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OPIOID ANALGESICS
Dr. Naila Abrar
LEARNING OBJECTIVES
After this session, you should be able to:
 Classify
opioids
 Describe opioid receptor distribution and the
mechanism of action of opioid analgesics
 Discuss pharmacological effects, adverse
effects and contraindications of opioids
 Outline salient features of various opioid
agonists, partial agonists and opioid
antagonist.
TERMINOLOGIES
• derived from Greek word “opos” for juice (exudate from
Opium
poppy)
• Contains many alkaloids (opiates)
• drugs derived from opium
Opiates
• Include morphine, codeine, thebaine & semisynthetic
derivatives
• all compounds related to opium- a natural or synthetic
Opioids
drug that binds to opioid receptors producing agonist
effects
SOURCE
OPIUM
 Poppy

Papaver somniferum
 P album


Prototype: Morphine
OPIUM
“Among the remedies
which it has pleased
Almighty God to
give to man to
relieve his
sufferings, none is
so universal and so
efficacious as
opium”
CHEMISTRY of OPIUM
ALKALOIDS

Phenanthrene der.
– Morphine
– Codiene
– Thebaine

Benzylisoquinoline der.
– Papaverine
– Noscapine
CLASSIFICATION (Based on source)
Naturally Occurring Opium Alkaloids:
 Morphine, Codeine
Semisynthetic Derivatives:
 Diamorphine (Heroin), Etorphine,
Buprenorphine, Hydromorphone,
Oxymorphone, Hydrocodone, Oxycodone
(phenanthrenes)
Synthetic Morphine Substitutes:

Phenylpiperidine series:
• Pethidine
• Fentanyl, sufentanil, alfentanil, remifentanil
• Diphenoxylate, Loperamide

Phenylheptylamines
• Methadone, d– Propoxyphene

Morphinans
• Levorphanol, levallorphan

Benzomorphan compounds
• Pentazocine, Cyclazocine
Terminology (recall)
Pure Agonist: has affinity for binding plus
efficacy
 Pure Antagonist: has affinity for binding but
no efficacy; blocks action of endogenous and
exogenous ligands
 Mixed Agonist-Antagonist: produces an
agonist effect at one receptor and an
antagonist effect at another
 Partial Agonist: has affinity for binding but
low efficacy

CLASSIFICATION OF OPIOID
ANALGESICS
OPIOID AGONISTS
-
-
Morphine
Methadone
Levorphanol
Fentanyl gp- sufentanil, remifentanil
Hydromorphone
Meperidine
Tramadol
PARTIAL AGONIST/weak agonist
-
-
Codeine
Oxycodone
Hydrocodone
Propoxyphene
Dextropropoxyphene
Diphenoxylate
MIXED AGONIST-ANTAGONIST
-
-
Nalbuphine
Nalorphine
Butorphenol
Pentazocine
Buprenorphine
ANTAGONISTS
-
-
Naloxone
Naltrexone
Nalmefene
Opioid alkaloids produce analgesia through actions
at regions in the brain that contain peptides which
have opioid-like pharmacologic properties
ENDOGENOUS OPIOID PEPTIDES


Naturally occurring ligands for opioid receptors
(endorphins)
– Pentapeptides
met-enkephalin & leu–enkephalin
These endogenous opioid peptides are derived
from three precursor proteins
PRECURSOR PROTIENS
1. Pre-proopiomelanocortin (POMC)
Met-enkephalin sequence, B-endorphin,
ACTH, B-lipotropin& MSH
2. Preproenkephalin
Six copies of met-enkephalin & one copy of
leu- enkephalin
3. Preprodynorphin
Dynorphin A, dynorphin B, alpha & beta
neoendorphins
Endomorphins
PHARMACOKINETICS
ABSORPTION
– Well absorbed
– First-pass metabolism
than parenteral dose
DISTRIBUTION
oral dose higher
– Bind to plasma proteins but rapidly leave the
blood and localize in highest concentrations
in tissues that are highly perfused
METABOLISM
– Polar metabolites excreted by kidneys
– Morphine conjugated to morphine-3glucuronide (neuroexcitatory)
– 10% metabolized to morphine-6glucoronide(more potent analgesic)
– Esters
hydrolyzed by common tissue
esterase
– Heroin hydrolyzed by common tissue esterases
to monoacetylmorphine
(contd.)
– Phenylpiperidines
hepatic oxidative
metabolism
– Meperidine is demethylated to normeperidine
(seizures in high conc.)
– Codiene-CYP2D6 (genetic polymorphism)
EXCRETION
– Polar metabolites, including glucuronide
conjugates are excreted mainly in the urine
PHARMACODYNAMICS
MECHANISM OF ACTION
– Opioid agonists produce analgesia by
binding to specific GPCRs
– Located primarily in brain & spinal cord
regions involved in the transmission and
modulation of pain
Mechanism of action

Activation of peripheral nociceptive fibersrelease of substance P and other pain-signaling
neurotransmitters from nerve terminals in the
dorsal horn of the spinal cord

Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by
exogenous opioid agonists by acting
presynaptically to inhibit substance P release,
causing analgesia
CELLULAR EFFECTS of Opioid
Receptor Activation
Inhibition of neurotransmission due to opioidinduced presynaptic inhibition of
neurotransmitter release
 Involves changes in transmembrane ion
conductance

1. Close voltage-gated Ca2+ channels on pre-synaptic
nerve terminals
reduce transmitter release
2. Open K+ channels thus hyperpolarize and inhibit
postsynaptic neurons
RECEPTOR TYPES

Three major classes
1. mu ()
2. kappa (k)
3. delta (d)

GPCRs
Majority of the opioid analgesics act primarily
at the  receptors
 Analgesia, euphoria, respiratory depression &
physical dependence properties of morphine
result principally from actions at the 
receptor
 Endogenous opioid peptides have more affinity
for the k & d receptors
 Reduced incidence for respiratory depression
and addiction & dependence with k receptors
but dysphoric effects

RECEPTOR DISTRIBUTION
– Dorsal horn of the
spinal cord
– Receptors present
both on:
 spinal cord pain
transmission neurons &
 primary afferents that
relay the pain message
to them
NEUROANATOMY OF PAIN
1. Afferent pathways
a) nociceptors (pain receptors)
b) afferent nerve fibres
c) spinal cord network
2. CNS-limbic system, reticular formation, thalamus,
hypothalamus and cortex
3. Efferent pathways- fibres connecting the reticular
formation, midbrain & substantia gelatinosa
(responsible for pain modulation)
Theory of pain production and
modulation




Gate control theory (created by Melzack and
Wall)
Nociceptive impulses are transmitted to the
spinal cord through large A- delta & small Cfibers
Synapses in the SG
Cells in this structure function as a gate,
regulating transmission of impulses to CNS
Theory of pain production and
modulation (contd.)
 Stimulation of
larger nerve fibers (Aa, Ab)
causes the cells in SG to "close the gate“
 A closed gate decreases stimulation of 2nd
afferent neuron, which decreases the
transmission of impulses, & diminishes pain
perception
Theory of pain production and
modulation (contd.)
Stimulation of small fiber input inhibits cells in SG
and "open the gate".
 An open gate increases the stimulation of 2nd order
neuron cells & increases transmission of impulses
and enhances pain perception
 In addition to gate control through large and small
fibers stimulation, the CNS, through efferent
pathways, may close, partially close, or open gate
 Cognitive functioning may thus modulate pain
perception

NEURAL MECHANISM OF ANALGESIA
– Opioid agonists inhibit the release of excitatory
transmitters from the primary afferents that
relay the pain message to them
– They directly inhibit the dorsal horn pain
transmission neurons
– Thus opioids exert a powerful analgesic effect
directly on the spinal cord
(contd.)
Inhibit neurons in painmodulating descending
pathways
 Inhibition of inhibitory
neurons in several
location
 Neurons that send
processes to the spinal
cord & inhibit pain
transmission are activated

ORGAN SYSTEM EFFECTS OF MORPHINE &
ITS SURROGATES
CNS EFFECTS
– Principal effects of opioid analgesics
with affinity for  receptors are on CNS
– Analgesia, euphoria, sedation &
respiratory depression, cough
suppression, miosis, truncal rigidity,
nausea vomiting, temperature
MIOSIS
– Valuable in the diagnosis of opioid
overdose (no tolerance)
– Can be blocked by opioid antagonists
– Mediated in part by parasympathetic
pathways
TRUNCAL RIGIDITY
– Increase in tone of the large trunk muscles
– Reduces thoracic compliance & thus
interferes with ventilation
– Prevented by concomitant use of
neuromuscular blocking agents
NAUSEA & vomiting
– Activate brainstem CTZ
TEMPERATURE
- Homeostatic regulation of body temperature
is mediated in part by endogenous opioid
peptides
– Hypothermia
PERIPHERAL EFFECTS
CARDIOVASCULAR SYSTEM
– No significant direct effect on the heart & cardiac
rhythm except bradycardia
– Meperidine may result in tachycardia due to its
antimuscarinic action
– Blood pressure is usually well maintained unless
the CVS is stressed, in which case hypotension
may occur (due to peripheral arterial & venous
dilation)
GASTROINTESTINAL TRACT
– Constipation
– Tolerance does not develop
– Opioid receptors present in high density
– Stomach motility decreases but tone increases
– Nonpropulsive contractions of intestine
– Delayed passage of fecal mass
BILIARY TRACT
– Constrict biliary smooth muscle, which may
result in biliary colic
– Sphincter of Oddi may constrict, resulting
in reflux of biliary & pancreatic secretions
and elevated plasma amylase & lipase levels
RENAL
–
–
–
–
–
–
Renal function is depressed
Due to decreased renal plasma flow
Opioids have an anti-diuretic effect
Enhance renal tubular sodium absorption
Ureteral & bladder tone are increased
Increased sphincter tone
UTERUS
– May prolong labor
NEUROENDOCRINE
– Stimulate release of ADH, prolactin, &
somatotropin
– Inhibit release of LH
PRURITIS
– Flushing & warming of the skin accompanied
sometimes by sweating & itching
MISCELLANEOUS
– Modulate the actions of the immune system
– Natural killer cell cytolytic activity &
lymphocyte proliferative responses usually
inhibited
– Mediated by the sympathetic NS in acute
administration & by the hypothalamicpituitary-adrenal system in prolonged
administration
CLINICAL USE OF OPIOID ANALGESICS
A. Analgesia
– Severe, constant pain
– Sharp, intermittent pain is not as effectively
controlled
– Useful in the management of pain associated
with cancer & other terminal illnesses
– Used during obstetric labor (meperidine)
B. Acute pulmonary edema
– Remarkable relief in dyspnea from pulmonary
edema associated with left ventricular failure
– Involves reduced perception of shortness of
breath & reduced patient anxiety as well as
reduced cardiac preload (reduced venous
return) and afterload (decreased peripheral
resistance)
– Useful in treating painful myocardial ischemia
with pulmonary edema
– morphine
Relief of anxiety & apprehension in pts with MI,
internal bleeding
 They are NOT anxiolytics or hypnotics
CARDIAC ASTHMA OR acute LVF
 Reduce preload & after load – VD
 Shift blood from pulm to systemic circuit
 Relieves air hunger by depressing resp centre
 Calms pt - decreases symp response –
decrease workload
C. Cough
– Suppression of cough (obtained at doses lower
than those needed for analgesia)
– Both central & peripheral effects
– Codeine, dextromethorphan, levopropoxyphene,
noscapine
D. Diarrhea
– Diarrhea from any cause
– Crude opium preparations used in the past
– Synthetic surrogates with more selective GI
effects & few or no CNS effects are used
(diphenoxylate, loperamide)
E. Anesthesia
– Frequently used as preanesthetic medication
because of their sedative, anxiolytic, and
analgesic properties
– Also used intra-operatively both as adjuncts
to other anesthetic agents and in high doses
– Fentanyl, as a primary component of
anesthetic regimen, most commonly in
cardiovascular surgery
– Neuroleptanesthesia
( contd. )
– Used as regional analgesics due to their
direct action on the neurons of the spinal
cord dorsal horn- epidural or subarachnoid
space
– Morphine is most frequently used
– Adverse effects are less common
– Respiratory depression, pruritis, nausea &
vomiting may occur and can be reversed
with naloxone
– Fentanyl + LA- pain management
– Post op shivering-meperidine used
PATIENT CONTROL ANALGESIA
(PCA)
Parenteral infusion device controlled by
the patient by pressing a button to deliver
a programmed dose of the desired opioid
analgesic
TOXICITY & UNDESIRED EFFECTS
Direct toxic effects are extensions of their
pharmacologic actions
 Include respiratory depression, nausea,
vomiting & constipation
 Tolerance & dependence
 Overdosage ( diagnosis & treatment)
 Contraindications

Stupor------- coma
 RR low------- apnea, cyanosis
 Hypotension
 Pinpoint pupil
 Hypothermia
 Death due to resp. failure
 TRIAD of pinpoint pupils, coma & resp.
depression strongly suggests opioid poisoning

TOLERANCE
– With frequently repeated administration of
therapeutic doses of morphine or its surrogate,
there is a gradual loss in effectiveness
– To reproduce the original response, a larger dose
must be administered
– Develops most readily when large doses are given
at short intervals & is minimized by giving small
amounts of drug with longer intervals between
doses
– Opioid rotation
– Receptor uncoupling
CROSS TOLERANCE
– Patient tolerant to morphine show a reduction in
analgesic response to other agonist opioids
PHYSICAL DEPENDENCE
– Occurrence of a characteristic withdrawal or
abstinence syndrome when the drug is stopped
or an antagonist is administered
– Signs & symptoms of withdrawal include
rhinorrhea, lacrimation, yawning, chills,
gooseflesh
(piloerection),
hyperventilation,
hyperthermia, mydriasis, muscular aches,
vomiting, diarrhea, anxiety & hostility
– Methadone is used in the detoxification of
heroin addicts as the slower subsidence of
effects is associated with a less intense
immediate syndrome
– Buprenorphine+ naloxone also used in
maintenance treatment plans
– Antagonist-precipitated withdrawal
PSYCHOLOGIC DEPENDENCE
Compulsive use promoted due to:
–
–
–
–
Euphoria
Indifference to stimuli
Sedation
Abdominal symptoms
DIAGNOSIS & TREATMENT OF OPIOID
OVERDOSAGE
– Known addict, needle marks, miosis
– Difficult to diagnose in comatose patients
– I/V injection of naloxone reverses coma due
to opioid overdose but not that due to other
CNS depressants
Degrees of tolerance that may
develop to some of the effects of
the opioid
High
Analgesia
Euphoria,dysphoria
Mental clouding
Sedation
Resp. depression
Antidiuresis
Nausea & vomiting
Cough suppression
Moderate
Minimal or none
Bradycardia
Miosis
Constipation
Convulsions
CONTRAINDICATIONS & CAUTIONS
IN THERAPY
1. Use of pure agonists with weak partial
agonists
2. Use in patients with head injuries
3. Use in patients with endocrine disease
4. Use in patients with impaired pulmonary
functions
5. Use in patients with impaired hepatic or
renal function
6.





Use during pregnancy
Fetus may become physically dependent in utero
& manifest withdrawal symptoms in the early
postpartum period
signs & symptoms of withdrawal syndrome in the
infant include irritability, shrill crying, diarrhea
or even seizures
treated with diazepam in mild withdrawal
Camphorated tincture of opium is given in severe
withdrawal
Oral methadone is also used
DRUG INTERACTIONS
Drug group
Sedativehypnotics
Interaction with opioids
Increased CNS depression,
particularly respiratory
depression
Increased sedation
Antipsychotics
Accentuation of CVS effects
Contraindicated because of high
MAO inhibitors
incidence of hyperpyrexic coma
METHADONE
 Long
acting MOR agonist
 potent & clinically useful analgesic (oral BA
better than morphine)
 Relieves difficult to treat pain
 Used in the treatment of opioid abuse (long t1/2)
 OPIOID ROTATION to methadone provides
superior analgesia
 For detoxification of a heroin-dependent
addict, low doses of methadone(5-10mg) are
given two or three times daily for 2 to 3 days
FENTANYL
Synthetic
 Sufentanil > fentanyl >alfentanyl
 Short time to peak analgesic effect, rapid
termination, minimal direct myocardium
depressant effect, reduce dosing requirement
for the volatile agents– useful in anesthesia
 Remifentanyl – ester – short t1/2, more rapid

onset, 1-1.5 mins after I/V –
CODEINE
Semisynthetic opioid - Methyl morphine
 Converted to morphine by CYP2D6 which is
responsible for analgesic action
 Used in cough
 Less efficacious than morphine & adverse
effects limit dose
 Oxycodone more potent – prescribed in
higher doses - abuse

HEROIN
Diacetylmorphine
 Hydrolyzed to 6-monoacetylmorphine

cross into CNS

morphine
Excreted in urine as free and conjugated
morphine
MEPERIDINE (Pethedine)
 Potent MOR agonist – strong analgesic effects
 Antimuscarinic effects
 Inhibits catecholamine re-uptake
 Contraindicated with tachycardia
 Negative inotropic effect on the heart
 Seizures with normeperidine
 Serotonin syndrome with MAO inhibitors
 Used in post anesthetic shivering
DIPHENOXYLATE & LOPERAMIDE
NOT for analgesia
 TREATMENT of DIARRHEA
 Diphenoxylate – metabolite difenoxin
 Poorly soluble (even salts are insoluble in
aqueous solution) so parenteral use is limited
 + atropine to reduce likelihood of abuse
 Loperamide – limited access to brain so abuse
potential very low

OPIOID AGONIST/ANTAGONIST &
PARTIAL AGONISTS
Pentazocine
 Nalbuphine
 Butorphanol
 Buprenorphine

competitive MOR
antagonist but
KOR agonist
partial agonist
PENTAZOCINE
KOR agonist
 Weak MOR antagonist or partial agonist
 Orally or parenterally but causes irritation so
not used S/C
 Morphine like CNS effects - analgesia,
sedation, respiratory depression.
 High dose – dysphoric effects
 CVS increase BP & HR

NALBUPHINE
Strong KOP agonist
 MOR antagonist
 Less likely to produce dysphoric effects
otherwise similar to pentazocine
 Ceiling effect- increases in dose beyond 30mg
produces no further respiratory depression or
analgesia
 Safer in patients with cardiac disease than
pentazocine

Precipitates abstinence syndrome in subjects
dependent on low doses of morphine
 Prolonged use can produce physical
dependence
 Parenteral only

BUPRENORPHINE
Buprenorphine- potent long acting partial
MOR agonist and KOR antagonist
 25-50X more potent than morphine]
 0.4mg = 10mg morphine
 S/L to avoid 1st pass
 Resistant to naloxone reversal
 Opioid dependence
 Slow dissociation from receptors

BUTORPHANOL
Similar to pentazocine & nalbuphine
 Predominantly KOR agonist
 MOR antagonist
 Used for relief of acute post-op pain
 Equal analgesia as nalbuphine but more
sedation
 Increase BP & HR
 incidence of psychotomimetic effects lower
than pentazocine but still present

TRAMADOL & TRAPENTADOL
Synthetic codeine analog
 Weak MOR agonist
 Analgesic effect predominantly due to
inhibition of reuptake of NE & 5HT
 As effective as morphine & meperidine in mild
to moderate pain
 Oral & I/M
 Active metabolite formed in liver by CYP2D6
 t1/2= 6-8hrs
 Max dose 400mg

Adverse effects:
 Nausea,
vomiting, dizziness, dry mouth,
sedation and headache
 Seizures
 Respiratory depression but less than morphine
 Not to be used in patients taking MAO
inhibitors, SSRIs or drugs that lower seizure
threshold
OPIOID ANTAGONISTS
MIXED
PURE
• Antagonist at 
• Antagonist at all
• Agonist at k
• Naloxone
• Nalorphine
• Naltrexone
• Levallorphan
• Nalmefene
PURE OPIOID ANTAGONIST
NALOXONE, NALTREXONE, NALMEFENE
Pure antagonists
 Morphine derivatives with
bulkier substituents at N17
 High affinity for -opioid
binding sites
 Naloxone – I/V, short t1/2 1-2hrs
 Naltrexone – oral, t1/2 10hrs
 Nalmefene – only I/V, t1/2 10hrs

Absence of an agonist – inert completely
reverse opioid effects in 1-3 mins
 Acute overdose – Normalizes respiration, level
of consciousness, pupil size, bowel activity, &
awareness of pain
 Dependent subjects – precipitate abstinence
syndrome

Treatment of acute opioid overdose
 1 mg naloxone = 25mg heroin
 Keep in mind the short duration of action
 Initial dose is 0.1-0.4 mg I/V (neonates 10ug/kg)
 Maintenance with 0.4-0.8 mg I/V repeat as
required
 Low dose 0.04 mg – treatment of adverse effects
associated with I/V or epidural opioids
 Methylnaltrexone & alvimopan

NALTREXONE – maintenance drug for addicts
 Decreases alcohol craving in chronic
alcoholics by increasing baseline bendorphins
 Facilitates abstinence from nicotine with
reduced weight gain
