Hospital Medicine
Amphetamine and methamphetamine toxicity
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Amphetamine and methamphetamine toxicity
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I. Problem/Condition.
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II. Diagnostic Approach
- A. What is the differential diagnosis for this problem?
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B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
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3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
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C. Criteria for Diagnosing Each Diagnosis in the Method Above.
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D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
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III. Management while the Diagnostic Process is Proceeding
- A. Management of amphetamine and methamphetamine toxicity.
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B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
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
IV. What's the evidence?
UNODC: World Drug Report 2015. United Nations Publication. 2015.
Results from the 2009 National Survey on Drug Use and Health. vol. I. Summary of National Findings. 2010.
"Methamphetamine use, abuse, and dependence: 2002, 2003, and 2004". NSDUH Report. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. September 2005.
The DAWN Report: Emergency Department Visits Involving Methamphetamine: 2007 to 2011. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. June 2014.
Richards, JR, Farias, VF, Clingan, CS.. "Association of leukocytosis with amphetamine and cocaine use". Scientific World Journal. vol. 2014. 2014 Jan 22. pp. 207651.
Karlsen, SN, Spigset, O, Slordal, L.. "The dark side of ecstasy, neuropsychiatric symptoms after exposure to 3,4-methylenedioxymethamphetamine". Basic Clin. Pharmacol. Toxicol.. vol. 102. 2008. pp. 15-24.
Richards, JR, Albertson, TE, Derlet, RW, Lange, RA, Olson, KR, Horowitz, BZ.. "Treatment of toxicity from amphetamines, related derivatives, and analogues: A systematic clinical review". Drug and alcohol dependence. vol. 150. 2015 May 1. pp. 1-13.
Leelahanaj, T, Kongsakon, R, Netrakom, P.. "A 4-week, double-blind comparison of olanzapine with haloperidol in the treatment of amphetamine psychosis". J. Med. Assoc. Thail.. vol. 88. 2005. pp. 43-52.
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