OPIOID ANALGESICS

• Pain or algesia is a unpleasant subjective sensation.

• Its a warning signal & indicates that there is an impairment
of structural & functional integrity of the body.
• Somatic pain- arising from skin, integumental structures,
muscles, bone & joints. Its caused by inflammation & well
defined/ sharp pain.
• Visceral pain arising from viscera is vague, dull aching
type, difficult to pinpoint to a site. It may be a due to
inflammation, spasm & ischemia.
• Referred pain- cardiac pain radiating to left arm.
 Analgesic are the drugs that relieve pain without altering
consciousness & affords symptomatic relief.
 Analgesic relieve pain with out affecting its cause.
 Analgesics are of 2 classes- Opioid & Non- Opioid’s.
 Opium alkaloid from Papaver somniferum.
 Morphine, Codeine, Thebaine & Papaverine.
 Opioid analgesics- drugs with morphine like actions.
 Earlier called as Narcotic analgesics.
Classification-
1.Opioid agonists-
a) Natural - Morphine, Codeine, Noscapine.
b) Semi synthetic -Heroin, Pholocodeine,
-Hydromorphone, Oxymorphine.
c) Synthetic opioids -Pethidine, Methadone, Tramadol,
-Fentanyl, Dextropropxyphene.
2. Pure opioid Antagonists- Naloxone, Naltrexone, Nalmefene
3.Mixed agonist-antagonists- Pentazocin, Nalorphine,
-Buprenorphine.
 Opioid Receptors

κ δ
µ
Analgesia (spinal level) Proconvulsant action
Dysphoria
µ1 µ2 Psychotomimetic effect
Resp. depression
Analgesia
(supra spinal)
Analgesia(spinal)
Euphoria
Resp. Depression
Dependence
Inhibition of GI motility
Opioid agonists- Morphine
M.O.A-acts through µ, δ , k receptors.
Location- spinal, supraspinal & peripheral nerves.
I) CNS-
1.Analgesia-potent analgesic
• Mediates through µ(spinal & supraspinal) receptors.
• Raises pain threshold levels & tolerability.
• Dull aching pain < sharp pricking pain.
• Higher doses- relieves sever pain.
• Alters both perception & reaction to pain.
• Alters emotional reaction to pain.
• Sedation & euphoria contribute for analgesic effect.
2.Euphoria, sedation & Hypnosis-
• Euphoria- sense of well being.
-Responsible for drug abuse.
• Rapid I.V inj- warm flushing of skin & pleasurable
sensation in lower abdomen- known as high, rush & Kick.
• Loss of rational thinking & have day dreams.
• Drowsiness, calming, inability to concentrate.
• Felling of detachment & indifference to surroundings.
• These effects may not be pleasurable to all.
• Person has to learn to perceive pleasurable effects.
3.Respiration-
• Directly depress the resp. centre dose dependently.
• Depress all phases of resp. ( rate & tidal volume).
• Causes irregular & periodic breathing.
• In poisoning- death due to resp. arrest.
• Sedation adds up.
4) Cough- directly depress the cough centre.
• Its an antitussive.
5) Nausea & emesis-
• Directly + CTZ  N & V.
• High dose – Vc = No emesis in poisoning.
• Emetics shouldn't use in morphine poisoning.
6) Pupils-
• Miosis- central effect.
• High dose- pinpoint pupil.
7) Vagus - + vagal centre bradycardia.
8) Heat regulation- body temperature falls.
9) Excitatory effect- high doses convulsions.
II) PNS Effects-

10) CVS- Hypotension, Vasomotor depression,

• Histamine release-fall in B.P ,skin rashes, itching,utricaria.
11)GIT-
– Stomach – motility, gastric secretion & delays
g.emptying.
– esophageal reflux, tone of duodenum.
– Oral absorption of drugs .
– Intestine- secretions, delays digestion, intestinal tone,
intestinal spasm & motility-Constipation.
12) Other Smooth muscle-
a) Biliary tract- spasm of oddi. intrabiliary pressure.
• Atropine antagonizes this spasm.
b) U. bladder- tone of bladder sphincter & volume.
• X urinary voiding reflex.
• Urinary retention in elder males- BPH.
c) Ureter- tone & contractions.
d) Uterus- May prolong labor
e) Bronchi - Constriction.
f) Renal function decrease.
g) Endocrine effects- GnRH, CRF, FSH, LH, ACTH.
- Tolerance develops & reversible on cessation of therapy.
Morphine P.K-
• Given orally- slowly absorbed.
• 1st pass metabolism
• Route of adm - I.V/ I.M/S.C/Oral & Suppositories.
• S/C- onset-15-20min, peak effect-1hr & duration-3-5hrs.
• TD patches - Fentanyl
• Widely distributed-cross BBB & placental barrier
• Metabolised-liver by glucuroinde conjugation
• Metabolite is active & undergoes E.H.C
A/E-
• N, V, constipation, Resp. depression, hypotension, drowsiness,
confusion, mental clouding, Urine retention.
• Skin rashes, pruritus & wheal (inj) due to H release.
• Anaphylaxis-I.V inj.
 Tolerance-
• Develops on repeated adm.
• Develops to analgesia, sedation, euphoria, Resp. & CNS
depressant actions.
• Doesn't develops to constipation & miosis.
• Lethal dose-250mg.
• Addicts & pt’ with pain can tolerate more doses.
• Addicts requires high doses to get Kick & Rush.
 Dependence-
• Opium- drug addiction.
• Euphoria- responsible for addiction.
• Both physical & psychological dependence.
• Sudden withdrawal of opioids or adm of O.antagonist-
withdrawal symptoms.
• withdrawal symptoms- lacrimation, sweating, yawing, anxiety,
restlessness, rhinorrhea & tremors-8hr after to last dose. (craving symptoms)
• Syndrome progresses to fever, insomnia, colic, sneezing,
yawning, diarrhoea, mydrasis, gooseflesh, HTN, & CVS
collapse.
• Adm. of suitable opioid- completely reverses withdrawal
symptoms.
• Without Rx symptoms disappears in 7-10days.
 Withdrawal in the newborn-
• Babies born to addicted mother are also be a dependent.
• Withdrawal symptoms- irritability, crying, tremors, suckling fists,
sneezing, yawning, vomiting, diarrhoea & fever.

• Tincture opium- 0.2ml/kg/3-4hrs is started at birth &

gradually withdrawn.
 Rx of morphine dependence-
a) Hospitalization
b) Gradual withdrawal of morphine.
c) Substitution therapy with methadone
d) Opioid agonist-Methadone is preferred because:
 It is orally effective & potent.
 It is longer acting & slowly released.
 So withdrawal symptoms are mild.
e) 1gm of methadone will substitute for 4gms of morphine.
f) Later morphine can withdrawn within 10days.
g) Naltrexone - opioid antagonist to prevent pleasurable
effects of opioid & also to relapse in pt’s.
h) Clonidine -suppress the autonomic withdrawal symptoms.
give for 7-10days & gradually with drawn.
i) Diazepam-sedation with hypnotic action.
j) Psychotherapy & occupational therapy,
k) Community treatment
l) Rehabilitation.
 Rx of acute morphine poisoning-
• Accidental, suicidal or homicidal.
• Lethal dose-250mgs.
• Features- Resp. depression & failure, pinpoint pupil, cyanosis,
hypotension, hypothermia, shock, convulsion ,coma, & death.
• Hospitalization
• Maintain BP.
• + ve pressure respiration.
• Gastric lavage-Kmno4
• Naloxone-0.4-0.8mg I.V-dose repeated till respiration
becomes normal.
• Its a shorter acting & repeated dosing required.
Precautions & C.I:-
1. Head injury- CSF pressure & ICT, Resp.depression, N, V,
miosis & clouding interferes with diagnosis.
2. Bronchial asthma & COPD-
3. Hypovolemic shock –
4. CNS depressants - adds up.
5. Hypothyroidism & hyperthyroidism-
6. Undiagnosed acute abdominal pain-
- it relives pain & may interfere with diagnosis. N,V & spasm-
drawbacks.
 Codeine-60mg=10mg of morphine.
• Its a naturally occurring opioid.
1. It is a
• Less potent analgesic
• Less resp. depression than Morphine
• Less constipating
• Has less addiction liability
• Well absorbed orally.
2.Antitussive --cough centre, dose-10-30mg QID.
3.It potentiates analgesic effect of aspirin & PCM.
• Duration of action 4hrs, converted to Morphine
S/E- constipation & sedation.
 Noscapine-
• Antitussive action – 15-30mg.TID.
• No opioid disadvantages.
• Histamine liberator- Br.constriction.
 Pholcodeine -
• Long acting antitussive- once daily.
 Dextromethorphan -
• No analgesic/ additive effect.
• Antitussive action- 10-30mg/TID.
 Tramadol- Codeine congener.(Orally/ I.V)
• Weak agonistic activity at µ receptors.
• X reuptake of NA & 5-HT.
Pharmacological actions-
• Analgesic
• Physical & psychological dependence.
A/E- N & V, constipation, Resp. depression, euphoria,
sedation, seizures- avoid in epileptic Pt’s.
Uses-mild-moderate pain due to trauma & surgery.
• Rx labour & cancer pain.
D.I-with MOA-I’s can ppt HTN crisis.
 Pethidine/ meperidine -
• Its 1/10 th potent as morphine.
• Its administered by oral, I.M/ S.C.
• Well absorbed from GIT
• B.A -50%- due to 1st pass.
• Quick onset & short acting.
• Widely distributed, cross placental barrier.
• Metabolised in liver, excreted- urine.
Properties-
• Its analgesic efficacy is similar to morphine.
• Produces corneal anaesthesia.
• Less constipating & dysphoria.
• Has anticholinergic effects
• CNS + tremors, restlessness, convulsions due to toxic
metabolite (nor-pethidine) .
Uses-
1. Analgesic- Rx visceral pain & other pains.
2. Obstetrical analgesia- preferred than morphine.
(less spasmogenic, less resp.depression, not interfere with uterus)
3.Pre-anaesthetic medication
S/E- similar to morphine.
 Tolerance & dependence are developed.
 Analgesic Dose-25-100mg I.M/S.C.
 Diphenoxylate- pethidine congener
• Used for Rx - diarrhoea,
• Combined with atropine to Rx T.diarrhoea.
• Rarely used due to S/E & paralytic ileus.
 Loperamide - pethidine congener.
• Reduces GIT motility & secretions.
• Increases the tone of anal sphincter.
• Used for Rx – diarrhoea.
 Fentanyl - synthetic opioid.
• Potent µ agonistic activity
• Potent than morphine as a analgesic action.
• Routes- I.V, epidural, intrathecal & TDS.
• Highly lipid soluble & fast acting.
• Has mild effects on CVS- safer.
• TD Patches-acts for 24hrs.
• It doesn't ICT.
• Commonly used opioid analgesic.
• Neuroleptanalgesia - short surgeries ( sedation + analgesic)
- Fentanyl 0.05mg+ droperidol 2.5mg/5ml-I.V/10min.
- Both have rapid onset & shorter duration.
Uses-
• Popular anaesthetic adjuvant because rapid on set of
analgesic effect.
• Neuroleptanalgesia – burns dressing, endoscopies, angiographies.
• Epidural fentanyl -postoperative & obstetric analgesia
• TD patch- used for chronic & cancer pain.
• Preferred in cardiovascular surgeries.
 Fentanyl analogues
• Sufentanil
• Alfentanil & Remifentanil are fast acting- short surgeries.
 Methadone-
• Synthetic opioid, agonist effect at µ receptors.
• Effective analgesic.
• Routes- oral & I.M
• Longer acting- suppress withdrawal symptoms in addicts.
• Highly bound to plasma ptn’s & tissues.
• Withdrawal symptoms are mild due to slow release from tissues.
• Tolerance develops slowly.
• Less euphoric effects & abuse.
• 10mg i.m /oral, 2mg in 5ml syrup
Uses-
1.Substitute therapy in opioid dependence-
- 1mg oral methadone for every 4mg morphine.

2.Opioid maintenance-
- Increase oral dose to produce tolerance. Such pt’s don’t
experience the pleasurable effects on I.V morphine.
- So pt give up the habit because of methadone tolerance.

3. Also used as a analgesic.

Therapeutic uses of opioids-
1. Analgesia-A/C MI, burns, pulmonary embolism, cancer,
acute pericarditis, fractures, bullet wound.
• Morphine-sever cancer pain
• Renal & Biliary colic- Morphine + atropine.
• Epidural analgesia – small doses of morphine.
• Obstetric analgesia- pethidine.
• Neuroleptanalgesia- fentanyl + droperidol.
• Postoperative & chronic pain- epidural morphine.
• M.I- relives pain & anxiety, Symp + HR & shock.
2.Preanesthetic medication- Morphine/ Pethidine.
• Opioid's are given 30min before anaesthesia because of their sedative,
analgesic & euphoria effects.
• Dose of anaesthetic can be reduced.

3. Cough- Codeine, Noscapine & Dextromethorphan.

4. Diarrhoea- diphenoxylate & loperamide
5. Sedative- relives anxiety in threatened abortion without affecting
uterine motility.

6.Acute left ventricular failure- Morphine relives dyspnoea of LVF &

Pul.edema due to cardiac workload & anxiety.
 Mixed Agonists & Antagonists

 Pentazocine -
• Its opioid agonist- antagonist.
• Agonistic to k & week antagonistic to µ R.
Pharmacological actions-
• CNS effects are similar to morphine.
• Sedation & Resp -- are less.
• Tolerance & dependence- repeated use.
• Euphoria – low doses.
• High doses-Dysphoria, hallucination & nightmares.
• CVS- HR, B.P, due to sympathetic + - cardiac work.
C.I- pt’s with HTN, IHD,MI.
Dose- 50-100mg orally , 30-60mg I.M
Uses- P.O.P & chronic pain due to less abuse liability.
Nalbuphine - agonist & antagonist.
•More potent than pentazocine
•Good analgesic.
•Resp. depression only at low dose & not above 30mg.
•High doses- dysphoria.
•Analgesic dose- 10-20mg IM
 Buprenorphine- Thebaine.
• Partial receptor µ agonist
• 25-50 times > morphine.
• Actions are similar to morphine.
• Has delayed onset & prolong action.
• Tolerance & dependence – less.
• Withdrawal syndrome appears late & is mild.
Routes- S.L/ I.M/ I.V.
Uses-
• P.O.P, Myocardial & cancer pain
• As a maintenance therapy in opioid addicts.
Note-it induces resp-- is not completely reversed by Naloxone.
• So its not used in labour pain.
 Nalorphine - agonist & antagonist
• Low dose- good analgesic.
• Low dose - dysphoria & resp. depression.
• So it can’t be used a analgesic.
• High doses- act as a antagonist & reverse all the actions of
opioids.
Uses- A/C opioid poisoning.
- diagnosis of opioid addiction.
 Opioid antagonists

 Naloxone & Naltrexone -

• Pure opioid antagonists (μ, κ, δ)
• Both competitively reverse the effects of both natural &
synthetic opioids.
• Can’t competitively reverse buprenorphine induced resp -- .
 Naloxone -
• Orally not effective & 1st pass.
• X analgesic effects of placebo, acupuncture & endogenous
opioid peptides.
• On I.V adm- X all the actions of morphine.
• I.V adm –ppt’s withdrawal symptoms in morphine &
heroine addicts.
Uses of Naloxone-
• Rx of morphine & opioid poisoning.
• Rx of opioid over dosage-I.V adm-reverses Resp.dep.
• Rx of neonatal asphyxia due to the use of opioids in mother
during labour.
• Used for diagnosis of opioid dependence.
• It can reverse endogenous opioid induced hypotension.
Uses of Naltrexone-
• Orally effective & long acting.
• Rx of alcoholism - reduces craving & prevents relapse.
• Used for opioid blockade therapy to prevent relapse in
opioid dependent individuals.
 Nalmefene -
• Orally effective & long acting.
• Better B.A.
• Not a hepatotoxcity.
•Thank u
 Cortex

Thalamus
Descending
modulation
pathway

Brain stem

Spinal cord

Peripheral stimulus
 Ca2+ Ca2+
Opioid

 opioid
receptor
Primary
afferent
nociceptor
terminal
Neurotransmitter
Opioid
glutamate
 opioid
receptor
Secondary
ascending K+ K+
neuron

Opioids binding to ion channel associated  receptors inhibit the influx of

calcium ions into the pre-synaptic terminal and increase the outflow of
potassium ions from the post-synaptic membrane. This has the effect of
reducing the release of the neurotransmitter glutamate and hyperpolarising the
post-synaptic membrane. Synaptic transmission is inhibited.
 Ca2+ Ca2+

Primary  opioid
afferent receptor
nociceptor
terminal
Neurotransmitter
glutamate
 opioid
receptor
Secondary
ascending K+ K+
neuron

Synapses between afferent nociceptive neurons and secondary ascending

neurons relay pain signals to the brain. The entry of Ca2+ into the pre-synaptic
primary neuron and the release of K+ from the post-synaptic secondary neuron
are processes involved in signal transmission across the synapse.
 What Causes Pain?

• Pain is caused by the stimulation of pain

receptors which are free nerve endings.
• “Nocireceptors are pain receptors that
are located outside the spinal column in
the dorsal root ganglion and are named
based upon their appearance at their
sensory ends. These sensory endings
look like the branches of small bushes(
2).”
• There are two types of nocireceptors
that mediate fast or slow pain signals
• The perception of pain is when these
receptors are stimulated and they
transmit signal to the central nervous
system via sensory neurons in the spinal
cord.
http://staff.washington.edu/chudler/gif/spiback1.gif
Locations involved in Pain
Signaling and Analgesia
 Selectivity of Opioid Drugs for
receptor subtypes

Mu Delta Kappa
Morphine, +++ + +
Codeine
Methadone ++ - -
Pethidine ++ + +
Pentazocine + + ++
Buprenorphine +++ - ++
Naloxone +++ + ++
Naltrexone +++ + +++
Agonist + Antagonist +
 Mu and Kappa Receptor Activation

Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory
Depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence

Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl Reactions
Withdrawl Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”