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Predictors of Opioid-Related Death During Methadone Therapy

Open AccessPublished:April 14, 2015DOI:https://doi.org/10.1016/j.jsat.2015.04.008

      Highlights

      • Psychotropic drugs were associated with an increased risk of opioid-related death among patients prescribed methadone for opioid use disorders.
      • Alcohol use, lung and heart disease increased the risk of opioid-related death.
      • New initiation of methadone increased the risk of opioid-related mortality 16-fold.

      Abstract

      We aimed to examine pharmacologic, demographic and medical comorbidity risk factors for opioid-related mortality among patients currently receiving methadone for an opioid use disorder. We conducted a population-based, nested case-control study linking healthcare and coroner's records in Ontario, Canada, from January 31, 1994 to December 31, 2010. We included social assistance recipients receiving methadone for an opioid use disorder. Within this group, cases were those who died of opioid-related causes. For each case, we identified up to 5 controls matched on calendar quarter. The primary analysis examined the association between use of psychotropic drugs (benzodiazepines, antidepressants or antipsychotics) and opioid-related mortality. Secondary analyses examined the associations between baseline characteristics, health service utilization, comorbidities and opioid-related mortality. Among 43,545 patients receiving methadone for an opioid use disorder, we identified 175 (0.4%) opioid-related deaths, along with 873 matched controls. Psychotropic drug use was associated with a two fold increased risk of opioid-related death (adjusted odds ratio (OR) 2.0; 95% confidence interval (CI) 1.2 to 3.5). Specifically, benzodiazepines (adjusted OR 1.6; 95% CI 1.1 to 2.5) and antipsychotics (adjusted OR 2.3; 95% CI 1.5 to 3.5) were independently associated with opioid-related death. Other associated factors included chronic lung disease (adjusted OR 1.7; 95% CI 1.2 to 2.6), an alcohol use disorder (adjusted OR 1.9; 95% CI 1.2 to 3.2), mood disorders (adjusted OR 1.8; 95% CI 1.0 to 3.2), and a history of heart disease (adjusted OR 5.3; 95% CI 2.0 to 14.0). Psychotropic drug use is associated with opioid-related death in patients receiving methadone. Mindfulness of these factors may reduce the risk of death among methadone recipients.

      Keywords

      1. Introduction

      In patients undergoing treatment for opioid use disorders, methadone therapy is associated with several improved outcomes, including retention in drug treatment as well as reduced opioid use, and some observational studies have observed reductions in all-cause mortality and risk of death from overdose (
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      ). On the basis of its effectiveness, the World Health Organization added methadone to its list of essential medicines in 2005. It is included on the complementary list of “essential medicines for priority diseases”, for which specialist care is needed (
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      Many challenges accompany methadone therapy, including multiple drug interactions and the risk of fatal QT prolongation (
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      Mortality among opiate users: Opioid maintenance therapy, age and causes of death.
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      Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995.
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      • Zanis D.A.
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      One-year mortality rates following methadone treatment discharge.
      ). Additionally, some evidence suggests an association between drug-related death and psychiatric disorders, during or after cessation of methadone treatment (
      • Cousins G.
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      • Motterlini N.
      • McCowan C.
      • Dimitrov B.D.
      • Fahey T.
      Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.
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      • Zanis D.A.
      • Woody G.E.
      One-year mortality rates following methadone treatment discharge.
      ).
      Methadone prescribing is highly regulated, and patients are closely monitored due to the associated risks of treatment. Clinical practice guidelines identify factors that may increase the risk of methadone toxicity (
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      • Cruciani R.A.
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      • Haigney M.C.
      • et al.
      Methadone safety: a clinical practice guideline from the American pain society and college on problems of drug dependence, in collaboration with the heart rhythm society.
      ,
      • Hillier W.
      Methadone Program: Methadone Maintenance Treatment Program Standards and Clinical Guidelines.
      ). Most methadone-associated deaths involve methadone obtained from non-prescription sources or methadone prescribed for pain (
      • Heinemann A.
      • Iwersen-Bergmann S.
      • Stein S.
      • Schmoldt A.
      • Püschel K.
      Methadone-related fatalities in Hamburg 1990-1999: Implications for quality standards in maintenance treatment?.
      ,
      • Paulozzi L.J.
      • Logan J.E.
      • Hall A.J.
      • McKinstry E.
      • Kaplan J.A.
      • Crosby A.E.
      A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia.
      ,
      • Weimer M.B.
      • Korthuis P.T.
      • Behonick G.S.
      • Wunsch M.J.
      The source of methadone in overdose deaths in Western Virginia in 2004.
      ), but safety concerns persist in light of the growing number of methadone-related deaths (
      • US Department of Health and Services
      Methadone mortality : A 2010 reassessment.
      ).
      Previous studies have examined various risk factors for overdose-related death among patients in drug treatment programs, including street drug use, demographic, and comorbidities (HIV, hepatitis status, and mental and physical health scores) (
      • Brådvik L.
      • Berglund M.
      • Frank A.
      • Lindgren A.
      • Löwenhielm P.
      Number of addictive substances used related to increased risk of unnatural death: A combined medico-legal and case-record study.
      ,
      • Brugal M.T.
      • Domingo-Salvany A.
      • Puig R.
      • Barrio G.
      • García de Olalla P.
      • de la Fuente L.
      Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain.
      ,
      • Gossop M.
      • Stewart D.
      • Treacy S.
      • Marsden J.
      A prospective study of mortality among drug misusers during a 4-year period after seeking treatment.
      ,
      • Peles E.
      • Schreiber S.
      • Adelson M.
      15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel.
      ). Others have examined cardiac mortality among subjects whose methadone levels precluded drug toxicity as the cause of death (
      • Chugh S.S.
      • Socoteanu C.
      • Reinier K.
      • Waltz J.
      • Jui J.
      • Gunson K.
      A community-based evaluation of sudden death associated with therapeutic levels of methadone.
      ). Still others have explored the role of systemic disease (
      • Darke S.
      • Kaye S.
      • Duflou J.
      Systemic disease among cases of fatal opioid toxicity.
      ) and medical and psychiatric comorbidity risk factors for all-cause mortality among individuals who entered methadone maintenance treatment (
      • Huang C.L.-C.
      • Lee C.W.
      Factors associated with mortality among heroin users after seeking treatment with methadone: A population-based cohort study in Taiwan.
      ).
      However, important gaps remain in the literature related to predictors of opioid-related deaths among patients currently in methadone maintenance treatment. Most studies in this area do not clearly differentiate among people who enter methadone therapy rather than drug treatment more generally (
      • Brådvik L.
      • Berglund M.
      • Frank A.
      • Lindgren A.
      • Löwenhielm P.
      Number of addictive substances used related to increased risk of unnatural death: A combined medico-legal and case-record study.
      ,
      • Gossop M.
      • Stewart D.
      • Treacy S.
      • Marsden J.
      A prospective study of mortality among drug misusers during a 4-year period after seeking treatment.
      ), those who remain on methadone therapy or those who discontinue (
      • Brugal M.T.
      • Domingo-Salvany A.
      • Puig R.
      • Barrio G.
      • García de Olalla P.
      • de la Fuente L.
      Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain.
      ), those who die while using prescribed or non-prescribed methadone treatment (
      • Chugh S.S.
      • Socoteanu C.
      • Reinier K.
      • Waltz J.
      • Jui J.
      • Gunson K.
      A community-based evaluation of sudden death associated with therapeutic levels of methadone.
      ,
      • Darke S.
      • Kaye S.
      • Duflou J.
      Systemic disease among cases of fatal opioid toxicity.
      ), or those who die of an opioid- or non-opioid overdose (
      • Huang C.L.-C.
      • Lee C.W.
      Factors associated with mortality among heroin users after seeking treatment with methadone: A population-based cohort study in Taiwan.
      ,
      • Peles E.
      • Schreiber S.
      • Adelson M.
      15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel.
      ).
      Methadone prescribers are advised to use caution when treating patients who use benzodiazepines or alcohol, as well as those who have lung disease. However, the extent to which other co-morbid conditions or concurrent prescriptions influence the risk of opioid-related death during methadone therapy is less well understood (
      • Chan G.M.
      • Stajic M.
      • Marker E.K.
      • Hoffman R.S.
      • Nelson L.S.
      Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: Analysis of medical examiner data.
      ,
      • Cousins G.
      • Teljeur C.
      • Motterlini N.
      • McCowan C.
      • Dimitrov B.D.
      • Fahey T.
      Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.
      ,
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ,
      • Pilgrim J.L.
      • McDonough M.
      • Drummer O.H.
      A review of methadone deaths between 2001 and 2005 in Victoria, Australia.
      ,
      • The DAWN Report
      Methadone-involved deaths in 8 metropolitan areas : 1997-2001.
      ). Previous studies of the extent to which psychotropic drugs increase the risk of drug-related death in methadone recipients used a restrictive case definition of “deaths caused directly by the consumption of one or more illegal drugs” (
      • Cousins G.
      • Teljeur C.
      • Motterlini N.
      • McCowan C.
      • Dimitrov B.D.
      • Fahey T.
      Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.
      ,
      • European Monitoring Centre for Drugs and Drug Addiction
      Drug-related deaths and mortality — An overview of the methods and definitions used.
      ,
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ). We examined the association between psychotropic drug use, among other factors, and opioid-related mortality in patients receiving methadone treatment for an opioid use disorder.

      2. Material and methods

      2.1 Setting and design

      We conducted a nested case-control study of Ontario residents between January 31, 1994 and December 31, 2010. These individuals had universal access to hospital care, physicians' services, and prescription drug coverage. The study was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre, Toronto, Ontario.

      2.2 Sources of data

      We identified prescription records using the Ontario Drug Benefit (ODB) Database, which contains comprehensive records of prescription medications dispensed to Ontarians whose prescriptions costs are reimbursed by the provincial government. In 2006 in Ontario, more than 70% of methadone recipients were insured under this program (
      • Hart A.W.
      Report of the Methadone Maintenance Treatment Practices Task Force.
      ). Methadone prescriptions are recorded in the ODB database for each date methadone was dispensed, regardless of whether doses were observed in a pharmacy. In Ontario, methadone prescribing guidelines specify that methadone must be dispensed daily for at least the first 2 months of treatment (
      • Hillier W.
      Methadone Program: Methadone Maintenance Treatment Program Standards and Clinical Guidelines.
      ). Methadone prescribers undergo regular mandatory practice audits by the College of Physicians and Surgeons of Ontario, and compliance with daily dispensing in the first 2 months is extremely high.
      Opioid-related deaths were identified using the records of the Chief Coroner for Ontario, as done previously (
      • Dhalla I.A.
      • Mamdani M.M.
      • Sivilotti M.L.A.
      • Kopp A.
      • Qureshi O.
      • Juurlink D.N.
      Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone.
      ,
      • Dhalla I.A.
      • Mamdani M.M.
      • Gomes T.
      • Juurlink D.N.
      Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario.
      ,
      • Gomes T.
      • Juurlink D.N.
      • Dhalla I.A.
      • Mailis-Gagnon A.
      • Paterson J.M.
      • Mamdani M.M.
      Trends in opioid use and dosing among socio-economically disadvantaged patients.
      ). The investigating coroner classified opioid-related deaths as those with toxicologic findings of opioid concentrations sufficiently high to cause death, or that a combination of drugs (including at least one opioid present at a clinically significant concentration) resulted in death (
      • Dhalla I.A.
      • Mamdani M.M.
      • Sivilotti M.L.A.
      • Kopp A.
      • Qureshi O.
      • Juurlink D.N.
      Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone.
      ). The Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD) was used to identify hospitalizations, which contains detailed diagnostic and procedural information regarding all acute care hospital admissions in the province. We used the Ontario Health Insurance Plan (OHIP) Database to determine physician billing claims, including visits to physicians licensed to prescribe methadone and claims for urine drug screens. Comorbidities were identified using the CIHI-DAD, CIHI Same-Day Surgery Database (CIHI-SDS), CIHI National Ambulatory Care Reporting System (CIHI-NACRS) and OHIP databases. The Adjusted Clinical Group (ACG) scoring system was used to measure comorbidity in the preceding year (
      • Weiner Jonathan P.
      The John Hopkins University Bloomberg School of Public Health, Health Services Research & Development Center. The John Hopkins ACG® Case-Mix System Version 6.0 Release Notes.
      ). Demographic information was obtained from the Registered Persons Database (RPDB). These datasets are linked in an anonymous fashion using encrypted health insurance numbers, contain little missing information (
      • Levy A.R.
      • O’Brien B.J.
      • Sellors C.
      • Grootendorst P.
      • Willison D.
      Coding accuracy of administrative drug claims in the Ontario Drug Benefit database.
      ), and are routinely used to study drug safety (
      • Juurlink D.N.
      • Mamdani M.M.
      • Lee D.S.
      • Kopp A.
      • Austin P.C.
      • Laupacis A.
      • et al.
      Rates of hyperkalemia after publication of the randomized aldactone evaluation study.
      ,
      • Juurlink D.N.
      • Gomes T.
      • Lipscombe L.L.
      • Austin P.C.
      • Hux J.E.
      • Mamdani M.M.
      Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: Population based cohort study.
      ,
      • Park-Wyllie L.Y.
      • Mamdani M.M.
      • Juurlink D.N.
      • Hawker G.A.
      • Gunraj N.
      • Austin P.C.
      • et al.
      Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women.
      ).

      2.3 Identification of cases and controls

      We defined case patients as those who died of opioid-related causes within 3 days of receiving a prescription for methadone. The date of death served as the index date for all analyses. For each case, we randomly selected up to 5 controls from the population of patients receiving methadone for an opioid use disorder who did not die of opioid-related causes on or before the index date. Control subjects were randomly assigned index dates based on the distribution of case index dates and matched to case patients on calendar quarter of index date to account for temporal trends in methadone prescribing. We also excluded patients whose death was classified as a homicide in the coroner's database, those receiving palliative care, and those who received methadone tablets in the preceding 60 days, because methadone tablets are exclusively indicated for the treatment of pain in Ontario.

      2.4 Statistical analysis

      We used conditional logistic regression to estimate odds ratios and 95% confidence intervals for the association between opioid-related death and receipt of benzodiazepines, antidepressants or antipsychotics in the preceding year. A secondary analysis examined the association for each of these classes individually. We adjusted all models for other medication exposures (other opioids, QT prolonging drugs, barbiturates and anticonvulsants), as well as for other potential risk factors including baseline characteristics (age, sex, and rural vs. urban place of residence), health service utilization (number of visits to a methadone prescriber in past 2 months, number of urine drug screens in the past 1 year, any ECG in the past year, and initiation of methadone 30 days prior to the index date), and comorbidities (Johns Hopkins adjusted clinical groups (
      • Weiner Jonathan P.
      The John Hopkins University Bloomberg School of Public Health, Health Services Research & Development Center. The John Hopkins ACG® Case-Mix System Version 6.0 Release Notes.
      )) in previous year, and diagnoses of chronic lung disease, sleep apnea, alcohol use disorder, chronic liver disease, mood disorder, psychosis/schizophrenia, and heart disease (coronary artery disease or arrhythmia). All analyses used a two-sided type I error rate of 0.05 as the threshold for statistical significance and were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina).

      3. Results

      During the 16-year study period, we identified 43,545 patients receiving methadone for an opioid use disorder. After exclusions, 175 died of an opioid-related cause and were matched to 873 matched controls. The characteristics of case and control subjects are shown in Table 1. The median age of case patients was 42 years (IQR 36 to 48), and 62% were men. Co-prescription of psychotropic medications and other opioids was frequent. As expected, compared with controls, case patients were more likely to have various comorbidities and to have initiated methadone treatment in the 30 days preceding the index date (Table 1).
      Table 1Characteristics of cases and controls.
      CharacteristicCasesn = 175Controlsn = 873Standardized difference
      Median (IQR) age42 (36–48)39 (31–45)0.36
      Male, no. (%)109 (62.3)543 (62.2)0.00
      Rural, no. (%)7 (4.0)72 (8.2)0.16
      Median (IQR) visits to a methadone prescriber in the 2 months prior7 (3–11)7 (4–10)0.03
      Median (IQR) urine drug tests in the 1 year prior2 (0–21)4 (0–27)0.13
      ECG, no. (%)
      In the 1year prior to the index date.
      77 (44.0)234 (26.8)0.38
      Initiation of methadone in the 30 days prior to index date, no. (%)9 (5.1)50.40
      John Hopkins ACG, no. (%)
      In the 1year prior to the index date.
       0–445 (25.7)414 (47.4)0.44
       5–966 (37.7)339 (38.8)0.02
       10–1454 (30.9)108 (12.4)0.52
       15–1910 (5.7)12 (1.4)0.30
      Diagnoses, no. (%)
      In the 1year prior to the index date.
       Chronic lung disease88 (50.3)251 (28.8)0.47
       Alcohol use disorder42 (24.0)73 (8.4)0.51
       Chronic liver disease40 (22.9)122 (14.0)0.25
       Heart disease (coronary artery disease or arrhythmia)16 (9.1)9 (1.0)0.54
       Mood disorders32 (18.3)53 (6.1)0.45
       Schizophrenia57 (0.8)0.03
      Benzodiazepines, antidepressants, and/or antipsychotics, no. (%)
      In the 1year prior to the index date.
      154 (88.0)627 (71.8)0.37
       Benzodiazepines, no. (%)116 (66.3)359 (41.1)0.51
       Antidepressants, no. (%)127 (72.6)487 (55.8)0.34
       Antipsychotics, no. (%)84 (48.0)197 (22.6)0.59
      Opioids, no. (%)
      In the 1year prior to the index date.
      100 (57.1)402 (46.0)0.22
       Short-acting oxycodone0 (0.0)0 (0.0)0.00
       Long-acting oxycodone12 (6.9)68 (7.8)0.04
       Codeine67 (38.3)221 (25.3)0.29
       Morphine13 (7.4)54 (6.2)0.05
       Hydromorphone12 (6.9)35 (4.0)0.14
       Fentanyl7 (4.0)12 (1.4)0.20
       Meripidine/Pethidine59 (1.0)0.01
       Methadone (for pain)550.04
      Anticonvulsants, no. (%)
      In the 1year prior to the index date.
      23 (13.1)43 (4.9)0.34
       Metabolic12 (6.9)22 (2.5)0.25
       Sedating13 (7.4)23 (2.6)0.26
      QT prolonging drugs, no. (%)
      In the 1year prior to the index date.
      These included alfuzosin, amiodarone, azithromycin, chloroquine, ciprofloxacin, clarithromycin, crizotinib, cyclobenzaprine, dasatinib, disopyramide, dolasetron, erythromycin, flecainide, granisetron, lapatinib, levofloxacin, ritonavir, moxifloxacin, nilotinib, norfloxacin, ondansetron, pazopanib, pentamidine, procainamide, propafenone, quinidine, saquinavir, solifenacin, sotalol, sunitinib, tacrolimus, telithromycin, tetrabenazine.
      62 (35.4)224 (25.7)0.22
      No.- number; IQR- interquartile range.
      a In the 1 year prior to the index date.
      b These included alfuzosin, amiodarone, azithromycin, chloroquine, ciprofloxacin, clarithromycin, crizotinib, cyclobenzaprine, dasatinib, disopyramide, dolasetron, erythromycin, flecainide, granisetron, lapatinib, levofloxacin, ritonavir, moxifloxacin, nilotinib, norfloxacin, ondansetron, pazopanib, pentamidine, procainamide, propafenone, quinidine, saquinavir, solifenacin, sotalol, sunitinib, tacrolimus, telithromycin, tetrabenazine.
      In the primary analysis, receipt of any prescription for benzodiazepines, antidepressants, or antipsychotic drug in the past year was associated with a twofold increase in the risk of opioid-related death (adjusted odds ratio 2.0; 95% confidence interval 1.2 to 3.5) (Table 2). In the secondary analysis of individual drug classes, we found that benzodiazepines (adjusted OR 1.6; 95% CI 1.1 to 2.5) and antipsychotics (adjusted OR 2.3; 95% CI 1.5 to 3.5) remained independently associated with opioid-related death during methadone therapy, while antidepressants did not (Table 2).
      Table 2Medications in the prior year associated with opioid-related death during methadone maintenance therapy.
      MedicationUnadjusted odds ratio (95% confidence intervalAdjusted odds ratio
      Adjusted for medication exposures, as well as for other potential risk factors including baseline characteristics (age, sex, and rural vs. urban place of residence), health service utilization (number of visits to a methadone prescriber in past 2months, urine drug screens in the past 1year, ECG in the past 1year, and initiation of methadone 30days prior to the index date), and comorbidities (Johns Hopkins adjusted clinical groups in previous year, and diagnoses of chronic lung disease, sleep apnea, alcohol use disorder, chronic liver disease, mood disorder, psychosis/schizophrenia, and coronary artery disease or arrhythmia).
      (95% confidence interval)
      Primary analysis
      Benzodiazepines, antidepressants, and/or antipsychotics2.88 (1.78 to 4.64)2.02 (1.18 to 3.47)
      Secondary analyses
      Benzodiazepines1.93 (1.33 to 2.80)1.64 (1.09 to 2.46)
      Antidepressants1.35 (0.91 to 1.99)1.22 (0.80 to 1.88)
      Antipsychotics2.46 (1.72 to 3.54)2.32 (1.54 to 3.48)
      Opioids1.70 (1.22 to 2.35)0.95 (0.64 to 1.42)
       Long-acting oxycodone0.59 (0.29 to 1.20)0.53 (0.25 to 1.11)
       Codeine1.37 (0.96 to 2.01)1.12 (0.74 to 1.68)
       Morphine0.69 (0.34 to 1.42)0.80 (0.37 to 1.70)
       Hydromorphone1.52 (0.72 to 3.23)1.18 (0.51 to 2.73)
       Fentanyl2.49 (0.84 to 7.37)1.60 (0.48 to 5.43)
       Meripidine/Penthidine0.74 (0.15 to 3.70)0.88 (0.16 to 4.73)
      Barbiturates1.84 (0.11 to 31.98)2.30 (0.11 to 48.80)
      Anticonvulsants2.02 (1.11 to 3.70)1.65 (0.86 to 3.18)
      QT prolonging drugs
      These included alfuzosin, amiodarone, azithromycin, chloroquine, ciprofloxacin, clarithromycin, crizotinib, cyclobenzaprine, dasatinib, disopyramide, dolasetron, erythromycin, flecainide, granisetron, lapatinib, levofloxacin, ritonavir, moxifloxacin, nilotinib, norfloxacin, ondansetron, pazopanib, pentamidine, procainamide, propafenone, quinidine, saquinavir, solifenacin, sotalol, sunitinib, tacrolimus, telithromycin, tetrabenazine.
      1.32 (0.91 to 1.91)1.06 (0.70 to 1.60)
      a Adjusted for medication exposures, as well as for other potential risk factors including baseline characteristics (age, sex, and rural vs. urban place of residence), health service utilization (number of visits to a methadone prescriber in past 2 months, urine drug screens in the past 1 year, ECG in the past 1 year, and initiation of methadone 30 days prior to the index date), and comorbidities (Johns Hopkins adjusted clinical groups in previous year, and diagnoses of chronic lung disease, sleep apnea, alcohol use disorder, chronic liver disease, mood disorder, psychosis/schizophrenia, and coronary artery disease or arrhythmia).
      b These included alfuzosin, amiodarone, azithromycin, chloroquine, ciprofloxacin, clarithromycin, crizotinib, cyclobenzaprine, dasatinib, disopyramide, dolasetron, erythromycin, flecainide, granisetron, lapatinib, levofloxacin, ritonavir, moxifloxacin, nilotinib, norfloxacin, ondansetron, pazopanib, pentamidine, procainamide, propafenone, quinidine, saquinavir, solifenacin, sotalol, sunitinib, tacrolimus, telithromycin, tetrabenazine.
      We also found associations between chronic lung disease, alcohol use disorders, mood disorders, heart disease (coronary disease or arrhythmia disorders), and initiation of methadone in the 30 days prior to death and opioid-related death (Table 3). We did not find associations between opioid-related death and co-prescription of individual opioids, barbiturates, anticonvulsants, or QT-prolonging drugs. Further, we did not find associations with number of visits to a methadone prescriber, number of urine drug screens, a prior ECG, chronic liver disease or schizophrenia and opioid-related death.
      Table 3Characteristics associated with opioid-related death during methadone maintenance therapy.
      CharacteristicUnadjusted odds ratio (95% confidence interval)Adjusted odds ratio
      Adjusted for medication exposures, as well as for other potential risk factors including baseline characteristics (age, sex, and rural vs. urban place of residence), health service utilization (number of visits to a methadone prescriber in past 2months, urine drug screens in the past 1year, ECG in the past 1year and initiation of methadone 30days prior to the index date), and comorbidities (Johns Hopkins adjusted clinical groups in previous year, and diagnoses of chronic lung disease, sleep apnea, alcohol use disorder, chronic liver disease, mood disorder, psychosis/schizophrenia, and coronary artery disease or arrhythmia).
      (95% confidence interval)
      Age1.04 (1.02 to 1.06)1.02 (1.00 to 1.04)
      Male1.00 (0.72 to 1.40)1.20 (0.81 to 1.78)
      Rural0.46 (2.01 to 1.02)0.74 (0.32 to 1.76)
      Number of visits to a methadone prescriber
      In the 2 months prior to the index event.
      1.01 (0.98 to 1.00)0.99 (0.95 to 1.03)
      Number of urine drug tests
      In the 1year prior to the index date.
      0.99 (0.99 to 1.00)1.00 (0.99 to 1.01)
      ECG
      In the 1year prior to the index date.
      2.15 (1.54 to 3.00)1.10 (0.72 to 1.67)
      Initiation of methadone in the 30 days prior to index date9.41 (3.11 to 28.44)15.19(4.40 to 52.46)
      John Hopkins ACG
      In the 1year prior to the index date.
       0–41.00 (reference)1.00 (reference)
       5–91.79 (1.19 to 2.69)1.06 (0.66 to 1.69)
       10–144.60 (2.94 to 7.20)1.58 (0.85 to 2.93)
       15–197.67 (3.14 to 18.74)1.78 (0.59 to 5.40)
      Chronic lung disease
      In the 1year prior to the index date.
      2.51 (1.80 to 3.49)1.74 (1.16 to 2.60)
      Alcohol use disorder
      In the 1year prior to the index date.
      3.46 (2.27 to 5.28)1.95 (1.18 to 3.23)
      Chronic liver disease
      In the 1year prior to the index date.
      1.82 (1.22 to 2.72)1.19 (0.74 to 1.92)
      Heart disease (coronary artery disease or arrhythmia)
      In the 1year prior to the index date.
      9.66 (4.20 to 22.24)5.32 (2.03 to 13.95)
      Mood disorders
      In the 1year prior to the index date.
      3.46 (2.16 to 5.56)1.80 (1.00 to 3.24)
      Schizophrenia
      In the 1year prior to the index date.
      0.71 (0.09 to 5.82)0.21 (0.02 to 2.02)
      a Adjusted for medication exposures, as well as for other potential risk factors including baseline characteristics (age, sex, and rural vs. urban place of residence), health service utilization (number of visits to a methadone prescriber in past 2 months, urine drug screens in the past 1 year, ECG in the past 1 year and initiation of methadone 30 days prior to the index date), and comorbidities (Johns Hopkins adjusted clinical groups in previous year, and diagnoses of chronic lung disease, sleep apnea, alcohol use disorder, chronic liver disease, mood disorder, psychosis/schizophrenia, and coronary artery disease or arrhythmia).
      b In the 2 months prior to the index event.
      c In the 1 year prior to the index date.

      4. Discussion

      In this population-based study spanning 16 years, we found that among methadone recipients psychotropic drug prescribing was associated with a two fold increased risk of opioid-related death. We also found that several other comorbidities were associated with an increased risk of opioid-related death among methadone recipients, as was initiation of methadone treatment in the past 30 days. Our study extends the literature by further characterizing the influence of concurrent prescriptions and co-morbid conditions on opioid-related deaths among individuals receiving methadone treatment for an opioid use disorder.
      Our findings confirm some previous findings, and also address several challenges identified in the most recent systematic review of this topic (
      • Weimer M.B.
      • Chou R.
      Research gaps on methadone harms and comparative harms: Findings from a review of the evidence for an American pain society and college on problems of drug dependence clinical practice guideline.
      ). Our findings reaffirm the increased risk of mortality during methadone initiation (
      • Degenhardt L.
      • Randall D.
      • Hall W.
      • Law M.
      • Butler T.
      • Burns L.
      Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: Risk factors and lives saved.
      ,
      • Srivastava A.
      • Kahan M.
      Methadone induction doses: Are our current practices safe?.
      ), as well as the high prevalence of, and risks associated with, benzodiazepine prescribing among patients receiving methadone (
      • Chou R.
      • Weimer M.B.
      • Dana T.
      Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American pain society and college on problems of drug dependence clinical practice guideline.
      ,
      • Cousins G.
      • Teljeur C.
      • Motterlini N.
      • McCowan C.
      • Dimitrov B.D.
      • Fahey T.
      Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.
      ,
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ). Recently, others have called for a better understanding of the mortality risk during methadone maintenance treatment associated with medical comorbidities and drug interactions (
      • Chou R.
      • Weimer M.B.
      • Dana T.
      Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American pain society and college on problems of drug dependence clinical practice guideline.
      ).
      Unlike previous studies, we did not find an association between antidepressant use and opioid-related mortality (
      • Chan G.M.
      • Stajic M.
      • Marker E.K.
      • Hoffman R.S.
      • Nelson L.S.
      Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: Analysis of medical examiner data.
      ,
      • Weimer M.B.
      • Korthuis P.T.
      • Behonick G.S.
      • Wunsch M.J.
      The source of methadone in overdose deaths in Western Virginia in 2004.
      ). One previous cohort paradoxically found that antipsychotic drugs and antidepressants were protective (
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ). In contrast, we found an association between antipsychotic use and opioid-related mortality. The high number of patients using antipsychotics compared with those diagnosed with schizophrenia suggests frequent use of antipsychotics for other indications.
      Previous research found pulmonary and hepatic disease common among coroners' cases of opioid toxicity (
      • Darke S.
      • Kaye S.
      • Duflou J.
      Systemic disease among cases of fatal opioid toxicity.
      ), and caution is typically advised when considering methadone prescriptions among individuals with respiratory illness or heavy alcohol consumption (
      • Hillier W.
      Methadone Program: Methadone Maintenance Treatment Program Standards and Clinical Guidelines.
      ). Our findings provide further support for lung disease and alcohol use disorder as independent risk factors for opioid-related death during methadone treatment. Accordingly, patients on methadone treatment should also be assessed for these risk factors and counseled about alcohol use. The identification of alcohol use is especially important in light of relevant literature indicating that alcohol intake does not decline during methadone maintenance treatment (
      • Srivastava A.
      • Kahan M.
      • Ross S.
      The effect of methadone maintenance treatment on alcohol consumption: A systematic review.
      ).
      Previous research has also described cardiac pathology among cases of death due to opioid toxicity (
      • Darke S.
      • Kaye S.
      • Duflou J.
      Systemic disease among cases of fatal opioid toxicity.
      ). However, our finding that heart disease was specifically associated with opioid-related death among patients prescribed methadone for an opioid use disorder is novel. This finding may reflect the known effects of methadone on the QT interval (
      • Chou R.
      • Weimer M.B.
      • Dana T.
      Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American pain society and college on problems of drug dependence clinical practice guideline.
      ). However, our findings that performance of an ECG and QT-prolonging drugs were not associated with opioid-related mortality suggest that not all cardiac risks are identifiable using ECG results alone.
      Several implications of these findings for methadone prescribers are worth noting. Patients with co-occurring alcohol use disorders or heart disease should be monitored closely. Further, caution is advised when prescribing antipsychotics unless clearly indicated. The lack of association with urine drug screening in our study merits further study, as drug testing represents a large cost during methadone maintenance treatment.
      In contrast to the majority of literature on mortality related to methadone (
      • Bernard J.-P.
      • Havnes I.
      • Slørdal L.
      • Waal H.
      • Mørland J.
      • Khiabani H.Z.
      Methadone-related deaths in Norway.
      ,
      • Chan G.M.
      • Stajic M.
      • Marker E.K.
      • Hoffman R.S.
      • Nelson L.S.
      Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: Analysis of medical examiner data.
      ,
      • Cousins G.
      • Teljeur C.
      • Motterlini N.
      • McCowan C.
      • Dimitrov B.D.
      • Fahey T.
      Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.
      ,
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ,
      • Pilgrim J.L.
      • McDonough M.
      • Drummer O.H.
      A review of methadone deaths between 2001 and 2005 in Victoria, Australia.
      ,
      • The DAWN Report
      Methadone-involved deaths in 8 metropolitan areas : 1997-2001.
      ,
      • Zador D.
      • Sunjic S.
      Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995.
      ) we focused on opioid-related mortality among patients prescribed methadone for an opioid use disorder because the most frequent cause of death among individuals on methadone therapy is drug-related (
      • McCowan C.
      • Kidd B.
      • Fahey T.
      Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.
      ,
      • Zador D.
      • Sunjic S.
      Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995.
      ). The existing literature suggests that the majority of deaths associated with methadone involve illicit use of the drug or use for the treatment of pain (“
      Vital signs: Risk for overdose from methadone used for pain relief - United States, 1999-2010.
      ,
      • Wikner B.N.
      • Ohman I.
      • Seldén T.
      • Druid H.
      • Brandt L.
      • Kieler H.
      Opioid-related mortality and filled prescriptions for buprenorphine and methadone.
      ).
      Some limitations of our study merit emphasis. First, our prescription data are limited to patients receiving social assistance, and whether these findings apply to more affluent patients is unknown. Second, we used administrative data and had no information regarding methadone adherence, doses of medications and use of nonprescription drugs. We also could not identify which patients received take-home doses of methadone. As expected in a case-control study, cases and controls differed substantially on several important characteristics. Finally, we could not ascertain the contributions of QT prolongation and respiratory depression among these deaths.
      In summary, we found that the use of psychotropic drugs as well as an alcohol use disorder, lung and heart disease, mood disorders, and the recent initiation of methadone was a factor associated with an increased risk of opioid-related mortality among patients receiving methadone for an opioid use disorder. Mindfulness of comorbidities and drug interactions, particularly those involving psychotropic medications, could reduce the risk of opioid-related death among patients on methadone.

      Author contributions

      Study concept and design: PL, CC, EMM, TG, MK, LS, DNJ.
      Acquisition of data: JL.
      Analysis and interpretation of data: JL, PL, CC, EMM, DNJ.
      Drafting of the manuscript: PL, EMM, DNJ.
      Critical revision of the manuscript for important intellectual content: PL, CC, EMM, TG, MK, AS, LS, JL, MMM, DNJ.
      Obtaining Funding: MMM, DNJ.
      Study supervision: CC, DNJ
      Jin Luo had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis.

      Declaration of interest

      This project was supported by research funds from Canadian Drug Safety and Effectiveness Research Network and by the Institute for Clinical Evaluative Sciences, which is funded by a grant from the Ontario Ministry of Health and Long-Term. During the past 3 years, Muhammad M. Mamdani has been on advisory boards and/or received honoraria from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly and Company, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk and Pfizer. Conflicts of Interest: None of the other authors have any conflicts of interest to disclose.

      Acknowledgements

      This project was supported by research funds from Canadian Drug Safety and Effectiveness Research Network (CDSERN) and by the Institute for Clinical Evaluative Sciences (ICES), which is funded by a grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Jin Luo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
      We thank Brogan Inc., Ottawa for use of their Drug Product and Therapeutic Class Database.

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