Methadone Poisoning

1. Methadone Poisoning Shiping Bao, MD Tarrant County Medical Examiner’s Office

2. 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. Case Report

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. 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 The upsurge of methadone abuse appeared linked to following factors: 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 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.

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.