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

Papaver somniferum, Opium poppy, common poppy

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)

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

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.

Opioid Issues Natural Semi-synthetic Synthetic 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

The Physical Exam Vitals GI Neurological Ophthalmologic 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

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

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 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)

Opiate Overdose Labs EKG CXR 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

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.

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.

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

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