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Review article: amphetamines and related drugs of abuse

Emergency Medicine Australasia (2008) 20, 391–402
Review article: Amphetamines and relateddrugs of abuse Shaun L Greene, Fergus Kerr and George BraitbergDepartment of Emergency Medicine, Austin Health and Victorian Poisons Information Service,Melbourne, Victoria, Australia Abstract
Acute amphetamine toxicity is a relatively common clinical scenario facing the Australa-sian emergency medicine physician. Rates of use in Australasia are amongst the highest inthe world. Clinical effects are a consequence of peripheral and central adrenergic stimula-tion producing a sympathomimetic toxidrome and a spectrum of central nervous systemeffects. Assessment aims to detect the myriad of possible complications related to acuteamphetamine exposure and to institute interventions to limit associated morbidity andmortality. Meticulous supportive care aided by judicial use of benzodiazepines forms thecornerstone of management. Beta blockers are contraindicated in managing cardiovascularcomplications. Agitation and hyperthermia must be treated aggressively. Discharge ofnon-admitted patients from the emergency department should only occur once physiologi-cal parameters and mental state have returned to normal. All patients should receiveeducation regarding the dangers of amphetamine use.
Key words:
An estimated half a million Australians used an Amphetamine was first synthesized in Germany in amphetamine-type stimulant during a 12-month period 1887. Plant-derived stimulant ephedra (ma huang) con- in 2003–2004, making amphetamines the second taining the alkaloids ephedrine and pseudoephridrine most commonly used illicit drugs in Australia after has been used in traditional Chinese medicine for over cannabis.1,2 Amphetamines and related substances are 5000 years to treat asthma and the common cold.
widely abused in New Zealand;3 hence, amphetamine Amphetamine was not used clinically until the 1920s toxicity is a relatively common clinical scenario facing following reduced availability of ephedrine, used to the Australasian emergency medicine physician.
treat asthma. The discovery of dextroamphetamine and Shaun Greene, Austin Health, 145 Studley Road, PO Box 5555, Heidelberg, Vic. 3084, Australia. Email: shaun.greene@austin.org.au or Shaun L Greene, MBChB, MSc, Registrar in Emergency Medicine, Clinical Toxicologist; Fergus Kerr, MB BS, FACEM, MPH, Director EmergencyMedicine, Clinical Toxicologist; George Braitberg, MB BS, FACEM, FACMT Dip Epi Biostats, Professor of Emergency Medicine, Director ofEmergency Medicine, Clinical Toxicologist.
2008 The AuthorsJournal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine methamphetamine quickly followed. A nasal deconges- sparse. A recent prospective 3-month study in Western tant containing amphetamine was marketed in 1932.4 Australia found presentations related directly or casu- Widespread abuse led the Food and Drug Administra- ally to amphetamine use comprised 1.2% of all ED tion (FDA) to ban amphetamine inhalers in 1959.5 presentations, with an associated admission rate of Amphetamines were widely used as stimulants 39.7% and psychiatry service assessment in 37.2% of during World War II, and for diverse clinical conditions, cases.20 An Australasian Triage Scale of 1, 2 or 3 was including shock, barbiturate overdose, encephalitis, assigned to 66.7% of patients, indicating a high degree obesity and postural hypotension. Over 10 billion tablets containing amphetamines had been legally manufactured by 1970; the majority were used illicitly.6,7 methamphetamine-related in Australia in 2005 (a rate Following passage of the Controlled Substance Act in of 5.9/million persons), a reduction from seventy-five 1970 in the USA, amphetamine abuse rates decreased.8 (6.6/million persons) in 2004.16 However, 26 deaths However, the 1980s witnessed an explosion in clandes- were classified as a direct result of methamphetamine tine production of ‘designer’ amphetamines, the best toxicity in 2005 compared with 17 in 2004.16 Although methamphetamine deaths attract regular media atten- (MDMA) and 3,4-methylenedioxyethamphetamine.9–11 tion, opioid-related deaths are far greater: 374 deaths A later resurgence in methamphetamine abuse fol- were reported in 2005 (32.5/million persons).16,21,22 lowed production of a high-purity formulation knownas ‘ice’.12,13 The 1990s rave scene brought widespreaduse of MDMA and methamphetamine in Europe, Structure and pharmacology
North America and Australasia. Production of otherdrugs with similar chemical structures, including Amphetamines are derived from phenylethylamines; 1-benzylpiperazine (BZP), followed.1–3,14–18 structural similarities to adrenaline are illustratedin Figure 1. Phenylethylamines are primarily central Epidemiology
nervous system (CNS) stimulants. Substitution of addi-tional chemical entities to ethyl chain carbon atoms Although the estimated 620 000 amphetamine users in (arrows in Fig. 1), aromatic ring and terminal amino Oceania account for only 2.5% of total worldwide users nitrogen produces variable clinical effects.
(estimated 24.8 million), this region has the highest total Entry of amphetamines into the cell cytoplasm occurs rate (2.9%) of use among 15- to 64-year-olds.14 MDMA predominantly via neuronal monoamine re-uptake use among Australasians is estimated at 3.0%, com- transporters.23 Amphetamines also act as substrate for pared with a global average of 0.2%.14 The Australian these transporters, stimulating an exchange diffusion 2007 National Drug Strategy Household Survey of 25 000 Australians aged 14 years and over found that transmitter release. Inhibition of cellular monoamine 2.3% reported use of amphetamine/methamphetamine re-uptake therefore occurs via direct drug-monoamine in the previous 12 months, a decrease from 3.2% in competition for the re-uptake transporter, and trans- 2004 and 3.4% in 2001.1 Lifetime use of amphetamine/ porter stimulation to act as a reverse carrier.23 Am- methamphetamine is higher among men (7.7%) versus phetamines inhibit intracellular vesicular monoamine women (4.9%).1 Lifetime use of amphetamine in NewZealand was reported at 9% in 2004.3 During 2006, 15% of New Zealanders aged 13– 45 years reported using legally available ‘party pills’, containing BZP or trifluorophenylmethylpiperazine(TFMPP).17 Legislation was passed in April 2008, classifying BZP as a restricted substance (C1).19 ED experience
Published information documenting amphetamine- Figure 1.
Chemical structure of adrenaline and phenylethy- related ED attendances globally and in Australasia is Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine transporter 2, reducing vesicular monoamine storage mixed with other pharmacologically active ingredients, and increasing cytoplasmic monoamine concentra- including ephridrine, cocaine and heroin. Amphet- tions.24 Ultimately, acute toxicity is produced by amines used for medicinal purposes can be abused: excessive extracellular noradrenaline, dopamine and methylphenidate used to treat ADHD and the anti- serotonin. The most obvious clinical manifestation obesity drug phentermine (Adipex-p, fastin).
is the alpha- and beta-adrenergic receptor-mediatedsympathomimetic toxidrome.
Amphetamines are lipophilic weak bases, have large Clinical effects
volumes of distribution and are not readily metabolizedby monoamine oxidase or catechol-O-methyl trans- Amphetamines produce a wide range of clinical effects ferase.25 As a group, amphetamines generally have good via modulation of peripheral and central catecholamine bioavailability, moderate to long durations of action neurotransmitter function. The typical clinical picture (half-lives 2.5–30 h), and are not amenable to extracor- is one of adrenergic system overdrive producing a poreal elimination methods. Long half-lives can lead to sympathomimetic toxidrome of tachycardia, tachyp- accumulation following repetitive dosing (associated noea, diaphoresis, hypertension, hyperthermia, mydria- with binge use).26 Routes of elimination vary, but are sis, hyperreflexia, tremor and a wide range of CNS predominantly a combination of hepatic biotransforma- states (hyperarousal, agitation, paranoia, hallucinations, tion and urine pH-dependent renal excretion.25,26 dis-inhibition, seizures and coma).9,28–30 Hyperthermia, hepatotoxicity and electrolyte abnor- malities are possible following amphetamine use.9,29,31 Manufacture
Serotonergic amphetamines can produce clinical mani-festations of serotonin toxicity.9,30,31 Clinical manifesta- tions of acute and chronic amphetamine toxicities are pharmaceutical, industrial and agricultural products available to the public. Other derivatives, includingMDMA, are more difficult to synthesize. Home produc-tion methods are easily found with the aid of an Internet Selected amphetamines
Methamphetamine is produced through reduction of Characteristics of the commonly abused amphetamines ephredrine or pseudoephedrine.27 Illicit methamphet- are summarized in Tables 2–4. Associated slang names amine production is not without risk. Corrosive injuries, dermal and inhalation burns, and chemical explosionscan occur.5,27 Methamphetamine
Methamphetamine is often mixed or ‘cut’ with other substances, including caffeine or talc, to add bulk, Improved production methods produce methamphet- improving profit margin. Amphetamines are often amine in the dextro-isomer form that is 80–90% pure.13 Clinical manifestations of amphetamine toxicity Tachycardia, hypertension, aortic dissection, arrhythmias, vasospasm, acute coronary syndrome, hypotension (late sign), acute cardiomyopathy Agitation, paranoia, euphoria, hallucinations, bruxism, hyperreflexia, intracerebral haemorrhage, choreoathetoid movements, anorexia, hyperthermia, seizures, coma Mydriasis, diaphoresis, tremor, tachypnoea Hepatitis, nausea, vomiting, diarrhoea, gastrointestinal ischaemia Hyponatraemia (dilutional/SIADH), acidosis Behavioural/psychiatric illness, cardiomyopathy, cardiac valve disease, pulmonary hypertension, vasculitis ARDS, Adult respiratory distress syndrome; SIADH, syndrome inappropriate anti diuretic hormone. Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Predominant sympathomimetic actions, greater peripheral sympathomimetic effects than VD 3–5 L/kg, 20% plasma protein bound, hepatic metabolism, 30% renal elimination, 10–13 h, Powder or tablet. Ingested, injected, vaporized (smoked), insufflated (snorted), taken Euphoria, hyper-stimulation, increased stamina and sexual drive, decreased appetite Predominant sympathomimetic actions, most potent cardiovascular effects of all amphetamines, greater central VD 3–7 L/kg, hepatic metabolism, 40–50% renal elimination, half-life 8–12 h, active metabolites – amphetamine, Powder, tablet, crystal, liquid. Ingested, injected, vaporized (smoked), insufflated (snorted), taken sublingually Euphoria, increased stamina, energy, concentration and sexual drive, decreased appetite Bruxism, agitation, paranoia, formication, violent behaviour, high-risk sexual activity Properties of 3,4-methylenedioxymethamphetamine5,11,27,33 Potent serotonergic agent, less sympathomimetic effects than amphetamine/methamphetamine 35% hepatic metabolism subject to CYP2D6 genetic polymorphism, 65% renal elimination, half-life 7–9 h, active metabolite 3,4-methylenedioxyamphetamine Colourful tablets most common, 50–200 mg per dose ‘enactogen’ – euphoria, inner peace, social facilitation, ‘heightens sexuality and expands consciousness’, mild hallucinogenic effects Bruxism, hyperthermia, ataxia, confusion, hyponatraemia (SIADH), hepatitis, muscular rigidity, rhabdomyolysis, DIC, renal failure, hypotension, serotonin syndrome, chronic mood/memorydisturbances 3,4-Methylenedioxymethamphetamine (love drug), 3,4-Methylenedioxyethamphetamine (Eve) SIADH, syndrome inappropriate anti-diuretic hormone; DIC, disseminated intravascular coagulation. Slang names of commonly abused amphetamines and piperazines Amp, Bennies, Black beauties, Browns, Cranks, Fives, Goey, Hearts, Louee, Speed, Uppers, Solid – Meth, Speed, Whiz, Fast, Base, Pure, Point, P, Rabbit, Tail, WaxLiquid – Red Speed, Liquid red, Leopard’s blood, Ox bloodCrystal – Ice, d-meth, Glass, Crystal, Batu, Shabu Adam, Bart Simpson, Clarity, Disco biscuits Essence, E, Ecstasy, Love drug, Red and black, Bliss, BNZ, Bolts, Charge, Exodus, Frenzy, Goodstuff, Grins, Herbal Ecstasy, Herbal party pills, Jumps, Kandy, Legal ecstasy, Legal E, Legal X, Nemesis, Red hearts, Sliver bullet Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Crystal methamphetamine is the hydrochloride salt Gee et al. documented 80 BZP presentations to a of methamphetamine. Heating and inhaling crystal- major New Zealand urban ED over a 6-month period line methamphetamine fumes (or ‘chasing the white in 2005.18 Fifteen (19%) suffered generalized seizures, dragon’) is the most rapid method of obtaining a ‘high’.34 two had status epilepticus and severe respiratory and Methamphetamine hydrochloride is dissolvable in metabolic acidosis. Common adverse effects (>15% water and can be injected or ingested as a liquid. Meth- of patients) included palpitations, vomiting, collapse, amphetamine powder is readily absorbed across mucus membranes and can be snorted, ingested or insertedrectally. Powder can be injected, as a ‘dry shot’.32 Assessment and management
drive and dis-inhibition. Widespread use in the gaycommunity in the USA has increased rates of HIV Immediate management
seroconversion and transmission of other sexuallytransmitted diseases.35,36 Airway, breathing and circulation are initial priorities.
Significant agitation, hyperthermia, cardiovascular, neu-rological or respiratory compromise mandates triage to a Substituted amphetamines
resuscitation area, and immediate assessment and treat- MDMA and related amphetamines with additions to ment. Patients with altered conscious state require a the aromatic ring structure are known as substituted bedside blood sugar level determination. Cardiac arrest amphetamines. Clinically, they are characterized by is treated using advanced life support protocols. Poten- enhanced hallucinogenic properties and potent CNS tial hyperkalaemia caused by muscle damage and acido- sis should be considered early during resuscitation.
Para-methoxyamphetamine is a powerful halluci- nogen and sympathomimetic, associated with intra-cerebral haemorrhage, hyperthermia and death.39 Assessment
2,5-Dimethoxy-4-methylamphetamine is a potent hal-lucinogen with narrow therapeutic index, produc- ing perceptual distortions and euphoria.40 4-Bromo- 2,5-dimethoxyamphetamine is an extremely potent (as reported by the patient), method, quantity and time of exposure. Knowledge of place of exposure is effects, and is commonly used as a preparation on important. Patients who have been in crowded clubs impregnated paper, similar to Lysergic acid diethyla- with high ambient temperatures are at increased risk mide (LSD). 4-Bromo-2,5-dimethoxyamphetamine pro- duces severe arterial spasm. One limb amputation has Complaints of chest pain, palpitations, dizziness, been reported.41 4-Bromo-2,5-dimethoxyphenethylamine headache, focal neurological changes and visual distur- (2CB, MFT), a popular rave drug known as ‘nexus’, bance suggest significant toxicity and require rapid produces relaxation, euphoria and altered perception.42 Relevant history following amphetamine exposure Piperazines
Presumed identity, route, time and quantity of amphetamine BZP and TFMPP are members of the piperazine family and therefore not strictly amphetamines. Related chemi- Presence of chest pain, palpitations, headache, focal neurological cal structures cause similar clinical effects, so that even regular amphetamine users are often unable to differen- Coingestants including ethanol and other stimulant drugs tiate between them.43 BZP inhibits re-uptake of dopam- Quantity of water and other fluids ingested ine and serotonin and stimulates peripheral alpha-2 Use of any CYP2D6 inhibitors (including SSRI, MAOI) receptors, but exhibits lower potency than amphet- Coexisting cardiac, respiratory or neurological disease amine.44,45 TFMPP is more serotonergic and produces Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Co-ingestants, including mononamine oxidase inhi- Clinical signs indicating significant amphetamine bitors, tricyclic antidepressants and other stimulant drugs, are synergistic.50 Cocaine is a hepatic microsomal CYP2D6 enzyme inhibitor and may reduce amphet- amine (particularly MDMA) metabolism.51 A history of fluid intake, including ethanol and water, is relevant.
Excessive fluid intake in an attempt to avoid dehydra- Medicinal drug use is important; CYP2D6 inhibi- tors, including the protease inhibitor ritonavir, some Coronary artery spasm and related sequelaeAutonomic instability and other major disturbance of selective serotonin re-uptake inhibitors, quinidine, imi- pramine and thioridazine, may prolong amphetaminetoxicity by reducing hepatic metabolism.53 Patients with underlying seizure disorders or cardio- • Electrolytes and renal function to exclude secondary respiratory disease will be less tolerant of amphetamine metabolic abnormalities, including hyponatraemia toxicity. The prevalence of CYP2D6 poor-metabolizer phenotype is 3–10% among Caucasians; these individu- • Creatinine kinase to look for rhabdomyolysis als might be more susceptible to amphetamines metabo- • Coagulation screen to exclude disseminated intravas- Young patients presenting to the ED with anxiety, • Liver function tests looking for hepatitis psychosis, agitation, seizures, supra-ventricular tachy- • Arterial blood gas analysis to detect inadequate res- cardias, stroke, hypertension, non-cardiogenic pulmo- piratory function, a metabolic acidosis secondary to nary oedema, pulmonary hypertension, vasculitis seizures, dehydration or inadequate tissue perfusion, and cardiomyopathy should be asked about ampheta- or a respiratory alkalosis secondary to direct amphet- • Serial cardiac enzymes to assess possible acute coro- Examination
• Electrocardiogram (serial) to assess for possible acute coronary syndrome/dysrhythmias, or underlying Examination will typically reveal signs of sympatho- mimetic overdrive as summarized in Table 1. Some • A chest X-ray looking for evidence of aortic dis- patients will be clinically well and a focused examina- section, pneumothorax, pulmonary aspiration or pos- tion directed at their presenting complaint will be • An abdominal X-ray if there is suspicion of ingested After airway, breathing and circulation assess- ment, patients with significant amphetamine toxicity • Computerized tomography of the brain to look for (particularly those with altered conscious state) require evidence of stroke or cerebral oedema (a normal com- a more structured examination. Toxicity may be present puted tomography brain scan does not exclude these in multiple organ systems and examination should diagnoses) or possible trauma-related injury seek to detect signs of life-threatening neurological, • Coronary artery angiography to assess possible cardiovascular, autonomic and metabolic disturbances amphetamine-induced coronary artery vasospasm or • Echocardiography looking for cardiomyopathy Investigations
Urine drug amphetamine screens have poor sensitiv- ity and should not be a routine component of assess- Investigations should be determined by specific find- ment. A positive urine amphetamine drug screen does ings on initial history and examination, and overall not definitively indicate that current illness is secondary seriousness of clinical toxicity. Investigations may to amphetamine toxicity.5,56,57 Amphetamines used days before ED presentation can produce positive urine • Bedside blood sugar level to exclude hypoglycaemia results.5 Cold preparations containing substances with similar structures can produce false positive results.56,57 Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Some amphetamines, including MDMA, are not reliably of aspiration during subsequent seizures or vomiting.58 Patients with severe toxicity who are intubated might Serum amphetamine concentrations are not available benefit from one dose of AC via a nasogastric tube.
in time to influence acute management and should not Although relatively rare in Australia, the possibility be routinely requested. Amphetamine and other stimu- of amphetamine leakage from packets within the gas- lant drug toxicity is initially a clinical diagnosis. Early trointestinal tract ingested by ‘body packers’ should be management of amphetamine, cocaine and piperazine considered in cases of severe ongoing clinical amphet- toxicity is identical and biochemical identification is amine toxicity. Simple digital examination of oral and seldom required during ED management. Serum rectal cavities early during management might detect a amphetamine concentrations are indicated in medico- leaking packet, preventing ongoing exposure.
legal circumstances, including suspected child abuse.
Enhanced elimination
Differential diagnosis
Amphetamines are weak bases.5,27 Urine acidification, while theoretically enhancing amphetamine elimination, system stimulation might mimic amphetamine toxi- is contraindicated because it will potentiate adverse city and, therefore, the differential diagnosis is wide effects of rhabdomyolysis (increased myoglobin preci- pitation in acidic urine) and worsen any metabolicacidosis.59 Haemoperfusion, haemodialysis and haemo-filtration are ineffective.5,27 General management
Meticulous supportive care is essential. Rapid correction Specific management
of hypoxia, hypotension, hyperthermia, acid-base andmetabolic abnormalities, and raised intracranial pres- Treatments for amphetamine-associated toxicity are sure will reduce associated morbidity and mortality.
The role of activated charcoal (AC) in managing amphetamine toxicity is limited for the majority of aggressively. Associated sympathomimetic overdrive patients. Although AC potentially decreases amphet- increases risk of hypertension, hyperthermia, acidosis, amine absorption if administered within 1 h of inges- rhabdomyolysis and malignant dysrhythmias. Rapid tion, most patients don’t present within this time frame.
control of agitation minimizes these complications and AC has not been shown to alter clinical outcome.58 allows safe, controlled patient assessment.
Potential benefits of AC (adult dose 50 g orally or via a Agitated patients should be cared for in a quiet nasogastric tube) need to be weighed against dangers environment, which still allows provision of criticalcare. Initially, patients may require physical restraint, Differential diagnosis of amphetamine toxicity but only to facilitate rapid pharmacological sedation.
Ideally, pharmacological agents are administered intravenously, allowing titration to clinical effect and achieving rapid onset of action. Obtaining i.v. access might be technically difficult or unsafe; initial i.m.
administration will facilitate eventual i.v. access.
Benzodiazepines are first-line agents for controll- ing agitation.60–63 By facilitating gamma-aminobutyric acid (GABA) receptor-mediated CNS inhibition, benzo- diazepines are indirect antagonists of amphetamine- stimulated sympathomimetic agitation, reducing CNS stimulation, heart rate, blood pressure and muscle monoamine-oxidase inhibitor; LSD, lysergic acid diethylamide. activity. Benzodiazepines should be administered in Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Specific interventions for non-cardiovascular related Table 10.
Specific interventions for cardiovascular related Midazolam – 5–10 mg i.m. initially if i.v. access Agitation associated with paranoia/hallucinations Droperidol – 2–5 mg i.v. (beware seizures, hypotension) Dysrhythmias (avoid moderate to long acting beta-blockers) Benzodiazepines if associated with CNS overstimulation Sedation with airway control using thiopentone/propofol Verapamil – 5 mg i.v. (beware of hypotension) Computed tomography brain scan in cases of incomplete Decreased conscious level (remember hyponatraemia) Hyponatraemia (beware central pontine myelinolysis) A butyrophenone is appropriate in patients with delirium or hallucinations and normal cardiovascular Fluid restrict in non-dehydrated patients Cautious administration of 3% saline in severe symptomatic cases (sodium concentration <115 mmol/L) – seek advice Seizures and reduced conscious state
Benzodiazepines – diazepam or clonazepam bolusesActive cooling measures – ice packs or baths Amphetamine-induced seizures are generally short- lived and respond to benzodiazepines.5,27 Phenobar- 5HT2 antagonist – cyproheptadine 12 mg orally or via a bitone is a second-line agent. Unresponsive seizures should be treated with general anaesthetic sedation using thiopentone, propofol or midazolam. Pheny- toin’s sodium channel-blocking properties and the Urinary alkalinization (beware increased amphetamine cardiotoxic properties of the i.v. preparation’s dilu- ent (propylene glycol) can theoretically precipitatedysrhythmias.5,27 incremental boluses, titrated to clinical effect. Large Hypertension, vasospasm and tachycardia can lead doses are often required. Diazepam as an initial 5-mg to intracerebral or subarachnoid haemorrhage, and cere- dose, followed by 2.5- to 5-mg boluses every 2–5 min, bral ischaemia or infarction. Any patient with reduced can be given intravenously. Intramuscular midazolam consciousness state or one who does not rapidly recover is a good initial choice in patients with no i.v. access.
neurologically following a seizure requires intracranial Antipsychotics, including droperidol, haloperidol and imaging. Patients with hyponatraemia can present with olanzapine lower seizure threshold, can induce hypoten- seizures and reduced conscious state.
sion and dysrhythmias, impair heat dissipation, gener-ally have slower onset times and are not recommended Movement disorders
as first-line agents for treatment of stimulant drug-induced agitation.61 Despite these concerns, there is little Repetitive movement disorders, including teeth grind- published evidence to support them. Antipsychotics ing (bruxism, commonly seen with MDMA) and chore- may therefore be used cautiously as second-line agents.
oathetoid movements, are caused by dopaminergic Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine stimulation of the nigrostriatal area, and usually settle Amphetamine-induced hyperthermia must be treated with observation. Oral or i.v. benzodiazepines are often aggressively. Large i.v. doses of benzodiazepines administered incrementally will control agitation andreduce muscle activity.69 Dehydration must be corrected Hypertension
with i.v. crystalloid. Ice baths or placing ice packs inthe groin and axilla are effective methods of external Hypertension can be severe, leading to intracranial cooling. Neuromuscular paralysis and ventilatory haemorrhage or seizures. In the presence of CNS stimu- support should be instituted early in patients not lation, benzodiazepines are first-line agents, used to reduce sympathomimetic overdrive.5,27 Further control Clinical evidence for the effectiveness of dantrolene in of blood pressure should be achieved using alpha- treating amphetamine-induced hyperthermia is sparse.
adrenergic receptor antagonists (oral prazosin or i.v.
phentolamine), glyceryl trinitrate (GTN) or nitroprus- muscle contraction, has no CNS effect and may worsen side. Beta-blockers are contraindicated as blockade of amphetamine-induced hyperthermia.70 Dantrolene offers beta2-receptors (mediating skeletal muscle vasodilation) no theoretical advantage in this scenario over neuromus- can produce unopposed alpha-receptor stimulation and Chlorpromazine and the 5HT2a antagonist cypro- heptadine appear efficacious in treating serotonin tox- Dysrhythmias
icity,71 although evidence for both is limited to casereports.72 These drugs should be considered in cases of Prehospital deaths are most likely secondary to malig- amphetamine-related refractory hyperthermia. Cypro- nant dysrhythmias.33 Isolated sinus tachycardia seldom heptadine is administered orally (12 mg, then 8 mg requires treatment, but will respond to benzodiazepines every 8 hours for 24 hours, via a nasogastric tube in if associated with a sympathomimetic toxidrome. Cor- unconscious patients). Chlorpromazine can be admin- rection of hypoxia, acidosis and metabolic abnormali- istered as an i.v. infusion (12.5- to 25-mg initial infu- ties minimizes risk of conduction abnormalities and sion over 1 h), but can cause hypotension. One animal improves efficacy of anti-dysrhythmic drugs.
study has shown beneficial effects of carvedilol Supraventricular tachycardia should be managed (alpha1-receptor and beta1,2,3-receptor antagonist) in using conventional therapies, including adenosine, treating MDMA-induced hyperthermia.68 Carvedilol verapamil and electrical cardioversion. If a beta- and olanzepine (5-HT2A and alpha1-receptor antago- blocker is necessary, esmolol should be considered nist) might be used routinely in the future, but are not to minimize risk of uncontrolled hypertension.5,27 Ventricular dysrhythmias are managed using standardprotocols.
Patients presenting with altered conscious state orseizures following amphetamine exposure may have Hyperthermia has been associated with amphetamine- related deaths, particularly MDMA.9,30,33 Hyperthermia prompts many users to ingest large quantities of water, is more likely following MDMA ingestion in crowded, producing dilutional hyponatraemia.52 MDMA-induced noisy environments with high ambient tempera- symdrome of inappropriate anti-diuretic hormore tures.47–49,63 MDMA-induced hyperthermia is often asso- (SIADH) may interfere with compensatory mechanisms ciated with clinical features of serotonin toxicity.9,30,33 Mechanisms underlying substituted amphetamine- Hyponatraemia should be excluded early (via venous induced hyperthermia are complex; however, serotonin or arterial blood gas analysis if necessary) in patients and noradrenaline neurotransmitter interaction with with altered conscious state or seizures, preventing 5HT2a and beta3-receptors within vasculature and inappropriate fluid therapy and worsening hypona- brown adipose tissue appear to contribute.64–67 Animal traemia. Mild to moderate hyponatraemia in a non- studies demonstrate that beta3-receptor and alpha1- dehydrated patient should resolve with fluid restriction.
Patients who do require i.v. fluids should receive normal saline. Hypotonic fluid therapy will worsen Journal compilation 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine hyponatraemia. Hyponatraemia should be corrected Chronic amphetamine abuse
over a similar time frame to which it occurred, but not ata total rate greater than 0.5 mmol/L/h during a 24-h There has been considerable debate about long-term effects of amphetamine and substituted amphetamines.
Severe hyponatraemia (<115 mmol/L) with coexist- Animal and some human data have shown that long- ing seizures or evidence of possible cerebral oedema term exposure to MDMA is toxic to serotonergic neu- should be treated cautiously with 3% saline to increase rones.75,76 This datum has been postulated to support the serum to a concentration where seizures terminate, but notion that long-term MDMA abuse might be associated not to a concentration above 120 mmol/L. In general with chronic depression as a result of changes in CNS an increase of Na of 4–6 mmol/L is enough to halt pro- gression of symptoms in severe hyponatraemia.
Sodium required to obtain a concentration of 120 mmo/L = (120 - sodium concentration) ¥ 0.6 ¥ weight (kg).
Alternatively, X mL/kg of 3% saline will raise thesodium by X mmol/L. Rapid correction of sodium Amphetamine abuse in Australia and New Zealand is should only be undertaken if clinically necessary and common. Patients present to ED with varying degrees can produce central pontine myelinolysis.
of amphetamine-related toxicity and secondary compli-cations. Agitation and hyperthermia are treated aggres-sively, initially with i.v. benzodiazepines. Beta-blockers Rhabdomyolysis
must be avoided in treating hypertension and dysrhyth-mias because of unopposed alpha-receptor stimulation MDMA increases muscle motor activity, reduces muscle and potential worsening toxicity. Focal neurological cell ATP stores and impairs muscle cell energy produc- signs, seizures without rapid neurological recovery and tion, potentially producing rhabdomyolysis.74 Rhab- reduced conscious level require intracranial imaging.
domyolysis should be treated with i.v. fluid therapy to Hyponatraemia should be considered in cases of altered ensure a urine output of >2 mL/kg/h. Agitation and conscious state or seizures and corrected cautiously to hyperthermia should be treated aggressively to limit avoid secondary complication. Secondary metabolic further muscle damage. Although urinary alkalinization complications and rhabdomyolysis must be excluded.
might be beneficial in treating rhabdomyolysis, it willinhibit amphetamine elimination and prolong toxicity.5 Competing interests
George Braitberg is a section (toxicology) editor forEmergency Medicine Australasia.
Patients discharged from the ED following treatment ofamphetamine toxicity should have a normal consciousstate, temperature and cardiovascular status. Those at References
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