慎解释研究结果。