Opiate Overdose

1. Opiate Overdose J. Ryan Altman, MD AM Report 17 February 2010

2. Papaver somniferum, Opium poppy, common poppy

3. Opiate Overview • Opiates are extracted from the poppy plant Papaver somniferum. • Opiates belong to a larger class of drugs, the opioids, which include synthetic and semi-synthetic drugs • Opioid pharmaceuticals are analagous to the three families of endogenous opioid peptides: enkephalins, endorphins, and dynorphin • There are three major classes of opioid receptor, with several minor classes (μ, κ, δ, nociceptin/orphanin)

4. Opiate Overview • Receptors in CNS and PNS; linked to variety of neurotransmitters • Analgesic effect • Inhibition of nociceptive information at points of transmission from peripheral nerve to spinal cord to brain • Euphoric effect • From increased dopamine released in mesolimbic system • Anxiolysis Effect • From effect of noradrenergic neurons in locus ceruleus

5. Opiate kinetics • Variable protein binding (89% methadone, 7.1% hydrocodone) • Given volume of distribution, difficult to remove via hemodialysis • Most are renally eliminated • Many metabolized in liver to active metabolites • Hydrocodone metabolized to hydromorphone by CYP2D6 • Morphine metabolized to morphine-6-glucuronide • Overdose issues • If multiple tablets are taken, dissolution and absorption will be delayed, prolonging the apparent half-life. • Duration of action may be shortened in overdose • Ex: when sustained release formulation of oxycodone is crushed before ingestion, the drug is rapidly absorbed.

6. Opioid Issues • Natural • Morphine (1.9h), codeine (2.9h) • Metabolized to active drug morphine in liver • Semi-synthetic • Hydromorphone (2.4h), oxycodone (2.6h), hydrocodone (4.24h), diacetylmorphine (heroin) • Synthetic • Meperidine (3.2h) • Excitatory neurotoxicity may occur when the renally excreted metabolite, normeperidine, accumulates. Seizures and serotonin syndrome. • Methadone (27h) • Very long acting; may cause QT prolongation, torsades de pointes • Propoxyphene • Seizures, IA antidysrhythmic properties (leads to widened QRS and negative inotropy) • Tramadol (5.5h) • Effects not completely revered by naloxone, seizures • Fentanyl (3.7h) • Ultrashort acting

7. The Physical Exam • Vitals • HR decreased or unchanged • BP decreased or unchanged • RR decreased (decreased tidal volume) • Temp decreased or unchanged • GI • Decreased bowel sounds • Neurological • Sedation or coma • Seizure (meperidine, propoxyphene, tramadol, or 2/2 hypoxia) • Ophthalmologic • miosis

8. PE Points to Ponder • Users of meperidine and propoxyphene may have nl pupils, and presence of coingestants (sympathomimetics or anticholinergics) may make pupils normal or large. • Best predictor of opioid poisoning is RR<12 (predicted response to naloxone in one study) • Mild hypotension (from histamine release) may be present • Hypothermia results from combination of environmental exposure and impaired thermogenesis may be present • In severely obtunded patients, room temperature may produce significant hypothermia • Elevated temperature may suggest early aspiration pneumonia or complications if IVDU (endocarditis) • Rales may indicate the presence of aspiration or acute lung injury • Examine the skin for medication patches that must be removed, track marks, or soft tissue infections

9. The DDx to the OD • Antihistamine • (anticholinergic toxidrome: dry skin and mouth, blurred vision, mydriasis, tachycardia, flushing of skin, hyperthermia, abdominal distension, urinary urgency/retention, confusion, hallucinations/delusions, excitation, coma) [atropine or belladonna alkaloids, tricyclics, phenothiazines, jimson seed] • Antipsychotics • (pupils and bowels normal) • Barbituates • (mild to severe hypotension, serum concentration) • Beta-adrenergic antagonists • (hypotension and bradycardia more prominent than mental status findings) • Calcium channel blockers • (hypotension, bradycardia, tachycardia more prominent that mental status findings) • Carbamazepine • (serum concentration) • Carbon monoxide • (carboxyhemoglobin level) • Clonidine • (bradycardia, hypotension more prominent than miosis and obtundation) • Cyclic antidepressants • (QRS prolongation, hypotension, tachycardia) • Ethanol • (pupils and bowels normal, serum concentration) • Ethylene glycol • (pupils and bowel sounds normal) • Hypoglycemic agents • (serum glucose concentration) • Isoniazid • (h/o seizure, nl pupils and bowel sounds) • Isopropanol • (pupils and bowels nl) • Lithium • (tremor, hyperreflexia, serum concentration) • Methanol • (pupils and bowels normal) • Organic phosphorous compounds • (cholinergic toxidrome: hypersalivation, bronchorrhea, bronchospasm, urination, defecation, neuromuscular failure, lacrimation) [acetylcholine, insecticides, bethanechol, methacholine, wild mushrooms] • Phencyclidine • (nystagmus: horizontal, vertical or rotary) • Sedative-hypnotic agents • (pupil size nl to decr, bowel sounds nl, less respiratory depression)

10. Opiate Overdose • Labs • Check serum glucose • Serum APAP level • Salicylate level (consider if tachypnea or incr anion gap) • CK (to exclude rhabo in setting of prolonged immobilization) • Serum creatinine • Electrolytes • Urine toxicology screen • Should not be routinely obtained • Positive test can indicate recent use but not current intoxication, or may represent false negative • Many opioids (especially synthetics) will produce false negative results in commonly available urine screens • EKG • Propoxyphene can produce prolongation of QRS and is responsive to sodium bicarbonate • Methadone can cause prolonged QTc and Torsades • CXR • Reserved for those patients with adventitious lung sounds or hypoxia that does not correct when ventilation is addressed. • May eval for body packing and stuffing

11. OMG it’s OOD Mgmt • Initial focus on airway and breathing • Administer IV naloxone • Apneic pts and pts with extremely low RR should be ventilated by bag-valve mask attached to O2 to reduce ALI. • Apneic pts should receive 0.2-1mg • Pts in cardiopulmonary arrest should be given minimum of 2mg • When spontaneous ventilations are present, give initial dose of 0.05mg and titrate upward every few minutes until RR >12. • The goal of naloxone is NOT a nl level of consciousness, but adequate ventilation. • In the absence of signs of opioid withdrawal, there is no maximum safe dose; if clinical effect does not occur after 5-10mg, reconsider your diagnosis. • Naloxone Infusion • If hypoventilation recurs following initial bolus, give additional boluses to restore adequate ventilation. • When ventilation is adequate, an infusion may be initiated at a rate of 2/3 the total dose of naloxone needed to restore breathing, delivered every hour • If respiratory depression develops despite an infusion, administer naloxone bolus (using ½ the original bolus dose) and repeat if necessary until adequate ventilation returns, then increase the infusion rate.

12. OMG it’s OOD Mgmt • Remember your NAVEL (an “inny”) for ET Tube code drugs • Narcan Atropine Vasopressin Epinepherine Lidocaine • If the clinician “overshoots” the appropriate dose in an opioid-dependent individual, withdrawal will occur. Manage expectantly, not with opioids. • Activated charcoal and gastric emptying are almost never indicated in opioid poisoning. The large volume of distribution of opioids precludes removal of a significant quantity of drug by hemodialysis. • In most cases, the pt may be discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone has not been administered for 2-3 hrs.

13. Additional Antidotes • APAP • N-Acetylcysteine • Anticholinesterases • atropine, pralidoxine [2-PAM]; if muscle weakness or fasciculations or respiratory distress • Benzodiazepines • Flumazenil • Carbon Monoxide • Oxygen • Cyanide • Amyl nitrate THEN sodium nitrate THEN sodium thiosulfate • Digoxin • Antidigoxin Fab’ fragments • Ethylene Glycol • Fomepizole or Ethanol • Extrapyramidal signs • Diphenhydramine or benztropine • Heavy metal • Chelators (calcium EDTA or dimercaprol [BAL] or Penicillamine or 2,3-Dimercaptosuccinic acid [DMSA, Succimer] • Iron • Deferoxamine mesylate • Isoniazid • Pyridoxine • Methanol • Ethanol • Methemoglobinemia • Methylene blue • Warfarin • Vitamin K1 or FFP

14. Bibliography • "Poisonous Plants of North Carolina," Dr. Alice B. Russell, Department of Horticultural Science; Dr. James W. Hardin, Botany; Dr. Larry Grand, Plant Pathology; and Dr. Angela Fraser, Family and Consumer Sciences; North Carolina State University. All Pictures Copyright @1997Alice B. Russell, James W. Hardin, Larry Grand. Computer programming, Miguel A. Buendia; graphics, Brad Capel. • Cooper, D. et. al. The Washington Manuel of Medical Therapeutics. 32nd Ed. 2007. • Opioid Intoxication in Adults. Uptodate.com