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

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

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 48-72 hours in 50-80% of infants

Methadone withdrawal may be delayed up to 6 days after birth

1935 - 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 ~ 24-25 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---

1982 – San FranciscoDesigner Drug that was supposed to mimic heroin

Seven heroin addicts at ERAll showed signs of severeParkinsons like Disease

Found that the drug had beencontaminated 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