What are opioid analgesics?

History
Morphine
Mechanism of opioids
Side effects
Adverse reactions
Addiction, and withdrawal symptoms
Opiophobia
Opioids of abuse
Heroin
Fentanyl
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 and
codeine
 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.
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
Appears to work by Brain, Analgesia, respiratory
elevating the pain
threshold, thus decreasing
μ spinal depression, euphoria,
the brain’s awareness of cord addiction, ALL pain
pain messages blocked

Brain, Analgesia, sedation, all

κ spinal non-thermal pain
cord messages blocked

Brain Analgesia,
δ antidepression,
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
 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
Morphine Fentanyl
 1959-Fentanyl first synthesized by Paul Janssen
under Janssen Pharmaceutica
 1960s-Introduced as intravenous anesthetic
 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.
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
Opioid antagonists such as naloxone (short acting)
and naltrexone (long-term), block  receptors and
reverse the action of opioids

However, antagonists can make clinical pain worse

 Partial-agonist
› Less reinforcing than a full agonist-milder effects
› Easier withdrawal
› Safety – overdose ceiling effect
 High affinity to the opiate receptor
 Long duration of action (24-72hr)
 Strong safety profile
› Little respiratory depression
› Little overdose potential
 100

90 Full Agonist
(Methadone)
80

70
“Activity” or
60
“Response” Partial Agonist
50 (Buprenorphine)
40

30

20

10
Antagonist (Naloxone)
0
-10 -9 -8 -7 -6 -5 -4

Log DOSE
 Formulations and routes
› BUPRENEX IV NOT for Opioid Dependence
 Long history within Anesthesiology
 History of use as mild analgesic
› SUBUTEX SL - Buprenorphine
 2 mg tablet
 8 mg tablet
 Really one indication… (Pregnancy)
› SUBOXONE SL – Buprenorphine/Naloxone
 2mg/0.5mg tablet
 8mg/2mg tablet
› (Buprenorphine Transdermal)
› (Buprenorphine Depot Injection)
 Advantages
› Advantages will differ with different drugs but may
include
 Reduced stress to the animal
 Smoother induction and recovery
 Decreased amount of induction and, possibly, maintenance agent
required
 Analgesia intraoperatively and post operatively
 Reduced secretions
 Reduced autonomic responses
 Handler safety
 Disadvantages
› Are minimal
 Cost is a common concern
 The higher cost may be offset by the use of decreased amounts of
induction and maintenance agents
 Time factor
 Premedication given subcutaneously usually takes 20 minutes to reach
peak effect but can last up to two hours
 If time is an issue, most premedication can be given intramuscularly
(IM) or even intravenously (IV) (with caution)
 Some (e.g. xylazine, acepromazine, opioids and diazepam) have
been associated with temporary behavior and personality changes
 Examples
› Anticholinergics
› Phenothiazines
› Benzodiazepines
› α2-Agonists
› Opioids
› Phencyclidines
› Neuroleptanalgesics
Tolerance can develop rapidly with opioid use,
requiring an increase in dose for effective analgesia.

Tolerance may be observed in side-effects too…

Tolerance may be observed in the mechanism that

results in respiratory depression but constipation is
worsened by large doses.