Opioid analgesics and antagonists

John Tiong
 Definitions
International Association for the Study of Pain (IASP):
Pain: An unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of such damage.

Acute pain
 Provoked by a specific disease or injury.
 Generally disappears when the injury heals.

Chronic pain
 Persistent noxious stimuli or repeated exacerbation of an injury.
 May be considered a disease state if pain outlasts the normal time of
healing ( > 3 months).
 Serves no biological purpose.
 No recognizable end-point.
 Types of pain
Nociceptive pain:
 Acute pain felt due to tissue damage  protective mechanism against
noxious stimuli.
 The pain signals start in the nociceptors located in the skin will be carried
by Aδ fibres (fast sharp pain) and C-fibres (slow dull pain) to the brain.

Neuropathic pain:
 Pain caused by structural damage and dysfunction nerve cells in the
PNS or CNS.

Inflammatory pain:
 Inflammation leads to the secretion of inflammatory mediators
(prostaglandins, interleukins, substance P, etc) that lower pain threshold
and amplify pain.
 Acute: temporary tissue damage
 Chronic: Osteoarthritis, rheumatism.
 Introduction
 Morphine, the prototypical opioid agonist, has long been known to
relieve severe pain with remarkable efficacy.

 The opium poppy is the source of crude opium from which

Sertürner in 1803 isolated morphine, the pure alkaloid, naming it
after Morpheus, the Greek god of dreams.

 After incision, the poppy seed pod exudes a white substance that
turns into a brown gum that is crude opium. Opium contains many
alkaloids, the principle one being morphine, which is present in a
concentration of about 10%.

 It remains the standard against which all drugs that have strong
analgesic action are compared.
Endogenous opioid peptides
 Opioid alkaloids (eg, morphine) produce analgesia through
actions at receptors in the central nervous system (CNS) that
contain peptides with opioid-like pharmacologic properties.

 The general term currently used for these peptides is

endogenous opioid peptides e.g. endorphins,
enkephalins, and dynorphins

 They are released naturally in your CNS to modulate pain by

hence diminishing the sensation of noxious stimuli.
 Opioids
 Although the opioids have a broad range of effects, their primary
use is to relieve intense pain, whether that pain results from
surgery, injury, or chronic disease.

 Unfortunately, widespread availability of opioids has led to abuse

of those agents with euphoric properties.

 Antagonists that reverse the actions of opioids are also clinically

important for use in cases of overdose and addiction.
Opioid receptors
 The major effects of the opioids are mediated by three receptor
families, which are commonly designated as:
 μ (mu)
 κ (kappa)
 δ (delta)

 Each receptor family exhibits a different specificity for

endogenous opioid peptides and the drugs it binds.

 The analgesic properties of the opioids are primarily mediated by

the μ receptors that modulate responses to thermal, mechanical,
and chemical nociception.
Opioid receptors
 Dynorphins interact more readily with the κ receptors in the
dorsal horn also contribute to analgesia whereas the
enkephalins interact more selectively with δ receptors in the
periphery.

 All three opioid receptors are members of the G protein–

coupled receptor family and inhibit adenylyl cyclase.

 All three major receptors are present in high concentrations

in the dorsal horn of the spinal cord.
 Opioid receptors
 Opioid agonists inhibit the release of excitatory transmitters
(e.g. glutamate and substance P) from these primary afferents,
and they directly inhibit the dorsal horn pain transmission
neuron. Thus, opioids exert a powerful analgesic effect directly
on the spinal cord.

 This spinal action has been exploited clinically by direct

application of opioid agonists to the spinal cord, which provides
a regional analgesic effect while reducing the unwanted
respiratory depression, nausea and vomiting, and sedation that
may occur from the supraspinal actions of systemically
administered opioids.
Mechanism of action of opioids
Binding of opioids to opioid receptors at the ascending pain
pathway will result in:
 closing of voltage-gated Ca2+ channels resulting in reduction
of presynaptic Ca2+ influx. This impedes neuronal firing and
transmitter release (such as glutamate, the principle
excitatory amino acid released from nociceptive nerve
terminals, as well as acetylcholine, norepinephrine,
serotonin, and substance P)
 increase of postsynaptic K+ efflux leading to
hyperpolarization preventing neuronal activation
Mechanism of action of opioids
Binding of opioids to opioid receptors at the descending
pain pathway will result in:
 the activation of descending inhibitory neurons that send
processes to the spinal cord and inhibit pain transmission
neurons.
 This activation has been shown to result from the inhibition
of inhibitory neurons in several locations
Pharmacokinetics
Absorption
 Most opioid analgesics are well absorbed when given by
subcutaneous, intramuscular, and oral routes.
 However, because of the first-pass effect, the oral dose of the
opioid (eg, morphine) may need to be much higher than the
parenteral dose to elicit a therapeutic effect.
 Considerable interpatient variability exists in first-pass opioid
metabolism, making prediction of an effective oral dose difficult.
 Certain analgesics such as codeine and oxycodone are effective
orally because they have reduced first-pass metabolism
 Pharmacokinetics
Distribution
 Although all opioids bind to plasma proteins with varying
affinity, the drugs rapidly leave the blood compartment and
localize in highest concentrations in tissues that are highly
perfused such as the brain, lungs, liver, kidneys, and spleen.

Metabolism
 The opioids are converted in large part to polar metabolites
(mostly glucuronides), which are then readily excreted by the
kidneys
 Esters (eg, heroin) are rapidly hydrolyzed by common tissue
esterases. Heroin (diacetylmorphine) is hydrolyzed to
monoacetylmorphine and finally to morphine, which is then
conjugated with glucuronic acid.
Pharmacokinetics
Excretion
 Polar metabolites, including glucuronide conjugates of opioid
analgesics, are excreted mainly in the urine.
 Small amounts of unchanged drug may also be found in the
urine.
 In addition, glucuronide conjugates are found in the bile, but
enterohepatic circulation represents only a small portion of
the excretory process.
CNS effects of opioids
Analgesia
 The principal effects of opioid analgesics with affinity for μ receptors are
on the CNS
 Pain consists of both sensory and affective (emotional) components.
 Opioid analgesics are unique in that they can reduce both aspects of the
pain experience, especially the affective aspect.
 In contrast, nonsteroidal anti-inflammatory analgesic drugs have no
significant effect on the emotional aspects of pain.

Euphoria
 Typically, patients or intravenous drug users who receive intravenous
morphine experience a pleasant floating sensation with lessened anxiety
and distress.
 However, dysphoria, an unpleasant state characterized by restlessness
and malaise, may sometimes occur.
CNS effects of opioids
Sedation
 Drowsiness and mental clouding are common effects of opioids.
There is little or no amnesia.
 Sleep is induced by opioids more frequently in the elderly than in
young, healthy individuals.
 Marked sedation occurs more frequently with compounds closely
related to the phenanthrene derivatives and less frequently with
the synthetic agents such as meperidine and fentanyl.
 In standard analgesic doses, morphine (a phenanthrene) disrupts
normal rapid eye movement (REM) and non-REM sleep patterns.
This disrupting effect is probably characteristic of all opioids.
CNS effects of opioids
Respiratory Depression
 All of the opioid analgesics can produce significant respiratory
depression by inhibiting brainstem respiratory mechanisms
Alveolar PaCO2 may increase
 A small to moderate decrease in respiratory function, as measured
by PaCO2 elevation, may be well tolerated in the patient without
prior respiratory impairment.
 However, in individuals with increased intracranial pressure,
asthma or chronic obstructive pulmonary disease, this decrease in
respiratory function may not be tolerated.
 Opioid-induced respiratory depression remains one of the most
difficult clinical challenges in the treatment of severe pain.
CNS effects of opioids
Cough Suppression
 Suppression of the cough reflex is a well-recognized action of
opioids.
 Codeine in particular has been used to advantage in persons
suffering from pathologic cough.
 However, cough suppression by opioids may allow
accumulation of secretions and thus lead to airway
obstruction and atelectasis.
CNS effects of opioids
Miosis
 Constriction of the pupils is seen with virtually all opioid
agonists.
 Miosis is a pharmacologic action to which little or no
tolerance develops thus, it is valuable in the diagnosis of
opioid overdose.
 Even in highly tolerant addicts, miosis is seen.
CNS effects of opioids
Nausea and vomiting
 The opioid analgesics can activate the brainstem chemoreceptor
trigger zone to produce nausea and vomiting.

Temperature
 Homeostatic regulation of body temperature is mediated in part
by the action of endogenous opioid peptides in the brain.
 This has been supported by experiments demonstrating that
administration of μ -opioid receptor agonists such as morphine
administered to the anterior hypothalamus produces
hyperthermia, whereas administration of κ agonists induces
hypothermia.
 Peripheral effects of opioids
Gastrointestinal tract
 Constipation has long been recognized as an effect of opioids, an
effect that does not diminish with continued use  tolerance
does not develop to opioid-induced constipation.
 In the large intestine, propulsive peristaltic waves are diminished
and tone (persistent contraction) is increased; this delays passage
of the fecal mass and allows increased absorption of water, which
leads to constipation.
 The large bowel actions are the basis for the use of opioids in the
management of diarrhea, while constipation is a major problem in
the use of opioids for control of severe cancer pain.
Peripheral effects of opioids
Cardiovascular System
 Most opioids have no significant direct effects on the heart and,
other than bradycardia, no major effects on cardiac rhythm.
 Meperidine is an exception to this generalization because its
antimuscarinic action can result in tachycardia.

Biliary Tract
 The opioids contract biliary smooth muscle, which can result in
biliary colic.
 The sphincter of Oddi may constrict, resulting in reflux of biliary
and pancreatic secretions and elevated plasma amylase and lipase
levels.
Peripheral effects of opioids
Pruritus
 Therapeutic doses of the opioid analgesics produce flushing
and warming of the skin accompanied sometimes by sweating
and itching; CNS effects and peripheral histamine release
may be responsible for these reactions.
 Opioid-induced pruritus and occasionally urticaria appear
more frequently when opioid analgesics are administered
parenterally.
 Clinical uses of opioids
Analgesia
 Severe, constant pain is usually relieved with opioid analgesics
although sharp, intermittent pain does not appear to be as effectively
controlled.
 Continuous use of potent opioid analgesics and are associated with
some degree of tolerance and dependence.
 Because opioids cross the placental barrier and reach the fetus, care
must be taken to minimize neonatal depression when opioids are
used during obstetric labor. If it occurs, immediate injection of the
antagonist naloxone will reverse the depression.
 The phenylpiperidine drugs (eg, meperidine) appear to produce less
depression, particularly respiratory depression, in newborn infants
than does morphine; this may justify their use in obstetric practice.
Clinical uses of opioids
Acute Pulmonary Edema
 The relief produced by intravenous morphine in dyspnea
from pulmonary edema associated with left ventricular heart
failure is remarkable.
 However, if respiratory depression is a problem, furosemide
may be preferred for the treatment of pulmonary edema.
 On the other hand, morphine can be particularly useful when
treating painful myocardial ischemia with pulmonary edema.
 Clinical uses of opioids
Cough
 Suppression of cough can be obtained at doses lower than those
needed for analgesia. However, in recent years the use of opioid
analgesics to allay cough has diminished largely because a number of
effective synthetic compounds have been developed that are neither
analgesic nor addictive

Diarrhea
 Diarrhea from almost any cause can be controlled with the opioid
analgesics, but if diarrhea is associated with infection such use must
not substitute for appropriate antimicrobial chemotherapy.
 Synthetic surrogates with more selective gastrointestinal effects and
few or no CNS effects, eg, diphenoxylate or loperamide, are used.
Clinical uses of opioids
Applications in anesthesia
 The opioids are frequently used as premedicant drugs before
anesthesia and surgery because of their sedative, anxiolytic, and
analgesic properties.
 They are also used intraoperatively both as adjuncts to other
anaesthetic agents and, in high doses (eg fentanyl), as a primary
component of the anesthetic regimen
 Tolerance and dependence
 Drug dependence of the opioid type is marked by a relatively
specific withdrawal or abstinence syndrome.
 Withdrawal from dependence on a strong agonist is associated
with more severe withdrawal signs and symptoms than
withdrawal from a mild or moderate agonist.
 Administration of an opioid antagonist to an opioid-dependent
person is followed by brief but severe withdrawal symptoms
 The potential for physical and psychological dependence of the
partial agonist-antagonist opioids appears to be less than that of
the strong agonist drugs.
 Tolerance
 Although development of tolerance begins with the first dose of
an opioid, tolerance generally does not become clinically manifest
until after 2–3 weeks of frequent exposure to ordinary
therapeutic doses.
 Nevertheless, perioperative and critical care use of ultrapotent
opioid analgesics such as remifentanil have been shown to induce
opioid tolerance within hours.
 Tolerance develops most readily when large doses are given at
short intervals and is minimized by giving small amounts of drug
with longer intervals between doses.
 However, the cross-tolerance existing among the µ-receptor
agonists can often be partial or incomplete.
Tolerance
 This clinical observation has led to the concept of "opioid
rotation" which has been used in the treatment of cancer pain
for many years.
 A patient who is experiencing decreasing effectiveness of one
opioid analgesic regimen is "rotated" to a different opioid
analgesic (eg, morphine to hydromorphone; hydromorphone
to methadone) and typically experiences significantly
improved analgesia at a reduced overall equivalent dosage.
Tolerance
 Physical dependence
 The development of physical dependence is an invariable
accompaniment of tolerance to repeated administration of an
opioid of the type.
 Failure to continue administering the drug results in a
characteristic withdrawal or abstinence syndrome that reflects
an exaggerated rebound from the acute pharmacologic effects
of the opioid.
 The signs and symptoms of withdrawal include rhinorrhea,
lacrimation, yawning, chills, gooseflesh (piloerection),
hyperventilation, hyperthermia, mydriasis, muscular aches,
vomiting, diarrhea, anxiety, and hostility.
Physical dependence
 The number and intensity of the signs and symptoms are
largely dependent on the degree of physical dependence that
has developed.
 Administration of an opioid at this time suppresses
abstinence signs and symptoms almost immediately.
 A transient, explosive abstinence syndrome—antagonist-
precipitated withdrawal—can be induced in a subject
physically dependent on opioids by administering naloxone
or another antagonist.
Psychological dependence
 The euphoria, indifference to stimuli, and sedation usually
caused by the opioid analgesics, tend to promote their
compulsive use.
 In addition, the addict experiences abdominal effects that
have been likened to an intense sexual orgasm.
 These factors constitute the primary reasons for opioid abuse
liability and are strongly reinforced by the development of
physical dependence.
 This disorder has been linked to dysregulation of brain
regions mediating reward and stress
Strong agonists
Phenanthrenes
 Morphine, hydromorphone, and oxymorphone are
strong agonists useful in treating severe pain

 Heroin (diamorphine, diacetylmorphine) is potent and fast-

acting, but its use is prohibited in the USA and Canada.

 Double-blind studies have not supported the claim that

heroin is more effective than morphine in relieving severe
chronic pain, at least when given by the intramuscular route.
 Phenylheptylamines
 Methadone is well absorbed from the gastrointestinal tract and its
bioavailability far exceeds that of oral morphine.

 Methadone is not only a potent µ-receptor agonist but its racemic mixture
of D- and L-methadone isomers can also block both NMDA receptors and
monoaminergic reuptake transporters. These nonopioid receptor properties
may help explain its ability to relieve difficult-to-treat pain (neuropathic,
cancer pain), especially when a previous trial of morphine has failed.

 Methadone is widely used in the treatment of opioid abuse. Tolerance and

physical dependence develop more slowly with methadone than with
morphine.

 The withdrawal signs and symptoms occurring after abrupt discontinuance

of methadone are milder, although more prolonged, than those of
morphine.
 Phenylpiperidines
 Fentanyl is one of the most widely used agents in the family of
synthetic opioids. The fentanyl subgroup now includes sufentanil,
alfentanil, and remifentanil in addition to the parent compound,
fentanyl.

 Sufentanil is five to seven times more potent than fentanyl.

 Alfentanil is considerably less potent than fentanyl, but acts more

rapidly and has a markedly shorter duration of action.

 Remifentanil is metabolized very rapidly by blood and nonspecific

tissue esterases, making its pharmacokinetic and pharmacodynamic
half-lives extremely short. Such properties are useful when these
compounds are used in anesthesia practice.
Phenylpiperidines
 Although fentanyl is now the predominant analgesic in the
phenylpiperidine class, meperidine continues to be used.
This older opioid has significant antimuscarinic effects. Given
its negative inotropic effect in the heart and potential to
cause seizure, it is rarely used as first line drug.
Mild to Moderate Agonists
Phenanthrenes
 Codeine, oxycodone, dihydrocodeine, and
hydrocodone are all somewhat less efficacious than
morphine or have adverse effects that limit the maximum
tolerated dose when one attempts to achieve analgesia
comparable to that of morphine.

 These compounds are rarely used alone but are combined in

formulations containing aspirin, acetaminophen, or other
drugs.
Phenylheptylamines
 Propoxyphene is chemically related to methadone but has
low analgesic activity.

 Various studies have reported its potency at only up to half as

potent as codeine.

 Its analgesic effect is additive to that of an optimal dose of

aspirin or acetaminophen.

 However, its low efficacy makes it unsuitable, even in

combination with aspirin, for severe pain.
Phenylpiperidines
 Diphenoxylate is not used for analgesia but for the
treatment of diarrhea (in combination with atropine).

 Loperamide is also a phenylpiperidine derivative used to

control diarrhea
Opioids with Mixed Receptor Actions
Benzmorphans
 Pentazocine is a κ agonist with weak µ antagonist or partial
agonist properties.

 It is the oldest mixed agent available.

 Pentazocine promotes analgesia by activating receptors in the

spinal cord, and it is used to relieve moderate pain.

 It has limited role in the management of chronic pain.

 Phenanthrenes
 Nalbuphine is a strong κ -receptor agonist and a µ-receptor antagonist.
Like pentazocine, it has limited role in management of chronic pain.

 Buprenorphine is a potent and long-acting phenanthrene derivative

that is a partial µ-receptor agonist and a κ -receptor antagonist.
Buprenorphine was approved by the FDA in 2002 for the management
of opioid dependence. It has shorter and less severe withdrawal
symptoms compared to methadone.

 Butorphanol produces analgesia equivalent to nalbuphine and

buprenorphine but appears to produce more sedation at equianalgesic
doses. Butorphanol is considered to be predominantly a κ agonist.
However, it may also act as a partial agonist or antagonist at the µ-
receptor. Butorphanol is available in a nasal formulation that has been
used for severe headaches, but has also been associated with abuse.
Miscellaneous
Tramadol:
 It is a centrally acting analgesic that binds to the μ opioid receptor.

 In addition, it weakly inhibits reuptake of norepinephrine and

serotonin.

 It is used to manage moderate to moderately severe pain. Its

respiratory depressant activity is less than that of morphine.

 Naloxone can only partially reverse the analgesia produced by

tramadol.
Miscellaneous
Tapentadol
 Tapentadol is an agonist at the μ opioid receptor and an
inhibitor of norepinephrine reuptake.

 It has been used to manage moderate to severe pain, both

chronic and acute.
Opioid antagonists
Opioid antagonists
 The opioid antagonists bind with high affinity to opioid
receptors, but fail to activate the receptor-mediated
response.

 Administration of opioid antagonists produces no profound

effects in normal individuals.

 However, in patients dependent on opioids, antagonists

rapidly reverse the effect of agonists, such as morphine or any
full μ agonist, and precipitate the symptoms of opioid
withdrawal.
Opioid antagonists
Naloxone
 It is s a competitive antagonist at μ, κ, and δ receptors, with
a 10-fold higher affinity for μ than for κ receptors
 It is used to reverse the coma and respiratory depression of
opioid overdose
 It rapidly displaces all receptor-bound opioid molecules and,
therefore, is able to reverse the effect of a morphine overdose.
Opioid antagonists
Naltrexone
 It has actions similar to those of naloxone.
 It has a longer duration of action than naloxone, and a single
oral dose of naltrexone blocks the effect of injected heroin for
up to 24 hours.
 Naltrexone in combination with clonidine (and, sometimes,
with buprenorphine) is used for rapid opioid detoxification.
WHO Analgesic Ladder
 Thank you!

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