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, 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.
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 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]
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 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]
Prevention
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]
