Decision Making in Emergency Critical Care

SECTION 11 - Toxicologic Critical Care

Drugs of Abuse

Rana Biary and Jane Marie Prosser



Opioids comprise both naturally occurring and synthetic compounds that bind to the μ opioid receptor. μ receptors are located throughout the body, notably in regions of the brain related to analgesia, which include the periaqueductal gray matter, nucleus raphe magnus, and the medial thalamus. They are also found in the respiratory center of the medulla and the gastrointestinal tract.1 Opioids have been used since ancient times as analgesics, appearing as early as 1500 BC in the Ebers Papyrus as a “remedy to prevent excessive crying in children.” By the 16th century, there were manuscripts detailing opioid addiction, tolerance, and withdrawal.2 In 1914, the Harrison Narcotic Act made nonmedical use of opioids illegal in the United States.1 Heroin is the classic opioid street drug of abuse; however, prescription opioids have become increasingly more common. In New York City, in 2009, prescription opioids surpassed motor vehicle collisions, cocaine, and heroin as the leading cause of accidental death.3,4

History and Physical Exam

Opioids can be ingested, injected, insufflated, inhaled, absorbed through the oral and rectal mucosa, or applied topically. The classic clinical presentation—or toxidrome—of an opioid overdose is similar regardless of which opioid is used. It includes miosis, a depressed respiratory rate, and a depressed mental status. Additionally, the patient may have decreased bowel sounds and a mildly decreased blood pressure.5,6

Patients with severe overdose may present with hypoxia and crackles on pulmonary exam, consistent with a noncardiogenic pulmonary edema.5,7 Another, albeit less common presentation, often attributed to rapid bolus injection of fentanyl, is the development of chest wall rigidity.8,9

Certain opioids are also known to cause unique complications. The opioid tramadol can cause seizures even in therapeutic doses. Tramadol also causes serotonin syndrome, characterized by hyperthermia, clonus, rigidity, and tremor.10,11 The synthetic opioids methadone and buprenorphine are known to prolong the QT interval, predisposing patients to torsade de pointes.12 Intravenous drug users are also at risk for developing complications associated with nonsterile venous puncture, including endocarditis, septic emboli, and epidural abscess.

Differential Diagnosis

Clonidine, an imidazole derivative, is used in the treatment of hypertension, pediatric behavioral disorders, and the treatment of opioid withdrawal. It has some effects on the μ receptor, producing clinical findings resembling opioid overdose, including meiosis and respiratory depression.1 Clonidine overdoses, by contrast, are usually associated with distinct vital sign abnormalities not common to opiate overdose, including significant bradycardia and hypotension. Benzodiazepines and barbiturates can, like opiates, result in a depressed mental status and respiratory rate.1 Gamma hydroxybuturate (GHB) may also lead to a depressed respiratory rate and mental status, though its effects are usually transient. The pupils in patients who have overdosed on GHB may also be mitotic and minimally responsive to light.1 Phencyclidine (PCP), typically described as a stimulant, may in large doses behave as a sedative. Patients will typically have a depressed mental status with mydriasis and rotary nystagmus.

In addition to these drugs, other common etiologies of depressed mental status, including trauma, metabolic disorders (hypoglycemia, hyponatremia), infection, hypoxia, and hypothermia, must always be considered.

Diagnostic Evaluation

Physical exam is the essential tool for the diagnosis of opioid intoxication. As noted, the exam of the patient with opioid intoxication will include pinpoint pupils with a depressed mental status and respiratory rate. Response to naloxone has been suggested to aid in diagnosis but can be associated with complications when used in the undifferentiated patient and is therefore not recommended.

Urine toxicology screens are of limited utility and are therefore not routinely recommended. The urine toxicology screen generally tests for morphine, and because of this, naturally occurring opioids such as heroin and morphine will result in a positive test. Synthetic opioids such as methadone and fentanyl, however, are not metabolized to morphine or its metabolites, and will not result in a positive test. Semisynthetic opioids such as oxycodone and hydrocodone produce variable results. Additionally, a positive result may persist long after acute intoxication. For example, heroin use can result in a positive urine drug screen for up to 4 days post ingestion, giving a potentially misleading explanation for the patient's current symptoms.13

Additional testing should include an ECG, liver function tests, and a serum acetaminophen concentration. On the ECG, particular attention should be given to the QTc interval length. Because of the increasing abuse of prescription opioids containing acetaminophen, routine laboratory testing is recommended. In patients who present with crackles, hypoxia, or tachypnea, chest radiography should be performed to look for pulmonary edema.

Management Guidelines

The most common cause of death from opioid overdose is respiratory arrest. The first step in management of a patient with suspected opioid intoxication is to ensure airway management. Administration of naloxone, an opioid antagonist, should be considered in patients with an opioid toxidrome. Studies suggest that naloxone is most likely to be of benefit in those patients whose respiratory rate is <12, or who have significant hypoventilation.36 To prevent precipitation of withdrawal, a low initial dose of 0.04 to 0.05 mg of naloxone should be administered. The dose can be titrated to an arousable mental status and a respiratory rate of approximately 8 to 10 breaths per minute.1 Bolus administration can be followed by an infusion, titrated to maintain the same goals. The recommended starting dose for the infusion is two-thirds of the effective bolus dose.14

In non–opioid dependent patients, naloxone has few side effects even in high doses.15 However, injudicious administration in opioid-dependent patients may result in withdrawal including vomiting and diarrhea. This can be harmful in several scenarios. If naloxone is administered to an opioid-dependent patient whose altered mental status is due to a different etiology, vomiting may occur without an increase in mental status, increasing the risk for aspiration. Opiate reversal with naloxone administration in the setting of marked hypoxemia and hypercarbia can also lead to a large catecholamine surge (as an appropriate response to respiratory deficits) and subsequent pulmonary edema. Administration of several breaths via bag valve mask prior to administration will minimize hypoxia and hypercarbia and reduce the likelihood of this response.16,17

The duration of action of naloxone is 20 to 90 minutes, shorter than the half-life of most opioids, including heroin.1 Therefore, patients requiring naloxone should be observed for at least 4 to 6 hours to ensure that they do not develop recurrent respiratory depression. Patients who overdose on long-acting opioids, such as methadone or extended-release oxycodone, will require observation for 24 hours. In patients with a depressed mental status, gastric decontamination with charcoal should be avoided due to the risk of aspiration.

Clinicians must also consider the possibility of unintentional coingestion of adulterants. While classic adulterants included strychnine and quinine, more recently levamisole, caffeine, acetaminophen, phenobarbital, methaqualone, scopolamine, and clenbuterol have also been used.18



Benzodiazepines were introduced in the 1960s, as sedatives with a safer side effect profile than that of barbiturates. In Florida, between 2003 and 2009, there was a 233.8% increase in reported deaths caused by alprazolam.19 A study from the United Kingdom evaluated 1,024 consecutive patients admitted to the hospital, and found that diazepam was the fourth most commonly abused drug overall (third most common among men).20 Benzodiazepines fall under the category of sedative hypnotics, and act on the GABAA receptor.1

History and Physical Exam

The typical presentation of a benzodiazepine overdose is a depressed mental status with normal vital signs. Patients may also present with slurred speech, gait ataxia, and coma. Respiratory depression is not expected with oral ingestion, unless coingestants such as ethanol or other sedatives have also been consumed.21 Controversy exists regarding respiratory depression after IV administration, with a few case reports suggesting it may occur.1

Another important consideration in cases of intravenous administration of benzodiazepines, particularly in a hospital setting, is the use of diluents. Lorezepam, for example, is typically carried in propylene glycol, which, when administered rapidly, can lead to hypotension. Prolonged exposure to propylene glycol, as occurs with continuous infusions, can lead to an elevated lactate metabolic acidosis.22

Differential Diagnosis

The differential diagnosis for benzodiazepines overdose is similar to opioid overdose, and includes any medical condition or toxic ingestion that can result in altered sensorium (e.g., ethanol or opioid ingestion, hypoglycemia, hypoxia, infection).

Diagnostic Evaluation

If the diagnosis is clear on presentation, few tests are likely to add to the clinical picture. As with all overdose patients, acetaminophen and salicylate concentrations and an ECG are useful screening tests to evaluate for potential coingestants.23 However, if the diagnosis is uncertain, as is often the case, then evaluation of a patient's altered mental status should proceed in the standard fashion, including comprehensive blood testing, head computed tomography, and cerebral spinal fluid (CSF) analysis. As with opioid intoxication, a urine toxicology screen is of limited utility due to false-positive and -negative results.

Management Guidelines

Initial management centers on assessing airway, breathing, and circulation. Intravenous access, cardiac monitoring, and close observation are also indicated. As noted, respiratory depression is not expected with oral benzodiazepine overdose, but sedation and loss of airway protection requiring intubation is possible. Gastric decontamination using charcoal should be avoided due to the risk of aspiration in patients with a depressed mental status.

Flumazenil is a benzodiazepine receptor antagonist and has been used to treat benzodiazepine overdose; however, its use is not routinely recommended due to its risk of precipitating withdrawal, which can be a life-threatening complication.24 Intubation and mechanical ventilation are generally considered safer than flumazenil in the treatment of benzodiazepine-associated respiratory depression.25 In circumstances in which the risk of preexisting benzodiazepine dependence is minimal—such as with pediatric patients or patients post procedural sedation—the likelihood of flumazenil precipitating withdrawal will be acceptably low and its use may be reasonable.

Patients with isolated benzodiazepine overdose are expected to have good outcomes, and generally improve with supportive care and close observation. Benzodiazepine withdrawal (covered in the following chapter) can, however, be life threatening.



Sympathomimetics are a large category of compounds that cause increased excitatory neurotransmitter release. They include drugs such as amphetamines, phenylethylamines such as MDMA, cocaine, and synthetic cathinone derivatives often referred to as “bath salts.” These compounds produce effects specific to each compound; however, common to all is the increased release of epinephrine, norepinephrine, and dopamine, which leads to increased activation of the sympathetic nervous system and euphoria. Certain sympathomimetics, such as the phenylethylamines, also modulate serotonin release.

Patients with sympathomimetic intoxication are at risk for hyperthermia, dysrhythmias, myocardial infarction, strokes, hyponatremia, and death. Stimulants such as ecstasy and bath salts often do not contain the ingredients they are sold as, and may contain different sympathomimetics, caffeine, or even placebo. Furthermore, compounds marketed as “legal highs” may contain illegal substances.2629

History and Physical Exam

Patients with sympathomimetic intoxication present with a variety of issues that occur as a result of increased sympathetic output. The sympathomimetic toxidrome includes mydriasis, hypertension, tachycardia, diaphoresis, hyperthermia, and psychomotor agitation.

The wide range of potential complications associated with sympathomimetic use highlights the importance of a thorough history and physical exam. Signs and symptoms may suggest stroke, seizure (either due to direct sympathomimetic toxicity or from secondary hyponatremia), intracranial hemorrhage, myocardial infarction, and other complications that can accompany increased sympathetic output.

Differential Diagnosis

The differential diagnosis of sympathomimetic toxicity includes any medication capable of causing a sympathomimetic toxidrome including cocaine, PCP/ketamine, amphetamines, and newer synthetic drugs of abuse including bath salts and synthetic cannabis/cannabinoid compounds such as “k2” or “Spice.” Patients who are withdrawing from a sedative/hypnotic may also present with altered mental status, diaphoresis, and autonomic instability that can clinically resemble the sympathomimetic toxidrome. As with any suspected overdose that produces a depressed mental status, unless the offending agent is clearly identified, a more comprehensive evaluation is necessary.

Diagnostic Evaluation

Unlike benzodiazepine overdose, patients who present after sympathomimetic intoxication require further diagnostic evaluation, including laboratory evaluation. Laboratory tests should include a basic metabolic panel to evaluate for hyponatremia secondary to drug-induced SIADH and increased free water consumption. Patients may also develop rhabdomyolysis secondary to sympathomimetic ingestion; therefore, a creatinine phosphokinase should be checked, as well as renal function. As in any overdose, acetaminophen and aspirin concentrations should be checked, given the concern for coingestants. As with other ingestions, a urine toxicology screen is of limited utility. Testing should include an ECG to ensure absence of ST-segment changes, as sympathomimetics may be associated with coronary vasospasm. Altered mental status in the setting of sympathomimetic use requires a CT head to rule out stroke, seizure, or intracranial hemorrhage.

Management Guidelines

Prioritization of treatment of sympathomimetic toxicity is guided by patient presentation. In a patient with uncontrolled psychomotor agitation, adequate dosing with benzodiazepines is necessary to ensure that the patient is appropriately sedated and not at risk of harm to self or others. While any benzodiazepine may be used, benzodiazepines with quicker onset, such as midazolam or diazepam, are preferred. Lorazepam, while acceptable, takes approximately 20 minutes to produce peak therapeutic effect.

Hyperthermia is the most common cause of death in patients with sympathomimetic toxicity. High ambient temperatures are known to compound sympathomimetic-induced hyperthermia; in a retrospective review of medical examiner cases from 1990 to 1995, a 33% increase in the mean daily number of cocaine overdose deaths was recorded when ambient temperatures exceeded 31.1°C (2.4 more deaths per day).30 Initial management should therefore include obtaining a core temperature. If hyperthermia is present, rapid and aggressive treatment is essential. Classically, a “mist and fan” technique has been suggested, although this requires fans of much stronger caliber than are available in most hospitals. For severe hyperthermia, an ice bath is a more efficient intervention. To avoid the risk of overshoot and secondary hypothermia, patients should be removed from the ice bath once core temperatures fall below 38°C.31

Because patients with psychomotor agitation and hyperthermia are at risk for muscle breakdown, rhabdomyolysis should be treated empirically with fluid hydration. Urine output should be maintained at a minimum of 1 mL/kg/h.

Patients reporting chest pain should have an ECG performed immediately. Cocaine use can produce coronary vasospasm, as well as increased platelet aggregation and coronary artery atherosclerosis. The management for patients who present with cocaine-induced chest pain parallels the management of ACS with two important exceptions. Cocaine-induced chest pain should be treated with benzodiazepines to decrease the central nervous system release of epinephrine and norepinephrine. Beta-blockers should be avoided, as there is risk not only of worsening the coronary vasospasm but also of further elevating the blood pressure from an unopposed alpha effect.32 Aspirin should be administered, especially given the increased risk of platelet aggregation that accompanies chronic cocaine use. Nitroglycerin can help with smooth muscle relaxation and may improve coronary vasospasm. In patients with refractory chest pain, phentolamine, an alpha-1 blocker, should be given.33 Finally, as patients who abuse cocaine and other sympathomimetics are predisposed to coronary artery disease, a cardiac catheterization in patients with ST-segment elevation is indicated.34

Seizures may occur in the setting of sympathomimetic overdose because of stimulation of excitatory neurotransmitters; seizures may also occur due to drug-induced hyponatremia.35 Drugs of abuse, such as MDMA, can lead to hyponatremia through a combination of SIADH and increased free water consumption. Hypertonic saline should be considered in any patient suspected of having ingested MDMA who is actively seizing or who has an altered mental status.


Patients with opioid, benzodiazepine, and sympathomimetic overdose commonly present to the ED. Once the emergency physician is familiar with the clinical toxidromes of these overdoses, a focused bedside physical exam will enable formulation of an accurate differential diagnosis and appropriate plan of care.



1.Lewis S, Nelson NAL, Howland MA, et al. Goldfrank's Toxicologic Emergencies. 9th ed. New York, NY: The McGraw-Hill Companies, Inc.; 2011.

2.Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993;90(12):5391–5393.

3.Tanne JH. Deaths from prescription opioids soar in New York. BMJ. 2013;346:f921.

4.Manchikanti L, et al. Opioid epidemic in the United States. Pain Physician. 2012;15(3 suppl):ES9–ES38.

5.Duberstein JL, Kaufman DM. A clinical study of an epidemic of heroin intoxication and heroin-induced pulmonary edema. Am J Med. 1971;51(6):704–714.

6.Afshari R., Maxwell SR, Bateman DN. Hemodynamic effects of methadone and dihydrocodeine in overdose. Clin Toxicol (Phila). 2007;45(7):763–772.

7.Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary edema: a case series. Chest. 2001;120(5):1628–1632.

8.Coruh B, Tonelli MR, Park DR. Fentanyl-induced chest wall rigidity. Chest. 2013;143(4):1145–1146.

9.Fahnenstich H, et al. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med. 2000;28(3):836–839.

10.Abadie D, et al. “Serious” adverse drug reactions with tramadol: a 2010–2011 pharmacovigilance survey in France. Therapie. 2013;68(2):77–84.

11.Shadnia S, et al. Recurrent seizures in tramadol intoxication: implications for therapy based on 100 patients. Basic Clin Pharmacol Toxicol. 2012;111(2):133–136.

12.Krantz MJ, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387–395.

13.Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66–76.

14.Goldfrank L, et al. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986;15(5):566–570.

15.Bracken MB, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990;322(20):1405–1411.

16.Mills CA, et al. Narcotic reversal in hypercapnic dogs: comparison of naloxone and nalbuphine. Can J Anaesth. 1990;37(2):238–244.

17.Mills CA, et al. Cardiovascular effects of fentanyl reversal by naloxone at varying arterial carbon dioxide tensions in dogs. Anesth Analg. 1988;67(8):730–736.

18.Hamilton RJ, et al. A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine. J Toxicol Clin Toxicol. 2000;38(6):597–608.

19.Centers for Disease, Control and Prevention. Drug overdose deaths—Florida, 2003–2009. MMWR Morb Mortal Wkly Rep. 2011;60(26):869–872.

20.Armstrong TM, et al. Comparative drug dose and drug combinations in patients that present to hospital due to self-poisoning. Basic Clin Pharmacol Toxicol. 2012;111(5):356–360.

21.Greenblatt DJ, et al. Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther. 1977;21(4):497–514.

22.Arroliga AC, et al. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med. 2004;32(8):1709–1714.

23.Lucanie R, Chiang WK, Reilly R. Utility of acetaminophen screening in unsuspected suicidal ingestions. Vet Hum Toxicol. 2002;44(3):171–173.

24.Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther. 1992;14(2):292–305.

25.Clemmesen C, Nilsson E. Therapeutic trends in the treatment of barbiturate poisoning. The Scandinavian method. Clin Pharmacol Ther. 1961;2:220–229.

26.Ramsey J, et al., Buying “legal” recreational drugs does not mean that you are not breaking the law. QJM. 2010;103(10):777–783.

27.Davies S, et al. Purchasing “legal highs” on the Internet—is there consistency in what you get? QJM. 2010;103(7):489–493.

28.Baggott M, et al. Chemical analysis of ecstasy pills. JAMA. 2000;284(17):2190.

29.Wood DM, et al. Case series of individuals with analytically confirmed acute mephedrone toxicity. Clin Toxicol (Phila). 2010;48(9):924–927.

30.Marzuk PM, et al. Ambient temperature and mortality from unintentional cocaine overdose. JAMA. 1998;279(22):1795–1800.

31.Costrini A. Emergency treatment of exertional heatstroke and comparison of whole body cooling techniques. Med Sci Sports Exerc. 1990;22(1):15–18.

32.Boehrer JD, et al. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med. 1993;94(6):608–610.

33.Hollander JE, Carter WA, Hoffman RS. Use of phentolamine for cocaine-induced myocardial ischemia. N Engl J Med. 1992;327(5):361.

34.McCord J, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117(14):1897–1907.

35.Ajaelo, I, Koenig K, Snoey E. Severe hyponatremia and inappropriate antidiuretic hormone secretion following ecstasy use. Acad Emerg Med. 1998;5(8):839–840.

36.Hoffman JR, et al. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991;20(3):246–252.