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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
Ingeneral, opioids act
upon mu-, delta-, and Receptor Location Effects
kappa-receptors on CNS type
neurons producing:
 Analgesia via
decreased
neuronal
transmitter
release and
decreased
μ Brain,
spinal
Analgesia, respiratory
depression, euphoria,
nociceptive cord addiction, ALL pain
impulse
propagation
messages blocked
Appears to work by
elevating the pain
threshold, thus
decreasing the
brain’s awareness of
κ Brain,
spinal
Analgesia, sedation, all
non-thermal pain
pain cord messages blocked

δ Brain Analgesia, antidepression,


dependence
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
 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
 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 non-
addictive 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

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