Opioid Analgesics

Department of Pharmacology
Zhang xiao-jie

Pain is the most common symptom for which patients

see a doctor. Different types of drugs are used for
treatment of pain. In general, they include:
A.Opioid analgesics (Narcotic analgesics)
Opiates-Morphine derivatives
Examples: morphine, codeine, heroin, fentanyl
Uses: moderate to severe pain
B. Non-opioid Analgesics
Weak analgesics (Non-narcotic analgesics or NSAIDs)
Examples: aspirin, acetaminophen , ibuprofen
Uses: mild pain, anti-inflammatory

Mechanisms of Pain and Nociception

Nociception is a consequence of tissue injury (trauma,
inflammation). It causes the release of chemical mediators
(bradykinin, PGE,5-HT,glutamate, endogenous opioid
peptides, adenosine). These mediators activate
nociceptors.
Nociceptors are pain-receptors. Nociceptors
transmit information by thin myelin (A-delta)
and non-myelin (C) fibers to the spinal cord and brain.

Main Types of Pain

Acute pain
transmitted principally by fast conducting myelin A-delta
fibers. It has major nociceptive input (physical trauma,
myocardial infarction, peptic ulcer).
The narcotic (opioid) and sometimes non-narcotic
analgesics are used for treatment of acute pain.

Chronic pain
transmitted principally by slow conducting non-myelinated
C fibers. It is depressing to the patient who sees no
prospect for relieving the suffering. Analgesics alone are
often insufficient and adjuvant drugs (antidepressants or
neuroleptics) needed

Opioid Analgesics
[Source]
Opium is obtained from the
unripe seed capsules of poppy
by incision of the seed pod.The
white latex that oozes out turns
brown and hardens on standing.
This sticky brown gum is
opium. It contains about 20
alkaloids, including morphine,
codeine etc.The principal
alkaloid in opium is
morphine,present in a
concentration of about 10%.

Opium contains two groups of alkaloids:

with phenanthrene structure
morphine, codeine, thebaine
with isoquinoline structure
papaverine, noscapine
Morphine and codeine are narcotic analgesics;
papaverine is a vasodilator;
Opium contains 10% morphine.

Some terminology
Opioid: is a natural or synthetic drug that
binds to opioid receptors producing
morphine-like effects
Opiate: is a drug extracted from the
exudate of the poppy.

Opioid is the preferred modern term.

Opioids can be divided into two groups:

- Morphine analogues with structure similar to
morphine
- Synthetics with structure unrelated to morphine
CH
N
3

CH
3
N CH3
O

HO

morphine

OH

CH

methadone

Mechanism of opioid analgesics

Effects are mediated via opioid receptors
-receptors are responsible for most of the analgesic effects of
opioids, and for some major unwanted effects (e.g. respiratory
depression, euphoria, sedation and dependence). Most of the
analgesic opioids are -receptor agonists.
-receptors are probably more important in the periphery, but
may also contribute to analgesia.
-receptors contribute to analgesia at the spinal level, and may
elicit sedation and dysphoria, but produce relatively few
unwanted effects, and do not contribute to dependence. Some
analgesics are relatively -selective.

Opioid Receptors
Opioids bind to specific receptor molecule that mediates its effects. Several opioid specific receptors have
been cloned: Mu (), Kappa (), and Delta () receptors. These receptors belong to G protein-coupled seven
transmembrane receptor family. The amino acid sequences are approximately 65% identical among these
receptors (see below the Figure).

Mechanism of Opioid Receptor Function

1. , , and are functionally coupled to G proteins (Gi) to inhibit adenylate cyclase activity.
2. Activates receptor-activated K+ currents which increase K+ efflux (hyperpolarization) reduces
voltage-gated Ca2+ entry.
3. Hyperploarization of membrane potential by K + currents and inhibition of the Ca2+ influx
prevents neurotransmitter release and pain transmission in varying neuronal pathways.

Functional effects and opioid receptors

Supraspinal

+++

Spinal

++

++

++

Peripheral

++

++

Resp.
depression

+++

++

Miosis

++

GI motility

++

++

Euphoria

+++

Dysphoria

+++

Sedation

++

++

Dependence

+++

Analgesia

Selectivity of Opioid Drugs for

receptor subtypes
Morphine,
Codeine
Methadone
Pethidine
Pentazocine
Buprenorphine
Naloxone
Naltrexone

+++

++
++
+
+++
+++
+++

+
+
+
+

+
++
++
++
+++

Agonist + Antagonist +

Endogenous opioid peptides

There are endogenous analgesic substances with
peptide structure and morphine-like action. They are
called endogenous opioid peptides and were
discovered during the investigation of the mechanism
of analgesic action of morphine.

Endogenous opioid peptides are:

a) enkephalins activate and -receptors;
b) endorphins activate , and -receptors;
c) dynorphins activate , and -receptors.

Opioid peptides act in CNS as:

- neurotransmitters
- modulators of response (usually inhibitory)

Morphine

Morphine
Pharmacological effects and Mechanisms
exert its effects through opioid receptors
CNS effects
1. Analgesia:
increasing tolerance of pain are the most
prominent effects. Therefore, help patients to
eliminate dysphoria, anxiety. Consciousness is
not lost, and the patient can usually still locate the
source of pain.

effective on various pains

chronic dull pain> acute sharp pain and colic

Morphine
2. Sedation and change in mood
After a dose of morphine, a patient in pain or
an addict experiences a pleasant floating
sensation and freedom from anxiety and
distress (euphoria). However, other patients
and some normal subjects (not in pain)
experience dysphoria rather than pleasant
effects after a dose of opioid analgesics.

 3. Respiratory depression:
Can produce significant respiratory depression by reducing the
responsiveness of the respiratory centers in the brain stem to
blood levels of carbon dioxide and inhibiting directly the
respiratory center

4. Cough suppression:
Opioids directly suppress the cough center in medulla.

5. Emesis
Nausea and vomiting are an unpleasant side effect by direct
stimulation of CTZ.

6. Miosis:
pinpoint pupils are indicative of toxic dosage prior to asphyxia.

[Peripheral effects ]
1. Cardiovascular effects:
Orthostatic hypotention can occur due to vasomotor medullary depression and
histamine release.
2. Effects on smooth muscles
(1) Gastrointestinal tract: Constipation has long been recognized as an effect of
opioids.motility(rhythmic contraction and relaxation) may decrease but tone
(persistent contraction) may increase, particularly in the central portion.
(2) Biliary tract: The opioids constrict biliary smooth muscle and sphincter of Oddi,
which may result in biliary colic.
(3) Other smooth muscle:
Uterus tone is decreased and duration of childbirth is prolonged.
Urinary tract: Ureteral and bladder tone are increased by therapeutic doses of the
opioid analgesics. Increased sphincter tone may precipitate urinary retention,
especially in postoperative patients.
Bronchial smooth muscle can constrict in higher dose of morphine, which may
precipitate bronchial asthma.

Pharmacokinetics of Morphine
Is well absorbed from the gastrointestinal tract. But it
has a significant first-pass metabolism(F:25%). So,
the analgesic effect is greater when drug is
administered intramuscularly or intravenously.
Morphine is metabolised to morphine-6-glucuronide,
which is more potent as an analgesic.
Ninety percent of a given dose is excreted in the
urine; the remaining 10% is excreted in the feces.

Therapeutic uses of Morphine

1.Analgesia:
relieve moderate to severe acute pain such as
the pain from myocardial infarction, terminal
illness, surgery, biliary colic and renal colic
(combined with atropine).

2.Cardiac asthma (acute pulmonary edema)

is a very serious syndrome in clinical. It is referred to a sudden
dyspnea caused by pulmonary edema of acute left ventricular
failure.
The relief produced by intravenous morphine in dyspnea from
pulmonary edema associated with left ventricular failure is
dramatic.

The mechanism probably include:

(1) reduction of the patient anxious and fear due to the sedative
effects of opioids;
(2) decrease in cardiac preload and afterload by lowering
peripheral resistance due to opioid-induced histamine releasing;
(3)decrease of the sensitivity of respiratory center to CO2 and
relief of shallow breathing.

3.Treating severe diarrhea because of constipating

effects.
4.Treating cough (usually insteaded by codeine).

Adverse effects
Respiratory depression is the most
important effect.
Nausea and sometimes dysphoria can occur.
Increase biliary tract pressure.
Allergic reactions.
Bronchoconstrictive action.
Tolerance and Dependence

Tolerance and dependence

Tolerance simply refers to a decrease in
effectiveness of a drug with its repeated
administration. it needs increasing of the dose
of a drug to produce the same effect as before.
It occurs rapidly with opioids (with morphine
1224 hours, e.g. the hot plate test in mice,
after 3 days the dose of morphine required
for analgesia increases 5-fold).
Important in drug addiction may need to
increase dose 50-fold.

Tolerance is not shown equally on all effects.

Tolerance extends to:
analgesia
euphoria
resp. depression
To much lesser extent on:
constipation
pupil constriction
This is why constipation can be such a big
problem with opioids.

Why does tolerance occur?

There are several potential reasons:
- Decreased receptor affinity
- Receptor desensitization and internalization
- Increased metabolism of the drug

DEPENDENCE
Takes two forms : physical and psychological
Physical dependence problems include
withdrawal syndrome (addiction):
- Irritability
- Weight loss
- Shakes
- Sweating
- Piloerection cold turkey
- Effects last off in 810 days

Psychological dependence
Problems are:
- Desire for the drug
- Want to experience the rush positive
- Dont want the withdrawal negative
- Some opioids, e.g. codeine & pentazocine,
are much less likely to cause dependence

[Toxicity ]
Acute morphine poisoning:coma, severe respiratory
depression and miosis with blood pressure decreased,
and urinary retention.
Respiratory paralysis often is the mainly lethal reason.
Treatment:
The first step is to establish a patent airway and
ventilate the patient.
The safest approach is to inject naloxone intravenously.

[contraindication and Cautions in therapy]

1. Use in patients with head in injuries: Carbon dioxide
retention caused by respiratory depression results in
cerebral vasodilation; in patients with elevated intracranial
pressure, this may lead to lethal alterations in brain
function.
2. Use in patients with impaired pulmonary function : The
respiratory depression properties of the opioid analgesics
may lead to acute respiratory failure.
3. Use during pregnancy and delivery :Since the opioid
analgesia readily traverse the placenta,their use for
obstetric analgesia can result in delivery of an infant with
depressed respiration.
4. Use in patients with impaired hepatic or renal function.

Codeine
1.codeine is 3-methyl ether of morphine.
2.pharmacologic effects are similar to morphine,
but its analgesic potency is 1/12 of morphine,
cough depressant potency is 1/4 of morphine.
3.analgesic effect is strongr than aspirin. 30mg of
codeine is equivalent to 600mg of aspirin.
4.less sedation, respiratory depression and fewer
gastrointestinal effects.
5.use: mild to moderate pains and severe cough by oral
administration.
6.physical dependence in long administration.

 Synthetic Analgesics
Pethidine (Meperidine,Dolantin)
1.activating opioid receptors, particularlyreceptors.
2.pharmacologic effects are similar to morphine
less potency and shorter duration in analgesis,
sedative and respiratory depression.
no effect on cough, bronchial and gastrointestinal
smooth muscles.

3.use
to replace morphine to relieve intense pains,
to treat acute pulmonary edema,
to induce artificial hibernation.
not useful for diarrhea or cough.
4.mild adverse effects similar to morphine
5.tolerance: being cross with the other opioids.
dependence: in long use.

METHADONE
A synthetic, orally effective opioid, equal in potency to morphine but
induces less euphoria and has a somewhat longer duration of action.
1. Mechanism of action: by the receptors.
2. Actions: The analgesic activity is equivalent to morphine.
Well-absorbed orally, in contrast to morphine. The miotic and respiratorydepressant actions have average half-lives of 24 hours.
It also increases biliary pressure and is also constipating.
3. Therapeutic uses:
Used in the controlled withdrawal of dependent abusers from heroin and
morphine.

It causes a withdrawal syndrome that is milder but more protracted (days

to weeks) than with other opioids
4. Pharmacokinetics: Readily absorbed after oral administration.
It accumulates in tissues, where it remains bound to protein, from which it
is slowly released.
used widely in treating morphine and heroine addiction (in presence of
methadone, morphine does not cause the normal euphoria)
5. Adverse effects: It can produce physical dependence like morphine.

FENTANYL
>80 times more potent than morphine
in analgesia
Actions similar to morphine
Main use is in anaesthesia, used in
conjunction with droperidol, a neuroleptic,
producing neuroleptanalgesia

Opioid Antagonists
Pure antagonists include naloxone (shortacting) and naltrexone (long-acting). They
block -, - and - receptors more-or-less
equally.
Naloxone does not affect pain threshold
normally, but blocks stress-induced
analgesia, and can exacerbate clinical pain.

Opioid Antagonists
Naloxone rapidly reverses opioid-induced
analgesia and respiratory depression, and is
used mainly to treat opioid overdose or to
improve breathing in newborn babies
affected by opioids given to the mother.
Naloxone precipitates withdrawal symptoms
in morphine-dependent patients or animals.

Clinical Use of Analgesic Drugs

The choice and route of administration of
analgesic drugs depends on the nature and
duration of the pain.
A progressive approach is often used,
starting with nonsteroidal anti-inflammatory
drugs, supplemented first by weak opioid
analgesics, and then by strong opioids.

Clinical Use of Analgesic Drugs

In general, severe acute pain (e.g. trauma, burns,
post-operative pain) is treated with strong opioid
drugs (e.g. morphine, fentanyl) given by injection.
Mild inflammatory pain (e.g. arthritis) is treated
with non-steroidal anti-inflammatory drugs (e.g.
aspirin) supplemented by weak opioid drugs
(codeine, pentazocine) given orally if required.
Severe pain (e.g. cancer pain, severe arthritis or
back pain) is treated with strong opioids given
orally, intrathecally, epidurally or by subcutaneous
injection.

Clinical Use of Analgesic Drugs

Chronic neuropathic pain is often
unresponsive to opioids, and treated with
tricyclic antidepressants (e.g. amitriptyline),
or other drugs, such as carbamazepine.