Dextromethorphan Toxicity

Etiology

The use and misuse of dextromethorphan can cause dextromethorphan toxicity.[3]

Epidemiology

Dextromethorphan received FA approval in 1958. Recreational misuse began shortly thereafter. Drug companies attempted to blunt its misuse by developing liquid formations that required consumption of a significant amount for CNS effects to be achieved. However, misuse was still common. In the United States, abuse of dextromethorphan leads to approximately 6000 emergency department visits a year.[3] Fifty percent of all emergency department visits due to dextromethorphan toxicity occur in patients between the ages of 12 and 20.  Dextromethorphan is often combined with antihistamines, pseudoephedrine, and acetaminophen in many cough and cold medications, which can cause additional adverse clinical effects in the setting of overdose.[1] Ethanol is a common coingestant.[4] Abusers will sometimes attempt to extract dextromethorphan from the cough and cold medications by performing a 1 or 2 phase acid extraction using household products such as ammonia, lighter fluid, and lemon juice.[5]

Pathophysiology

Dextrorphan, the active metabolite of dextromethorphan, causes a variety of physiological effects via several different mechanisms. Like ketamine and phencyclidine, dextrorphan blocks NMDA receptors resulting in hallucinations, euphoria, dissociation, agitations, and coma.[3] Dextrorphan binds serotonin receptors, potentially leading to serotonin syndrome (seizures, muscle rigidity, autonomic instability, rhabdomyolysis).[6][7][8] This activity can occur in the settings of overdose and standard doses when combining dextromethorphan with SSRIs, SNRIs, MAOIs, cocaine, TCAs, or other serotonergic agents.[7][8] Dextrorphan also blocks the reuptake of peripheral adrenergic neurotransmitters, causing hypertension, tachycardia, mydriasis, and diaphoresis.[3][2] Dextrorphan does not bind mu or delta opioid receptors but binds sigma opioid receptors leading to antitussive effects.[1]

Toxicokinetics

Dextromethorphan has a half-life of 3 to 30 hours.  It is metabolized in the liver by the cytochrome p450 system and is mainly excreted by the kidneys.[3]  The volume distribution is 5 to 6.7 L/kg.[3]  Peak plasma concentration occurs at 2.5 hours.[9]  In immediate-release formulations, standard doses range from 5mg to 30mg with the maximum amount of 120mg in a 24 hour period.[9]  In extended released formations, 60mg is the standard dose with a maximum amount of 120mg in a 24 hour period.  At doses of 100mg to 300 mg, symptoms ranging from mild stimulation to euphoria and hallucinations can occur.  At doses of 300mg to 600mg, dissociation can occur. At doses of 600mg or higher, complete dissociation and coma can occur.[9]

History and Physical

Depending on the dose and coingestants, dextromethorphan can cause a broad spectrum of clinical effects ranging from mild agitation to psychosis to seizures and coma. Many times, patients are unable to give a clear history due to altered mental status. Obtaining a history from emergency medical personnel, family, friends, and witnesses can be helpful. Familiarity with street names for dextromethorphan can be helpful as well.

• General – hyperthermia, diaphoresis, altered mental status (ranging from mild agitation to coma)
• HEENT – mydriasis, nystagmus
• Cardiovascular – tachycardia, hypertension
• Respiratory- respiratory depression
• Neurological – mild to severe agitation, confusion, hallucination, ataxia, muscular rigidity, seizures, coma

Trauma -  thorough examination for evidence of trauma should take place in the examination as injury secondary to dextromethorphan intoxication can occur due to altered mental status.[3][4][8][10]

Evaluation

The workup considered should include the following:

• Dextromethorphan level - not available at many hospitals
• Fingerstick blood glucose - helpful in all patients with altered mental status
• Complete blood count – leukocytosis can be seen
• Basic metabolic panel- identify electrolyte abnormalities, evaluation of kidney function as dextromethorphan predominantly undergoes renal excretion.
• Liver function tests - acetaminophen can be toxic to the liver and is often combined with dextromethorphan in many medications.
• Creatine kinase - evaluation for rhabdomyolysis
• Acetaminophen level - acetaminophen is often combined with dextromethorphan in many medications.
• Salicylate level - helpful in evaluating patients with acid-base disturbances, altered mental status
• Ethanol level is useful in evaluating patients with altered mental status and is often a coingestant with dextromethorphan toxicity.
• EKG - evaluation tachycardia
• Imaging studies - should be performed when there is a concern for trauma or aspiration secondary to dextromethorphan toxicity.
• Urine drug screen- can be helpful to identify potential substance coingestion[3][6][9]

Treatment / Management

Most patients with dextromethorphan toxicity are successfully managed with supportive care. Airway, breathing, circulation, and hemodynamic monitoring are essential to the care of patients with dextromethorphan toxicity. Intubation with ventilator support may be necessary for airway protection.  A medical toxicologist consult should also take place.[9]

Sedation with medication and physical restraints may be required to control agitation, violent behavior, and psychosis due to dextromethorphan toxicity. Placing the patient in a calm environment such as a quiet room with the light dimmed may be helpful. Benzodiazepines are the preferred medication for chemical sedation in patients with dextromethorphan toxicity. Lorazepam 2 mg to 4 mg intravenous or intramuscular is recommended for chemical sedation. Repeated doses every 10 minutes may be required for adequate sedation.[3]

Gastrointestinal decontamination with activated charcoal is most efficacious for dextromethorphan overdose when given within one hour of ingestion.  Activated charcoal (1 g/kg, max 50g) by mouth or nasogastric tube is recommended if there are no contraindications to activated charcoal. Gastric lavage or induced emesis is not recommended.[9]

Naloxone can treat respiratory depression and central nervous system depression due to dextromethorphan toxicity. Naloxone 0.1mg/kg with a maximum dose of 2mg IV is the recommendation.[11]

Hyperthermia induced by dextromethorphan toxicity should be treated with active cooling measures such as evaporative cooling, cold IV fluids, and cold inspired oxygen.[4][9]

It is important to consider that dextromethorphan is routinely combined with acetaminophen, decongestants, and antihistamines in many cough and cold medications, evaluating and treating acetaminophen toxicity decongestant toxicity and anticholinergic toxicity should be considered.[3][12]

Patients with dextromethorphan toxicity can be discharged home if they are asymptomatic for six hours after ingestion if they are not suicidal and have a negative acetaminophen level. Symptomatic patients and patients with complications such as hyperthermia, serotonin syndrome, hypertensive crisis, or rhabdomyolysis should be admitted to the ICU. Patients who are suicidal should have a psychiatric consultation.[3][4]

Differential Diagnosis

• Alcohol intoxication
• Amphetamine intoxication
• Anticholinergic poisoning
• Bipolar disorder
• Brain neoplasms
• Cocaine toxicity
• Diphenhydramine toxicity
• Delirium tremors
• Encephalitis
• Hyperthyroidism
• Hypoglycemia
• Hyponatremia
• Hypoxia
• Lysergic acid diethylamide (LSD) toxicity
• Malignant hyperthermia
• MDMA toxicity
• Neuroleptic malignant syndrome
• Serotonin syndrome
• Salicylate poisoning
• Toxic alcohol poisoning
• Trauma (self-induced or accidental)
• Meningitis/encephalitis
• Schizophrenia
• Sepsis
• SSRI toxicity[3][4][13]

Prognosis

Management of most patients with dextromethorphan toxicity is with supportive care. Airway, breathing, circulation, and hemodynamic monitoring are essential to the care of patients with dextromethorphan toxicity. Intubation with ventilator support may be necessary for airway protection.[4]

Complications

• Seizures
• Hypertensive emergency
• Coma
• Serotonin syndrome
• Rhabdomyolysis
• Psychosis
• Respiration depression/apnea[3][4][12]