Amphetamine and methamphetamine toxicity

I. Problem/Condition.

Amphetamine and methamphetamine are both sympathomimetic amines that are classified as phenethylamines.

These substances are best known for their central nervous system (CNS) stimulation, anorexiant and euphoric effects, with methamphetamines having both greater CNS activity and half-life to that of amphetamines. They elicit their effects by three neurochemical mechanisms: (1) stimulating catecholamine release of norepinephrine, dopamine, and serotonin, (2) blocking reuptake of these catecholamines, and (3) inhibiting monoamine oxidase. The designer derivative of amphetamine (3,4-methylenedioxymethamphetamine [MDMA]) is more selective for the serotonin transporter whereas methamphetamine and amphetamine are more selective for the norepinephrine and dopamine transporters.

Amphetamine toxicity should be suspected in patients with diaphoresis, hypertension, hyperthermia, tachycardia, mydriasis, severe agitation, and/or psychosis (paranoia, hallucinations, violent behavior).

Amphetamine and methamphetamine are classified as schedule II drugs by the Drug Enforcement Administration/Food and Drug Administration (DEA/FDA), and in the United States, they are clinically prescribed for the treatment of attention deficit disorder with hyperactivity (ADHD), obesity and narcolepsy.

Due to their stimulatory effects resulting in euphoria, increased alertness, energy and sexual pleasure, they also have a high propensity for abuse. Amphetamines are noted to produce a euphoria similar to that of cocaine, however with a much longer duration of action. The duration of action of methamphetamine is about 20 hours, whereas the duration of action of cocaine is about 30 minutes.

Due to its highly lipophilic structure, methamphetamine can be taken in a variety of ways including inhalation (smoking), per oral (PO), intravenously (IV), intramuscularly (IM), intranasally, via nasal insufflation (snorting), and rectally. Due to its varying routes of absorption, longer duration of action and cheap cost, it remains attractive to users.

Because of euphoric effects, relative ease of synthesis, low cost, and increase in demand, amphetamines and their derivatives are widely abused among North Americans. After marijuana, methamphetamines and amphetamine type stimulants (i.e., MDMA) are the second most widely abused drugs worldwide.

According to the 2014 National Survey on Drug Use and Health, approximately 1.6 million Americans aged 12 or older were current users of nonmedical stimulants.

Users cross all socioeconomic lines; men were slightly more likely to use than women. The average age of first use is between the ages of 18 to 25. In 2007, there were 67,954 amphetamine related emergency department visits, which rose to 102,961 visits in 2011. In 2011, 62% of patients seen for a methamphetamine-related emergency department visit also tested positive for one or more other drugs, thus indicating that methamphetamine use is often concomitant with other drugs of abuse.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Central nervous system

• CNS stimulation (agitation, delirium or psychosis)

• Altered mental status

• Seizure

• Heat stroke

• Intracranial hemorrhage

Cardiovascular

• Hypertensive urgency or emergency

• Cardiac arrhythmias/ventricular arrhythmias

• Myocardial infarction/ischemia

• Congestive heart failure

• Cardiovascular collapse

Respiratory

• Pulmonary edema

• Pneumothorax

• Reactive airways disease

Integumentary

• Cellulitis/erysipelas

• Abscess

• Excoriation

• Thermal burns

Renal

• Acute renal failure

• Pheochromocytoma

• Rhabdomyolysis

• Hyperkalemia

Endocrine/metabolic

• Thyroid storm

• Metabolic acidosis

Infectious disease

• Sepsis

• Hepatitis B, C

• Human immunodeficiency virus (HIV)

Gastrointestinal

• Obstruction

• Ulcers

• Ischemic colitis

Psychiatric

• Acute manic episode

• Schizophrenia

Toxicological

• Cocaine toxicity

• Amphetamine/methamphetamine derivative toxicity

• Serotonin syndrome

• Monoamine oxidase inhibitors (MAOI) overdose

• Phencyclidine poisoning

• Theophylline poisoning

• Hallucinogenic toxicity

• Anticholinergic overdose

• Neuroleptic malignant syndrome

B. Describe a diagnostic approach/method to the patient with this problem

Amphetamine toxicity is largely a clinical diagnosis where the clinician recognizes the key features of sympathomimetic stimulation: diaphoresis, tachycardia, hypertension, mydriasis, hyperthermia and agitation. Urine toxicology screens can aide in the diagnosis, but should not be relied upon given that several substances can interfere with the assay (i.e., buproprion, labetalol, and fenofibrates can cause a false positive result). Furthermore, drug toxicology can be erroneous and delaying care while awaiting their results can have negative implications on patient outcome. In cases of amphetamine and methamphetamine toxicity, it may not be possible to assess and evaluate a patient because severe agitation, paranoia, hallucinations, and/or psychosis may be present, requiring sedation.

1. Historical information important in the diagnosis of this problem.

As with any ingestion, whenever possible, obtaining a detailed history is of the utmost importance. Type of drug, amount taken, last ingestion time, frequency of use, route, and co-ingestants can guide in therapeutic interventions. It is important to remember that often times these drugs are manufactured illegally, without oversight, and therefore the true composition and purity are difficult to establish. However, it is not recommended to delay care while identifying the offending agent or agents.

Other obstacles to evaluation may be during the acute withdrawal phase, defined as the first week of abstinence, where the user “crashes”, and may appear lethargic, paranoid and have greater need for sleep. Many users go on “binges,” which can last for days to even weeks, and can result in catecholamine depletion, worsening these symptoms. Special attention should be made for individuals who have attempted to conceal drugs to avoid arrest or are attempting to transport large quantities internally as “body packers.”

The user can present with a wide variety of signs and symptoms following use. Some of these issues can be acute, while other issues chronic. During the acute phase, diaphoresis, hypertension, tachycardia, mydriasis, agitation, and even psychosis can be present.

Constitutional

• Fevers, chills, night sweats

• Malaise/lethargy

• Weight loss

• Poor intake

Cardiovascular

• Chest pain

• Palpitations/tachycardia

Central nervous system

• Headache

• Abnormal movements

Respiratory

• Wheezing

• Dyspnea

• Shortness of breath

Integumentary

• Excessive sweating

• Rash, pruritus

• Abscess, cellulitis

Gastrointestinal

• Abdominal pain

• Nausea/vomiting

• Constipation/diarrhea

• Jaundice

• Rectal pain

Psychiatric

• Akathisia

• Agitation

• Anxiety

Gynecologic/obstetric

• Abnormal bleeding

Dental

• Mouth/tooth pain

• Tooth decay

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

General

• Diaphoresis

• Malnourishment, on average methamphetamine users have lower BMI

• Disheveled appearance

Head, eyes, ears, nose, throat

• Minimally reactive mydriasis

• Bruxism

• Trismus

• Mucosal injury/burns

• Poor dentation/tooth decay (“meth mouth”)

• Dental abscess

Cardiovascular

• Tachycardia

• Hypertension

• Murmur

Pulmonary

• Tachypnea

• Wheezing

Central nervous system

• Hyperthermia

• Confusion

• Focal deficits

• Seizures

• Coma

• Akathisia

Psychiatric

• Anxiety

• Agitation

• Delirium

• Psychosis

• Hallucinations

Integumentary

• Diaphoresis

• Bruising and injuries

• Track marks

• Abscess

• Excoriation

Gastrointestinal

• Abdominal pain

• Nausea/Vomiting

Musculoskeletal

• Muscle rigidity

• Myoclonic jerks

• Twitching

• Choreiform movements

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory and radiological testing depends on the severity of the intoxicated patient and should be expanded based on the history and physical. It is important to consider the patient's preferred method or methods of drug administration, which can guide the clinician in what additional testing may be most beneficial. One must always consider infection (endocarditis, abscess, cellulitis, hepatitis, HIV, etc.) in individuals who administer the drug IV.

As amphetamine intoxicated patients are at risk for developing hyperthermia, metabolic acidosis, renal failure, and rhabdomyolysis, a basic metabolic panel along with a creatinine phosphokinase (CPK) is indicated in all patients. Additional testing should be tailored to each patient.

• Basic metabolic panel: to monitor for hyperkalemia, acute renal failure and metabolic acidosis

• Fingerstick glucose: to rule out hypoglycemia

• Acetaminophen and salicylate levels: to rule out common coingestants

• Urine toxicology screen: used to support diagnosis and to determine concurrent use of other intoxicants

• Electrocardiogram (EKG): to evaluate for conduction impairment (prolonged QRS complex, Q-T interval), ventricular arrhythmias and ischemia

• Liver function test: to monitor for acute hepatotoxicity or liver failure

• Lactate: if concern for acidosis

• Clotting times: (prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, platelets) if disseminated intravascular coagulopathy is suspected

• Complete blood count (CBC): if concern for infection. Note, idiopathic leukocytosis can be present in acute amphetamine toxicity

• CPK and urine myoglobin: if rhabdomyolysis is suspected

• Pregnancy test: for women of childbearing age

• Lumbar puncture: if concern for infection

• Computed tomography (CT) head: if concern for an intracranial process

• HIV: for individuals who practice high-risk sexual behaviors or use IV

• Viral hepatitis panel: for individuals who practice high-risk sexual behaviors or use IV

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

N/A

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Urine drug testing for amphetamines and methamphetamines can be erroneous and therefore supportive care should not be delayed while awaiting their results. It however may support the clinical diagnosis and also provides information on common drugs of abuse, which may have been taken concurrently.

III. Management while the Diagnostic Process is Proceeding

A. Management of amphetamine and methamphetamine toxicity.

Amphetamine and methamphetamine clinically manifest as a sympathomimetic toxidrome characterized by tachycardia, hypertension, agitation, dilated pupils, and bronchodilatation. Management and treatment of the symptomatic patient is mainly supportive care in addition to monitoring heart rate, blood pressure, temperature, and mental status.

Following the acronym ABC (airway, breathing, circulation) along with establishing good intravenous access is essential. Management of the patient’s agitation is of the utmost importance. Patients may suffer from severe agitation, psychosis, hallucinations, and show tendencies of extreme violence towards others. In some cases the patient requires physical restraint to protect themselves and others. In severe cases, patients may require paralysis and intubation.

Benzodiazepines are the drug of choice for controlling anxiety, agitation, hypertension, and tachycardia. Patients with evidence of end-organ damage, focal neurological deficits, arrhythmias, delirium, or uncontrolled agitation should be admitted for observation.

Consultation with a toxicologist and/or the local poisoning control center may be indicated. Substance abuse referral should also be made prior to discharge.

Activated charcoal

It is recommended to give activated charcoal if the ingestion occurred within the previous hour. 1–2 gram/kilogram (g/kg) up to 100 g PO.

Anxiety and agitation

Cardiovascular collapse has been precipitated by severe agitation requiring physical restraints.

Benzodiazepines:

• Diazepam: 5–10 milligram (mg) IV every 15 minutes, titrated to effect

• Lorazepam: 2–6 mg IV every 15 minutes, titrated to effect

• In general, benzodiazepines were successful in controlling agitation, but not psychosis

Treating psychosis with first and second generation antipsychotics is the first line treatment.

Butyrophenones:

• Haloperidol lactate: 5-10 mg IV or IM, may repeat every hour as needed

• Droperidol: 2.5 mg IV or IM initially, with 1.25 mg incremental doses (consider risk benefit ratio, obtain baseline EKG and monitor EKG for prolonged QT interval).

Antipsychotics:

• Ziprasidone 10 mg PO or IM

• Olanzapine 5-10 mg po

• Quetiapine 100 mg po

Hypertension and tachycardia

• Nitroprusside: 0.1–0.5 microgram/kilogram/minute (mcg/kg/min) IV, increase by 0.5 mcg/kg/min (titrated to blood pressure)

• Phentolamine: (class IIb) 1–5 mg IV over 5 minutes (titrated to blood pressure)

• Hydralazine 10–20 mg IV push slow, may be repeated every 4–6 hours

A beta-blocker may be used, but given the theoretical risk of unopposed alpha stimulation, it is recommended that a combined beta and alpha blocker be utilized, such as carvedilol or labetalol. Use of a beta-blocker without alpha blockade may result in paradoxical increase in blood pressure (BP) given unopposed alpha-receptor stimulation.

Labetalol:

• 20 mg IV push over 2 minutes. May repeat 20 to 80 mg every 10 minutes (up to 300 mg total dose) until desired BP is reached or start continuous infusion: 2 mg/minute (range: 1 to 3 mg/minute), titrate to blood pressure.

Esmolol:

• 500 mcg/kg IV bolus over 1 minute, followed by infusion 50-100 mcg/kg/min titrated to effect

Seizures

• Diazepam: 5–10 mg IV push initially, may repeat every 5–10 minutes as needed. Consider a second agent if seizures persist or recur after diazepam 30 mg

• Lorazepam: 2–4 mg IV push initially, may repeat every 10 minutes as needed

• Phenobarbital: 15–20 mg/kg at 25–50 mg/minute until cessation of seizure activity

Rhabdomyolysis

• Trend CPK, renal function and potassium frequently

• IV hydration with 0.9% saline

• Monitor intake and output with a goal of at least 2–3 milliliters/kilogram

• Nephrology consult

Hyperthermia

• IV hydration with 0.9% saline

• Cooling blanket

• Evaporative cooling

• Frequent monitoring of temperature

• Antipyretics such as acetaminophen are of no benefit

• For severe cases intubation and sedation with a non-depolarizing neuromuscular blocker is indicated

• Avoid succinylcholine as it may lead to life threatening hyperkalemia

Myocardial infarction

• EKG

• Cardiac enzymes

• Aspirin

• Heparin

• Morphine

• Nitrates

• Oxygen

• Cardiology consultation

• Refrain from utilizing beta blockers

Cerebrovascular accident

• Non contrast CT of the head

• Frequent neurological checks

• Consult neurology

Cardiac arrhythmias

• Many arrhythmias are self-limiting

• Cardiac monitoring

• Advanced cardiac life support (ACLS) protocol if indicated

• Cardiology consultation

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

• Failure to diagnose and treat the following:

  • - Disseminated intravascular coagulopathy

  • - Rhabdomyolysis

  • - Hyperthermia

  • - Myocardial infarction

• Failure to identify patients who have concealed large amounts of amphetamines or methamphetamines within body cavities (body packers)

• Failure to recognize that cardiovascular collapse has been precipitated by severe agitation requiring physical restraints

• Failure to consult a board certified toxicologist or the local poison control center