The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in combination with other drugs) is the manifestation of a complex, and multifaceted problem consisting of psychological, psychosocial, medical, legal, regulatory, economic, cultural, and political components, among others. Because the problem involves issues related to both supply and demand, the solution is not obvious, simple, or quick. There is no easy fix. Preventing and treating opioid misuse and abuse requires a comprehensive, time-intensive, and expensive intervention supported by public policy and support through coordinated medical, regulatory, legal, and financial guidelines and practice. But until the long-term problems can be fixed, the immediate crisis of overdose deaths can be ameliorated by making available an opioid receptor antagonist to reverse the respiratory depression that is the cause of death to those who are in the best position to administer it in time (professionals, untrained bystanders, and even fellow drug abusers). The statistics overwhelmingly demonstrate that this is a life-saving medical intervention. Yet, there is still uncertainty about this intervention, and even some opposition to it. We describe the scientific basis for the approach and the issues surrounding its use to treat accidental or intentional overdose by pain patients, recreational opioid users, and addicts. We also describe the calls to limit the number of times it should be available to a user and the limitations of its effectiveness—mainly that it only addresses the acute death crisis, not the underlying problems that led to it.
Rudd, R., Seth, P., David, F. and Scholl, L. (2016) Increases in Drug and Opioid-Involved Overdose Deaths—United States 2010-2015. Morb Mortal Wkly Report, 65, 1445-1452. https://www.cdc.gov/mmwr/volumes/65/wr/mm655051e1.htm https://doi.org/10.15585/mmwr.mm655051e1
Gladden, R.M., Martinez, P. and Seth, P. (2016) Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths—27 States, 2013-2014. Morb Mortal Wkly Report, 65, 837-843. https://www.cdc.gov/mmwr/volumes/65/wr/mm6533a2.htm https://doi.org/10.15585/mmwr.mm6533a2
Dahan, A., Aarts, L. and Smith, T. (2010) Incidence, Reversal, and Prevention of Opioid-Induced Respiratory Depression. Anesthesiology, 112, 226-238. https://doi.org/10.1097/ALN.0b013e3181c38c25
Melichar, J.K., Nutt, D.J. and Malizia, A.L. (2003) Naloxone Displacement at Opioid Receptor Sites Measured in Vivo in the Human Brain. European Journal of Pharmacology, 459, 217-219. https://doi.org/10.1016/S0014-2999(02)02872-8
Clarke, S., Dargan, P. and Jones, A. (2005) Naloxone in Opioid Poisoning: Walking the Tightrope. Emergency Medicine Journal, 22, 612-616.
FDA (2016) FDA Advisory Committe on the Most Appropriate Dose or Doses of Naloxone to Reverse the Effects of Life-Threatening Opioid Overdose in the Community Settings. Vol. 2017, Rockville, MD. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/ anestheticandanalgesicdrugproductsadvisorycommittee/ucm522688.pdf
Alcorn, T. (2014) America Embraces Treatment for Opioid Drug Overdose. The Lancet, 383, 1957-1958. https://doi.org/10.1016/S0140-6736(14)60928-4
Evolutions (2017) Which States Offer Naloxone over the Counter? https://cvshealth.com/thought-leadership/naloxone-opioid-overdose-reversal-medication
Davis, C.S. and Carr, D. (2015) Legal Changes to Increase Access to Naloxone for Opioid Overdose Reversal in the United States. Drug and Alcohol Dependence, 157, 112-120. https://doi.org/10.1016/j.drugalcdep.2015.10.013
Davis, C. and Carr, D. (2017) State Legal Innovations to Encourage Naloxone Dispensing. Journal of the American Pharmaceutical Association, 57, S180-S184. https://doi.org/10.1016/j.japh.2016.11.007
Brodrick, J.E., Brodrick, C.K. and Adinoff, B. (2016) Legal Regimes Surrounding Naloxone Access: Considerations for Prescribers. The American Journal of Drug and Alcohol Abuse, 42, 117-128. https://doi.org/10.3109/00952990.2015.1109648
Weaver, L., Palombi, L. and Bastianelli, K.M. (2017) Naloxone Administration for Opioid Overdose Reversal in the Prehospital Setting: Implications for Pharmacists. Journal of Pharmacy Practice, 31, 91-98. https://doi.org/10.1177/0897190017702304
WHO (2014) Community Management of Opioid Overdose. http://apps.who.int/iris/bitstream/handle/10665/137462/9789241548816_eng.pdf; jsessionid=F0223501860DF35AA622874D9094C8ED?sequence=1
Bacon, J. (2017) Ohio Councilman: After 2 Overdoses, No More EMS. USA Today, New York. https://www.usatoday.com/story/news/nation/2017/06/28/ohio-councilman-suggests-three-strikes-law-halt-overdose-rescues/434920001/
Stein, M.D., Flori, J.N., Risi, M.M., Conti, M.T., Anderson B.J. and Bailey, G.L. (2017) Overdose History Is Associated with Post-Detoxification Treatment Preference for Persons with Opioid Use Disorder. Substance Abuse, 38, 389-393. https://doi.org/10.1080/08897077.2017.1353570
Wheeler, E. (2012) Community-Based Opioid Overdose Prevention Programs Providing Naloxone. Morbidity and Mortality Weekly Report, 61, 101-105. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6106a1.htm
Mostaghim, R. and Bengali, S. (2016) Iran’s Growing Drug Problem: “No Walk of Society is Immune”. Los Angeles Times, Los Angeles. http://www.latimes.com/world/la-fg-iran-drug-addiction-2016-story.html
Giglio, R.E., Li, G. and DiMaggio, C.J. (2015) Effectiveness of Bystander Naloxone Administration and Overdose Education Programs: A Meta-Analysis. Injury Epidemiology, 2, 10. https://doi.org/10.1186/s40621-015-0041-8
Tenenbein, M. (1984) Continuous Naloxone Infusion for Opiate Posioning in Infancy. Journal of Pediatrics, 105, 645-648. https://doi.org/10.1016/S0022-3476(84)80440-0
Berkowitz, B. (1976) The Relationship of Pharmacokinetics to Pharmacological Activity: Morphine, Methadline and Naloxone. Clinical Pharmacokinetics, 1, 219-230. https://doi.org/10.2165/00003088-197601030-00004
Schumann, H., Erickson, T., Thompson, T., Zautcke, J. and Denton, J. (2008) Fentanyl Epidemic in Chicago, Illinois and Surrounding Cook Country. Clinical Toxicology, 46, 501-506. https://doi.org/10.1080/15563650701877374
Prosser, J., Jones, B. and Nelson, L. (2010) Complications of Oral Exposure to Fentanyl Transdermal Delivery System Patches. Journal of Medical Toxicology, 6, 443-447. https://doi.org/10.1007/s13181-010-0092-8
Kim, D., Irwin,K. and Khoshnood, K. (2009) Expanded Access to Naloxone: Options for Critical Response to the Epidemic of Opioid Overdose Mortality. American Public Health Association, 99, 402-407. https://doi.org/10.2105/AJPH.2008.136937
Kim, H.K. and Nelson, L.S. (2015) Reducing the Harm of Opioid Overdose with the Safe Use of Naloxone: A Pharmacologic Review. Expert Opinion on Drug Safety, 14, 1137-1146. https://doi.org/10.1517/14740338.2015.1037274
Wermeling, D.P. (2015) Review of Naloxone Safety for Opioid Overdose: Practical Considerations for New Technology and Expanded Public Access. Therapeutic Advances in Drug Safety, 6, 20-31. https://doi.org/10.1177/2042098614564776
Buajordet, I., Naess, A.C., Jacobsen, D. and Brors, O. (2004) Adverse Events after Naloxone Treatment of Episodes of Suspected Acute Opioid Overdose. European Journal of Emergency Medicine, 11, 19-23. https://doi.org/10.1097/00063110-200402000-00004
Boyer, E.W. (2012) Management of Opioid Analgesic Overdose. New England Journal of Medicine, 367, 146-155. https://doi.org/10.1056/NEJMra1202561
Avetian, G.K., Fiuty, P., Mazzella, S., Koppa, D., Heye, V. and Hebbar, P. (2017) Use of Naloxone Nasal Spray 4 mg in the Community Setting: A Survey of Use by Community Organizations. Current Medical Research and Opinion, 34, 573-576. https://doi.org/10.1080/03007995.2017.1334637
Dowling, J., Isbister, G.K., Kirkpatrick, C.M., Naidoo, D. and Graudins, A. (2008) Population Pharmacokinetics of Intravenous, Intramuscular, and Intranasal Naloxone in Human Volunteers. Therapeutic Drug Monitoring, 30, 490-496. https://doi.org/10.1097/FTD.0b013e3181816214
Arthurs S. (2017) Community-Wide Naloxone Training Planned Monday. The Courier, Findlay. https://thecourier.com/local-news/2017/04/20/community-wide-naloxone-training-planned-monday/
Targeted News Service (2017) Virginia Receives $9.7 Million Grant to Fight Opioid Crisis. Newsbank Inc., Richmond. https://www.governor.virginia.gov/newsroom/all-releases/2018/may/headline-825499-en.html
Jones, C.M., Lurie, P.G. and Compton, W.M. (2016) Increase in Naloxone Prescriptions Dispensed in US Retail Pharmacies since 2013. American Public Health Association, 106, 689-690. https://doi.org/10.2105/AJPH.2016.303062
Donoghoe, M. (1999) Opioid Overdose: An International Perspective. Addiction, 94, 1745-1746. https://doi.org/10.1046/j.1360-0443.1999.9411174511.x
Binswanger, I.A., Blatchford, P.J., Mueller, S.R. and Stern, M.F. (2013) Mortality after Prison Release: Opioid Overdose and Other Causes of Death, Risk Factors, and Time Trends from 1999 to 2009. American College of Physicians, 159, 592-600. https://doi.org/10.7326/0003-4819-159-9-201311050-00005
Krinsky, C.S., Lathrop, S.L., Brown, P. and Nolte, K.B. (2009) Drugs, Detention, and Death: A Study of the Mortality of Recently Released Prisoners. American Journal of Forensic Medicine and Pathology, 30, 6-9. https://doi.org/10.1097/PAF.0b013e3181873784
Davoli, M., Bargagli, A.M., Perucci, C.A., et al. (2007) Risk of Fatal Overdose during and after Specialist Drug Treatment: The VEdeTTE Study, a National Multi-Site Prospective Cohort Study. Addiction, 102, 1954-1959. https://doi.org/10.1111/j.1360-0443.2007.02025.x
Cornish, R., Macleod, J., Strang, J., Vickerman, P. and Hickman, M. (2010) Risk of Death during and after Opiate Substitution Treatment in Primary Care: Prospective Observational Study in UK General Practice Research Database. BMJ, 341, c5475. https://doi.org/10.1136/bmj.c5475
Darke, S., Williamson, A., Ross, J., Mills, K.L., Havard, A. and Teesson, M. (2007) Patterns of Nonfatal Heroin Overdose over a 3-Year Period: Findings from the Australian Treatment Outcome Study. Journal of Urban Health, 84, 283-291. https://doi.org/10.1007/s11524-006-9156-0
Bennett, T., Holloway, K. and Bird, S.M. (2014) Does Take-Home Naloxone Reduce Non-Fatal Overdose? The Lancet, 383, 124-125. https://doi.org/10.1016/S0140-6736(14)60022-2
Gossop, M., Griffiths, P., Powis, B., Williamson, S. and Strang, J. (1996) Frequency of Non-Fatal Heroin Overdose: Survey of Heroin Users Recruited in Non-Clinical Settings. BMJ, 313, 402. https://doi.org/10.1136/bmj.313.7054.402
Brugal, M.T., Barrio, G., De, L.F., Regidor, E., Royuela, L. and Suelves, J.M. (2002) Factors Associated with Non-Fatal Heroin Overdose: Assessing the Effect of Frequency and Route of Heroin Administration. Addiction, 97, 319-327. https://doi.org/10.1046/j.1360-0443.2002.00058.x
Park, T.W., Lin, L.A., Hosanagar, A., Kogowski, A., Paige, K. and Bohnert, A.S. (2016) Understanding Risk Factors for Opioid Overdose in Clinical Populations to Inform Treatment and Policy. Journal of Addiction Medicine, 10, 369-381. https://doi.org/10.1097/ADM.0000000000000245
Darke, S., Kaye, S. and Duflou, J. (2006) Systemic Disease among Cases of Fatal Opioid Toxicity. Addiction, 101, 1299-1305. https://doi.org/10.1111/j.1360-0443.2006.01495.x
Bohnert, A.S., Valenstein, M., Bair, M.J., et al. (2011) Association between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA, 305, 1315-1321. https://doi.org/10.1001/jama.2011.370
Dunn, K.M., Saunders, K.W., Rutter, C.M., et al. (2010) Opioid Prescriptions for Chronic Pain and Overdose: A Cohort Study. American College of Physicians, 152, 85-92. https://doi.org/10.7326/0003-4819-152-2-201001190-00006
Hall, A.J., Logan, J.E., Toblin, R.L., et al. (2008) Patterns of Abuse among Unintentional Pharmaceutical Overdose Fatalities. JAMA, 300, 2613-2620. https://doi.org/10.1001/jama.2008.802
Wise, J. (2016) Most US Patients Continue to Be Prescribed Opioids after Overdose. BMJ, 352, h7010. https://doi.org/10.1136/bmj.i701
Gregg, J. (2016) Follow-Up to Nonfatal Opioid Overdoses: More of the Same or an Opportunity for Change? American College of Physicians, 164, 62-63. https://doi.org/10.7326/M15-2687
Unick, G.J., Rosenblum, D., Mars, S. and Ciccarone, D. (2013) Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid-Related Overdoses, 1993-2009. PLoS ONE, 8, e54496. https://doi.org/10.1371/journal.pone.0054496
Fulton-Kehoe, D., Garg, R.K. and Turner, J.A., et al. (2013) Opioid Poisonings and Opioid Adverse Effects in Workers in Washington State. American Journal of Industrial Medicine, 56, 1452-1462. https://doi.org/10.1002/ajim.22266
Bonar, E.E., Ilgen, M.A., Walton, M. and Bohnert, A.S. (2014) Associations among Pain, Non-Medical Prescription Opioid Use, and Drug Overdose History. American Journal on Addictions, 23, 41-47. https://doi.org/10.1111/j.1521-0391.2013.12055.x
Yoon, Y.H., Chen, C.M., Yi, H.Y. and Moss, H.B. (2011) Effect of Comorbid Alcohol and Drug Use Disorders on Premature Death among Unipolar and Bipolar Disorder Decedents in the United States, 1999 to 2006. Comprehensive Psychiatry, 52, 453-464. https://doi.org/10.1016/j.comppsych.2010.10.005
Turner, B.J. and Liang, Y. (2015) Drug Overdose in a Retrospective Cohort with Non-Cancer Pain Treated with Opioids, Antidepressants, and/or Sedative-Hypnotics: Interactions with Mental Health Disorders. Journal of General Internal Medicine, 30, 1081-1096. https://doi.org/10.1007/s11606-015-3199-4
Man, L.H., Best, D., Gossop, M., Stillwell, G. and Strang, J. (2004) Relationship between Prescribing and Risk of Opiate Overdose among Drug Users in and Out of Maintenance Treatment. European Addiction Research, 10, 35-40. https://doi.org/10.1159/000073724
Modarai, F., Mack, K., Hicks, P., et al. (2013) Relationship of Opioid Prescription Sales and Overdoses, North Carolina. Drug and Alcohol Dependence, 132, 81-86. https://doi.org/10.1016/j.drugalcdep.2013.01.006
Bunn, T.L., Yu, L., Spiller, H.A. and Singleton, M. (2010) Surveillance of Methadone-Related Poisonings in Kentucky Using Multiple Data Sources. Pharmacoepidemiol Drug Safety, 19, 124-131. https://doi.org/10.1002/pds.1901
Roxburgh, A., Darke, S., Salmon, A.M., Dobbins, T. and Jauncey, M. (2017) Frequency and Severity of Non-Fatal Opioid Overdoses among Clients Attending the Sydney Medically Supervised Injecting Centre. Drug and Alcohol Dependence, 176, 126-132. https://doi.org/10.1016/j.drugalcdep.2017.02.027
Schug, S.A. and Ting, S. (2017) Fentanyl Formulations in the Management of Pain: An Update. Drugs, 77, 747-763. https://doi.org/10.1007/s40265-017-0727-z
Frank, R. and Pollack, H. (2017) Addressing the Fentanyl Threat to Public Health. JAMA, 376, 605-607.
Tomassoni, A.J., Hawk, K.F., Jubanyik, K., et al. (2017) Multiple Fentanyl Overdoses—New Haven, Connecticut, June 23, 2016. Morbidity and Mortality Weekly Report, 66, 107-111. https://www.cdc.gov/mmwr/volumes/66/wr/mm6604a4.htm https://doi.org/10.15585/mm6604a4
Somerville, N.J., O’Donnell, J., Gladden R.M., et al. (2017) Characteristics of Fentanyl Overdose—Massachusetts, 2014-2016. Morbidity and Mortality Weekly Report, 66, 382-386. https://www.cdc.gov/mmwr/volumes/66/wr/mm6614a2.htm https://doi.org/10.15585/mmwr.mm6614a2
Villiger, J.W., Ray, L.J. and Taylor, K.M. (1983) Characteristics of [3H]Fentanyl Binding to the Opiate Receptor. Neuropharmacology, 22, 447-452. https://doi.org/10.1016/0028-3908(83)90162-4
Kim, S., Wagner Jr., H.N., Villemagne, V.L., et al. (1997) Longer Occupancy of Opioid Receptors by Nalmefene Compared to Naloxone as Measured in Vivo by a Dual-Detector System. Journal of Nuclear Medicine, 38, 1726-1731.
Centers for Disease C, Prevention (2010) Emergency Department Visits Involving Nonmedical Use of Selected Prescription Drugs—United States, 2004-2008. Morbidity and Mortality Weekly Report, 59, 705-709. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5923a1.htm
Bennett, A.S., Golub, A. and Elliott, L. (2017) A Behavioral Typology of Opioid Overdose Risk Behaviors among Recent Veterans in New York City. PLoS ONE, 12, e0179054. https://doi.org/10.1371/journal.pone.0179054
Elzey, M.J., Barden, S.M. and Edwards, E.S. (2016) Patient Characteristics and Outcomes in Unintentional, Non-Fatal Prescription Opioid Overdoses: A Systematic Review. Pain Physician, 19, 215-228.
Calvo, M., MacFarlane, J., Zaccaro, H., et al. (2017) Young People Who Use Drugs Engaged in Harm Reduction Programs in New York City: Overdose and Other Risks. Drug and Alcohol Dependence, 178, 106-114. https://doi.org/10.1016/j.drugalcdep.2017.04.032
Frank, D., Mateu-Gelabert, P., Guarino, H., et al. (2015) High Risk and Little Knowledge: Overdose Experiences and Knowledge among Young Adult Nonmedical Prescription Opioid Users. International Journal of Drug Policy, 26, 84-91. https://doi.org/10.1016/j.drugpo.2014.07.013
Martins, S.S., Sampson, L., Cerda, M. and Galea, S. (2015) Worldwide Prevalence and Trends in Unintentional Drug Overdose: A Systematic Review of the Literature. American Public Health Association, 105, e29-e49. https://doi.org/10.2105/AJPH.2015.302843
McAuley, A., Aucott, L. and Matheson, C. (2015) Exploring the Life-Saving Potential of Naloxone: A Systematic Review and Descriptive Meta-Analysis of Take Home Naloxone (THN) Programmes for Opioid Users. International Journal of Drug Policy, 26, 1183-1188. https://doi.org/10.1016/j.drugpo.2015.09.011
Richert, T. (2015) Wasted, Overdosed, or beyond Saving—To Act or Not to Act? Heroin Users’ Views, Assessments, and Responses to Witnessed Overdoses in Malmo, Sweden. International Journal of Drug Policy, 26, 92-99. https://doi.org/10.1016/j.drugpo.2014.07.006
Baca, C.T. and Grant, K.J. (2007) What Heroin Users Tell Us about Overdose. Journal of Addictive Diseases, 26, 63-68. https://doi.org/10.1300/J069v26n04_08
Davidson, P.J., Ochoa, K.C., Hahn, J.A., Evans, J.L. and Moss, A.R. (2002) Witnessing Heroin-Related Overdoses: The Experiences of Young Injectors in San Francisco. Addiction, 97, 1511-1516. https://doi.org/10.1046/j.1360-0443.2002.00210.x
Vilke, G.M., Sloane, C., Smith, A.M. and Chan, T.C. (2003) Assessment for Deaths in Out-Of-Hospital Heroin Overdose Patients Treated with Naloxone Who Refuse Transport. Academic Emergency Medicine, 10, 893-896. https://doi.org/10.1197/aemj.10.8.893
Wampler, D.A., Molina, D.K., McManus, J., Laws, P. and Manifold, C.A. (2011) No Deaths Associated with Patient Refusal of Transport after Naloxone-Reversed Opioid Overdose. Prehospital Emergency Care, 15, 320-324. https://doi.org/10.3109/10903127.2011.569854
Koester, S., Mueller, S.R., Raville, L., Langegger, S. and Binswanger, I.A. (2017) Why Are Some People Who Have Received Overdose Education and Naloxone Reticent to Call Emergency Medical Services in the Event of Overdose? International Journal of Drug Policy, 48, 115-124. https://doi.org/10.1016/j.drugpo.2017.06.008
Willman, M.W., Liss, D.B., Schwarz, E.S. and Mullins, M.E. (2017) Do Heroin Overdose Patients Require Observation after Receiving Naloxone? Clinical Toxicology, 55, 81-87. https://doi.org/10.1080/15563650.2016.1253846
Robertson, T.M., Hendey, G.W., Stroh, G., and Shalit, M. (2009) Intranasal Naloxone Is a Viable Alternative to Intravenous Naloxone for Prehospital Narcotic Overdose. Prehospital Emergency Care, 13, 512-515. https://doi.org/10.1080/10903120903144866
DEA (2016) 2016 National Drug Threat Assessment. https://www.dea.gov/documents/2017/10/01/2017-national-drug-threat-assessment
Sutter, M.E., Gerona, R.R., Davis, M.T., et al. (2016) Fatal Fentanyl: One Pill Can Kill. Academic Emergency Medicine, 24, 106-113. https://doi.org/10.1111/acem.13034
Volpe, D.A., McMahon Tobin, G.A., Mellon, R.D., et al. (2011) Uniform Assessment and Ranking of Opioid Mu Receptor Binding Constants for Selected Opioid Drugs. Regulatory Toxicology and Pharmacology, 59, 385-390. https://doi.org/10.1016/j.yrtph.2010.12.007
University of Wisconsin Pain & Policy Studies Group (2018). http://www.painpolicy.wisc.edu/country/profile/japan
Shimane, T., Matsumoto, T. and Wada, K. (2015) Clinical Behavior of Japanese Community Pharmacists for Preventing Prescription Drug Overdose. Psychiatry and Clinical Neurosciences, 69, 220-227. https://doi.org/10.1111/pcn.12232