Dr Pramod K Sharma

 Morphine, the prototype agonist is a natural

alkaloid derived from P. somniferum
 Semisynthetic and synthetic agents are also
available
 These drugs are used where strong analgesic
action is required
 The term opioid refers broadly to all
compounds related to opium
 Opiates are drugs derived from opium
 Classification
 Strong agonists: morphine, heroin, pethidine (meperidine),
methadone, fentanyl, sufentanil, remifentanil, alfentanil,
oxymorphone, hydromorphone, levorphanol

 Moderate/low agonists: codeine, oxycodone, hydrocodone,

propoxyphene, diphenoxylate, difenoxin, loperamide

 Mixed agonists
agonists--antagonists: nalbuphine, buprenorphine,
butorphanol, pentazocine

 Others: tramadol, tapentadol

 Antitussives: noscapine, dextromethorphan, codeine,

levopropoxyphene

 Antagonists: naloxone, naltrexone, nalmefene, alvimopan,

methylnaltrexone bromide
 Endogenous opioid peptides
 Peptides with opioid like pharmacological
properties
 Three families have been described
- endorphins
- enkephalins (leu and met-
met-enkephalin)
- dynorphins
 Endogenous peptides endomorphin
endomorphin--1 & 2
also share properties of opioid peptides
e.g. analgesia and high affinity to μ
receptors
 Present at CNS sites involved in pain
modulation
 Released during pain or anticipation of
pain
 Mechanism of action of opioids
 Act through activating opioid receptors
 Opioid receptors are involved in
transmission and modulation of pain
 Some effects are mediated partly through
action on peripheral receptors
 Opioid receptors
 Three major classes (μ(μ, δ, & κ)
 Various subtypes also exist
 All are G
G--protein coupled receptors
 Receptors are located in brain, spinal cord
(dorsal horn) and peripheral tissues
(primary afferents relaying pain sensation)
Opioid Receptor Subtypes, their functions, and their endogenous
peptide affinities

Receptor Functions Endogenous

Subtype Opioid Peptide
Affinity
(mu) Supraspinal and spinal analgesia; sedation; Endorphins
inhibition of respiration; slowed > enkephalins >
gastrointestinal transit; modulation of dynorphins
hormone and neurotransmitter release

(delta) Supraspinal and spinal analgesia; modulation Enkephalins >

of hormone and neurotransmitter release endorphins and
dynorphins

(kappa) Supraspinal and spinal analgesia; Dynorphins > >

psychotomimetic effects; slowed endorphins and
gastrointestinal transit enkephalins
Cellular action of opioid : Inhibition of cyclic adenosine monophosphate (cAMP)
formation leads to opening of potassium channels and closing of calcium channels.
Potassium efflux causes membrane hyperpolarization. The closing of calcium
channels inhibits the release of neurotransmitters from nociceptive nerve terminals
(glutamate, substance P, Ach, NE, serotonin etc.)
 Opioids cause analgesia partly by activating
inhibitory descending pathways, partly by
inhibiting transmission in the dorsal horn, and
partly by inhibiting excitation of sensory nerve
terminals in the periphery
 Repetitive C-
C-fibre activity facilitates transmission
through the dorsal horn ('wind-
('wind-up') by
mechanisms involving activation of NMDA and
substance P receptors
Summary of modulatory mechanisms in the nociceptive pathway. 5-HT, 5-
hydroxytryptamine; BK, bradykinin; CGRP, calcitonin gene-related peptide; NA,
noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal anti-
inflammatory drug; PG, prostaglandin; SP, substance P.
Supraspinal control system: Opioids excite neurons in the periaqueductal grey matter (PAG) and
in the nucleus reticularis paragigantocellularis (NRPG), which in turn project to nucleus raphe magnus
(NRM). From the NRM, 5-hydroxytryptamine (5-HT)- and enkephalin-containing neurons run to the
substantia gelatinosa of the dorsal horn, and exert an inhibitory influence on transmission. Opioids
also act directly on the dorsal horn, as well as on the peripheral terminals of nociceptive afferent
neurons. The locus coeruleus (LC) sends noradrenergic neurons to the dorsal horn, which also inhibit
transmission.
Schematic diagram of the gate control system. This system regulates the passage of impulses from the peripheral afferent fibres
to the thalamus via transmission neurons originating in the dorsal horn. Neurons in the substantia gelatinosa (SG) of the dorsal horn
act to inhibit the transmission pathway. Inhibitory interneurons are activated by descending inhibitory neurons or by non-nociceptive
afferent input. They are inhibited by nociceptive C-fibre input, so the persistent C-fibre activity facilitates excitation of the transmission
cells by either nociceptive or non-nociceptive inputs. This autofacilitation causes successive bursts of activity in the nociceptive
afferents to become increasingly effective in activating transmission neurons.
Pharmacological effects: Morphine
 Analgesia: strong analgesic (spinal &
supraspinal action); analgesia increases
with dose; reduce both aspect of pain
experience (sensory & affective);
selectively suppress pain without affecting
other sensations or producing
proportionate generalized CNS depression;
intrathecal injection cause regional
analgesia
Analgesia is primarily through action on μ
receptor; morphine does act at δ and κ
receptor sites but to what extent this
contributes to analgesic action is unclear

Morphine action at μ receptor may evoke

release of endogenous opioids that
additionally act at δ and κ receptors
 Euphoria: IV morphine in patients & drug
users produce pleasant floating sensation
(↓anxiety and stress);
Dysphoria (restlessness and malaise) may
also occur;
Euphoric effects are due to DA release in
nucleus accumbance
 Sedation: drowsiness, clouding of
mentation but little or no amnesia;
induces sleep more frequently in elderly
(easily arousable); disrupts both REM and
NREM sleep
combination with other CNS depressants
may induce very deep sleep
 Respiratory depression: by inhibiting
brainstem respiratory mechanism;
rate and TV both reduced (↑
(↑ in alveolar
Pco2);
depression is dose related and is
influenced by degree of sensory input
occurring at that time
Problematic in ↑ICT, asthma, COPD etc.
 Tolerance & physical dependence:
mechanism is unclear, may be due to,
- upregulation of cAMP system
- receptor recycling
- receptor uncoupling (dysfunction of
structural interaction b/w μ receptors, G
proteins, 2nd messenger and their target
ion channels)
- role of NMDA receptor ion channel complex
 Cough suppression: cough reflex is
depressed, more sensitive to depressant
action of morphine than respiratory
depression
 Miosis: due to III cranial nerve
stimulation; central action; valuable in
diagnosis of overdose
 Truncal rigidity: increase in tone of
large truncal muscles usually apparent
with high doses of highly lipid soluble
agents (fentanyl, alfentanil etc.) if
administered IV rapidly;
It is due to supraspinal effect;
May reduce thoracic compliance;
may necessitate use of NMBs
 Nausea & vomiting: through activation
of CTZ (also vestibular component
involved)
 Temperature: Opioids alter the
equilibrium point of the hypothalamic
heat--regulatory mechanisms such that
heat
body temperature usually falls slightly;
However, chronic high dosage may
increase body temperature
 CVS: bradycardia (pethidine cause
tachycardia on i.v. inj); may cause
hypotension (due to vasodilatation
secondary to histamine release, VMC
depression) if CVS is stressed
Cerebral vasodilatation if Pco2 is increased
→ ↑ ICT
There is a shift of blood from pulmonary
to systemic circuit due to greater
vasodilatation in the latter
 GIT: cause constipation through action in
CNS and on ENS (increased tone and
decreased propulsive movements), ↓
secretion, increased water absorption: no
tolerance

 Biliary tract: contract biliary smooth

muscles (colic), constrict sphincter of Oddi
(elevated plasma amylase and lipase)
 Uterus: slightly prolong labor due to
reduce uterine tone (central & peripheral
action)
 Bronchi: constriction due to histamine
release – dangerous in asthmatics
 Neuroendocrine: stimulate release of
ADH, GH, prolactin but inhibit release of
LH
 Renal effects: function are depressed
due to decrease renal plasma flow; ↑es
ureteral and bladder tone;
tone; ↑ tone of
sphincter - Urinary retention
 Pruritus: at therapeutic dose produce
flushing, warming and itching of the skin
(CNS effect plus histamine release) –
More common with parenteral
administration; spinal/epidural injection
cause intense pruritus of lips and torso
 Immune system: modulate immune
response through action on lymphocytes
proliferation, Antibody production and
chemotaxis
 Pharmacokinetics: opioids
 Oral dose of the opioid (eg, morphine)
much higher than the parenteral dose
(because of the first-pass effect)
 Considerable interpatient variability exists:
prediction of an effective oral dose difficult
 Codeine and oxycodone are effective
orally
 All opioids bind to plasma proteins with
varying affinity
 Distribute and localize in highest
concentrations in tissues that are highly
perfused (brain, lungs, liver, kidneys, and
spleen)
 Skeletal muscles serves as the reservoir
 May accumulate in fatty tissue after
frequent high-dose or continuous infusion
of highly lipophilic opioids eg, fentanyl
 The opioids are converted in large part to
polar metabolites (mostly glucuronides)
 Morphine, is conjugated to M3G
(neuroexcitatory) & M6G (only 10%)
 Accumulation of these metabolites may
occur in patients with renal failure
 Hydromorphone 3 Glucuronide (H3G), also
has CNS excitatory properties
 Esters (eg, heroin, remifentanil) are
rapidly hydrolyzed by esterases
 Hepatic oxidative metabolism is the
primary route of degradation for
meperidine, fentanyl, alfentanil, sufentanil
 Accumulation of a demethylated
metabolite of meperidine (i.e.
normeperidine) may occur in patients with
decreased renal function or during
overdose – causes excitement (seizures,
tremors, hyperreflexia etc.)
 Also non-
non-selective MAOIs interfere with
hydrolysis but not with demethylation of
pethidine: norpethidine excess – seizures
 Codeine, oxycodone, and hydrocodone
undergo metabolism in the liver by P450
isozyme CYP2D6
 Genetic polymorphism of CYP2D6 may
cause variation in analgesic response to
codeine
 Polar metabolites, are excreted mainly in
the urine with small amounts of
unchanged drug sometimes
 Adverse Effects
 Sedation; restlessness, lethargy,
hyperactivity ((dysphoric
dysphoric reaction)
reaction)
 Respiratory depression – infants &
elderly are more susceptible, may cause
apnea in newborn if given to mother
during labor; dangerous in patient with
respiratory insufficiency - acute respiratory
failure
 Nausea & vomiting
 Constipation – does not diminish with
continued use
 Increased ICT
 Postural hypotension – exaggerated
response if person is hypovolemic
 Urinary retention – elderly individuals
are more susceptible
 Allergy – itching, urticaria more frequent with
parenteral and spinal administration
 Tolerance: begin with 1st dose; develops more
readily if large doses given at short intervals;
tolerance may be as great as 35 fold;
develops to analgesic, sedating, respiratory
depressant, antidiuretic, emetic & hypotensive
effects but not to the miotic, constipating &
convulsant actions
Develops due to PK and PD factors
Tolerance dissipates within days to months after
discontinuation;
Rate (appearance & disappearance) & degree
depend on drug and individual;
Tolerance also develops to mixed agonist-
agonist-
antagonist but to a lesser extent;
No tolerance develops to antagonistic actions of
mixed or pure antagonistic agents
Cross tolerance among μ agonists is often
partial or incomplete - basis for “opioid
rotation” (improved analgesia at a
reduced overall equivalent dosage of a
different opioid)
NMDA antagonist (ketamine) & δ
antagonist with μ receptor agonist action
may prevent tolerance
 Physical dependence – withdrawal
syndrome on discontinuation of drug
s/s rhinorrhea, lacrimation, chills, diarrhea
gooseflesh, hyperventilation, mydriasis,
vomiting, anxiety, and hostility etc.

Number and intensity of the s/s depend

on the degree of physical dependence
The time of onset, intensity, and
duration of abstinence syndrome vary
based on the drug previously used
Morphine / heroin,
heroin, Onset – 6 to 10 hrs,
Peak - 36 to 48 hrs, Duration - 5 days
Meperidine - syndrome subsides in 24 h
Methadone several days to reach the
peak and it may last as long as 2 weeks
Antagonist precipitated withdrawal -
Within 3 minutes after injection of the
antagonist, peaking in 10–
10–20 min and
largely subsides after 1 hour
In the case of agents with mixed effects,
effects,
syndrome appears to be somewhat
different from that produced by morphine
and other agonists
 Psychologic dependence – euphoria,
indifference to stimuli, sedation &
abdominal effects akin to orgasm on iv
administration
Abuse liability is high b’coz of these
factors and it is further reinforced by
development of physical dependence
 Patients with Addison’s disease and those
with myxedema may have prolonged and
exaggerated responses to opioids
 Acute morphine poisoning

 In nonusers adults 50 mg i.m. may cause

serious toxicity
 Lethal dose is about about 250 mg
 S/S: Stupor or coma, shallow and
occasional breathing, cyanosis, pinpoint
pupil (dilated in pethidine poisoning), fall
in BP, convulsions, pulmonary edema,
death is due to respiratory failure
 Establish airway and ventilate the patient,
maintain BP; gastric lavage with KMnO4;
Naloxone: 0.4 0.4--0.8 mg i.v. repeat every
2-3 min till respiration picks up and
subsequently every 1- 1-4 hr based on
response to therapy
Care should be taken to avoid
precipitating withdrawal in dependent
patients (extremely sensitive to
antagonists)
The safest approach is to dilute the
standard naloxone dose (0.4 mg) and
slowly administer it intravenously,
monitoring arousal and respiratory
function

For reversing opioid poisoning in children,

the initial dose of naloxone is 0.01 mg/kg
 The DOA of the available antagonists is
shorter than that of many opioids
(patients can slip back into coma) e.g.
methadone
 In such cases, continuous infusion of
naloxone should be considered
 Toxicity owing to overdose of pentazocine
and other opioids with mixed actions may
require higher doses of naloxone
 Cautions during therapy
 Avoid combining full agonist with partial agonist
(eg. Pentazocine with morphine)
 Don’t use in patient with head injuries
 In patients with impaired respiratory function -
may lead to acute respiratory failure
 Use in Patients with Impaired Hepatic or Renal
Function - dosage should be reduced
 Patients with adrenal insufficiency and
hypothyroidism may have prolonged and
exaggerated responses to opioids
 Drug interactions
 Depressant effects of some opioids may be
exaggerated and prolonged by phenothiazines,
MAOIs and TCAs - mechanisms not clear
 Some phenothiazines reduce the opioid required
to produce a given level of analgesia
 Depending on the specific agent, the
respiratory-
respiratory-depressant effects also seem to be
enhanced, the degree of sedation is increased,
and the hypotension accentuated
 Some phenothiazine may be antianalgesic
 Amphetamine increase the analgesic and
euphoriant effects and decrease sedation
 Some (e.g., hydroxyzine) enhance the analgesic
effects of low doses of opioids
 TCAs may enhance morphine-
morphine-induced analgesia
 Sedative
Sedative--hypnotics increase CNS depression
particularly respiratory depression
 MAOIs – high incidence of hyperpyrexic coma
 Clinical uses
 Analgesia – used in cancer pain,
postoperative pain, during labor, severe
colics etc.
Severe, constant pain is better controlled
than sharp intermittent pain
ROA: oral, rectal, parenteral, transdermal,
buccal transmucosal, intranasal etc.
 Acute pulmonary edema: i.v. morphine
produces rapid relief from dyspnea in LVF
- reduce anxiety (↓
(↓perception of shortness
of breath, ↓ sympathetic stimulation)
stimulation)
- reduce cardiac pre & afterload
- shift blood from pulmonary to systemic
circuit
* If respiratory depression is a problem,
furosemide is a preferred option
 Diarrhea: may control diarrhea of any cause
synthetic agents with more selective GI action
and with few or no CNS effects are used. e.g.
loperamide, diphenoxylate
 Cough: lower than analgesic doses are
required, synthetic agents with no analgesic and
addictive action are preferred
eg. Dextromethorphan, noscapine, codeine etc.
 Anaesthesia:
- As preanaestheic medication
- As adjunct to other anaestheic agents
- In high doses (eg. Fentanyl) as primary
component of anaesthetic regimen
Commonly used in CV and other types of
high risk surgery where primary aim is to
minimize CV depression
 Shivering: all opioid reduce shivering
(postanaesthetic or infusion related) but
pethidine has most marked effect

block shivering through action on a

subtype of alpha 2 adrenoceptor
 CODEINE
 Potency – 1/10th of the morphine
 Approximately 60% as effective orally as
parenterally as an analgesic and as a
respiratory depressant
 Low affinity for opioid receptors -
analgesic effect is due to its conversion to
morphine (via CYP2D6)
 Antitussive actions may involve distinct
receptors that bind codeine itself
 TRAMADOL
 Weak μ agonist (affinity 1/6000 of morphine)

 Inhibits NE & 5HT uptake (analgesia partly)

 As effective as morphine in mild-

mild-to
to--moderate
pain (less effective in severe or chronic pain)

 As effective as meperidine in labor pain and may

cause less neonatal respiratory depression

 An active metabolite (2-

(2-4 times as potent) may
account for part of the analgesic effect
 Supplied as a racemic mixture
 RD < morphine; constipation < codeine
 Can cause seizures
 Analgesia is not entirely reversible by naloxone
 RD can be reversed (but naloxone increases the risk
of seizure)
 Avoid in patients with a history of addiction
 Avoid with MAOIs/ drugs lowering seizure threshold
 Tapentadol: like tramadol in activity, efficacy & SEs
 MEPERIDINE (PETHIDINE)
 A potent μ receptor agonist with LA property
 Constipation & urinary retention is less common
 Analgesic potency; 1/8-
1/8-1/10 of morphine
 1/3rd as effective when given orally
 No longer recommended for chronic pain
 Not to be used for >48 h; or in doses greater
than 600 mg/day
 Produces less neonatal respiratory depression
than morphine/methadone - used during labor
 Can block neuronal uptake of 5HT
 Should not be used with MAOIs (or at
least for 14d after discontinuation of
MAOIs) – can cause
- serotonin syndrome (if patient is on
MAOIs)
- or features of acute pethidine overdose
(if patient is on pethidine)
 FENTANYL
 Synthetic, MOR agonist
 100 times more potent than morphine
 Do not release histamine
 Commonly used in anaesthesia (rapid
peak analgesia and rapid termination of
action after small bolus dosing; MAC
sparing effect; minimal CVS depression)
 Also in management of severe pain
 Agonist/antagonists
 Developed with the hope that they would
have less addictive potential and less RD
than morphine and related drugs
 A "ceiling effect," limiting the amount of
analgesia attainable, often is seen
 Pentazocine and nalorphine, can produce
severe psychotomimetic effects
 Nalbuphine & butorphanol – MOR
antagonist but KOR agonist
 Pentazocine – weak MOR antagonist or
partial MOR agonist + KOR agonist
 Buprenorphine – partial MOR agonist
(dissociates very slowly) + KOR antagonist
 Pentazocine
 CNS effects similar to morphine (ceiling for
RD effect)
 Higher doses can produce dysphoric and
psychotomimetic effects
 At high doses - ↑ HR & BP due to
activation of supraspinal receptors
(reversed by naloxone) - avoid in IHD
 Does
Does’’nt reverse morphine induced RD but
can ppt withdrawal in morphine addicts
 Available as FDC with naloxone (tablet)
 Nalbuphine
 Similar to pentazocine but less likely to
cause dysphoria and relatively safe in
patients with stable IHD
 Show ceiling effect for analgesia & RD
 Can produce withdrawal in morphine
dependent
 Abuse potential in nonusers is similar to
pentazocine
 Butorphanol
 Best suited for relief of acute pain
 Cardiac effects are similar to pentazocine
 Available also as nasal formulation –
useful for acute pain relief including
migraine pain
 Can produce physical dependence
 Buprenorphine
 20-50 times more potent than morphine
20-
but is a partial MOR agonist (limited IA)
 Analgesia longer and RD is slower and last
longer than morphine
 May produce withdrawal in dependent
 RD is not a problem (ceiling ??)
 Prior naloxone administration prevent RD,
but RD not reversed once it has developed
 Available as sublingual formulation also
 Can produce physical dependence
 Injectable preparations are used as
analgesic
 Oral formulation (alone or FDC with
naloxone) – is used for treatment of opioid
dependence but has limited role in t/t of
addicts who require high maintenance
dose of opioids (as it is a partial agonist)
 Antitussives
 Among the most effective drug for cough
suppression
 Act at doses below those required to
produce analgesia
 Different opioid receptors may be involved
 MOA ??? both central & peripheral effects
 e.g. dextromethorphan, noscapine,
levopropoxyphene, codeine etc.
 Antidiarrheal
Diphenoxylate:
- A meperidine congener
- At therapeutic doses - little or no
morphine like effects
- At high doses – typical opioid effects
- Available only in combination with
atropine sulfate
- Difenoxin – a metabolite of diphenoxylate
Loperamide:
- Slow motility by action on Sm muscles of GIT
- May also reduce GI secretion
- Poorly absorbed from GIT, poor penetration
in CNS (efflux by P-
P-glycoprotein)
- Verapamil, quinidine enhance its CNS effects
- Even large doses do not produce pleasurable
effects of opioids
- Dose 22--8mg/d (max 16 mg in a day)
 OPIOID ANTAGONOSTS
 Bind competitively to opioid receptors
 Little or no intrinsic activity
 Few effects in absence of agonist (exogenous)
 Visible effects in certain situations ie. Shock,
endogenous opioid system activated
 No withdrawal syndrome on discontinuation
 No known abuse potential
 Opioid receptor upregulation in brain
 Naloxone
 More selective for μ receptors
 Not given orally – very high FPE in liver
 Prevent/reverse effects of an agonist
 Respiration improves in minutes, reverse
sedation, improves BP if depressed
 Reverse psychotomimetic & dysphoric
effects of pentazocine (high dose needed)
 May produce “overshoot phenomenon”
 DOA depends on dose (1-
(1-4 h)
Uses: opioid overdose; low dose (0.04 mg) to treat
ADRs associated with iv/epidural opioids, prevent
RD in neonates

 Naltrexone: active by oral route; longer acting

(~24h); more potent than naloxone; may produce
hepatotoxicity
Uses: - treatment of alcohol dependence
- prevention of relapse to opioid dependence,
following opioid detoxification
- available also as ER injectable suspension
(i.m.) given every 4 weeks (380 mg)
 Methylnaltrexone bromide: block
peripheral μ receptors in gut, poor CNS
penetration;
Use: opioid-
opioid-induced constipation in
patients with advanced illness, when
response to laxative therapy inadequate
Dose 88--12mg s.c every other day
 May cause GI perforation
 Alvimopan: accelerate the time to GI
recovery following partial bowel resection
surgery (for hospital use only)

Peripherally acting μ-
μ-opioid receptor
antagonist

 Nalmefene: relatively pure MOR

antagonist; more potent; longer acting;
used i.v.