1. OPIOID INTOXICATION Foroud shahbazi PharmD

2. Introduction Opioid analgesic overdose is a preventable and potentially lethal condition that results from prescribing practices, inadequate understanding on the patient's part of the risks of medication misuse, errors in drug administration, and pharmaceutical abuse

3. Opioid classification 1.Opioid refers to natural and synthetic substances with morphine-like activity. 2.Opiate: alkaloid compounds extracted from opium, including morphine, heroin, codeine, and semisynthetic derivatives of the poppy plant 3.Endorphins are endogenous peptides that produce pain relief

4. Opioid classification 4)Prescription opioids 5)"Designer" opioids are synthetic derivatives of opioids created in makeshift laboratories and include 3-methylfentanyl (Moscow theater hostage crisis of 2002), α-fentanyl (“China White”), desomorphine (“krokodil”), and other agents, such as MPTP.

5. Krocodil Desomorphine It has been used commercially in Switzerland under the brand name Permonid® Is a l-receptor agonist and synthetic derivative of morphine Desomorphine with morphine in patients with cancer, a 1:10 dosing ratio of desomorphine to morphine was used Shorter duration of action After 3 weeks of desomorphine use, the patients experienced withdrawal symptoms if the drug was withheld for as little as 4 hours

6. PHARMACOLOGY Mechanism of action and pharmacokinetics — Three types of receptors have been identified: mu (µ), kappa (k), and delta (δ); most opioids interact with more than one type. An opioid-receptor-like 1 (ORL-1) receptor or “orphan” receptor has also been described. The primary sites of opioid action are the limbic system, thalamus, and hypothalamus

7. Half-life Mayo Clin Proc. 2009;84(7):602-612

8. Potency

10. EPIDEMIOLOGY Opioid abuse is a major international public health problem with up to 22 million people using opium or heroin worldwide Mortality Increase rate opioid abuse

11. Volkow ND et al. N Engl J Med 2014;370:2063-2066. Opioid Sales, Admissions for Opioid-Abuse Treatment, and Deaths Due to Opioid Overdose in the United States, 1999–2010.

12. Methadone ???? In studies by the US Centers for Disease Control and Prevention (CDC) from 1999-2010, methadone accounted for 4.5-18.5% of narcotics sold in the United States and was involved in 31% of opioid deaths in the 13 states involved in the study. In addition, CDC analysis of data collected from 2004-2009 revealed a significant increase in the nonmedical use of methadone alone or in combination with other drugs J Forensic Sci. 2011;56:1072-5 MMWR Morb Mortal Wkly Rep. 2012 ;61:493-7.

13. Toxicokinetics of Opioid Analgesics The pharmacokinetics of particular opioid analgesic agents are often irrelevant in overdose Bezoars formation after ingestions No linear dose elimination (zero order elimination) N Engl J Med 2012;367:146-55.

15. CLINICAL MANIFESTATIONS The diagnosis of opioid overdose is based upon the history and physical examination Family members, EMS Ingestion time, quantity, and co-ingestants are important aspects of the history and should be ascertained. Naloxone test

16. Clinical features Apnea, stupor, and miosis suggests the diagnosis of opioid toxicity, all of these findings are not consistently present. The sine qua non of opioid intoxication is respiratory depression. A respiratory rate of 12 breaths per minute or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Miosis? Polysubstance ingestions may produce normally reactive or mydriatic pupils, as can poisoning from meperidine, propoxyphene, or tramadol

17. Failure of oxygenation and non cardiogenic pulmonary edema Cardiovascular (bradycardia, hypotension, QT prolongation Seizure (IV fentanyl administration, the prolonged use of meperidine, and large ingestions of tramadol Gastrointestinal Muscle rigidity and rhabdomyolysis

19. Toxicities of specific agents Buprenorphine – Partial opioid agonist, may induce withdrawal in opioid-dependent patients Dextromethorphan – Serotonin syndrome, Fentanyl – Very short acting Hydrocodone – Often combined with acetaminophen Meperidine – Seizure, serotonin syndrome (in combination with other agents) Methadone – Very long-acting; QTc prolongation, Torsades de Pointes Oxycodone – Often combined with acetaminophen; possible QTc interval prolongation Propoxyphene – QRS prolongation, seizure Tramadol – Seizure

20. DIFFERENTIAL DIAGNOSIS CLONIDINE: miosis and obtundation, bradycardia, and hypotension are more prominent than in patients with opioid intoxication ETHANOL: intoxication produces little to no miosis and no change in bowel sounds THE SEDATIVE-HYPNOTIC AGENTS: much less respiratory depression than the opioids, (PO). Pupils are typically not pinpoint and ataxia may be a prominent feature in children. BACLOFEN: can cause coma, bradycardia, and hypotension after ingestion in children and adolescents. Miosis is typically not present

21. LABORATORY EVALUATION AND ANCILLARY STUDIES Glucose monitoring Pulse oximetry ABG Serum acetaminophen concentration Serum ethanol levels Serum CPK in prolonged immobilization Urine toxicologic screens should NOT be routinely obtained. Phenytoin when indicated Rapid pregnancy test Chest radiograph Electrocardiography

22. First step, pre-hospital care Respiratory stabilization If advanced life support (ALS) is available, intravenous naloxone may be given to reduce respiratory depression

23. Hospital Airway control and adequate oxygenation remain the primary intervention if not already established by EMS If occult trauma is suspected, implement cervical spine immobilization Administer naloxone for significant central nervous system (CNS) and/or respiratory depression The usual dose administered by EMS is between 0.4 and 2 mg in the adult and 0.1 mg/kg in the child or infant To avoid precipitous withdrawal use lower dose especially in patients suspected of taking another CNS depressant(s) (eg, benzodiazepines, tricyclic antidepressants, ethanol

24. Role of activated charcoal Should be reserved for patients who present within 1 hour after ingestion; Offers no benefit outside this time frame and complicates visualization of airway anatomy during orotracheal intubation Whole-bowel irrigation can be considered for removal of ingested drug packets in body packers,

25. N Engl J Med 2012;367:146-155. Decision Tree for Managing Opioid Analgesic Overdose in Adults.

26. Naloxone Is a competitive mu opioid–receptor antagonist that reverses all signs of opioid intoxication. It is active when the parenteral, intranasal, or pulmonary route of administration is used Negligible bioavailability after oral administration In patients with opioid dependence, plasma levels of naloxone are initially lower? Onset of action 2min, Duration 20-90min Dosing protocols

27. N Engl J Med 2012;367:146-155. Naloxone Dosing.

28. Continue If no response after 8-10 mg? Buprenorphine and naloxone: dose response ? Once the respiratory rate improves after the administration of naloxone, the patient should be observed for 4 to 6 hours before discharge is considered

29. Thanks for your attention