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

Brain Analgesia,
δ 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 B 7) 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