OPIOID ANALGESICS

Dr. NISHA.A.R
ANALGESICS
 Drugs that selectively relieve pain
 by acting on Central Nervous System or
on peripheral mechanisms
 without affecting consciousness
Depending on chemical structure and
general pharmacological properties, the
analgesics are divided into
 Opioid analgesics
 Non opioid analgesics
 Opioid analgesics

 Central opioid receptor stimulation analgesia

 Sedation, tolerance, physical dependence

 Primary use to reduce pain and accompanying anxiety,

fear, suffering, distress etc

 Opioids
-natural,synthetic,semisynthetic
-morphine-like effects
-blocked by naloxone
-structure different from morphine
 Opiate
-morphine-like drugs
-obtained from juice of opium poppy
-structure resemble to morphine
Opium
dried juice of poppy plant
(Papaver somniferum)

powdered opium has 25 alkaloids

Phenanthrenes Benzylisoquinolones
(morphine,codeine,thebaine) (papaverine,noscapine)
 Narcotic
◦ (Narcosis = deep sleep)
◦ Occasionally used to refer opioid analgesics
◦ Therapeutics-drug that induces deep sleep
 Classification
A. Opioid agonist
-agonist at opioid receptors
B. Opioid mixed agonist-antagonist and partial agonist
-agonist at one receptor
-antagonist at another receptor
-partial agonist at some receptor

Pure opioid antagonist-naloxone

 Classification
A. Opioid agonist
I. Natural opium alkaloids
morphine
codeine
II. Semisynthetic opioids
heroin
hydromorphone
oxymorphone
hydrocodone
oxycodone
etorphin
 Classification
III. synthetic opioids
1. Phenyl piperidine & piperidine derivatives/
pethidine & analogues
pethidine
fentanyl
diphenoxylate
loperamide
2. Diphenyl heptane & diphenyl butane derivatives/
methadone & congeners
methadone
propoxyphene
3. Morphinans
levorphanol
4. Benzomorphans
phenazocine
 Classification
 B. Opioid mixed agonist-antagonist and partial
agonist
1. Semisynthetic opioids/morphine analogues
buprenorphine
nalbuphine
2. Synthetic opioids
1. Benzomorphans
pentazocine
cyclazocine
2. Morphinans
butorphanol
 Chemistry of morphine
 Phenanthrene nucleus
 Oxide link
 A nitrogen containing structure(ethanamine)
 2 hydroxyl groups(3 & 6 position)

 Substitution at OH groups and at nitrogen atom

 Change properties like lipid solubility, resistance to
metabolism, affinity to receptors etc
Thebaine
Both OH groups are methylated
Ring has = bonds
No analgesic action
Precursor of oxycodone, etorphine,
buprenorphine
 MECHANISM OF ACTION
 4 families of opioid receptors
µ(mu),κ(kappa),δ(delta),
σ(sigma)
ε(epsilon)
subtypes of µ,κ,δ
NOP receptors
 Specific pharmacological profile and pattern of
distribution
 Variation in response in different species
distribution & concentration in CNS
affinity for opioids
 RECEPTORS
 Mu(µ) receptors
major receptor mediating actions of morphine and congeners
Location-periaquidectal grey matter, thalamus, NTS,
nucleus ambiguus, area prostema
Stimulation analgesia, respiratory depression, miosis,
reduced GI motility, sedation, euphoria,
muscular rigidity, physical dependence
Endogenous ligands-endomorphins 1 & 2, β-endorphin,
enkephalins(m), dynorphins(W)
2 subtypes-µ1-higher affinity for morphine(supraspinal
analgesia)
µ2-lower affinity for morphine(spinal analgesia,
respiratory depression, constipation)
 RECEPTORS
 Kappa(κ) receptors
higher affinity for ketocyclazocine
Location-deep layers of cerebral cortex, spinal cord
Stimulation analgesia(spinal(κ1),supraspinal(κ3),
dysphoria, reduced g I motility,
less intense respiratory depression,
miosis, sedation, physical dependence
Endogenous ligand- Dynorphin A
3 subtypes- κ1-spinal analgesia
κ2
κ3 –relieve low intensity pain
 RECEPTORS
 Delta(δ) receptors
higher affinity for leu/met enkephalins
Location-dorsal horn of spinal cord,myenteric plexus
Stimulation analgesia(spinal), proconvulsant action,
reduced GI motility

Endogenous ligand- leu/met enkephalins

2 subtypes -δ1
-δ2
 RECEPTORS
 Sigma(σ) receptors
-Neither activated by morphine nor blocked
by naloxone
-pentazocine, butarphanol, some hallucinogens
bind
-mediate dysphoria,psychomimetic action,
tachycardia and mydriasis effects
-do not mediate analgesic effects
 Morphine-agonist on µ, κ, δ
 Pentazocine –agonist at κ, antagonist at µ
 Buprenorphine- partial agonist at µ, antagonist at κ
 Diprenorphine-antagonist with slight agonist action
 Naloxone –pure antagonist
 Cellular effects
 GPCR

-inhibition of adenylate cyclase

-activation of k+ channels

-suppression of Ca+ channels

Endogenous opioid peptides
 Opioids produced in the body that bind opioid receptors
 1970-isolated peptides with morphine like action
 Blocked by naloxone
Endorphins-β endorphin
◦ Precursor-pro-opio-melanocortin(POMC)
◦ Primarily µ agonist
◦ Also has δ action
Enkephalin-
 methionine(met) and leucine(leu)enkephalin
◦ Met –equal affinity for µ and δ
◦ Leu-prefers δ
Dynorphin (A & B)
 More potent on κ receptors. also activate µ and δ
Endomorphin,nociceptin(orphanin FQ)
 Natural opium alkaloids
 Morphine
◦ Principal alkaloid of opium
◦ 1st alkaloid to be isolated(1805)
◦ Isolated and named by F W A Serturner
◦ Insoluble in water
◦ SO4 and HCl salts-readily soluble
◦ Darkens on exposure to light
 Morphine-pharmacological effects
 CNS
-species specific
-site specific depressant and stimulant action
-interact primarily with µ receptors
o Analgesic action
-strong analgesic-spinal & supraspinal analgesia
-modifies pain perception and behavioural reaction
-normal doses-selectively relieves visceral pain
-high doses-mitigate all types of pain
Morphine-pharmacological effects on CNS
o CNS depression/sedation
-species difference
minor initial stimulation followed by depression
-dogs, rodents, monkeys, human
maniacal excitement-cats
-sedating and calming effect in all animals in pain
-no anticonvulsant effect-precipitate fits and seizures
Morphine-pharmacological effects on CNS
o Emetic centre
-species variation
-dogs and cats (at higher doses) sensitive
-other species (including swine) do not respond
-direct stimulation of CTZ.
-depresses vomiting centre, but CTZ stimulation
overrides
o Cough centre
-suppress cough centre
-effective antitussive in dogs
Morphine-pharmacological effects on CNS
o Respiratory centre
-potent depressant-dose dependent
-dogs-initial stimulation and panting
-later depression
-acute overdoses death due to respiratory failure
-moderate to high doses bronchoconstriction
o Thermoregulatory centre
-species variation
Dogs, rabbits, human-hypothermia(initial
hyperthermia)
Cats,cattle,goat,horses-hyperthermia
Morphine-pharmacological effects on CNS
o Spinal cord
-stimulant and depressant
-monosynaptic reflexes-
stimulated/unaffected
-polysynaptic reflexes-depressed
o Neuroendocrine functions
increased ADH, GH, prolactin
decreased FSH,LH,ACTH
Morphine-pharmacological effects on CNS
o Eye
-pupil size-species variation
dogs,rats,human-miosis
occulomotor nerve stimulation
no miosis on topical application
cats, sheep, horses-mydriasis
-decrease in intra ocular tension
Morphine-pharmacological effects on CNS
 Other CNS effects
-depresses vasomotor centre
decreased BP
-stimulation of vagal nucleus
parasympathetic responses(bradycardia)
 Cardiovascular effects

Complex-direct and indirect effects

Analgesic dose peripheral vasodilation
depression of vasomotor centre
release of histamine from mast cells,
vagal stimulation
 Digestive system
 constipation-prominent feature
◦ Increase segmentation but decrease propulsive
movement-direct effect on CNS and intestine
◦ Spasm of sphincters
◦ Decrease in secretions-peripheral action
(mainly).central also
◦ Absorption of fluid increase due to stasis
◦ Inattention to defecation reflex due to central
action
No tolerance develops to this effect
Can use in management of diarrhoea
 Urinary system
 Initially induce micturition later urinary secretion

 Reasons for urinary retension

in ADH release
Contraction of sphincter
• Tone of dextrusor muscles & ureters increased
• Urinary urgency but difficulty in micturition
 Other effects
 Biliary tract Spasm of sphincter of oddi
intrabiliary pressure biliary colic
 Uterus-slightly prolong labor
 ANS-Mild hyperglycemia central sympathetic
stimulation
 Bronchi-Release of histamine from mast cells
bronchoconstriction
• Depresses immune system susceptibility
to infections
 Pharmacokinetics
 iv, im, sc- readily absorbed
 Effects in 2 to 10 minutes
 Maximum effect after 30-60 minutes
 Orally-well absorbed but high first pass effect
 Concentrates in kidney, liver and lungs
 Freely crosses placenta,but not brain
 Metabolism by glucuronide conjugation (exception-
cat)
 Enterohepatic circulation persist in blood
 excretion primarily in urine
 T1/2-90 min (horses),3hrs in cats
 SIDE EFFECTS
 Blurring of vision
 Peripheral vasodilation
 Hypotension
 Vomiting
 Constipation
 Urinary retension
 Exaggerated spinal cord reflexes
 Sweating
Side effects-contd
 Respiratory depression
 CNS effects-dose & species specific
-animals stimulated by morphine
-appear restless and
convulsions
-hyperthermia
Idiosyncrasy,allergy-rare
Apnoea of new born
• Overdosages
Treatment –naloxone
- respiratory support
 Tolerance
• Mainly pharmacodynamic(cellular effects)
• Some pharmacokinetic(metabolism)
• Tolerance to all effects except constipating
and miotic actions
• Cross tolerance –high degree
Dependence
• Psychological and physical dependence
• Rarely encountered in animals
• NMDA antagonists & nitric oxide-block
morphine tolerance & dependence
Contraindications and precautions
 Contraindicated in
biliary spasm
acute renal insufficiency
severely debilitated patients
head injury(raise intracranial pressure and
obscure neurological examination)
Respiratory dysfunction
pregnant animals
 Contraindications and precautions
 Abrupt cessation absence of endogenous opioid
substances noradrenergic / dopaminergic
activities behavioural syndrome or withdrawal
syndrome (abstinence)
 Drug interaction
 Depressant effect potentiated by CNS
depressants
 Analgesic effect potentiated by Tricyclic
antidepressants
 Contraindicated -Monoamine oxidase
inhibitors
 Morphine retards absorption of orally
administered drugs
 immunosuppressive effects of steroids
 Clinical uses
 Analgesic
 Preanaesthetics
 Antitussive
 Antidiarrhoeal
 Adjunctive therapy for cardiac abnormalities in
dogs
 High addictive properties in human
 Use cautiously in cats
 In horse concurrently with acepromazine /
xylazine
 Codeine (methyl morphine)
 Second most important alkaloid
 Similar to morphine but less potent1/6 to1/10
 Partial agonist at µ receptor
 Less sedation or respiratory depression
 Constipaton –at analgesic dose
 Tolerance develops less rapidly
 Dependence rare
 In human, codeine demethylated (CYP2D6) morphine
liver (analgesic)
 Good activity by oral route
 Used primarily as cough depressant
(subanalgesic dose)
 Occasionally as analgesic(combination with
NSAIDS)
 Antidiarrhoeal agent
 SEMISYNTHETIC OPIOIDS
 Pharmacologically similar to morphine
 Derived from morphine or thebaine
Heroine/diacetyl morphine/diamorphine
• More potent
• More lipid soluble enters brain
• Sedative, emetic, hypotensive actions-less
prominant
• Highly addicting drug
• More euphorient in human
• Not used clinically
Hydromorphone (dihydromorphinone)
 5-10 times more potent as an analgesic
 Less sedation, vomiting, nausea, constipation
 Antitussive property similar to codeine
 High abuse potential in man
 Used rarely
 Oxymorphone
 10 times more potent as analgesic
 High incidence of vomiting and respiratory
depression
 Euphoria in human
 High addiction liability
 Limited use in animals
 Occasionally used in human for preoperative
sedation and obstetrical analgesia
 Vet medicine-combination with acepromazine
(neuroleptanalgesia)
 Hydrocodone
 Structurally similar to codeine
 More potent analgesic than codeine
 Less potent than morphine
 Primarily as an antitussive agent
 Oxycodone
 Semisynthetic thebaine derivative
 Analgesic
 Antitussive
 Less used in therapy
 Etorphine HCl (M-99,Oripavine)
 Semisynthetic thebaine derivative
 300 times more lipid soluble than morphine
 Used in vet medicine for immobilisation of
domestic & exotic species
-alone
-combination with neuroleptic agent
(acepromazine)
 Etorphine-pharmacological effects
 Highly potent analgesic(1000-10000 times)
 Affinity for opioid receptors-20 times
greater(high efficacy)
 High lipid solubility(rapid action)
Less likely to cause emesis or initial excitement in dogs
Bradycardia, arterial hypotension in dogs, cats, monkeys
Tachycardia in horses
 Pharmacokinetics
 Absorbed rapidly from injection site
 High lipid solubility crosses blood
brain barrier
 Metabolised primarily in liver
 Excreted in bile in conjugated form
 Undergoes enterohepatic circulation
 Side effects
 Similar to morphine-tachycardia in horses and
bradycardia in dogs
 High doses-severe respiratory depression
 6-8 hrs excitement after remobilization of
animal due to enterohepatic circulation
 Contraindications and precautions
 Similar to morphine
 Caution while using in elderly and pregnant
animals (respiratory depression in new born)
 Should wear surgical gloves while handling
etorphine
 High temperature increases absorption
toxicity
• Should not be used in animals intended for
human consumption
 CLINICAL USES
 Immobilize domestic and wild animals
(alone or in combination)
• projectile/dart injections
-dose heavily and reverse immediately with
suitable opioid antagonist-diprenorphine.
Otherwise immobilised stage will persist for
30-60 min
 Synthetic opioids
Phenyl piperidines
Pethidine(meperidine)
• Chemically unrelated to morphine
• But interacts with opioid receptors and action similar to
morphine
• µ receptor agonist
 Pharmacological effects
 Similar to morphine but some differences
-Prompt but short acting analgesia
-1/8-1/10th as potent as morphine
-In cats and horses, less prone to produce
excitement at normal doses but at high doses
produces excitement
-Antimuscarinic activity antispasmodic on
smooth muscles of large intestine
 Only opioid that has vagolytic action
 Does not effectively suppress cough
 Less likely to cause vomiting
 Less respiratory depression. so more suitable for
pregnant animals
 Less likely to produce narcosis, vasodepression,
constipation, urinary retension, miosis, histamine
release
 Possess some local anaesthetic effect
 Produces euphoria in human abuse potential
 Pharmacokinetics
 Absorbed well after oral administration but
high first pass effect
 Therefore administered parenterally
preferably i/m
 Inactivated in liver by hydrolysis to
meperidinic acid and by demethylation to
norpethidine and then conjugated with
glucuronic acid
 Cats –rapid detoxification
Side effects
 Similar to morphine but less likely to cause vomiting,
respiratory depression
 s/c-Irritating
 Rapid i/v hypotension & bronchoconstriction in dogs
 Orally irritating to buccal mucosa salivation
 Overdosage respiratory, cardiovascular, CNS
depression
 Cats-CNS excitability and seizures
 Tolerance and physical dependence develop slowly
Treatment-naloxone
 Clinical uses
 Analgesic
 Small animals-sedative/analgesic for post-
operative pain, thermal burns, acute
pancreatitis
 Smooth muscle pain and equine colic as it is
spasmolytic
 Combination with acepromazine
 Fentanyl
 Pethidine congener
 50-100 times more potent than morphine
 µ receptor agonist
 High lipid solubility
 Rapid onset of action but shorter duration
 Metabolised in liver by hydroxylation and dealkylation
 Highly protein bound
 Undergoes tissue redistribution
 Few cardiovascular effects in analgesic doses
 Less propensity to release histamine
 Vet medicine-
combination with droperidol or fluanisone (neuroleptanalgesia)
fentanyl transdermal patches
Fentanyl transdermal patch(duragesic)
◦ Prolongs duration for 72 hrs
◦ Control of post operative pain and other pain
associated with medical conditions like cancer,
pancreatitis, peritonitis
◦ Respiratory depression & bradycardia
◦ Rashes at patch site
◦ Should not be applied in febrile animals
Buccal use also possible
Injectable form-to supplement anaesthesia
 Sufentanil
 Fentanyl analogue
 Selective µ receptor agonist
 5-10 times more potent than fentanyl
 Safety margin(6 times) larger than fentanyl
 Shorter duration of action
 Anaesthetic adjuvant
 Continuous infusion with a tranquiliser or
inhalant anaesthetic
 Alfentanil
 Fentanyl analogue
 More lipid soluble
 Greater protein binding
 Less potent than fentanyl
 Shorter half life(redistribution & rapid
metabolism)
 Anaesthetic adjuvant and post operative
analgesia
 Carfentanil

 Fentanyl analogue
 10,000 more potent than morphine
 Immobilisation of wild animals
Remifentanyl
 Potency equal to fentanil and 20-30 times
greater than alfentanil
 Wide margin of safety
 Extremely short half life(7.5 minutes)
 Very safe when used alone
Diphenoxylate and loperamide
• Selective µ receptor agonist
• Treatment of diarrhoea
 Diphenyl heptane
 Methadone
◦ Chemically dissimilar but pharmacologically similar to
morphine
◦ µ receptor agonist
◦ l-isomer has 25 times the analgesic property than d-
isomer
◦ Analgesic property equal to morphine
◦ Less sedation
◦ Repeated administration accumulation
gradual release prolonged duration
Pharmacokinetics
 Parenteral & oral administration readily absorbed
• Firmly bound to protein
• Accumulates in tissues
 Excreted in bile & urine
Side effects
 Similar to morphine
 Slow and persistent nature of action
 Abuse potential is lower than morphine
 Tolerance develop more slowly
Clinical use
 Analgesic
 Preanaesthetic
 Antitussive
 Analgesia and chemical restraint in horses
Methadone-acepromazine
combination
 Treatment of opioid absistence
 Propoxyphen
 structurally related to methadone
 Analgesic effect and side effect-similar to
codeine
 Analgesic effect in dextroisomer
 µ receptor agonist
 Human –With aspirin and caffeine-
treatment of chronic pain
 Limited use in veterinary medicine
 Horses-combination with sedative or
tranquiliser
 morphinans
 Closest chemical relatives of morphine
 Carry phenanthrene nucleus but lack oxygen
bridge,hydroxyl alicyclic =bond of morphine
Levorphanol
Only commercially available morphinan opioid agonist
d isomer(dextrorphan) devoid of analgesic action,
posses antitussive activity
5 times more potent than morphine as an analgesic,
greater sedative effect
Acts through µ receptors,
Posses k3 receptor action at high doses
Human medicine-potentiate & prolong general
anaesthesia
Used when analgesia with greater sedation is needed
 Benzomorphans
 Phenazocine
3 times more potent than morphine
Rapid relief of pain
No spasm of sphincter of oddi useful in
treating biliary and pancreatic pain
Premedication and post operative pain
 Mixed agonist-antagonist and partial
agonist
Semisynthetic opioids
Buprenorphine
 Highly lipophilic
 Partial agonist & antagonist at µ receptor
 Synthetic thebaine congener
Pharmacological effects
 Analgesic
 30 times more potent
 Slow onset
 Long duration of action(high affinity for µ receptor)
 No constipation
Antagonist action
equal to naloxone- antagonise depression produced by fentanyl
Pharmacokinetics-
rapid absorption after i/m
oral-first pass metabolism
highly bound to plasma protein
metabolised by N-alkylation and glucuronidation
elemination by biliary secretion
 Side effects
 Similar to morphine
 But less sedation and respiratory depression
 High safety index
 Lower addiction potential in human
 Lower degree of dependence
Treatment
• Naloxone-high dose
Contraindications
• Impaired respiratory function
• Repeated use cumulative effect
Clinical uses
 Post-operative pain
 Cancer pain
 Neuroleptanalgesia in horses
 Synthetic opioids
 Benzomorphans
Pentazocine
Available clinically as racemate
l-isomer-analgesic and respiratory depressant activity
d-isomer-little affinity for opioid receptors
1st agonist-antagonist to be used as analgesic
Strong agonist at κ receptors
Weak antagonist/partial agonist at µ receptor
 Pharmkacological effects
 Effects -similar to morphine
Difference
 Spinal analgesia(κ receptor)
 Analgesia -1/3rd of morphine
 Sedation & respiratory depression- 1/3rd to
1/2 of morphine
 Tachycardia and rise in BP
 Little effect on GI tract
 Pharmacokinetics
 Effective orally but first pass effect
 Distributed widely, crosses placenta
 Glucuronide conjugation, excretion by kidney
Side effects
• Similar to morphine
• Dogs-salivation after parenteral administration
• Horses-ataxia and excitement
• Cattle-dysphoria
• Human-abuse liability is lower
• Tolerance & dependence but milder withdrawal
symptoms
Treatment-naloxone-repeated doses
Contraindications
 Not recommended in cats
Clinical uses
Analgesic in dogs-musculoskeletal and visceral pain
Symptomatic relief of colic in horses
Post operative pain
Pain in burns,trauma,fracture, cancer etc
 Morphinans
 Butorphanol
Similar to pentazocine
4-7 times more potent analgesia
Κ analgesic,weak σ agonist at higher doses
Weak interaction with µ receptor
Sedation,other side effects-similar to pentazocine
Low abuse potential
 Pharmacokinetics
 Well absorbed after oral (first pass effect)/im
 Well distributed
 Metabolised by hydroxylation, N-alkylation
and conjugation
Side effects
• Horses-ataxia and excitement
• Very high doses-nystagmus, salivation, seizures,
hyperthermia, GI motility
 Clinical uses
 Analgesic(combination with medetomidine)
 Antitussive in dogs in non-productive cough with inflammatory
conditions of upper respiratory tract.
 Visceral pain & colic in horses(combination with
detomidine/romifidine)
 Preanaesthetic medication
 Antiemetic
 Induce anaesthesia of short duration(combination with
medetomidine)
 Neuroleptanalgesics
 Analgesia+sedation
 Neurolept/tranquilising drug +opioid analgesic
 Does not respond to surroundings but not
totally consciousness
 similar to light plane of anaesthesia
 Minor surgical procedures may be carried out
 Effects show marked variation on species
 Advantages
 Deeper & more reliable sedation
 More reliable analgesia
 Less marked respiratory depression
 Neurolept component abolishes emetic
effect, lessens bradycardia
 Produce suitable immobilisation
 Fentanyl and droperidol(INNOVAR VET)
 Droperidol-butyrophenone neuroleptic
 1:50
• i/v,s/c
• Rapid i/v-30-40 minutes-wood chest syndrome
• Remain sedated for several hours
• Both metabolised in liver & eliminated in urine
 Should not be used in food producing animals
 Not normally rec. in cats
 Prior administration of atropine
Clinical use
Alone-minor surgical manipulations
Combination with GA-major manipulations
Restraining aggressive dogs

Etorphine hydrochloride (2.25mg)+

acepromazine maleate (7.38mg)
 Highly potent-supplied together with diprenorphine
 Highly toxic-use gloves
 Butorphanol – acepromazine
 Methadone –acepromazine
 Buprenorphine-acepromazine
 Oxymorphone-acepromazine
Opioid antagonists
classification
 Pure opioid antagonists
naloxone
naltrexone
nalmefene
 Opioid antagonists with weak agonistic activity
nalorphine
diprenorphine
levallorphan
 Naloxone
 Allyl –nor-oxymorphone
 Comp.antagonist at all receptors-high affinity for µ
 Antagoises all actions. but sedation less reversed
 Also blocks actions of endogenous opioid peptides
 Does not prevent the emetic action of apomorphine(D2
mediated)
 Inactive orally-first pass metabolism
 Parenteral administration
Clinical uses
• Reversing agent for opioid analgesia
• Intoxication with morphine and opioids(except buprenorphine)
• Diagnosis of opioid dependence
• Adjunct to intraspinal analgesia-reverse respiratory depression
• Reverse pulmonary depression
 Nalorphine
 Allyl normorphine
 Strong µ antagonist
 Weak agonist at κ receptors
 Less used in therapy
Diprenorphine
• Structurally related to etorphine
• Specifically reverse of etorphine
• 2:1(Diprenorphine: etorphine)