Articles19 January 2010
A Cohort Study
    Author, Article, and Disclosure Information



    Long-term opioid therapy for chronic noncancer pain is becoming increasingly common in community practice. Concomitant with this change in practice, rates of fatal opioid overdose have increased. The extent to which overdose risks are elevated among patients receiving medically prescribed long-term opioid therapy is unknown.


    To estimate rates of opioid overdose and their association with an average prescribed daily opioid dose among patients receiving medically prescribed, long-term opioid therapy.


    Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at the time of overdose.




    9940 persons who received 3 or more opioid prescriptions within 90 days for chronic noncancer pain between 1997 and 2005.


    Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes—nonfatal and fatal overdoses—were identified through diagnostic codes from inpatient and outpatient care and death certificates and were confirmed by medical record review.


    51 opioid-related overdoses were identified, including 6 deaths. Compared with patients receiving 1 to 20 mg/d of opioids (0.2% annual overdose rate), patients receiving 50 to 99 mg/d had a 3.7-fold increase in overdose risk (95% CI, 1.5 to 9.5) and a 0.7% annual overdose rate. Patients receiving 100 mg/d or more had an 8.9-fold increase in overdose risk (CI, 4.0 to 19.7) and a 1.8% annual overdose rate.


    Increased overdose risk among patients receiving higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation.


    Patients receiving higher doses of prescribed opioids are at increased risk for overdose, which underscores the need for close supervision of these patients.

    Primary Funding Source:

    National Institute of Drug Abuse.


    • 1. Caudill-Slosberg MASchwartz LMWoloshin SOffice visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs. 2000. Pain2004;109:514-9. [PMID: 15157714] CrossrefMedlineGoogle Scholar
    • 2. Boudreau D, Von Korff M, Rutter CM, Saunders K, Ray GT, Sullivan MD, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf. 2009. [Epub ahead of print.] [PMID: 19718704] Google Scholar
    • 3. Franklin GMMai JWickizer TTurner JAFulton-Kehoe DGrant LOpioid dosing trends and mortality in Washington State workers' compensation, 1996-2002. Am J Ind Med2005;48:91-9. [PMID: 16032735] CrossrefMedlineGoogle Scholar
    • 4. Paulozzi LJBudnitz DSXi YIncreasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf2006;15:618-27. [PMID: 16862602] CrossrefMedlineGoogle Scholar
    • 5. Shah NGLathrop SLReichard RRLanden MGUnintentional drug overdose death trends in New Mexico, USA, 1990-2005: combinations of heroin, cocaine, prescription opioids and alcohol. Addiction2008;103:126-36. [PMID: 18028518] CrossrefMedlineGoogle Scholar
    • 6. Wysowski DKSurveillance of prescription drug-related mortality using death certificate data. Drug Saf2007;30:533-40. [PMID: 17536879] CrossrefMedlineGoogle Scholar
    • 7. Paulozzi LJRyan GWOpioid analgesics and rates of fatal drug poisoning in the United States. Am J Prev Med2006;31:506-11. [PMID: 17169712] CrossrefMedlineGoogle Scholar
    • 8. Fernandez WHackman HMcKeown LAnderson THume BTrends in opioid-related fatal overdoses in Massachusetts, 1990-2003. J Subst Abuse Treat2006;31:151-6. [PMID: 16919742] CrossrefMedlineGoogle Scholar
    • 9. Washington State Department of HealthThe Health of Washington State, 2007. Olympia, WA: Washington State Department of Health; 2007. Google Scholar
    • 10. Hall AJLogan JEToblin RLKaplan JAKraner JCBixler Det alPatterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA2008;300:2613-20. [PMID: 19066381] CrossrefMedlineGoogle Scholar
    • 11. Kuehn BMEfforts aim to curb opioid deaths, injuries. JAMA2009;301:1213-5. [PMID: 19318643] CrossrefMedlineGoogle Scholar
    • 12. Fishman SMCommentary in response to Paulozzi et al.: prescription drug abuse and safe pain management. Pharmacoepidemiol Drug Saf2006;15:628-31. [PMID: 16862601] CrossrefMedlineGoogle Scholar
    • 13. Reidenberg MMWillis OProsecution of physicians for prescribing opioids to patients. Clin Pharmacol Ther2007;81:903-6. [PMID: 17329989] CrossrefMedlineGoogle Scholar
    • 14. Won ALapane KLVallow SSchein JMorris JNLipsitz LALong-term effects of analgesics in a population of elderly nursing home residents with persistent nonmalignant pain. J Gerontol A Biol Sci Med Sci2006;61:165-9. [PMID: 16510860] CrossrefMedlineGoogle Scholar
    • 15. Ballantyne JCOpioid analgesia: perspectives on right use and utility. Pain Physician2007;10:479-91. [PMID: 17525783] CrossrefMedlineGoogle Scholar
    • 16. Hartung DMMiddleton LHaxby DGKoder MKetchum KLChou RRates of adverse events of long-acting opioids in a state Medicaid program. Ann Pharmacother2007;41:921-8. [PMID: 17504834] CrossrefMedlineGoogle Scholar
    • 17. Ballantyne JCMao JOpioid therapy for chronic pain. N Engl J Med2003;349:1943-53. [PMID: 14614170] CrossrefMedlineGoogle Scholar
    • 18. Martell BAO'Connor PGKerns RDBecker WCMorales KHKosten TRet alSystematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med2007;146:116-27. [PMID: 17227935] LinkGoogle Scholar
    • 19. Furlan ADSandoval JAMailis-Gagnon ATunks EOpioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ2006;174:1589-94. [PMID: 16717269] CrossrefMedlineGoogle Scholar
    • 20. Breivik HOpioids in chronic non-cancer pain, indications and controversies. Eur J Pain2005;9:127-30. [PMID: 15737800] CrossrefMedlineGoogle Scholar
    • 21. Ballantyne JCShin NSEfficacy of opioids for chronic pain: a review of the evidence. Clin J Pain2008;24:469-78. [PMID: 18574357] CrossrefMedlineGoogle Scholar
    • 22. Von Korff MSaunders KThomas Ray GBoudreau DCampbell CMerrill Jet alDe facto long-term opioid therapy for noncancer pain. Clin J Pain2008;24:521-7. [PMID: 18574361] CrossrefMedlineGoogle Scholar
    • 23. Saunders KWDavis RLStergachis AGroup Health Cooperative.. In: Strom B, eds. Pharmacoepidemiology. West Sussex, UK: J Wiley; 2005:223-39. Google Scholar
    • 24. Fishman PAGoodman MJHornbrook MCMeenan RTBachman DJO'Keeffe Rosetti MCRisk adjustment using automated ambulatory pharmacy data: the RxRisk model. Med Care2003;41:84-99. [PMID: 12544546] CrossrefMedlineGoogle Scholar
    • 25. Romano PSRoos LLJollis JGFurther evidence concerning the use of a clinical comorbidity index with ICD-9-CM administrative data. J Clin Epidemiol1993;46:1085-90. CrossrefGoogle Scholar
    • 26. Therneau TMGrambsch PMModeling Survival Data: Extending the Cox Model. New York: Springer-Verlag; 2000. Google Scholar
    • 27. SAS/STAT 9.2 User's Guide. Cary, NC: SAS Publishing; 2008. Google Scholar
    • 28. Grambsch PMTherneau TMProportional hazards tests and diagnostics based on weighted residuals. Biometrika1994;81:515-26. CrossrefGoogle Scholar
    • 29. Chou RFanciullo GJFine PGAdler JABallantyne JCDavies Pet alAmerican Pain Society-American Academy of Pain Medicine Opioids Guidelines PanelClinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain2009;10:113-30. [PMID: 19187889] CrossrefMedlineGoogle Scholar
    • 30. Trescot AMHelm SHansen HBenyamin RGlaser SEAdlaka Ret alOpioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians' (ASIPP) Guidelines. Pain Physician2008;11:S5-S62. [PMID: 18443640] MedlineGoogle Scholar
    • 31. Von Korff MDeyo RAPotent opioids for chronic musculoskeletal pain: flying blind? [Editorial]. Pain2004;109:207-9. [PMID: 15157679] CrossrefMedlineGoogle Scholar
    • 32. Eriksen JSjøgren PBruera EEkholm ORasmussen NKCritical issues on opioids in chronic non-cancer pain: an epidemiological study. Pain2006;125:172-9. [PMID: 16842922] CrossrefMedlineGoogle Scholar
    • 33. McLellan ATTurner BPrescription opioids, overdose deaths, and physician responsibility [Editorial]. JAMA2008;300:2672-3. [PMID: 19066389] CrossrefMedlineGoogle Scholar