Opiate OverdoseOpiate Overdose

J. Ryan Altman, MDJ. Ryan Altman, MD

AM ReportAM Report

17 February 201017 February 2010

Papaver somniferumPapaver somniferum, Opium poppy, common poppy, Opium poppy, common poppy

Opiate OverviewOpiate Overview

Opiates are extracted from the poppy plant Opiates are extracted from the poppy plant Papaver somniferumPapaver somniferum..

Opiates belong to a larger class of drugs, the Opiates belong to a larger class of drugs, the opioids, which include synthetic and semi-opioids, which include synthetic and semi-synthetic drugssynthetic drugs

Opioid pharmaceuticals are analagous to the Opioid pharmaceuticals are analagous to the three families of endogenous opioid peptides: three families of endogenous opioid peptides: enkephalins, endorphins, and dynorphinenkephalins, endorphins, and dynorphin

There are three major classes of opioid There are three major classes of opioid receptor, with several minor classes (receptor, with several minor classes (μμ, , κκ, , δδ, , nociceptin/orphanin)nociceptin/orphanin)

Opiate OverviewOpiate Overview

Receptors in CNS and PNS; linked to variety of Receptors in CNS and PNS; linked to variety of neurotransmittersneurotransmitters

Analgesic effectAnalgesic effect Inhibition of nociceptive information at points of Inhibition of nociceptive information at points of

transmission from peripheral nerve to spinal cord to transmission from peripheral nerve to spinal cord to brainbrain

Euphoric effectEuphoric effect From increased dopamine released in mesolimbic From increased dopamine released in mesolimbic

systemsystem Anxiolysis EffectAnxiolysis Effect

From effect of noradrenergic neurons in locus From effect of noradrenergic neurons in locus ceruleusceruleus

Opiate kineticsOpiate kinetics

Variable protein binding (89% methadone, 7.1% Variable protein binding (89% methadone, 7.1% hydrocodone)hydrocodone)

Given volume of distribution, difficult to remove via Given volume of distribution, difficult to remove via hemodialysishemodialysis

Most are renally eliminatedMost are renally eliminated Many metabolized in liver to active metabolitesMany metabolized in liver to active metabolites

Hydrocodone metabolized to hydromorphone by CYP2D6Hydrocodone metabolized to hydromorphone by CYP2D6 Morphine metabolized to morphine-6-glucuronideMorphine metabolized to morphine-6-glucuronide

Overdose issuesOverdose issues If multiple tablets are taken, dissolution and absorption will be If multiple tablets are taken, dissolution and absorption will be

delayed, prolonging the apparent half-life.delayed, prolonging the apparent half-life. Duration of action may be shortened in overdoseDuration of action may be shortened in overdose Ex: when sustained release formulation of oxycodone is Ex: when sustained release formulation of oxycodone is

crushed before ingestion, the drug is rapidly absorbed. crushed before ingestion, the drug is rapidly absorbed.

Opioid IssuesOpioid Issues

NaturalNatural Morphine (1.9h), codeine (2.9h)Morphine (1.9h), codeine (2.9h)

Metabolized to active drug morphine in liverMetabolized to active drug morphine in liver Semi-syntheticSemi-synthetic

Hydromorphone (2.4h), oxycodone (2.6h), hydrocodone (4.24h), Hydromorphone (2.4h), oxycodone (2.6h), hydrocodone (4.24h), diacetylmorphine (heroin)diacetylmorphine (heroin)

SyntheticSynthetic Meperidine (3.2h)Meperidine (3.2h)

Excitatory neurotoxicity may occur when the renally excreted metabolite, Excitatory neurotoxicity may occur when the renally excreted metabolite, normeperidine, accumulates. Seizures and serotonin syndrome. normeperidine, accumulates. Seizures and serotonin syndrome.

Methadone (27h)Methadone (27h) Very long acting; may cause QT prolongation, torsades de pointesVery long acting; may cause QT prolongation, torsades de pointes

PropoxyphenePropoxyphene Seizures, IA antidysrhythmic properties (leads to widened QRS and negative Seizures, IA antidysrhythmic properties (leads to widened QRS and negative

inotropy)inotropy) Tramadol (5.5h)Tramadol (5.5h)

Effects not completely revered by naloxone, seizuresEffects not completely revered by naloxone, seizures Fentanyl (3.7h)Fentanyl (3.7h)

Ultrashort actingUltrashort acting

The Physical ExamThe Physical Exam

VitalsVitals HR decreased or unchangedHR decreased or unchanged BP decreased or unchangedBP decreased or unchanged RR decreased (decreased tidal volume)RR decreased (decreased tidal volume) Temp decreased or unchangedTemp decreased or unchanged

GIGI Decreased bowel soundsDecreased bowel sounds

NeurologicalNeurological Sedation or comaSedation or coma Seizure (meperidine, propoxyphene, tramadol, or 2/2 hypoxia)Seizure (meperidine, propoxyphene, tramadol, or 2/2 hypoxia)

OphthalmologicOphthalmologic miosismiosis

PE Points to PonderPE Points to Ponder

Users of meperidine and propoxyphene may have nl pupils, and Users of meperidine and propoxyphene may have nl pupils, and presence of coingestants (sympathomimetics or anticholinergics) presence of coingestants (sympathomimetics or anticholinergics) may make pupils normal or large.may make pupils normal or large.

Best predictor of opioid poisoning is RR<12 (predicted response Best predictor of opioid poisoning is RR<12 (predicted response to naloxone in one study)to naloxone in one study)

Mild hypotension (from histamine release) may be presentMild hypotension (from histamine release) may be present Hypothermia results from combination of environmental exposure Hypothermia results from combination of environmental exposure

and impaired thermogenesis may be presentand impaired thermogenesis may be present In severely obtunded patients, room temperature may produce In severely obtunded patients, room temperature may produce

significant hypothermiasignificant hypothermia Elevated temperature may suggest early aspiration pneumonia or Elevated temperature may suggest early aspiration pneumonia or

complications if IVDU (endocarditis)complications if IVDU (endocarditis) Rales may indicate the presence of aspiration or acute lung injuryRales may indicate the presence of aspiration or acute lung injury Examine the skin for medication patches that must be removed, Examine the skin for medication patches that must be removed,

track marks, or soft tissue infectionstrack marks, or soft tissue infections

The DDx to the ODThe DDx to the OD Antihistamine Antihistamine

(anticholinergic toxidrome: dry skin and mouth, blurred vision, mydriasis, tachycardia, flushing of skin, hyperthermia, abdominal distension, urinary (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]urgency/retention, confusion, hallucinations/delusions, excitation, coma) [atropine or belladonna alkaloids, tricyclics, phenothiazines, jimson seed]

AntipsychoticsAntipsychotics (pupils and bowels normal)(pupils and bowels normal)

Barbituates Barbituates (mild to severe hypotension, serum concentration)(mild to severe hypotension, serum concentration)

Beta-adrenergic antagonists Beta-adrenergic antagonists (hypotension and bradycardia more prominent than mental status findings)(hypotension and bradycardia more prominent than mental status findings)

Calcium channel blockersCalcium channel blockers (hypotension, bradycardia, tachycardia more prominent that mental status findings)(hypotension, bradycardia, tachycardia more prominent that mental status findings)

Carbamazepine Carbamazepine (serum concentration)(serum concentration)

Carbon monoxide Carbon monoxide (carboxyhemoglobin level)(carboxyhemoglobin level)

Clonidine Clonidine (bradycardia, hypotension more prominent than miosis and obtundation)(bradycardia, hypotension more prominent than miosis and obtundation)

Cyclic antidepressants Cyclic antidepressants (QRS prolongation, hypotension, tachycardia)(QRS prolongation, hypotension, tachycardia)

Ethanol Ethanol (pupils and bowels normal, serum concentration)(pupils and bowels normal, serum concentration)

Ethylene glycol Ethylene glycol (pupils and bowel sounds normal)(pupils and bowel sounds normal)

Hypoglycemic agents Hypoglycemic agents (serum glucose concentration)(serum glucose concentration)

Isoniazid Isoniazid (h/o seizure, nl pupils and bowel sounds)(h/o seizure, nl pupils and bowel sounds)

Isopropanol Isopropanol (pupils and bowels nl)(pupils and bowels nl)

Lithium Lithium (tremor, hyperreflexia, serum concentration)(tremor, hyperreflexia, serum concentration)

Methanol Methanol (pupils and bowels normal)(pupils and bowels normal)

Organic phosphorous compounds Organic phosphorous compounds (cholinergic toxidrome: hypersalivation, bronchorrhea, bronchospasm, urination, defecation, neuromuscular failure, lacrimation) [acetylcholine, (cholinergic toxidrome: hypersalivation, bronchorrhea, bronchospasm, urination, defecation, neuromuscular failure, lacrimation) [acetylcholine,

insecticides, bethanechol, methacholine, wild mushrooms]insecticides, bethanechol, methacholine, wild mushrooms] Phencyclidine Phencyclidine

(nystagmus: horizontal, vertical or rotary)(nystagmus: horizontal, vertical or rotary) Sedative-hypnotic agents Sedative-hypnotic agents

(pupil size nl to decr, bowel sounds nl, less respiratory depression)(pupil size nl to decr, bowel sounds nl, less respiratory depression)

Opiate OverdoseOpiate Overdose

LabsLabs Check serum glucoseCheck serum glucose Serum APAP levelSerum APAP level Salicylate level (consider if tachypnea or incr anion gap)Salicylate level (consider if tachypnea or incr anion gap) CK (to exclude rhabo in setting of prolonged immobilization)CK (to exclude rhabo in setting of prolonged immobilization) Serum creatinineSerum creatinine ElectrolytesElectrolytes Urine toxicology screenUrine toxicology screen

Should not be routinely obtainedShould not be routinely obtained Positive test can indicate recent use but not current intoxication, or may represent false negativePositive 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 Many opioids (especially synthetics) will produce false negative results in commonly available

urine screensurine screens EKGEKG

Propoxyphene can produce prolongation of QRS and is responsive to sodium Propoxyphene can produce prolongation of QRS and is responsive to sodium bicarbonatebicarbonate

Methadone can cause prolonged QTc and TorsadesMethadone can cause prolonged QTc and Torsades CXRCXR

Reserved for those patients with adventitious lung sounds or hypoxia that does not Reserved for those patients with adventitious lung sounds or hypoxia that does not correct when ventilation is addressed.correct when ventilation is addressed.

May eval for body packing and stuffingMay eval for body packing and stuffing

OMG it’s OOD MgmtOMG it’s OOD Mgmt

Initial focus on airway and breathingInitial focus on airway and breathing Administer IV naloxoneAdminister IV naloxone

Apneic pts and pts with extremely low RR should be ventilated by bag-valve mask Apneic pts and pts with extremely low RR should be ventilated by bag-valve mask attached to O2 to reduce ALI.attached to O2 to reduce ALI.

Apneic pts should receive 0.2-1mgApneic pts should receive 0.2-1mg Pts in cardiopulmonary arrest should be given minimum of 2mgPts in cardiopulmonary arrest should be given minimum of 2mg

When spontaneous ventilations are present, give initial dose of 0.05mg and titrate When spontaneous ventilations are present, give initial dose of 0.05mg and titrate upward every few minutes until RR >12.upward every few minutes until RR >12.

The goal of naloxone is NOT a nl level of consciousness, but adequate ventilation.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 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.effect does not occur after 5-10mg, reconsider your diagnosis. Naloxone InfusionNaloxone Infusion

If hypoventilation recurs following initial bolus, give additional boluses to restore adequate If hypoventilation recurs following initial bolus, give additional boluses to restore adequate ventilation. ventilation.

When ventilation is adequate, an infusion may be initiated at a rate of 2/3 the total dose 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 hourof naloxone needed to restore breathing, delivered every hour

If respiratory depression develops despite an infusion, administer naloxone bolus (using 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 ½ the original bolus dose) and repeat if necessary until adequate ventilation returns, then increase the infusion rate. increase the infusion rate.

OMG it’s OOD MgmtOMG it’s OOD Mgmt

Remember your NAVEL (an “inny”) for ET Tube code drugsRemember your NAVEL (an “inny”) for ET Tube code drugs NNarcan arcan AAtropine tropine VVasopressin asopressin EEpinepherine pinepherine LLidocaineidocaine

If the clinician “overshoots” the appropriate dose in an opioid-If the clinician “overshoots” the appropriate dose in an opioid-dependent individual, withdrawal will occur. Manage expectantly, dependent individual, withdrawal will occur. Manage expectantly, not with opioids.not with opioids.

Activated charcoal and gastric emptying are almost never Activated charcoal and gastric emptying are almost never indicated in opioid poisoning. The large volume of distribution of indicated in opioid poisoning. The large volume of distribution of opioids precludes removal of a significant quantity of drug by opioids precludes removal of a significant quantity of drug by hemodialysis. hemodialysis.

In most cases, the pt may be discharged or transferred for In most cases, the pt may be discharged or transferred for psychiatric evaluation once respiration and mental status are psychiatric evaluation once respiration and mental status are normal and naloxone has not been administered for 2-3 hrs.normal and naloxone has not been administered for 2-3 hrs.

Additional AntidotesAdditional Antidotes

APAP APAP N-AcetylcysteineN-Acetylcysteine

Anticholinesterases Anticholinesterases atropine, pralidoxine [2-PAM]; if muscle weakness or fasciculations or respiratory distressatropine, pralidoxine [2-PAM]; if muscle weakness or fasciculations or respiratory distress

BenzodiazepinesBenzodiazepines FlumazenilFlumazenil

Carbon MonoxideCarbon Monoxide OxygenOxygen

CyanideCyanide Amyl nitrate THEN sodium nitrate THEN sodium thiosulfateAmyl nitrate THEN sodium nitrate THEN sodium thiosulfate

DigoxinDigoxin Antidigoxin Fab’ fragmentsAntidigoxin Fab’ fragments

Ethylene GlycolEthylene Glycol Fomepizole or EthanolFomepizole or Ethanol

Extrapyramidal signsExtrapyramidal signs Diphenhydramine or benztropineDiphenhydramine or benztropine

Heavy metal Heavy metal Chelators (calcium EDTA or dimercaprol [BAL] or Penicillamine or 2,3-Dimercaptosuccinic acid [DMSA, Succimer]Chelators (calcium EDTA or dimercaprol [BAL] or Penicillamine or 2,3-Dimercaptosuccinic acid [DMSA, Succimer]

IronIron Deferoxamine mesylateDeferoxamine mesylate

IsoniazidIsoniazid PyridoxinePyridoxine

MethanolMethanol EthanolEthanol

MethemoglobinemiaMethemoglobinemia Methylene blueMethylene blue

WarfarinWarfarin Vitamin K1 or FFPVitamin K1 or FFP

BibliographyBibliography

"Poisonous Plants of North Carolina," Dr. Alice B. Russell, Department of Horticultural Science"Poisonous Plants of North Carolina," Dr. Alice B. Russell, Department of Horticultural Science ; Dr. ; Dr. James W. Hardin, Botany; Dr. Larry Grand, Plant Pathology; and Dr. Angela Fraser, Family and Consumer James W. Hardin, Botany; Dr. Larry Grand, Plant Pathology; and Dr. Angela Fraser, Family and Consumer Sciences; Sciences; North Carolina State UniversityNorth Carolina State University. All Pictures Copyright @1997Alice B. Russell, James W. Hardin, . All Pictures Copyright @1997Alice B. Russell, James W. Hardin, Larry Grand. Computer programming, Miguel A. Buendia; graphics, Brad Capel. Larry Grand. Computer programming, Miguel A. Buendia; graphics, Brad Capel.

Cooper, D. et. al. The Washington Manuel of Medical Therapeutics. 32Cooper, D. et. al. The Washington Manuel of Medical Therapeutics. 32 ndnd Ed. 2007. Ed. 2007. Opioid Intoxication in Adults. Uptodate.com Opioid Intoxication in Adults. Uptodate.com