Chapter 10
Opiates


alkaloids found in the opium poppy (Papaver
somniferum)
[Gk. opion = “poppy juice”]
Opioids

compounds with opiate-like actions, including,
but not confined to opiates (e.g., synthetic,
endogenous opioids)


Opiates are natural and
synthetic compounds that come
from or are copied from OPIUM –
the resin of the opium poppy
Natural Narcotics



Opium
Extracts – Morphine & Codeine
Semisynthetic Narcotics

Slight changes to chemical
composition of morphine


Heroin
Synthetic Narcotics - Produce
opiate-like responses


Methadone, Talwin, Darvon,
Demerol
BUPRENORPHINE – Partial agonist

Native to many regions
Middle East in areas bordering
Mediterranean
 Laos, Thailand, Afghanistan
 Mexico & Colombia




Use dates back 6000 years to
Sumerians
Egyptians used it medically
3500 years ago
Common use among Islamic
peoples for medical &
recreational purposes
Arab traders took to India &
China
 Western Europe learned
about it from Arabs during
crusades
 1680 Laudanum – Opium
tincture (alcohol)
 Next 200 years, primary
consumption of opium is as
drink
 18th century - development
of opium smoking in China
 China - first laws against
Opium use in 1729


Dependence problem recognized
Western societies
 Used opium as aspirin
 Cheaper than liquor
 No negative public
opinion
 No real problem with
cops
 Used to soothe infants
& children


Teething, colic, or to keep
them quiet
Females used it more
than males

Greater # addicted
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
 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

 1803



- morphine separated from opium
Increased dependence potential
Morphine 10 X opium potency
Morpheus, the Greek God of dreams
 1856



- development of hypodermic needle
Use became widespread
Doctors began injecting opium solutions (thought to sidestep
addiction, thought to be purer & safer )
Used during Civil War for injuries (dependency known as
“soldier’s disease”)
 In
1874, British chemist altered morphine
into heroin

Unnoticed until rediscovered in 1898 (Bayer)
3-4 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
Harrison Act of 1914
 No ban on opiates, but doctors had to register with
IRS

Decreased prescriptions
 Users
not seen as victims but as weak
 Heroin drug of choice in black market

Shift of users from women to white urban adult males
 Three

Crackdown caused shortage of heroin &
increased smuggling & price




Major Social Developments
Increased levels of crime
Increased used by urban minorities
Drug culture
Vietnam War

Many veterans came back hooked
Fentanyl “China White”








Surgical anesthetic & prescription painkiller
10 to 10,000 X stronger than heroin
Growing illegal market = growing deaths
Heroin – Schedule I
Morphine – Schedule II
Vast majority of therapeutic opiates are
synthetic
Huge illegal market and trade with large
dependence problem in U.S. and abroad
 Killers
 OC
 OXY
 Oxycotton
 Hillbilly
 Cotton
 Blue
Heroin


Studies indicate that the nonmedical use of prescription
medications is increasing in the U.S. among adolescents and
young adults.
The nonmedical use of prescription medications is associated
with higher rates of tobacco, alcohol and other drug use
 5% of 12 to 17 year olds reported nonmedical use of
scheduled pain medications*;

12% of 18 to 25 year olds reported nonmedical use of
scheduled pain medications*.
* lifetime
15
Percent Using in Past Year
NSDUH, 2005
16
Monitoring the Future, 2005 12th grade
17
Past Year Nonmedical Use
% reporting medical use
*
**
**
•*p < 0.05, ** p < 0.01 based on Pearson chi-square tests
Source: McCabe, Teter, Boyd, 2006
18
Specific Prescription Opioids
Used Nonmedically
(Past Year)
%
The past year use was 2% or less for fentanyl, hydromorphone, meperidine, methadone, and tramadol.
SLS, 2005
Source: McCabe, Cranford, Boyd19& Teter, 2007"Addict Behav
Gender Differences in Motives for
nonmedical Use of Prescription Opioids
***
***
*p<.05, **p<.01, ***p<.001
SLS, 2005; check all that apply
Source: McCabe Cranford, Boyd 20
& Teter, Add Behaviors, 2007
 Most
opiates poorly absorbed through GI tract
(except codeine)



Effective nasally and through lungs
Opium frequently smoked, heroin snorted
Most effective IV (heroin 100 times more potent IV than
orally)
 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

Heroin more lipid soluble, so penetrates BBB better
- Heroin converted to morphine once it crosses the
BBB
All have somewhat different
pharmacological effects



Differ in potency, duration of action & oral
effectiveness
Heroin more potent than morphine when
injected, but same when taken orally

Act via the endogenous
opiate system

1960s - discovery of the opiate
antagonist naloxone
1973 - discovery of "opiate
receptors“ in brain
 Led to discovery of several
“endogenous opiates” in
1975




Endorphin
Enkephalin
Dynorphin
 Subtype



Mu (µ)
Delta ()
Kappa ()
 Subtypes
subtypes
have
 Primary

sites of action - CNS and GI tract
Abuse of opiate use due to


Analgesia (best for dull continuous pain, not sharp)
 Due to CNS not PNS effects
Euphoria (dream-like state with intense visions)
 Relieves negative mood states
Analgesia
Sedation - markedly differs between
individuals
•
•

poor sedative in general
Anti-diarrheal agents
•


extremely effective for dysentery (1800s)
were the only effective agents in that time
Spinal actions

inhibit incoming pain signals
Projection
neuron
Opioid receptor
Sensory
neuron
+
Spinal
cord
12.8

All classical opioid drugs of
abuse have a preference for
µ sites (e.g., morphine,
heroin, methadone, fentanyl
etc.)
µ compounds:
Increase DA cell firing
 Increase DA release in NA
Kappa compounds have
opposite effect


Dynorphin likes kappa
receptors
 Vomiting

very common with first dose
 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
 Biliary
Constriction
Body temperature

Resetting of body temperature thermostat

with limited use, lowers temperature by about 1 degree

can persist for a month
Sex hormones

Inhibited


Males - decreased testosterone levels, decreased sex
drive
Females - decreased estrogen

Cardiovascular effects



increased skin blood flow - gives them a warm feeling
Blood pressure decrease upon standing - faint
Pinpoint pupils


Signs of overdose
Seizures





Develops fast with repeated
use
More rapidly and to greater
degree as potency increases
Constipation and biliary
constriction not subject to
tolerance
Cross-tolerance based on
receptor affinity
Neuroadaptation to
numerous brain areas leads
to dependence
 Withdrawal
- onset related half-life of opiate.
6-8 hrs => drug seeking behavior, restless, anxious
 8-12 hrs => Pupils dilated, reactive to light; increased
pulse rate, blood pressure, yawning; chills;
rhinorrhea;
lacrimation;
gooseflesh;
sweating;
restless sleep
 48-72 hrs (peak) => All of the above plus muscular
weakness, aches (cramps) and twitches; nausea,
vomiting and diarrhea; temperature and respiration
rate elevated; heart rate and blood pressure
elevated; dehydration.

 Withdrawal
– managed in a number of ways
Cold Turkey
 Medically managed
 Ultra-rapid Detox

Methadone used as a replacement for heroin and
other opiates in dependent individuals






Longer half-life
Slower, less intense effects – no euphoria
Can be taken orally – no needles
Cheap
Blocks heroin effect
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
 Partial


Low levels = agonist
High levels = antagonist
 Can

Agonist
be managed by physician
Taken sublingually every 24-48 hours
 Can
bridge the gap between methadone and
nothing or used long-term