Two Pediatric Methadone Fatalities: Case Reports from the Office of ...

Two Pediatric Methadone 

Fatalities: Case Reports 

from the Office of the Medical 

Examiner 

Phoenix, Arizona 

Kim McCall Tackett, BS; Amy Lais, BS; 

Diane Mertens Maxham, BS; Vladimir 

Shvarts, MD; and Norman A. Wade, MS 

Methadone 

• Synthetic Opioid 

• Synthesized during WW II by 

German Scientists (morphine 1803) 

• Clinically available in US in 1947 

• Used for treatment of narcotic 

addictions (early 1970’s) 

• Later used for treatment of chronic 

pain

Methadone 

• Prior use and cellular tolerance 

significant when evaluating blood 

concentrations 

• Fatal concentrations vary greatly 

• Overlapping therapeutic and lethal 

ranges 

• Little information about incidence and 

associated toxicity in pediatrics 

Methadone Emphasis 

• Comparison with morphine: Much longer 

duration of action 

• Stereochemistry: Used as a racemic mixture 

• Variability: In both pharmacokinetics and 

pharmacodynamics 

• Adverse effects: Respiratory depression and 

ventricular arrhythmias (?) 

• Caution: In initiation or alteration of therapy 

Structure of Methadone 

Pharmacokinetics A 

• Oral Availability: 92% 

• Plasma protein binding: 89% 

• Clearance: 2.3 mL/min/kg 

• Volume of distribution: 3.6 L/kg 

• Elimination half-life: 27 (15-40 hr) (5-130 

hr): similar for the stereoisomers 

• Peak effect ~ 1 hr sc or im; 4 hr po 

• Dosing interval after first dose may be 

shorter due to redistribution than after 

chronic (accumulation)

Pharmacokinetics B 

• Urinary excretion about 24%, (10-35%) 

and depends on pH because of ion 

trapping in acid urine 

• Up to 90% can be eliminated by hepatic 

biotransformation 

– P450 N-demethylation followed by cyclization 

to pyrrolidines and pyrroline 

– Other metabolites 

– CYP3A4, CYP2C8 and CYP2D6 all participate 

in the stereoselective oxidative metabolism 

Drug Interactions 

• Barbiturates, carbamazepine, efavirenz (NNRTI), 

nevirapine (induction of CYP3A4), phenytoin and 

rifampin accelerate metabolism of methadone 

and can precipitate withdrawal symptoms 

• Fluvoxamine (SSRI) decreases metabolism of 

methadone and can lead to methadone toxicity 

• Potential methadone toxicity: 

– Ketoconazole (CYP3A4 selective inhibitor) 

– Trimethoprim (CYP2C8 selective inhibitor) 

– Paroxetine (CYP2D6, CYP3A4, CYP2C8 inhibitor) 

Accumulation 

• With repeated doses steady-state plasma 

drug concentrations are reached in about 

4 times the elimination half-life 

• For methadone that usually takes 60-160 

hours (3-7 days); also same for excretion 

• Impaired metabolism by liver disease, 

inhibition of CYP enzymes, and/or 

genetically slower metabolism may give 

accumulation time of 520 hours (22 days)

Pharmacodynamics 

• Stereoisomers: d(S) and l(R) racemic mixture 

• The analgesic activity of the racemic mixture is 

almost entirely the result of the content of levo - 

methadone, which is 8-50 times more potent 

than the d-isomer 

• D-methadone also lacks significant respiratory 

depressant action and addiction liability but does 

have possess antitussive activity 

Mu Opioid Receptor 

• Methadone (l) is an agonist at this receptor 

• G protein linked 

• Located in the respiratory control areas of 

pons (rate of respiration) and medulla 

(rhythm, drive/force, integration, 

chemoreception) of the brain 

• Activated by exogenous/endogenous 

opioids 

• Blocked by Naloxone 

Respiratory Depression 

• Potassium Channel 

– Opioids increase conductance by increasing the flow 

of K ions which hyperpolarizes neurons so they will 

not fire 

• Adenyl Cyclase 

– Inhibition by opioids decreases cAMP 

• Chloride Channel 

– Opioids have no effect here but others do 

e.g. Benzodiazepines, Propofol and Phenobarbital 

increase conductance 

Increase in Methadone Rxs 

• Change in Rx pattern for chronic pain 

• Less rigid regulatory environment for 

providers 

• Changing knowledge basis 

– Physiology of pain 

– Molecular biology of nociception 

– Applied pharmacology in pain Rx 

– Cost and the 3 rd party payers !!!!

Methadone Death Investigations 

• Decedent Hx – Rx and illicit drug 

abuse 

• Signs/Symptoms – euphoria, slurred 

speech, ataxia,unable to arouse, 

snoring, coma, death 

• Pathology – pulmonary and cerebral 

edema 

• Scene Markers – drug paraphernalia; 

Rxs 

Interacting Factors 

• Pharmacologic 

– Low or lost opioid tolerance 

– Slower or altered opioid metabolism 

– Drug interactions (e.g. benzodiazepines) 

– Time of death in relation to ingestion 

• Postmortem 

– Acute, rapid death vs. delayed death 

– Postmortem redistribution 

Mechanism of Death 

• Methadone produces hypoventilation, 

sleep-disordered breathing and sleep 

apnea…even in stable MMT patients 

• Effect of benzodiazepines were not related 

to postmortem concentrations…low levels 

result in relaxation of respiratory 

muscles…potentially leading to obstruction 

• Occlusion of airway is more likely in slow 

developing cumulative toxicity of the drug

Why People Die… 

Suicide by a 12 Year Old 

• Moderate to high doses of drug not 

tolerated well in opioids naïve patients 

• Prior experience with opioids (tolerance) 

cannot protect one from the adverse 

effects of methadone (CNS depression) 

• Co-ingestion of ethanol and other CNS 

depressant drugs leads to synergism 

• Other factors include long half-life, etc. 

Case # 1 

• 12 y.o. female found unresponsive in 

bedroom by family 

• Suicide history; self mutilations 

• EMS summoned 

• Resuscitation efforts unsuccessful 

• Death pronounced at scene 

• Frothy purge noted from mouth 

Autopsy 

• Performed 55 hours after death 

• 120 lb./ 65 inches - Caucasian Female 

• Lungs congested: Left 500g, Right 510g 

• Cerebral edema: Brain 1350g 

• Heart wt: 250g 

• Liver: 1000g 

• Spleen: 200g Kidneys: 120 g 

• Gastric: 150 mL brown semisolid fluid

Specimens Collected 

• Pleural Fluid 

• Bile 

• Vitreous Fluid 

• Gastric Contents 

• Liver 

• Spleen 

• Brain 

Analytical Protocol 

• Volatile screen on vitreous and pleural fluid 

by GC-FID –Positive ethanol 

• ELISA screen on pleural fluid –Negative 

• Qualitative analysis for basic drugs on 

pleural fluid and bile – Positive Methadone 

• Analyzed by GC-NPD and GC/MS 

• Only Methadone and low ethanol found 

• Quantitated by GC-NPD / 5 point calibration 

Levels in Pediatric Suicide 

Murder? of a Five Year Old 

• Pleural fluid 0.7 mg/L 

– Ethanol 0.07 g% 

• Brain - 1.15 mg/kg 

• Spleen - 3.43 g/kg 

• Liver - 5.98 mg/kg 

• Gastric- 111.27 mg/kg 

• 16.7 mg total

Case #2 

• Five year old male Caucasian child 

• 43 inches tall, 44 pounds = “normal” 

• Treated for Autism (??) 

• Rx for Risperdal 

• Living alone with father (mother deceased) 

• Hx of fever and congestion & ear infection 

• Apparently snoring / raspy breathing 

Specimens Collected 

• Cardiac Blood 

• Bile 

• Gastric 

• Urine 

• Vitreous 

• CSF 

• Lung Tissue 

• Culture Swabs 

Autopsy Findings 

• Externally no injuries or trauma 

• Heart 108 gm and normal 

• Lungs 164 / 212 gm & well expanded 

• Spleen/thymus/ lymphatic all normal 

• GI all normal with 75 mL brown/red 

PDF 

• 729 gm liver and pancreas normal 

• Kidneys 63 / 46 gm –grossly normal 

• Brain 1650 gm – no 

hemorrhages/fractures 

Levels in Pediatric Homocide 

• Cardiac blood 

• Methadone 0.34 mg/L 

• EDDP metabolite 

• Dextromethorphan 0.24 mg/L 

• Doxylamine 0.36 mg/L 

• Acetaminophen 69 mg/L 

• Risperidone < 0.005 mg/L 

• 9-Hydroxyrisperidone 0.006 mg/L

Levels in Five Year Old 

• Bile 

• Gastric 


• Methadone 23.8 mg/L (1.8 mg total) 


• Dextromethorphan 

• Doxylamine 

Levels Continued 

• Urine 



• EMDP metabolite 

• Dextromethorphan 

• Doxylamine 

• Doxylamine metabolite 

• Borate 7 mg/L – by NMS 

Methadone Lethal Levels 

• Segal/Catherman (1974) 

• Robinson & William (1971) 

• Manning et al. (1976) 

• Garriott/Sterner (1973) 

• Drummer (1992) 

• Clark et al. (1995) 

• Li et al. 

• Karch 2000 (2000) 

0 - 0.5 mg/L 

0.22 – 3.04 mg/L 

1.3 – 5.8 mg/L 

0.08 – 1.4 mg/L 

0.27 – 2.5 mg/L 

0.20 – 1.86 mg/L 

0.30 – 0.60 mg/L 

0.27 – 2.5 mg/L 

• Ther. Drug Monitoring, Vol 24, No. 4, 2002 - K. Woolf 

Phoenix OME Hx Levels 

Phoenix OME Hx Levels 

• Lowest Levels in Blood 

– Average 0.04 – 0.08 mg/L 

• Highest Levels in Blood 

– Range 2.3 – 7.0 mg/L (mean 3.0 

mg/L) 

– “Methadone is a lipophilic organic 

base known to concentrate to a 

considerable extent in solid organs, 

thus providing a gradient for passive 

diffusion after death. 

– This uneven distribution of 

methadone might account for some 

but not all of the differences in blood 

concentrations reported at autopsy” 

• Karch

Conclusions 

• Cause of death 

– Drug overdose for both cases 

• Manner of death 

– Suicide (12 y/o); Undetermined (5 

y/o) Homocide or Accident by father 

• Levels found versus historical data 

indicate a clear finding of lethal 

levels 

– 0.70 mg/L and 0.36 mg/L in blood 

References 

• SOFT Methadone Workshop 2003 

• G. D. Olsen, M.D. 

• Bruce A. Goldberger, Ph.D. 

• David Moody, Ph.D. 

• Kim Woolf, Ph.D. 

• Randall Baselt, Ph.D. “ Red Book “

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