OPIOID ANALGESICS &

ANTAGONISTS
KILEMI MITHEU
 Introduction
• Opium is an extract of the juice of the poppy papaver
somniferum and P album.
• Prototype: Morphine, opioid agonist( 10%) and other
related alkaloids.
• Used for social and medicinal purposes as an agent to
produce euphoria, analgesia, sleep and to prevent
diarrhea for many years.
• It’s the standard against which all drugs that have strong
analgesic action are compared.
• Actions are blocked by nonselective antagonist naloxone.
 Pharmacodynamics
• Opioid a generic term for natural or synthetic substances that
bind to specific opioid receptors in CNS & produce an agonist
action.
• MoA: Reduce the intensity and unpleasantness of pain
through GPCRs in the brain, spinal cord and PNS.
• Activate phospholipase C or inhibit adenyl cyclase.
• Open the potassium channels to cause hyperpolarization and
prevent the opening of calcium channel (N-type).
• This reduces neuronal pain excitability and inhibits the release
of pain neurotransmitters.
• Opioid alkaloids (e.g., morphine) produce analgesia
through actions at central nervous system (CNS)
receptors.
• That also respond to certain endogenous peptides
with opioid-like pharmacologic properties.
• Endogenous substances is endogenous opioid
peptides
 Receptors

Three major opioid receptors.

• The μ (mu)-opioid receptor (major)
• The δ (delta) receptors
• The k (kappa) receptors.
 Ligands (Endogenous opioid peptides)

a) Endorphins.
b) Enkephalins-: methionine-enkephalin, leucine-
enkephalin.
c) Dynorphins.
NB: The three families of opioid receptors have
overlapping affinities for these endogenous peptides.
 Affinity & physiologic effect

• Endorphins- high affinity for μ (mu)-opioid

receptor-: respiratory depressant actions of opioids,
analgesia, euphoriant and physical dependence.
• Slows gastrointestinal transit together with kappa
receptors.
• Enkephalins- affinity for δ(delta)-development of
tolerance
• Dynorphins- k (kappa) receptors- sedation action.
 Site of action to produce analgesia

• Opioid receptors are widely distributed in the brain and spinal cord.
• Receptors are present both on spinal cord pain transmission neurons
and on the primary afferents that relay the pain message to them.
• At the spinal level, morphine inhibits transmission of nociceptive
impulses through the dorsal horn and suppresses nociceptive spinal
reflexes, even in patients with spinal cord resection.
• It can act presynaptically to inhibit release of various
neurotransmitters from primary afferent terminals in the dorsal horn
as well as acting postsynaptically to reduce the excitability of dorsal
horn neurons
 Cont…

• Opioids exert a powerful analgesic effect directly on

the spinal cord has been exploited clinically by direct
application of opioid agonists to the spinal cord.
• This spinal action 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.
Sites of action
Pain modulation
 Opioid receptor subtypes, their
functions, and their endogenous
peptide affinities.
 Classification

• Spectrum of clinical uses-: Analgesics, antitussives, and

antidiarrheal.
• Strength of analgesia-: strong, moderate, and weak
agonist
• Ratio of agonist to antagonist effect/ structure.
(i) agonists( full or partial agonist).
(ii) antagonists(receptor blockers).
(iii) mixed(agonist-antagonist).
 Specific agents
STRONG AGONISTS
a) Phenanthrenes-: Morphine, Hydromorphone,
Oxymorphone, Heroin(diamorphine, diacetylmorphine).
b) Phenylheptylamines-: Methadone .
c) Phenylpiperidine-:Fentanyl, Sufentanil, Alfentanil,
Remifentanil, Meperidine. Used extensively in
anaesthesia, may be given intrathecally, skin patches.
Rapid onset advantageous in breakthrough pain.
d) Morphinans-: Levorphanol
 Phenylheptylamine: Methadone
• Administered orally, IV, SC, spinal, and rectal routes.
• Well absorbed from the GIT and its bioavailability far exceeds
that of oral morphine.
• Has activity at other non-opioid receptors-explain it wide range
side effects.
• Relieve difficult-to-treat pain (neuropathic, cancer pain), when a
previous trial of morphine has failed.
• Long half-life (25–52 hours) and slow liver metabolism.
• Monitor initial administration closely to avoid potentially
harmful adverse effects, especially respiratory depression.
 Methadone cont…
• Metabolized by CYP3A4 and CYP2B6 isoforms in the liver.
• Inhibition of its metabolic pathway associated with overdose effects, e.g.
respiratory depression, prolonged QT-based cardiac arrhythmias.
• Uses-: opioid abuse, detoxification of a heroin-dependent addict.
• Tolerance and physical dependence develop more slowly compared with
morphine.
• Withdrawal signs and symptoms after abrupt discontinuance are mild &
prolonged compared to morphine.
• Buprenorphine, a partial μ- receptor agonist, long-acting , effective in
opioid detoxification and associated with a low risk of overdose fatalities.
 Phenylpiperidine

• Phenylpiperidine-:Fentanyl, Sufentanil, Alfentanil,

Remifentanil, Meperidine(pethidine)
• Differ in their potency e.g. Sufentanil is 5 to 7 times
more potent than fentanyl.
• Alfentanil is less potent than fentanyl, but acts more
rapidly and has a markedly shorter duration of
action.
 Pethidine(meperidine)
• Pethidine causes restlessness rather than sedation.
• Has antimuscarinic action that cause dry mouth and blurring of
vision as side effects.
• Duration of action shorter than that of morphine
• Metabolized in the liver to norpethidine which has hallucinogenic&
convulsant effects.
• Preferred in labor- does not reduce force of uterine contraction.
• Eliminated slowly in neonate- naloxone given to reverse respiratory
depression.
• Produce euphoria and high incidence of dependence.
 MILD TO MODERATE
AGONISTS

• Phenanthrenes-: Codeine, Dihydrocodeine(DF118) ,

Hydrocodone, Oxycodone
• Low binding affinity to μ-opioid receptors than morphine.
• Adverse effects limit maximum tolerated dose to achieve analgesia
comparable to morphine.
• Oxycodone-: more potent, prescribed alone in higher doses as
immediate-release/ controlled-release for the treatment of
moderate to severe pain.
• Phenylheptylamines-:Propoxyphene-withdrawn in the United
States.
 Mild to moderate cont…

• Phenylpiperidines-: Diphenoxylate and its

metabolite difenoxin
• Used for treatment of diarrhea and not for
analgesia.
• Loperamide a phenylpiperidine derivative used to
control diarrhea.
 OPIOIDS WITH MIXED
RECEPTOR ACTIONS

➢ Buprenorphine -:potent and long-acting phenanthrene

derivative, a partial μ-receptor agonist and an antagonist at
the δ and κ receptors (mixed agonist-antagonist).
➢ Nalbuphine-: a strong κ-receptor agonist and a partial μ-
receptor antagonist.
• Route: given parenterally.
• Definite ceiling at higher doses, absent with morphine to the
respiratory depressant effect.
➢ Others: Butorphanol and Pentazocine
 MISCELLANEOUS OPIOIDS

➢ Tramadol -:
• centrally acting analgesic.
• MoA -:blockade of serotonin reuptake.
• Inhibit norepinephrine transporter function.
• Uses-: adjunct with pure opioid agonists in the treatment of
chronic neuropathic pain.
• Toxicity -: seizures, serotonin syndrome
• Relatively contraindicated in patients with a history of epilepsy and
use with drugs that lower the seizure threshold.
• Other’s -: nausea and dizziness, abate after several days of therapy.
 Miscellanous cont..

➢ Tapentadol
• It is an analgesic with modest μ-opioid receptor affinity
• MoA-:Inhibit norepinephrine reuptake.
• Uses-: moderate to severe pain.
• Adverse effects: reduced profile of GI complaints such
as nausea.
• Seizures in patients with seizure disorders and serotonin
syndrome.
 OPIOID ANTAGONISTS

➢ Naloxone, Naltrexone, Nalmefene.

• MoA: Blocks the actions of endogenous opioid peptides as well as those of
morphine like drugs.
• Route- given IV acts within minutes, less rapid IM.
• Metabolized in the liver.
• Has a short duration of action (1-2hrs)
• Uses: treatment of acute opioid overdose, reverse effects opioid analgesia on
respiration of newborn.
• Because of its relatively short duration of action, a severely depressed patient
may recover after a single dose only to relapse into coma after 1-2hours.
• Naltrexone-: long acting, half life 10hrs.
 ANTITUSSIVES
• Opioid analgesics are effective for the suppression of cough.
• Effect achieved at doses below those needed to produce analgesia.
• Receptors involved different from those associated with the other
actions of opioids.
• e.g. dextromethorphan, codeine, levopropoxyphene, and
noscapine
• levopropoxyphene and noscapine are not available in the USA.
• Used with caution in patients taking monoamine oxidase inhibitor.
• Contain expectorants to thin and liquefy respiratory secretions.
• Dextromethorphan- dextrorotatory stereoisomer of
methylated derivative of levorphanol.
• Free of addictive properties.
• Produces less constipation than codeine.
• Banned in children younger than 6 years of age by the FDA.
• Enhances the action of morphine and other μ-receptor
agonists.
• Abuse of its purified (powdered) form lead to serious adverse
events including death.
 Pharmacokinetics
Absorption:
• Well absorbed when given by subcutaneous,
intramuscular, and oral routes.
• Variable first-pass metabolism among patients.
• The oral dose of the opioid (e.g., morphine) to elicit a
therapeutic effect may need to be much higher than the
parenteral dose.
• Other routes: Nasal insufflation, Oral mucosa via
lozenges, Transdermal patches and Rectal suppositories
 Distribution

• Uptake by various organs and tissues is variable.

• Bind to plasma proteins with varying affinity.
• 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.
• Concentrations in skeletal muscle low, serves as the main
reservoir because of its greater bulk.
• Accumulation in fatty tissue of highly lipophilic opioids
that are slowly metabolized, eg, fentanyl.
 Metabolism
• Converted in to polar metabolites (glucuronides), which are
then readily excreted by the kidneys.
• Morphine metabolites:
• morphine-3-glucuronide-: neuroexcitatory.
• morphine-6-glucuronide -:potency four to six times.
• Metabolites have limited ability to cross the blood brain
barrier and do not contribute significantly to the usual CNS
effects of a single dose of morphine.
• Accumulation of metabolites may produce unexpected
adverse effects in patients with renal failure.
 Metabolism cont..
• CNS uptake of M3G and M6G can be enhanced by coadministration of
probenecid or of drugs that inhibit the P-glycoprotein drug transporter.
• Hepatic metabolism by CYP 450 of the phenylpiperidine opioids eg
fentanyl, meperidine, alfentanil, sufentanil.
• Leaves only small quantities of the parent compound unchanged for
excretion.
• Metabolite accumulation of meperidine, normeperidine occur in patients
with decreased renal function and in those receiving multiple high doses
of the drug.
• High concentrations of normeperidine cause seizures.
• No active metabolites of fentanyl have been reported.
• Esters e.g., Heroin, Remifentanil are rapidly hydrolyzed by
common tissue esterases.
• Codeine, oxycodone, and hydrocodone undergo metabolism
in the liver by P450 isozyme CYP2D6, resulting in the
production of metabolites of greater potency.
• Hydromorphone like morphine(H3G) has CNS excitatory .
• Codeine is demethylated to Morphine.
• Polymorphism of CYP2D6 has been documented and
linked to the variation in analgesic response seen among
patients properties.
 Excretion

• Metabolites are excreted mainly in the urine.

• Small amounts of unchanged drug in the urine.
• Glucoronide conjugates in bile.
 Clinical uses

• Analgesia-severe, constant pain e.g. cancer & other terminal illness,

obstetric labor, acute severe pain of renal and biliary colic.
• Acute pulmonary edema: Morphine is mainly used for relief of
dyspnea related to pulmonary edema.
• Cough suppression: achieved at doses lower than those needed
for analgesia. Their use greatly diminished due to new agents that
are neither analgesic nor addictive.
• Diarrhea: Crude opium preparations e.g. Paregoric used in the past
to control diarrhea. Currently diphenoxylate or loperamide are used.
 Uses cont…
• Shivering: Meperidine has the most pronounced anti
shivering properties through action on alpha2 adrenoceptors.
• Application in Anesthesia: Opioids are used as a
premedication in GA due to their sedative, anxiolytic, and
analgesic properties.
• Used intraoperatively both as adjuncts to other anesthetic
agents and in high doses as a primary component of the
anesthetic regimen.
• Used in high risk surgeries e.g. CVS where the primary goal
is to reduce CVS depression.
 Pharmacological actions

• Morphine is typical of many opioid analgesics taken as the

reference compound.
• CNS effects: analgesia, euphoria, sedation and respiratory
depression.
• Analgesia-: both sensory and affective(limbic system).
• Euphoria-: powerful sense of contentment and wellbeing.
• Agitation and anxiety associated with pain are reduced.
• Dysphoria and hallucinations may occur.
 Effects cont…
• Sedation: drowsiness and clouding of mentation. Patients easily
aroused from sleep. Phenanthrenes derivatives major cause.
• Respiratory depression: result from increased arterial PCO2.
• The sensitivity of the respiratory center to hypercarbia and
hypoxemia is reduced by opioids.
• Hypoventilation due to inhibition of respiratory rhythm.
• Most difficult clinical challenge in treatment of severe pain.
• Cough suppression: by depressing the cough reflex. Codeine and
pholcodine suppress cough in sub analgesic doses but they cause
constipation as unwanted effect.
 Effects cont…
• Miosis: pupillary constriction seen in all opioid agonists.
• Pinpoint pupils are an important diagnostic feature of opioid
poisoning.
• Other causes of coma and respiratory depression produce
pupillary dilatation.
• Tolerance does not develop to pupillary constriction induced
by opioids.
• Nausea & vomiting: occur in 40% of patients. Opioids
activate the brainstem chemoreceptor trigger zone to produce
nausea and vomiting.
 Effects cont…

• Temperature: Hemostatic regulation of body

temperature is mediated in part by action of
endogenous opioid peptides in the brain.
• Opioids agonists administered to the anterior
hypothalamus produces hyperthermia.
 Peripheral effects
• GIT: opioids increase smooth muscle tone, reduce
motility and delay gastric emptying cause constipation.
• Management-increase fiber content in diet, use of stool
softener eg docusate sodium.
• Biliary tree-: Contract the sphincter of Oddi, patients
experience colicky pain due to biliary spasms. Relieved by
a small dose of naxolone.
R • Renal: urinary retention due to raised tone in dextrusor
muscle and contraction of the external sphincter, together
with inhibition of the voiding reflexes.
 EFFECTS CONT…

• CVS: Opioids cause peripheral vasodilatation and impair

sympathetic vascular reflexes leads to bradycardia.
• Meperidine cause tachycardia.
• Uterus: prolong labor.
• Neuroendocrine: stimulate release of ADH, prolactin
and somatotropin but inhibit the release of LH.
 Effects cont…

• Pruritus: produce flushing and warming of the skin

accompanied by sweating and itching.
• Immune— modulate the immune system by effects on
lymphocyte proliferation, antibody production, and chemotaxis.
• leucocytes migrate to the site of tissue injury and release opioid
peptides, which in turn help counter inflammatory pain.
• Natural killer cell activity and lymphocyte proliferative
responses to mitogens are inhibited by opioids, which play a
role in tumor progression.
 Effects for which no tolerance
occurs
• Miosis- valuable in the diagnosis of opioid overdose.
• Constipation- effect that does not diminish with
continued use. That is, tolerance does not develop to
opioid-induced constipation
• Convulsions
Adverse effects
 Toxicity and undesired effects

• Tolerance- loss of efficacy with repeated therapeutic doses. To

reproduce original response, larger doses must be used.
• Occur after 2-3wks of exposure to therapeutic doses.
• Develops faster when large doses are given at short intervals.
• Tolerance results from desensitization of the μ (mu)-opioid
receptor & from long-term adaptive changes at cellular,
synaptic and network levels
• Minimized by giving small amounts of drug with longer interval
between doses.
 Toxicity cont…

• Physical dependence is a state in which withdrawal of

drug causes adverse physiological effects e.g. abstinence
syndrome.
• Its pronounced and psychological dependence( or
craving) is the driving force.
• Addiction- euphoria, indifference to stimuli and sedation
caused by opioids promote their compulsive use.
• Addiction is rare in patient receiving opioids to control
pain.
 Toxicity cont…
Signs and symptoms of withdrawal.
• Rhinorrhea
• Lacrimation,
• yawning, chills, gooseflesh,
• hyperventilation, hyperthermia,
• mydriasis, muscular aches,
• vomiting, diarrhea,
• anxiety and hostility.
 Contraindications and Cautions
in Therapy
• Use of full agonist with partial agonist opioids-It
diminishes analgesia and causes withdrawal.
• Patients with elevated intracranial pressure e.g. head
injury- lead to lethal alterations in brain function.
• Pregnant women who chronically use opioids- fetus
become physically dependent in utero, present with
withdrawal symptoms after birth e.g. irritability, shrill
crying, diarrhea, and seizures.
 Contraindications cont…

• Patients with Pulmonary dysfunction- lead to acute

respiratory failure.
• Patients with impaired liver or renal function.
Morphine and its congeners are metabolized in the
liver and excreted in urine. Require dose adjustment.
• Patients with endocrine diseases e.g. Addison’s
disease and hypothyroidism- prolonged and
exaggerated responses to opioids.
 Symptoms of opioid overdose

• Three key symptoms -: Referred to as the “opioid

overdose triad”.
(i) Pinpoint pupils.
(ii) Slowed or stopped breathing.
(iii) Unconsciousness/non-responsiveness
Others: Limp body, Pale face, Clammy skin, Purple or
blue color to lips and fingernails and Vomiting.
 Signs of overdosing
Slow Breathing

Breathing Stops

Lack of oxygen may cause brain damage

Heart Stops

Seizure, stroke, or even death

 Pain assessment

• pain experienced by the patient is measured by means of-:

• Pain Numeric Rating Scale (NRS) ranging from no pain (0) to
excruciating pain (10).
• Values indicate the magnitude of pain as: mild (1–3), moderate
(4–6), or severe (7–10).
• A similar scale can be used with children (Face,Legs, Activity,
Cry, Consolability [FLACC] or Wong-Baker scales).
• Patients who cannot speak; the Wong-Baker scale depicts five
faces ranging from smiling (no pain) to crying (maximum pain).
 Adverse effects
• Sedation
• Euphoria
• Dysphoria
• Respiratory depression
• Constipation
• Pruritus
• Increased intracranial pressure
• Nausea &Vomiting
• Hypothalamus function impairment- loss of libido, impotence & infertility
 Analgesics Video

• https://www.youtube.com/watch?v=Mi-
O8uiX0no&t=26s
 References

• Basic and Clinical Pharmacology Katzung 12th

Edition.
• A Text Book of Clinical Pharmacology and
Therapeutics 5th Edition
• Rang and Dales Pharmacology, 7th edition.