Download Opioid Analgesics

What are opioid analgesics?
History
Morphine
Mechanism of opioids
Side effects
Adverse reactions
Addiction, overdose and withdrawal symptoms
Opiophobia
Opioids of abuse
Heroin
Fentanyl
Future of opioids
Analgesics,
or pain killers, that bind to opioid receptors which are
found principally in the:
 CNS
 Gastrointestinal tract
There
are a number of broad classes of opioids:
 Natural opiates
 Alkaloids contained in the resin of the opium poppy including morphine,
codeine and thebaine
 Semi-synthetic Opiates
 Created from the natural opioids such as hydromorphone, oxycodone
and diacetylmorphine (heroin)
 Fully synthetic opioids
 Fentanyl, methadone and tramadol
 Endogenous opioid peptides
 Proudced naturally in the body, such as endorphins, enkephalins,
dynorphins and endomorphins
Opioids have been the mainstay of pain treatment for thousand of
years, and they remain so today
The search for a safe, orally active, and non-addictive analgesic
based on the opiate structure is one of the oldest fields in medicinal
chemistry
The opiates are perhaps the oldest drugs known to humanity
The first undisputed reference to opium is found in the writings
of Theophrastus in the third century B.C.
The use of opium was recorded in China over 2000 years ago,
and was known in Mesopotamia before that
Its use in medicine is quoted in a twelfth-century prescription:
Take opium ,mandragora, and henbane in equal parts and mix
with water. When you want to saw or cut a man, dip a rag in this
and put it to his nostrils. He will sleep so deep that you may do
what you wish.

Opium contains a complex mixture of 20 alkaloids,
principle one being morphine
› Responsible for analgesic activity


Because of morphine’s poor oral bioavailability, it
was little used in medicine until the hypodermic
syringe was invented in 1853
Morphine was used during the American Civil War
and the Franco-Prussian war.
› Due to poor understanding about:
 Safe dose levels
 Effects of long-term use
 And increased risks of addiction, tolerance and respiratory
depression
› Many casualties were either killed by overdoses or
became addicted to the drug
3-D Structure of Morphine
In
general, opioids act
upon mu-, delta-, and
kappa-receptors on CNS
neurons producing:
 Analgesia via
decreased
neuronal
transmitter
release and
decreased
nociceptive
impulse
propagation
to work by
elevating the pain
threshold, thus
decreasing the brain’s
awareness of pain
Receptor Location
type
Effects
μ
Brain,
spinal
cord
Analgesia, respiratory
depression, euphoria,
addiction, ALL pain
messages blocked
κ
Brain,
spinal
cord
Analgesia, sedation, all
non-thermal pain
messages blocked
δ
Brain
Analgesia,
antidepression,
dependence
Appears
As
with many drug therapeutics that cross the BBB and take
effect in the CNS, the mechanism of opioid derivatives is not
completely understood
For this reason, there is still biochemical/pharmacological
studies being conducted to try to understand how these drugs
work
A new study from last year was able to biotinylate various
opioid derivatives to aid in these types of studies which are still
very common
 Biotinylation-process of covalently attaching a biotin (vitamin H
or B7) tag to a molecule or surface
Depression of the respiratory centre
Constipation
Excitation
Euphoria
Nausea
Pupil constriction
Tolerance and dependence

Dangerous side effects are those of
tolerance and dependence, allied with
the effects morphine can have on
breathing
› Most common cause of death from
morphine overdose is suffocation
› These side effects in one drug are
particularly dangerous and lead to severe
withdrawal symptoms when the drug is no
longer taken
Anorexia
Weight loss
Pupil
dilation
Chills
Excessive
sweating
Abdominal
cramps
Muscle spasms
Hyperirritability
Lacrimation
Tremor
Increased heart
rate
Increased blood
pressure
A
study was done in W. Virginia to evaluate persons
dying of unintentional pharmaceutical overdose, the
types of drugs involved and role of drug abuse in the
deaths
Opioid analgesics were taken by 93.2% (275/295) of all
people who died of pharmaceutical overdoses in W.
Virginia in 2006
Only 44.4% (122/275) of those people had ever been
prescribed these drugs
The majority of overdose deaths in West Virginia in 2006
were associated with nonmedical use and diversion of
pharmaceuticals, primarily opioid analgesics
The fear of prescribing opioid
pain medications is known as
"opiophobia”
 Goodman and Gillman’s
Pharmacological Basis of
Therapeutics insists that although
physical dependence and
tolerance may develop, this
should not in any way prevent
physicians from fulfilling their
primary obligation to ease the
patient’s discomfort
 No patient should ever wish for
death because of a physician’s
reluctance to use adequate
amounts of effective opioids
 Physical dependence is not
equivalent to addiction

Morphine
Heroin
2X more potent
First synthesized in 1874
by an English chemist
but only became
popular more than 20
years later
 From 1898 through
1910, under the name
heroin,
diacetylmorphine was
marketed as a nonaddictive morphine
substitute and cough
suppressant

A
heroin overdose is usually treated with an opioid antagonist,
such as naloxone (Narcan) which has high affinity for opioid
receptors but does not activate them
Many fatalities reported as overdoses are probably caused by
interactions with other depressant drugs like alcohol or
benzodiazepines
It has been speculated that an unknown portion of heroin
related deaths are the result of an overdose or allergic reaction
to quinine, which may sometimes be used as a cutting agent
A final factor contributing to overdoses is place conditioning.
Heroin use is a highly ritualized behavior
Morphine
Fentanyl
1959-Fentanyl first synthesized by Paul
Janssen under Janssen Pharmaceutica
 1960s-Introduced as intravenous
anesthetic (Sublimaze)
 1990’s-same company produced
Duragesic patch
 Next came Actiq, flavored lollipop of
fentanyl citrate
 Present-Effervescent tab for buccal
absorption and buccal spray device

The pharmaceutical industry has developed several analogues of
fentanyl:
 Alfentanil (Alfenta), an ultra-short acting (5-10 minutes) analgesic
 Sufentanil (trade name Sufenta), a potent analgesic (5 to 10 times
more potent than fentanyl) for use in heart surgery
 Remifentanil (trade name Ultiva), currently the shortest acting
opioid, has the benefit of rapid offset, even after prolonged
infusions
 Carfentanil (Wildnil) is an analogue of fentanyl with an analgesic
potency 10,000 times that of morphine and is used in veterinary
practice to immobilize certain large animals such as elephants
Fentanyl is normally sold on the black market in the form of
transdermal fentanyl patches such as Duragesic, diverted from
legitimate medical supplies
the patches may be cut up and eaten, or the gel from inside
the patch smoked
Another dosage form of fentanyl that has appeared on the streets is
fentanyl lollipops Actiq, which are sold under the street name of
"percopop”
They are sold for anywhere from $15-$40 per unit
Some heroin dealers mix fentanyl powder with larger amounts of
heroin in order to increase potency or compensate for low-quality
heroin, and to increase the volume of their product
As of December 2006, a mix of fentanyl and either cocaine or
heroin have caused an outbreak in overdose deaths in the United
States
The mixture of fentanyl and heroin is known as "magic" or "the
bomb", among other names, on the street
Generic Name
Brand Name
buprenorphine
Buprenex
butorphanol
Stadol
codeine
Tylenol with codeine
fentanyl
Duragesic
hydrocodone
Vicodin
hydromorphone
Dilaudid
methadone
Dolophine
morphine
Astramorph
oxycodone
OxyContin
porpoxyphene
Darvon