Drugs for the Treatment of Heroin Addiction

1. Drugs for the Treatment of Heroin Addiction Karina Garrett CHEM 5398 April 6, 2006

2. diacetylmorphine morphine What is heroin? • Heroin is an opioid, derived from the opium poppy • Chemical name: diacetylmorphine • Morphine, the active ingredient in opium, is substituted with two acetyl units

3. Effects of heroin • “Positive” effects • Heroin's main effect is a sense of euphoria • Also, flushing of the skin and heavy extremities • The onset of these effects differs based on the method of administration • Smoked/snorted = 10-15 min • Injected = 7-10 seconds • The sense of euphoria lasts for several hours • Negative effects • Drowsiness and mental cloudiness • Nausea and vomitting • Itchy skin • Slowed breathing and cardiac function

4. History of heroin • Originally created by the Bayer company in 1895 as an alternative to morphine • It had the same effects as morphine without the negative side effects of morphine, and was thought to be much safer • It was used as a step-down drug for morphine addicts • By 1905, heroin addiction had risen to alarming rates • In 1923, it became illegal to sell narcotics • The Heroin Act was passed in 1924, making it illegal to manufacture or produce heroin

5. How heroin works • Because of the two acetyl groups, heroin is less polar than morphine • This allows heroin to cross the blood-brain barrier with much greater effeciency • Once in the brain, heroin is converted to morphine, and becomes “trapped” by the barrier • The morphine interacts with receptors and causes the effects.

6. How heroin works • Three analgesic receptors where morphine interacts (as an agonist) • µ-receptor • κ-receptor • δ-receptor • Receptors located non-uniformly throughout Central Nervous System • Cerebral cortex has most • Spinal cord has significantly less • Morphine reacts differently at each receptor site • At µ-receptor, morphine binds most strongly – causes euphoria and negative side effects – causes addiction! • At κ-receptor, morphine binds less strongly – cause sedation and analgesic effect without negative side effects • At δ-receptor, morphine binds strongly – causes analgesic effect

7. Receptors • µ-receptor - changes shape after morphine binds, opens up a K+ ion channel

8. Receptors • κ-receptor – changes shape after morphine binds, closes Ca2+ ion channel

9. Receptors • δ-receptor – G-protein-linked – when morphine binds, causes fragmentation of G-protein, no cAMP produced (necessary for pain transmission)

10. How users become addicted • The body cannot completely eradicate drugs. It metabolizes them, and the metabolites get stored in fatty tissue. When the fatty tissue is broken down, the metabolites are released and act on the brain again, causing a craving.

11. Drugs used in the United States • Methadone • Levo-alpha-acetyl-methadol (LAAM) • buprenorphine • naltrexone

12. Methadone • History • Created during World War II in Germany as a morphine substitute • In 1960’s Dr.’s Nyswander and Cole carried out clinical trials for methadone treatment for heroin addiction • Ten years of studies showed that methadone eliminated withdrawal symptoms and cravings • Approved by the FDA for heroin addiction maitenance treatment in 1972

13. Methadone • How it works • Methadone is broken down in the liver and stored • When the brain opiate receptors are ready, methadone is mobilized and fills the receptors • Methadone is an agonist, so it works similar to heroin, but does not produce the extreme highs and lows • If patients are on blockade doses (70 mg), they can go 2 days between doses

14. Methadone • Methadone is folded to fit into the opioid receptor • Controls cravings by keeping receptors active without producing euphoria

15. Drugs used in the United States • Methadone • Levo-alpha-acetyl-methadol (LAAM) • buprenorphine • naltrexone

16. Levo-alpha-acetyl-methadol • Similar to methadone • Agonist • Controls cravings without producing a sense of euphoria • Long-lasting • Methadone =24-48 hours • LAAM = 72 hours

17. Levo-alpha-acetyl-methadol • History • First produced in 1948 as an analgesic • Studies from 1952 showed it was effective at suppressing opiate withdrawal symptoms • Studies from the 70’s showed that LAAM is safe and effective for heroin addiction treatment • After a decade of little research, the NIDA submitted for FDA approval • After one final study, in addition to the studies from the 70’s, LAAM was approved by the FDA in 1993

18. How it works • Metabolized in liver to nor-LAAM and dinor-LAAM • Both have slower metabolism times than LAAM • Causes the long-lasting effect • Acts using the same mechanism as methadone

19. Levo-alpha-acetyl-methadol • Problems and questions • No travel dosage is allowed • Methadone is given for emergency travel • Not enough information on the effect of using LAAM during pregnancy • Currently, the FDA suggests pregnant women switch to methadone

20. Drugs used in the United States • Methadone • Levo-alpha-acetyl-methadol (LAAM) • Buprenorphine • Naltrexone

21. Buprenorphine • Partial agonist • Controls cravings • Still some sense of euphoria • Safer than heroin • Not as addictive, little risk of overdose • Longer-lasting than methadone, not as long as LAAM • 24-60 hours • Lowest category drug for treatment of heroin addiction (cat. III) • Easier than methadone to escape dependency

22. Buprenorphine • History • In 1978, Dr. Donald Jasinski first suggested the possibility of buprenorphine as a treatment for opiate addiction • Several studies over the next 15 years were conducted • A treatment plan was approved by the FDA in 2003 • It included a buprenorphine pill during the initial tolerance phase • The maintenance phase uses a different pill, containing buprenorphine and naloxone **Not all buprenorphine is approved for heroin addiction treatment! Buprenorphine is not safe in an unsupervised setting!

23. Buprenorphine • How it works • It is partial agonist, meaning it uses the same mechanism as heroin, methadone, and LAAM • Metabolized in the liver to metabolites that are more effective • The effects increase linearly, but only to a certain dosage – after that, the effects plateau (the “ceiling effect”) • Prevents overdose • Helps lower addictiveness – not as high of a high

24. Buprenorphine • Problems and Questions • There is little information on the effect of buprenorphine on pregnant women • A few cases have showed no problems • The withdrawal effects are not completely masked by buprenorphine • They are much milder

25. Drugs used in the United States • Methadone • Levo-alpha-acetyl-methadol (LAAM) • Buprenorphine • Naltrexone

26. Naltrexone • Used mainly for alcoholism treatment • New method in other countries, currently being researched in the United States • Opioid antagonist – blocks effect of opioids by blocking receptors • Non-addictive

27. Naltrexone • History • Approved by the FDA in 1984 for opioid treatment • Approved by the FDA in the last five years for alcoholism treatment

28. Naltrexone • How it works • Naltrexone is attached to the opioid receptors, competitively inhibiting the attachment of opioids to the receptors • Completely blocks euphoria feeling, but some still feel nauseous

29. Naltrexone • Problems and Questions • Not used in pregnant women • Why not? • No evidence showing harm to either mother or fetus • Studies have shown that patients taking naltrexone rarely maintain the dosage prescribed by their doctor • High relapse numbers • Australia research

30. Naltrexone • The Australian Medical Procedures Research Foundation has started a new and revolutionary treatment plan • Starts with rapid de-tox • Naltrexone implants to maintain steady level

31. Rapid de-tox • Rapid de-tox is a relatively new procedure (began in 1997) • Patient is given some anesthesia and a drug cocktail to rapidly remove all drugs from the system • Drugs include: • Narcan – removes all opioids from receptors • Naltrexone – blocks receptors

32. Naltrexone implants • Done to maintain natrexone levels over an extended period of time • Naltrexone tablets are stacked in a biodegradable tube • Inserted into the abdominal wall • Tablets dissolve slowly, exposing tablet underneath • Usually three implants, which will last 12-18 months

33. Results • The clinic statistics show that 95% of patients remain opioid-free at the 6 month mark after the treatment • This is significantly higher than with oral naltrexone • Pregnancy is not an issue, and has been showed to have many positive effects on the baby • No withdrawal post-natal

34. References www.opioids.com www.drugabuse.gov www.health.org buprenorphine.samhsa.gov www.drugs.com