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]
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
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:
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. In areas where fentanyl or fentanyl analogues are prevalent or are emerging, knowledge of local EMS protocols is useful due to variation in naloxone dose and frequency.
Ingestion time, quantity, and co-ingestants are important aspects of the history and should be ascertained.
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 in 2010 because of the risk of serious cardiac toxicity, even when used at therapeutic doses.[29] Nevertheless, as recently as 2018, rare cases of exposure to acetaminophen plus propoxyphene continued to be reported.[15]
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:
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.[33]
An ECG should be obtained on all patients with intentional overdose (possible cardiotoxic co-ingestants) or those with significant toxicity.
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, as larger doses may precipitate opioid withdrawal. Judicious application of restraints in a potentially violent patient is advisable in close quarters.
Alternate routes of naloxone administration include intranasal, intramuscular, intraosseous, 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 administration of naloxone has similar effectiveness as the route as a first-line treatment for isolated opioid overdose in the prehospital setting.[34]
The US Food and Drug Administration (FDA) has approved intranasal naloxone for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. Intranasal naloxone is packaged in a ready-to-use single-dose sprayer. Initial approval, in 2015, was for a 4-mg dose.[35] In 2021, the FDA approved a higher-dose version (Kloxxado) that delivers an 8-mg dose.[36] The brand name product (Narcan Nasal Spray), which delivers a 4-mg dose, was the first opioid antagonist granted over-the-counter (OTC) designation, in March 2023.[37] A second OTC product (ie, RiVive) was approved in July 2023 that delivers a 3-mg dose.
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 the patient becoming violent 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 patient's continued health. In these cases, ED physicians may be asked to 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.
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 injected dose administered by EMS is 0.4 to 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 intramuscular or 4 mg of intranasal naloxone. Clinical reversal occurs within 5-10 minutes. Devices for intranasal delivery of 4 or 8 mg of naloxone per single-dose spray are available.[37, 35]
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 opiate intoxication impairs gastric emptying and GI motility, activated charcoal may still 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) toxicity 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] Sublingual use of buprenorphine/naloxone to reverse acute narcotic overdose has also been reported. 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]
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.
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 may occur—including to the epidural space, which 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 second only to respiratory arrest as the most serious complication of IVDA. 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 but should not be considered a requirement for inclusion in the differential diagnosis. Repeated septic pulmonary emboli may be the only presenting signs, usually in cases involving S aureus. 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]
In 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 (FDA) 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] In 2023, the FDA approved over-the-counter sale of naloxone nasal spray.[37]
Over the past two decades, many countries around the world have implemented harm reduction initiatives that involve providing naloxone training and overdose management education, as well as take-home naloxone kits to opioid users and others likely to witness an opioid overdose. These initiative have proved highly effective.[53]
In April 2023 the FDA began requiring manufacturers of opioid analgesics dispensed in outpatient settings to make prepaid mail-back envelopes available to outpatient pharmacies and other dispensers. The goal is to provide patients a safe way to dispose of their unused opioid medications, in order to reduce the chances of nonmedical use, accidental exposure, and overdose.[54]
Naloxone is a pure competitive antagonist of opioid receptors and lacks any agonist activity. Adverse effects are rare at therapeutic doses. Effects of withrawal may follow administration, and may be confused as adverse effects by the the layperson. Naloxone can be given by the intravenous (IV), intramuscular (IM), endotracheal (ET), subcutaneous (SC), or intranasal (IN) route. IN naloxone has the advantage of posing no risk of needlestick injury.
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, SC, or IN administration, onset is 2-5 minutes. Discontinue treatment as soon as the desired degree of opioid reversal is achieved. Higher doses may be necessary to reverse the effects of 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.
Clinical Context: Historically, naloxone is 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. A high-dose (5 mg/0.5 mL) IM/SC injectable solution in a prefilled syringe (Zimhi) is also available. In pharmacokinetic studies, a single IM dose of 5-mg provided significantly higher peak plasma concentration and area under the curve (AUC) compared with a single 2-mg IM injection.
If patients do not respond to multiple doses of naloxone, consider alternative causes of unconsciousness.
Clinical Context: 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. The brand name product (ie, Narcan Nasal Spray) was the first opioid antagonist granted over-the-counter (OTC) designation, in March 2023, and delivers a 4-mg dose. A second OTC product (RiVive) was approved in July 2023; it delivers a 3-mg dose. A higher concentration intranasal product (Kloxxado) that is available by prescription delivers 8 mg/actuation. Generics that deliver 4 mg/actuation are also prescription products.
These agents reduce or eliminate the effects of opioid agents on their receptors.