title: Out-of-hospital mortality among patients receiving methadone for noncancer pain.
abstract: OBJECTIVE
  Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias.
  
  
  OBJECTIVE
  To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate.
  
  
  METHODS
  A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively.
  
  
  METHODS
  The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital.
  
  
  RESULTS
  There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P < .001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (<60 mg/d).
  
  
  CONCLUSIONS
  The increased risk of death observed for patients receiving methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for noncancer pain.
authors.affiliation: Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Ray
authors.affiliation: Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Cecilia P
authors.initials: CP
authors.lastname: Chung
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee4Division of Cardiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Murray
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: William O
authors.initials: WO
authors.lastname: Cooper
authors.affiliation: Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Kathi
authors.initials: K
authors.lastname: Hall
authors.affiliation: Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee3Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003645:Death, Sudden; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000506:poisoning*; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000506:poisoning; D059408:Pain Management / Q000009:adverse effects*; D012189:Retrospective Studies
chemical_list: D003692:Delayed-Action Preparations; D009020:Morphine; D008691:Methadone