Opioid Analgesics

& Antagonists
Dr. Hayder B Sahib
Ph.D. Pharmacology
• The opioids include natural opiates and
semisynthetic alkaloids derived from the opium
poppy

• pharmacologically similar synthetic substitutes,

and endogenous peptides.

• On the basis of their interaction with opioid

receptors, the drugs are classified as agonists,
mixed agonist-antagonists, and antagonists.
• Opioid peptides released from nerve endings
modulate transmission in
• 1- the brain
• 2- spinal cord
• 3- primary afferents
• via their interaction with specific receptors.

• Many of the pharmacologic actions of opiates

and synthetic opioid drugs are effected via their
interactions with endogenous opioid peptide
receptors.
 CLASSIFICATION
A. Spectrum of Clinical Uses
•Opioid drugs can be subdivided on the basis of their
major therapeutic uses (eg, analgesics, antitussives, and
antidiarrheal drugs).

•B. Strength of Analgesia

•On the basis of their relative abilities to relieve pain,
the analgesic opioids may be classified as
•1- strong, moderate, and weak agonists. Partial
agonists are opioids that exert less analgesia than
morphine, the prototype of a strong analgesic, or full
agonist.
C. Ratio of Agonist to Antagonist Effects
•Opioid drugs may be classified as agonists
(receptor activators [full or partial]), antagonists
(receptor blockers) or mixed agonist-antagonists,
which are capable of activating one opioid receptor
subtype and blocking another subtype.
 PHARMACOKINETICS
• A. Absorption and Distribution
• Most drugs in this class are well absorbed when taken
orally, but morphine, hydromorphone, and oxymorphone
undergo extensive first-pass metabolism.

• In most cases, opioids can be given parenterally, and

sustained-release forms of some drugs are now available,
including morphine and oxycodone. Opioid drugs are widely
distributed to body tissues.

• They cross the placental barrier and exert effects on the

fetus that can result in both respiratory depression and,
with continuous exposure, physical dependence in
neonates.
 Metabolism
• With few exceptions, the opioids are metabolized
by hepatic enzymes, usually to inactive glucuronide
conjugates, before their elimination by the kidney.

• However, morphine-6-glucuronide has analgesic

activity equivalent to that of morphine, and
morphine-3-glucuronide (the primary metabolite) is
neuro-excitatory.

• Codeine, oxycodone, and hydrocodone are

metabolized by cytochrome CYP2D6, an isozyme
exhibiting genotypic variability.
• In the case of codeine, this may be responsible for
variability in analgesic response because the drug
is demethylated by CYP2D6 to form the active
metabolite, morphine.

• The ingestion of alcohol causes major increases in

the peak serum levels of several opioids including
hydromorphone and oxymorphone.

• Meperidine is metabolized to normeperidine,

which may cause seizures at high plasma levels.
• Depending on the specific drug, the duration of their
analgesic effects ranges from 1–2 h (eg, fentanyl) to
6–8 h (eg, buprenorphine).

• However, long-acting formulations of some drugs

may provide analgesia for 24 h or more.

• The elimination half-life of opioids increases in

patients with liver disease.

Remifentanil, a congener of fentanyl, is metabolized by

plasma and tissue esterases and has a very short half-
life.
 MECHANISMS OF ACTION
• Receptors
• Many of the effects of opioid analgesics have been
interpreted in terms of their interactions with specific
receptors for endogenous peptides in the CNS and peripheral
tissues.

• Certain opioid receptors are located on primary afferents and

spinal cord pain transmission neurons (ascending pathways)
and on neurons in the midbrain and medulla (descending
pathways) that function in pain modulation

• Other opioid receptors that may be involved in altering

reactivity to pain are located on neurons in the basal ganglia,
the hypothalamus, the limbic structures, and the cerebral
cortex.
• Three major opioid receptor subtypes have been
extensively characterized pharmacologically:
• μ, δ, and κ receptors.

• All 3 receptor subtypes appear to be involved in

antinociceptive and analgesic mechanisms at both
spinal and supraspinal levels.

• The μ-receptor activation plays a major role in the

respiratory depressant actions of opioids and together
with κ-receptor activation slows gastrointestinal transit

κ-receptor activation also appears to be involved in

sedative actions; δ-receptor activation may play a role
in the development of tolerance.
 B. Opioid Peptides
• Opioid receptors are thought to be activated by
endogenous peptides under physiologic
conditions. These peptides, which include
endorphins such as β-endorphin, enkephalins, and
dynorphins, are synthesized in the soma and are
transported to the nerve endings where they
accumulate in synaptic vesicles.

• On release from nerve endings, they bind to

opioid receptors and can be displaced from
binding by opioid antagonists.
• Endorphins have highest affinity for μ receptors,
enkephalins for δ receptors, and dynorphins for κ
receptors.

• Although it remains unclear whether these peptides

function as classic neurotransmitters, they appear
to modulate transmission at many sites in the brain
and spinal cord and in primary afferents.

• Opioid peptides are also found in the adrenal

medulla and neural plexus of the gut.
 C. Ionic Mechanisms
• Opioid analgesics inhibit synaptic activity partly through direct
activation of opioid receptors and partly through release of the
endogenous opioid peptides, which are themselves inhibitory to
neurons.

• All 3 major opioid receptors are coupled to their effectors by G

proteins and activate phospholipase C or inhibit adenylyl
cyclase. At the postsynaptic level, activation of these receptors
can open potassium ion channels to cause membrane
hyperpolarization (inhibitory postsynaptic potentials).

• At the presynaptic level, opioid receptor activation can close

voltage-gated calcium ion channels to inhibit neurotransmitter
release Presynaptic actions result in the inhibition of release of
multiple neurotransmitters, including acetylcholine (ACh),
norepinephrine, serotonin, glutamate, and substance P.
• Strong agonist e.g. morphine , meperidine , fentanyl
• Moderate agonist e.g. codeine , oxycodone

• Weak agonist e.g. propoxyphene

• Partial agonist: are opioids that exert less analgesia

than morphine(activate opioid receptor to
submaximal response) e.g. buprenorphine
b-Sedation and euphoria:-

-These effects may occur at doses below those

required for maximal analgesia.
-The sedation is additive with other CNS
depressants, but there is little amnesia.
-Some patients show dysphoric effects from
opioid drugs.
c-Respiratory depression:-

-Morphine causes respiratory depression by

reduction the sensitivity of respiratory center
neurons to CO2 At higher doses, there will be
respiratory arrest.

-Respiratory depression is the most common

cause of death in acute opioids overdose.
d-Depression of cough reflex:-

-Both morphine and codeine have antitussive

properties.
-Cough suppression does not correlate closely
with analgesic and respiratory depressant
properties of opioid drugs.
-The receptors involved in the antitussive
action appear to be different from those
involved in analgesia.
e-Miosis:-
-:f-Emesis
Morphine directly stimulate the chemoreceptor trigger
zone that causes emesis.
 
-:g-GIT
-Morphine relieves diarrhea by decreasing the motility
and increasing the tone of intestinal smooth muscle.
-It can also increase biliary tract pressure due to
contraction of gallbladder and constriction of the
biliary sphincter.
-:h-Cardiovascular
In large doses, morphine may cause-
hypotension and bradycardia
-:i-Histamine release
Morphine is contraindicated in patient with
?? asthma. why
Morphine may cause urticaria, sweating and
?vasodilation. why
j-Hormonal actions:-

-Inhibit release of gonadotropin-releasing

hormone
-Inhibit release of corticotrophin-releasing
hormone
-:Decrease the concentration of-
luteinizing hormone●FSH●ACTH●and●
endorphin ß-
Testesterone and cortisol level decrease-
-Increase prolactin and GH release by diminishing
dopaminergic inhibition
:k-Chronic effects
:A-Tolerance
Marked tolerance can developed to acute pharmacological -
.effects, with exception of miosis and constipation
Antagonists of glutamate NMDA receptors (e.g. ketamine) -
and δ receptors antagonists are reported to block opioid
.tolerance
:B-Dependence
Is a physiological response to chronic therapy with -
.opioid especially strong agonists
Abstinence syndrome: abrupt discontinuance of opioid may cause-
rhinorrhae, lacrimation, chills, muscle ache, diarrhea, anxiety and hostility
 
 Degrees of Tolerance That May Develop to
Some of the Effects of the Opioids.

• High Moderate Minimal orNone

Analgesia Bradycardia Miosis
Euphoria, dysphoria Constipation
Mental clouding Convulsions
Sedation
Respiratory depression
Antidiuresis
Nausea and vomiting
Cough suppression
 -:Pharmacokinetics of morphine
Oral morphine is subjected to extensive 1st pass -
metabolism

)only 20% of the dose reach systemic circulation(

Given s.c or i.m morphine is rapidly absorbed but in-
.circulatory shock it is better to be given i.v

Morphine is metabolized by liver and kidney: the-

conjugated metabolites include the pharmacologically
active morphine-6-glucuronide and morphine-3-
.glucuronide
The t½ is 3 h (active metabolites slightly longer) and the -
.duration of useful analgesia is 6 h
Morphine cross the placenta and suppresses respiration-
.of the fetus at birth
-:Therapeutic uses of morphine●
:Analgesia-1
.Treatment of constant moderate to severe pain -
:Acute pulmonary edema-2
I.V morphine dramatically relieves dyspnea caused by -
pulmonary edema associated with LVF –possibly by
.vasodilator effects
:Anasthesia-3
Opioids are used as preoperative medication and as -
.intraoperative agents
High –dose I.V morphine and fentanyl are the major components -
.of anesthesia of cardiac surgery
 
●Adverse effects of morphine:

.Respiratory depression-
Vomiting, dysphorea and allergy-enhanced-
hypotensive effect -Elevation of CSF
Acute urinary retention (in prostatic-
hypertrophy)
Morphine should be used with caution in-
asthma and liver failure
 
■Fentanyl:

Administered parenterally-
It has shorter duration of action(1-2 h) than -
morphine
Available as transdermal patch which-
provide analgesia for 72 hrs
 
■ Meperidine (pethidine):
It has shorter duration of action (2-3 h) than-
morphine
Produced less neonatal respiratory -1-
depression than morphine (so, it preferred in
obstetrics)
.Has no effects on cough reflex -2-
.It is less likely to cause constipation -3-
.Has little hypnotic effect -4
.Less likely to cause urinary retention -5-
May cause mydriasis and tachycardia due -6-
.to weak anticholenergic activity
■Methadone:
Act mainly at μ receptors-
Well absorbed from GIT (morphine is partially-
absorbed)
It has longer duration of action than morphine (24-
-:h) and this allow using methadone in
Chronic pain (palliative care)-1
treatment of opioid withdrawal (it allow-2
smoother withdrawal with tapered dose
reduction)
Methadone dependency occur, but it is less-
severe than in morphine
.Sedation is less than that of morphine-
 ■Diamorphine (Heroin):
 
 
The most potent of all dependence-producing-
.opioids
.More lipid-soluble than morphine-
Rapid onset of action (than morphine)-
.Produce greater euphoria than morphine-
.Not approved for clinical use- •
:И-MODERATE AGONISTS
 
Codeine■
:

IS a much less potent analgesic than morphine, but it

has higher oral effectiveness
It has good antitussive activity at doses that do not-
.cause analgesia
It has lower potential for abuse and less euphoria-
.than morphine
.Is often used with aspirin and acetaminophine-
In cough preparation, codeine has been replaced by-
dextromethorphan – a synthetic cough
suppressant that has no analgesic action and a low
.potential for abuse
 
■ Oxycodone:
 
Is a semi-synthetic derivative of morphine-
Used to treat moderate to severe pain-
Usually used with aspirin-
Orally effective and undergo less 1st –pass-
.metabolism than morphine
Less respiratory depression, and dependence-
.liability than morphine
 

:Ш-WEAK AGONISTS
Propoxyphene■
.Is a derivative of methadone-
:There is 2 isomer-
.Dextro isomer is used is used as analgesic*
.Levo isomer is used as antitussive*
.It is weaker analgesic than codeine-
Used in combination with aspirin and-
.acetaminophine
.It can produce nausea, anorexia, and constipation-
In toxic doses, respiratory depression, convulsion,-
and in some individuals, cardiotoxicity and pulmonary
.edema
 
 
ІV-MIXED AGONIST-ANTAGONISTS
 
The effects of these drugs depend on-
.previous exposure to opioids
In individuals who have not recently-
received opioids, it show agonist activity
.and are used to relieve pain
In patients with opioids dependency, it-
shows primarily blocking effects-that is,
.produce withdrawal symptoms
ІV-MIXED AGONIST-ANTAGONISTS
:Pentazocine■
 

Act as agonist on κ-Receptors and is a weak antagonist-

.at μ- and δ Receptors
.Produce analgesia by activating receptors in spinal cord-
.Used for moderate pain-
High doses increase BP and can cause hallucination,-
.nightmare, tachycardia, and dizziness
In angina, it increases the mean aortic pressure and-
pulmonary arterial pressure and thus, increases the
work of heart and should not used for pain of MI
.
.It also decreases the renal plasma flow-
It does not antagonize the respiratory depression-
of morphine, but it can precipitate withdrawal
.symptoms in morphine abusers

Severe respiratory depression, although-

uncommon

.is resistance to naloxone reversal

■Buprenorphine:
. Is classified as partial agonist at μ-receptors-
-It precipitate withdrawal in morphine abusers.
A major use is in opiate detoxification, because it has-
less severe and shorter duration of withdrawal
.symptoms compared to methadone
It causes little sedation, respiratory depression, and-
.hypotension even at high doses
Severe respiratory depression, although uncommon, is-
.resistance to naloxone reversal
 
  
V-OTHER ANALGESICS(CENTRALLY
  ACTING)
:Tramadol■
A centrally acting analgesic that binds to the μ-opioid-
.receptors
Also it weakly inhibits re-uptake of norepinephrine and-
.serotonin
.It may have special use for neuropathic pain-
Associated with increased risk of seizures and is-
.contraindicated in patients with epilepsy
.Its action is only partially reversed by naloxone-
.Should not administered to patients taking MAOIs-
  •
VI-OPIOID ANTAGONISTS
Binds with high affinity to opioid receptors,-
but fail to activate the receptor-mediated
.response
It produce no profound effects in normal-
.individuals
In patients dependent on opioid, it rapidly-
reverse the effects of agonist, and precipitate
.the symptoms of opioid withdrawal
Naloxone■
:

Used to reverse the coma and respiratory depression of --

opioid over dose and also for diagnoses of opioid

.dependency
.Has half life of 30-100 min-
Naloxone is competitive antagonist at μ-, κ- and δ-
.Receptors
With 10 fold higher affinity for μ- receptor than for κ- and
.δ Receptors
This may explain why naloxone readily reverse respiratory-
depression with only minimal reversal of analgesia that
result from agonist stimulation of κ- receptors in the
.spinal cord
:Naltrexone■
It has longer duration of action than naloxone-
.(48 h)
Indication is similar to that of naloxone in-
addition , it may be used to decrease craving
.for alcohol