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1232 SECTION 15: Toxicology level. Some rebound in toxic alcohol levels may occur after hemodialy sis is stopped, so metabolic blockade therapy should be continued for several hours after cessation of dialysis, with blood level rechecked to ensure that the toxic alcohol level remains low. 59,87 Vitamin Therapy Adjunctive treatment with B vitamins (including folate) is recommended to help clear the toxic metabolites of methanol and ethylene glycol more quickly, although no solid evidence exists to indicate that this treatment is necessary or even helpful. In methanol poisoning, high doses of folate or folinic acid may facilitate breakdown of formic acid into carbon dioxide and water (Figure 185-5). Experimental animals with very large folate stores do not develop acidosis and toxicity from methanol poisoning unless they are artificially depleted of folate. Theoretically, increasing folate stores should hasten the detoxification of formate and prevent it from accumulating and causing end-organ damage. Folinic acid, the activated form of folic acid, is preferred, but folic acid may be used if the former is not available. Recommended dosing is 1 milligram/kg (up to 50 milligrams) IV every 4 to 6 hours. In ethylene glycol poisoning, adjunctive therapy with pyridoxine, thiamine, and magnesium may be used to facilitate metabolism of glyoxylate to nontoxic glycine and α-hydroxy-β-ketoadipoic acid (Figure 185-6). Magnesium can be given as a one-time dose of magnesium sulfate 2 grams IV . The two B vitamins are given in large doses: thiamine 100 milligrams IV and pyridoxine 50 to 100 milligrams IV , both every 6 hours for 2 days. Visual impairment can be a permanent complication of methanol poisoning.109,110 Although treatment with fomepizole or ethanol and bicarbonate can prevent ocular toxicity, there is no other proven therapy to restore established visual damage. DISPOSITION AND FOLLOW-UP Because of the complex management decisions required with methanol or ethylene glycol poisoning, consultation with a medical toxicologist or a regional poison control center is strongly recommended. Symptoms of methanol or ethylene glycol intoxication may be delayed, particularly if ethanol has been co-ingested. A patient with suspected ethylene glycol ingestion should be observed and monitored for 6 hours. If no ethanol is present, the patient remains completely asymptomatic, there is no osmolar gap, and no metabolic acidosis develops, the patient can be discharged. Methanol toxicity may be delayed longer, so a patient with suspected methanol ingestion should be observed for 12 hours using the same criteria. Patients with significant signs and symptoms should be admitted to an intensive care setting. Patients seen at facilities unable to provide hemodialysis or intensive care should be transferred as soon as possible, if in sufficiently stable condition, to institutions capable of providing such care. Suicidal patients should receive a psychiatric evaluation when their condition improves and prior to discharge. REFERENCES The complete reference list is available online at www.TintinalliEM.com.

uld be transferred as soon as possible, if in sufficiently stable condition, to institutions capable of providing such care. Suicidal patients should receive a psychiatric evaluation when their condition improves and prior to discharge. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 185-7 Indications for Hemodialysis After Methanol or Ethylene Glycol Ingestion •   Refractory metabolic acidosis: pH <7.25 with anion gap >30 mEq/L and/or base deficit <–15 •   Visual abnormalities* •   Renal insufficiency •   Deteriorating vital signs despite aggressive supportive care •   Electrolyte abnormalities refractory to conventional therapy •   Serum methanol or ethylene glycol level of >50 milligrams/dL† *Applies only to methanol; visual abnormalities may not resolve immediately, so their persistence in the absence of other indications once hemodialysis is started is not an indication for continued hemodialysis. †Although previously considered an indication for hemodialysis, there are reports of patients with levels of ≥50 milligrams/dL (methanol ≥15 mmol/L or ethylene glycol ≥7.5 mmol/L) being successfully treated with fomepizole with or without bicarbonate and no hemodialysis. Opioids Jennifer S. Love Jeanmarie Perrone  INTRODUCTION Opioids refers broadly to all compounds related to opium that possess analgesic and sedative properties. Opiate describes the alkaloids codeine and morphine found naturally in the opium poppy plant, Papaver somniferum. Narcotic refers to a broader group of soporific drugs, a term predominantly used by law enforcement to refer to con trolled substances with abuse or addictive potential; use of this term in medical practice is discouraged. Opioid abuse is a significant public health issue in the United States with a dramatic increase in ED visits related to opioids in the past 20 years. 1,2 Opioids were responsible for 66% of drug overdose deaths in the United States during 2016. 3 The majority of prescription opioid overdose deaths were associated with diversion, doctor shopping, and nonmedical use. PHARMACOLOGY Opioids modulate nociception at the terminals of afferent nerves in the CNS, peripheral nervous system, and GI tract. Opioids are agonists at the three primary opioid receptors: µ (mu), κ (kappa), and δ (delta). Opioid receptors are similar to other G protein-coupled receptors; transmembrane proteins that undergo conformation change when activated by external molecules that then alters some aspect of intracellular func tion. Opioid receptors vary widely in morphology and distribution. In addition, the specificity and affinity of an opioid for a particular receptor are variable. For example, tramadol possesses 1/6000th the affinity of morphine at the µ-receptor site. Stimulation of the µ-receptors results in analgesia, sedation, miosis, respiratory depression, cough suppression, euphoria, and decreased GI motility. Stimulation of κ-receptors results in weaker analgesia, seda tion, miosis, decreased intestinal motility, dysphoria, and hallucinations. Stimulation of the δ-receptors results in some analgesia and antidepressant effect. All currently available opioid agonists possess µ-receptor activity and result in some degree of respiratory depression. Opioids can be categorized as naturally occurring compounds (termed opiates), chemical modifications of natural compounds (semisynthetic), and the synthetic derivatives ( Table 186-1). Some opioids are agonists at all opioid receptors (e.g., morphine and hydromorphone), whereas others are partial agonists–antagonists (e.g., pentazocine, butorphanol, nalbuphine, and buprenorphine) at the opioid receptors.

modifications of natural compounds (semisynthetic), and the synthetic derivatives ( Table 186-1). Some opioids are agonists at all opioid receptors (e.g., morphine and hydromorphone), whereas others are partial agonists–antagonists (e.g., pentazocine, butorphanol, nalbuphine, and buprenorphine) at the opioid receptors. PHARMACOKINETICS Opioids are readily absorbed, achieving peak blood levels 30 to 60 minutes after ingestion of standard oral formulations. But other pharmacokinetic elements can vary depending on whether the opioid is a short-acting, long-acting, or sustained-release formulation. Longacting opioids, such as methadone, reach peak blood levels in 30 to 60 minutes, but have a long duration of effect and half-life. Sustainedrelease forms take longer to achieve peak blood levels; for example, morphine sulfate controlled-release tablets reach peak blood levels at 90 minutes compared with 30 minutes for standard morphine tablets. As the name implies, sustained-release forms also have a long duration of effect compared to the immediate-release formulations. After GI absorption, most opioids undergo first-pass hepatic metabolism, so bioavailability can vary from as low as 10% to as high as 80% after PO administration. Thus, at equal doses, most opioids are more potent given parenterally than PO. The opioids with good oral bio availability are codeine, oxycodone, methadone, hydromorphone, and tapentadol. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1232 8/2/19 8:39 PM CHAPTER 186: Opioids 1233 TABLE 186-1 Classification and Characteristics of Major Pharmaceutical Opioids

PHARMACOKINETICS Opioids are readily absorbed, achieving peak blood levels 30 to 60 minutes after ingestion of standard oral formulations. But other pharmacokinetic elements can vary depending on whether the opioid is a short-acting, long-acting, or sustained-release formulation. Longacting opioids, such as methadone, reach peak blood levels in 30 to 60 minutes, but have a long duration of effect and half-life. Sustainedrelease forms take longer to achieve peak blood levels; for example, morphine sulfate controlled-release tablets reach peak blood levels at 90 minutes compared with 30 minutes for standard morphine tablets. As the name implies, sustained-release forms also have a long duration of effect compared to the immediate-release formulations. After GI absorption, most opioids undergo first-pass hepatic metabolism, so bioavailability can vary from as low as 10% to as high as 80% after PO administration. Thus, at equal doses, most opioids are more potent given parenterally than PO. The opioids with good oral bio availability are codeine, oxycodone, methadone, hydromorphone, and tapentadol. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1232 8/2/19 8:39 PM CHAPTER 186: Opioids 1233 TABLE 186-1 Classification and Characteristics of Major Pharmaceutical Opioids Oral Dose Equianalgesic to Morphine 10 milligrams SC (milligrams) Parenteral Dose Equianalgesic to Morphine 10 milligrams SC (milligrams) Duration of Analgesic Action* (h) Elimination Half-Life* (h) Opiate Codeine 200 120 4–6 2.5–4 Morphine 30 10 3–4 2–4 Semisynthetic Buprenorphine 4 SL 0.3 6–24 20–44 Hydrocodone 30 Not available 4–6 8 Hydromorphone 7.5 1.5 2–4 2–3 Oxycodone 20 Not available 3–6 3–4 Oxymorphone 6 1.5 4–6 7–11 Synthetic Diphenoxylate 2.5 Not available Not applicable 2 h for diphenoxylate and 12–14 h for difenoxin † Fentanyl 0.125 0.100 1 3–4 Meperidine 300 100 1–3 3–4 h for meperidine and 15–30 h for normeperidine † Methadone 20 10 8–12 12–18 Tapentadol 75 Not available 4–6 4–5 Tramadol 100 100 4–6 5–7 Abbreviation: SL = sublingual. *Initial doses in therapeutic amounts. †Active metabolite. The metabolism of codeine, meperidine, methadone, morphine, and oxycodone is primarily hepatic and subject to drug interactions and genetic variations. For example, antiretroviral medications can enhance the metabolism of methadone, which results in lower plasma methadone concentrations. As another example, codeine is metabolized to mor phine via cytochrome P450 isoenzyme 2D6, an enzyme with genotypic and phenotypic variability. Patients with rapid cytochrome P450 enzyme 2D6 metabolism produce more morphine after a fixed dose of codeine. These interactions and genetic variations may influence the therapeutic effect of opioids (see Chapter 35, “ Acute Pain Management”). In drug misuse, unconventional routes of administration (insufflating or injecting ground opioid tablets, heating fentanyl patches or applying multiple patches to the skin) may alter the drug’s pharmacokinetics and often increase the rate of opioid absorption. Similarly, in opioid over doses resulting in high plasma levels, the pharmacokinetics are altered due to enzymatic saturation. This may increase the severity of poison ing, delay the onset, and prolong the duration of action, as compared with the expected therapeutic actions.  OPIOID INTOXICATION CLINICAL FEATURES The brief descriptor of the widely recognized opioid toxidrome would include the triad of miosis, lethargy, and respiratory depres sion. The full effects associated with opioid intoxication also can include orthostatic hypotension, nausea and vomiting (especially in opioid-naive patients), histamine release resulting in localized urticaria (Figure 186-1) bronchospasm, ileus secondary to decreased GI motility, and urinary retention secondary to increased vesical sphincter tone. 4,5 The depression in mental status can be profound. The respiratory depression is characterized by slow and shallow respirations that can produce hypercarbia, hypoxia, and cyanosis. Miosis is not universally present from intoxication with every opioid; normal or even enlarged pupils have been documented secondary to pentazocine and meperidine toxicity. Mydriasis may also signal severe cerebral hypoxia or result from co-ingestants (diphenoxylate, heroin, scopolamine). FIGURE 186-1. Urticaria on a forearm from local histamine release due to IV morphine. [Photo used with permission of J. S. Stapczynski, MD.] Tintinalli_Sec15_p1187-1332.indd 1233 8/2/19 8:39 PM

toxicity. Mydriasis may also signal severe cerebral hypoxia or result from co-ingestants (diphenoxylate, heroin, scopolamine). FIGURE 186-1. Urticaria on a forearm from local histamine release due to IV morphine. [Photo used with permission of J. S. Stapczynski, MD.] Tintinalli_Sec15_p1187-1332.indd 1233 8/2/19 8:39 PM 1234 SECTION 15: Toxicology TABLE 186-2 Medications Causing False-Positive Results on Urine Opioid Screens14 False-Positive Urine Opioid Screen False-Positive Urine Methadone Screen Poppy seeds Rifampin, rifampicin Quinine Diphenhydramine Fluoroquinolones Dextromethorphan Chlorpromazine Clomipramine Diphenhydramine Doxylamine Ibuprofen Quetiapine Thioridazine Verapamil TABLE 186-3 Naloxone Drug Route Initial Dose* Onset of Action Duration of Action † Naloxone

False-Positive Urine Methadone Screen Poppy seeds Rifampin, rifampicin Quinine Diphenhydramine Fluoroquinolones Dextromethorphan Chlorpromazine Clomipramine Diphenhydramine Doxylamine Ibuprofen Quetiapine Thioridazine Verapamil TABLE 186-3 Naloxone Drug Route Initial Dose* Onset of Action Duration of Action † Naloxone IV 0.04 milligrams if breathing spontaneously and suspected of chronic opioid use 0.4 milligrams if breathing spontaneously and opioid naive 2 milligrams if apneic or cyanotic 1–2 min 20–90 min IM or SC 2 milligrams 5–6 min Intranasal 2 milligrams (1 milligram in each nostril) 6–8 min Nebulized 2 milligrams in 3 mL normal saline 5 min *See text regarding subsequent dosing. †Duration dependent on amount of opioid agonist present. Other possible findings in opioid toxicity include hypothermia, rhab domyolysis, compartment syndrome, myoglobinuric renal failure, and seizures associated with overdoses of tramadol and meperidine. Opioid-induced acute lung injury, previously known as noncardiogenic pulmonary edema, is an uncommon complication associated with opioid overdose. 5,6 Acute lung injury can occur immediately or be delayed up to 24 hours after overdose and presents with tachypnea, rales, decreased oxygen saturation, and bilateral pulmonary infiltrates with a normal cardiac silhouette on chest radiograph. 7 The incidence of acute lung injury is 10% in patients with severe overdose requiring naloxone.8 The pathophysiology of opioid-induced acute lung injury is poorly understood and may be multifactorial. Pulmonary edema may result from direct alveolar injury from hypoxia, opioid-induced histamine release, capillary leak due to negative inspiratory pressure, or neurogenic injury. 4,9 Treatment includes oxygen supplementation and ventilatory support, with either noninvasive or invasive modalities. Additional naloxone, diuretics, and digoxin are not indicated. The combination of meperidine, tramadol, or dextromethorphan with monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, or linezolid can result in serotonin syndrome (see Chapter 178, “ Atypical and Serotonergic Antidepressants”). 10 Serotonin syndrome is characterized by a spectrum of altered mentation from anxiety to delirium, hyperthermia, autonomic instability, hyperreflexia, and mus cle rigidity, especially in the lower extremities. Although uncommon, deaths have been reported. Naloxone is not effective in treating opioidinduced serotonin syndrome. 10,11 DIAGNOSIS The triad of lethargy, miosis, and respiratory depression strongly suggests opioid intoxication, and in many clinical scenarios, specific evi dence of opioid use is present. The combination of a respiratory rate of <12 breaths/min, miosis, and circumstantial evidence of opioid use (drug paraphernalia, needle marks, presence of a tourniquet, bystander corroboration) was highly sensitive for opioid overdose in the prehos pital setting. Physical examination should be thorough: patients should be undressed completely yet carefully because drug use paraphernalia including needles and syringes may be hidden within clothing. Look for evidence of injection drug use, concealed opioids, or fentanyl patches on all parts of the body, including mucous cavities. Listen for ausculta tory findings suggestive of pulmonary edema; palpate muscle groups to detect signs of compartment syndrome. The differential diagnosis of opioid intoxication includes toxicologic exposure to drugs and compounds that produce similar findings, such as clonidine, organophosphates and carbamates, phenothiazines and atypical antipsychotic medications, sedative-hypnotic medications, and carbon monoxide.

ns of compartment syndrome. The differential diagnosis of opioid intoxication includes toxicologic exposure to drugs and compounds that produce similar findings, such as clonidine, organophosphates and carbamates, phenothiazines and atypical antipsychotic medications, sedative-hypnotic medications, and carbon monoxide. Clonidine overdoses are characterized by coma, bradycardia, hypotension, miosis, and periods of apnea that respond to tactile or auditory stimulation. Organophosphate and carbamate over doses cause the cholinergic toxidrome: miosis, muscle fasciculations, profuse vomiting and diarrhea, and sweating. Phenothiazines, olan zapine, and risperidone cause neurologic depression and miosis from decreased adrenergic tone. 13 Gamma-hydroxybutyrate intoxication is associated with profound CNS depression, bradypnea, and, occasionally, miosis. Sedative-hypnotic agents and carbon monoxide cause profound neurologic depression but are not usually associated with miosis. Hypoglycemia, hypoxia, CNS infections, postictal states, and pontine and intracranial hemorrhages should also be considered in the differential diagnosis.  OPIOID SCREENS A qualitative urine opioid screen may aid in the diagnosis, but available tests have limitations. The assay in most commercially available urine opioid screens recognizes morphine. 14 Opioids that are metabolized to morphine, such as codeine and heroin, as well as hydromorphone are detected by this urine assay as opiates. Specific immunoassay screens are available for oxycodone, fentanyl, or methadone. 15,16 Confirmation of a positive immunoassay screen requires gas chromatography/mass spectroscopy testing. Some common medications will produce falsepositive results on opioid drug screens (Table 186-2). A urine opioid screen can be positive up to 2 to 4 days after a single use of codeine, morphine, or heroin. The oxycodone, fentanyl, and methadone-specific screens can be positive up to 3 days after ingestion. As with most urine drug screening in the ED, detection of a drug taken in the recent past may not correctly identify the toxicologic cause of the patient’s current condition. Serum acetaminophen concentration should be obtained in all suicidal ingestions and all cases of combination opioid–acetaminophen ingestions. TREATMENT Airway protection and ventilatory assistance are the most important treatment steps for opioid intoxications, because respiratory depression is the major morbidity and the cause of mortality. 4,5 Use bag-valve mask ventilatory support as needed to initially maintain adequate oxygenation and ventilation. After adequate ventilation is ensured, administer naloxone (Table 186-3). Endotracheal intubation may be necessary in some cases of opioid or polysubstance overdose with respiratory depression unresponsive or poorly responsive to naloxone or in cases in which acute lung injury is suspected. 4,5 Intubation offers the advantages of airway protection, easy access for suctioning, and provision of an alternate route of administration for some medications. Single-dose activated charcoal (1 gram/kg PO) may be indicated in some patient populations, such as pediatric oral ingestion, if the patient is fully awake, or after the airway is protected with an endotracheal tube. Under special circumstances, delayed and multiple doses of activated charcoal may be useful, as in diphenoxylate hydrochloride–atropine sulfate overdoses and in cases of large ingestions of sustained-release preparations. Tintinalli_Sec15_p1187-1332.indd 1234 8/2/19 8:39 PM

irway is protected with an endotracheal tube. Under special circumstances, delayed and multiple doses of activated charcoal may be useful, as in diphenoxylate hydrochloride–atropine sulfate overdoses and in cases of large ingestions of sustained-release preparations. Tintinalli_Sec15_p1187-1332.indd 1234 8/2/19 8:39 PM CHAPTER 186: Opioids 1235  OPIOID ANTAGONISTS Naloxone, a derivative of oxymorphone, is a pure competitive antago nist at all opioid receptors, with particular affinity for µ-receptors. Therefore, naloxone fully reverses all the effects of opioids, including respiratory depression, sedation, miosis, and analgesia. The elimination half-life of naloxone is 60 to 90 minutes, but the duration of action is as short as 20 minutes if a large amount of opioid agonist is present. Naloxone has poor oral bioavailability but is well absorbed when given by injection (IV , SC, or IM), inhaled, or deposited on mucosa (intratracheally or intranasally, but not sublingual). Inhaled naloxone by nebulization is reasonably effective in reversing depressed mental status and respirations in opioid toxicity, with about 10% requiring additional rescue parenteral naloxone. 18-20 Intranasally administered naloxone provides a pharmacokinetic profile similar to that of IM or SC naloxone and is used by EMS personnel and in bystander naloxone administration programs. 21-24 Naloxone effectiveness is dependent on the dose administered and the amount of opioid that needs to be reversed, balanced against the risk of precipitating withdrawal. There is wide variation in recommended nal oxone doses to treat opioid toxicity. 25 It is prudent to use a small starting dose of naloxone, 0.04 milligram IV , in opioid-dependent patients who present with mental status depression and modest respiratory depres sion, because larger doses can induce opioid withdrawal symptoms in these individuals. 26 An initial dose of naloxone, 0.4 milligram IV , is recommended in non–opioid-dependent patients who present with mental status depression and modest respiratory depression. Subsequent doses of naloxone of 0.04 milligram to 0.4 milligram IV are administered every 2 to 3 minutes until the desired effect is reached. Incremental dosing of naloxone mitigates the precipitation of acute opioid withdrawal. For patients presenting with apnea or near-apnea and cyanosis, a large starting dose of naloxone, 2 milligrams IV , should be adminis tered regardless of drug use history. Repeated doses of 2 milligrams IV every 3 minutes are recommended until a maximum of 10 milligrams IV is reached or respiratory depression is reversed. Exposures to fen tanyl, novel synthetic opioids, and sustained-release preparations may require these larger-than-ordinary doses. Toxicity from leaking opioidcontaining packets in the intestinal tract (i.e., in “body packers”) can be extremely severe, and such patients require large and sustained naloxone doses until the drug-containing packets are expelled or removed. The duration of action of naloxone may be shorter than that of the offending opioid, so naloxone infusions are occasionally required to support respiration over several hours as the opioid is metabolized. This is especially true for certain long-acting opioids, such as buprenorphine and methadone; for exposures to sustained-release preparations; and for ingestions of transdermal fentanyl patches. A continuous infusion should be considered only if the patient responded to the initial nalox one bolus and subsequently required repeat administration. To calculate the naloxone continuous infusion dose, determine the “wake-up dose” and administer two thirds of that dose per hour by IV infu sion.

mal fentanyl patches. A continuous infusion should be considered only if the patient responded to the initial nalox one bolus and subsequently required repeat administration. To calculate the naloxone continuous infusion dose, determine the “wake-up dose” and administer two thirds of that dose per hour by IV infu sion. Adjustments may be required if the patient develops respiratory depression (by repeating a bolus and increasing infusion rates) or with drawal symptoms (by decreasing infusion rates). It is recommended that patients on naloxone infusions be admitted to a monitored unit. Naloxone has a remarkable safety profile. When administered to opioid-naive patients, naloxone has no adverse effects. Although adverse effects are seen in about one third of patients who receive it for a sus pected opioid overdose, serious complications are rare. 28 The most common adverse effects associated with naloxone are anxiety, nausea, vomiting, diarrhea, abdominal cramps, piloerection, yawning, and rhinorrhea, which are expected signs and symptoms of opioid withdrawal. Careful dosing of naloxone can prevent the precipitation of opioid withdrawal symptoms. 27,29 Naltrexone, an oral opioid antagonist, is primarily used to maintain opioid abstinence after detoxification. Naltrexone, compounded into an extended-release monthly injection (Vivitrol®), is available to treat alcohol or opioid abstinence. Nalmefene, both an oral and parenteral opioid antagonist, has not been available in the United States since August 2008 but is available in Europe. Both naltrexone and nalmefene are longacting reversal agents, so opioid-dependent patients who receive either of these reversal medications intentionally or inadvertently may require protracted management of withdrawal symptoms. DISPOSITION AND FOLLOW-UP The optimal observation period after an opioid intoxication is deter mined by the history and clinical picture. Patients with presumed heroin intoxication who respond to naloxone can be safely discharged 1 hour after administration of naloxone if they have independent mobility, normal vital signs, and normal mental status. 30-32 In cases of exposure to opioids other than heroin, an observation period of 4 to 6 hours in the ED is recommended after the last naloxone administration. In long-acting opioid overdose, observation should be extended for a minimum of 8 hours. 4 Moderate to severely symptomatic patients usually require hospital admission to monitored settings and may require continued administration of naloxone. A behavioral health evaluation is needed in cases with suicidal intent. SPECIAL CONSIDERATIONS  BUPRENORPHINE Buprenorphine is a mixed opioid agonist–antagonist, with partial ago nist activity at µ-receptors and antagonist activity at κ- and δ-receptors. Because buprenorphine is only a partial agonist at µ-receptors, it has decreased intrinsic activity that causes its clinical effects to plateau at higher dosages. 33 Buprenorphine has high affinity for and slow disso ciation from the µ-receptor, which results in a long duration of action. Furthermore, other opioid agonists (such as heroin) or antagonists (such as naloxone) cannot easily displace buprenorphine from the µ-receptor. Buprenorphine has poor oral bioavailability because of extensive firstpass metabolism and is therefore administered using sublingual films or tablets or parenterally. The most frequently prescribed sublingual buprenorphine formulation is in combination with naloxone in a 4:1 ratio. Because naloxone has poor bioavailability from PO or sublingual administration, it was introduced into the preparation to discourage and limit parenteral abuse of the buprenorphine portion while not interfer ing with therapeutic use in the form of the sublingual film.

ion is in combination with naloxone in a 4:1 ratio. Because naloxone has poor bioavailability from PO or sublingual administration, it was introduced into the preparation to discourage and limit parenteral abuse of the buprenorphine portion while not interfer ing with therapeutic use in the form of the sublingual film. Buprenorphine can be associated with three distinct clinical sce narios. First, the opioid-naive patient who overdoses on buprenorphine will experience mental status depression, nausea, vomiting, miosis, and respiratory depression (usually with a plateau). In this situation, low-dose naloxone may not be fully effective in reversing mental status and respiratory depression. 34 Because of the long duration of action of buprenorphine, naloxone infusions are necessary, and admission to the hospital is necessary in symptomatic patients. The second possible scenario is buprenorphine exposure in the opioid-dependent patient. In this case, buprenorphine will precipitate opioid withdrawal symptoms, because the partial agonist buprenorphine behaves like an antagonist in the presence of an agonist. Buprenorphine-induced withdrawal is best managed with symptom-driven therapy, including antiemetics, nonopioid analgesics, antidiarrheal medications, and nonbenzodiazepine sedatives. The third possible clinical scenario is buprenorphine exposure in the opioid-dependent patient who is suffering from opioid withdrawal, in whom buprenorphine will act as a partial agonist and alleviate the symptoms of opioid withdrawal. Thus, buprenorphine is unique in that it can both induce and treat opioid withdrawal, depending on the timing of its administration. Buprenorphine can be used in the ED to alleviate opioid withdrawal 35 and be prescribed upon ED discharge to transition patients with opioid use disorder to medicationassisted treatment.  METHADONE Methadone is a synthetic opioid used as opioid replacement therapy in opioid dependence and can be prescribed as an analgesic for chronic pain. The initial analgesic duration is 8 to 12 hours with an elimina tion half-life of 12 to 18 hours. With repetitive dosing, analgesic action duration and elimination half-life increase to approximately 22 to 36 hours and up to 59 hours, respectively. The long duration of activity enables once-a-day dosing during chronic therapy. Methadone has a higher risk for overdose-related deaths than other opioids, often with co-ingestants. 37,38 Acute methadone overdoses present similarly to other Tintinalli_Sec15_p1187-1332.indd 1235 8/2/19 8:39 PM

to 59 hours, respectively. The long duration of activity enables once-a-day dosing during chronic therapy. Methadone has a higher risk for overdose-related deaths than other opioids, often with co-ingestants. 37,38 Acute methadone overdoses present similarly to other Tintinalli_Sec15_p1187-1332.indd 1235 8/2/19 8:39 PM 1236 SECTION 15: Toxicology opioid intoxications, but the duration can be much longer, requiring naloxone infusions with close neurologic and respiratory monitoring.39 Methadone has several drug–drug interactions that can precipitate toxicity or withdrawal in patients on chronic therapy. 40 Interactions between methadone and human immunodeficiency virus medications are common and complex, creating potential for both increased toxic ity and withdrawal. The relevant interactions for emergency physi cians include ciprofloxacin, fluconazole, ketoconazole, and omeprazole, which can increase toxicity. Drug–methadone interactions that have potential to precipitate withdrawal include macrolides (especially clar ithromycin), phenobarbital, phenytoin, spironolactone, and verapamil. Methadone prolongs the QT interval in acute overdose or during long-term methadone treatment, providing the potential for cardiac dysrhythmias, such as torsades de pointes. 41 In patients with acute methadone overdose resulting in QT interval prolongation, serum electrolytes should be optimized and the patient should be admitted to a monitored unit until the condition resolves. Patients on long-term methadone therapy who develop a QT c interval between 450 and 500 milliseconds do not require a dosage adjustment, but electrolyte imbalances should be corrected if present, and patients should be fol lowed on an outpatient basis with frequent ECGs. Patients who develop a QT c interval of >500 milliseconds should be considered for methadone dosage reduction or discontinuation.42  TRAMADOL Tramadol is being increasingly prescribed in the United States for chronic pain. Tramadol binds norepinephrine and serotonin reuptake inhibitors to contribute to its analgesic effects. Tramadol has no direct opiate-binding capacity, but after it is metabolized by cytochrome P450 enzymes, the active metabolite, O-desmethyltramadol, binds the µ-opioid receptor. Tramadol’s opioid effects can vary widely because of genetic variation, liver disease, renal disease, and co-prescribed drugs that affect cytochrome P450 metabolism capacity. 43,44 Tramadol overdoses are associated with lethargy, nausea, tachycardia, and seizures.45,46 At doses exceeding 500 milligrams, coma, hypertension, respiratory depression, and apnea are seen. 11,47 Features consistent with serotonin syndrome have been seen in isolated tramadol overdoses. 48 Tramadol-induced seizures are common, and naloxone is ineffective in preventing them. Fortunately, tramadol-induced seizures are usu ally single, and anticonvulsants are not necessary. 49,50 Tramadol has also been associated with higher rates of hypoglycemia compared to codeine, especially within the first 30 days of use. 44,51 Dependence during chronic therapy and withdrawal symptoms upon discontinuation have been reported with tramadol.  MIXED AGONISTS–ANTAGONISTS The mixed agonists–antagonists include pentazocine, butorphanol, and nalbuphine. These agents have variable but mostly antagonist activity at the µ-receptor and agonist effects at the κ-receptor. They may cause significant respiratory depression in overdose, and naloxone will reverse this respiratory depression. Mixed agonists–antagonists usually precipitate withdrawal when taken by an opioid-dependent individual, which reduces their potential for abuse. Pentazocine overdose can cause seizures.

the κ-receptor. They may cause significant respiratory depression in overdose, and naloxone will reverse this respiratory depression. Mixed agonists–antagonists usually precipitate withdrawal when taken by an opioid-dependent individual, which reduces their potential for abuse. Pentazocine overdose can cause seizures.  DIPHENOXYLATE HYDROCHLORIDE–ATROPINE SULFATE Diphenoxylate hydrochloride–atropine sulfate is a frequently prescribed antidiarrheal agent. The medication is formulated as a combination tablet or liquid, containing diphenoxylate, 2.5 milligrams, and atropine, 0.025 milligram, in each tablet or 5 mL of liquid. In an overdose, ini tially the anticholinergic toxidrome dominates the clinical picture (see Chapter 202, “ Anticholinergics”). The second phase of intoxication is characterized by the opioid toxidrome. Children <6 years of age can be symptomatic after ingestion of a single tablet. In pediatric patients, absorption can be delayed up to 6 to 12 hours in some cases because of the effect of atropine on GI motility. Admission and observation for 24 hours are recommended for children <6 years of age after ingestion of a combination tablet of diphenoxylate and atropine. Older children and adults should be observed in the ED for 6 hours. Administration of activated charcoal is recommended unless contraindicated.  FENTANYL AND NOVEL SYNTHETIC OPIOIDS Fentanyl and novel synthetic opioids have contributed to rising opioid overdose deaths since 2016. 54 Novel synthetic opioids include both fen tanyl analogs (acetylfentanyl, butyrlfentanyl, furanylfentanyl, carfentanil) and nonfentanyl µ-opioid agonists (U47700), all with varying and usu ally high potencies. 55-57 Illicitly manufactured fentanyl is 50 to 100 times more potent than morphine and has been detected in >50% of opioid overdose deaths in some states. 54 Illicitly manufactured fentanyl has been found as a contaminant in opioids, benzodiazepines, and cocaine.55 Due to their ultrapotency, overdoses of illicitly manufactured fentanyl and novel synthetic opiods may require rapidly escalating and higher doses of naloxone, up to 10 to 20 milligrams IV , to reverse respiratory depression related to overdose. 55,56  MIXED DRUGS AND CONTAMINANTS Heroin is often mixed with other compounds, such as cocaine, scopolamine, clenbuterol, and fentanyl, which may contribute to varied opioid toxi dromes. Adulterants found in illicit heroin may include strychnine, quinine, lactose, and talc. Scopolamine is an antimuscarinic agent that produces the anticholinergic toxidrome. Clenbuterol is a long-acting β-adrenergic agonist similar to albuterol and is used in veterinary medicine. A potent neurotoxin, 1-methyl-4-phenyl-1,2,3-tetrahydropyridine, has been used as a meperidine adulterant, producing parkinsonism in users. Starting in Russia in 2010, episodes of deaths and gangrene were reported associated with IV desomorphine or “Krokodil, ” a synthetic alternative to heroin crudely made from codeine tablets with a high concentration of tissue-toxic impurities. The colloquial name is derived from the appearance of the skin after it is injected.  KRATOM Kratom (Mitragyna speciosa) has mitragynine as its principal alkaloid, with stimulating effects at low doses (cocaine-like effect) and sedative effects (opioid-like effect) at high doses. 60 Kratom has been used since the early 1930s in Africa and Southeast Asia for medicinal purposes and more recently to prevent opioid withdrawal symptoms by smoking, consuming, brewing, or mixing into drinks. 61 There has been growing use of kratom in Western countries due to its availability in smoke shops and on the Internet.

has been used since the early 1930s in Africa and Southeast Asia for medicinal purposes and more recently to prevent opioid withdrawal symptoms by smoking, consuming, brewing, or mixing into drinks. 61 There has been growing use of kratom in Western countries due to its availability in smoke shops and on the Internet. 62 Since 2010, there has been a 10-fold increase in reported use in the United States.63 Kratom is used in the United States for three distinct indications: (1) to help manage chronic pain, (2) to mitigate withdrawal symptoms from opioids or alcohol, and (3) for acute euphoric effects. 64 Daily kratom use can lead to dependence, craving, and withdrawal symptoms.64,66 Kratom can produce seizures, 67 serious toxicity, or even death, often associated with other drug use, such as decongestants, antidepressants, and benzodiazepines. 68 Krypton, a combination containing kratom, O-desmethyltramadol, and caffeine, has also been associated with fatalities.  LOPERAMIDE Loperamide, also known as “the poor man’s methadone, ” has seen rising rates of misuse, abuse, and suicide ingestion since 2010. 70,71 At high doses (between 50 and 300 milligrams, 20 to 150 times the therapeutic dose of 2 milligrams), loperamide binds the µ-opioid receptor and has greater CNS penetration, leading to euphoria and mental depression. It can also cause severe cardiotoxic effects, including QT c prolongation, QRS wid ening, ventricular tachycardia, ventricular fibrillation, and other cardiac dysrhythmias, due to both sodium and potassium channel blockade. 71,72 Treatment of loperamide overdose should target three modes: GI decontamination, respiratory depression, and cardiotoxicity. Activated charcoal may be used for GI decontamination and repeated because loperamide inhibits peristalsis. Standard doses of naloxone (0.04 to 0.4 milligram) should be used to reverse respiratory depression. Car diotoxicity due to sodium channel blockade potential with widened QRS Tintinalli_Sec15_p1187-1332.indd 1236 8/2/19 8:39 PM

oal may be used for GI decontamination and repeated because loperamide inhibits peristalsis. Standard doses of naloxone (0.04 to 0.4 milligram) should be used to reverse respiratory depression. Car diotoxicity due to sodium channel blockade potential with widened QRS Tintinalli_Sec15_p1187-1332.indd 1236 8/2/19 8:39 PM CHAPTER 186: Opioids 1237 TABLE 186-4 Clinical Features of Opioid Withdrawal Initial Features Additional Features About 12 h After Onset Subsequent Features About 12–24 h After Onset Peak effects: 36–72 h Anxiety Yawning Drug craving Lacrimation Rhinorrhea Diaphoresis Myalgias Peak effects: 72 h Irritability Tremor Piloerection Mydriasis Peak effects: 72 h Insomnia Muscle spasms Abdominal pain Nausea, vomiting, diarrhea TABLE 186-5 Clinical Opiate Withdrawal Scale (COWS) Resting Pulse Rate (beats/min) Measured after patient is sitting or lying for 1 min 0 – Pulse rate ≤80 1 – Pulse rate 81–100 2 – Pulse rate 101–120 4 – Pulse rate >120 Sweating Over past 1/2 h not accounted for by room temperature or patient activity 0 – No report of chills or flushing 1 – Subjective report of chills or flushing 2 – Flushed or observable moistness on face 3 – Beads of sweat on brow or face 4 – Sweat streaming off face Restlessness Observation during assessment 0 – Able to sit still 1 – Reports difficulty sitting still, but is able to do so 3 – Frequent shifting or extraneous movements of legs/arms 5 – Unable to sit still for more than a few seconds Pupil Size 0 – Pupils smaller or normal size for room light 1 – Pupils possibly larger than normal for room light 2 – Pupils moderately dilated 5 – Pupils so dilated that only the rim of the iris is visible Bone or Joint Aches If patient was having pain previously, only the additional component attributed to opiate withdrawal is scored 0 – Not present 1 – Mild diffuse discomfort 2 – Patient reports severe diffuse aching of joints/muscles 4 – Patient is rubbing joints or muscles and is unable to sit still because of discomfort Runny Nose or Tearing Not accounted for by cold symptoms or allergies 0 – Not present 1 – Nasal stuffiness or unusually moist eyes 2 – Nose running or tearing 4 – Nose constantly running or tears streaming down cheeks GI Upset Over last 1/2 h 0 – No GI symptoms 1 – Stomach cramps 2 – Nausea or loose stool 3 – Vomiting or diarrhea 5 – Multiple episodes of diarrhea or vomiting Tremor Observation of outstretched hands 0 – No tremor 1 – Tremor can be felt, but not observed 2 – Slight tremor visible 4 – Gross tremor or muscle twitching Yawning Observation during assessment 0 – No yawning 1 – Yawning once or twice during assessment 2 – Yawning 2 or more times during assessment 4 – Yawning several times per minute Anxiety or Irritability 0 – None 1 – Patient reports increasing irritability or anxiousness 2 – Patient obviously irritable or anxious 4 – Patient so irritable or anxious that participation in the assessment is difficult Gooseflesh Skin 0 – Skin is smooth 3 – Piloerection of skin can be felt or hairs standing up on arms 5 – Prominent piloerection Total Score is the sum of all 11 items Assessment: 5–12 = mild; 13–24 = moderate; 25–36 = moderately severe; >36 = severe withdrawal. complex is treated with sodium bicarbonate 1 to 2 mEq/kg IV , along with potassium and magnesium replacement. For patients with torsades de pointes, case reports have demonstrated success with cardiac overdrive pacing and isoproterenol IV infusions at 2 to 10 micrograms/min. 72,73 Other advanced therapies including intravenous lipid emulsion therapy and extracorporeal membrane oxygenation have had limited success in individual cases.  OPIOID WITHDRAWAL Downregulation of endogenous endorphins, dynorphins, and opioid receptors occurs with long-term use of opioids.

at 2 to 10 micrograms/min. 72,73 Other advanced therapies including intravenous lipid emulsion therapy and extracorporeal membrane oxygenation have had limited success in individual cases.  OPIOID WITHDRAWAL Downregulation of endogenous endorphins, dynorphins, and opioid receptors occurs with long-term use of opioids. Abrupt cessation of opioid use does not allow time for upregulation of receptors and results in increased neuronal firing and the opioid withdrawal syndrome. Opioid withdrawal typically starts 6 to 12 hours after last use of shortacting opioids and 30 hours after abstinence from long-acting opioids. Opioid withdrawal can be abruptly precipitated by the administration of antagonists such as naloxone or naltrexone or the administration of partial agonist–antagonists such as buprenorphine. Opioid withdrawal usually starts with anxiety and progresses with development of additional symptoms over the next 12 to 24 hours ( Table 186-4). withdrawal symptoms usually peak on the third day of abstinence and resolve by the fifth or sixth day. Opioid withdrawal symptoms are very uncomfortable but are not life-threatening and rarely fatal. Vomiting and aspiration of gastric contents can cause pneumonitis and dehydration. Clinical scoring tools have been developed to assist in the assessment of opioid withdrawal. 75 The commonly used Clinical Opiate Withdrawal Scale calculates a score based on the severity of 11 symptoms and can be used to assess appropriateness for buprenorphine or methadone and to monitor response to treatment (Table 186-5). Tintinalli_Sec15_p1187-1332.indd 1237 8/2/19 8:39 PM