Opioid Toxicity 

Updated: Jun 06, 2020
Author: Everett Stephens, MD; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD 

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. Indeed, overdose deaths from opioids have increased almost six-fold since 1999 in the United States; opioids have accounted for two thirds of deaths in the drug overdose epidemic.[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]  

From 2016 to 2017, overdose deaths involving prescription opioids and heroin remained stable, but overdose deaths involving all opioids increased, from 42,249 deaths in 2016 to 47,600 in 2017.[3]  Although provisional data indicate that opioid-related deaths fell slightly in 2018 and 2019, the decline was almost entirely to a decrease in fatal overdoses of prescription opioids, while deaths from synthetic opioids continued to rise.[4]

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.[5] 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.[6]  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.[7]

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.)

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.[8, 9] From 2013 to 2014, however, rates of opioid overdose deaths increased 14%, from 7.9 to 9.0 per 100,000 population.[9] The number of fatal drug overdoses involving opioids declined from 47,600 in 2017 to 46,800 in 2018.[10]

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").[11] 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[12] (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.[13, 12]

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 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.[14] Tramadol is also metabolized by CYP2D6, and ultrarapid metabolizers are at increased risk for opioid toxicity from it.[15]

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.[16]

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.[17]

In 2018, US poison control centers reported a total of 33,667 single exposures to pure opioids, which resulted in 920 cases of major toxicity and 124 deaths, as well as 8534 exposures to combinations of hydrocodone or oxycodone with acetaminophen, aspirin, or ibuprofen, with 274 cases of major toxicity and 19 deaths.[18]  

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.[19]  

Opioids—prescription and illicit—are currently the leading cause of drug overdose deaths. Opioids were involved in 46,802 of the 67,367 drug overdose deaths (69.5%) that occurred in the United States in 2018. Over 31,000 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 15,000 drug overdose deaths in 2018, a decrease of 4.1% from 2017 to 2018.[10]

Most of the deaths from synthetic opioids are from fentanyl,[20]  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 deaths involving prescription opioids and illicit synthetic opioids—except for illicitly manufactured fentanyl, from which deaths increased 11%.[21]

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.[3, 22] The rate of overdose deaths involving methadone decreased from 1.4 per 100,000 in 2011 to 1.1 in 2016, with 3,493 deaths reported in 2016.[23]

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 2018 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 from 17.7 million in 2015 to 19.4 million in 2016. For opioids overall, the UNODC estimates that globally, 34 million people were past-year users in 2016.[24]

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.[25]

Prognosis

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.[26]

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.[27]

Intent of the overdose also plays a role. The addition of suicidal intent is linked to increased emergency department usage,[28]  and such intent could suggest higher dosages of narcotics or co-ingestants

Patient Education

In April 2014, the US Food and Drug Administration (FDA) approved naloxone (Evzio) as 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 subcutaneouslyin the anterolateral aspect of the thigh. The device includes visual and voice instruction, including directions to seek emergency medical care immediately after use.[29]

For patient education resources, see the following:

 

Presentation

History

Pertinent history may be obtained from bystanders, family, friends, or emergency medical services (EMS) providers. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis.

Occasionally, a trial of naloxone administered by EMS is helpful to establish the diagnosis in the prehospital setting.

Ingestion time, quantity, and co-ingestants are important aspects of the history and should be ascertained.

Physical Examination

Patients with opioid toxicity characteristically present with a depressed level of consciousness. Opiate toxicity should be suspected when the clinical triad of central nervous system (CNS) depression, respiratory depression, and pupillary miosis are present. It is important for the clinician to be aware that opioid exposure does not always result in miosis (pupillary constriction) and that respiratory depression is the most specific sign. Drowsiness, conjunctival injection, and euphoria are seen frequently.

Needle tracks are observed occasionally, depending on the route of abuse. Street users commonly use heroin and morphine by subcutaneous ("skin popping") and intravenous ("mainlining") injection. Raw opium usually is eaten or smoked, and sometimes the powder is sniffed ("snorted"). Transdermal opioid patches, such as fentanyl, also may produce toxicity.

Other important presenting signs are ventricular arrhythmias, acute mental status changes, and seizures. Reliance on pupillary miosis to diagnose opioid intoxication can be misleading. If sufficiently severe, hypertension and pupillary dilation may be present because of CNS hypoxia. Morphine, meperidine, pentazocine, diphenoxylate/atropine (Lomotil), and propoxyphene sometimes are associated with mydriasis or midpoint pupils.

The respiratory effort frequently is impaired in opiate intoxication. Both bradypnea and hypopnea are observed. Rates as slow as 4-6 breaths per minute often are observed with moderate-to-severe intoxication. The body retains the hypoxic drive to breathe but this may be overridden by the CNS sedative effects of a severe overdose.

Mild peripheral vasodilation may occur and result in orthostatic hypotension. However, persistent or severe hypotension should raise the suspicion of co-ingestants and prompt reevaluation. Opioids prolong GI transit times, possibly causing delayed and prolonged absorption. Initial tendencies for nausea and emesis are transient. Pink frothy sputum, muscular rigidity, dyspnea, hypoxia and bronchospasm strongly suggest acute lung injury.

Nightmares, anxiety, agitation, euphoria, dysphoria, depression, paranoia, and hallucinations are encountered infrequently, mainly with high doses. Pruritus, flushed skin, and urticaria may arise because of histamine release. Generalized seizures are infrequent; they occur most commonly in infants and children because of initial CNS excitation. In contrast, seizure activity in adults is suggestive of meperidine or propoxyphene ingestions; tramadol may lower the seizure threshold, and so may rarely lead to seizures at therapeutic doses as well as in overdoses. Hearing loss has been associated with heroin and alcohol but is generally considered recoverable.

Propoxyphene, a frequently prescribed narcotic often paired with acetaminophen, was withdrawn from the US market on November 19, 2010 because of the risk of serious cardiac toxicity, even when used at therapeutic doses.[30] Nevertheless, as recently as 2018, rare cases of exposure to acetaminophen plus propoxyphene continued to be reported.[18]

 

DDx

Diagnostic Considerations

Illicit use of narcotics for recreation or the use of methadone for opioid dependence can be associated with co-ingestants including cocaine, benzodiazepines, cyclic antidepressants,[31]  methamphetamine, or other substances.[21] Suspicion of co-ingestants should be nurtured when the patient's clinical course does not conform closely to known opiate effect profiles, especially given the cardiac toxicity of the tricyclics.

The delivery of narcotics via inhalation is a relatively new methodology with limited mechanism but potentially significant clinical impact. Butorphanol, a combined agonist-antagonist, is currently available in an intranasal form but is not entirely aerosolized. Fentanyl is available in an intranasal form that is indicated for breakthrough cancer pain in adults who are tolerant to opioid therapy for their underlying persistent cancer pain.

Transdermal delivery of opioids, specifically fentanyl, has become a mechanism of analgesia. A prolonged time to peak effect and a long elimination half-life are characteristics of this delivery mechanism. Because of the relatively prolonged onset, this route is rarely the sole precipitant of overdose. However, transdermal patches can contribute to the toxicity of orally or parentally administered opioids.

Dextromethorphan, an opioid derivative with specific antitussive properties, is widely available in many over-the-counter cough preparations, which increases the chances of abuse. Although high doses may cause sedation, the other components of the preparation (eg, antihistamines) often require additional treatment. Observation for 3-4 hours in uncomplicated overdoses is sufficient. One documented case of respiratory depression in an adult overdose was reversed with naloxone. Administration of dextromethorphan or meperidine in pd. Serious manifestations of the serotonin syndrome may result, in some cases, compromising cardiovascular function.

Tramadol (Ultram), although classified as a nonopioid analgesic, uses a dual mode of action through opioid and nonopioid receptors. Tramadol has a relatively long duration of action of 5-6 hours. In a known overdose of tramadol, a trial of naloxone is suggested; however, repeat doses of naloxone may be required.

Efforts by back-room chemists have brought very potent and potentially deadly opioid derivatives to the street. Normal toxicologic screens cannot detect such designer drugs because of the extremely low dose involved. Synthetic fentanyl derivatives, such as china white (alpha-methylfentanyl), are extremely potent. Abusers have been found dead with needles still in their arms. Even more powerful derivatives, such as 3-methylfentanyl, have been synthesized and are estimated to be 2000 times more potent than morphine. These drugs may require unusually high doses of naloxone to reverse. Deaths from such highly potent drugs often occur in clusters as the new product or batch reaches the street for use.

Pentazocine is a combined agonist-antagonist. Although the effects of pentazocine can be reversed by naloxone, high doses (10-15 mg) of naloxone frequently are required.

Similarly, propoxyphene can be reversed by high doses of naloxone. Propoxyphene is known for its rapid onset of toxic effects, and prolonged observation is recommended. Cardiac effects also may be observed with propoxyphene toxicity because of its quinidinelike effects. Naloxone is not effective in treating propoxyphene-induced arrhythmias.

Propoxyphene and its metabolite norpropoxyphene impair cardiac conduction and contractility. These agents are quinidinelike type IA antidysrhythmic agents that block fast-sodium channels. Clinical effects may include sinus bradycardia, prolonged PR, QRS, and QTc intervals on ECG; hypotension; bundle-branch blocks; and ventricular dysrhythmias. Sodium bicarbonate is effective treatment and recommended for patients who are hypotensive or have a prolonged QRS segment following propoxyphene ingestion.

The combination drug diphenoxylate/atropine (Lomotil) can produce signs of anticholinergic toxicity in addition to opioid toxicity. Because of the prolonged duration of action, respiratory depression may occur as late as 14 hours postingestion. Any child younger than 5 years who has ingested Lomotil should be observed for up to 24 hours. Adults and children older than 5 years should be given gastric decontamination and observed for 6 hours in the ED. They may be discharged home if asymptomatic.

The transport of illegal drugs may involve so-called body packers, or people who intentionally ingest packets of drugs for purposes of evading police. These packets are usually well wrapped, but they can still cause unintended complications such as intestinal obstruction. Three cases of intestinal perforation in this setting have been reported.[32]

In contrast to body packers, so-called body stuffers are created in the stress of pursuit, usually by police. In an effort to avoid prosecution, hurriedly packaged drugs are ingested without the careful preparation characteristic of body packers. Such persons who body stuff are much more likely to experience the consequences of drug overdose and should be treated very aggressively. Surgical removal may be indicated in those patients who are symptomatic or show evidence of obstruction. Even aggressive surgical treatment is not without sequelae.[33]

Differential Diagnoses

 

Workup

Laboratory Studies

Drug screens are widely available but rarely alter clinical management in uncomplicated overdoses. Drug screens are most sensitive when performed on urine. Positive results are observed up to 36-48 hours postexposure, but wide variations are possible depending upon test sensitivity, dose, route, and the patient's metabolism.

In patients with moderate-to-severe toxicity, performing the following baseline studies is appropriate:

  • Complete blood cell count
  • Comprehensive metabolic panel
  • Creatine kinase level
  • Arterial blood gas determinations

Imaging Studies

Obtain chest radiographs if acute lung injury is suspected. Abdominal films may be helpful when evaluating a suspected body stuffer or body packer. Although the body stuffer (ie, a person who quickly swallows drug packages in an effort to hide evidence from police) is more prone to toxicity from hasty preparation, body packers (ie, individuals who carefully seal large amounts of drugs in packages and then swallow them for transport) have much larger amounts of drug liberated should their packages leak. Films suggestive of ingestion are helpful in making a diagnosis, but films negative for drug packages do not rule out potentially life-threatening ingestions.[34]

Electrocardiography

An ECG should be obtained on all patients with intentional overdose (possible cardiotoxic co-ingestants) or those with significant toxicity.

 

Treatment

Prehospital Care

Adequate prehospital care hinges on aggressive airway control. Expedient endotracheal intubation is indicated for patients who are unable to protect their airway.

In patients lacking spontaneous respirations, orotracheal intubation is preferred. If advanced life support (ALS) is available, intravenous naloxone (Narcan) may be given to reduce respiratory depression. Exercise caution when giving naloxone in the confines of an ambulance because it can transform a peacefully sleeping patient into an agitated, belligerent one. If naloxone is used for a suspected long-term opiate user, only an amount sufficient to return spontaneous respirations is recommended. Judicious application of restraints in a potentially violent patient is advisable in close quarters.

Alternate routes of naloxone administration include intraosseusly, intramuscularly, intranasally, or via endotracheal tube. Recommending these routes for routine use in an uncomplicated overdose is difficult because primary attention should be focused on airway maintenance. Intranasal (IN) route of administration of naloxone is of similar effectiveness to the (IM) route as a first-line treatment for isolated opioid overdose in the prehospital setting.[35]

In November 2015, the US Food and Drug Administraiton approved intranasal naloxone for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. The ready-to-use single-dose sprayer delivers a 4-mg dose by intranasal administration. Approval was based on pharmacokinetic studies that compared IM and intranasal dosage forms. The National Institute on Drug Abuse also was crucial to the approval by forming a public-private partnership by designing and conducting the clinical trials required to determine that the intranasal formulation delivered naloxone as quickly and as effectively as an injection.[36, 37]

In the case of a patient who is unconscious for unknown reasons, naloxone can be administered judiciously by emergency medical services (EMS) personnel; adequate precautions against violent patients should be taken (eg, application of restraints concurrent or before naloxone administration). Aggressive airway control must take precedence over pharmacologic reversal because the vast majority of morbidity and mortality results from respiratory depression.

In some instances, treatment in the field with naloxone results in an oriented patient refusing further treatment and transport to the hospital for evaluation and observation. This may require EMS or responsible friends to stay with the patient until they can ensure the continued health of the patient. In these cases, ED physicians should provide direct medical control; it is recommended that ED physicians talk to patients by phone to ensure that they fully understand the risks associated with refusing transport and further evaluation and treatment.

Emergency Department Care

Airway control and adequate oxygenation remain the primary intervention if not already established by EMS. Endotracheal intubation is indicated in patients who cannot protect their airway.

If occult trauma is suspected, implement cervical spine immobilization. As with all unknown unconscious patients, determination of serum glucose level is mandated.

Administer naloxone for significant central nervous system (CNS) and/or respiratory depression. The usual dose administered by EMS is between 0.4 and 2 mg in the adult and 0.1 mg/kg in the child or infant. In suspected habituated opiate users, if the situation allows, slowly administer 0.1-0.4 mg of IV aliquots every 1-2 minutes for a more controlled and partial reversal of opiate effect. Assisted bag-valve-mask breathing can be provided until the patient is ventilating adequately. The onset of effect following IV naloxone administration is typically 1-2 minutes; maximal effect is observed within 5-10 minutes. A repeat dose is indicated for partial response and can be repeated as often as needed.

To avoid precipitous withdrawal (nausea, vomiting, agitation) and consequent aspiration, especially in patients suspected of taking one or more other substances that are CNS depressants (eg, benzodiazepines, tricyclic antidepressants, ethanol), recommended reversal practice is to start with a very low dose of naloxone of 0.05 to 0.1 mg and titrate it up gradually until reversal of respiratory depression is achieved.

If an intravenous line cannot be established (eg, in a long-term intravenous heroin user with poor intravenous access), administer 2 mg of IM or intranasal naloxone. Clinical reversal occurs within 5-10 minutes. An intranasal dosage form (Narcan Nasal Spray) was approved in November 2015 that delivers 0.4 mg per single-dose spray.[36, 37]

The clinical half-life of naloxone is roughly 20-60 minutes, with a duration period of 2-3 hours. Some variation exists because of dosage and route.

In the non–opiate-addicted patient who has recrudescent opiate toxicity following naloxone administration, naloxone may be administered safely and effectively by continuous intravenous infusion. This practice is dangerous for patients who have opiate addiction because of the concern for precipitating opiate withdrawal. The dose recommended for constant infusion is two-thirds to 1 full reversal dose as a drip rate per hour. Naloxone may be mixed in isotonic saline solution or 5% dextrose in water (D5W) to the desired concentration. This drip may be titrated to the desired effect. Constant infusions are particularly useful for overdoses of long-acting opioids, such as methadone.

Larger doses of naloxone may be required to reverse toxicity from diphenoxylate/atropine (Lomotil), methadone, propoxyphene, pentazocine, and the fentanyl derivatives. Repeat doses of 2 mg can be given every 3-5 minutes as needed, up to a total of 10 mg. Reconsider the diagnosis if the patient fails to respond after 10 mg.

In a California report of an outbreak of fentanyl toxicity, one of the 18 patients had recurrent toxicity 8 hours after naloxone discontinuation and four required prolonged naloxone infusions (26-39 hours). The outbreak resulted from fentanyl-adulterated tablets that were purchased on the street as hydrocodone/acetaminophen and were virtually indistinguishable from authentic hydrocodone/acetaminophen tablets.[38]

A gradual accumulation of naloxone is preferential to isolated larger doses. The precipitation of withdrawal, while not life threatening, is disconcerting to the patients and the staff. The best way to reverse respiratory depression and coma, while avoiding precipitant withdrawal, is by gradual measured administration of naloxone.

Activated charcoal is the GI decontamination method of choice for patients with opiate intoxication following ingestion. Because of impairment of gastric emptying and GI motility produced by opiate intoxication, activated charcoal still may be effective when patients present late following ingestion. Decontamination with activated charcoal should be attempted in all symptomatic patients (as long as it is not contraindicated), regardless of the time of ingestion in relation to hospital presentation.

The airway has to be protected (ET tube, adequate gag reflex, appropriate level of consciousness) prior to administration of charcoal in order to prevent converting relatively benign opioid overdose into catastrophic charcoal aspiration. Although orogastric lavage is not often necessary, it may be considered in addition to activated charcoal when patients present obtunded within 1 hour of ingestion.

Whole-bowel irrigation can be considered for removal of ingested drug packets in body packers, but data from controlled trials documenting improvement in clinical outcome after whole-bowel irrigation are lacking. Contraindications to whole-body irrigation include bowel obstruction, perforation, or ileus; hemodynamic instability; and a compromised unprotected airway.[39]

In a few isolated cases of pure opioid toxicity, patients may fail to respond to aggressive airway control and high-dose naloxone. In the absence of other etiology, prolonged hypoxia may cause a terminal state unresponsive to naloxone. Buprenorphine (Buprenex) has been reported to respond only partially to naloxone.

Cardiac arrest in the setting of pure opioid toxicity is almost certainly an indication of severe hypoxia and poor neurologic outcome.

In the pediatric setting, the dose of naloxone is 0.1 mg/kg in patients who weigh less than 20 kg or are younger than 5 years. In patients who weigh more than 20 kg or are older than 5 years, use 0.1-2 mg/dose. Doses may be repeated up to a maximum cumulative dose of 10 mg. Repeat doses may be indicated for relapses caused by the comparatively longer duration of action of most opioids compared with naloxone.

A naloxone drip may be instituted, with two thirds of the initial successful dose given over 1 hour in a continuous infusion.

Case reports have surfaced of laypersons using buprenorphine/naloxone intravenously to reverse a heroin overdose.[40] Use of buprenorphine/naloxone has also been reported being used sublingually to reverse acute narcotic overdose. A combined overdose can potentially provide false reassurance to the practitioner, and caution should be exercised in patients receiving both medications.

Narcotic bowel syndrome is also a possible manifestation of opiate toxicity, characterized by abdominal pain that worsens with short- or long-term use of escalating doses of narcotic pain medication. It may occur in patients who have no preexisting gastrointestinal problems, either in acute settings in which opiates are administered for another injury or when the potential hyperalgesic effects of long-term opiate use are not recognized.

Methadone, a long-acting narcotic often used to attenuate withdrawal symptoms and used in narcotics recovery programs, also has extensive potential for abuse. It can be ingested orally or pills can be crushed and used intravenously or intranasally.[41] In studies by the US Centers for Disease Control and Prevention (CDC) from 1999-2010, methadone accounted for 4.5-18.5% of narcotics sold in the United States and was involved in 31% of opioid deaths in the 13 states involved in the study. In addition, CDC analysis of data collected from 2004-2009 revealed a significant increase in the nonmedical use of methadone alone or in combination with other drugs.[42]

In recent years, methadone has also been used increasingly for treatment of chronic pain. However, patients using methadone face serious risks related to risk of overdose and cardiac arrhythmias, and consequently require careful dose initiation and titration, along with diligent monitoring and follow-up.[43]

Hospitalization

Because the half-life of naloxone is shorter than that of many opioids (a particular concern with exposure to long-acting opioid preparations), any patient who is exhibiting significant respiratory depression, recurrent sedation, or any other complicating factors of opioid ingestion should be admitted for a minimum of 12-24 hours of observation. Appropriate cardiorespiratory monitoring should be initiated until the effects of opioid toxicity subside.

Most physicians recommend admission of any patient who requires a second dose of naloxone or who fails a 6-hour observation period in the ED. Some authorities recommend admission of patients with heroin overdose who present with significant respiratory depression caused by the increased risk of acute lung injury. However, this complication usually is evident within minutes of patient arrival. Thus, the patient who is asymptomatic following heroin overdose and has not demonstrated recrudescent toxicity during a 6-hour period of observation may be discharged safely.

Complications

Acute lung injury (ALI) is a well-documented sequelae of heroin overdose. It also is associated with propoxyphene and methadone and almost always is present in fatal cases of opioid overdose. Although the etiology is still unclear, the putative culprit is hypoxia and hypoventilation. The clinical findings are similar to those found in cardiogenic pulmonary edema (eg, cyanosis, dyspnea, pink frothy sputum, rales, tachypnea, tachycardia). ALI has also been reported in pediatric patients who ingest opiates in excess.[44]

Unless fatal, the ALI clears in 24-48 hours with vigorous airway control and oxygen. Typical pulmonary edema therapy (eg, vasodilators, cardiac glycosides) is not necessary, and diuretics actually may contribute to severe hypotension.

Intravenous drug abuse (IVDA) carries an additional list of complications. Cellulitis and abscesses are frequent complications of IVDA, usually with staphylococcal or streptococcal infection; however, anaerobic bacteria are observed occasionally. Hematogenous dissemination of bacteria, commonly to the epidural space, can cause spinal epidural abscess. This also may occur from spread of vertebral osteomyelitis. Staphylococcus aureus is the most common organism, but gram-negative bacilli may be observed. Osteomyelitis in IVDA is well known; if a patient with long-term IVDA presents with back pain, this diagnosis should be added to the differential.

Site-specific sequelae, such as Horner syndrome from patients injecting into the neck region, may be observed. Particulate matter poses a threat because of embolic phenomena. Pulmonary emboli and peripheral emboli are two common complications. Thrombi initiated by vessel intimal damage from the needle may lead to similar syndromes. Inadvertent intra-arterial injection is another potential complication, possibly resulting in necrosis of the affected extremity. Intraneural injection may cause transient or permanent neuropathy.

Endocarditis is the most serious complication of IVDA. The diagnosis is difficult to make in the ED and requires a high index of suspicion. Although either side of the heart may be affected, the right side is involved more commonly than the left. The tricuspid valve is the most frequent site of endocardial infection. Murmurs may be heard. Repeated septic pulmonary emboli may be the only presenting signs, usually involving S aureus as the etiologic agent. Left-sided endocarditis can result from a variety of pathogens, including Escherichia coli or Streptococcus, Klebsiella, or Pseudomonas species. Physical findings consistent with endocarditis are observed more frequently in left-sided disease than in right-sided disease.

Pneumonia often is observed, particularly in the long-term abuser. Normal pathogens should be considered, but aspiration should be added in patients who have been unconscious. Tuberculosis should be added early to the differential diagnosis to avoid unnecessary exposure to health care workers and other patients and to ensure timely and adequate treatment.

Rhabdomyolysis, with or without a compartment syndrome, should be sought in patients who have experienced a potentially long period of unconsciousness. Necrotizing fasciitis is a life-threatening infection that is characterized by septic necrosis. A dusky, erythematous, tender, confluent rash that spreads rapidly and is associated with fever, chills, tachycardia, tachypnea, and leukocytosis should prompt aggressive resuscitation, aggressive therapy, and surgical consultation.

Certain medications can increase the risk of seizures; however, this is not common. Meperidine, propoxyphene, heroin, tramadol, intravenous fentanyl, or sufentanil may cause grand mal seizures. Prolonged or unusual seizure activity should prompt reevaluation and consideration of intracranial injury or prolonged hypoxia.

Withdrawal from opioids is a complication that is not observed universally. Generally, the withdrawal syndrome is not nearly as severe as that observed with barbiturates or alcohol. The onset depends on the drug of abuse, varying 8-12 hours with meperidine and 2-4 days with methadone. Symptoms include piloerection, lacrimation, yawning, sweating, rhinorrhea, nasal congestion, myalgia, emesis, diarrhea, and abdominal cramping. Symptoms peak between 36 and 48 hours and subside after 72 hours. Occasionally, symptoms last as long as 7-10 days.

Treatment of withdrawal is symptomatic. The use of opioids on an outpatient basis to alleviate symptoms should be avoided. Alternate therapy may include clonidine, particularly when methadone is inappropriate, unsuccessful, or unavailable. The involvement of local substance abuse programs is key in avoiding long-term relapse.

The administration of naloxone to patients with true opioid dependence may precipitate withdrawal. Signs and symptoms similar to typical withdrawal are observed. The onset of action is often within 5 minutes and subsides in 1-2 hours. Symptomatic treatment is recommended. Opiate withdrawal is not usually life-threatening. Opiate withdrawal has been reported after the use of buprenorphine, an agonist/antagonist.

Adulterants, contaminants, and diluents are often added to illicit narcotics, often without the knowledge of the end user. In certain cases, these additives can be biologically active. In 1995, an epidemic of this nature was noted in New York City when heroin adulterated with scopolamine was circulated among heroin users. The intravenous use of the heroin was associated with severe anticholinergic toxicity; 370 cases were reported to local poison centers. Anticholinergic toxicity has also been reported as a complication of inhaled cocaine.[45]

Therapy to assist patients in avoiding complications of narcotic overdose include implants and depot injections of naltrexone. First appearing in the 1990s, commercial preparations provide sustained release of naltrexone. However, the 3-year mortality rates using naltrexone sustained release and methadone maintenance are similar.[46]

Prevention

In March of 2015, the United States Department of Health and Human Services identified expanded use and distribution of naloxone as a priority area to reduce opioid use disorders and overdose. Both prescribers and pharmacists can play a role in overdose prevention.[47]

Coprescribing naloxone to primary care patients prescribed opioids for pain may reduce the risk of opioid toxicity. Coffin and colleagues reported that patients who received a naloxone prescription had 47% fewer opioid-related emergency visits per month in the 6 months after receipt of the prescription and 63% fewer visits after 1 year, compared with patients who did not receive naloxone. The study was not randomized; naloxone was more likely to be prescribed to patients receiving higher doses of opioids and those with an opioid-related ED visit in the past 12 months.[48]

Coprescription of naloxone is recommended for patients prescribed opioids with a history of overdose or substance use disorder.  Intranasal naloxone is often preferred over injectable devices.[49, 50]

The US Food and Drug Administration has approved a hand-held auto-injector that can be prescribed to family members or caregivers for treating a person known or suspected to have had an opioid overdose.[51] In addition, organizations that provide naloxone kits to laypersons are proliferating across the United States.[52]  [50]

A New Mexico program that allows pharmacists to prescribe naloxone offers a possible model for expanding access to opioid overdose prevention. Of the 133 naloxone rescue kits prescribed, the majority 89.5%) were first-time prescriptions. The most common reason for a prescription was patient request (56.4%), followed by a pharmacist's recommendation due to prescription high-dose opioids (28.6%) and history of opioid misuse or abuse (15.0%).[53]

 

 

Long-Term Monitoring

The suddenness and potential severity of narcotics overdose, especially with intravenous use, have prompted some physicians to consider providing naloxone as a “take-home” medication, targeting high-risk narcotics users.[54]  Currently, naloxone is not approved for therapy of narcotics overdose in an outpatient setting and cannot be recommended on a routine basis; however, the premise is interesting, given the rise in opiate abuse and potential morbidity and mortality.

 

Medication

Medication Summary

Naloxone is a pure competitive antagonist of opioid receptors and lacks any agonist activity. Adverse effects are rare at therapeutic doses. Naloxone can be given by the intravenous (IV), intramuscular (IM), endotracheal (ET), or subcutaneous (SC) route. The use of intranasal naloxone has also been reported and holds promise, given the absence of need for intravenous access and reduced risk for needle stick to healthcare providers.[55]

By the IV or ET route, the onset of action of naloxone is 1-2 minutes. A second dose can be repeated every 2-3 minutes. With IM or SC administration, onset is 2-5 minutes.D iscontinue treatment as soon as the desired degree of opioid reversal is achieved. Higher doses may be necessary to reverse methadone, diphenoxylate, propoxyphene, butorphanol, pentazocine, nalbuphine, designer drugs, or veterinary tranquilizers.

Nalmefene (Revex) and naltrexone are newer opioid antagonists that have longer half-lives than naloxone (4-8 h and 8-12 h vs 1 h). The routine use of a long-acting antagonist in the patient who is unconscious for unknown reasons is not recommended. In addition, the fear of precipitating prolonged opioid withdrawal likely prevents the widespread use of these antagonists for emergency reversal of opiate intoxication.

In theory, nalmefene might be useful for persons with opiate addiction who accidentally overdose on heroin but refuse to stay for continued observation after an initial reversal dose of naloxone. However, this practice can be fatal to the patient who is discharged and then uses an excessive dose of opioids in order to counteract the withdrawal symptoms caused by the nalmefene. The routine use of this agent is not recommended.

Opioid Reversal Agents

Class Summary

These agents reduce or eliminate the effects of opioid agents on their receptors.

Naloxone (Narcan, Evzio)

Historically, the most commonly used opioid receptor antagonist in the United States. It is used to reverse opioid intoxication or overdose. Prevents or reverses opioid effects (hypotension, respiratory depression, sedation), possibly by displacing opiates from their receptors. Half-life is 1 h. The injectable solution is available in vials and syringes (0.4 mg/mL, 1 mg/mL) for IV/IM/SC administration by healthcare providers. It is also available as an autoinjector (delivers 0.4 mg IM/SC) for home use by family or caregivers.

If patients do not respond to multiple doses of naloxone, consider alternative causes of unconsciousness.

Naloxone intranasal (Narcan Nasal Spray)

Competitive opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. The intranasal form is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

 

Questions & Answers

Overview

What is fentanyl?

What are the mortality rates for opioid toxicity?

When should opioid toxicity be suspected?

What is opioid toxicity?

What is the pathophysiology of opioid toxicity?

What is the prevalence of opioid toxicity in the US?

What is the global prevalence of opioid toxicity?

What is the morbidity associated with opioid toxicity?

What is the role of naloxone (Evzio) in the treatment of opioid toxicity?

Presentation

Which clinical history findings are characteristic of opioid toxicity?

Which physical findings are characteristic of opioid toxicity?

DDX

When should co-ingestants be considered in the differential diagnoses of opioid toxicity?

How does the delivery route affect opioid toxicity?

Which opioid derivatives should be included in the differential diagnoses of opioid toxicity?

What are the differential diagnoses for Opioid Toxicity?

Workup

What is the role of lab tests in the workup of opioid toxicity?

What is the role of imaging studies in the workup of opioid toxicity?

What is the roe of ECG in the diagnosis of opioid toxicity?

Treatment

What is included in prehospital care for opioid toxicity?

What is included in emergency department care for opioid toxicity?

What is the role of activated charcoal in the treatment of opioid toxicity?

What is the role of whole-body irrigation in the treatment of opioid toxicity?

What are the signs and symptoms of hypoxia in opioid toxicity?

What is the role of naloxone in the treatment of pediatric opioid toxicity?

What is the role of buprenorphine/naloxone in the treatment of opioid toxicity combined with another narcotic?

How is narcotic bowel syndrome managed in opioid toxicity?

What is the prevalence of methadone opioid toxicity?

When is inpatient treatment of opioid toxicity indicated?

How is acute lung injury (ALI) treated in opioid toxicity?

What are the possible complications of opioid toxicity in IV drug users?

What are possible complications of opioid toxicity?

How are withdrawal symptoms managed during opioid toxicity treatment?

What are the possible complications of opioid toxicity with adulterants, contaminants, and diluents?

What is the role of naltrexone in the treatment of opioid toxicity?

How is opioid toxicity prevented?

What is the role of naloxone in the outpatient treatment of opioid toxicity?

Medications

What is the role of medications in the treatment of opioid toxicity?

Which medications in the drug class Opioid Reversal Agents are used in the treatment of Opioid Toxicity?