Drug intoxication and withdrawal

• A poisoned or withdrawing patient is often identified by a toxidrome: a repeating pattern of changes in vital signs, pupils, skin and behaviour caused by a class of drugs, long before a laboratory result returns.
• Always secure the airway, breathing and circulation first; check glucose; look for life threats (opioid or sedative respiratory depression, cholinergic bronchorrhoea, hyperthermia, seizures).
• In an agitated patient, think sympathomimetic, anticholinergic, serotonergic, alcohol withdrawal or hypoglycaemia; in a comatose patient, think opioid, sedative-hypnotic, alcohol, hypoglycaemia or anticholinergic.
• Many intoxications have no antidote: the cornerstone is supportive care, decontamination where appropriate, and the correct reversal agent when it exists (naloxone, atropine plus pralidoxime, physostigmine, flumazenil in selected cases).
• Withdrawal can kill: alcohol (and barbiturate/benzodiazepine) withdrawal can produce seizures and delirium tremens; opioid withdrawal is profoundly distressing but not usually fatal; stimulant withdrawal is usually self-limited.

By the end of this page you should be able to:

1. Recognise and name the principal toxidromes from vital signs, pupils, skin and mental state, and list the agents that cause each.
2. Run through a structured approach to an agitated or unconscious patient with possible intoxication, including red flags and immediate priorities.
3. Explain how opioid, stimulant, anticholinergic, cholinergic, sedative-hypnotic and serotonergic intoxications present and how each is treated.
4. Describe the timing, clinical features and treatment of alcohol withdrawal, including delirium tremens, CIWA-Ar scoring, benzodiazepines, and thiamine given before glucose.
5. Outline benzodiazepine/barbiturate, opioid and stimulant withdrawal, including buprenorphine, methadone, clonidine and symptomatic treatment.
6. Apply the CIWA-Ar and COWS severity categories and state the corresponding management thresholds.
7. List the features of Wernicke encephalopathy and the thiamine regimen used to treat it.

Intoxication and withdrawal are presentations, not single diagnoses: one patient can be co-intoxicated with several agents, and intoxication can mask or mimic a medical emergency such as sepsis, head injury, hypoglycaemia or thyrotoxicosis. ^[1] The clinical task has three parts: (1) make the patient safe by reversing or supporting the failing system (airway, breathing, circulation, temperature, seizures); (2) match the clinical picture to a toxidrome, which narrows the likely agents and guides reversal; (3) treat the underlying disorder and, when the patient is ready, address the substance use itself.

Intoxication follows exposure to a psychoactive substance. Withdrawal follows a reduction or cessation in a person who is dependent, and it can also be triggered by giving an antagonist (for example, naloxone or naltrexone to an opioid-dependent person, or flumazenil to a benzodiazepine-dependent person). ^[3] Withdrawal from central nervous system (CNS) depressants (alcohol, benzodiazepines, barbiturates, and other sedative-hypnotics) is potentially life-threatening because the brain loses its inhibitory GABA tone and becomes hyperexcitable. ^{[1] [10] [11]}

The following features demand urgent senior review and often intensive care, regardless of the agent involved:

• Airway not protected, or actual or impending respiratory depression
• Bradypnoea (under 10 breaths per minute), hypoxaemia, cyanosis
• Seizures, or a rising or depressed level of consciousness
• Hyperthermia (38 degrees C or more with rigidity or clonus) or hypothermia
• Hypotension unresponsive to fluids, or arrhythmia
• Chest pain, hyperthermia or severe agitation after a stimulant
• Severe alcohol withdrawal, especially if delirium, fever, marked tachycardia or a previous complicated withdrawal is present
• Possible body packing/stuffing, or ingestion of a sustained-release or enteric-coated product

Patients are often unable to give a reliable history, so gather information from ambulance staff, family, friends, bystanders, pill bottles, and the scene itself: ^[11]

• What was taken, how much, when, and by what route (ingested, inhaled, insufflated, injected, transdermal)
• Whether there are co-ingestants, especially alcohol, benzodiazepines, opioids or antidepressants
• Time of last use (essential for buprenorphine or naloxone decisions in opioid dependence)
• Prior substance use, tolerance, and previous withdrawals, especially alcohol withdrawal seizures or delirium tremens
• Symptoms suggestive of a medical mimic: chest pain, fever, head injury, focal neurological signs, suicidal intent

Polypharmacy and co-intoxication are the rule, not the exception, and they blunt the classic toxidromes. ^[10]

The bedside examination is the core diagnostic skill. Note vital signs (especially temperature, heart rate, blood pressure, respiratory rate and oxygen saturation), pupil size and reactivity, skin temperature, moisture and colour, muscle tone and reflexes, and the level of consciousness. The table groups the classic intoxication toxidromes that medical students are expected to recognise.

The single bedside clue that best separates anticholinergic from sympathomimetic toxicity is the skin: anticholinergic patients are dry and hot, sympathomimetic patients are sweating. ^[5] Serotonergic patients also sweat but are distinguished by clonus and hyperreflexia, especially in the lower limbs. ^[4]

Investigations support care and exclude mimics; they rarely make the diagnosis:

• Capillary glucose in every altered or agitated patient
• Venous blood gas, electrolytes, renal and liver function, creatine kinase, full blood count
• ECG (QRS/QTc, ischaemia; arrhythmias occur with cocaine, tricyclics and propoxyphene)
• Paracetamol and salicylate levels in any deliberate overdose
• Urine pregnancy test in women of childbearing age
• Urine drug screen: quick but insensitive (will miss many benzodiazepines, and positivity only proves recent exposure, not intoxication) and should never delay treatment ^{[4] [10]}
• Chest X-ray for aspiration/pulmonary oedema; abdominal imaging for body packers
• Consider head CT if there are focal neurological signs or trauma

For organophosphate poisoning, plasma or red-cell cholinesterase may be sent, but results are slow and many laboratories outsource them; treatment starts on clinical grounds. ^[6]

Typical overdose presents with the triad of respiratory depression, sedation and pinpoint pupils. ^[11] Miosis may be absent with meperidine, tramadol, fentanyl, hypoxia or co-ingestants. ^[11]

Treatment. Support airway and ventilation. Naloxone reverses respiratory depression: 0.4 to 1 mg IV (adults), titrated to restore breathing in chronic users to avoid precipitating withdrawal; repeat every 2 to 3 minutes, and higher doses (up to 10 mg or more) may be needed for fentanyl, methadone, buprenorphine or diphenoxylate. ^[11] Because naloxone has a short half-life, patients who overdosed on long-acting opioids need prolonged observation or a naloxone infusion (about three quarters of the dose that restored breathing, per hour). ^[11] Failure to respond to 10 mg of naloxone suggests another or additional cause. ^[11] Reversal can be complicated by non-cardiogenic pulmonary oedema and by agitation or withdrawal; the initial goal is restoration of adequate breathing, not full consciousness. ^[11]

Stimulant toxicity is a sympathomimetic toxidrome: agitation, hypertension, tachycardia, mydriasis, hyperthermia, diaphoresis, with possible seizure, arrhythmia, myocardial ischaemia, intracranial haemorrhage, rhabdomyolysis and renal failure. ^[9] Cocaine has three described stages of acute toxicity, ending in hypotension, ventricular fibrillation and cardiac arrest in the most severe form. ^[7]

Treatment. There is no specific antidote. Benzodiazepines are first-line for neuroexcitation, autonomic instability and seizures; external cooling for hyperthermia (rapid cooling when temperature exceeds about 41 degrees C); IV fluids and renal protection for rhabdomyolysis. ^{[8] [9]} Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) reliably lower hypertension in cocaine toxicity, and phentolamine is an option; labetalol is considered safe and effective for combined hypertension and tachycardia in cocaine or methamphetamine-related acute coronary syndrome. ^[7] Beta-blockers should not be used as the sole antihypertensive in stimulant toxicity because of the risk of unopposed alpha-adrenergic stimulation. ^{[8] [9]} Antipsychotics are adjuncts for predominant psychosis; avoid phenytoin, fosphenytoin and valproate for stimulant-induced seizures. ^[8] Body packers need early and careful management with laxatives and observation; never give activated charcoal purely to prevent absorption in an awake, airway-protected minor ingestion unless clinically justified.

Presents as "red, dry, hot, mad": flushed skin, hot dry mucous membranes, urinary retention, ileus, dilated sometimes unreactive pupils, confusion, hallucinations and possible seizures or wide-complex dysrhythmias (diphenhydramine). ^[5] Onset is usually within two hours of ingestion. ^[5]

Treatment. Supportive care; IV benzodiazepines are first-line for agitation because large doses may be needed; IV sodium bicarbonate for wide-complex dysrhythmias; activated charcoal within an hour (longer is reasonable because gut motility is reduced); cooling for hyperthermia. ^[5] Physostigmine (0.5 to 2 mg IV in adults; 0.02 mg/kg, maximum 0.5 mg, in children) reverses both central and peripheral features in pure anticholinergic poisoning refractory to benzodiazepines; have atropine and resuscitation equipment ready, and avoid it in mixed overdoses (for example, tricyclic antidepressants). ^[5]

Pesticide or nerve-agent exposure produces an acute cholinergic crisis: DUMBELS (defecation/diaphoresis, urination, miosis, bronchospasm/bronchorrhoea, emesis, lacrimation, salivation) plus CNS depression and, nicotinically, fasciculations, weakness and paralysis. ^[6] It is common in rural and agricultural settings and in deliberate self-poisoning; the skin and respiratory secretions are contaminated and dangerous to staff. ^[6]

Treatment. Universal precautions and three cycles of soap-and-water skin decontamination; protect the airway and remove secretions; do not use succinylcholine for intubation (it is not metabolised). Atropine 2 to 5 mg IV repeated, doubling every 3 to 5 minutes until secretions clear and bronchospasm resolves ("atropinisation" may require hundreds of milligrams over days); pralidoxime 30 mg/kg IV over 30 minutes then 8 mg/kg/h to reactivate acetylcholinesterase before ageing; benzodiazepines for seizures. ^[6] Atropine must be given before pralidoxime to avoid worsening muscarinic symptoms. Monitor tidal volumes and inspiratory force, because neuromuscular failure can occur without warning. ^[6]

Benzodiazepines, barbiturates and related sedatives cause CNS depression with normal or near-normal vital signs in isolated ingestion; respiratory depression becomes dangerous with co-ingestants such as ethanol. ^[10] Barbiturates have a narrower safety margin than benzodiazepines. ^[10]

Treatment. Supportive care and airway protection. Flumazenil reverses benzodiazepine sedation but is reserved for selected, non-dependent patients (for example, accidental paediatric ingestion, procedural sedation) because it can precipitate seizures and acute withdrawal in dependent users. ^[10] It does not treat barbiturate toxicity.

Serotonin syndrome results from excessive serotonergic activity, usually within a day of starting or increasing a serotonergic drug, or of an interaction. ^[4] Presentation is the triad of mental status change, autonomic dysfunction and neuromuscular hyperactivity (clonus, hyperreflexia, tremor, hypertonia; severity can reach 41 degrees C or above). ^[4] The Hunter Toxicity Criteria are the most accurate diagnostic rules and require recent serotonergic exposure plus one of: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation and diaphoresis; tremor with hyperreflexia; or hypertonia with temperature over 38 degrees C and clonus. ^[4] Most cases present within 6 to 24 hours of the serotonergic change. ^[4] Monoamine oxidase inhibitors and intentional overdoses tend to produce the most severe cases. ^[4]

Treatment. Stop all serotonergic agents; IV fluids and oxygen; benzodiazepines as the preferred sedative because they have no anticholinergic or serotonergic activity; management of autonomic instability with short-acting agents (esmolol, nicardipine, nitroprusside), avoiding longer-acting beta-blockade; external cooling. ^[4] Hyperthermia at 41 degrees C or above requires sedation, paralysis and intensive care. ^[4] Cyproheptadine is an oral antidote with inconclusive evidence. ^[4] Activated charcoal is not generally used unless very early. Antipyretics such as paracetamol are ineffective because the heat is generated by muscle activity and central dysregulation, not infection. ^[4]

Ethanol intoxication produces cerebellar and CNS depression. Severe respiratory depression is unusual with alcohol alone but common with co-ingestants. Supportive care, fluids and thiamine when indicated are the mainstay; hypoglycaemia must be excluded.

Alcohol is a CNS depressant through GABA enhancement and glutamate antagonism; chronic use upregulates glutamate. When alcohol is removed, a relative GABA deficit and glutamate excess produce withdrawal. ^[1]

Timing. Symptoms begin within hours of the last drink and peak around 72 hours. ^[1] Approximately half of people who suddenly stop heavy drinking develop alcohol withdrawal; only 3 to 5% progress to delirium tremens. ^[1] Withdrawal seizures typically occur between 8 and 48 hours after the last drink, and delirium tremens can occur up to 3 to 8 days (some reports state 3 to 5 days). ^[1] Kindling means each withdrawal episode tends to be more severe, particularly the seizure risk. ^[1]

Clinical picture. Tremor, insomnia, agitation, diaphoresis, hypertension, tachycardia; alcohol hallucinosis (auditory/visual/tactile) in a minority of patients; withdrawal seizures; delirium tremens (fever, tachycardia, hypertension, disorientation, hallucinations, severe agitation). ^[1] A history of complicated withdrawal markedly raises the risk of recurrence. ^[1]

Severity scoring with CIWA-Ar. CIWA-Ar is used only in patients who are awake and alert; if the patient cannot participate, use the MINDS scale instead. ^[1]

Risk factors for progression to severe withdrawal include prior withdrawal seizures or delirium tremens, medical comorbidity, age over 65 and physiological dependence on benzodiazepines. ^[1]

Benzodiazepines are the main treatment. ^[1] They may be given fixed-dose or symptom-triggered (CIWA-driven). Unless there is concern about significant hepatic dysfunction, diazepam is preferred first-line because of rapid onset and long duration; lorazepam is the alternative. For patients already in severe withdrawal or at highest risk, a loading dose of benzodiazepine or phenobarbital is appropriate; phenobarbital can be used as monotherapy or rescue. ^[1] Gabapentin may be used in mild outpatient withdrawal. Observe patients who have had a withdrawal seizure closely for about 24 hours. ^[1]

Thiamine before glucose (Wernicke encephalopathy). Patients in alcohol withdrawal are often thiamine and folate deficient and should receive high-dose intravenous or intramuscular thiamine because oral absorption is unpredictable. ^{[1] [2]} Thiamine should be given before or concurrently with glucose solutions, because glucose administration increases thiamine utilisation and can precipitate or worsen Wernicke encephalopathy. ^[2] Hypoglycaemia must still be treated without delay; do not wait for thiamine before giving glucose for hypoglycaemia. ^[2]

Wernicke encephalopathy is a medical emergency: an acute neurological syndrome from thiamine deficiency, classically with a triad of ocular motor abnormalities, gait ataxia and confusion. In reality the full triad is present in only a minority of cases; many patients have none of the classic features at first presentation. ^[2] Caine criteria (two of four: dietary deficiency, oculomotor abnormality, cerebellar dysfunction, altered mental state or mild memory impairment) improve recognition. ^[2] Thiamine 500 mg IV every 8 hours for 3 days, then 250 mg IV/IM daily until improvement plateaus, is one guideline-consistent regimen; the European Federation of Neurological Societies uses 200 mg IV every 8 hours; magnesium should be repleted because hypomagnesaemia limits recovery. ^[2] Mortality of Wernicke encephalopathy is estimated at about 17%. ^[2] Untreated or inadequately treated disease can progress to Korsakoff syndrome, a persistent severe anterograde amnesia with confabulation; recovery varies and management is rehabilitative. ^{[2] [6] [4]}

Historically the mortality of delirium tremens was 20%; with prompt modern care it is about 1%. ^[1]

Benzodiazepine and barbiturate withdrawal resembles alcohol withdrawal and can be life-threatening, with seizures possible; the two conditions may need to be managed simultaneously in a patient who uses several depressants. ^{[1] [10]} Barbiturates in particular have a narrow safety margin and high mortality in overdose compared with benzodiazepines. ^[10] Management is with a long-acting benzodiazepine tapered gradually, with phenobarbital as an alternative in barbiturate dependence; treat seizures and autonomic instability supportively. ^{[1] [10]} Flumazenil is contraindicated in dependent or chronic benzodiazepine users because it can precipitate acute withdrawal and seizures. ^[10]

Opioid withdrawal is highly distressing and drives relapse, but it is not usually fatal in itself. Symptoms include lacrimation, rhinorrhoea, yawning, piloerection, myalgia, diarrhoea, nausea and vomiting, pupillary dilatation, photophobia, insomnia, autonomic hyperactivity (tachycardia, sweating, hypertension, hyperthermia, tachypnoea) and restlessness. ^[3] Symptoms relate to loss of locus coeruleus inhibition.

Severity. The COWS (Clinical Opiate Withdrawal Scale; 11 items, total 0 to 47) grades severity as mild 5 to 12, moderate 13 to 24, moderately severe 25 to 36 and severe over 37. ^[3]

Treatment. Long-term opioid replacement uses methadone or buprenorphine; symptomatic relief includes loperamide for diarrhoea, antiemetics for nausea, analgesics for myalgia and clonidine for blood pressure. ^[3]

• Methadone: starting dose 10 mg oral/IV every 4 to 6 hours as needed; the 24-hour total becomes the next day's dose, rarely above 40 mg in 24 hours; then convert to once- or twice-daily dosing and titrate to a maintenance dose. ^[3]
• Buprenorphine: 4 to 12 mg sublingually initially. It is a partial agonist and can precipitate withdrawal unless the patient is already in withdrawal; start 12 to 18 hours after the last short-acting opioid (heroin, oxycodone) and 24 to 48 hours after long-acting opioids such as methadone. ^[3]
• Lofexidine, an alpha-2 agonist, is licensed for opioid withdrawal and may be used where regulations permit; non-opioid options otherwise are supportive.

The substituting opioid should be introduced only once withdrawal has started (COWS 5 or more or clear objective signs), because early dosing risks precipitated withdrawal. ^[3]

Stimulant withdrawal is not typically dangerous but is often dominated by dysphoria, fatigue, hypersomnia, increased appetite, psychomotor retardation, vivid dreams, anxiety and strong craving; post-acute symptoms can persist for weeks. ^[12] There is no accepted FDA-approved pharmacotherapy for stimulant use disorder; management is supportive (sleep, nutrition, hydration) with cognitive or contingency behavioural therapy. ^[12] Antidepressants or dopamine agonists are not established treatments. ^[12] Any concurrent psychiatric illness, psychosis or suicidality must be assessed separately.

Refer to senior emergency medicine, critical care, toxicology (regional poison centre) or addiction services when:

• A patient remains unconscious, hypoxic, seizing or unstable despite initial treatment
• Delirium tremens, complicated alcohol withdrawal or significant opioid/benzodiazepine withdrawal is suspected
• Hyperthermia, arrhythmia, chest pain or focal neurological signs are present
• There is a high risk of suicide, severe dependence, or uncertainty about the agent or management
• Body packing/stuffing or a massive overdose is suspected

• Children: a lower threshold is required; infants and young children present mainly with ataxia and sedation after benzodiazepines; single-tablet ingestions of some agents (for example opioids, tricyclics) can be lethal in toddlers.
• Older adults: anticholinergic burden from ordinary medications is a common and under-recognised cause of confusional states.
• Pregnancy: acute management prioritises maternal physiology; there is no reason to withhold naloxone or other life-saving treatments, and fetal outcome depends on maternal stabilisation.
• Low-resource settings: the diagnosis is clinical. The most life-saving actions require little technology: airway positioning, oxygen, glucose, aggressive cooling and sedation for hyperthermia, atropine for organophosphate poisoning, and naloxone where available. Transfer early if critical care is not present. ^[6]

• A toxidrome is a pattern of vital signs, pupils, skin and behaviour; recognising it precedes any laboratory confirmation. ^{[5] [6]}
• Always start with ABC, glucose and temperature; life threats first, antidotes second. ^[9]
• Anticholinergic patients are dry and hot; sympathomimetic patients sweat; serotonergic patients sweat and have clonus. ^{[4] [5]}
• Opioid overdose is recognised by pinpoint pupils, respiratory depression and coma, and treated with naloxone titrated to breathing. ^[11]
• Stimulant toxicity is managed with benzodiazepines, cooling, fluids and renal protection; there is no antidote. ^{[8] [9]}
• Sedative-hypnotic overdose needs airway support; flumazenil is only for selected non-dependent patients. ^[10]
• Serotonin syndrome: stop serotonergic drugs, sedate with benzodiazepines, cool; cyproheptadine is an adjunct. ^[4]
• Organophosphate poisoning: soap-and-water decontamination, atropine before pralidoxime, benzodiazepines for seizures, no succinylcholine. ^[6]
• Alcohol withdrawal has a peak around 72 hours; 3 to 5% progress to delirium tremens; seizures occur at 8 to 48 hours. ^[1]
• CIWA-Ar grades severity (8 or less mild, 8 to 15 moderate, above 15 severe) and guides benzodiazepine dosing; diazepam is first-line unless liver disease is significant. ^[1]
• Give IV/IM thiamine before or with glucose, but do not delay glucose for hypoglycaemia. ^{[1] [2]}
• Wernicke encephalopathy is an emergency with a high mortality (about 17%) and often lacks the full classical triad; early parenteral thiamine matters more than any test. ^[2]
• Benzodiazepine/barbiturate withdrawal can be fatal and is treated with a gradual long-acting benzodiazepine taper; flumazenil is contraindicated in dependence. ^{[1] [10]}
• Opioid withdrawal is not usually fatal but is treated effectively with methadone or buprenorphine; buprenorphine precipitates withdrawal if started too early. ^[3]
• Stimulant withdrawal has no approved pharmacotherapy; it is self-limited but needs supportive care and psychiatric assessment. ^[12]

• Alcohol use disorder
• Opioid use disorder
• Anxiety and panic disorders
• Delirium and confusion in the elderly
• Seizures and status epilepticus
• Wernicke encephalopathy and Korsakoff syndrome
• Management of poisoning and overdose
• Emergency department psychiatric assessment
• Acute coronary syndrome (stimulant-associated)
• Rhabdomyolysis