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
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
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
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
Classification of Opiates
 Opium, morphine, heroin, thebaine &
codeine referred to as opiates
 Synthetic Narcotics referred to a synthetic
opiates or synthetic opiate-like drugs
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
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
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
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
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)
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
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
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
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”)
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
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
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
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
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
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
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
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%
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
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)
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
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
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
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)
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?
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
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
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
Pharmacological Actions
 Primary effect of narcotics is sedativehypnotic
 Some cause stimulation immediate after
injection
 Cats and some humans are the only mammals that
show stimulation
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)
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?
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
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
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
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
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 levelsdecreased sex drive
females-decreased estrogen
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)
RECEPTOR TYPES MEDIATING
OPIOID EFFECTS
 m1
 spinal & supraspinal analgesia
 m2






respiratory depression
GI motility
nausea
euphoria
physical dependence (withdrawal symptoms)
pupillary contraction
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
Receptor Location
 m receptors - pain modulating regions of
brain






dorsal horn of spinal cord
brain stem
PAG
thalamus
hypothalamus
striatum
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
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
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
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
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
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?
Treatment
 Substituting narcotics w/less disruptive
(Methadone)
 Developed by Nazis in WWII
 Dole and Nyswander (1976)—narcotic addicitions
 Gave large levels of methadone
 Despite addiction went back to school, got jobs
etc.,
Treatment
 Withdrawal symptoms in addicts with
naloxone admin
 Administer both heroin & naloxone
repeatedly together
 no tolerance or dependence develops
 interesting way to see what receptor type
mediates what responses