AP Dr.

Marlar Myint

Narcotic (Opioid) analgesics

 Learning Objectives
1. Define analgesic

2. Classify analgesics

3. Describe the source and mechanism of

opioid analgesics

4. Describe the role of different opiate

receptors and drugs acting on them

5. Correlate the pharmacological actions with its therapeutic

use and untoward effects of

morphine (prototype of opioids)

 Learning Objectives
6. State the routes and the therapeutic
dosage of morphine

7. List the opioid antagonists and describe

their clinical uses and therapeutic efficacy

8. Describe the clinical features of opiod withdrawal and

opioid poisoning and treatment of both conditions

 Learning Objectives
9. Describe the comparative analgesic potency,
therapeutic uses and peculiarity of :

(a) codeine (b) heroin (c) pethidine

(d) methadone (e) fentanyl (f) pentazocine

 What is an analgesic?

Drugs that relieve pain in general

(non-specific)
Analgesia: Absence of pain

Pain:
An unpleasant sensory and emotional
experience with actual or potential tissue
damage
 Mechanism of Pain
• Stimulus (cause of pain) detected by p
ain receptors (nociceptors) → sensor
y nerve → pain centre (perception) →
emotional reaction (pain threshold)
 Types of Pain
1. Intensity: mild, moderate, severe
2. Origin: somatic, visceral, neuropathic
I. Somatic: superficial, burning, dull aching
II. Visceral: deep, diffuse, nagging, associated
with nausea/ vomiting, sweating, may be
referred to other sites
III. Neuropathic pain – associated with
paresthesia, dysthesia, hyperalgesia
 Types of Pain
3. Duration: acute, chronic
4. Characteristics: intermittent, continuous
5. Location: superficial, deep
– Superficial: stimulation of skin and mucous
membranes, fast response
– Deep: arises from muscles, joints, tendons, heart
etc., slow response
6. Mechanism: Nociceptic (somatic, visceral)
and neuropathic
 Classification of Analgesics
1. Opioid analgesics
(Narcotic analgesics)

2. Non-opiod analgesics
(Non narcotic analgesics)
(Nonsteroidal anti-inflammatory drugs -
NSAIDs)
 OPIOID ANALGESICS
(NARCOTIC ANALGESICS)

• Mechanism of Action
– Act on the opioid receptors:
Mu(μ), kappa(k), delta(δ),
– In brain & spinal cord,  inhibit the
release of excitatory neurotransmitters
 decrease synaptic transmission of
pain pathway.
Spinal sites of opioid action. Mu ( ), delta ( ), and kappa ( ) agonists reduce
transmitter release from presynaptic terminals of nociceptive primary afferents. Mu-
agonists also hyperpolarize second-order pain transmission neurons by increasing
K+ conductance, evoking an inhibitory postsynaptic potential.
Spinal Cord Sites of Opioid
Action
 Opioid Receptors
1 receptor – both spinal & supraspinal
analgesia, euphoria, dependence
2 receptor – respiratory depression and
inhibition of gut motility
 receptor – spinal analgesia and dysphoria
 receptor - role is not clear in human
may be supraspinal analgesia,
Chemical Classification of Opioid
Analgesics
1. Natural alkaloids:
Phenanthrenes (morphine, codeine, thebaine)
2. Semisynthetic derivatives:
Dihydromorphinone; heroin (diacetyl morphine)
3. Synthetic substitutes:
pethidine; methadone; pentazocine; tramadol
fentanyl; alfentanil; remifentanil,, sufentanil
Classification of Opioids and their antagonists
based on pharmacological action
1. Pure agonists
(primarily at , perhaps at  & ):
morphine, codeine
diamorphine (HEROIN), methadone
pethidine (meperidine)
fentanyl, levorphanol
oxycodone, tramadol
 OPIOIDS

2. Partial agonist and

mixed agonist antagonists
butorphanol,
pentazocine
(agonist at  antagonist at ),
nalorphine, nalbuphine
buprenorphine (partial  agonist)
 Classification of Opioids and their
antagonists based on pharmacological action

3. Antagonist at all receptors:

 naloxone,

 naltrexone

 nalmefeme
Classification of Opioids by Analgesic
Efficacy

• Low efficacy agents for mild to moderate

pain
– codeine, dihydrocodeine,
dextropropoxyphene, nalbuphine,
pentazocine
• High efficacy agents for severe pain
– morphine, pethidine, tramadol, methadone,
buprenorphine, diamorphine, meptazinol,
 EQUI-ANALGESIC DOSES
(OPIATES)
Drug Route Dose (mg)

Morphine IM, SC 10
O 60
Heroin IM, SC 5
(diacetylmorphine) O 60
Pethidine IM, SC 75
O 300
Codeine IM 130
(methylmorphine) O 200

Methadone IM 10

O 20

Fentanyl IM 0.1

Pentazocine IM, SC 30-60

O 180
At equianalgesic doses, untoward-effects are about equal (respiratory
depression, nausea, vomiting)
 • One of the alkaloids
MORPHINE obtained from
• Papaver somniferum
• Prototype of opioids
Pharmacological Action

1. (a) CNS: both stimulation and

depression
• Analgesia
• Eliminates both acute and chronic pain
by raising pain threshold and also allow
subject to tolerate pain by reducing the
distress (emotional reaction to pain) (μ1)
Respiratory depression

•Occurs with analgesic dose,

• Dose-related effect on respiratory

center,

•Cause of death in acute opioid poisoning

•μ1 receptors by reducing sensitivity of

respiratory center to raised blood PaCO2
 Sedation (μ1 & k)
– Mood changes: Euphoria – Action on μ1
pleasant sensation with free from anxiety
and fear

– Dysphoria - Action on k – unpleasant

feeling with anxiety, restlessness although
analgesia

– Depressing cough reflex by central action

 CNS excitation
Miosis - due to excitatory action on
parasympathetic nerve innervating the pupil (It is
diagnostic feature of overdose and addiction)
CNS excitation
Vomiting
– By stimulating the CTZ, disappear with
repeated injection

– Ambulation ↑ the incidence of vomiting

Peripheral nervous system - analgesia

2. CVS:
– Central action  impairs sympathetic vascular
reflexes causing venous and arteriolar dilatation

– Reducing mental distress by

tranquilizing/sedation

– Ignore the afferent impulses

from the dyspnoeic lungs

– All these effects are useful for

acute left ventricular failure
3. Smooth muscle
 GIT - ↑ segmental contraction of the circular
muscle and ↓ the propulsive movement of GIT
 constipation

 Biliary tract - sphincter of Oddi spasm  ↑

intrabiliary pressure (μ)

 Contraindicated in biliary colic

 Bronchial smooth muscle spasm partly due to

histamine release
Urinary tract - retention of urine
 Due to spasm of the bladder sphincter and
sedation (ignore afferent message from full
bladder) – particularly post-op patient ..
Contraindicated in BPH
Increased ureteral tone – worsen ureteric colic
due to renal calculus
Uterus – uterine smooth muscle relaxation
causing prolonged labour
4. Diuresis by releasing ADHoss
5. Others: sweating, histamine release,
pruritus and piloerection.
 Pharmacokinetics
• extensive first-pass metabolism

• absorption is variable

• after oral administration, t l/ 2 is 3-6 hrs.

• can cross placenta

• metabolized by conjugation with glucuronide in

liver.

• well absorbed from IM, SC, mucosa of mouth and

nose.
Therapeutic Uses of Opiod Analgesics

1. To relieve moderate to severe pain of any origin, eg.

fracture, postoperative pain, acute myocardial
infarction, renal colic, obstetric pain

2. To produce euphoria and pain relief in dying patients

3. To relieve anxiety in serious and frightening disease

with pain e.g. trauma, severe haemorrhage, shock

4. to relieve dyspnoea in acute left ventricular failure

Therapeutic Uses of Opiod Analgesics

5. To relieve sufferings in terminal stages of illness

e.g. terminal cancer

6. Preanaesthetic medication

7. Symtomatic treatment of severe cough (codeine)

8. Symptomatic control of severe diarrhoea

(diphenoxylate, loperamide)

9. Balanced anaesthesia (by reducing GA doses)

 Adverse Effects
• Tolerance (within l2-24 hrs), physical and
psychological dependence (after repeated use),
addiction

• Respiratory depression, drowsiness, mental

clouding, impaired reasoning ability

• Nausea, vomiting, constipation, biliary colic,

urinary retention, bronchospasm, viscid
bronchial secretion
Contraindications of opiods
• Respiratory insufficieny
• Undiagnosed abdominal pain
• BPH
• Head injury
• ↑ICP
 PA of Morphine USES Unt. E

1. CNS:
stimulates & depresses CNS
CNS depression
i. Analgesia ( 1 ) by to relieve severe pain of any
- raising pain threshold origin, eg. fracture,
- reducing the mental distress postoperative pain, acute
myocardial infarction, renal
colic, obstetric pain ( Pethidine)

ii. sedation ( & )

- By reduce the mental distress
by triquilizing action
- to relieve anxiety in serious drowsiness
disease with pain e.g. trauma,
severe haemorrhage, shock
- Preanaesthetic medication
-Adjunct to anaesthesia
 PA of Morphine USES Unt. E

iii. respiratory depression: respiratory depression

occurs with analgesic (cause of death in acute
dose, (dose-related opioid poisoning)...CI -
depressant effect on respiratory insufficiency
respiratory center) (2) (emphysema, bronchial
asthma)

iv. cough suppression: dry cough

(central action by (codeine can be used
depressing cough reflex) in place of morphine)
 PA of Morphine USES Unt. E
v. mental clouding impair reasoning
ability

vi. mood changes:

- Euphoria (a sense of to produce euphoria -Abuse potential
contentment and well as well as pain-relief
being) in patients with pain in the painful terminal
or in addicts) (1) case

-Dysphoria (restlessness &

- Restlessness,
feeling of malaise) occurs
malaise
in normal persons ()
 PA of Morphine USES Unt. E

vii. dependence - physical and psychological

dependence (after repeated use),
addiction,
tolerance - tolerance (within 12-24 hrs)

CNS excitation leading to

i. stimulating the CTZ Nausea, vomiting
(chemoreceptor triger zone)

ii. excitatory action on miosis (It is a pinpoint pupil (miosis)

diagnostic feature
parasympathetic nerve of overdose and
innervating the pupil addiction)
Overdose – Coma, Miosis, Resp▼

iii. Convulsion - rare Convulsion

 PA of Morphine USES
Unt.
E
2. On CVS
- No significant direct effect with to relieve
therapeutic dose
dyspnoea in
- By central action, it impairs
acute left
sympathetic vascular reflexes causing
venous & arteriolar dilation → ↓ ventricular
preload failure
- induces release of histamine →
vasodilation & ↓ in cardiac workload
- ↓ing mental distress by triquilizing

- Renders the respiratory center

insensitive to afferent stimuli from the
congested lungs because of respiratory
 PA of Morphine USES Unt. E
Cerebral vasodilation d/t ↑ intracranial
opioid induced pressure
respiratory depression CI - head injury
and CO2 retention →
↑ ICP

It also stimulates vagal Bradycardia

centre ( minimal)
 PA of Morphine USES Unt. E

3. Smooth muscle symptomatic control of constipation

i. GIT- ↑ the segmental diarrhoea (diphenoxylate,
contraction of the circular lopermide can be used in
muscle and ↓ the perstalsis place of morphine)

ii. Biliary tract: sphincter of biliary colic

Oddispasm (  ) → CI - undiagnosed
↑ intrabiliary pressure abdominal pain

iii. Uterus - decrease uterine Prolong labour

tone

iv. Urinary tract: spasm of Urinary retention

the bladder sphincter & CI – BPH
sedation
 PA of Morphine USES Unt. E

v. Bronchial smooth Bronchospasm

muscle constriction (CI - bronchial
partly due to histamine asthma)
release

4. Others: - Urticaria, pruritus,

itching, hypotension,
- histamine release
- antidiuresis by releasing ADH - ↓ urine output
- LOA - Wt loss
- Hypothalamus - ↓ body temperature
• Opiod Overdose (Opiod Poisoning)

• coma, pinpoint pupil (miosis), respiratory

depression

• Itching, hypotension (due to histamine release)

• Cerebral vasodilatation - increased intracranial

pressure due to respiratory depression and
CO2 retention

Treatment: pure opioid antagonist-naloxone

Supportive therapy, Assisted respiration

 Opiod Withdrawal Signs and Symptoms
1. Signs & symptoms due to hyperactivity of ANS
(due to upregulation of ANS receptors)
- Increased lacrimation, rhinorrhea, sweating, salivation
- Hyperpyrexia, pupil dilatation
- Diarrhea, increased BP
2. CNS hyperactivity
- Nervousness, restlessness, anxiety, over activity
- Yawning ( not sleepiness), insomnia, goose flesh
- Increased respiration,muscle twitching, tremors,
convulsions
 Treatment for opoid withdrawal

• Replacement with methadone (long acting opioid),

then gradual withdrawal

• Clonidine (2 agonist) for ↓reduction of rebound sy

mpathetic activity (relief of central symptoms)

• Chlorpromazine, diazepam

• Opioid antagonists after successful therapy (Naltre

xone blocks euphoriant action & prevents relapse)
 METHADONE
• Synthetic opioid, primarily μ agonist, orally
effective and longer acting with less sedative
effect
• Physical dependence developed slowly than
morphine and the withdrawal signs and
symptoms are milder
• Used for maintenance of chronic relapsing
addicts, and
• RX of opioid abstinence syndrome
• (opiod withdrawal syndrome)
 PETHIDINE

– Synthetic substance, bind to μ & k receptor.

– Lower analgesic action, shorter duration of

action, less spasmogenic effect on smooth
muscles than morphine.
– Does not interfere with birth process or
uterine involution
– Does not delay labour like morphine and so
it is widely used in obstetrics; but it enters the
fetus and can depress respiration at birth.
 Differences between Morphine and Pethidine
 Pethidine - synthetic substance
 Morphine is natural opium alkaloids
 Pethidine has lower analgesic potency, shorter dur
ation of action, less spasmogenic effect on smooth
muscles than morphine
 Pethidine causes no urinary retention, no interferin
g with birth process or uterine involution, does not
delay labour, no antitissusive action and no antidia
rrhoeal action
 HEROIN
• Is semisynthetic diacetylmorphine and converted
to morphine in the body
• 2.5 times more potent than morphine and is more
euphorichigh abuse potential
 CODEINE
• Natural alkaloid, methylmorphine

• Converted in the body to morphine

• Can be given orally.

• Used as anticough and antidiarrhoeal

agent (symptomatic treatment)

• Used in mild to moderate pain

• lLss addictive potential than morphine

• Respiratory depression is the same degree

with morphine
 FENTANYL
Synthetic, 80 times as potent as morphine
Short duration of action
Used together with droperidol (neuroleptanalgesia)
This combination together with N2O inhalation will
produce neuroleptanaesthesia.
Can produce profound respiratory depression and may
need assisted respiration
Analgesia last 30-60 mins, Given for chronic and
intractable cancer pain as self-adhesive patches
• Sufentanil, alfentanil and remifentanil are the fentanyl
subgroup

• Sufentanil is five to seven times more potent than

fentanyl

• Alfentanil is less potent, acts more rapidly and has

shorter duration of action

• IV → provide maximal analgesia in 90 seconds, last 5-10

min. Used for brief operations

• Remifentanil has extremely short half - lives. So suited

for continuous IV infusion without accumulation
 PENTAZOCINE

• Synthetic substance with agonist action at k

receptor and weak antagonist at μ receptor
• Effective analgesic with little or no abuse
potential (due to dysphoria)
• Used as analgesics (in chronic severe pain) in
patients with drug abuse problem
 BUPRENORPHINE

• Partial μ agonist, antagonist action at k receptor

• Less dependence and respiratory depression

• In over dose, respiratory depression can partially

reversed by naloxone due to its high receptor
affinity
 TRAMADOL

• Opioid with additional actions

• Analgesic effects appears to derive from a
combination of weak μ agonist action, neuronal
inhibition of uptake of NA and serotonin
• Rapidly absorbed from the GIT, 20% of an oral dose
undergoes first-pass metabolism and <30% dose is
excreted unchanged in the urine
• As effective as pethidine for postoperative pain and
as morphine for moderate chronic pain
• Side effects  less likely to constipate, depress
respiration and addict
• Confusion, convulsions (CI in patient with epilepsy),
hallucinations and anaphylaxis have been occurred
 OPIOD ANTAGONISTS
NALOXONE
• Pure competitive antagonist at all opioid receptors
• In the absence of agonist it produce no effect
• In the presence of agonist, it can reverse the effect of
agonist within l - 2 minutes; In chronic narcotic users, it can
precipitate withdrawal syndrome.
• Uses: in the treatment of acute opiate overdose, diagnosis
for addicts and shock caused by anaphylaxis, endotoxins,
hypovolemia and spinal cord injury.
• Side effects - drowsiness, cardiac arrhythmias (overdose)
 NALTREXONE
• Similar to naloxone
• Higher oral efficacy and a longer duration of action
(1-3 days)
• Used orally for maintenance of the opioid-free state
in former addicts because it blocks euphoriant action
and it prevents relapse
NALMEFENE - derivative of naltrexone
• used in opioid overdose
• Route – I.V
 Endogenous opioid peptides

• Enkephalins, endorphins, dynorphins,

opiopeptins
– serve as pain inhibitory system in spinal cord and in
the brain
– stimulated by norciceptive stimuli and other input
(Acupuncture)
 DI with ANALGESICS

i. Morphine/Pethidine + Atropine/Hyoscine = Preanaesthetic

medication
(USE)

ii. Fentanyl + Droperidol = Neuroleptanalgesia (USE)

(Potent opioid (Potent (Profound analgesia without
analgesic) neuroleptic) loss of consciousness:
safer for high risk cases.
No need of premedication
& post-op. analgesia.)

(resp .depression) (resp. depression) = Resp. depression incr.

(Respirator)
iii. Morphine + G.A. - (see G.A). incr. analgesia (USE)
a. need lower dose of G.A.
b. smooth induction
resp. paralysis (adjust dose)

iv. Morphine/Pethidine + Chlorpromazine = Resp. depression (AVOID)

v. Pethidine + Cimetidine = Potentiation of Pethidine

(substrate) (enz. inhibitor)
PREPARATIONS AND DOSAGES OF DRUGS
YOU NEED TO KNOW
Drugs Preparation Dosages

Morphine SO4 15 mg/ml inj: 10 – 20 mg

SC, IM, IV

Pethidine HCl 50/100 mg/ml 50/100 mg

inj: SC, IM, IV

Codeine PO4 30 mg tab. 30 – 60 mg

orally
Summary
Classification of Opiod Analgesiocs
Opiod receptors and mechanism of action
Prototype – Morphine
Correlation of pharmacological actions, uses
and untoward effects of morphine
Differences in individual agents
Opiod antagonists (pure and partial)
Opiod withdrawal symptoms and treatment
Opiod poisoning and treatment
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