Methadone Poisoning

1
Methadone Poisoning

• Shiping Bao, MD
• Tarrant County Medical Examiners Office

2
Case Report

• A 36 year old white 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.

3
The History and Medical Use

• Most content of this presentation comes from the
  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.

4
The History and Medical Use

• Since 1950, methadone has been used to treat 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.

5
The upsurge of methadone abuse appeared linked to
following factors

• 1st, There have been ongoing increases in abuse
  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.

6
The upsurge of methadone abuse appeared linked to
following factors

• 4th, methadone is very 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
7
Pharmacology The Mode of Action

• Methadone acts by binding to the µ-opioid
  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

8
Overdose Treatment

• Naloxone is the drug of choice to treat 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.

9
Pharmacology Metabolism

• Methadone has a slow metabolism and very high 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).

10
Pharmacology Metabolism

• Methadone is stored extensively in the liver and
  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 days 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.

11
The Adverse effects

• 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.

12
Withdrawal Symptoms

• Lacrimation, rhinorrhea, sneezing.
• Nausea, vomiting, diarrhea.
• Fever, chills, tremors.
• Tachycardia, elevated blood pressure.
• Suicidal ideation, depression, anxiety.
• Insomnia, spontaneous orgasm.
• Delirium, delusion, paranoia, hallucination

13
Nationwide Problems Associated with Opioid Pain
Medications

• The number of new non-medical user of opioid 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.

14
The Mortality of Methadone overdose

• According to the National Center for Health
  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.

15
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.

16
The Analysis of Methadone in Toxicology Lab

• Methadone may be determined in 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.