Opioid, sedative, tricyclic and cardiac drug overdose

• Opioids, benzodiazepines, tricyclic antidepressants (TCAs), beta-blockers, calcium channel blockers (CCBs) and digoxin are common causes of poisoning, and several can kill by shutting down breathing or the circulation before any laboratory result returns. ^[1][7]
• The specific antidotes are naloxone for opioid toxicity, flumazenil for isolated benzodiazepine toxicity, sodium bicarbonate for TCA and other sodium-channel blocker toxicity, glucagon (then high-dose insulin) for beta-blocker and CCB poisoning, and digoxin-specific antibody fragments for digoxin. ^{[1][3][4][5][6][7]}
• In an opioid overdose, naloxone is titrated to breathing rather than to full wakefulness, because the goal is to restore a safe airway, and because the opioid can outlast naloxone, which has a duration of action of roughly 90 to 180 minutes. ^[1][2]
• Flumazenil can wake a patient from benzodiazepine sedation, but it can trigger seizures and withdrawal and is avoided in mixed overdoses and in patients with signs of TCA toxicity. ^[3][7]
• High-dose insulin therapy is recommended early in life-threatening beta-blocker and CCB poisoning, and digoxin-specific antibody fragments can reverse life-threatening dysrhythmias from digoxin. ^[4][5][6][7]
• Where a clear cause is not obvious, call a medical toxicologist or regional poison centre early; AHA and poison centre guidance emphasise that specialised treatments are rarely used but time-critical. ^[7]

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

1. Recognise the toxidrome of each of the six drug groups and explain why it occurs. ^{[1][3][4][5][6]}
2. Explain why naloxone is titrated to breathing, how to dose it in adults and children, and why repeated or infusion dosing may be needed. ^[1][2]
3. State the cautions that limit the use of flumazenil, including mixed overdose and TCA co-ingestion. ^[3][7]
4. Describe the pathophysiology of TCA cardiac toxicity and its treatment with sodium bicarbonate, including the target QRS and pH. ^[7]
5. Write the rescue sequence for beta-blocker and calcium channel blocker poisoning: glucagon, high-dose insulin, calcium, lipid emulsion and vasopressors. ^[4][5]
6. Explain digoxin toxicity, its electrolyte associations and when digoxin-specific antibodies are given. ^[6]
7. Plan initial investigations and low-resource management for all six poisonings. ^{[1][3][4][5][6][7]}

These are not one disease but six families of poisoning that are taught together because they often arrive the same way: an unconscious or unstable patient, an unknown or only partly known ingestion, and a narrow window in which the right antidote matters. A useful way to group them is by the system they shut down.

• Opioids and opiates. Natural and synthetic agonists at the mu-opioid receptor: morphine, heroin, codeine, oxycodone, fentanyl, methadone, buprenorphine, tramadol and others. The defining danger is respiratory depression from reduced medullary drive. ^[1]
• Benzodiazepines and related sedatives. Diazepam, lorazepam, midazolam, alprazolam, clonazepam and the Z-drugs act at the benzodiazepine site on the GABA-A receptor. Most isolated overdoses cause drowsiness rather than death, but co-ingestion with opioids or alcohol is lethal. ^[3]
• Tricyclic (and related cyclic) antidepressants. Amitriptyline, imipramine, nortriptyline, clomipramine, desipramine and dothiepin. Toxicity is driven by sodium channel blockade, which widens the QRS complex and causes ventricular arrhythmia, with anticholinergic and alpha-blocking effects as well. ^[7]
• Beta-blockers. Lipophilic agents such as propranolol cause both beta-receptor blockade (bradycardia, hypotension, hypoglycaemia) and membrane-stabilising sodium or potassium channel block (QRS or QT prolongation). ^[4]
• Calcium channel blockers. Verapamil, diltiazem and the dihydropyridines. They block L-type calcium channels, producing hypotension, bradycardia or reflex tachycardia, insulin resistance and hyperglycaemia. ^[5]
• Digoxin (and other cardiac glycosides). Digoxin, and plant or toad glycosides such as oleander, foxglove and Bufo species. They inhibit the sodium-potassium ATPase, raise intracellular calcium and increase vagal tone. ^[6]

Each has its own antidote, and several have more than one antidote used in sequence.

Opioids dominate the global poisoning picture. Drug overdose is the leading cause of accidental death in the United States, with opioids the most common culprit; reported daily emergency department visits related to opioid misuse exceed 1,000, with roughly 91 overdose deaths a day in recent years, and close to 108,000 overdose deaths in 2022. ^[1][7] Among US poison centre data, 18,425 exposures to pure opiates were reported in 2015 with 68 fatalities, and over 14,000 more involved combinations with alcohol, benzodiazepines or analgesics. ^[1]

The other groups are smaller individually but common in overdose cohorts:

• Beta-blockers: 10,577 single exposures reported in 2015, of which 9.6% had a moderate or major outcome and 82% were unintentional. ^[4]
• Calcium channel blockers: 11,764 overdoses reported by American Poison Control Centers in 2011, with 78 deaths, second only to beta-blockers among cardiovascular drug deaths. ^[5]
• Digoxin: 2,513 cases of digitalis toxicity reported in 2011, with 27 deaths. ^[6]

For each group, the route of toxicity differs:

• Opioids. Substance abuse, intentional self-harm, therapeutic dosing errors, returning to use after abstinence, combining opioids with sedatives, and taking escalating doses. Risk is higher with male sex, younger age (20 to 40 years in the StatPearls series) and serious medical or psychiatric illness; poor liver or lung function slow elimination. ^[1]
• Benzodiazepines. Usually co-ingestion with opioids or alcohol, therapeutic error, or suicidal intent; chronic users develop tolerance and dependence. ^[3]
• TCAs. Self-harm overdose (often a month's supply), accidental ingestion in children, and toxicity from drug interactions raising levels (for example, with fluoxetine or verapamil) or from therapeutic error.
• Beta-blockers. Accidental or suicidal ingestion, including children ingesting medicines not meant for them; patients who overdosed were more likely to be women (3 to 1) with a mean age of 30 years, and two-thirds overdosed on someone else's medication or used beta-blockers for a non-cardiac indication. ^[4]
• CCBs. Accidental ingestion in children, suicidal overdose, therapeutic misadventure, and drug interactions that increase levels. Older adults and those on multiple heart drugs are at higher risk. ^[5]
• Digoxin. Chronic toxicity from renal impairment or dose escalation is the commonest pattern; acute over-ingestion, dosing error, and electrolyte disturbance (hypokalaemia, hypercalcaemia, hypomagnesaemia) precipitate it. Drug interactions with amiodarone, verapamil, macrolides and azole antifungals reduce clearance. ^[6]

Opioids. Excessive mu-opioid receptor agonism in the brain and medulla reduces the ventilatory response to carbon dioxide and hypoxia, producing sedation, miosis and respiratory arrest. Partial or mixed agonists such as buprenorphine and pentazocine may need higher or repeated doses of naloxone. ^[1]

Benzodiazepines. They act on GABA-A benzodiazepine receptors to produce central nervous system depression. Given alone, respiratory depression is modest; combined with opioids or alcohol the effects multiply. Sudden stopping of chronic benzodiazepine therapy can precipitate withdrawal, so flumazenil can be dangerous in dependent users. ^[3]

TCAs and other sodium-channel blockers. These drugs slow cardiac sodium channels (phase 0 of the action potential), widening the QRS complex and producing ventricular arrhythmia, hypotension and a wide-complex tachycardia that can degenerate into cardiac arrest. Additional effects include anticholinergic delirium, alpha-adrenergic blockade, seizures, and QRS/QT prolongation. ^[7]

Beta-blockers. Beta-adrenergic blockade produces bradycardia, hypotension, decreased contractility and hypoglycaemia (glycogenolysis and gluconeogenesis are blocked). Lipophilic agents cross the blood-brain barrier and can cause seizures. Some agents (especially propranolol) also block sodium or potassium channels, prolonging QRS or QTc. ^[4]

CCBs. Blockade of L-type calcium channels reduces sinoatrial automatism, atrioventricular conduction and myocardial contractility, and vasodilates the periphery. All classes reduce insulin secretion and cause insulin resistance, so hyperglycaemia is a marker of severity. Hyperglycaemia and metabolic acidosis are common. ^[5]

Digoxin. By inhibiting the sodium-potassium ATPase, digoxin raises intracellular sodium and, in turn, intracellular calcium (improving contractility at therapeutic doses) and increases vagal tone, slowing sinoatrial and atrioventricular conduction. Electrolyte shifts are the major complication: hyperkalaemia is the hallmark of acute toxicity. Hypokalaemia, hypomagnesaemia and hypercalcaemia sensitise the myocardium. ^[6]

The toxidrome tells you a lot before the bloods arrive.

Digoxin deserves particular care. Its clinical toxicity runs from gastrointestinal upset (anorexia, nausea, vomiting) and neurological symptoms (headache, malaise, insomnia, altered mental status) to visual disturbance and arrhythmia. Visual changes, especially a yellow tint to vision, are well described. The ECG may show a "digitalis effect" with scooped ST segments and T-wave changes. ^[6]

A patient with unexplained sedation, hypotension or a wide QRS complex should prompt you to consider co-ingestants. In opioid overdose the differential includes barbiturates, benzodiazepines, ethanol, gamma-hydroxybutyrate, clonidine, carbon monoxide, hypoglycaemia, hypothermia and head injury; in sodium-channel blocker toxicity, other class I antiarrhythmics, cocaine and local anaesthetics. ^[1][7] In practice, mixed overdoses are the rule rather than the exception in self-harm, so an ECG should be obtained in every suspected opioid overdose because of the possibility of a co-ingested TCA. ^[1]

The first investigations are clinical. The history (substances, amounts, times, receipts and bottles) and the examination (vital signs, GCS, pupils, chest, abdomen and skin) are more useful than any single test. Then:

• Airway, breathing, circulation first, with 100% oxygen and assisted ventilation in opioid toxicity. ^[1]
• Blood glucose in every unexplained collapse, because hypoglycaemia can mimic and accompany poisoning. ^[1][4]
• ECG: rate, rhythm, QRS width and QT interval. QRS widening is the signature of sodium-channel blocker toxicity and beta-blockers with membrane-stabilising activity. ^[4][7]
• Laboratory tests: full blood count, urea and electrolytes (potassium, calcium, magnesium), creatinine, arterial blood gas, CK and, where available, acetaminophen and salicylate screens. Expect hyperkalaemia in digoxin and beta-blocker poisoning and hyperglycaemia in CCB poisoning. ^[1][5][6]
• Digoxin level: take no earlier than 6 hours after ingestion because distribution takes several hours; the accepted range is narrow (0.5 to 0.9 nanograms per mL, or up to 2 ng/mL in some laboratories). Levels do not correlate closely with clinical toxicity. ^[6]
• Imaging: chest radiograph if aspiration or lung injury is suspected; abdominal radiograph or CT if the patient may be a body packer. ^[1]

Almost all of these patients are managed the same way in the first five minutes: airway protection and oxygen, ventilation (look specifically for hypoxia/hypercapnia in opioid and sedative poisoning), intravenous access, cardiac monitoring, warming, judicious crystalloid and glucose correction. In opioid poisoning give 100% inspired oxygen with bag-valve ventilation before and during naloxone, and keep the lowest dose that restores adequate breathing. ^[1][2]

Naloxone administration has not failed when the patient does not immediately wake; the endpoint is adequate respiration, not full arousal. Because opioid effects often outlast naloxone (half-life about 30 to 45 minutes, duration 90 to 180 minutes), the risk of recurrent respiratory depression remains high with longer-acting opioids such as methadone, buprenorphine, fentanyl analogues and modified-release formulations. ^[1][2]

Typical adult dosing. 0.4 to 2 mg intravenously initially, repeated at 2 to 3-minute intervals; intramuscular or intranasal dosing (2 mg) is used when there is no intravenous access. If there is no response after 10 mg, question the diagnosis and look for co-ingestants or a non-opioid cause. ^[1][2]

Titration in suspected chronic users. Give 0.04 to 0.4 mg intravenously every 1 to 3 minutes, or start at 0.05 to 0.1 mg and titrate, because rapid reversal precipitates withdrawal (agitation, vomiting, pain, sweating) and may be dangerous to staff and patient. ^[1]

Children. 0.1 mg/kg (maximum 2 mg) for children under 5 years or under 20 kg; 0.1 to 0.2 mg/kg (maximum 2 mg) for older children; a subsequent 0.1 mg/kg dose may be given if the first is inadequate. Doses may be repeated every 3 to 4 minutes up to a cumulative 10 mg. ^[1][2]

Neonates. 0.01 mg/kg intravenously, intramuscularly or subcutaneously. ^[2]

Infusion. In persistent or recurrent toxicity, especially with long-acting opioids, use a continuous infusion at three-quarters of the bolus dose that reversed the respiratory depression. A common preparation is 2 mg in 500 mL of normal saline or 5% dextrose (0.004 mg/mL), with the rate titrated to response; the mixture is stable for 24 hours. ^[1][2]

Escalation. Repeat dosing of 2 mg every 3 to 4 minutes up to 10 mg may be needed for diphenoxylate, methadone, butorphanol, nalbuphine, pentazocine, propoxyphene or body-packer fentanyl. If the patient remains apnoeic, intubate. ^[1][2]

Nalmefene. A longer-acting opioid antagonist with a half-life of 4 to 8 hours, but routine use is discouraged because it can precipitate prolonged withdrawal. ^[1]

Most isolated benzodiazepine overdoses need only airway protection, monitoring and time; benzodiazepines alone rarely cause death. Flumazenil is a competitive benzodiazepine antagonist given intravenously: 0.2 mg over 30 seconds, then 0.3 mg and then 0.5 mg at 1-minute intervals, up to 3 mg total (5 mg in partial responders); the effect lasts roughly 19 to 50 minutes with a half-life of about 54 minutes, so re-sedation is expected and repeat 20-minute interval dosing may be needed. ^[3]

Flumazenil is not a routine antidote and should not be given when:

• the overdose is mixed (with opioids, alcohol, other sedatives or an unknown combination);
• there are signs of tricyclic antidepressant toxicity (QRS widening, ventricular arrhythmia, anticholinergic features), because seizures can be precipitated;
• the patient is on long-term benzodiazepines or has a history of seizures, head injury, panic disorder or alcohol dependence. ^[3][7]

When appropriate, flumazenil reverses sedation and respiratory depression within 1 to 2 minutes, with peak effect at 6 to 10 minutes. ^[3] AHA guidance makes the same point: flumazenil reverses central nervous system and respiratory depression from benzodiazepine poisoning, but important risks and contraindications limit its use. ^[7] Flumazenil (0.01 mg/kg, maximum 0.2 mg, repeated to a maximum of 1 mg or 0.05 mg/kg, whichever is lower) is also used for reversal of conscious sedation or general anaesthesia. ^[3]

TCA and other sodium-channel blocker toxicity is treated with sodium bicarbonate. The AHA focused update (2023) recommends standard advanced life support with the addition of sodium bicarbonate for life-threatening dysrhythmias caused by cocaine or other sodium channel blockers, and specifically for TCAs: sodium bicarbonate boluses, titrated to resolution of hypotension and QRS prolongation, given as a hypertonic solution (1000 mEq/L in adults, 500 mEq/L in children). ^[7]

Practical points from that guidance:

• Treat hypotension and wide QRS together with sodium loading and alkalinisation; the two have additive effect. ^[7]
• Keep serum sodium no higher than 150 to 155 mEq/L and arterial pH no higher than 7.50 to 7.55, and monitor and treat hypokalaemia during therapy. ^[7]
• If necessary, adjust sodium and pH separately: hypertonic saline for sodium, and ventilation for pH in an intubated patient. ^[7]
• Lidocaine (and, second-line, phenytoin) may be used for wide-complex tachycardia after sodium bicarbonate; intravenous lipid emulsion is of uncertain benefit in TCA poisoning. ^[7]

Propoxyphene toxicity illustrates the same mechanism: arrhythmias from its quinidine-like effect are treated with sodium bicarbonate, and they are not reversed by naloxone. ^[1]

These three are managed as a sequence rather than a single drug.

Beta-blocker poisoning. Glucagon is the traditional first-line antidote (5 to 10 mg intravenously), although controlled trial evidence is limited; it can cause vomiting and hyperglycaemia. Calcium salts may help hypotension. If there is no response to fluids, atropine and glucagon, use high-dose insulin euglycaemia (HIE): 1 U/kg regular insulin bolus with 0.5 g/kg intravenous dextrose (omit the dextrose bolus if glucose is above 400 mg/dL), then 1 to 10 U/kg/hour infusion, with glucose checked every 30 minutes for up to four hours and 10% or 50% dextrose to keep glucose between 100 and 200 mg/dL. Monitor potassium closely. HIE's inotropic effect can take 15 to 60 minutes, so vasopressors (norepinephrine is preferred in vasodilatory shock) may be needed; phosphodiesterase inhibitors such as milrinone can be added. Decontamination follows the usual rules (activated charcoal within an hour for minor ingestions, whole-bowel irrigation for sustained-release preparations), and renal elimination works for water-soluble, renally excreted beta-blockers such as atenolol, nadolol, acebutolol and sotalol. Refractory cases may need ECMO. ^[4][7]

CCB poisoning. Give calcium (chloride 10 to 20 mL of 10% solution, or gluconate 30 to 60 mL of 10% solution) as an initial bolus, repeated every 10 to 20 minutes for 3 to 4 doses, or an infusion at 0.2 to 0.4 mL/kg/hour, accepting that the response is variable and often transient. Add glucagon (5 to 10 mg bolus, then 2 to 10 mg/hour infusion) and high-dose insulin (same regimen as for beta-blockers). Intravenous lipid emulsion (1.5 mL/kg bolus of 20%, then 0.25 to 0.5 mL/kg/minute for 30 minutes) is reserved for refractory shock with very lipophilic agents. Norepinephrine or epinephrine are the preferred vasopressors in vasodilatory shock, and whole-bowel irrigation is used for sustained-release preparations. ^[5][7]

Digoxin poisoning. First-line therapy for dysrhythmia from suspected digoxin toxicity is digoxin-specific antibody fragments (Fab): an empiric 10 vials in adults and 5 vials in children. Because binding digoxin shifts potassium, serum potassium must be monitored frequently. Activated charcoal is worth giving within 2 hours of an acute ingestion. Hyperkalaemia is the acute marker of severity. Supportive measures include hydration, oxygen, correction of electrolyte disturbance (magnesium is not recommended because it can worsen bradycardia or AV block), and atropine or lidocaine/phenytoin for arrhythmia; cardioversion is avoided because it can precipitate ventricular arrhythmia, although defibrillation follows standard ALS. AHA guidance states that administration of digoxin-specific immune antibody fragments can reverse life-threatening dysrhythmias from digoxin poisoning. ^[6][7]

High-dose insulin is recommended early in life-threatening beta-blocker and CCB poisoning, and the AHA top recommendations list it explicitly. ^[7]

• Activated charcoal within 1 to 2 hours for most non-caustic ingestions, repeated at 0.5 g/kg every 2 to 4 hours in large repeated doses where motility permits. ^[4][5]
• Whole-bowel irrigation for body packers and large ingestions of sustained-release preparations. ^[4][5]
• Gastric lavage is rarely used now and is limited to early presentations of massive ingestion.
• Avoid activated charcoal in a patient with a depressed level of consciousness or unprotected airway.

Children. Doses of antidotes scale by weight (naloxone, flumazenil, calcium). Young children are particularly dangerous around household medicines: a single adult tablet of many of these agents can poison a toddler. Digoxin and TCA toxicity in a child should trigger poison centre consultation. ^[1][2][5][6]

Pregnancy. Naloxone and antidotes are used as for the non-pregnant patient when the mother's life is at risk; mass poisoning with digoxin and other agents has been described in pregnancy. Flumazenil in pregnancy carries the usual benzodiazepine-reversal precautions. ^[3][6]

Older adults. Reduced renal and hepatic function prolongs digoxin and drug clearance; comorbidity makes hypotension less tolerable. ^[5][6]

Dependence and chronic use. Naloxone titration and flumazenil restraint are the main safeguards in chronic users. ^[1][3]

Limited availability of assays or infusions should not prevent rational treatment:

• Diagnosis is clinical. The opioid triad (pinpoint pupils, respiratory depression, depressed consciousness), hypoglycaemia in beta-blocker overdose and hyperglycaemia in CCB overdose, and a widened QRS in sodium channel blocker poisoning all point the way without an antidote level. ^[1][4][5][7]
• Naloxone and flumazenil are inexpensive and stable; stock them where opioids and benzodiazepines are used.
• Digoxin-specific antibodies are costly; support, correct electrolytes and use short-acting beta-blockers or lidocaine for rhythm control when antibodies are unavailable, but seek poison centre and cardiology advice early. ^[6]
• High-dose insulin requires only regular insulin and dextrose, plus glucose and potassium monitoring; calcium chloride or gluconate, magnesium and sodium bicarbonate are also cheap staple antidotes. ^[4][5][7]
• ECMO, lipid emulsion and pacemakers are for centres that have them; early transfer and close supportive care (airway, fluids, warming) remain the realistic first steps. ^[7]
• Poison centre contact. In the United States, call 1-800-222-1222; UK readers use TOXBASE or the National Poisons Information Service. Cited guidelines support timely toxicology consultation as a key step in every severe poisoning. ^[5][7]

• Opioid overdose: respiratory arrest, acute lung injury/non-cardiogenic pulmonary oedema, aspiration, hypoxic brain injury, arrhythmia from co-ingestants. ^[1]
• Benzodiazepine overdose: aspiration pneumonia, rhabdomyolysis; rarely death in isolation. ^[3]
• TCA toxicity: ventricular tachycardia, hypotension, seizures, death. ^[7]
• Beta-blocker and CCB toxicity: refractory shock, ARDS, end-organ ischaemia (bowel, myocardial infarction, renal failure, stroke), pulseless electrical activity. ^[4][5]
• Digoxin toxicity: any arrhythmia, AV block, ventricular tachycardia and cardiac arrest; mortality in optimal care is 1 to 5%. ^[6]

• Poisons that share a bed: opioids, benzodiazepines, TCAs, beta-blockers, CCBs and digoxin. Treat the patient's airway and circulation first, then match the antidote to the mechanism. ^[1][7]
• Naloxone is given to restore breathing, not wakefulness; titrate slowly in chronic users and admit or observe because the opioid outlasts the antidote. ^[1][2]
• Flumazenil can reverse benzodiazepine sedation but risks seizures; it is not for mixed overdoses and not when TCA toxicity signs are present. ^[3][7]
• Sodium bicarbonate is the antidote for TCA and other sodium-channel blocker poisoning, dosed to QRS and blood pressure with defined sodium and pH limits. ^[7]
• Beta-blocker and CCB poisoning are treated as a sequence: fluids and atropine, then glucagon, then calcium, then high-dose insulin with dextrose; add lipid emulsion and vasopressors; ECMO for refractory shock. ^[4][5][7]
• Digoxin toxicity is treated with digoxin-specific antibody fragments (10 vials adult, 5 vials child) with close potassium monitoring. ^[6]
• Digoxin levels are taken no sooner than 6 hours and correlate poorly with toxicity; hyperkalaemia marks acute severity. ^[6]
• Hypoglycaemia signals beta-blocker poisoning; hyperglycaemia and acidosis signal CCB poisoning; wide QRS signals a sodium-channel blocker. ^[4][5][7]
• Most mixed overdoses are self-harm; ECG and poison centre consultation should be early. ^[7]
• Activated charcoal, whole-bowel irrigation and decontamination apply selectively and never at the expense of the airway. ^[4][5]

Poisoning in children; opioid use disorder; benzodiazepine withdrawal and sedative toxicity; tricyclic antidepressants; beta-blocker therapy; calcium channel blocker therapy; digoxin and cardiac glycosides; shock and haemodynamic support; ECG interpretation; acute coronary syndrome from sodium-channel blockade; hyperkalaemia; hypoglycaemia; paediatric poisoning.