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Opioid Toxicity

  • Author: Everett Stephens, MD; Chief Editor: Asim Tarabar, MD  more...
Updated: Jul 14, 2016


Pain is arguably the most common reason why patients seek treatment, especially in the emergency department (ED). The modern physician wields many tools to relieve pain, the most potent of which are opioids. The term narcotic specifically refers to any substance that induces sleep, insensibility, or stupor, and it is used to refer to opioids or opioid derivatives. It is derived from the Greek "narke" that means "numbness or torpor." It is common, however inaccurate, that the public uses the term narcotics for any illicit psychoactive substance.

In cultivation since approximately 1500 BC, pure opium is a mixture of alkaloids extracted from the sap of unripened seedpods of Papaver somniferum (poppy). Opiates, such as heroin, codeine, or morphine, are natural derivatives of these alkaloids. The term opiate is often used (albeit slightly incorrectly) to refer to synthetic opiate derivatives, such as oxycodone, as well as true opiates.

Although opioids constitute a relatively small percentage of total overdoses encountered in the ED, they merit particular attention because of the potential mortality/morbidity they cause when unrecognized and untreated, as well as the relative ease of reversing their effects. The notable prevalence of opioids in current prescribing patterns, as well as recreational uses, mandates that physicians maintain a high index of suspicion when treating the patient who is unconscious for unknown reasons.

From 2002 through 2010, prescriptions for opioid analgesics, rates of opioid diversion and abuse, and opioid-related deaths increased significantly in the United States. All three plateaued or decreased from 2011 through 2013.[1, 2] From 2013 to 2014, however, rates of opioid overdose deaths increased 14%, from 7.9 to 9.0 per 100,000 population.[3]

The medical profession, licensing agencies, and federal enforcement have been increasingly focusing on prescribing practices for short- and long-term use of narcotic substances. In addition, legislation to create prescription-drug monitoring programs has been enacted in 49 states[4] (eg, Kentucky HB1, which requires physicians to consult the state's online drug database before prescribing pain medication to a patient).

Such legislation affects the prescribing practices of providers in an attempt to reduce diversion of legitimate opiate prescriptions. Statewide registers of controlled substances are available in many states and can help providers track use patterns among patients in an effort to identify those at high risk of abuse or diversion. While increased availability certainly plays a role in opioid abuse, the link between legitimate use and abuse is not well proven.[5, 4]



Activation of opioid receptors results in inhibition of synaptic neurotransmission in the central nervous system (CNS) and peripheral nervous system (PNS). Opioids bind to and enhance neurotransmission at three major classes of opioid receptors. It is also recognized that several poorly defined classes of opioid receptors exist with relatively minor effects.

The physiological effects of opioids are mediated principally through mu and kappa receptors in the CNS and periphery. Mu receptor effects include analgesia, euphoria, respiratory depression, and miosis. Kappa receptor effects include analgesia, miosis, respiratory depression, and sedation.

Two other opiate receptors that mediate the effects of certain opiates include sigma and delta sites. Sigma receptors mediate dysphoria, hallucinations, and psychosis; delta receptor agonism results in euphoria, analgesia, and seizures. The opiate antagonists (eg, naloxone, nalmefene, naltrexone) antagonize the effects at all four opiate receptors.

Common classifications divide the opioids into agonist, partial agonist, or agonist-antagonist agents and natural, semisynthetic, or synthetic. Opioids decrease the perception of pain, rather than eliminate or reduce the painful stimulus. Inducing slight euphoria, opioid agonists reduce the sensitivity to exogenous stimuli. The GI tract and the respiratory mucosa provide easy absorption for most opioids.

Peak effects generally are reached in 10 minutes with the intravenous route, 10-15 minutes after nasal insufflation (eg, butorphanol, heroin), 30-45 minutes with the intramuscular route, 90 minutes with the oral route, and 2-4 hours after dermal application (ie, fentanyl). Following therapeutic doses, most absorption occurs in the small intestine. Toxic doses may have delayed absorption because of delayed gastric emptying and slowed gut motility.

Most opioids are metabolized by hepatic conjugation to inactive compounds that are excreted readily in the urine. Certain opioids (eg, fentanyl, buprenorphine) are more lipid soluble and can be stored in the fatty tissues of the body. All opioids have a prolonged duration of action in patients with liver disease (eg, cirrhosis) because of impaired hepatic metabolism. This may lead to drug accumulation and opioid toxicity. Opiate metabolites are excreted in the urine. Impaired renal function can lead to toxic effects from accumulated drug or active metabolites (eg, normeperidine).

Long-acting opioids also may increase mortality from cardiorespiratory and other causes. In a retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care, prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, hazard ratios were 1.64 for total mortality, 1.65 for cardiovascular deaths, and 4.16 during the first 30 days of therapy.[6]



United States

Opioids are prescribed widely, often in concert with other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen or muscle relaxants. Analysis of data from the Automation of Reports and Consolidated Orders System (ARCOS) from 2004 to 2011 showed that overall, medical use of opioids increased 100%; use of codeine decreased 20%, but use of other opioids increased as follows[7] :

  • Buprenorphine: 2318%
  • Fentanyl: 35%
  • Hydromorphone: 140%
  • Oxycodone: 117%
  • Hydrocodone: 73%
  • Morphine: 64%
  • Methadone: 37%

Retrospective analysis of data from the Drug Abuse Warning Network (DAWN) for drug misuse data show that abuse of buprenorphine increased 384% from 2006 to 2011. From 2004 to 2011, increases in abuse of other opioids were as follows[7] :

  • Hydromorphone: 438%
  • Oxycodone: 263%
  • Morphine: 146%
  • Hydrocodone: 107%
  • Fentanyl: 104%
  • Methadone: 82%
  • Codeine: 39%

Data from the DAWN indicated that in 2011, 420,040 of the approximately 1.4 million ED visits that involved the nonmedical use of pharmaceuticals were related to opioid analgesics.[8]

Dart et al examined 2002-2013 data from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System and found that opioid prescriptions peaked in the fourth quarter of 2012. Opioid diversion or abuse peaked in mid-2010 in all groups studied except for college students, where nonmedical use of opioids rose from 0.14 per 100,000 population in 2008 to 0.35 per 100,000 by the end of 2013. Prescription opioids covered in the study were hydrocodone, hydromorphone, fentanyl, morphine, oxycodone, and tramadol.[1, 2]

The study found that heroin use remained problematic during that period. The rate of heroin-related deaths was stable from 2002 to 2010, but rose steadily in subsequent years.[1, 2]

In 2014, US poison control centers reported a total of 19,688 single exposures to pure opioids, which resulted in 764 cases of major toxicity and 58 deaths, as well as 19,716 exposures to combinations of opioids with acetaminophen, aspirin, or ibuprofen, with 260 cases of major toxicity and 35 deaths.[9] The Centers for Disease Control and Prevention (CDC) reports that opioids, including heroin, accounted for 61% of the 47,055 lethal drug overdoses that occurred in 2014; 18,893 involved prescription pain relievers and 10,574 involved heroin.[10]

From 2013 to 2014, the largest increase in the rate of drug overdose deaths involved synthetic opioids other than methadone, which nearly doubled from 1.0 per 100,000 to 1.8 per 100,000. This category includes both prescription synthetic opioids (eg, fentanyl and tramadol) and non-pharmaceutical fentanyl manufactured in illegal laboratories. The increase in deaths coincided with law enforcement reports of increased availability of illicitly manufactured fentanyl.[3, 11]

The CDC has reported a strong positive correlation between the rate of methadone distribution and the rates of overdose death from methadone. Methadone distribution rose from 2002-2006 and then declined; the methadone overdose death rate peaked during 2005–2007 and declined in subsequent years. The 3400 methadone overdose deaths reported in 2014 is the lowest number since 2003.ref43}

The etiology of overdoses presenting to an ED often reflects local prescribing tendencies. Polypharmacy overdoses that include opioids can be a challenge for even the most experienced clinician. Fortunately, pharmacologic reversal of the opioid component can assist in the diagnosis of these potentially complex cases.



The predominant cause of morbidity and mortality from pure opioid overdoses is respiratory compromise. Less commonly, acute lung injury, status epilepticus, and cardiotoxicity occur in the overdose setting. Case reports of increased incidence of mortality have been documented in patients with coexistent stenosing lesions of the upper airway.[12]

Morbidities due to co-ingestants must be considered in polypharmacy overdoses, and they vary depending on the co-ingestant. Intent of the overdose also plays a role; the addition of suicidal intent is linked to increased emergency department usage,[13] and such intent could suggest higher dosages of narcotics or co-ingestants

Contributor Information and Disclosures

Everett Stephens, MD Assistant Clinical Professor, Department of Emergency Medicine, University of Louisville School of Medicine

Everett Stephens, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Mark Louden, MD Assistant Professor of Clinical Medicine, Division of Emergency Medicine, Department of Medicine, University of Miami, Leonard M Miller School of Medicine

Mark Louden, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

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