 sensory event of both PNS and CNS  emotional component  cognitive component

 acute pain  chronic pain

 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)

 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

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

 1970 – ◦ established current schedules of drugs

 opium – juice or sap from the poppy  opiate – drug extracted from the sap morphine codeine

 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

 enkephalins  dynorphins  beta endorphins

 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)

 analgesic potency of the agonist correlates with affinity of agonist for opioid receptor  at least 3 types of opioid receptors ◦ mu- ◦ kappa ◦ delta

 some areas have all 3 types of opioid receptors ◦ (spinal cord)  some have predominantly one type of receptor

 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,

 may modulate mu receptors

 minor analgesic effects;  pinpoint pupils  modest analgesia  no addiction potential  dysphoria

 pure agonists –  mu agonists ◦ produces analgesia, reward, respiratory depression

 morphine  codeine  heroin  meperidine (Demerol)  methadone (Dolophine)  oxymorphone (Numorphan)  hydromorphone (Dilaudid)  fentanyl (Sublimaze)  oxycodone

 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

 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

 block opiate receptors  naloxone, naltrexone  depot injections of naltrexone

 pure agonist  more potent and represents about 10% of crude sap  codeine much less potent

 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

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

 analgesia  euphoria  respiratory depression  cough suppression  pupillary constriction  nausea and vomiting  GI symptoms  endocrine symptoms  immune system effects  histamine release

 codeine – ◦ one of the most commonly prescribed opioid ◦ usually combined with aspirin or acetaminophen for relief of mild to moderate pain

 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

 (Percodan, OxyContin)- semisynthetic opioid  percodan short-acting; oxycontin – long- acting  current abuse high;

 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

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

 many of the effects observed are opposite of opiate

 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)

◦ 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

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

 first federal "narcotics farm" (U.S. Public Health Prison Hospital) opens in Lexington, Kentucky  Role of cues

 substitution therapy  What are the advantages of substitution therapy?

 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

 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 ~ hours ◦ When used for treating addiction – 1/day ◦ For pain management – more likely 3 – 4 times/day

 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

 Subutex –  advantages – longer ½ life  Suboxone-  buprenorphine/naloxone  advantages of buprenorphine

 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

How was it discovered – 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

 Vanguard ◦ “The Oxycontin Express” ◦ Can be found on Hulu

June 2010

 July 1, 2001, nationwide law in Portugal decriminalized all drugs, including cocaine and heroin ◦ drugs were "decriminalized," not "legalized.” ◦ drug possession for personal use and drug usage itself are still legally prohibited  FINES BUT NOT JAIL ◦ trafficking still a criminal offense