Opioid Toxicity

Updated: Aug 08, 2023
  • Author: Everett Stephens, MD; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD  more...
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Practice Essentials

Opioids are prescribed widely, often in concert with other analgesics, and this legitimate use, along with diversion of pharmaceutical opioids and abuse of illicit opioids, results in large numbers of overdoses. In 2020, opioids were involved in 75% of all drug overdose deaths in the United States. [1] The Centers for Disease Control and Prevention notes three waves of opioid overdose deaths in the US: the first beginning in the 1990s, from prescription opioids; the second beginning in 2010, involving heroin; and the third beginning in 2013 and involving synthetic opioids, especially fentanyl. [2] In 2020, 82.3% of opioid-involved overdose deaths involved synthetic opioids. [1]

Although overdose deaths involving prescription opioids and heroin have remained stable since 2016, overdose deaths involving all opioids have increased, due to rising numbers involving synthetic opioids. Overall opioid-related deaths rose from 42,249 in 2016 to 68,630 in 2020. [3, 1]

Fentanyl or its analogues—either diverted or illegally produced—appears to be responsible for much of the increase in synthetic opioid overdoses. Fentanyl, which is often mixed with heroin, cocaine, or both, is 50 to 100 times more potent than morphine. [4] Fentanyl analogues, such as carfentanil, which is 100 more times more potent than fentanyl and is approved only for veterinary use, are also a rising cause of opioid overdoses, often fatal. [5]  By 2016, overdose deaths involving fentanyl surpassed those from heroin and exceeded those from any other drug. From 2016 to 2017, the rate of drug overdose deaths involving synthetic opioids other than methadone (eg, fentanyl, fentanyl analogs, and tramadol) increased 45%, from 6.2 to 9.0 per 100,000 population. [6]

Opiate toxicity should be suspected when the clinical triad of central nervous system (CNS) depression, respiratory depression, and pupillary miosis are present; respiratory depression is the most specific sign (see Presentation). In the emergency department, airway control and adequate oxygenation remain the primary intervention. Administer naloxone for significant CNS and/or respiratory depression. See Treatment and Medication.)



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.

Opioids constitute a notable percentage of total overdoses encountered in the ED and 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. From 2013 to 2014, however, rates of opioid overdose deaths increased 14%, from 7.9 to 9.0 per 100,000 population. [7] By 2020, the overall rate of drug overdose deaths, 74.8% of which involved opioids,  increased to 28.3 per 100,000 population. [1]

The increase in opioid use, and thus in overdoses, may have been an unintended consequence of attempts to address the problem of undertreated pain (eg, designating pain as "the fifth vital sign"). [8] In response, 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 [9] (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. [10, 9]



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 oral 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.

The hepatic CYP2D6 enzyme metabolizes codeine, converting it to its active metabolite, morphine. Individuals who carry more than two normal-function copies of the CYP2D6 gene—so-called ultrarapid metabolizers—can metabolize codeine to morphine more rapidly and more completely, and thus may develop morphine toxicity even with normal doses of codeine. [11] Tramadol is also metabolized by CYP2D6, and ultrarapid metabolizers are at increased risk for opioid toxicity from it. [12]

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, hazard ratios were 1.64 for total mortality, 1.65 for cardiovascular deaths, and 4.16 for death during the first 30 days of therapy, in patients prescribed long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants. [13]



United States

Opioids are prescribed widely, often in concert with other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen or muscle relaxants. The overall opioid prescribing rate in the United States peaked and leveled off from 2010-2012 and has been declining since 2012. Despite significant decreases, the amount of opioids prescribed in 2015 remained approximately three times as high as in 1999, although rates varied substantially across the country. In 2017, almost 58 opioid prescriptions were written for every 100 Americans. [14]

In 2021, US poison control centers reported a total of 21,364 single exposures to pharmaceutical and illegal opioid preparations, which resulted in 4311 cases of major toxicity and 284 deaths, as well as 6716 exposures to combinations of hydrocodone or oxycodone with acetaminophen, aspirin, or ibuprofen, with 670 cases of major toxicity and 22 deaths. [15]  

The Centers for Disease Control and Prevention (CDC) reports that opioid overdoses treated in emergency departments rose 30% from July 2016 through September 2017 in 52 areas in 45 states. Overdoses in the Midwest increased by 70% during that period, and opioid overdoses in large cities increased by 54% in 16 states. [16]  

Opioids—prescription and illicit—are currently the leading cause of drug overdose deaths. Opioids were involved in 80,411 (75.4%) of the 106,699 drug overdose deaths that occurred in the United States in 2021. Synthetic opioids other than methadone were involved in 70,601 overdose deaths, while prescription opioids were involved in 16,706 daths.Drug overdose deaths involving heroin continued their downward trend; after peaking at 15,482 in 2017, they fell to 13,165 deaths in 2020 and 9173 in 2021. More than 70% of drug overdose deaths involving opioids occurred in males. [17]

Most of the deaths from synthetic opioids are from fentanyl, [18]  and most of the increases in fentanyl deaths in recent years do not involve prescription fentanyl but are related to illicitly-made fentanyl that is being mixed with or sold as heroin—with or without the users’ knowledge—and increasingly as counterfeit pills. [1]  From July–December 2017 to January–June 2018 in 25 states, opioid deaths decreased 5% overall. Decreases were reported in deaths involving prescription opioids and illicit synthetic opioids—except for illicitly manufactured fentanyl, from which deaths increased 11%. [19]

Although methadone treatment reduces mortality in patients with opioid use disorder, methadone can also contribute to overdoses. In 2002–2014, the number of prescriptions of methadone as an analgesic correlated strongly with reports of diverted methadone and of methadone-involved overdose deaths. [20] Following interventions to reduce the prescribing of methadone for analgesia, methadone-involved overdose deaths declined even as increasing numbers of patients received methadone as treatment for opioid use disorder. [21]

However, overdose deaths involving methadone, both with and without other synthetic opioids, increased during the 12-month period after March 2020, especially among Hispanic and Black individuals. This corresponded with—but was not necessarily caused by—relaxation in federal regulations limiting take-home methadone doses, which was prompted by the COVID-19 pandemic. [21]

The etiology of overdoses presenting to an emergency department 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 United Nations Office on Drug and Crime (UNODC) estimated that in 2020, 1.2% of the global population aged 15-64 years had used opiates (heroin, morphine, and opium) or had used pharmaceutical opioids for non-medical purposes in the past year; overall, 61 million people were past-year users of opioids for non-medical reasons in 2020. The number of opioid users worlwide increased twofold in 2010–2020, but use overall was stable in 2019-2020. The UNODC estimates that worldwide, opioids contributed to 69% of direct drug-related deaths in 2019. [22]

In Europe, illicit use of fentanyl and its analogues (eg, 3-methylfentanyl ) have been identified as a rising cause of overdose deaths. In countries affected by heroin shortages, these drugs have been marketed as a replacement for heroin. [23] with 160jkl;jkl;jl



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. [24]

Morbidities due to co-ingestants must be considered in polypharmacy overdoses, and they vary depending on the co-ingestant. A Canadian study found that the risk for fatal opioid toxicity was almost twofold higher in patients taking an opioid and more than 2500 mg of gabapentin daily; like opioids, gabapentin can also suppress respiration. [25] In some US states, gabapentin has been reclassified as a Schedule V controlled substance. [26]

Intent of the overdose also plays a role. The addition of suicidal intent is linked to increased emergency department usage, [27]  and such intent could suggest higher dosages of narcotics or co-ingestants


Patient Education

The US Food and Drug Administration (FDA) has approved naloxone (Evzio) in an autoinjector dosage form for home use by family members or caregivers. The product delivers 0.4 mg that may be administered either intramuscularly or subcutaneously in the anterolateral aspect of the thigh. The device includes visual and voice instruction, including directions to seek emergency medical care immediately after use. [28]

For patient education resources, see the following: