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Acute opioid intoxication in adults

Andrew Stolbach, MD, MPH, FAACT, FACMT, FACEP
Robert S Hoffman, MD
Section Editor
Stephen J Traub, MD
Deputy Editor
Jonathan Grayzel, MD, FAAEM


Opiates extracted from the poppy plant (Papaver somniferum) have been used recreationally and medicinally for millennia. Opiates belong to the larger class of drugs, the opioids, which include synthetic and semi-synthetic drugs, as well. Opioid abuse is a worldwide problem and deaths from opioid overdose are numerous and increasing [1-5].

This topic review will discuss the mechanisms, clinical manifestations, and management of acute opioid toxicity. A summary table to facilitate emergent management is provided (table 1). Issues related to opioid withdrawal, chronic opioid abuse, and general management of the poisoned patient are found elsewhere. (See "Opioid withdrawal in the emergency setting" and "Pharmacotherapy for opioid use disorder" and "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "General approach to drug poisoning in adults".)


The opioid pharmaceuticals are analogous to the three families of endogenous opioid peptides: enkephalins, endorphins, and dynorphin. The most recent classification scheme identifies three major classes of opioid receptor, with several minor classes [6]. Within each receptor class there are distinct subtypes. Each subtype produces a variety of distinct clinical effects, although there is some overlap (table 2). For most clinicians, the nomenclature derived from the Greek alphabet is more familiar, although the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature has recommended a change from the original Greek system to make opioid receptor names more consistent with other neurotransmitter systems [6].

The opioid receptors are distinct in their locations and clinical effects, but they are structurally similar (table 2). Each consists of seven transmembrane segments, with amino acid and carboxy termini. Although the opioid receptors are all coupled to G proteins, they use a variety of signal transduction mechanisms [6]. These include reducing the capacity of adenylate cyclase to produce cAMP, closing calcium channels that reduce the signal to release neurotransmitters, or opening potassium channels to hyperpolarize the cell [6]. The net result of these mechanisms is to modulate the release of neurotransmitters.

Opioid receptors exist throughout the central and peripheral nervous system and are linked to a variety of neurotransmitters, which explains the diversity of their clinical effects. The analgesic effects of opioids result from inhibition of nociceptive information at multiple points of its transmission from the peripheral nerve to the spinal cord to the brain. Euphoria results from increased dopamine released in the mesolimbic system [7]. Anxiolysis results from effects on noradrenergic neurons in the locus ceruleus [8].

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Literature review current through: Nov 2017. | This topic last updated: Aug 21, 2017.
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  1. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005; 23:589.
  2. Substance Abuse and Mental Health Services Administration. Results from the 2004 National Survey on Drug Use and Health: National Findings Office of Applied Studies, NSDUH Series H-28, DHHS Publication No. SMA 05-4062, Rockville, MD 2005.
  3. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-28, DHHS Publication No. (SMA) 06-4143, Rockville, MD 2006.
  4. QuickStats: Number of Deaths From Poisoning,* Drug Poisoning,† and Drug Poisoning Involving Opioid Analgesics§ — United States, 1999–2010 www.cdc.gov/mmwr/preview/mmwrhtml/mm6212a7.htm?s_cid=mm6212a7_e (Accessed on April 08, 2013).
  5. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med 2015; 372:241.
  6. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem 2004; 73:953.
  7. Bonci A, Bernardi G, Grillner P, Mercuri NB. The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction? Trends Pharmacol Sci 2003; 24:172.
  8. Aghajanian GK, Wang YY. Common alpha 2- and opiate effector mechanisms in the locus coeruleus: intracellular studies in brain slices. Neuropharmacology 1987; 26:793.
  9. Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet 1996; 31:410.
  10. Darke S, Zador D. Fatal heroin 'overdose': a review. Addiction 1996; 91:1765.
  11. Binswanger IA, Blatchford PJ, Mueller SR, Stern MF. Mortality after prison release: opioid overdose and other causes of death, risk factors, and time trends from 1999 to 2009. Ann Intern Med 2013; 159:592.
  12. Leach D, Oliver P. Drug-related death following release from prison: a brief review of the literature with recommendations for practice. Curr Drug Abuse Rev 2011; 4:292.
  13. Ghoneim MM, Dhanaraj J, Choi WW. Comparison of four opioid analgesics as supplements to nitrous oxide anesthesia. Anesth Analg 1984; 63:405.
  14. Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med 1991; 20:246.
  15. Fahmy NR, Sunder N, Soter NA. Role of histamine in the hemodynamic and plasma catecholamine responses to morphine. Clin Pharmacol Ther 1983; 33:615.
  16. Viglino D, Bourez D, Collomb-Muret R, et al. Noninvasive End Tidal CO2 Is Unhelpful in the Prediction of Complications in Deliberate Drug Poisoning. Ann Emerg Med 2016; 68:62.
  17. Eggleston W, Nacca N, Marraffa JM. Loperamide toxicokinetics: serum concentrations in the overdose setting. Clin Toxicol (Phila) 2015; 53:495.
  18. Spinner HL, Lonardo NW, Mulamalla R, Stehlik J. Ventricular tachycardia associated with high-dose chronic loperamide use. Pharmacotherapy 2015; 35:234.
  19. Wightman RS, Hoffman RS, Howland MA, et al. Not your regular high: cardiac dysrhythmias caused by loperamide. Clin Toxicol (Phila) 2016; 54:454.
  20. Vakkalanka JP, Charlton NP, Holstege CP. Epidemiologic Trends in Loperamide Abuse and Misuse. Ann Emerg Med 2017; 69:73.
  21. Eggleston W, Clark KH, Marraffa JM. Loperamide Abuse Associated With Cardiac Dysrhythmia and Death. Ann Emerg Med 2017; 69:83.
  22. Borron SW, Watts SH, Tull J, et al. Intentional Misuse and Abuse of Loperamide: A New Look at a Drug with "Low Abuse Potential". J Emerg Med 2017; 53:73.
  23. Manini AF, Stimmel B, Vlahov D. Racial susceptibility for QT prolongation in acute drug overdoses. J Electrocardiol 2014; 47:244.
  24. Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med 1989; 18:1035.
  25. Marraffa JM, Holland MG, Sullivan RW, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila) 2014; 52:952.
  26. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003; 23:802.
  27. Berling I, Whyte IM, Isbister GK. Oxycodone overdose causes naloxone responsive coma and QT prolongation. QJM 2013; 106:35.
  28. Mills CA, Flacke JW, Flacke WE, et al. Narcotic reversal in hypercapnic dogs: comparison of naloxone and nalbuphine. Can J Anaesth 1990; 37:238.
  29. Berlot G, Gullo A, Romano E, Rinaldi A. Naloxone in cardiorespiratory arrest. Anaesthesia 1985; 40:819.
  30. Bertini G, Russo L, Cricelli F, et al. Role of a prehospital medical system in reducing heroin-related deaths. Crit Care Med 1992; 20:493.
  31. Osterwalder JJ. Naloxone--for intoxications with intravenous heroin and heroin mixtures--harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol 1996; 34:409.
  32. Dowling J, Isbister GK, Kirkpatrick CM, et al. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit 2008; 30:490.
  33. Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986; 15:566.
  34. Duberstein JL, Kaufman DM. A clinical study of an epidemic of heroin intoxication and heroin-induced pulmonary edema. Am J Med 1971; 51:704.
  35. Osler W. Oedema of the left lung—morphia poisoning. Montreal General Hospital Reports Clinical and Pathological, vol 1, Dawson Bros Publishers, Montreal 1880. p.291.
  36. Frand UI, Shim CS, Williams MH Jr. Methadone-induced pulmonary edema. Ann Intern Med 1972; 76:975.
  37. Hoffman RS, Howland MA, Lewin NA, Nelson LN. Antidotes in depth: Sodium bicarbonate. In: Goldfrank’s Toxicologic Emergencies, 10th ed, Goldfrank LE, Kirstein MD (Eds), McGraw-Hill, New York 2015.
  38. Manini AF, Nair AP, Vedanthan R, et al. Validation of the Prognostic Utility of the Electrocardiogram for Acute Drug Overdose. J Am Heart Assoc 2017; 6.
  39. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007; 100:609.
  40. Drug Enforcement Agency. DEA Intelligence Brief. Counterfeit Prescription Pills Containing Fentanyls: A Global Threat. 2016. https://www.dea.gov/docs/Counterfeit%20Prescription%20Pills.pdf (Accessed on July 24, 2017).
  41. Miller JM, Stogner JM, Miller BL, Blough S. Exploring synthetic heroin: Accounts of acetyl fentanyl use from a sample of dually diagnosed drug offenders. Drug Alcohol Rev 2017.
  42. Gladden RM, Martinez P, Seth P. Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths - 27 States, 2013-2014. MMWR Morb Mortal Wkly Rep 2016; 65:837.
  43. Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem 2002; 35:513.
  44. van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology 2006; 105:51.
  45. Mégarbane B, Buisine A, Jacobs F, et al. Prospective comparative assessment of buprenorphine overdose with heroin and methadone: clinical characteristics and response to antidotal treatment. J Subst Abuse Treat 2010; 38:403.
  46. Pedapati EV, Bateman ST. Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine/naloxone. Pediatr Crit Care Med 2011; 12:e102.
  47. Gahr M, Freudenmann RW, Hiemke C, et al. "Krokodil":revival of an old drug with new problems. Subst Use Misuse 2012; 47:861.
  48. Grund JP, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. Int J Drug Policy 2013; 24:265.
  49. Helpern M, Rho YM. Deaths from narcotism in New York City. Incidence, circumstances, and postmortem findings. N Y State J Med 1966; 66:2391.
  50. Hoffman RS, Kirrane BM, Marcus SM, Clenbuterol Study Investigators. A descriptive study of an outbreak of clenbuterol-containing heroin. Ann Emerg Med 2008; 52:548.
  51. Hamilton RJ, Perrone J, Hoffman R, et al. A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine. J Toxicol Clin Toxicol 2000; 38:597.
  52. Maxwell S, Bigg D, Stanczykiewicz K, Carlberg-Racich S. Prescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deaths. J Addict Dis 2006; 25:89.
  53. Loimer N, Hofmann P, Chaudhry HR. Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict 1994; 29:819.
  54. Willman MW, Liss DB, Schwarz ES, Mullins ME. Do heroin overdose patients require observation after receiving naloxone? Clin Toxicol (Phila) 2017; 55:81.
  55. Doyon S, Aks SE, Schaeffer S. Expanding access to naloxone in the United States. J Med Toxicol 2014; 10:431.
  56. Albert S, Brason FW 2nd, Sanford CK, et al. Project Lazarus: community-based overdose prevention in rural North Carolina. Pain Med 2011; 12 Suppl 2:S77.