Two Pediatric Methadone Fatalities: Case Reports from the Office of the Medical Examiner Phoenix, Arizona

Transcription

1 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

2 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)

3 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 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)

4 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!!!!

5 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

6 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

7 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 mg/kg Spleen g/kg Liver mg/kg Gastric mg/kg 16.7 mg total

8 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 < mg/l 9-Hydroxyrisperidone mg/l

9 Levels in Five Year Old Bile Gastric Methadone 0.63 mg/l Methadone 23.8 mg/l (1.8 mg total) EDDP metabolite Dextromethorphan Doxylamine Levels Continued Urine Methadone 8.36 mg/l EDDP metabolite 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) mg/l mg/l mg/l mg/l mg/l mg/l mg/l mg/l Ther. Drug Monitoring, Vol 24, No. 4, K. Woolf Phoenix OME Hx Levels Phoenix OME Hx Levels Lowest Levels in Blood Average mg/l Highest Levels in Blood Range 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

10 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