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wikitox:2.1.1.3_opioids [2025/07/14 23:03] – kharriswikitox:2.1.1.3_opioids [2025/07/17 22:35] (current) – [Educational Resources] kharris
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 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 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.+[[wikitox:opioidtoxicity|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. 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. 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 ===== ===== Mechanism of toxic effects =====
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 ===== Kinetics in Overdose ===== ===== Kinetics in Overdose =====
  
-==== Absorption: ====+==== 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. 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.
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 Buprenorphine is used as opiate replacement therapy and administered sublingually due to high first pass metabolism. Buprenorphine is used as opiate replacement therapy and administered sublingually due to high first pass metabolism.
  
-==== Distribution: ====+==== Distribution ====
  
 These drugs have volumes of distribution of 1-5 L/kg and cross well into the central nervous system. These drugs have volumes of distribution of 1-5 L/kg and cross well into the central nervous system.
  
-==== Metabolism: ====+==== 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. 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: ====+==== 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. 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.
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 ===== Treatment ===== ===== Treatment =====
  
-==== Supportive: ====+==== Supportive ====
  
 Management of opioid toxicity is centred on the maintenance of respiration and cardiopulmonary function, as well as appropriate use of an opioid antagonist. Management of opioid toxicity is centred on the maintenance of respiration and cardiopulmonary function, as well as appropriate use of an opioid antagonist.
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 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. 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: ====+==== 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: Gastrointestinal decontamination can potentially reduce the duration and severity of toxicity. Consider offering activated charcoal to an awake, co-operative patient who has ingested:
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 **Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)** **Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)**
  
-==== Enhanced Elimination: ====+==== Enhanced Elimination ====
  
 There is no role for enhanced elimination following opioid ingestion. There is no role for enhanced elimination following opioid ingestion.
  
-==== Antidote: ====+==== 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. 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.
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 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. 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: ====+==== 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. 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.
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 **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).** **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: =====+===== Educational Resources ===== 
 + 
 +[[https://player.vimeo.com/video/551812296?h=8e20711df8|Video: The possibilities of intramuscular naloxone - A/Prof Katherine Isoardi - TAPNA ASM 2021]] 
 + 
 +[[https://player.vimeo.com/video/551889547?h=0fd9cdd7b5|Video: Approaching the unknown opioid - Dr Zeff Koutsogiannis - TAPNA ASM 2021]] 
 + 
 +[[https://player.vimeo.com/video/742096486?h=6e07e40c06|Video: Tapentadol Studies - A/Prof Betty Chan - TAPNA regional Meeting 2022]] 
 + 
 +[[https://player.vimeo.com/video/981044115?h=3ab849a80d|Video: Randomised placebo-controlled trial of 1600mcg IM naloxone vs IV titration - A/Prof Katherine Isoardi - TAPNA ASM 2024]] 
 + 
 +[[https://player.vimeo.com/video/981338745?h=0803068bb6|Video: A Fresh perspective on opioid overdose antidotes - A/Prof Ktherine Isoardi - TAPNA ASM 2024]] 
 + 
 +[[https://player.vimeo.com/video/1102057885?h=9ac7786e25|Video: Clinical Experiences with Nitazenes - A/Prof Darren Roberts - TAPNA ASM 2025]] 
  
-===== Further Reading: =====+===== Further Reading =====
  
-  - Boyer EW. Management of opioid analgesic overdose. N Engl J Med 2012;367(2):146–55. PDF +  - Boyer EW. Management of opioid analgesic overdose. N Engl J Med 2012;367(2):146–55. {{:wikitox:management_of_opioid_analgesic.pdf|PDF}} 
-  - 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 +  - 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. {{:wikitox:population_pharmacokinetics_of_intravenous_intramuscular_and_intranasal_naloxone_in_human_volunteers.pdf|PDF}} 
-  - 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 +  - Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986;15(5):566–70. {{:wikitox:goldfrank-naloxoneinfusiondosing.pdf|PDF}} 
-  - 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 +  - 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. {{:wikitox:rzasa_naoloxonedosing.pdf|PDF}} 
-  - 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 +  - 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. {{:wikitox:effectiveness_of_intramuscular_naloxone_1_600_g_in_addition_to_titrated_intravenous_naloxone_100_g_for_opioid_poisoning_a_randomised_controlled_tri.pdf|PDF}} 
-  - 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 +  - 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. {{:wikitox:isoardi_ambulance_naloxone.pdf|PDF}} 
-  - 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+  - 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. {{:wikitox:emerg_medicine_australasia_-_2022_-_isoardi_-_dedicated_nursing_care_pathway_improved_management_of_opioid‐poisoned.pdf|PDF}}