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

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

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

4. History of heroin Originally created by the Bayer company in 1895 as an alternative to morphine 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 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 It was used as a step-down drug for morphine addicts By 1905, heroin addiction had risen to alarming rates By 1905, heroin addiction had risen to alarming rates In 1923, it became illegal to sell narcotics In 1923, it became illegal to sell narcotics The Heroin Act was passed in 1924, making it illegal to manufacture or produce heroin 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 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 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 Once in the brain, heroin is converted to morphine, and becomes “trapped” by the barrier The morphine interacts with receptors and causes the effects. The morphine interacts with receptors and causes the effects.

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

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

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

9. Receptors δ -receptor – 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. 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 Methadone Levo-alpha-acetyl-methadol (LAAM) Levo-alpha-acetyl-methadol (LAAM) buprenorphine buprenorphine naltrexone naltrexone

12. Methadone History History Created during World War II in Germany as a morphine substitute 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 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 Ten years of studies showed that methadone eliminated withdrawal symptoms and cravings Approved by the FDA for heroin addiction maitenance treatment in 1972 Approved by the FDA for heroin addiction maitenance treatment in 1972

13. Methadone How it works How it works Methadone is broken down in the liver and stored Methadone is broken down in the liver and stored When the brain opiate receptors are ready, methadone is mobilized and fills the receptors 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 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 If patients are on blockade doses (70 mg), they can go 2 days between doses

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

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

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

17. Levo-alpha-acetyl-methadol History History First produced in 1948 as an analgesic First produced in 1948 as an analgesic Studies from 1952 showed it was effective at suppressing opiate withdrawal symptoms 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 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 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 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 How it works Metabolized in liver to nor-LAAM and dinor- LAAM Metabolized in liver to nor-LAAM and dinor- LAAM Both have slower metabolism times than LAAM Both have slower metabolism times than LAAM Causes the long-lasting effect Causes the long-lasting effect Acts using the same mechanism as methadone Acts using the same mechanism as methadone

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

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

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

22. Buprenorphine History History In 1978, Dr. Donald Jasinski first suggested the possibility of buprenorphine as a treatment for opiate addiction 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 Several studies over the next 15 years were conducted A treatment plan was approved by the FDA in 2003 A treatment plan was approved by the FDA in 2003 It included a buprenorphine pill during the initial tolerance phase It included a buprenorphine pill during the initial tolerance phase The maintenance phase uses a different pill, containing buprenorphine and naloxone 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 How it works It is partial agonist, meaning it uses the same mechanism as heroin, methadone, and LAAM 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 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”) The effects increase linearly, but only to a certain dosage – after that, the effects plateau (the “ceiling effect”) Prevents overdose Prevents overdose Helps lower addictiveness – not as high of a high Helps lower addictiveness – not as high of a high

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

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

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

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

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

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

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

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

32. Naltrexone implants Done to maintain natrexone levels over an extended period of time Done to maintain natrexone levels over an extended period of time Naltrexone tablets are stacked in a biodegradable tube Naltrexone tablets are stacked in a biodegradable tube Inserted into the abdominal wall Inserted into the abdominal wall Tablets dissolve slowly, exposing tablet underneath Tablets dissolve slowly, exposing tablet underneath Usually three implants, which will last 12-18 months 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 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 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 Pregnancy is not an issue, and has been showed to have many positive effects on the baby No withdrawal post-natal No withdrawal post-natal

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