Opioid Toxicity

Updated: Nov 01, 2018
  • Author: Everett Stephens, MD; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD  more...
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Overview

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 2016, drug overdoses involving an opioid accounted for 42,249 US deaths, compared with 33,091 deaths in 2015 and 28,647 in 2014. [1] 49 From 2015 to 2016, deaths involving synthetic opioids other than methadone (eg, fentanyl, tramadol) doubled, to more than 19,000 deaths, and deaths involving heroin rose almost 25%, to almost 15,500 deaths. [2]

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. [3] 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. [4]

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.)

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Background

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. [5, 6] From 2013 to 2014, however, rates of opioid overdose deaths increased 14%, from 7.9 to 9.0 per 100,000 population.6 The number of fatal drug overdoses involving opioids rose from 33,091 in 2015 to 42,249 in 2016. [1, 7]

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]

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Pathophysiology

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. [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, 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. [13]

 

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Epidemiology

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 2016, US poison control centers reported a total of 14,474 single exposures to pure opioids, which resulted in 721 cases of major toxicity and 42 deaths, as well as 4472 exposures to combinations of hydrocodone or oxycodone with acetaminophen, aspirin, or ibuprofen, with 135 cases of major toxicity and 10 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 vy 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 42,249 of the 63,632 drug overdose deaths (66.4%) that occurred in the United States in 2016. Over 19,000 of those deaths involved synthetic opioids (other than methadone), which include both prescription synthetic opioids (eg, fentanyl and tramadol) and non-pharmaceutical fentanyl manufactured in illegal laboratories; the largest increase in synthetic opioid overdose death rates was in men aged 25-44 years. Heroin accounted for almost 15,500 drug overdose deaths in 2016, an increase of almost 20% over the previous year. [7] \\

Most of the deaths from synthetic opioids are from fentanyl, [17]  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. [2]

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 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.

International

According to the 2017 report of the United Nations Office on Drug and Crime (UNODC), the global prevalence of opiate (heroin, morphine, and opium) use was estimated at 0.4% of the population aged 15-64 years. The global number of opiate users increased marginally, from 17.3 million in 2014 to 17.7 million in 2015. Globally, heroin use appears to have been decreasing slightly since 2009, while opium use has remained largely stable. However, the overall prevalence of opiate use in Europe has shown a marginal upward trend since 2010, and heroin use has been increasing for some time in North America, particularly in the United States, and increasing sharply in parts of Africa. [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]

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Mortality/Morbidity

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

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