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Acute opioid intoxication in adults

Acute opioid intoxication in adults
Authors:
Andrew Stolbach, MD, MPH, FAACT, FACMT, FACEP
Robert S Hoffman, MD
Section Editor:
Stephen J Traub, MD
Deputy Editor:
Michael Ganetsky, MD
Literature review current through: Nov 2022. | This topic last updated: Dec 02, 2022.

INTRODUCTION — Opiates extracted from the poppy plant (Papaver somniferum) have been used recreationally and medicinally for millennia. Opiates belong to the larger class of drugs, the opioids, which include synthetic and semi-synthetic drugs, as well. Opioid abuse is a worldwide problem and deaths from opioid overdose are numerous and increasing [1-5].

This topic review will discuss the mechanisms, clinical manifestations, and management of acute opioid toxicity. A summary table to facilitate emergent management is provided (table 1). Issues related to opioid withdrawal, chronic opioid abuse, and general management of the poisoned patient are found elsewhere:

(See "Opioid withdrawal in the emergency setting".)

(See "Medication for opioid use disorder".)

(See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis".)

(See "General approach to drug poisoning in adults".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — The opioid pharmaceuticals are analogous to the three families of endogenous opioid peptides: enkephalins, endorphins, and dynorphin. The most recent classification scheme identifies three major classes of opioid receptor, with several minor classes [6]. Within each receptor class there are distinct subtypes. Each subtype produces a variety of distinct clinical effects, although there is some overlap (table 2). For most clinicians, the nomenclature derived from the Greek alphabet is more familiar, although the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature has recommended a change from the original Greek system to make opioid receptor names more consistent with other neurotransmitter systems [6].

The opioid receptors are distinct in their locations and clinical effects, but they are structurally similar (table 2). Each consists of seven transmembrane segments, with amino acid and carboxy termini. Although the opioid receptors are all coupled to G proteins, they use a variety of signal transduction mechanisms [6]. These include reducing the capacity of adenylate cyclase to produce cAMP, closing calcium channels that reduce the signal to release neurotransmitters, or opening potassium channels to hyperpolarize the cell [6]. The net result of these mechanisms is to modulate the release of neurotransmitters.

Opioid receptors exist throughout the central and peripheral nervous system and are linked to a variety of neurotransmitters, which explains the diversity of their clinical effects. The analgesic effects of opioids result from inhibition of nociceptive information at multiple points of its transmission from the peripheral nerve to the spinal cord to the brain. Euphoria results from increased dopamine released in the mesolimbic system [7]. Anxiolysis results from effects on noradrenergic neurons in the locus ceruleus [8].

KINETICS — The vast number of opioids precludes presenting pharmacokinetic data for each one, but a few clinically important generalizations can be made. Most opioids are hepatically metabolized and undergo first-pass metabolism before reaching systemic circulation. The majority of opioids have volumes of distribution of 1 to 10 L/kg, which makes removal of a significant quantity of drug by hemodialysis impossible. They have variable protein binding (from 7.1 percent for hydrocodone to 89 percent for methadone) and are renally eliminated. Many opioids are metabolized via phase I metabolism in the liver to active metabolites. As an example, hydrocodone is metabolized to hydromorphone by Cytochrome P450 (CYP) 2D6. CYP polymorphisms cause variations in clinical effect, especially for codeine. A person with limited or slow CYP2D6 function would be less likely to experience the therapeutic effects of codeine, which must be converted to morphine to have an analgesic effect. Phase II metabolism is also important, as exemplified by morphine's metabolism to morphine-6-glucuronide [9].

Clinically, the most important pharmacokinetic difference among opioids is the wide variation in serum half-life (table 3). The half-life data in this table, taken from healthy subjects receiving therapeutic doses, should serve only as a rough guide to the duration of clinical effect. Actual effects are influenced by dose, an individual's tolerance, and the presence of active metabolites.

In overdose, the apparent half-life may vary significantly from therapeutic dosing. If many tablets are taken, dissolution and absorption will be delayed, prolonging the apparent half-life. Duration of action may also be shortened in overdose. As an example, when a sustained-release formulation of oxycodone is crushed before ingestion, the drug is rapidly absorbed. While the user's intent is to increase euphoria, the chance of significant morbidity is increased as well.

Although active metabolites of some opioids (eg, morphine) accumulate in patients with impaired kidney function, such metabolites are not dialyzable and management is unchanged [10].

CLINICAL FEATURES OF OVERDOSE — Important clinical features related to opioid toxicity are discussed here. A general approach to the overdose patient is found elsewhere. (See "General approach to drug poisoning in adults".)

History — The clinician should attempt to identify the specific drug, dose, and formulation to which the patient was exposed, the presence of nonopioid co-exposures, and the individual's prior history of opioid use. One review found the "typical" heroin death to involve experienced users in their 20s to 30s using coingestants [11]. In the United States, alcohol and benzodiazepines are common coingestants [12]. Recently released prisoners are at higher risk of opioid overdose in the post-release period because of lost tolerance during incarceration [13,14].

While not essential for management, historical features help predict the expected duration of poisoning. History should also determine the reason for poisoning, as the patient's intention will influence post-overdose management. Generally, opioid exposures will fall into one of several categories: therapeutic use, recreational use, intended self-harm, attempt to hide drugs from law enforcement out of fear for arrest ("body stuffing"), swallowing large quantities of packaged drugs in order to transport them across borders ("body packing"), and unintentional pediatric exposures.

Physical examination — Physical examination helps to: confirm the diagnosis of opioid poisoning; determine the extent of toxicity; identify other conditions requiring treatment; and prevent further exposure (table 4).

The classic signs of opioid toxicity include:

Depressed mental status

Decreased respiratory rate

Decreased tidal volume

Decreased bowel sounds

Miotic (constricted) pupils

Normal pupil examination does not exclude opioid toxicity. Users of meperidine [15] often present with normal pupils, and the presence of coingestants (such as sympathomimetics or anticholinergics) make pupils appear normal or large. The best predictor of opioid toxicity is a respiratory rate <12/minute, which predicted response to naloxone in virtually all patients in one series [16]. The clinician should measure the respiratory rate and pay close attention to chest wall excursion, as subtle changes in respiratory effort are often not identified using triage vital signs.

While decreased respiratory rate is the most notable vital sign abnormality, heart rate ranges from normal to low, although this is not usually consequential. Mild hypotension (from histamine release) may develop in some patients [17]. Pulse oximetry should be performed in every patient, although the clinician should be wary that mild hypercapnia can be present in the setting of normal oxygen saturation when breathing room air and can be particularly severe when the patient is placed on supplemental oxygen. To monitor end-tidal CO2 (EtCO2), and thereby ventilation, directly, clinicians can use capnography. When increased, EtCO2 often predicts respiratory complications, although a normal value does not exclude such problems [18]. (See "Carbon dioxide monitoring (capnography)".)

Obtain a core temperature from any patient with more than minimal symptoms. Hypothermia, which results from a combination of environmental exposure and impaired thermogenesis, should be identified and treated. In a severely obtunded patient, even room temperature can produce significant hypothermia. Elevated temperature suggests early aspiration pneumonia or complications of injection drug use, such as endocarditis.

Mental status can range from euphoria to coma, or be nearly normal. Seizures typically occur in the setting of tapentadol, tramadol, or meperidine overdose, or as a result of hypoxia from any opioid.

During the secondary survey, look for signs of trauma, particularly to the head. Not only do opioids predispose the patient to trauma, but obtundation from traumatic brain injury can be misidentified as drug toxicity. Pulmonary findings such as crackles indicate the presence of aspiration or acute respiratory distress syndrome. If the patient is suspected of attempting to hide drugs out of fear for arrest, rectal and vaginal examination should be performed, with the patient's permission if they are conscious. If the patient cannot give consent because of poisoning, consent is inferred based on medical necessity. Examination of the skin may identify medication patches that must be removed, track marks suggesting history of chronic injection drug use, or coexisting soft tissue infections (picture 1).

Toxicities of specific agents — In addition to the general features described above, some agents have specific toxicities. A brief description of the notable, albeit infrequent, effects and characteristics of several opioids commonly encountered in the overdose patient follows:

Buprenorphine – Partial opioid agonist; induces withdrawal in opioid-dependent patients who have full agonists in their system

Dextromethorphan – Serotonin toxicity; at high doses exhibits some µ effects of opioids (miosis, respiratory and CNS depression) but is not a pure opioid agonist

Fentanyl – Very short acting; may be associated with an acute amnestic syndrome in overdose [19] and chest wall rigidity even at therapeutic doses

Hydrocodone – Often combined with acetaminophen

Loperamide – QRS and QT interval prolongation; wide-complex tachycardia; loses specificity for gastrointestinal tract in overdose [20-25]

Meperidine – Seizure, serotonin toxicity (in combination with other agents) (see "Serotonin syndrome (serotonin toxicity)")

Methadone – Very long-acting; QT interval prolongation, Torsade de Pointes (see 'Electrocardiography' below)

Oxycodone – Often combined with acetaminophen; possible QT interval prolongation [26]

Tramadol and tapentadol – Seizure

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of opioid toxicity includes toxic and nontoxic conditions.

There are myriad drugs that produce coma (table 5). Ethanol, clonidine, and sedative-hypnotics (eg, benzodiazepines, gabapentin [27]) may be the most clinically-relevant drugs in the differential diagnosis, because they occur frequently. While clonidine produces miosis and obtundation, bradycardia, and hypotension are more prominent. Ethanol intoxication produces little to no miosis and no change in bowel sounds. The sedative-hypnotic agents result in much less respiratory depression than the opioids, especially when taken orally. (See "Ethanol intoxication in adults".)

The presence of coingestants often confounds the diagnosis of opioid toxicity. While it is frequently impossible to determine the exact substances to which the patient was exposed, a careful history, physical examination, and judicious use of laboratory studies will determine the correct course of management. The sine qua non of opioid toxicity is a clinical response to an antagonist, although giving large doses of antagonist to establish the diagnosis of opioid toxicity is usually not helpful and potentially dangerous, and therefore not recommended. (See 'Management' below and "General approach to drug poisoning in adults".)

Any medical condition that produces coma may be mistaken for (or occur in conjunction with) opioid toxicity. The most important conditions to exclude are those in which delay of diagnosis will delay definitive care, such as stroke, electrolyte abnormality, and sepsis (table 6). (See "Stupor and coma in adults".)

LABORATORY EVALUATION AND ANCILLARY STUDIES

Laboratory evaluation — A rapid serum glucose concentration should be obtained in all suspected cases of opioid toxicity. Hypoglycemia is prevalent, easily detectable, rapidly correctable, and potentially confused with opioid toxicity. Most patients with mild or moderate unintentional or recreational toxicity can be managed successfully without any further laboratory investigation.

After any overdose in which the opioid is formulated with acetaminophen, or any overdose that is the result of intended self-harm, serum acetaminophen concentration should be obtained. In one series, 1 in 365 individuals with suicidal ingestion and history negative for acetaminophen ingestion had a potentially hepatotoxic acetaminophen concentration [28]. It is not essential to obtain a salicylate concentration in the absence of clinical suspicion or signs of overdose (eg, tachypnea or increased anion gap). (See "Acetaminophen (paracetamol) poisoning in adults: Treatment" and "Salicylate (aspirin) poisoning in adults".)

To exclude rhabdomyolysis in the patient presenting after prolonged immobilization, serum creatine phosphokinase concentration should be obtained. Further testing, such as serum creatinine and electrolytes, may be needed depending on clinical circumstances. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Clinical manifestations'.)

Urine toxicologic screens should not be routinely obtained. Acute opioid toxicity is a clinical diagnosis; the management of a patient with an opioid toxidrome is unchanged by the result of a urine opioid screen. A positive test indicates recent use but does not confirm active toxicity and may even represent a false positive. Conversely, many opioids, especially the synthetic drugs, will produce false-negative results in many urine screens. Commonly available laboratory assays (eg, for phenytoin) can be performed if the history or examination suggests coingestion. (See "Testing for drugs of abuse (DOAs)".)

Electrocardiography — An electrocardiogram (ECG) should be obtained when the patient is suspected of intended self-harm or a coexposure likely to cause cardiovascular complications is possible (eg, cocaine or a cyclic antidepressant). With a few exceptions, electrocardiography can be omitted in other types of opioid exposure.

Loperamide is associated with cardiac conduction disturbances ranging in severity from QRS widening to QT interval prolongation, ventricular tachycardia (polymorphic and monomorphic), and idioventricular rhythm [29]. Methadone also increases the QT interval and can cause Torsade de Pointes. This phenomenon more commonly occurs in patients taking high daily doses of the drug [30]. However, the observations that most people who take very large doses of methadone tolerate it well and that some have developed QT interval prolongation from lower doses suggest individual susceptibility to the condition varies. There may also be an association with oxycodone toxicity and QT interval prolongation [26,31]. (See 'Treatment of toxicity of specific opioids' below and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

The benefit of performing an ECG on every individual with a history of methadone or loperamide or oxycodone exposure is unstudied and cannot be recommended. Rather, the test should generally be reserved for those patients presenting after a large dose increase or with complaints suggesting a dysrhythmia, such as palpitations or syncope.

If QRS or QT interval prolongation is identified on the initial ECG, continuous cardiac monitoring including serial ECGs should be continued until intervals normalize or return to baseline. If the initial ECG is normal, it is reasonable to repeat the test in four to six hours if there is suspicion of a large exposure.

Imaging — Chest radiography is reserved for those patients with adventitious lung sounds or hypoxia that does not correct when hypoventilation is addressed. Abnormal lung sounds suggest aspiration pneumonia or acute respiratory distress syndrome. (See 'Lung injury and ARDS' below and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Imaging of drug packets is discussed below. (See 'Body packing and body stuffing' below.)

MANAGEMENT

Basic measures and antidotal therapy — General management of the overdose patient is discussed elsewhere. (See "General approach to drug poisoning in adults".) Specific management strategies for opioid toxicity are discussed below. A summary table to facilitate emergent management is provided (table 1).

Once opioid toxicity is suspected, initial management should focus on support of the patient's airway and breathing. Attention should be paid to the depth and rate of ventilation. While pulse-oximetry is useful for monitoring oxygenation, it is not useful for gauging ventilation when supplemental oxygen is being given. Capnography can be used to monitor patient ventilation. The presence of elevated end tidal CO2 (EtCO2) in opioid-toxic patients may predict complications, although its absence cannot exclude them. In a prospective cohort study of 201 patients poisoned with respiratory depressants, noninvasive end tidal EtCO2 >50 mmHg predicted complications of hypoventilation with 46 percent sensitivity and 86 percent specificity [18]. (See "Carbon dioxide monitoring (capnography)".)

Administer naloxone, a short-acting opioid antagonist, preferably by the intravenous route. The apneic patient and patients with extremely low respiratory rates or shallow respirations should be ventilated by bag-valve mask attached to supplemental oxygen prior to and during naloxone administration to reduce the chance of acute respiratory distress syndrome [32]. Apneic patients should receive higher initial doses of naloxone (0.2 to 1 mg). Patients in cardiorespiratory arrest following possible opioid overdose should be given a minimum of 2 mg of naloxone [33,34]. (See "Basic airway management in adults" and 'Lung injury and ARDS' below and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

When spontaneous ventilations are present, an initial dose of 0.04 to 0.05 mg intravenously is an appropriate starting point, and the dose should be titrated upward every few minutes until the respiratory rate is 12 or greater [35,36]. The goal of naloxone administration is not a normal level of consciousness, but adequate ventilation. In the absence of signs of opioid withdrawal, there is no maximum safe dose of naloxone. However, if a clinical effect does not occur after 5 to 10 mg, the diagnosis should be reconsidered.

Naloxone may be given nasally, subcutaneously, or intramuscularly if there is a delay in securing intravenous access. When given by these routes, there is slower absorption and delayed elimination, making the drug much more difficult to titrate. Naloxone is also absorbed in the respiratory tract, and thus, can be administered into an endotracheal tube or nebulized. Conceptually, there is little role for nebulized or nasal naloxone in the hospital setting because the dose administered is determined by the patient's ventilation, thus the most severely poisoned patients will absorb the least amount of antidote [37]. The respiratory route and other routes of administration are less predictable. In addition, intravenous access is required in these patients as other medications (such as hypertonic dextrose) may be needed.

If the clinician "overshoots" the appropriate dose of naloxone in an opioid-dependent individual, withdrawal will ensue. Symptoms of withdrawal should be managed expectantly only, not with additional opioids. To overcome naloxone antagonism requires a large dose of opioids. More importantly, because naloxone has a short duration of action, any opioid administered will result in even more toxicity once the effects of naloxone subside. (See "Opioid withdrawal in the emergency setting".)

After ventilation is restored with naloxone, repeat doses may be required, depending on the quantity and duration of action of the opioid. As an alternative to repeat dosing, a naloxone infusion can be prepared by determining the total initial dose required to reinstate breathing, and delivering two thirds of that dose every hour [38]. If the patient develops withdrawal signs or symptoms during the infusion, stop the infusion. If toxicity returns, restart the infusion at half the initial rate. If the patient develops respiratory depression during the infusion, re-administer half the initial bolus every few minutes until symptoms improve, then increase the infusion by half the initial rate.

Gastrointestinal decontamination — Activated charcoal and gastric emptying are almost never indicated in opioid toxicity. Gastrointestinal decontamination has some risk and opioid toxicity is readily treatable by other means. While orogastric lavage could remove tablets still in the stomach, and activated charcoal binds opioids, each of these therapies produces a risk of aspiration, especially in the obtunded, opioid-poisoned patient. Gastrointestinal decontamination should be reserved for patients presenting with potentially life-threatening coingestants, not for opioids alone, and should be performed only if the airway is secure. (See "Gastrointestinal decontamination of the poisoned patient".)

Extracorporeal removal — The large volume of distribution of the opioids precludes removal of a significant quantity of drug by hemodialysis.

Body packing and body stuffing — Body packing is described as the act of swallowing packets or containers of drug for the purposes of smuggling. Body packers are generally participants in international drug networks who are transporting massive amounts of well-packaged drugs across international borders. Heroin and cocaine are more frequently implicated than other drugs. "Body stuffing" refers to the swallowing of a smaller quantity of drug because of fear of arrest. Compared with body packers, body stuffers typically carry a far smaller quantity of drug, but the drug is more poorly packaged.

In many cases, body packers or stuffers are identified by law enforcement officials and referred to clinicians for evaluation, but a substantial number of body packers present to physicians with symptoms either related to intestinal obstruction or drug toxicity. Recognition of body packing is accomplished through the history, examination findings, and diagnostic imaging. Severe toxicity from leaking packages or large ingestions poses a major threat to these patients and aggressive interventions may be needed. Large amounts of heroin or other opioids may be released from a leaking package, requiring extremely high doses of naloxone. The presentation, diagnosis, and management of body packers and body stuffers is reviewed in detail separately. (See "Internal concealment of drugs of abuse (body packing)" and "Acute ingestion of illicit drugs (body stuffing)".)

Lung injury and ARDS — Acute Respiratory Distress Syndrome (ARDS) is a potential adverse effect of morphine, heroin, methadone, and other opioids [39-41]. The signs, which typically include crackles, hypoxia, and occasionally frothy sputum, often occur as a patient is recovering from opioid-induced respiratory depression. The pathophysiology is unclear, but in some cases ARDS occurs in the setting of iatrogenic reversal of opioid toxicity (such as with naloxone). In such cases, rapid precipitation of withdrawal in the setting of elevated PCO2 is associated with a surge in catecholamine concentrations, thereby increasing afterload, which causes interstitial edema followed by alveolar filling [32]. Because of this, very small doses of naloxone (0.04 to 0.05 mg to start) should be used on those patients with marked hypoventilation and they should be ventilated with a bag-valve mask prior to administration of naloxone. (See 'Basic measures and antidotal therapy' above and "Basic airway management in adults".)

Management of opioid and naloxone-related ARDS is supportive and the prognosis is generally good if it is identified and addressed promptly. The clinical manifestations and management of ARDS are discussed elsewhere. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Ventilator management strategies for adults with acute respiratory distress syndrome" and "Acute respiratory distress syndrome: Supportive care and oxygenation in adults".)

TREATMENT OF TOXICITY OF SPECIFIC OPIOIDS — Several opioids possess uncommon toxicities that may require specific interventions.

Loperamide — In extreme overdose (doses many times those used for antidiarrheal treatment – typically 30 to 40 pills or more), loperamide can cause ventricular conduction disturbances including QRS and QT interval prolongations, idioventricular rhythm, and ventricular tachycardia (monomorphic and polymorphic) [42,43]. Sodium bicarbonate is recommended for management of other drug-induced sodium channel toxicity [44]. The clinical benefit of this intervention is unknown, but if QRS prolongation is encountered, we recommend administering a bolus of 1 to 2 mEq/kg of sodium bicarbonate intravenously in the absence of contraindications. If the complex narrows, a bicarbonate infusion is reasonable. We mix 132 mEq of NaHCO3 in one liter of D5W, and infuse at 250 mL/hour. Since loperamide also causes QT interval prolongation, it is important to monitor potassium and magnesium if bicarbonate is given, as depletion will increase the risk for QT interval prolongation. Cardiac toxicity may persist for several days, requiring admission, ongoing cardiac monitoring, and treatment as indicated.

The management of patients with acquired QT prolongation or Torsade de Pointes is discussed separately. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.)

Methadone — Methadone can cause QT interval prolongation and Torsade de Pointes. If the QT is determined to be greater than 500 msec [45], we recommend that the patient be observed on a cardiac monitor for a 24-hour period. Hypocalcemia, hypokalemia, and hypomagnesemia should be corrected when present [46]. The clinician should consider either stopping methadone therapy, or switching to buprenorphine, if the patient's psychosocial situation permits this. (See 'Electrocardiography' above and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Fentanyl and fentanyl analogs — Fentanyl and fentanyl analogs (commonly called "fentalogs") are increasingly entering the drug supply as counterfeit tablets [47-49] or substituted for heroin [50]. These analogs include drugs such as alfentanil, remifentanil, and sufentanil, as well as drugs that are not approved for use in humans, such as carfentanil, furanylfentanyl, and others. Fentanyl is 50 to 100 times more potent than morphine and some analogs are even stronger. Despite anecdotal reports of a higher naloxone requirements for treatment, standard doses of naloxone should be sufficient to restore ventilation. (See 'Basic measures and antidotal therapy' above.)

Buprenorphine and naloxone — Buprenorphine is a partial agonist at the opioid receptor. When taken alone, buprenorphine can cause respiratory depression, but likely to a limited degree. Although most fatalities associated with buprenorphine have occurred in the setting of mixed overdose where the coingestant produced or contributed to respiratory depression (eg, alcohol or benzodiazepines), fatalities have occurred from buprenorphine toxicity alone [51].

Buprenorphine binds to the opioid receptor with high affinity. In experimental models, high doses of naloxone were needed to reverse respiratory depression. Interestingly, because of complex physiology, respiratory depression can recur with very high doses of naloxone. This effect is described as a "bell-shaped" dose-response curve and may be a result of the high affinity of buprenorphine for the opioid receptor compared to naloxone [52].

Such research has led some to conclude that respiratory depression from buprenorphine may be difficult to reverse with naloxone. In observational studies of buprenorphine toxicity, the response to naloxone is mixed. In a case series of patients with buprenorphine or methadone overdose, none of the 19 patients administered 0.4 to 0.8 mg of naloxone had an adequate response [53]. In contrast, standard naloxone doses were adequate for reversal of buprenorphine effects in a small series of pediatric patients treated in an intensive care unit for buprenorphine toxicity [54].

In the adult patient with buprenorphine-associated respiratory depression, start with naloxone 0.4 to 0.8 mg intravenously (IV) but be prepared to titrate to higher doses (single doses of up to 2 mg, for a total of 10 mg) than are typically required to treat respiratory depression from other opioids. It is unlikely that an adult patient develops significant respiratory depression from buprenorphine alone; thus, evaluate for co-ingestants that can synergistically contribute to respiratory depression. After initial reversal is achieved, a naloxone infusion is often preferable to serial boluses. Infusion dosing is described above. (See 'Basic measures and antidotal therapy' above.)

Opioid adulterants, including krokodil — Illicitly purchased drugs frequently contain adulterants, some of which may cause clinical problems distinct from the desired compound. From the perspective of the drug seller, the ideal adulterant would be inexpensive, appear and taste similar to the desired drug, and not harm the user. Nonetheless, opioids containing harmful adulterants are common.

One example is "krokodil" (from the Russian word for crocodile), a homemade formulation of the potent, short-acting opioid desomorphine [55,56]. Derived from codeine, which is available without prescription in Russia, krokodil is reported to contain solvents, such as gasoline and lighter fluid. Other potential contaminants include iodine, hydrochloric acid, and red phosphorous. Subcutaneous injection has resulted in local tissue damage, including ulcers, skin necrosis, and infection. The name of the drug is derived from the scaly skin lesions observed in some users. Such lesions are likely the result of infection and/or direct tissue injury from adulterants, as desomorphine itself would not be expected to cause tissue toxicity, and similar findings were commonly seen with subcutaneous injection of impure heroin in the 1980's in the United States. Although there is an epidemic of cases of tissue damage from krokodil injection in former Soviet republics, cases outside this region remain uncommon [55].

Alkaloids, such as quinine and strychnine, are additional examples of harmful adulterants that have been implicated in heroin-related deaths [57]. Heroin has also been tainted with the anticholinergic scopolamine and the beta-adrenergic agonist clenbuterol, both of which have caused widespread toxicity [58,59]. Xylazine, an alpha-2 receptor agonist used as a veterinary sedative that is increasingly being found in illicit heroin and fentanyl, causes clinical toxicity similar to opioids, and with repeat injection can lead to severe, necrotic skin ulcerations [60,61]. (See "Strychnine poisoning" and "Anticholinergic poisoning" and "Clonidine and related imidazoline poisoning".)

DISPOSITION — With the exception of overdoses involving long-acting opioids such as methadone, most adult patients with opioid toxicity can be managed in the emergency department (ED) without need for hospital admission, assuming there is no other medical issue of sufficient concern. Generally, the patient may be discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone has not been administered for two to three hours. Although the half-life of naloxone is just over one hour, the duration of the drug's effect is shorter. Therefore, following injection opioid use, a two- to three-hour period of observation is generally sufficient. However, in the case of a large oral ingestion, the clinician should consider the possibility of late absorption of drug (even if the drug is short acting), and a longer period of observation may be needed [62-65].

A longer period of observation is also recommended for patients who have been reversed with large doses (2 to 4 mg) of intranasal naloxone. Because of the dose administered and slow absorption, high-dose intranasal naloxone can result in "therapeutic" naloxone concentrations for three hours or even longer [66].

Management of opioid toxicity in children is discussed separately. (See "Opioid intoxication in children and adolescents".)

PREVENTION OF RECURRENT OPIOID OVERDOSE — In patients who present to the emergency department (ED) surviving an opioid overdose, the one-year mortality rate is 5.5 percent; 20 percent of those patients die in the first month after the index ED visit [67]. In individuals who have survived an opioid overdose, initiation of opioid agonist therapy is associated with decreased all-cause and opioid-related mortality compared with no medication treatment [68]. (See "Approach to treating opioid use disorder".)

ED initiation of medications for opioid use disorder (MOUD) – ED initiation of MOUD is feasible and cost effective [69,70]. When ED-initiated buprenorphine was compared with a brief psychosocial intervention and referral, patients who received buprenorphine were significantly more engaged in substance use disorder treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services [69]. Many United States EDs have successfully implemented similar programs despite multiple barriers, such as the federally required "X-waiver" for buprenorphine prescribing [71]. Similarly, EDs that made systematic efforts to implement and maintain MOUD-initiation programs were able to increase rates of buprenorphine prescribing [72]. Because at-home buprenorphine induction strategies are safe and effective, patients do not have to wait in the ED to develop opioid withdrawal prior to initiation of therapy [73]. (See "Medication for opioid use disorder".)

Take-home naloxone – The use of bystander-administered intranasal naloxone to resuscitate opioid overdose patients is well reported [64,74,75]. Providing naloxone and education to patients with OUD, as well as their family members and friends, reduces overdose mortality [76]. In one study, overdose deaths decreased from 46.6 to 29 per 100,000 following implementation of a comprehensive opioid overdose prevention program that included take-home naloxone [77]. Since 2018, all states in the United States have enacted naloxone access laws permitting dispensing and administering naloxone without a physician's prescription [78].

Other harm reduction strategies – In addition to community naloxone and MOUD initiation, harm reduction strategies include peer recovery specialist availability, brief motivational interviews, patient and family education, arranging same-day or next-day appointments at substance use disorder programs, and distributing alcohol swabs, sterile injection equipment, and fentanyl test strips [79,80]. (See "Prevention of lethal opioid overdose in the community".)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use" and "Society guideline links: Poisoning prevention".)

SUMMARY AND RECOMMENDATIONS

Background – Opioid use disorder (OUD) is a worldwide problem, and deaths from opioid overdose are numerous. (See 'Introduction' above.)

Clinical feature of overdose – Opioid intoxication a clinical diagnosis. The classic signs include depressed mental status, decreased respiratory rate, decreased tidal volume, decreased bowel sounds, and miotic pupils (table 4). The best predictor of opioid toxicity is a respiratory rate <12 breaths per minute. Normal pupil examination does not exclude opioid toxicity. In addition to suppression of respiratory rate, opioid toxicity can be complicated by hypothermia, coma, seizure, head trauma, aspiration pneumonia, and rhabdomyolysis. (See 'Clinical features of overdose' above.)

Loperamide can cause ventricular conduction disturbances, including prolongation of QRS and QT interval duration, idioventricular rhythm, ventricular tachycardia, and torsade de pointes in overdose. Methadone can cause QT interval prolongation and torsade de pointes. (See 'Toxicities of specific agents' above.)

Differential diagnosis – Any medical condition that produces coma may be mistaken for (or occur in conjunction with) opioid toxicity. The most important conditions to exclude are those in which delay of diagnosis will delay definitive care, such as intracranial hemorrhage, electrolyte abnormality, and sepsis. (See 'Differential diagnosis' above.)

Laboratory investigations – A rapid serum glucose concentration should be obtained in all suspected cases of opioid toxicity. Most patients with mild or moderate unintentional poisoning can be managed successfully without any further laboratory investigation. Urine toxicologic screens should not be routinely obtained since these screens do not change the management of a patient with an opioid overdose, a positive test indicates recent use but does not confirm active toxicity, and many synthetic opioids will produce false-negative results. (See 'Laboratory evaluation' above.)

Management – Management starts with support of the patient's airway and breathing. Bag-mask ventilation should be performed prior to and during administration of naloxone in apneic patients and patients with very low respiratory rates. Activated charcoal and gastric emptying are almost never indicated in opioid poisoning. (See 'Basic measures and antidotal therapy' above.)

In cases of suspected opioid toxicity, we recommend treatment with the short-acting opioid antagonist naloxone (Grade 1B). While the intravenous (IV) route is preferred, naloxone may be given intranasally, subcutaneously, or intramuscularly if IV access is unavailable. If a clinical effect does not occur after 5 to 10 mg, the diagnosis should be reconsidered. (See 'Basic measures and antidotal therapy' above.)

In patients with spontaneous ventilations, an initial naloxone dose of 0.04 to 0.05 mg is an appropriate starting point, and the dose should be titrated upward every few minutes until the patient is able to maintain a room air oxygen saturation above 90 percent without supplemental oxygen.

Naloxone should be titrated to a goal of adequate ventilation instead of a normal level of consciousness since "overshooting" in an opioid-dependent individual will cause withdrawal.

In apneic patients, start with a higher initial dose of naloxone (0.2 to 1 mg).

Patients in cardiac arrest should receive a dose no less than 2 mg.

Prevention of recurrent opioid overdose – The one-year mortality in an emergency department (ED) patient who survives an opioid overdose is 5.5 percent. Initiation of opioid agonist therapy (eg, buprenorphine) is associated with decreased all-cause and opioid-related mortality and is feasible and cost effective. Other harm reduction strategies include take-home naloxone, peer recovery specialist availability, arranging urgent appointments at substance use disorder programs, and distributing sterile injection equipment. (See 'Prevention of recurrent opioid overdose' above.)

Disposition – In most cases, the patient may be discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone administration has not been necessary for two to three hours. (See 'Disposition' above.)

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