title: Tramadol for noncancer pain and the risk of hyponatremia.
abstract: BACKGROUND
  Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine.
  
  
  METHODS
  Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles.
  
  
  RESULTS
  The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54).
  
  
  CONCLUSIONS
  In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization.
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Fournier
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Medicine, Division of Nephrology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Nessim
authors.affiliation: Laboratoire de Pharmacologie Médicale et Clinique, Equipe de PharmacoEpidémiologie, Faculté de Médecine, Université Paul Sabatier, Toulouse, France; Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de PharmacoEpidémiologie et d'Information sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montastruc
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montreal, Quebec, Canada. Electronic address: laurent.azoulay@mcgill.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D003061:Codeine / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D007010:Hyponatremia / Q000097:blood / Q000139:chemically induced* / Q000453:epidemiology; D015994:Incidence; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D016017:Odds Ratio; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D012964:Sodium / Q000097:blood*; D014147:Tramadol / Q000008:administration & dosage / Q000009:adverse effects*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D012964:Sodium; D003061:Codeine
keywords: Adverse drug reaction; Codeine; Cohort study; Hyponatremia; Tramadol