Opioid Toxicity

Updated: Oct 06, 2017
  • 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. The Centers for Disease Control and Prevent reports that in 2015, drug overdoses involving an opioid accounted for 33,091 US deaths, a 15.6% increase from 2014. Much of the increase was due to deaths involving heroin, which increased by 20.6%, and to synthetic opioids other than methadone (eg, tramadol, fentanyl), which increased by 72.2%. [1]

Fentanyl—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. [2] 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. [3]

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.

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. [4, 5] From 2013 to 2014, however, rates of opioid overdose deaths increased 14%, from 7.9 to 9.0 per 100,000 population. [6]

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"). [7] 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 [8] (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. [9, 8]



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.

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. [10] Tramadol is also metabolized by CYP2D6, and ultrarapid metabolizers are at increased risk for opioid toxicity from it. [11]

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. [12]




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 [13] :

  • 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 [13] :

  • 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. [14]

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. [4, 5]

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. [4, 5]

In 2015, US poison control centers reported a total of 18,4253 single exposures to pure opioids, which resulted in 764 cases of major toxicity and 68 deaths, as well as 14,632 exposures to combinations of opioids with acetaminophen, aspirin, or ibuprofen, with 288 cases of major toxicity and 32 deaths. [15]

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. [16]

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. [6, 17]

The CDC reports that in 2015, drug overdoses involving an opioid accounted for 33,091 US deaths, constituting 63.1% of all drug overdose deaths. From 2014 to 2015, the age-adjusted opioid-involved death rate increased by 15.6%, from 9.0 to 10.4 per 100,000 in 2014. Much of the increase was due to deaths involving heroin, which increased by 20.6%, and to synthetic opioids other than methadone, which increased by 72.2%. [1]

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. [18] Deaths from methadone showed a further 9.1% decrease in 2014-2015. [1]

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.


According to the 2014 report of the United Nations Office on Drug and Crime (UNODC), the global prevalence of opiate (heroin and opium) use was estimated at 0.4% of the population, or 12.8-20.2 million people. Levels of opiate use were much higher than the global average in Southwest Asia (1.21%), Eastern and Southeastern Europe (0.82%), and in Central Asia and Transcaucasia (0.81%). [19]

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. [20]



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. [21]

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. [22]

Intent of the overdose also plays a role. The addition of suicidal intent is linked to increased emergency department usage, [23] and such intent could suggest higher dosages of narcotics or co-ingestants