Junqing Xie1, Victoria Y Strauss1, Daniel Martinez-Laguna2,3,4,5, Cristina Carbonell-Abella2,3,4,6, Adolfo Diez-Perez2,3,4,5,7, Xavier Nogues2,5,7,8, Gary S Collins1,9, Sara Khalid1, Antonella Delmestri1, Aleksandra Turkiewicz10, Martin Englund10, Mina Tadrous11,12, Carlen Reyes2,4, Daniel Prieto-Alhambra1,13. 1. Centre for Statistics in Medicine and NIHR Biomedical Research Centre Oxford, NDORMS, University of Oxford, Oxford, United Kingdom. 2. Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFes), Instituto Carlos III, Madrid, Spain. 3. Gerència Territorial de Barcelona, Institut Català de la Salut, Barcelona, Spain. 4. Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. 5. Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain. 6. Universitat de Barcelona, Barcelona, Spain. 7. Musculoskeletal Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. 8. Internal Medicine Department, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. 9. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom. 10. Department of Clinical Sciences Lund, Orthopedics, Clinical Epidemiology Unit, Faculty of Medicine, Lund University, Lund, Sweden. 11. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. 12. Women's College Hospital Research Institute, Toronto, Toronto, Ontario, Canada. 13. Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Abstract
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.
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.
Authors: Sebastian Schneeweiss; Jeremy A Rassen; Jeffrey S Brown; Kenneth J Rothman; Laura Happe; Peter Arlett; Gerald Dal Pan; Wim Goettsch; William Murk; Shirley V Wang Journal: Ann Intern Med Date: 2019-03-12 Impact factor: 25.391
Authors: Daniel H Solomon; Jeremy A Rassen; Robert J Glynn; Katie Garneau; Raisa Levin; Joy Lee; Sebastian Schneeweiss Journal: Arch Intern Med Date: 2010-12-13
Authors: Markus C Elze; John Gregson; Usman Baber; Elizabeth Williamson; Samantha Sartori; Roxana Mehran; Melissa Nichols; Gregg W Stone; Stuart J Pocock Journal: J Am Coll Cardiol Date: 2017-01-24 Impact factor: 24.094
Authors: Junqing Xie; Victoria Y Strauss; Gary S Collins; Sara Khalid; Antonella Delmestri; Aleksandra Turkiewicz; Martin Englund; Mina Tadrous; Carlen Reyes; Daniel Prieto-Alhambra Journal: Front Pharmacol Date: 2022-06-08 Impact factor: 5.988