The Major Opiates

1. The Major Opiates • Most common used drug for relief of pain • Only true Narcotics (stupor, sleep, analgesia) • compare to marijuana and cocaine which have other effects such as euphoria, stimulant properties. • Also cough suppressant & antidiarrea properties • “Narcotics” is Greek word for “stupor” • not for illicit psychoactive drug

2. The Major Opiates • Opium derived from juice of poppy plant • What is an opiate? • Analgesic • Acts on endorphan/enkephalin receptors • Antagonized by naloxone • Most potent painkiller, but severe dependence

3. The Major Opiates • Endogenous Opiods • Endorphine, Enkephalin, Dynorphin • in pituitary • in pain sensors (spinal cord & midbrain) • affective states (amygdala, hippocampus, locus coeruleus, and cerebral cortex) • autonomic system (e.g. medulla) • stomach and intestines

4. Classification of Opiates • 3 specific groups of opiates used • Natural Narcotics • Opium & extracts (morphine, codeine & thebaine) • Semisynthetic Narcotics • Slight changes to chemical composition of morphine • E.g. heroin • Synthetic Narcotics • Not related to morphine, but produce opiate like responses

5. Classification of Opiates • Opium, morphine, heroin, thebaine & codeine referred to as opiates • Synthetic Narcotics referred to a synthetic opiates or synthetic opiate-like drugs

6. History of Opium • Native to Middle East in areas bordering Mediterranean • Also Laos, Thailand, Afghanistan, Mexico & Columbia • Use dates back 6000 years to Summarians • Egyptians used it medically 3500 years ago • Excavation of ceramic opium pipe in Cypres • Common use among Islamic peoples for medical & recreational purposes • not forbidden in Koran as were alcohol & many other drugs

7. History of Opium • Arab traders took to India & China • Also, western Europe learned about it from Arabs during crusades • 1520 Paracelsus & laudanum • 1680 Thomas Sydenham & his version of laudanum • Next 200 yrs primary consumption of opium is as drink

8. China & Opium • Up to 1700’s Chinese use limited to “painkiller” • 18th century development of opium smoking • China first laws against Opium use in 1729 • dependence problem recognized • British traded for tea with Chinese • 1773 Brits control of India-begin to supply opium to China • basis for Opium wars between China & British

9. China & Opium • China tried to control drug problem • 1839 Defiance of European power • Confiscation of large quantities of opium • Burned it in Canton • Start of opium war

10. Opium Wars • First War • 1839-1842 Hong Kong ceded to British (‘til 1997), Canton & Shanghai opened for trade • Second War • 1858-1860 British joined by French & American forces • 20 mill. pounds sterling, opening of remaining ports, legalization & regulation of opium trade (ended 1906)

11. Difference in Opium Use • Major difference between opium use in China & West was method of consumption • laudanum • Identified with Victorian Era • Opening of “respectable parlors” • Chinese smoked it • Identified with Opium Dens • Ideal of “lazy” Chinese • Seen as degrading & dirty vice

12. Opium & the West Western societies • Used opium as aspirin • Cheaper than liquor • No negative public opinion • No real problem with cops • Used to sooth infants & children • Teething, colic or to keep them quite • Women used it more than male • Greater # addiction

13. Problems in the West Collision of cultures • Chinese building railroad • 1875 San Francisco outlawed opium dens & opium smoking • Laws targeted not at opium (laudanum legal), but at Chinese • Federal laws prohibiting opium smoking followed

14. Morphine & the West • 1803 Sertürner separated morphine from opium • Increased dependence potential • Morphine 10 X opium potency • Morpheus; Greek God of dreams • 1856 development of hypodermic needle • Use became widespread • Doctors began injecting opium solutions (thought sidestep addiction-thought purer & safer ) • Used during Civil War for injuries (dependency known as “soldier’s disease”)

15. Heroin: From Bad to Worst • In 1874 British chemist altered morphine • but unnoticed until rediscovered in 1898 • 1898 German Heinrich Dreser • Heroin-altered form of morphine • 3X-4 X more potent than morphine • Thought to be safer than morphine • Sold by Bayer beginning in lieu of codeine as medicine for coughs, bronchitis, tuberculosis • Heroin also began to replace morphine in addicted individuals

16. Opiates in the US • By 1900 250, 000 “opium dependent people” in US • By 1913, 400,000 lbs of opium imported into U.S. for consumption by U.S. population of 90 mill. people • Laws began cropping up around this time and formed the cornerstone of American drug laws today

17. Opiates in US Early 1900’s Harrison Act of 1914 • No ban on opiates, but doctors had to register with IRS • Decreased prescriptions • Users not seen as victims but weak • heroin drug of choice in black market • Shift of users not women, but white urban adult males

18. Opiates Use in 1960’s 3 Major Social Developments • Crackdown cause shortage of heroin & increased smuggling & price • Increased levels of crime • Increased used by urban minorities • Peace movement, hippies & drug culture • Vietnam War

19. Opiates Use in 1980, 90’s • “Golden Triangle” • Laos, Burma & Thailand • Afghanistan, Pakistan, Iran & Mexico • Dominate heroin supply route • Shift from Turkey as main supplier • Opened a large vacuum • Fentanyl “China White” used as surgical anesthetic & prescription painkiller • 10 to 10,000 X stronger than heroin • Sometimes found itself on black market

20. Opiates in 20th century US • Morphine is schedule II • Heroin schedule I • In Britain comparably seems as “Schedule II” • Schedule I = no accepted medical use • Schedule V = has medical use, not too addictive • most legally used opioids are either semisynthetic or synthetic • no legal U.S. use for heroin - purely illicit drug (in the US) with large worldwide market today

21. Opiates in 20th century US • about 4-5000 metric tons opium produced in 1990 (2,200 lbs) • compared to 200-225,000 metric tons coca in same year

22. Business of Opiates opium grown in 2 primary regions of world using simple farming techniques • poppies grown, petals fall, small incisions, liquid oozes out - opium • opium - 10% morphine 0.5% codeine • morphine refined in growing areas then transported or processed • heroin - equal amount - then diluted to 1-10%

23. Business of Opiates • extremely profitable as a business • kg morphine in Italy $12,500 - heroin in U.S. 1.7 million • 10 kg opium $300 in production region • heroin in New Delhi $10,000 • in U.S. 1.5 million

24. Absorption, Distribution, Metabolism & Excretion • Most opiates poorly absorbed through GI tract (except codeine) • Effective nasally and through lungs • Opium frequently smoked, heroin snorted • Most effective i.v. (heroin 100 times more potent i.v. than orally)

25. Absorption, distribution & excretion • In bloodstream distributed throughout body • accumulating in kidney, lung, liver, spleen, muscle & brain • Opiates and blood brain barrier • Morphine does not cross BBB well • only 20% of circulating enters brain • 30-60 min to reach significant brain concentrations

26. Absorption, distribution & excretion • Heroin more lipid soluble so penetrates BBB better • Both morphine & heroin cross placenta • heroin converted to morphine once it cross the BBB • once crossed BBB codeine 10% converted to morphine

27. Absorption, distribution & excretion • Most opiates rapidly metabolized in liver and excreted by kidney • Half-life about 2.5-3 hrs • Duration of effect 4-5 hrs • 5-15 mg optimal analgesic dose for morphine - addicts 2 g H

28. Opiates • Opium, morphine, codeine • Derivatives or semisynthetic (minor modification in structure) • heroin, nalorphine, and hydromorphone • Synthesized—have different structures, but similar properties • Meperidine (Demerol) • Fentanyl (Sublimaze) • Proxyphene (Darvon, Darvocet) – lousy analgesic • Methadone (Dolophine)

29. Absorption, distribution & excretion • Have somewhat different pharmacological effects • Differ in potency, duration of action & oral effectiveness • Because of differences in pharmacokinetics • Heroin more potent than morphine when injected, but same when taken orally. • slight modification of heroin from morphine allows it to cross BBB better—What would this do?

30. Absorption, distribution & excretion • Metabolized into morphine in brain • because it gets there quicker, more rapid intense effects. • Codeine- 12x less potent that morphine when injected • better absorbed orally (morphine\heroin weak alkaloids) • Endogenous opiates more potent than heroin • But inactivated quickly • Fentanyl-50 times more powerful than heroin (IM) • Used for surgery, but easy for addicts to OD

31. Medical Use • analgesia • sedation-markedly differs between individuals • poor sedative in general • anti-diarrhea agents • extremely effective for dysentery (1800's) • were the only effective agents in that time

32. Mechanism of Action • act via the endogenous opiate system • 1960's discovery of the opiate antagonist naloxone (Narcan7) • implication of common receptor site for opiates actions • 1973 Pert and Snyder discovery of "opiate receptors" • led to discovery of several endorphins in 1975 • beta-endorphin • enkephalin • dynorphin

33. Pharmacological Actions • Primary effect of narcotics is sedative-hypnotic • Some cause stimulation immediate after injection • Cats and some humans are the only mammals that show stimulation

34. Pharmacological Actions • Primary sites of action - CNS and GI tract • For both medicine and abuse, opiate use due to 3 actions • Analgesia (best for dull continuous, not sharp) • still feel sensations, can remain alert • vision, hearing, touch okay • Euphoria (dream like state with intense visions) • Constipation (used for diarrhea and dysentery)

35. Pharmacological Actions • Natural pain relief system • Used for chronic, not sharp, acute pains • childbirth, battlefield injuries, strenuous exercise, acupuncture • addiction to exercise related to endorphin release • can you be addicted to an endogenous substance?

36. Pharmacological Actions • Opiates also relieve psychological pain • anxieties, feelings of inadequacy, hostility & aggression • produce extremely pleasant mood states - euphoria • pain relief due to central effect - no effect on sensory nerve transmission • begins at spinal cord & continues throughout CNS

37. Abuse Potential Abuse is related to euphoriant actions (CNS action) 2 main groupings • visual illusions-dream like states • clarity of thought and alleviation of psychological pain

38. Abuse Potential Trance-like state - visual illusions • dream-like images - great deal of clarity • doesn't influence sensory input • the only perceptual effect is on pain • can alleviate physical pain • can alleviate psychological pain • strong emotionally pleasant feelings

39. Side Effects • vomiting • very common with first dose • chance-may be due to effect on the vestibular apparatus • respiratory depression • decrease sensitivity to CO2 • occurs at low doses-those common for analgesia • increase dose-increase depression • most common cause of death in overdose

40. Side Effects Body temperature • resetting of body temperature thermostat • with limited use-lowers temperature by about 1 degree • can persist for a months Sex hormones • inhibited • males-decreased testosterone levels-decreased sex drive • females-decreased estrogen

41. Side Effects • Cardiovascular effects • increased skin blood flow-gives them a warm feeling • blood pressure decrease upon standing -faint • Pinpoint pupils • signs of overdose • seizures • Catatonia (only at very high doses)

42. RECEPTOR TYPES MEDIATING OPIOID EFFECTS • m1 • spinal & supraspinal analgesia • m2 • respiratory depression • GI motility • nausea • euphoria • physical dependence (withdrawal symptoms) • pupillary contraction

43. RECEPTOR TYPES MEDIATING OPIOID EFFECTS • k (kappa) • spinal & supraspinal analgesia • sedation • pupil contraction • dysphoria, psychotomimetic • d (delta) • spinal & supraspinal analgesia • positive reinforcing effects • modulate activity of m receptors

44. Receptor Location • m receptors - pain modulating regions of brain • dorsal horn of spinal cord • brain stem • PAG • thalamus • hypothalamus • striatum

45. Receptor Location • k receptors - broad distribution • deep layers of cerebral cortex • limbic system • hypothalamus • d receptors - emotional response regions of brain • limbic system (amygdala) • frontal cortex • nucleus accumbens

46. Receptor Location • opioid induced euphoria not well understood • seems to involve m2 receptors & also d • definitely not k • opioids act as modulators and inhibit release of excitatory amino acid neurotransmitters • all act via second messenger systems • found on presynaptic nerve terminals • also found to serve as cotransmitters (released with NE

47. Tolerance & Dependence • develop with repeated use • More rapidly and to greater degree as potency increases • Heroin & methadone develop different patterns for withdrawal • Heroin withdrawal begins 4-5 hrs after last dose • strong flu like symptoms • greatest magnitude of symptoms between 24-72 hrs • pretty much done in a couple of weeks

48. Tolerance & Dependence • Methadone withdrawal 24-48 hrs after last dose • withdrawal symptoms reported to be less intense • however, much greater duration • can take months to clear all withdrawal symptoms • Methadone admin subcu for analgesia • Same potency as morphine, half potency as heroin • More effective orally than both • Suppresses opiate withdrawals • actions 3 to 4 time longer than morphine

49. Tolerance & Dependence Why do we pay for people to be maintained on methadone? 1) effective orally - limits needle use 2) long duration action 3) effective dose remains stable 4) cheap 5) does not produce euphoria as well actually blocks to heroin 6) prevents opiate withdrawal

50. Treatment • Therapeutic groups (Synanon & Daylop) • In West Berlin- 15% abstained compared to 4% • Elimin of cond craving (to drug related stim) through extinction & class cond • Mostly blocking narcotic effects • Antagonist break up drug taking from reinforcement • Naloxone (Narcan7)-not too effective • Naltrexen (Trexen7 or ReVia7) block up to 3 days • What may be a problem with antagonist?