Opiates

1. Opiates

2. PAIN • sensory event of both PNS and CNS • emotional component • cognitive component

3. Is pain useful? • acute pain • chronic pain

4. pain can be modulated, enhanced or diminished by both central and peripheral mechanisms • peripheral aspect – non steroidal antiinflammatory drugs • central aspects – opioid analgesics • Roxicet, Tylox (acetaminophen and oxycodone) • Percocet – (oxycodone with paracetamol)

5. History of Opioids • opium extracted from opium poppy • used for thousands of years to produce euphoria, analgesia, sleep and relief from diarrhea and cough • ancient times – primarily for constipating effects • Homer, Hippocrates, et • sleep producing effects

6. Early 1800’s – morphine isolated from opium as its active ingredient • treating severe pain • 1856- invention of the hypodermic syringe • Civil War – “soldiers disease” • 1910 – concern about dangers of opioids and dependence • 1914- Harrison Narcotic Act • use of most opioids strictly controlled

7. Controlled Substances Act • 1970 – • established current schedules of drugs

12. Terminology • opium – juice or sap from the poppy • opiate – drug extracted from the sap codeine morphine

13. opioid – any exogenous drug (natural, semisynthetic or synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects • endorphin – endogenous substance that exhibits pharmacological properties like morphine • 3 familes of endogenous opioid peptides

14. endogenous opioids • enkephalins • dynorphins • beta endorphins

15. opioids occur in nature in 2 places • the juice of the poppy • in our bodies…… • all other opioids are either prepared from morphine (semisynthetic opioids like heroin) or synthesized from other precursors (synthetic opioids such as fentanyl)

16. Opioid Receptors • analgesic potency of the agonist correlates with affinity of agonist for opioid receptor • at least 3 types of opioid receptors • mu- • kappa • delta

17. regional distribution • some areas have all 3 types of opioid receptors • (spinal cord) • some have predominantly one type of receptor

18. mu receptors • brain, sc, and periphery • morphine – mu agonist • exerts effects in thalamus and striatum • brain stem (affects respiration) • spinal cord (analgesic effects) • PAG, brain stem, nucleus accumbens,

19. delta receptors • may modulate mu receptors

20. kappa receptors • minor analgesic effects; • pinpoint pupils • modest analgesia • no addiction potential • dysphoria

21. Opioid analgesics • pure agonists – • mu agonists • produces analgesia, reward, respiratory depression

22. examples of pure mu agonists • morphine • codeine • heroin • meperidine (Demerol) • methadone (Dolophine) • oxymorphone (Numorphan) • hydromorphone (Dilaudid) • fentanyl (Sublimaze) • oxycodone

23. mixed agonist/antagonists • produces agonist effects at one receptor and antagonist at another • clinically useful mixed drugs – kappa agonist and weak mu antagonist • useful for moderate pain • not good if someone is dependent on opiates

24. partial agonists • binds to opioid receptors but has low intrinsic activity (low efficacy) • can produce analgesia – but ceiling lower than pure agonist • buprenorphine (Suboxone) • binds to all 3 receptors

25. antagonists • block opiate receptors • naloxone, naltrexone • depot injections of naltrexone

26. morphine • pure agonist • more potent and represents about 10% of crude sap • codeine much less potent

27. morphine pharmacokinetics • usually administered via injection although rectal or oral is possible • intranasal system under development • absorption from GI slow and incomplete compared to other routes • morphine crosses bbb fairly slowly (more H20 soluble than lipid soluble) • heroin, fentanyl – cross bbb much more quickly

28. liver metabolizes morphine; one metabolite is actually 10 – 20X more potent than morphine for analgesia

29. pharmacological effects of opioids • analgesia • euphoria • respiratory depression • cough suppression • pupillary constriction • nausea and vomiting • GI symptoms • endocrine symptoms • immune system effects • histamine release

30. opioid agonists • codeine – • one of the most commonly prescribed opioid • usually combined with aspirin or acetaminophen for relief of mild to moderate pain

31. heroin • heroin • (diacetylmorphine) • 3X more potent than morphine • produced by a slight modification of morphine structure • increased lipid solubility • metabolized to monoacetylmorphine and morphine • legally available in Great Britain

32. oxycodone • (Percodan, OxyContin)- semisynthetic opioid • percodan short-acting; oxycontin – long-acting • current abuse high;

33. other full agonists • hydromorphone (Dilaudid), oxymorphone (Numorphan) • both structurally related to morphine • as effective but 6 – 10X more potent • meperidine (Demerol) • structurally different from morphine – different side effect profile

34. tolerance and dependence • rate at which tolerance develops can vary widely; pattern of use plays a role • cross-tolerance • physical dependence can develop

35. opiate withdrawal • many of the effects observed are opposite of opiate

36. Do opiates produce chemical dependence? • Opiate withdrawal: • Acute symptoms: restlessness, lacrimation, runny nose, yawning, perspiration, goose flesh ("cold turkey"), restless sleep and dilated pupils during the first 24 hours (onset usually 8 to 12 hours after a reduction in dose or cessation of use)

37. 5 – 7 days into withdrawal; • symptoms can become more severe • can be characterized by twitching and spasms of muscles; kicking movements (“kicking the habit”), severe aches in the back, abdomen, and legs; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, and diarrhea; sneezing; fever

38. Neonatal abstinence syndrome • Jittery, high pitched cry, hyperactive reflexes, restlessness, GI upset, etc. • heroin withdrawal occurs within 48-72 hours in 50-80% of infants • Methadone withdrawal may be delayed up to 6 days after birth

39. Treatment • 1935 - first federal "narcotics farm" (U.S. Public Health Prison Hospital) opens in Lexington, Kentucky • Role of cues

40. treating opiate dependence • substitution therapy • What are the advantages of substitution therapy?

41. full agonists used for treatment • methadone – • synthetic mu agonist • 2 primary legitimate users • substitution for opiate dependent heroin users • long acting analgesic for chronic pain syndromes • Physicians who are not in licensed methadone programs cannot prescribe methadone for opioid dependence • methadone clinics locations • diversion

42. methadone • Oral administration – reaches peak levels in ~ 2 hrs; • Half life – the amount of time necessary for ½ of the drug to be metabolized in the body; for methadone – very variable but for most people ~ 24-25 hours • When used for treating addiction – 1/day • For pain management – more likely 3 – 4 times/day

43. LAAM • levo-alpha acetylmethadol • approved in mid 1993 for clinical management of opioid dependence • longer ½ life • not currently available because of possible serious cardiac complications

44. buprenorphine • Subutex – • advantages – longer ½ life • Suboxone- • buprenorphine/naloxone • advantages of buprenorphine

45. opiate antagonists • naloxone (Narcan) • treating overdose • what happens in opiate dependent individuals? • must be given by injection- short ½ life • naltrexone (Trexan, ReVia) • longer duration of action and can be taken orally • downside to naltexone

46. Vivitrol

48. MPTP-induced Parkinsonism How was it discovered--- 1982 – San Francisco Designer Drug that was supposed to mimic heroin Seven heroin addicts at ER All showed signs of severe Parkinsons like Disease Found that the drug had been contaminated with a toxin called MPTP First human cohort of MPTP-induced parkinsonism

49. Documentary • Vanguard • “The Oxycontin Express” • Can be found on Hulu