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Opiates. PAIN. sensory event of both PNS and CNS emotional component cognitive component. Is pain useful?. acute pain chronic pain. pain can be modulated, enhanced or diminished by both central and peripheral mechanisms peripheral aspect – non steroidal antiinflammatory drugs

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Opiates
PAIN

  • sensory event of both PNS and CNS

  • emotional component

  • cognitive component


Is pain useful
Is pain useful?

  • acute pain

  • chronic pain


Opiates

  • 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)


History of opioids
History of central and peripheral mechanismsOpioids

  • 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


Opiates

  • 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


Controlled substances act
Controlled Substances Act active ingredient

  • 1970 –

    • established current schedules of drugs


Terminology
Terminology active ingredient

  • opium – juice or sap from the poppy

  • opiate – drug extracted from the sap

codeine

morphine


Opiates


Endogenous opioids
endogenous synthetic) that binds to an opiate receptor and produces agonist or morphine-like effectsopioids

  • enkephalins

  • dynorphins

  • beta endorphins


Opiates

  • opioids occur in nature in 2 places synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • 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)


Opioid receptors
Opioid synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects Receptors

  • analgesic potency of the agonist correlates with affinity of agonist for opioid receptor

  • at least 3 types of opioid receptors

    • mu-

    • kappa

    • delta


Regional distribution
regional distribution synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • some areas have all 3 types of opioid receptors

    • (spinal cord)

  • some have predominantly one type of receptor


Mu receptors
mu receptors synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • 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,


Delta receptors
delta receptors synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • may modulate mu receptors


Kappa receptors
kappa receptors synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • minor analgesic effects;

  • pinpoint pupils

  • modest analgesia

  • no addiction potential

  • dysphoria


Opioid analgesics
Opioid synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects analgesics

  • pure agonists –

  • mu agonists

    • produces analgesia, reward, respiratory depression


Examples of pure mu agonists
examples of pure mu agonists synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • morphine

  • codeine

  • heroin

  • meperidine (Demerol)

  • methadone (Dolophine)

  • oxymorphone (Numorphan)

  • hydromorphone (Dilaudid)

  • fentanyl (Sublimaze)

  • oxycodone


Mixed agonist antagonists
mixed agonist/antagonists synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • 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


Partial agonists
partial agonists synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • 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


Antagonists
antagonists synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • block opiate receptors

  • naloxone, naltrexone

  • depot injections of naltrexone


Morphine
morphine synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • pure agonist

  • more potent and represents about 10% of crude sap

  • codeine much less potent


Morphine pharmacokinetics
morphine pharmacokinetics synthetic) that binds to an opiate receptor and produces agonist or morphine-like effects

  • 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


Opiates


Pharmacological effects of opioids
pharmacological effects of – 20X more potent than morphine for analgesiaopioids

  • analgesia

  • euphoria

  • respiratory depression

  • cough suppression

  • pupillary constriction

  • nausea and vomiting

  • GI symptoms

  • endocrine symptoms

  • immune system effects

  • histamine release


Opioid agonists
opioid – 20X more potent than morphine for analgesia agonists

  • codeine –

    • one of the most commonly prescribed opioid

    • usually combined with aspirin or acetaminophen for relief of mild to moderate pain


Heroin
heroin – 20X more potent than morphine for analgesia

  • 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


Oxycodone
oxycodone – 20X more potent than morphine for analgesia

  • (Percodan, OxyContin)- semisynthetic opioid

  • percodan short-acting; oxycontin – long-acting

  • current abuse high;


Other full agonists
other full agonists – 20X more potent than morphine for analgesia

  • 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


Tolerance and dependence
tolerance and dependence – 20X more potent than morphine for analgesia

  • rate at which tolerance develops can vary widely; pattern of use plays a role

  • cross-tolerance

  • physical dependence can develop


Opiate withdrawal
opiate withdrawal – 20X more potent than morphine for analgesia

  • many of the effects observed are opposite of opiate


Do opiates produce chemical dependence
Do opiates produce chemical dependence? – 20X more potent than morphine for analgesia

  • 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)


Opiates

  • 5 – 7 days into withdrawal; – 20X more potent than morphine for analgesia

    • 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


Neonatal abstinence syndrome
Neonatal abstinence syndrome – 20X more potent than morphine for analgesia

  • 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


Treatment
Treatment – 20X more potent than morphine for analgesia

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

  • Role of cues


Treating opiate dependence
treating opiate dependence – 20X more potent than morphine for analgesia

  • substitution therapy

  • What are the advantages of substitution therapy?


Full agonists used for treatment
full agonists used for treatment – 20X more potent than morphine for analgesia

  • 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


Methadone
methadone – 20X more potent than morphine for analgesia

  • 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


Opiates
LAAM – 20X more potent than morphine for analgesia

  • 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


Buprenorphine
buprenorphine – 20X more potent than morphine for analgesia

  • Subutex –

  • advantages – longer ½ life

  • Suboxone-

  • buprenorphine/naloxone

  • advantages of buprenorphine


Opiate antagonists
opiate antagonists – 20X more potent than morphine for analgesia

  • 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


Vivitrol
Vivitrol – 20X more potent than morphine for analgesia


Mptp induced parkinsonism
MPTP-induced Parkinsonism – 20X more potent than morphine for analgesia

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


Documentary
Documentary – 20X more potent than morphine for analgesia

  • Vanguard

    • “The Oxycontin Express”

    • Can be found on Hulu


Opiates

June 2010 – 20X more potent than morphine for analgesia


Opiates


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