title: Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain.
abstract: OBJECTIVE
  Tramadol is a weak opioid analgesic whose use has increased rapidly, and it has been associated with adverse events of hypoglycemia.
  
  
  OBJECTIVE
  To assess whether tramadol use, when compared with codeine use, is associated with an increased risk of hospitalization for hypoglycemia.
  
  
  METHODS
  A nested case-control analysis was conducted within the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database of all patients newly treated with tramadol or codeine for noncancer pain between 1998 and 2012. Cohort and case-crossover analyses were also conducted to assess consistency of the results.
  
  
  METHODS
  Cases of hospitalization for hypoglycemia were matched with up to 10 controls on age, sex, and duration of follow-up. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated comparing use of tramadol with codeine. A cohort analysis, with high-dimensional propensity score-adjusted hazard ratios (HRs) and 95% CIs, was performed comparing tramadol with codeine in the first 30 days after treatment initiation. Finally, a case-crossover analysis was also performed, in which exposure to tramadol in a 30-day risk period immediately before the hospitalization for hypoglycemia was compared with 11 consecutive 30-day control periods. Odds ratios and 95% CIs were estimated using conditional logistic regression analysis.
  
  
  RESULTS
  The cohort included 334,034 patients, of whom 1105 were hospitalized for hypoglycemia during follow-up (incidence, 0.7 per 1000 per year) and matched to 11,019 controls. Compared with codeine, tramadol use was associated with an increased risk of hospitalization for hypoglycemia (OR, 1.52 [95% CI, 1.09-2.10]), particularly elevated in the first 30 days of use (OR, 2.61 [95% CI, 1.61-4.23]). This 30-day increased risk was confirmed in the cohort (HR, 3.60 [95% CI, 1.56-8.34]) and case-crossover analyses (OR, 3.80 [95% CI, 2.64-5.47]).
  
  
  CONCLUSIONS
  The initiation of tramadol therapy is associated with an increased risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada2Department 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, Canada3Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
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: Laboratoire de Pharmacologie Médicale et Clinique, Equipe de Phamacoepidémiologie Institut National de la Santé et de la Recherche Médicale U1027, Faculté de Médecine, Université Paul Sabatier, Toulouse, France5Service de Pharmacologie Clinique, Centre Mi.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montastruc
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada2Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
authors.forename: Samy
authors.initials: S
authors.lastname: Suissa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000009:adverse effects*; D016022:Case-Control Studies; D003061:Codeine / Q000009:adverse effects; D015331:Cohort Studies; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D014147:Tramadol / Q000009:adverse effects*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D003061:Codeine