Discussion on Analgesic
- Dr. Tarun Yadav
"Pain is an unpleasant
sensory and emotional
with actual or potential
tissue damage, or
described in terms of
Opioids Analgesics and
Algesia : is an ill defined , unpleasent
sensation, usually evoked by an external or
internal noxious stimulus.
Analgesic: is a drug that selectively relieves
pain by acting in CNS or on peripheral pain
mechanism , without significantly altering
Analgesics are of two types
Today we will be discussing Opioids.
Opium : A dark brown ,resinous material obtained from
poppy(Papaver somniferum) capsule.
It contains two types of alkaloids.
a) Phenanthrene derivatives
Morphine(10 % in opium)
Codeine( 0.5% in opium)
Thebaine ( 0.2 % in opium)(Nonanalgesic)
b) Benzoisoquinoline derivatives
Morphine is the
principal alkaloid in
opium Therefore it is
described as prototype.
Sertuner a pharmacist,
isolated the active
principle of opium in
1806 and named it
‘morphine’ after the
greek god of dreams
Pharmacological Actions of
1. CNS :Morphine has site specific depressant
and stimulant actions in the CNS by interacting
primarily with the μ opioid receptors as a full
The depressant actions are:
c. Mood and subjective effects : euphoric effect.
d. Respiratory centre : depression
e. Cough centre : depression
f. Temperature regulating centre: depression
g. Vasomotor centre : depression : fall in bp
a) CTZ : Nausea & vomiting
b) Edinger Westphal nucleus of III nerve
producing miosis. This is central
action not produced by tropical
Vagal centre: leading : bradycardia
c) Certain cortical areas & hippocampal
2 Neuro-endocrine :
Hypothalamic activation by afferent
collaterals is dampened. Hypothalamic
influence on pitutary is reduced. As a
result FSH, LH, ACT levels are lowered,
while prolactin and GH levels are
raised(these are under predominant
inhibitory control. The sex harmone and
corticosteriods are lowered for short term
but then tolerence develops in
longterm.It can release ADH and reduce
3 CVS : Morphine causes vasodilatation due
a) Histamine release
b) Depression of vasomotor centre
c) Direct action decreasing tone of blood
There is a shift of blood from pulmonary to
systemic circuit due to greater
vasodilatation in the latter.
HR decreases due to vagal stimulation
Cardiac work is reduced due to decrease in
4 GIT : Constipation is a prominent feature of
morphine action due to
a) Action directly on intestines and in CNS
increases tone and segmentation but
decreases propulsive movements.Tone of
duodenum and colon may be increased to
the level of spasm.
b) Spasm of pyloric, ileocaecal and anal
c) Decrease in all gastrointestinal secretions
d) Central action causing inattention to
No tolerance develops to this effects and
subject remains constipated.
5 Other smooth muscles :
a) Biliary tract :
spasm of spincter of Oddi -> intrabiliary pressure to
increase -> biliary colic
This action is only partly counteracted by atropine but
more completely by naloxone and nitrates.
b) Urinary bladder: tone of detrusor and sphinter is
increased -> urinary urgency and difficulty in micturition.
c) Uterus : may slightly prolong labour.
d) Bronchi : morphine releases histamine that causes
6. ANS : It causes mild hyperglycemia due to central
sympathetic stimulation. It has weak anticholinestrase
Absorption: oral absorption is unreliable cz of high and
variable first pass metabolism. Oral bioavailablity id 1/6th to
1/4th of parenterally administered drug. About 30 % is bound
to plasma proteins.
Distribution : is wide conc. In liver, kidney spleen is higher
than plasma. Only a small fraction enters brain slowely.
Morphine crosses placenta freely and can effect foetus.
Metabolism : primarily metabolised in liver by glucuronide
conjugation.Morphine -6-glucuronide is an active
metabolite(more potent than morphine) which accumulates
during chronic dosing and contributes to analgesia but can
not cross BBB. Another metabolite morphine-3-gluronide is
Plasma t ½ 2-3 hours. Parental dose lasts for 4-6 hours.
Elimination is complete in 24 hours and morphine is
noncumumulative. Small amount may persist due to
Side effects: Sedation, mental clouding,
lethargy, dysphoric effects, vomiting
constipation, respiratory depression, blurring
of vision, urinary retention, hypotension,
Acute morphine poisoning: lethal dose is 250
mg : coma, stupor, flaccidity, shallow and
pupil,fall in bp nd shock,covulsions may be
seen nd pulmonary edema occurs at terminal
Tolerance and dependence is the major side
Dose 10-50 mg oral/ 10-15 mg i.m. or sc, 2-6
mg iv/ 2-3 mg epidural/intrathecal. Children
It is methyl-morphine, occurs naturally
in opium and is partly converted in
body to morphine.It is analgesic and
can relieve mild to moderate pain.
It is cough supressor(only 1/3rd as
potent as morphine).
Coedine has a good activity by oral
route. Single oral dose acts for 4-6
Constipation is a prominent side
Pholcodeine : It has a codeine like
properties and has been used mailnly as
antitussive; claimed to be less
Heroin : It is about 3 times more potent
than morphine, more lipid soluble ,enters
brain more rapidly.It is considered more
euphorient and highly addicting.It has no
outstanding therapeutic advantage over
morphine and has been banned in most
of countries except uk.
Pethidine is indicated for the treatment of moderate to severe
pain, and is delivered as a hydrochloride salt in tablets, as a
syrup, or by intramuscular, subcutaneous or intravenous
injection. For much of the 20th century, pethidine was the
opioid of choice for many physicians
Compared to morphine, pethidine was supposed to be safer
and carry less risk of addiction, and to be superior in treating
the pain associated with biliary spasm or renal colic due to its
putative antispasmodic effects. In fact, pethidine is no more
effective than morphine at treating biliary or renal pain, and its
low potency, short duration of action, and unique toxicity (i.e.,
seizures, delirium, other neuropsychological effects) relative
to other available opioid analgesics have seen it fall out of
favor in recent years.
It is used as an analgesic and in preanaesthetic medication.
It has also been used to control shivering during recovery
It is preffered analgesic during labour as neonatal respiratory
depression is less marked.
Short acting potent analgesic generally given i.v. at the
begninning of painful surgical procedures. Reflex effects
of painful stimuli are abolished. It is frequently used to
suppliment anaesthetics in balanced anaesthesia. This
permits use of lower anaesthetics concentrations with
better haemodynamic stability.Combined with BZDs, it
can obviate the need of inhaled anaesthetics for
diagnostic, endoscopic, angiographic and other
Anaesthetic awareness with dreadful recall is a risk.
After iv fentanyl (2-4 microgrm/kg) the patient remains
drowsy but conscious.Respiratory depression is
marked. Tone of chest muscle may be increased so a
muscle relaxant is then required to facilitate mechanical
HR decreased : due to stimulation of vagus, fall in BP is
Nausea, vomiting and itching often occurs during
used medically as an analgesic and a
maintenance anti-addictive for use in patients
with opioid dependency.
Methadone is useful in the treatment of opioid
dependence. It has cross-tolerance with other
opioids including heroin and morphine, offering
very similar effects and a long duration of effect.
Oral doses of methadone can stabilise patients
by mitigating opioid withdrawal syndrome. Higher
doses of methadone can block the euphoric
effects of heroin, morphine, and similar drugs.
A majority of patients in outpatient treatment
programs require 80–125 mg/d of methadone, or
more, to achieve these effects and require
treatment for an indefinite period of time, since
methadone maintenance is a corrective but not a
curative treatment for opiate addiction
It is centrally acting analgesic relieves
pain as well as additional mechanism.
Injected i.v. 100 mg tramadol is
equianalgesic to 10 mg im morphine.
Oral bioavailablity is good. T1/2 is 5
hours and effect lasts for 5-6 hours.
Causes : respiratory depression,
sedation, constipation, urinary retention,
rise in intrabiliary pressure.
Side effects : dizziness, nausia, vomiting,
dry mouth, sweating, lowering of seizure
Receptors: Many subtypes: ALL are G-proteincoupled receptors. Most important for our
1. Mu – ( ) receptor – primarily responsible for
analgesia, euphoria, respiratory depression and
Agonists: Endorphins, enkephalins, morphine, fentanyl,
methadone, meperidine, and others
2. Kappa ( ) receptor - responsible for mixed-action
agonists and analgesia at the level of the spinal
cord, sedation and dysphoria
Agonists: Dynorphins, pentazocine, butorphanol
3. Delta ( ) receptor - MAY contribute to analgesia
Agonists: Enkephalins, endorphins, morphine, codeine
Opioid receptor transducer
All three types of opioid receptors (mu, kappa
,delta) have been cloned; all are G protein
coupled receptors located mostly on
prejunctional neurons. They generally excerise
inhibitory modulation by decreasing release of
the junctional transmitter. As such various
monoaminergic (NA,DA, 5-HT),GABA ,
Glutamate (NMDA/AMPA) pathways are
intricately involved in opioid actions.
Opiod receptor activation reduces intracellular
cAMP formation and opens K+ channels (mainly
through mu and delta receptors) or supressess
voltage gated N type Ca2+ channels(mainly
kappa receptors). These actions result in
neurohyperpolarization and reduced availability
of intracellular Ca2+ -> decreased
neutotransmitter release by CNS and myentric
Complex Action Opioids and
1. Agonist- antagonists( k analgesics)
2. Partial/weak mu agonist + k
3. Pure antagonists
It is N allyl – normophine and not used
now because of its dysphoric and
It is the first agonist-antagonist to be used as an analgesic.
It has a weak mu anatagonistic and more marked k agonistic actions.
Profile action is similar to morphine ; important differences are
a) Analgesia caused by pentazocine is primarily spinal(k1) and has a different
character than that caused by morphine. Parenterally 30 mg pentazocine = 10 mg
morphine; but ceiling effect is lower i.e. @ higher doses increase proportionate
increase in analgesia does not occur.
b) Sedation and respiratory depression is 1/3 to ½ of morphine at lower doses,
and has a lower ceiling , doesn’t increase much beyond 60 mg dose.
c) Trachycardia and rise in Bp are produced due to sympathetic stimulation. This
may increase cardiac work so it is avoided in cardiac ischemia & MI
d) Biliary spasm and constipation are less serve.
e) Vomiting is less frequent.
f) Subjective effects are pleasurable(morphine- like) at low doses but becomes
unpleasurable at high dosage.
Tolerance , psychological and physical dependence to pentazocine develops on
It is indicated in moderately severe pain in burns , trauma, fracture.
Also used as anaesthetic premedication in children.
Dose oral: 50-100mg, parental 30-60 mg im.sc //0.5 mg/kg IV
It is k analgesic, similar to but more potent than
pentazocine( 2 mg butorphanol = 30mg
pentazocine) > likewise analgesia and respiratory
depression have a lower ceiling than morphine.
Sedation nausea, cardiac stimulation and other
side effects are similar to pentazocine, but
subjective effects are less dysphoric.
Psychotomimetic effects are less marked. BP is
It may produce physical dependence; withdrawal
can be done with high dose of naloxone,but
syndrome is mild.
The most outstanding feature is it can neither
substitute nor antagonize morphine.
It should be avoided in patients with cardiac
It is highly lipid soluble Mu analgesic that is 25 times potent than
morphine. It has slower oncet and longer duration of action.After
single dose analgesia lasts for 6-8 hours; but with repeated use,
duration of action increases upto 24 hours.
Sedation , vomiting ,miosis, subjective effects are similar to
morphine but constipation is less marked. Postural hypotension is
prominent. Respiratory depression exhibit ceiling effect. It is
substitutes for morphine at low level of dependence but precipitates
withdrawal in highly dependent subjects.
Lower degree if tolerance and physical dependence develops on
chronic use.withdrawal resembles morphine but delayed.
Naloxone only partially reverses buprenorphine.
It has good efficacy by sublingual route, is highly plasma protein
bound and remains in tissue for several days. T1/2 is 40 hours.
Mostly excreated unchanged in bile and finds its way out of body in
Indicated for long lasting painful conditions. It has been
recommended for premedication,postoperative pain, in mycardial
infarction and in treatment of morphine dependence.
It is not suitable in labour as causes respiratory depression in the
Also used as a additive to spinal anaesthetic drung to prolong its
Pure Opioid Antagonists
Naloxone: it is the drug of choice in
morphine poising (0.4-.8mg iv every 2-3 min:
max 10 mg) and for neonatal asphyxia due to
opioid use during labour (10 microgm /kg in
Used to reverse respiratory depression 0.10.2 mg in this dose also provide analgesia.
Used as a adjunct to intra spinal opioid
analgesia: reverses respiratory depression
without abolishing pain relief.
It partially reverses alcohol intoxication.
It has been found to elevate BP in endotoxic
or hypovolumic shock,stroke and spinal
Naltrexone it is chemically related to
naloxone and used to prevent relapse
of heavy drinking.Side effects are
nausea , vomitting and headache,
hepatotoxicity in high dosage.
Nalmefene: Pure opioid antagonist
lacks hepatotoxicity of naltrexone, has
higher oral bioavailability and is longer