Transcript Methadone Poisoning

Methadone Poisoning
Shiping Bao, MD
Tarrant County Medical Examiner’s Office
Case Report
• A 36 year old white
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male with history of
polycystic kidney
disease and using
multiple pain
medications.
He ran out other
medications, so used
too much methadone
and died of overdose.
The History and Medical Use
• Most content of this presentation comes from the
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publications of Substance Abuse and Mental
Health Services Administration (SAMHSA – an
agency of U.S. Dept. of Health and Human
Services).
Methadone is a synthetic opioid and was
developed in Germany in 1937.
Methadone was introduced into the United States
in 1947 by Eli Lilly and Company as an analgesic
and was approved by FDA.
The History and Medical Use
• Since 1950, methadone has been used to treat
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the painful symptoms of withdrawal from heroin
and other opioids.
So called “methadone maintenance treatment”
emerged from trials in New York City in 1964 in
response to the dramatic and continuing increase
of heroin abuse and addiction following World
War II.
Methadone has become more popular up to today.
The upsurge of methadone abuse
appeared linked to following factors:
• 1st, There have been ongoing increases in abuse
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of heroin and opioid analgesics, when other drugs
are unavailable, some persons are turning to
methadone.
2nd, methadone has become more widely
available as an increasing number of physicians
prescribe it for pain relief.
3rd, in at least some States, methadone has
become more accessible to unauthorized users as
opioid treatment programs.
The upsurge of methadone abuse
appeared linked to following factors:
• 4th, methadone is very
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cheap, as compared to
most other equivalent
analgesics.
5th, methadone has
long duration of
action.
6th, Methadone is
almost as effective
when administered
orally as by injection
40 mg of Methadone
Pharmacology: The Mode of Action
• Methadone acts by binding to the µ-opioid
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receptor for the effects of analgesia and
respiratory depression.
Methadone also binds to the glutamatergic NMDA
(N-methyl-D-aspartate) receptor. Glutamate is
the primary excitatory neurotransmitter in the
CNS. Acting as an NMDA antagonist may be one
mechanism by which methadone decreases
craving for opioids and tolerance
Overdose Treatment
• Naloxone is the drug of choice to treat
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methadone and other opioid overdose
including heroin and morphine.
Naloxone is specifically used to counteract
life-threatening depression of the central
nervous system and respiratory system
Naloxone has an extremely high affinity
for μ-opioid receptor in the CNS.
It rapidly blocks μ-opioid receptor.
Pharmacology: Metabolism
• Methadone has a slow metabolism and very high
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fat solubility, making it longer lasting than
morphine-based drugs. Methadone has a typical
elimination half-life of 15 to 60 hours with a
mean of around 22. However, metabolism rates
vary greatly between individuals.
Methadone metabolism is largely a function of
liver enzyme activity involving cytochrome P450
isoforms (CYP450 enzymes).
Pharmacology: Metabolism
• Methadone is stored extensively in the liver and
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secondarily in other body tissues.
The major urinary excretion products are
methadone itself, and metabolites (EDDP and
EMDP).
Metabolism rates vary greatly between
individuals. Methadone can be toxic to anyone
who is not tolerant.
A single day’s maintenance dose in a tolerant dult
can cause life-threatening respiratory depression
in an adult who is not tolerant, and as little as 10
mg can be fatal in a child.
The Adverse effects
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Respiratory depression – hypoventilation.
Decreased bowl motility – constipation.
Nausea, vomiting, anorexia, and stomach pain.
Hypotension, hallucination, and headache.
Perspiration, flushing, itching, and skin rash.
Blurred vision, insomnia, and impotence.
Mood changes.
• Cardiac arrhythmia, seizure, and
death.
Withdrawal Symptoms
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Lacrimation, rhinorrhea, sneezing.
Nausea, vomiting, diarrhea.
Fever, chills, tremors.
Tachycardia, elevated blood pressure.
Suicidal ideation, depression, anxiety.
Insomnia, spontaneous orgasm.
Delirium, delusion, paranoia, hallucination
Nationwide Problems Associated
with Opioid Pain Medications
• The number of new non-medical user of opioid
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pain medications consistently and sharply
increased from 400,000 in the mid-1980 to about
2 million in 2000, primarily for recreational
purposes.
The incidence of emergency department visits
related to opioid analgesic abuse dramatically
increased from 1994 to 2001.
In 2001 alone, emergency department visits:
Methadone related 10, 725, hydrocodone related
21,567, oxycodone related 18,409. 72% of cases
involved more than one drugs.
The Mortality of Methadone overdose
• According to the National Center for Health
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Statistics, medical examiners listed methadone as
contributing to 3,849 deaths in 2004, up from 790
in 1999.
Approximately 82% of those deaths were listed
as accidental and most deaths involved
combinations of methadone with other drugs
(especially benzodiazepines).
So called “Poison cocktail: Methadone,
benzodiazepines, and alcohol.
The Cause and Manner of
Death in Methadone Overdose
• The cause of death is methadone
intoxication, or mixed drug
intoxication if more than one
drugs are involved.
• The manner of death is
accidental if no evidence of
suicide or homicide.
The Analysis of Methadone
in Toxicology Lab
• Methadone may be determined in
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biological samples by Gas Chromatography
(GC), Liquid Chromatography (LC) or Mass
Spectrometry (MS).
Urine screen can be performed by enzyme
immunoassay or radioimmunoassay.
In our toxicology lab, methadone is
screened by GC/MS, and quantitated by
LC/MS/MS. Multiple drugs can be
detected at the same time.