Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes

Junqing Xie; Victoria Y. Strauss; Daniel Martinez-Laguna; Cristina Carbonell-Abella; Adolfo Diez-Perez; Xavier Nogues; Gary S. Collins; Sara Khalid; Antonella Delmestri; Aleksandra Turkiewicz; Martin Englund; Mina Tadrous; Carlen Reyes; Daniel Prieto-Alhambra

doi:10.1001/jama.2021.15255

Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes

Junqing Xie
, Victoria Y. Strauss
, Daniel Martinez-Laguna
, Cristina Carbonell-Abella
, Adolfo Diez-Perez
, Xavier Nogues
, Gary S. Collins
, Sara Khalid
, Antonella Delmestri
, Aleksandra Turkiewicz
, Martin Englund
, Mina Tadrous
, Carlen Reyes^*
, Daniel Prieto-Alhambra

^*Corresponding author for this work

Medical Informatics

University of Oxford
Instituto de Salud Carlos III
Generalitat de Catalunya
Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol)
Autonomous University of Barcelona
University of Barcelona
Hospital del Mar Medical Research Institute (IMIM)
John Radcliffe Hospital
Lund University
University of Toronto

Research output: Contribution to journal › Article › Academic › peer-review

61 Citations (Scopus)

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 1093064 patients with a tramadol or codeine dispensation during the study period (326921 for tramadol, 762492 for codeine, 3651 for both drugs concomitantly), a total of 368960 patients (184480 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..

Original language	English
Pages (from-to)	1504-1515
Number of pages	12
Journal	JAMA - Journal of the American Medical Association
Volume	326
Issue number	15
DOIs	https://doi.org/10.1001/jama.2021.15255
Publication status	Published - 19 Oct 2021

Bibliographical note

Funding Information:
Funding/Support: This work was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAP Jordi Gol Foundation; grant 4R18/060-1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Dr Prieto-Alhambra is funded through an NIHR Senior Research Fellowship (grant SRF-2018-11-ST2-004). Mr Xie has been awarded a Jardine-Oxford Graduate Scholarship and a titular Clarendon Fund Scholarship outside the submitted work.

Funding Information:
reported receiving grants from Amgen. Dr Martinez-Laguna reported receiving personal fees from Amgen, Italfarmaco, Ferrer, Novartis, and Rubio. Dr Carbonell-Abella reported receiving fees for lectures/classes from Amgen, Theramex, Stada, and Gebro. Dr Diez-Perez reported receiving personal fees from Amgen, Lilly, and Theramex; receiving grants from Instituto Carlos III; and owning shares of Active Life Scientific. Dr Nogues reported receiving personal fees from Amgen, UCB, and Lilly and a grant from the Foundation for Advanced Education in the Sciences. Dr Turkiewicz reported serving as associate editor for Osteoarthritis and Cartilage. Dr Englund reported receiving personal fees from Pfizer for serving as a 1-day advisory board panel member (Tanezumab; November 26, 2019). Dr Prieto-Alhambra reported receiving grant support from Les Laboratoires Servier; that his research group has received grants and advisory or speaker fees from Amgen, Astellas, AstraZeneca, Chiesi-Taylor, Johnson & Johnson, and UCB; and that Janssen, on behalf of Innovative Medicines Initiative–funded European Health Data Evidence Network and European Medical Information Framework consortiums and Synapse Management Partners, have supported training programs, open to external participants, organized by his department. No other authors reported disclosures.

Publisher Copyright:
© 2021 American Medical Association. All rights reserved.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527363/

Cite this

Xie, J., Strauss, V. Y., Martinez-Laguna, D., Carbonell-Abella, C., Diez-Perez, A., Nogues, X., Collins, G. S., Khalid, S., Delmestri, A., Turkiewicz, A., Englund, M., Tadrous, M., Reyes, C., & Prieto-Alhambra, D. (2021). Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes. JAMA - Journal of the American Medical Association, 326(15), 1504-1515. https://doi.org/10.1001/jama.2021.15255

@article{a81d3a276973407dae1723f15f59d9ad,

title = "Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes",

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 1093064 patients with a tramadol or codeine dispensation during the study period (326921 for tramadol, 762492 for codeine, 3651 for both drugs concomitantly), a total of 368960 patients (184480 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..",

author = "Junqing Xie and Strauss, \{Victoria Y.\} and Daniel Martinez-Laguna and Cristina Carbonell-Abella and Adolfo Diez-Perez and Xavier Nogues and Collins, \{Gary S.\} and Sara Khalid and Antonella Delmestri and Aleksandra Turkiewicz and Martin Englund and Mina Tadrous and Carlen Reyes and Daniel Prieto-Alhambra",

note = "Funding Information: Funding/Support: This work was funded by the Fundaci{\'o} Institut Universitari per a la recerca a l{\textquoteright}Atenci{\'o} Prim{\`a}ria de Salut Jordi Gol i Gurina (IDIAP Jordi Gol Foundation; grant 4R18/060-1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Dr Prieto-Alhambra is funded through an NIHR Senior Research Fellowship (grant SRF-2018-11-ST2-004). Mr Xie has been awarded a Jardine-Oxford Graduate Scholarship and a titular Clarendon Fund Scholarship outside the submitted work. Funding Information: reported receiving grants from Amgen. Dr Martinez-Laguna reported receiving personal fees from Amgen, Italfarmaco, Ferrer, Novartis, and Rubio. Dr Carbonell-Abella reported receiving fees for lectures/classes from Amgen, Theramex, Stada, and Gebro. Dr Diez-Perez reported receiving personal fees from Amgen, Lilly, and Theramex; receiving grants from Instituto Carlos III; and owning shares of Active Life Scientific. Dr Nogues reported receiving personal fees from Amgen, UCB, and Lilly and a grant from the Foundation for Advanced Education in the Sciences. Dr Turkiewicz reported serving as associate editor for Osteoarthritis and Cartilage. Dr Englund reported receiving personal fees from Pfizer for serving as a 1-day advisory board panel member (Tanezumab; November 26, 2019). Dr Prieto-Alhambra reported receiving grant support from Les Laboratoires Servier; that his research group has received grants and advisory or speaker fees from Amgen, Astellas, AstraZeneca, Chiesi-Taylor, Johnson \& Johnson, and UCB; and that Janssen, on behalf of Innovative Medicines Initiative–funded European Health Data Evidence Network and European Medical Information Framework consortiums and Synapse Management Partners, have supported training programs, open to external participants, organized by his department. No other authors reported disclosures. Publisher Copyright: {\textcopyright} 2021 American Medical Association. All rights reserved.",

year = "2021",

month = oct,

day = "19",

doi = "10.1001/jama.2021.15255",

language = "English",

volume = "326",

pages = "1504--1515",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "15",

}

Xie, J, Strauss, VY, Martinez-Laguna, D, Carbonell-Abella, C, Diez-Perez, A, Nogues, X, Collins, GS, Khalid, S, Delmestri, A, Turkiewicz, A, Englund, M, Tadrous, M, Reyes, C & Prieto-Alhambra, D 2021, 'Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes', JAMA - Journal of the American Medical Association, vol. 326, no. 15, pp. 1504-1515. https://doi.org/10.1001/jama.2021.15255

TY - JOUR

T1 - Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes

AU - Xie, Junqing

AU - Strauss, Victoria Y.

AU - Martinez-Laguna, Daniel

AU - Carbonell-Abella, Cristina

AU - Diez-Perez, Adolfo

AU - Nogues, Xavier

AU - Collins, Gary S.

AU - Khalid, Sara

AU - Delmestri, Antonella

AU - Turkiewicz, Aleksandra

AU - Englund, Martin

AU - Tadrous, Mina

AU - Reyes, Carlen

AU - Prieto-Alhambra, Daniel

N1 - Funding Information: Funding/Support: This work was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAP Jordi Gol Foundation; grant 4R18/060-1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Dr Prieto-Alhambra is funded through an NIHR Senior Research Fellowship (grant SRF-2018-11-ST2-004). Mr Xie has been awarded a Jardine-Oxford Graduate Scholarship and a titular Clarendon Fund Scholarship outside the submitted work. Funding Information: reported receiving grants from Amgen. Dr Martinez-Laguna reported receiving personal fees from Amgen, Italfarmaco, Ferrer, Novartis, and Rubio. Dr Carbonell-Abella reported receiving fees for lectures/classes from Amgen, Theramex, Stada, and Gebro. Dr Diez-Perez reported receiving personal fees from Amgen, Lilly, and Theramex; receiving grants from Instituto Carlos III; and owning shares of Active Life Scientific. Dr Nogues reported receiving personal fees from Amgen, UCB, and Lilly and a grant from the Foundation for Advanced Education in the Sciences. Dr Turkiewicz reported serving as associate editor for Osteoarthritis and Cartilage. Dr Englund reported receiving personal fees from Pfizer for serving as a 1-day advisory board panel member (Tanezumab; November 26, 2019). Dr Prieto-Alhambra reported receiving grant support from Les Laboratoires Servier; that his research group has received grants and advisory or speaker fees from Amgen, Astellas, AstraZeneca, Chiesi-Taylor, Johnson & Johnson, and UCB; and that Janssen, on behalf of Innovative Medicines Initiative–funded European Health Data Evidence Network and European Medical Information Framework consortiums and Synapse Management Partners, have supported training programs, open to external participants, organized by his department. No other authors reported disclosures. Publisher Copyright: © 2021 American Medical Association. All rights reserved.

PY - 2021/10/19

Y1 - 2021/10/19

N2 - 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 1093064 patients with a tramadol or codeine dispensation during the study period (326921 for tramadol, 762492 for codeine, 3651 for both drugs concomitantly), a total of 368960 patients (184480 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..

AB - 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 1093064 patients with a tramadol or codeine dispensation during the study period (326921 for tramadol, 762492 for codeine, 3651 for both drugs concomitantly), a total of 368960 patients (184480 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..

UR - https://www.scopus.com/pages/publications/85117856385

U2 - 10.1001/jama.2021.15255

DO - 10.1001/jama.2021.15255

M3 - Article

C2 - 34665205

AN - SCOPUS:85117856385

SN - 0098-7484

VL - 326

SP - 1504

EP - 1515

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 15

ER -

Association of Tramadol vs Codeine Prescription Dispensation with Mortality and Other Adverse Clinical Outcomes

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