AUTHORS
R. Gentry Wilkerson, MD, Assistant Professor, Assistant Residency Program Director, Department of Emergency Medicine, University of Maryland Medical Center, Baltimore
John David Gatz, MD, Resident, Department of Emergency Medicine, University of Maryland Medical Center, Baltimore
Mei Ling Liu, MD, Resident, Department of Emergency Medicine, University of Maryland Medical Center, Baltimore
PEER REVIEWER
Dan Quan, DO, FAAEM, FACEP, Director of Medical Toxicology, Maricopa Integrated Health System; Clinical Assistant Professor, Department of Emergency Medicine, University of Arizona College of Medicine, Phoenix
I get upset whenever I read an article saying that narcotics are prescribed almost like candy from the emergency department (ED). Emergency physicians are some of the most skeptical physicians I know. Often, we are the stingiest with pain medications, so stingy that just a few years ago, we were criticized as not adequately treating a patient’s pain. As discussed in previous issues, pain management in the ED is a complex subject, with opioids playing an appropriate role. This issue of EM Reports discusses one complication of opioid use: the assessment and treatment of acute opioid toxicity, from prehospital to disposition.
— J. Stephan Stapczynski, MD, Editor
Introduction
The rapid increase in the use of prescription and nonprescription opioids in the United States that began in the late 1990s has led to levels of abuse and overdose deaths that have reached epidemic proportions. Claims of safety by drug manufacturers and requirements to treat pain fueled a rapid rise in the use of opioids to treat a variety of painful conditions. As the number of opioid prescriptions rose, so, too, did the number of prescription opioid overdose deaths. Between 1999 and 2010, there was a fourfold increase in the number of opioid prescriptions that was paralleled by a fourfold increase in the number of opioid overdose deaths.1 Recent measures to reduce the distribution of prescription opioids have had the unintended consequence of increasing the use of heroin. Opioid overdose is now a leading cause of death of Americans younger than 50 years of age. In 2015, more than 33,000 deaths were attributable to opioid overdose — a rate of 91 deaths per day.2
As a result of this epidemic, EDs have seen a rise in nonlethal opioid overdoses. This article aims to provide acute care providers with advanced techniques in the management of opioid overdoses, including the use of naloxone, the opioid receptor antagonist, as well as harm reduction management strategies aimed at long-term risk mitigation in this vulnerable population.
Pharmacology
Opioids are substances that are functionally similar to opiates, which are compounds structurally related to opium, the resin produced from the poppy plant, Papaver somniferum. The term opioid is used to describe opiates, the natural plant alkaloids such as morphine and codeine, as well as synthetic compounds such as fentanyl and methadone. Several types of opioid receptors are found in humans, termed the μ-, κ-, and δ-opioid receptors. Response to opioid action at these receptors modulates numerous functions, including response to pain, body temperature, respiratory drive, gastrointestinal activity, and mood.3 The analgesic effect of opioids is accomplished primarily through action on the μ-opioid receptor, which, in turn, activates dopaminergic receptors in the limbic system and leads to sensations of euphoria. Repeated administration of opioids alters the opioid receptors and leads to the development of tolerance, such that progressively higher doses of opioid medications are required to achieve the same clinical effect. Excessive doses, even in a habitual user, can lead to life-threatening overdose. The most significant threat to the patient with an opioid overdose is respiratory depression, leading to hypoxia and eventually cardiopulmonary arrest.
Clinical Presentation
The classic clinical triad of an opioid overdose consists of respiratory depression, depressed mental status, and miosis (pupillary constriction). Although the presence of all three is highly suspicious for opioid intoxication, this toxidrome is not consistently reliable in clinical practice. The presence of any of the findings typically associated with opioid overdose should lead the healthcare provider to consider it while still seeking other life-threatening causes.4 (See Table 1.)
Miosis, in particular, is an unreliable finding for opioid overdose. Other causes of miosis include cholinergic toxicity, pontine lesions (infarct or hemorrhage), bilateral Horner’s syndrome, and neurosyphilis (Argyll Robertson pupil). Additionally, opioid overdose can occur in the setting of polysubstance abuse. Concomitant ingestions may result in normally reactive or even mydriatic pupils. Other signs and symptoms that may be associated with opioid overdose include hypotension, hypothermia, and hypoactive bowel sounds.
Table 1. Differential Diagnosis
Condition |
Differentiating Factors |
|
Alcohol intoxication |
• Presents with altered mental status without miosis • Respiratory depression occurs at extreme levels |
|
Sedative-hypnotic overdose (barbiturates and benzodiazepines) |
• Presents with altered mental status without miosis • Respiratory depression parallels degree of central nervous system depression |
|
Gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL) overdose |
• Closely resembles opioid overdose — altered mental status with respiratory depression and miosis |
|
Clonidine (imidazoline) overdose |
• Presents with altered mental status, respiratory depression, and miosis • More profound bradycardia and hypotension than expected for opioid overdose |
|
Ketamine overdose |
• Presents with altered mental status • Respiratory effort is generally preserved • Pupils may be miotic • Rotatory nystagmus frequently is seen |
|
Pontine hemorrhage/infarct |
• Presents with altered mental status with miosis • Typically does not have bradypnea |
|
Cholinergic poisoning |
• Altered mental status with miosis • Variable effect on heart rate due to combined muscarinic and nicotinic effects • No respiratory depression |
As a result of variable but potentially prolonged duration of depressed mental status, patients may present with associated complications. Hypothermia can result from exposure to the elements.5 Prolonged immobilization from opioid overdose may cause muscle breakdown of sufficient severity to result in rhabdomyolysis and acute kidney injury.6 In extreme cases, fasciotomy has been required to treat compartment syndrome resulting from immobility following opioid overdose.7
Risk Factors for Overdose
Although the opioid epidemic has affected minority populations with poor socioeconomic status the hardest, its impact has been felt across the United States regardless of race, age, gender, and socioeconomic status. Sweeping recommendations have been made to reduce the risk of patients developing opioid addiction, to prevent overdose, and to provide treatment options for those who are addicted. Understanding the risk factors associated with developing addiction or experiencing an overdose can help refine efforts to reduce harm.
Rates of opioid overdose are highest among men, people between the ages of 20 and 64 years of age, non-Hispanic whites, those in lower economic classes, and those in rural populations.8 Individuals who are opioid dependent constitute the most likely group to experience an overdose. It has been estimated that for every fatal overdose, there are 25 to 50 nonfatal overdoses.9
Several risk factors increase the likelihood of an overdose. A history of opioid overdose is a strong predictor of future overdose.10 People who use intravenous heroin have a high risk of overdose; this risk is even greater among those injecting for the first time.11 A long period of abstinence followed by a return to opioid use markedly increases the risk of overdose. This association is evidenced by the high rate of opioid overdose among people immediately after they are released from prison.12 Other risk factors include higher opioid dosage, concurrent use of sedative hypnotics, and mental health disorders.13
A major contributor to the rise of unintentional opioid deaths in the United States is the abuse of prescription drugs. Understanding opioid prescribing behaviors among healthcare providers as well as the characteristics of the patients at risk for developing addiction and experiencing an overdose can lead to establishment of safer practice guidelines for physicians who are prescribing opioids.
In particular, patients taking more than 50 morphine milligram equivalents per day have a higher risk of overdose than patients taking lower daily doses. High-potency opioids, such as fentanyl and carfentanil, also are associated with a higher risk of overdose in comparison to lower-potency opioids. Prescribing opioids on an as-needed basis to patients who are taking opioids for cancer-related pain also is associated with a high risk of unintentional overdose.14 Cancer patients are likely to experience unpredictable escalations of pain, which can result in more frequent use of unscheduled pain medication.
Despite significant research efforts, appropriately prescribing opioid medication to patients enduring chronic pain remains a challenge. Studies evaluating individually tailored treatment guidelines are necessary to increase the safety of opioid prescriptions for pain management.
Diagnostic Approach
Opioid overdose usually is diagnosed based on clinical manifestations. As noted before, signs and symptoms that are highly suggestive of acute opioid intoxication include respiratory depression (especially with a respiratory rate < 12 breaths/minute), miosis, and depressed mental status.4 Additional findings that are useful in identifying opioid overdose are the presence of needle marks, finding pill bottles or drug paraphernalia at the scene, and bystander reports of the patient’s activity prior to the change in clinical status. Any report of body packing or body stuffing will help to alert the provider to the risk of delayed effects of opioid overdose due to possible rupture of opioid-containing packages.
A thorough physical examination should be performed on every patient suspected of opioid overdose. This includes assessment of the degree of respiratory effort, pupil size and reactivity, and auscultation of the lungs for findings suggestive of pulmonary edema. In addition, the patient should be undressed completely to look for signs of trauma, indications of infection, as well as the presence of transdermal medication patches, which could be delivering a constant flow of an opioid such as fentanyl.15 All extremities should be palpated to evaluate for signs of swelling and the development of compartment syndrome.
During the primary assessment, if the respiratory effort becomes diminished to the degree that there is an imminent threat to the patient, then the opioid receptor antagonist naloxone should be administered immediately, and consideration should be given to establishing a definitive airway. When the diagnosis of opioid overdose is not certain, a positive response to the administration of naloxone provides supporting evidence, although it does not positively confirm the diagnosis.
Urine drug screening (UDS) is not routinely required to make the diagnosis of opioid overdose, since it rarely changes the management strategy.4 UDS assays vary from institution to institution regarding the substances detected and the technique used to detect them. Comprehensive urine drug testing consists of a two-step process: an immunoassay screen (IAS) followed by a confirmatory test.
During the emergency management of a patient being evaluated for possible opioid overdose, the only test that reasonably would be expected to yield a result is the qualitative IAS. This screen assesses the presence or absence of certain categories of drugs. Typically, the urine drug testing immunoassay for opioids detects only specific agents, including free morphine, and has various degrees of cross reactivity with codeine, oxycodone, and hydromorphone and its conjugated metabolites.16
The IAS provides inconsistent results for the detection of semisynthetic and synthetic opioids.17 Additionally, the IAS does not measure the concentrations of detected substances. Even when quantitative results are available, it is often difficult to interpret them in a frequent user because of development of drug tolerance.
The fact that IASs have the potential for false-positive results makes UDS an even less useful diagnostic tool for opioid overdose. False-positive results have occurred in the setting of quinolone and rifampin use and ingestion of poppy seeds.18 However, given their relatively low cost, there may be some justification for requesting these tests, especially if there is concern for co-ingestion or significant diagnostic uncertainty.
Because of the recent increase in the use of high-potency synthetic opioids, including fentanyl and its analogues such as carfentanil, there is growing interest in a cost-effective and efficient diagnostic tool for detecting the presence of synthetic opioids. Recent studies have demonstrated that it is possible to detect fentanyl and carfentanil in human samples with various mass spectrometry assays.19,20 This research is in its early stages, so additional studies are needed to understand the role of testing for fentanyl and its analogues and its implications for the acute management of opioid overdose.
Acute Management
Prehospital management of opioid overdose focuses on early recognition, airway management, naloxone administration, continuous monitoring of cardiac and respiratory status, and transport to a nearby facility.
When prehospital care providers encounter any unconscious person, first they should determine if a pulse is present. If the person does not have a pulse, the Advanced Cardiac Life Support (ACLS) guidelines should be followed. The 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend that basic life support (BLS) providers should prioritize standard resuscitative measures over naloxone administration; however, administration of naloxone is not excluded and might be reasonable. The guidelines make no formal recommendations for ACLS providers regarding the use of naloxone in confirmed opioid-associated cardiac arrest.21
If an unconscious patient has a pulse and if there is high suspicion for opioid-induced respiratory depression (OIRD), then the prehospital care providers should direct their effort toward airway management and naloxone administration. Specifically, the provider should perform chin-lift and jaw-thrust maneuvers to open the airway and then provide oxygenation and ventilation assistance with a bag valve mask, with the plan of intubation if the respiratory depression does not improve. Oropharyngeal and nasopharyngeal airways may be placed to maintain airway patency.
Providers also can use carbon dioxide (CO2) monitoring (capnography) to assess a patient’s respiratory status and his or her response to any treatments given. When available, capnography should be initiated in the prehospital setting. Waveform capnography detects spontaneous respirations and the level of end-tidal CO2 (ETCO2), which is a reliable indicator of the patient’s ventilatory status. If ETCO2 worsens or fails to improve, then definitive airway management with endotracheal intubation should be considered.22
Opioid Receptor Antagonists
Naloxone, naltrexone, and nalmefene are morphine derivatives that function as pure opioid receptor antagonists. These agents have high affinity for the μ-opioid receptor, resulting in the displacement of opioids and allowing the reversal of OIRD, the most immediate threat to patients with an opioid overdose.
Naloxone was synthesized first in 1961. Its usefulness as an antidote for opioid overdoses was soon realized, and the U.S. Food and Drug Administration (FDA) approved it for this purpose in 1971.23 Naloxone currently is the preferred medication for OIRD. In 2010 and 2011, naloxone was administered in approximately 430,000 ED visits in the United States, more than double the 207,000 cases seen in 2002 and 2003.24
Because of its excellent absorption, naloxone can be administered by multiple routes: intravenous, intramuscular, subcutaneous, intranasal, and inhalational via nebulization. Oral administration conveys minimal bioavailability as a result of extensive first-pass hepatic metabolism.25 Administration of naloxone through intraosseous access devices has been described, but data are lacking regarding the pharmacokinetic and clinical effectiveness of this approach.26
Naloxone’s onset of action is determined by multiple factors, including the route of administration as well as the type of opioid it is displacing from the μ-opioid receptors. The affinity of an opioid for the μ-opioid receptor is determined by the equilibrium dissociation constant (KD). The lower the KD value, the higher the affinity for the receptor. Commonly encountered opioids with low KD values and thus high receptor affinity are hydromorphone and buprenorphine.
Regardless of the type of opioid ingested or route of naloxone administration chosen, prompt administration of naloxone is critical. A study of fatal heroin overdoses in Sydney, Australia, concluded that 43% of deaths occurred within the first 20 to 30 minutes of drug exposure.27
Intravenous formulations of naloxone are widely available but require the placement of an intravenous catheter, which may pose a significant challenge in intravenous drug users, a population at great risk for opioid overdose. In one small study, the median time to peak blood concentration after intravenous administration of naloxone was just four minutes.28 The onset of clinical effect usually is seen within minutes.29
Naloxone also is commonly administered intramuscularly, thus avoiding the requirement that an intravenous catheter be placed. Via this route, the relative bioavailability is 36% that of intravenous administration and the time to peak concentration is 12 minutes.30 The clinical effect usually is seen within a few minutes. In contrast to the time and supplies needed to establish intravenous access, the convenience and readiness of intramuscular administration offset the reduced bioavailability and delayed absorption.
The bioavailability of intranasal naloxone is only 4% that of the intravenous route.30 The package insert for the recently approved NARCAN Nasal Spray cites a dose-normalized relative bioavailability of approximately 40%. This figure is based on a comparison of the intranasal administration of 4 mg and 8 mg vs. intramuscular administration of 0.4 mg.31 Given intranasally, the time to 50% of maximal concentration is eight minutes.28
Few clinical trials have compared the effectiveness of intranasal naloxone to that of other routes of administration. The published studies all have significant methodologic limitations. A systematic review addressing this issue concluded that the use of intranasal naloxone at a concentration of 2 mg/mL is as effective as the intramuscular route of administration.32
One of the prospective studies was a randomized trial published in 2005 by Kelly and colleagues, who demonstrated that patients who received naloxone via the intramuscular route rather than the intranasal route were more likely to have normalization of their respiratory rate within eight minutes (82% vs. 63% ; P = 0.0173). This trial used a dilute form of naloxone (2 mg/5 mL), which likely affected the clinical response in the intranasal group.33
A more recent randomized clinical trial that compared administration of 2 mg of naloxone given intranasally using a concentration of 2 mg/mL with intramuscular administration found equal efficacy, with no significant difference between the percentage of patients responding to the medication within 10 minutes (72.3% vs. 77.5%) and no difference in the mean response time (8.0 vs. 7.9 minutes). Four times as many patients in the intranasal group required additional doses of naloxone when compared to the intramuscular group (18.1% vs. 4.5%).34
A delay in clinical response to intranasal administration compared with intravenous administration was found in a retrospective case series conducted in the prehospital setting (12.9 vs. 8.1 minutes; P = 0.02). However, no difference was found in the time to clinical response based on the time the patient was first encountered (20.3 vs. 20.7 minutes; P = 0.9). The additional time required to establish intravenous access accounted for this finding.35
The intranasal route may be preferable for prehospital care providers for two reasons: faster time to administration and avoidance of the risk of needlestick injury. Paramedics have been shown to have a high risk of exposure to blood and bodily fluids. The results of a survey published in 2009 estimated that the 12-month rate of non-intact skin exposure to blood and bodily fluids was 8.7%.36 People who inject drugs have a high rate of hepatitis C and HIV seropositivity.37,38 Concern about exposure to bloodborne pathogens might decrease the likelihood that a first responder will administer naloxone via routes requiring the use of a needle.
Use of the subcutaneous route for naloxone administration also benefits from the lack of need for intravenous access. Wagner and colleagues performed a prehospital study comparing subcutaneous and intravenous administration of naloxone (0.8 mg and 0.4 mg, respectively). The two groups had similar mean intervals to improvement of respiratory rate (9.6 vs. 9.3 minutes). The investigators concluded that the delay in subcutaneous absorption was offset by the time it took to establish intravenous access.39
In a relatively stable patient, the use of nebulized naloxone (2 mg in 3 mL of normal saline) may be considered. Its use can be initiated while intravenous access is obtained. Nebulization provides a steady, low-concentration dose of naloxone. A proposed benefit is that the patient will remove the mask when an effective dose has been delivered and likely prior to development of severe withdrawal symptoms. An early case report involving this method demonstrated improvement within five minutes after initiation of treatment. However, that patient went on to develop rebound respiratory depression and was given additional doses of naloxone intravenously. The patient subsequently developed pulmonary edema and required intubation.40
In an observational study, nebulized naloxone was used in 26 patients seen in a busy urban ED. It improved level of consciousness (the median Glasgow Coma Scale score increased from 11 prior to naloxone to 13 after administration) and reduced the requirement for supplemental oxygen (81% to 50%). Repeat administration of naloxone was required in 42.3% of the patients.41
The majority of adverse effects associated with the use of naloxone are related to the development of antagonist-precipitated withdrawal. There are no significant side effects associated with naloxone administration to an opioid-naïve person. While it is possible to precipitate opioid withdrawal, the predominant symptoms are not life-threatening and largely are limited to nausea, vomiting, diarrhea, rhinorrhea, and myalgia. Serious complications are rare, but there are case reports of rapidly induced withdrawal being complicated by rhabdomyolysis with acute kidney injury and esophageal perforation,42 Takotsubo cardiomyopathy,43 ventricular fibrillation,44 and even death.45
Pulmonary edema has been associated with naloxone administration, often in the perioperative setting; however, causation has not been established. The surge in catecholamines that results from opioid reversal has been proposed as the mechanism for the development of pulmonary edema. There is no high-quality evidence to suggest that naloxone precipitates seizures, and such events are more likely related to other aspects of a patient’s presentation.46
A more likely complication is conversion of a patient with pending respiratory arrest to an agitated patient when naloxone reversal precipitates acute opioid withdrawal. This is of significant concern for prehospital care providers who deliver patient care in a small, enclosed space.47 In a retrospective review, Belz and colleagues found that 15% of patients who received naloxone for suspected opioid overdose became agitated and combative.48
Despite its favorable side-effect profile, naloxone should not be administered automatically to many patients with opioid intoxication. If a patient with stable vital signs can be aroused by either verbal or minimal noxious or physical stimuli and the ingestion of opioids can be confirmed, then monitoring alone may be sufficient without the administration of naloxone.
Regardless of the route chosen, the starting dose of naloxone is not standardized. Many sources cite an initial starting dose of 0.4 mg administered intravenously. This recommendation was extrapolated from the dose used by anesthesiologists to reverse sedation in opioid-naïve patients. The intravenous administration of a low dose of naloxone, such as 0.04 mg, often is enough to assess responsiveness and is less likely to precipitate withdrawal in the stable patient.49 Some experts now are recommending the initial use of low-dose naloxone followed by escalating doses given every two to three minutes until an appropriate response is seen.4,50,51 (See Figure 1.)
An absolute maximum dose has not been defined, but if a patient does not respond to doses in excess of 10 mg, the healthcare provider should consider alternative causes of the clinical presentation and evaluate the need for definitive airway management.
In an unstable patient, it is appropriate to start empirically at higher doses (0.4 to 2 mg rapid IV push), as the threat to life and need to assess for responsiveness significantly outweigh the potential complications of acute withdrawal.
Figure 1. Sample Algorithm for Escalating Doses of Naloxone
Rebound toxicity occurs when respiratory or central nervous system depression develops in patients treated successfully for opioid overdose.52 Naloxone’s duration of action depends on several factors but generally is limited to a maximum of 90 minutes, shorter than the duration of most opioids. For patients with rebound toxicity, a continuous intravenous infusion of naloxone may be indicated. A common rule of thumb is to use an hourly infusion dose of two-thirds the total amount used to obtain an initial response.53 For a patient who responded after being given an initial dose of 0.4 mg followed by 2 mg of IV naloxone for treatment of a methadone overdose, an infusion of 1.6 mg/hour would be appropriate.
Infusions should be titrated as needed to maintain the proper level of reversal. The emergency physician should be aware of the potential time delay in initiation of an infusion and, therefore, should be prepared to administer additional bolus dosing in the interim.
High-potency Opioids
In recent years, the number of opioid overdoses related to ingestion of high-potency opioids has increased. Fentanyl is the standard example of a high-potency opioid. It is 50 to 100 times more potent than morphine by weight.54 Starting in 2013, there was a marked increase in the frequency that illicitly manufactured fentanyl (IMF) was associated with opioid overdoses and deaths.55 Because of the lag of legislation governing the import and sale of drugs combined with the innovation of illicit drug manufacturers, analogues of fentanyl such as acetylfentanyl,56 butyrfentanyl,57 and furanylfentanyl58 also have been seen more commonly.
Carfentanil is an opioid used as a sedative in large animal veterinary medicine. Its potency is 5,000 to 10,000 times greater than that of morphine. Unfortunately, it has seen rising popularity as an IMF. It was first detected in Cincinnati and then spread rapidly to other areas in the United States, to Canada,59 and to England.58 The U.S. Drug Enforcement Administration (DEA) estimated that more than 300 overdoses occurred during the initial outbreak of the abuse of carfentanil in August and September 2016.60
Nationwide alerts were issued by the DEA and the Centers for Disease Control (CDC) in 2015, identifying fentanyl, particularly IMFs, as a threat to public safety.61 Table 2 is a partial list of synthetic opioids involved in recent overdoses and their relative strengths compared to morphine.
Because of the increasing frequency with which IMFs are associated with opioid overdoses, it has been proposed that patients should be treated empirically with a higher dose of naloxone. Higher initial requirements for naloxone were reported in association with the presence of fentanyl and IMFs.62 It is reasonable for healthcare providers to consider regional trends in opioid abuse to help guide these decisions.
Prehospital care providers might need to have larger quantities of naloxone readily available to help reverse these overdoses. Once the patient has been brought to the ED, it is important for prehospital personnel to tell the receiving provider about the doses of naloxone that were administered en route so that subsequent doses can be titrated appropriately.
Large doses of anesthetic fentanyl have been associated with iatrogenic chest wall rigidity. Typically seen with doses in excess of 3 to 5 micrograms/kg, this complication significantly impairs ventilation. Although this association has not been delineated clearly, it seems reasonable that chest wall rigidity could be a factor in the rapid deaths of some fentanyl users (as determined by a lack of the fentanyl metabolite norfentanyl).63
With a tightening of the supply of prescription opioids has come an increase in the use of heroin and illicitly manufactured opioids. Products being sold on the streets obviously are not subject to any quality control mechanisms, and the end user usually is unaware that he or she has purchased a drug that contains a high-potency opioid. The presence of IMF was associated with two opioid overdose outbreaks in California: Counterfeit pills containing fentanyl were being sold as “Xanax” and “Norco.”60 Drugs are being sold illicitly through cryptomarkets such as Silk Road, available on the deep (or hidden) web, which are web sites not indexed by standard search engines such as Google. Quintana and colleagues studied the chemical composition of four samples reportedly bought as “heroin” through cryptomarkets found on the deep web. Analysis of the samples revealed that they contained combinations of heroin, ocfentanil, acetaminophen, and caffeine.64
According to the DEA, the current fentanyl crisis is being fueled by chemical manufacturing laboratories, predominantly in China, that are producing high-potency products. The availability of these potent versions of fentanyl and its analogues makes these substances immensely profitable for drug traffickers. First, only a small amount of initial product is needed to produce the street product, so upfront costs are low. A kilogram of fentanyl costs approximately $4,000 from manufacturers in China, similar to the cost of a kilogram of heroin. Because the potency of fentanyl is so much higher than that of heroin, the fentanyl can be diluted with much more filler to produce several million dollars worth of street-ready product. Since the potency of fentanyl is so high, the total amount of pure product that needs to be smuggled into the United States, typically by way of Canada or Mexico, is significantly less. A single kilogram of carfentanil can produce the same amount of street-ready product as 50-100 kilograms of fentanyl. Such small quantities are relatively easy to conceal and transport.65
As recently as March 2017, China enacted laws that ban the sale of carfentanil, but it is reasonable to expect that high-potency opioid formulations will continue to be produced in that country. The United States sustains a large demand for these drugs, and China likely will have an overwhelming number of producers that will continue to manufacture these compounds and have the potential to develop new analogues.
Recently, there has been concern that inadvertent exposure to synthetic opioids may result in serious harm to the provider.66 This concern has been propagated by several stories in the lay media about law enforcement and first responder exposure.67 While data on derivatives like carfentanil are limited, crystalized and powdered versions of fentanyl are known to require pharmacologic delivery mechanisms to allow meaningful absorption through the skin.68
Recent recommendations from the American College of Medical Toxicology and American Academy of Clinical Toxicology propose the use of a single pair of nitrile gloves while caring for an overdose patient. Alcohol-based hand sanitizer may lead to increased transdermal absorption; therefore, instead providers should wash exposed skin with water. The routine use of a mask is not recommended, as clinically significant contact of dust with mucus membranes is unlikely. Any dust on a provider’s clothing should be removed with a wet wipe and gloved hand.69
Table 2. Potencies of Select Synthetic Opioids65
Opioid Agent |
Relative Potency to Morphine |
|
Carfentanil |
5,000 to 10,000 |
|
Fentanyl |
50 to 100 |
|
Acetylfentanyl |
16 |
|
U-47700 |
7.5 |
|
Butyrfentanyl |
7 |
|
Valerylfentanyl |
Suspected < 7 |
|
AH-7921 |
1.7 |
Special Considerations
Long-acting Opioids
Another high-risk opioid overdose scenario involves patients who have ingested long-acting agents. Prior to the proliferation of novel synthetic opioids and IMF, methadone, a long-acting opioid, accounted for a disproportionate one-third of overdose deaths, despite only representing 3% of opioid prescriptions nationwide.70 In the past two decades, additional long-acting agents have come onto the market.
Opioids that otherwise would be short-acting can be made long-acting with the use of transdermal delivery devices, such as the fentanyl patch. Fentanyl is an ideal medication for transdermal delivery because of its small size and high lipophilicity. Abuse of fentanyl patches through various methods of ingestion has been documented: They have been boiled and then the liquid has been drunk,71 smoked, chewed,72 and administered rectally.73 Used and discarded transdermal patches can contain 28% to 84% of the original drug.74 Fentanyl patches can be a source of accidental overdose, especially in the elderly and as a result of well-intentioned placement on children.
Regardless of the intent, in the event of an overdose, it is imperative for the patches to be removed and the skin to be cleaned thoroughly. If the skin is not cleaned at the point of contact, the subcutaneous tissue will continue to absorb residual amounts of drug from the skin. In cases of opioid overdose from transdermal administration, it can take up to 17 hours for blood concentrations to decrease by 50%.75
Loperamide is an over-the-counter medication used to treat the symptoms of diarrhea. It functions by binding the µ-opioid receptors in the intestines and thus reducing gut motility. As a result of poor oral bioavailability and limited crossing of the blood-brain barrier, it typically is not associated with central effects, but with high doses, these effects can be seen.76 Loperamide abuse at doses of 200 to 400 mg per day is being reported with increasing frequency.77 High-dose loperamide sometimes is abused in an effort to ameliorate the symptoms of opioid withdrawal and as a primary recreational drug. It has been described as the “poor man’s methadone.”78
In 2016, the FDA released a safety warning that high doses of loperamide are associated with cardiotoxicity79 manifested as arrhythmias and sudden cardiac death as a result of QRS complex widening and QTc prolongation.80 The precise mechanism of this cardiac conduction disturbance is not known. Widening of the QRS complex may be the result of cardiac sodium channel blockade. QTc prolongation could be caused by inhibition of the rapid delayed rectifier current channels (IKR) that conduct potassium out of myocytes.77
A potentially dangerous presentation of opioid overdose can be precipitated by a pill bezoar. A bezoar is a concretion of foreign material that develops anywhere in the gastrointestinal tract. A pharmacobezoar is a bezoar that is composed specifically of medicine. Pharmacobezoars can cause mechanical obstruction and present a unique danger to the patient because they are associated with inconsistent levels of drug absorption. Case reports have demonstrated unpredictable rates of absorption from pharmacobezoars. Although most ingested drugs are absorbed at a consistent rate, the patient with a pharmacobezoar may experience sudden increases in absorption.81
A pharmacobezoar composed of opioids does not appear to be a great risk, but the use of opioids may be a risk factor for the development of other forms of pharmacobezoars, owing to impaired gastrointestinal motility.82
Tramadol
Tramadol has been called an atypical opioid because it acts on opioid receptors but also as a serotonin-norepinephrine reuptake inhibitor (SNRI). Tramadol is a pro-drug that is converted in the liver by specific cytochrome p450 (CYP) enzymes to its primary metabolite, O-desmethyltramadol (destramadol), in the same manner that codeine is demethylated to morphine. The active metabolite has a much higher affinity for the µ-opioid receptor than the parent compound. There are racial differences in the expression of different polymorphisms of the CYP genes responsible for this conversion; poor metabolizers are found more frequently in the African-American population.
Serotonin syndrome has been reported when tramadol is combined with medications such as serotonin reuptake inhibitors, SNRIs, tricyclic antidepressants, triptans, antipsychotics, and dextromethorphan-containing medications. This combination produces autonomic symptoms not typical of a purely opioid overdose, i.e., tachycardia, diaphoresis, and mydriasis.83
Tramadol has been shown to lower seizure thresholds. A retrospective analysis of more than 500 isolated tramadol poisonings in Iran found that 46.1% of patients had tonic-clonic seizures. Apnea occurred in 3.6% of these cases. The authors noted that people of Middle Eastern descent are likely to be ultrarapid metabolizers of tramadol.84 It is unclear if naloxone given for a tramadol overdose will reduce the rate or frequency of seizures.85
Buprenorphine
Buprenorphine is a partial μ-opioid receptor agonist that is available alone or in combination with naloxone. It has good analgesic properties, but its use is primarily as an agent for medication-assisted treatment (MAT) programs for opioid addiction. The effects of buprenorphine last between 24 and 36 hours and function to reduce cravings.
Because buprenorphine is only a partial agonist, it has a “ceiling effect,” such that there is a plateau in many clinical parameters such as respiratory depression. The risk of overdose with buprenorphine is significantly lower than the risk associated with methadone.86 The risk of overdose is increased in patients taking buprenorphine and benzodiazepines as coingestants.87
Buprenorphine has a high affinity for the μ-opioid receptors, which limits the ability of naloxone to displace it from them. Higher doses of naloxone likely are required in the treatment of respiratory depression caused by buprenorphine overdose.88
Mixed Overdose
Adding to the diagnostic challenge for the emergency physician is the frequent ingestion of multiple intoxicants. Multiple substances are detected in many patients who die from overdose. The diagnostic fundamentals remain the same — address airway, breathing, and circulation. While some coingestants can dampen respiratory drive, a few stimulate it. It is reasonable to try naloxone in any patient with respiratory depression despite a lack of additional classic findings for opioid intoxication.
Laboratory testing is not indicated frequently in opioid overdose, but obtaining an acetaminophen level might be beneficial if the abuse of combined medications, such as acetaminophen/hydrocodone or acetaminophen/oxycodone, is suspected.
Disposition
Several variables affect how long a patient should be observed after receiving naloxone. A principle factor is its duration of action. Naloxone generally does not have clinical effects beyond 90 minutes. An opioid overdose patient who responds promptly to naloxone without any evidence of complications (pulmonary edema, aspiration pneumonia, recurrent somnolence) may be discharged reasonably after observation extending beyond the period of clinical effectiveness of naloxone. Prior to discharge, the patient should have stable vital signs, show return of normal mental status, and be capable of walking unassisted.
The duration of action of the opioid is of little importance unless continued absorption is a concern. Extended-release prescription medications, such as oxycodone, do not reach their peak levels until approximately three hours after ingestion.89 Of course, repeat exposure through continued opioid abuse remains a concern. No duration of observation can eliminate that risk.
Clinical assessment one hour after administration of naloxone is a good, but not perfect, predictor of subsequent complications. Etherington and colleagues studied the ability of healthcare providers to make an assessment of opioid overdose patients one hour after administration of naloxone.90 The healthcare providers were asked to assess the information at hand and decide if the patients were safe for discharge or required further observation and treatment. Of the 587 patients assessed, 282 were placed in the “discharge now” category, and six of them had an adverse event within the next 24 hours. All six required supplemental oxygen, and two required repeat naloxone administration.90
Patients with obvious complications, such as recurrent or persistent OIRD, hypoxia, pulmonary edema, or altered mental status, require further observation and treatment in the hospital. Hospitalization also may be necessary if the patient has other complications from the opioid overdose, such as soft tissue injury.89
With the changing landscape of the opioid epidemic, including more instances of fentanyl and fentanyl derivatives, it has been argued that the observation requirement needs to be changed. Recent proposals have suggested that patients receiving naloxone require prolonged periods of observation, in excess of four hours, because of the potency of these opioids.4 Whether injected or inhaled, fentanyl has a rapid onset of action because of its rapid rate of absorption and high bioavailability through the nasal mucosa.91 Studied in the setting of breakthrough cancer pain, intranasal fentanyl had a relatively rapid onset of approximately seven minutes and a total duration of just two hours.92 It also has a relatively rapid half-life, approximately 6.5 minutes.91 Except under circumstances of delayed or continued absorption, if the patient is stable when the naloxone has worn off, then there should be no concern for rebound OIRD.
Perhaps more relevant to the question of how long a patient should be observed is the route of naloxone administration. The pharmacokinetics of intravenous naloxone support a relatively brief observation period of 60 to 90 minutes. Naloxone that is administered intranasally might not reach peak concentrations until approximately 15 to 30 minutes after administration. This timeframe may result in a slightly longer period of observation before the care provider safely can ensure that the patient is unlikely to experience clinically significant recurrent symptoms.28
Refusal of Transport and Leaving Against Medical Advice
After treatment by prehospital personnel of an opioid overdose with naloxone, it is not uncommon for the patient to recover full consciousness and refuse transport to the hospital. Providers need to balance respecting the autonomy of the individual and ensuring that the patient is safe from harm.
A recent systematic review93 identified four unique studies that assessed the outcomes of patients who refused transport.94,95,96,97 The data set consisted of 3,875 cases of refusal, with only three patient deaths attributed to rebound toxicity. Because these studies are observational, the strength of evidence is moderate at best. Based on the data at hand, it appears that allowing the patient to refuse transport likely will result in no increased risk of death as a result of rebound toxicity.
Refusal of transport represents a lost opportunity to provide education and offer entrance into treatment programs. People with substance use disorders constitute a population at risk for all-cause mortality. The Wampler study demonstrated a 2% mortality rate at 30 days.96 Patients who refuse transport should be assessed for stability and decisional capacity. They should be counseled on the immediate risks of harm as well as the short-term risk of death.
Similarly, reversal with naloxone is associated with a high rate of patients leaving the ED prior to completion of their evaluation and treatment. If the provider still has concerns about harmful effects of the opioids due to the relatively short duration of action of naloxone, then the patient should be considered to be leaving against medical advice.
As with any patient wishing to leave against medical advice, the provider must assess the patient’s capacity to make medical decisions. The discussion should include all the possible risks of repeat overdose, including death. The provider should verify that the patient has a full understanding of these risks. The autonomy of any fully informed patient deemed to have capacity should be respected, even if there is inherent danger to that patient as a result of the decision made. All appropriate paperwork documenting the process of the patient leaving against medical advice should be completed.
Harm Reduction Strategies
Successful long-term treatment of opioid use disorder is most successful with psychosocial support as well as pharmacotherapy. The time immediately after treatment for an opioid overdose might be when the person is most receptive to long-term treatment. Emergency care providers are in a unique position to assess patients’ readiness for treatment and to counsel them about available resources.
However, many patients might not be ready for this step. The stages-of-change model for addiction recovery recognizes that, for many people, lasting exit from addiction requires a transition through a series of stages, including precontemplation, contemplation, preparation, action, and maintenance.98
For patients who are not ready to enter treatment, the goal should be to reduce the potential for harm as they continue to use drugs. A number of evidence-based practical strategies can be implemented in the ED. A key is non-judgment on the part of the provider so that compassionate care can be provided while maintaining dignity and respect. The harm-reduction strategy does not condone drug use but accepts the reality that it occurs. The primary aims of harm reduction are to prevent the spread of infection and reduce the risk of fatal overdose.
Recognizing that drug use is likely to continue in patients with opioid use disorder, healthcare providers can provide counseling that focuses on some basic steps that the patient can take to reduce the risk of harm. Examples of safer injection strategies include practicing good hygiene, using clean needles (e.g., via a needle exchange program), never using alone, never injecting into an artery, and always having naloxone available.
Take-home Naloxone
Treatment in the ED presents an opportunity beyond immediate life-saving efforts to reduce the effects of opioid overdose. All patients who are treated for overdose or are at high risk of opioid overdose should receive naloxone.
Take-home naloxone programs have been in place since at least 1991.99 The goal of these programs is to distribute naloxone to people likely to witness an opioid overdose so that the drug can be administered as soon as possible. In response to the current epidemic, many state legislatures have enacted laws aimed at increasing access to naloxone as well as protecting the person who administers it. Good Samaritan laws are designed to protect laypeople from civil and criminal penalties associated with the administration of naloxone when done in a prudent manner. Fear of criminal prosecution was cited by 52% of surveyed active drug users in New York City as a reason for not seeking help in the event of witnessing an overdose.100
Currently, take-home naloxone programs do not use a standard formulation of naloxone. The options include kits for intramuscular injection or intranasal delivery. (See Table 3.) Improvised intranasal naloxone kits typically include a vial of naloxone, a syringe, and a mucosal atomization device. In 2014, the FDA approved a handheld naloxone autoinjector that uses voice-prompting technology to instruct the user on the proper technique for administration. In 2015, the FDA approved a self-contained unit for the administration of intranasal naloxone.
Table 3. Take-home Naloxone Formulations
Formulation |
Brand |
Dosage |
Notes |
|
Injectable |
Generic |
0.4 mg and 1 mg in 1 mL |
Requires assembly of multiple parts at time of use; requires use of a needle. |
|
Auto-injector |
EVZIO® |
0.4 mg and 2 mg in 0.4 mL |
FDA approved; audio guidance; easy to use; protected needle; prohibitive cost |
|
Intranasal spray |
NARCAN® Nasal Spray |
2 mg and 4 mg in 0.1 mL |
FDA approved; easy to use; does not require assembly; moderate pricing |
|
Improvised intranasal device |
Generic |
Typically uses 2 mg in 2 mL injectable solution |
Not FDA approved; requires assembly of multiple parts at time of use; does not require a needle; inexpensive |
Significant cost and usability factors must be considered when choosing a formulation of naloxone to dispense as part of a take-home naloxone program. The cost of naloxone has risen dramatically in recent years. The price of a 2 mg vial of naloxone (1 mg/mL) that can be used for intravenous or intranasal administration increased from $20.34 in 2009 to $39.60 in 2016.101 Alarmingly, in 2016 the list cost of the autoinjector increased from $690 to $4,500 for a pack of two with a trainer device.
In terms of usefulness, take-home naloxone programs will not be successful if the person attempting to administer the medication is unable to do so because of complex assembly or administration requirements. In a study of volunteers likely to encounter a person with an opioid overdose, only 12.5% could assemble and deliver a dose of naloxone using an improvised intranasal delivery system in a simulated scenario. The importance of education was underscored by the fact that the rate of success increased to 83.3% after training.102
Screening, Brief Intervention, and Referral to Treatment
Screening, brief intervention, and referral to treatment (SBIRT) protocols implemented by trained providers have been shown to be an effective tool for unhealthy alcohol consumption. They now are endorsed by multiple governmental agencies and specialty societies. The success of SBIRT in the setting of aberrant alcohol use has led to its implementation in substance use disorders. The data are somewhat more mixed regarding the effectiveness of these protocols in preventing and reducing disease and injury associated with substance abuse.103,104,105
The final component of the SBIRT process entails a referral to treatment. Treatment programs vary in duration and intensity. They often use medication-assisted treatment (MAT) as well as counseling and behavioral therapies. The lag in SBIRT intervention and getting the patient into treatment results in numerous dropouts.
Some centers are using a more proactive approach involving initiation of treatment with subsequent referrals. This approach has been called screening, treatment initiation, and referral (STIR). In this approach, MAT is initiated at the initial encounter. The recent D’Onofrio study compared engagement in treatment among three groups: referral only, traditional SBIRT, and the STIR approach. At 30 days, the levels of active engagement were 37%, 45%, and 78%, respectively.106
Three medications have been approved by the FDA for the treatment of opioid use disorder: methadone, buprenorphine, and naltrexone. The characteristics of each drug are described in Table 4. Currently, only buprenorphine-containing products have utility for ED initiation.
Table 4. Drugs Used for Medication-assisted Treatment of Opioid Addiction
Characteristics |
Buprenorphine |
Methadone |
Naltrexone |
|
Common commercial names |
Subutex, Suboxone (formulations that include naloxone) |
Dolophine, Methadose |
Depade, ReVia, Vivitrol |
|
Mechanism of action |
Partial agonist at the μ-opioid receptor |
Full opioid agonist |
Antagonist of the opioid receptors |
|
Special characteristics |
High affinity but low intrinsic activity; hence, very effective in displacing opioid agonists Results in lower abuse potential, with less withdrawal discomfort Minimal respiratory depression |
Highly efficacious for patients who do not respond to other treatments, as long as patients adhere to regimen Adverse effects: sedation, overdose, potential for abuse |
Decrease craving for opioids, effective for some patients; however, poor compliance due to its side effects, which are analogous to opioid withdrawal symptoms |
|
Who can prescribe? |
Any care provider who has completed training and obtained a Drug Enforcement Administration “X” waiver |
Therapy typically initiated in outpatient treatment programs in which patients need to obtain medication daily |
Licensed physicians |
Several studies have demonstrated that MAT is an effective method in helping patients with recovery and reducing the risk of fatal overdose. A heroin abuse study from Baltimore demonstrated that patients who received MAT had a 50% decrease in the number of fatal overdoses.107 Another study demonstrated that high-risk behavior patients who stay in methadone/buprenorphine programs for at least five years have a reduction in their 25-year mortality rate from 25% to 6%.108
Although there are good data supporting the efficacy of MAT, it is underutilized for various reasons. In 2012, the National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA) showed that fewer than 1 million of the estimated 2.5 million Americans who abuse opioids received MAT.109 A factor that contributes to this underutilization is the lack of trained providers as well as lack of coordination of care. With the passage of the Drug Addiction Treatment Act of 2000 (DATA 2000), more providers now are eligible to prescribe and dispense buprenorphine for the treatment of opioid addiction. Under this act, providers who have completed eight hours of required training may apply for a waiver through SAMHSA.102
There also is an exception to the DATA 2000 waiver requirement known as the “three-day rule.” This exception allows providers who have not obtained a DATA 2000 waiver to administer buprenorphine for the purpose of alleviating symptoms of acute opioid withdrawal while setting up outpatient MAT. Under the three-day rule, the providers can administer medication only one day at a time, and the treatment period may not exceed 72 hours. The patient is required to return on subsequent days to receive additional doses of buprenorphine-containing medication.
Of the three medications approved for MAT, only buprenorphine, with or without naloxone, is well suited for initiation of therapy in the ED. Because of the possibility of inducing withdrawal symptoms in patients taking buprenorphine, generally, it is reserved for those in whom signs and symptoms of withdrawal already have developed. Only a subset of patients qualifies for buprenorphine initiation in the ED based on withdrawal symptoms.
In addition to the initiation of medication, emergency care providers need to ensure that the patients have appropriate outpatient follow-up. EDs that are participating in MAT should establish clear practice guidelines as well as strengthen their relationship with community MAT sites to optimize addiction treatment.
Conclusion
The impact of the opioid epidemic continues to be felt across the United States. Opioid addiction crosses all socioeconomic, gender, ethnic, and geographic boundaries. Emergency physicians play a role in helping to curb the growth of this epidemic through safe prescribing practices in the management of acute pain. Additionally, they must be knowledgeable in the management of opioid-induced respiratory depression with the use of naloxone as well as techniques in airway management.
A visit to the ED presents an opportunity for the emergency physician to engage the patient in harm reduction strategies and potentially to initiate long-term MAT. Strategies that have been shown to be effective at reducing complications of opioid use include programs for take-home naloxone and needle exchange. Emergency physicians are on the front line in this battle and will continue to play a leading role, in collaboration with other specialists, to stem the tide of the opioid epidemic.
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This article aims to provide acute care providers with advanced techniques in the management of opioid overdoses, including the use of naloxone, the opioid receptor antagonist, as well as harm reduction management strategies aimed at long-term risk mitigation in this vulnerable population.
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