You are here: start » wikitox » 2.1.1.3_opioids

Opioids

Opioids

Overview

Opioid drugs include buprenorphine, codeine, dihydrocodeine, diphenoxylate, fentanyl and its analogues—alfentanil and remifentanil, heroin, hydromorphone, loperamide, methadone, morphine, oxycodone, pethidine, tramadol and tapentadol.

Opioid toxicity presents as the triad of sedation, respiratory depression and miosis. Opioids are the most common cause of drug-related death in Australia, often occurring as an accidental consequence of recreational use.

Management is primary supportive with the aim of maintaining airway and ventilation. Antidotal therapy with naloxone may also be required.

Synthetic opioids, including fentanyl (and its analogues) and nitazenes are increasingly being detected in illicitly obtained drugs, often sold as heroin or other agents. They are highly potent and may require higher doses or longer duration of naloxone provision.

Mechanism of toxic effects

Opioids are opioid receptor agonists. Stimulation of these receptors in the central nervous systems leads to analgesia, respiratory depression and sedation in a dose dependent manner.

Effects are potentiated by other sedative drugs (e.g. alcohol, benzodiazepines) and the majority of fatal overdoses involve other substances.

Many opioids are thought to also have serotonergic effects. The agents where serotonergic effects are more commonly seen include fentanyl, tramadol, pethidine and methadone.

Tramadol: In addition to its mu-opioid receptor agonism, tramadol also inhibits both serotonin and noradrenaline re-uptake. At higher doses tramadol also acts as a GABAA antagonist.

Tapentadol: In addition to its mu-opioid receptor agonism it is also an inhibitor of noradrenaline re-uptake. As with tramadol, seizures can occur but seem comparatively less frequent. Effects on serotonin uptake are minimal.

Buprenorphine: Often used as opioid replacement therapy, buprenorphine is a partial agonist at the mu-receptor. It has a ceiling effect on respiratory depression but is still associated with death, particularly if taken by opioid naive patients.

Risk Assessment

Toxicity is dose dependant, but tolerance develops with repeated use making prediction of toxicity based on dose difficult. Factors that increase the severity of opioid toxicity include:

  • Potency: Particularly relevant for highly potent synthetic opioids where small doses can lead to profound opioid toxicity
  • Duration of action: Occurring either due to the intrinsic prolonged activity of the agent (e.g. buprenorphine, methadone) or slow-release preparations (e.g. hydromorphone, oxycodone, morphine).
  • Opioid naivety: Those without prior opioid exposure are at increased risk of adverse outcomes. Children are particularly at risk due to immature metabolism mechanisms.

Seizures can occur post tramadol ingestions of >2g in adults or 10mg/kg children (they may occur at lower doses, including at therapeutic doses, in those with a history of seizures).

Kinetics in Overdose

Absorption

The opioids are a diverse group of substances. The most important kinetic difference between them is their half-life in overdose which varies from hours to days.

Opioids are generally rapidly absorbed, with peak concentrations within two hours of oral ingestion, one hour of IM administration and minutes of IV injection.

First pass metabolism is noted with some of these drugs (codeine, morphine, propoxyphene) however these drugs also have active metabolites. Oral controlled release formulations of morphine and oxycodone and topical preparations of fentanyl are also available and are frequently used in palliative care. Absorption from these preparations will continue for up to 12 hours.

Buprenorphine is used as opiate replacement therapy and administered sublingually due to high first pass metabolism.

Distribution

These drugs have volumes of distribution of 1-5 L/kg and cross well into the central nervous system.

Metabolism

Most opioids undergo hepatic metabolism via phase I (CYP450 enzymes) and/or phase II (glucuronidation) pathways. Drugs like codeine, oxycodone, and tramadol require bioactivation by CYP2D6, while others like methadone are primarily metabolised by CYP3A4 and CYP2B6. Morphine and buprenorphine are mainly metabolised via glucuronidation (UGT enzymes). Genetic polymorphisms (especially in CYP2D6) and drug interactions can significantly affect opioid metabolism, impacting both efficacy and toxicity.

Elimination

Opioid metabolites are predominantly eliminated via the renal route, either as unchanged drug or conjugated metabolites. For example, morphine-3-glucuronide and morphine-6-glucuronide are renally cleared and can accumulate in renal impairment, potentially causing toxicity. Some opioids (e.g. fentanyl) have minimal active metabolites and are less affected by renal function. Hepatic elimination also plays a role for certain opioids (e.g. methadone). Impaired elimination can prolong effects and increase the risk of adverse outcomes, particularly with repeated dosing or in renal dysfunction.

Clinical effects

  • Respiratory: Respiratory depression is the most clinically important effect seen in overdose. This can present as both reduced respiratory rate, reduced minute volume or in the most severe cases apnoea and respiratory arrest. Aspiration pneumonitis/pneumonia is a common complication in those with opioid induced sedation/coma.
  • CNS: CNS depression ranging from mild sedation to coma can occur depending on dose and tolerance. Serotonergic toxicity can occur when opioids with serotonergic effects are taken but is only significant if another serotonergic agent is co-ingested. Tramadol ingestion can lead to seizures, which in sustained-release preparation ingestion can be delayed up to 24hrs post ingestion. Tapentadol and tramadol ingestion may lead to a degree of agitation.
  • Ophthalmological: Miosis is common but not present in all. It is not specific to opioid ingestion and whilst its presence may add evidence to opioid exposure its absence should not be used to exclude it.
  • CVS: QT-prolongation can be seen following ingestions of loperamide, methadone and oxycodone. QRS widening and AV blocks are seen with dextropropoxyphene, although this agent is no longer widely available.
  • GI: nausea, vomiting, constipation

Investigations

  • Bloods gas: pCO2 is the most reliable measure of hypoventilation and helps to both diagnoses ventilatory impairment and monitor response to treatment.
  • CXR: particularly in the setting of hypoxia to detect evidence of aspiration or (negative) pulmonary oedema (which may happen if the patient obstructed their airway due to sedation). Also helpful for detecting trauma - It is not uncommon for patients to received pre-hospital CPR (often by bystanders).
  • Other: The need for other investigations will depend on the clinical context, particularly if there was any complication such as a long-lie (creatinine kinase, d-dimer, creatinine), or cardiac arrest (troponin).

Differential Diagnosis

The differential diagnosis for a patient presenting with a typical opioid syndrome is any other sedating drug. The presence of miosis is not limited to opioid drug overdose but occurs in benzodiazepine, chloral hydrate, barbiturate, phenothiazine, alcohol, GHB, clonidine and organophosphate overdose. A failure to respond to naloxone indicates ingestion (or co-ingestion) of one of these other drugs is more likely.

Treatment

Supportive

Management of opioid toxicity is centred on the maintenance of respiration and cardiopulmonary function, as well as appropriate use of an opioid antagonist.

Patients should be closely observed for the development of respiratory depression. If necessary, naloxone can be given to counteract the effects of opioids. Intubation and ventilation will occasionally be required for patients who have developed respiratory complications of their overdose.

Decontamination

Gastrointestinal decontamination can potentially reduce the duration and severity of toxicity. Consider offering activated charcoal to an awake, co-operative patient who has ingested:

  • Large ingestion of immediate-release opioids (up to 2 hours post ingestion)
  • Opioids with a long half-life, such as methadone (up to 6 hours post ingestion)
  • Modified-release preparations (up to 6 hours post ingestion)
  • Intubated patients can be given activated charcoal at any time post ingestion via a nasogastric or orogastric tube.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

Enhanced Elimination

There is no role for enhanced elimination following opioid ingestion.

Antidote

Naloxone is an opioid antagonist that is used to reverse the effects of opioid induced hypoventilation. It has a short half-life, giving a duration of action of a single dose that is usually less than 1-2 hours. As this is shorter than the duration of action of most opioids, repeat doses are often required to maintain effect.

Its use is indicated when there is respiratory depression compromising ventilation – hypoxia, respiratory rate of <10 per minute, or significant sedation. Patients with more mild sedation, who do not have evidence of respiratory depression, do not require naloxone, but should be observed closely for worsening toxicity.

The initial dose should be given as a bolus with subsequent boluses given if toxicity recurs. In some cases, particularly of long-acting agents, a continuous infusion may be required.

There are a number of naloxone dosing regimens that are used. The aim is to reverse opioid induced respiratory depression (Target RR>10, Oxygen Saturations >92% on room air) whilst avoiding precipitation opioid withdrawal (only relevant in those on regular opioids). Suggested dosing is given below.

Bolus doses

Give:

  • Intravenous: Naloxone 0.1 - 0.2mg (Child: 0.01-0.02mg) intravenously, every 2 to 3 minutes according to clinical effect. If there is no effect after 2mg considered another diagnosis.
  • Intramuscular: Naloxone 0.8-1.6mg. Onset of action is delayed by approximately 5 minutes but there is prolonged action up to 2-3hours.
  • Intranasal: Naloxone 1.8mg/0.1ml, single spray to one nostril

Naloxone Infusion

If a patient responds to naloxone but has recurrent episodes of toxicity as the bolus effects wane, then an infusion can be started.

Give: Naloxone 4 mg in sodium chloride 0.9% 100 mL by intravenous infusion. Start the infusion at an hourly rate of approximately two-thirds of the total effective bolus dose required.

If the initial rate is not sufficient to maintain respiratory rate and saturations, first give further boluses and when the end points are met, increase the infusion rate by the total additional bolus rate. For example, if the infusion was running at 0.2mg/hr and 2 boluses of 0.1mg were required to reach the end points then increase the infusion rate to 0.4mg/hr.

Observation and Disposition

Observe asymptomatic patients for at least 6 hours post an immediate release opioid ingestion (12 hours in children) and 12 hours for modified release ingestion (24 hours in children). Avoid discharge at nighttime when recurrent opioid toxicity may go unnoticed.

Additionally, if a patient has required naloxone they should be observed for at least 2 hours post the last IV dose or 4 hours after the last IM dose or infusion cessation.

Tramadol: Those ingestion >1g of tramadol (Child: >10mg/kg) should be observed for seizures- 12 hours for immediate release preparations 12 hours for modified release preparations.

If a patient is at risk of further episodes of opioid toxicity e.g. recreational use or ongoing opioid prescription, you should provide take-home naloxone along with education on its use at discharge (IN and IM forms are available).

Educational Resources

Further Reading

  1. Boyer EW. Management of opioid analgesic overdose. N Engl J Med 2012;367(2):146–55. PDF
  2. Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit 2008;30(4):490-6. PDF
  3. Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986;15(5):566–70. PDF
  4. Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018 Jan;9(1):63-88. PDF
  5. Isoardi KZ, Harris K, Currey E, Buckley NA, Isbister GK. Effectiveness of intramuscular naloxone 1,600 μg in addition to titrated intravenous naloxone 100 μg for opioid poisoning: a randomised controlled trial. Clin Toxicol (Phila). 2024 Oct;62(10):643-650. PDF
  6. Isoardi KZ, Parker L, Harris K, Rashford S, Isbister GK. Acute Opioid Withdrawal Following Intramuscular Administration of Naloxone 1.6 mg: A Prospective Out-Of-Hospital Series. Ann Emerg Med. 2022 Aug;80(2):120-126. PDF
  7. Isoardi K, Learmont B, Horan B, Isbister G. Dedicated nursing care pathway improved management of opioid-poisoned patients in the emergency department: A before-after observational study. Emerg Med Australas. 2023 Feb;35(1):69-73. PDF
wikitox/2.1.1.3_opioids.txt · Last modified: 2025/07/17 22:35