Narcotic analgesia

Compiled by
Dr . Jahangir Kaboutari
DVM, PhD Assistant professor of Pharmacology
Faculty of Veterinary Medicine, University of
Shahrekord, Shahrekord .Iran
 Definition

Narcotics: Those chemical alkaloid compounds

which binds stereo specifically to the Opiate
receptors and used to alleviate severe and visceral
pains
Opioid :refer to drugs in a generic sense, natural or
synthetic, with morphine- like actions
 Opioids classification
: Natural
Phenathrenes: morphine 10%
Codeine 5%
Thebaine 0.2%
Bezylisoquinolines:papverin
Noscapine
Semi synthetics : Heroin, Oxymorphone,
Hydromorphone
Synthetics : Meperidine, Methadone,
Morphinians, Benzomorphans
 Morphine chemistry
pentacyclic alkaloid
oxygen bridge at 4,5 position
)three major rings )a, b, c
phenolic groups )s/a hydroxyl, alcoholic, OH)
at position 3 and 6, modifications at those
positions changes pharmacokinetics and
. potency of drug
changing nitrogen at 16 position )n16) by
adding an alkyl group converts it to Naloxane
))i.e. go from a agonist to an antagonist
Sulfate salt
Spp response variation due to difference in
number, distribution &sensitivity of opiate
.receptors in the body
General CSN effects:Analgesia, sedation
. &respiratory depression
: Generally
CNS depressant :human, monkey& dog
CNS stimulator : goat, cat, sheep, horse & cow
 Receptor Stimulation
µ
Gi protein mediated increase in K conductance, neural
hyperpolarization & decrease synaptic transmission.
Endogenous ligand: Enkephaline
P hysical dependence
E uphoria
Analgesia )µ1 supraspina,)µ2 spinal analgesia
R espiratory depression
G asrtointestinal upset
 Κ
G protein mediated decrease in Ca inward,
.decrease NT release
Endogenous ligand: Dynorphin
Sedation
A )nalgesia )spinal
M iosis
D ysphoria
 δ
Gi protein mediated increase in K conductance, neural
hyperpolarization & decrease synaptic transmission,
interactive molecular complex with.µ
Endogenous ligand: Enkephaline
A )nalgesia )spinal & supra spinal
Re lease ofg rowthh ormone
σ
Excitatory ,no analgesic, insensitive to Naloxane
D )ysphoria )opposite of euphoria
H)allucination )both visual & auditory
R espiratory and vasomotor stimulation
M ydriasis
Pshycotomimetic & mania
 Opiate receptors

.CNS distribution is not uniform

.they are at areas concerned with pain
receptor locations beginning with highest concentration
:areas
cerebral cortex .1
amygdala .2
septum .3
thalamus .4
hypothalamus .5
midbrain .6
spinal cord .7
 Endogenous Opioid Peptides

Three distinct families of peptides have been

identified: theEnkephalins, theEndorphins,
and theDynorphins. Each family is derived
.from a distinct precursor polypeptide
These precursors are now designated as
proenkephalin )also proenkephalin A),
proopiomelanocortin )POMC), and
)prodynorphin )also proenkephalin B
 Endogenous Opioid Peptides :
Enkephalins
met enkephalin )methionine at 5' position) &
leu enkephalin. ) )leucine at 5' position
Neuromodulators in Thalamus ,hypothalamus,
brain stem, dorsal horn of spinal cord,
plasma, PNS, G.I.T
short interneurons in substantia gelatinosa at
the ending of the efferent neurons which
inhibit release of P. substance
 : Endogenous Opioid Peptides
β.Endorphin

.Neurohormone
hypothalamus, hypophysis, placenta, small
.intestine & plasma
.Analgesia and pain decrease while stress
. conservation between species
. little difference in humans
 Endogenous Opioid Peptides :
Dynorphin

Central control of CVS

Neuromodulator of CNS
Spinal analgesia
 Important

Synergism withά2 adrenergic agonists due to

activation of presynaptic inhibitory receptor of
.nociceptive fibers
Potency.: affinity for opiate receptors
Efficacy. : a function of analgesic property
Involvement of Serotoninergic & GABAergic
.pathways in opioid analgesia
 Pharmacokinetics
Absorption
Readily absorbed from GI tract )small
intestine), nasal mucosa, lung subcutaneous,
.intramuscular, IV route & Sc
.Dermal absorption especially in damaged skins
CNS is primary site of action: analgesia&
.sedation
.Intensive distribution to almost tissues
 Metabolism/Excretion
.Hepatic metabolism, glucuronide conjugation
.Renal excretion
Plasma half life : 2.5 to 3 h, analgesic time
.h 4-5
.250mg IT: up to 24h in obstetrics
morphine 3 glucuronide : main metabolite
morphine 6 glucuronide : active metabolite
.which accumulate while hepatic failure
Intensive 1st. pass effect
 Administration
Oral morphine not given due to erratic oral
.availability
Significant variable first pass effect from
person to person and have intraspecies effect
.))same dose will vary in person day to day
IV morphine acts promptly and its main effect
.is at the CNS
CNS is primary site of action of
morphine

analgesia
sedation
euphoria
mood change
mental cloudiness
 Morphine analgesia
Changes our reaction and our perception**
of pain
severe cancer pain is tolerated more when
. person is given morphine
relieves all types of pain, but most effective
. against continuous dull aching pain
sharp, stabbing, shooting pain also relieved by
morphine

Morphine given to a pain free individual

first experience is dysphoric
not experienced in person in pain
 Sedation
morphine causes sedation effect, but no loss of
consciousness

Euphoria
sense of well being
reason why morphine is abused
Effects of morphine on respiration

There is a primary and continuous depression

of respiration related to dose
decrease rate
decrease volume
decrease tidal exchange
Dog : at firstσ stimulation cause panting, then
µ2stimulation cause respiratory depression
µ receptor activation produces respiratory
depression; with increase in dose can cause
.further respiratory depression
CNS becomes less responsive to pCO2 thereby
. causing a build up of CO2
rhythm and responsiveness causes irregular
breathing patterns; one will see periods of
. apnea
 Nausea and vomiting
Stimulation of CTZ, in area postrema of
medulla
stimulation by stretch receptors causes nausea
and vomiting , afferents from gut and ear
involved in motion sickness
Dog is more sensitive than cat
min after Sc injection: emesis 5-10
 pupil size
Miosis )pinpoint pupils): human, dog , rabbit &rat via
kappa receptor
Mydriasis: cat, sheep, horse, monkey via sigma
receptors variation due to number or distribution of
.sigma receptors in Oculomotor nucleus
Birds: no sensitive
pinpoint pupils still responsive to bright light
oculomotor nerve )CN3) is stimulated by kappa
receptor
if kappa receptor is blocked, mydriasis from sigma
effect will result
atropine partially blocks effect indicating
parasympathetic system involved
 CVS effects
Vascular effects more than cardiac
coronary vasodilatation in human while c
vasoconstriction in dog
Human :used in cardiac diseases : post acute
MI pain, acute pulmonary edema
.&postoperative pain
Release of histamine ,suppression of central
adrenergic tone ,decrease catecholamine secretion,
suppression of reflex vasoconstriction:
Vasodilation , hypotension & decrease MDF
Dog : vagotonic ,sedative &protective against vent.
fibrillation
 Morphine effects on the G.I.T
increase in tone and decrease in mobility leads to
constipation
Initially excitation of myenteric plexus& defecation, then
increased tone in stomach, small intestine, large intestine
,spasm of anal sphincter &suppression of deification reflex
in brain result in constipation.
. decreased concentration of HCl secretion
delay of passage of food )gastric contents) so more reabsorption
of water ,used in diarrhea
tolerance does not develop )i.e. same amount of effect each**
time) to this constipation effect
 Morphine effects on smooth muscles
biliary tract
marked increase in pressure in the biliary tract up
to 10 fold, due to contraction of Sphincter of
Oddi
bronchial muscle
bronchoconstriction can result
contraindicated in asthmatics, particularly before**
surgery
uterus
contraction of uterus can prolong labor
Morphine effects on smooth muscles
cont
:Urinary system
Initially contraction of smooth muscles of the
wall of U .bladder & urether and urination
then, Increase in ADH secretion &
contraction of the sphincter of the U .bladder
result in urinary retention up to 10%
 Neuro endocrine Effects
inhibit the release of GnRH , CRF thus
decreasing circulating concentrations of LH,
FSH, ACTH, and b- endorphin; the
concentrations of testosterone and cortisol in
plasma decline disturbance of oesrtus
.cycle
Secretion of thyrotropin is relatively
.unaffected
Modulator agent in Hypothalamus, Hypophysis
& Dopaminergic- Serotoninergic nuclei
 Addiction
.Physical &mental dependence
.Mental dependence: tolerance to euphoria
Physical dependence: withdrawal signs which start 8h
:after last dose, peak in 36-72h
lacrimation,nasal discharge, sweating, yawning,
.nausea, diarrhea, muscular pain
.h later: uncalm sleep 13
24h later: goose flesh, pupil dilation, tremor
.&agitation
h later peak of signs: insomnia, tremor, 48-72
intestinal cramps, nausea ,vomiting, diarrhea, severe
yawning, muscular pain in leg, severe pain in lower
part of vertebral column, hypertension, sweating &
.goose flesh
signs last for 7-10days, mild sings last for months
 Addiction cont

Negative feedback of exogenous opioids

especiallyβ-endorphine &receptor down
.regulation
Ca accumulation in some parts of neurons and
inhibition of NT release during use of drug ,
after stoping use of drug Ca release and NT
.secretion cause withdrawal signs
 Tolerance to morphine
Depends on: type of Opioid ,amount of use, times of
. use
Nausea
Analgesia
Sedation
Respiratory depression
Cardiovascular
Euphoric
:not to
Miosis
Constipation
 Indication
.Decrease severe &visceral pains
As pre anesthetic: 30-50%decraese in anesthetic dose
.especially in preoperative pains
As post operative drug: decrease incidence & relapse
of hallucination of Pentobarbital anesthesia
.recovery
. Acute pulmonary edema
.Constipating effect
. Anti tussive
Obstetrical analgesia
 Advantages
No inhibition of motor activity or
.consciousness
Increase pain threshold: suppress moderate
.pains, decrease severe& sharp pains
.Anti anxiety
.Control visceral& traumatic pains
 Contraindications
.Uremia &toxemia : increase ADH secretion
.Traumatic shocks : hypertension
. Head trauma &injuries :increase ICP
Strychnine poisoning & epileptic seizures:
spinal cord stimulation & increase central
.seizures
Cautions
C. section: fetal respiratory depression &
.interference with uterine contractions
.Large animals: restlessness & excitation
 Toxicity of morphine
Primarily: Cold pale skin then cyanotic, slow surface
irregular breath, bradycardia& hypotension up to
shock and then bilateral pin point pupil, respiratory
.depression &coma
excitatory and spinal reflexes
high doses of many OPIOID cause convulsions
due to stimulation at sigma receptor
Treatment
establish adequate ventilation .1
1a. 4 point restraints needed
giving OPIOID antagonist :Naloxane .2
Heathing the body, fluid therapy, artificial.3
respiration
Drug interactions with Opioids

in general, the coadministration of CNS**

depressants with OPIOID often produces at
)least an additive depression )potentiation
 OPIOID and phenothiazines
produces an additive CNS depression as well as
enhancement of the actions of OPIOID )respiratory
depression) . this combination may also produce a
greater incidence of orthostatic hypotension

OPIOID and tricyclics antidepressants

. can produce increased hypotension
meperidine and MOA inhibitors : severe and
immediate reactions that include excitation, rigidity,
hypertension, and severe respiratory depression
 OPIOID and barbiturates
Increased clearance

morphine and amphetamine

Enhanced analgesic effect
 Codeine
.Semi synthetic
.change in the methyl group on 3 position
. 0.1the potency )analgesic properties) of morphine
absorbed readily from GI tract more regular and more
. predictable than morphine
. given orally
.metabolized like morphine through glucuronic acid
physical dependence is necessity of drug so you don't
.go through withdrawal
tolerance and physical dependence is protracted from
.morphine since potency of codeine is low
withdrawal from codeine is mild in relation to
. morphine
Anti tussive drug as phosphate &sulfate salts
 )Heroin )diacetylmorphine

Severely addictive, no therapeutic usage, most

.lipophilic of all the OPIOID
More euphoria, rapidly hydrolyzed, better penetration
.to brain &more rapid acting
IV use: tremor in the lower region of abdomen with
.warmth & itching like sexual orgasm
it is anywhere from 3 to 4 times the analgesic potency
of morphine
When heroin is ingested, it crosses the blood brain
barrier rapidly )morphine crosses slow) where it is
hydrolyzed to monoacetyl morphine )acetyl group
got cleaved off) and then it is hydrolyzed to
morphine making more of the drug in the brain
.making it 3 to 4 times more potent
withdrawal symptoms of heroin similar to morphine,
.)but more intense )rebound effect
mydriasis
diarrhea
vasoconstriction
dysphoria
.etc
 )Hydromorphone HCl )trade name : dilaudid
.Semi synthetic
.times more potent than morphine 5
more sedation than morphine so less euphoric feeling
.so not abused much
.less constipation
.does not produce miosis
tolerance and physical dependence is more intense
. than morphine because of its high potency
.respiratory depression &narcosis > morphine
 )Fentanyl citrate )Sublimaze
synthetic drug active
More lipophilic: 80 - 100 times > morphine, rapidly
. acting drug
.Sympatholytic with the least cardiac depression
Preoperative medication with Butyrophenones as:
.Neurolepanalgesia
.short acting )30-45 min), onset of action is 5 minutes
Transdermal patch
highly abused ,known aschina white as street name
less histamine release than morphine
 Sufentanil citrate

More lipophilic than fentanyl&5-10 times more

.potent
.Safety margin>6
Excellent anesthesia with excellent CVS
.stability
 Carfentanil citrate

.more potent than morphine 10000>

.Hunting wild animals
Intensive care when use, always with an
.antagonist such as: Dipernorphine
 Alfentanil HCl

More lipophilic than Fentanyl but less potency

.&half life
. Redistribution& short action period: infusion
Rapid hepatic metabolism not accumulates in
.body
 Ramifentanil citrate

.times more potent than Fentanyl 20-30

.Half life:7.5minutes
TI:33000
 )Meperidine )Pethideine BP
. Synthetic, efficacy same as morphine
Op: rapid absorption, Sc: pain &irritation, IV
.the best route
.Histamine release& hypotension, spasmolytic
Less fetal respiratory depression: C. section&
.delivery pain
Horse : C. section, colic especially acute colic
.superior to: Xylazine, Dipyrone, Pentazocine
.Cattle: calming nervous heifers
. Safe up to 750 morphine dose
Hepatic metabolism :Normeperidine can cause:
epilepsy &myclonus ,accumulates in body in
renal insufficiency so not suitable for chronic
.use
.Caution in patients receiving MAO inhibitors
.Toxicity: fetal seizure treated with Barbiturates
 :unlike morphine
more respiratory depression
more bronchoconstriction activity
less constipation
no anti tussive activity
)it causes mydriasis )not miosis**
toxic effects similar to atropine
dry as a bone, blind as a bat, red as a beet,
mad as a hatter
have dry mouth
drug absorbed orally
drug most abused by health care professionals
due to its availability
withdrawal similar to morphine
 Methadone
Synthetic substitute for morphine in Germany.
Efficacy similar to morphine, less 1st pass
.effect
. long duration of activity ,cumulative
.Absorbed well orally
.to 20 hour duration of action 16
powerful pain reliever, longer duration but
.milder withdrawal signs
maintenance program for narcotic treatment,
. chronic severe pains
LA substitute: L-α-acetyl methadone )LAAM)
.a single PO dose 2-4 days duration
 Diphenoxylate HCl
.Synthetic ,derivative of Meperidine, OTC drug
Combined with Atropine: Lomotil for treatment
. of severe diarrhea
has very little analgesic properties at therapeutic
. dose , no anti tussive effect
at high doses it has analgesic problems,
. respiratory depression and euphoria
Metabolites: Diphenoxyne, Loperamide: an OTC
.anti diarrhea agent
Caution in coadministration with CNS
.depressants: Barbiturates, tranquilizers
.Very low water solubility: no parental
Intensive entro-hepatic circulation, little
.addictive effect
Don’t use in children less than 2 years
 Etorphine HCl
.Up to1000 times more efficacy then morphine
Combined with Acepromazine )large animal) :
.capturing wild animals
Combined with Methotrimeprazine in small
.animal
Contra indication in human food producing
.animals
Caution when use due to accidental human use
.and death
 Agonist-antagonists
Agonistic effect on kappa while antagonistic
.effect on mu receptors
Nalbuphine HCl
Pentazocine lactate
Butorphanol tartrate
 Nalbuphine HCl
Limited analgesic& respiratory depression , the
.least CVS activity
Used in cardiac diseases & reversion of opioids
.induced respiratory depression
 Pentazocine lactate
Synthetic, no addictive
Efficacy: 25-50% of morphine, Less emesis,
.constipation &respiratory depression effects
.No euphoria& excitation
Cross placenta reach 60% of maternal blood
. concentration
.Used in ophthalmic surgeries
 Butorphanol tartrate
When dose increases response reach a plateau then
.decreases
.Efficacy 4-7 > morphine, similar to Nalbuphine
.Potent cough center depressant
&Combined in H with Detomidine :sedation-analgesia
In small animals: with Tranquilizers as a part of
preanesthetic regimen to control mild to moderate
.pains
.In cat :unlike other opioids no excitatory property
 Partial narcotic agonists
In the presence of Opioids act as Antagonist
.while in their absence act like Agonist
Bupernorphine HCl
Tramadol HCl
Nalorphine HCl
Levallorphane tartrate
 Bupernorphine HCl

A derivative of Thebaine with high affinity for

.Mo receptors
Highly lipophilic, slow attachment –
detachment to opiate receptors: slow onset&
.long acting
Efficacy 30>morphine , little emetic &
.digestive effects
.Appropriate post operative analgesic agent
 Levallorphan tartrate

In the absence of Opioids induces respiratory

.depression
.Antagonist for CNS effects of Opioids
Not only ineffective in reversal of respiratory
depression of : anesthetic agents,
barbitutates& non narcotic agents but also
.facilitates it
 Nalorphine HCl
Administration Sc, Im, Iv but Iv route is the
.best
.Shorter acting than morphine
No constipative, little CVS effects, decrease or
inhibit narcotics induced respiratory
.depression
If 1st dose failed to reverse narcotic effects.
.later doses not recommended
 Tramadol HCl

A metabolite of anti depressant drug:

.Trazodone
Weak agonist of Mu receptors& weak inhibitor
.of NEP reuptake
.Less& better side effects than other Opioids
.Post operative analgesic agent
 Antagonism of Morphine
Naloxane
Naltrexone
Nalmefene
Nalmexone
Dipernorphine
 Naloxane
Competitive antagonist for all opiate receptors except
.)of sigma )also endogenous Opioid angents
.Receptor affinity: Mu> Delta20-30> Kappa
.Antagonistic dose>agonist dose
Duration is 30-45 minutes :must be reinjected every15
. )minutes, effects are immediate )3-5 min
Drug of choice: reverse narcotics induced respiratory
. depression, use in morphine poisoning DX
.Increase catecholamine release: MCF
Antagonizes inhibition of LH secretion due to
.Opioids
 Naloxane advantages in shock
Inhibits hypotension due toβ..endorphine
.Increases catecholamine release
Decreases amount of Myocardial Depressant
.Factor
Decreases release of lysosomal enzymes,
.proteolysis &toxic material production
Totally : increases CVS efficacy in endotoxic
.& hemorrhagic shocks
 Naloxane – drug interaction
:Compatible with
Methoxyflurane
Phenobarbital
Thiamylal
Procaine
Oxymorphone
Morphine
Meperidine
Phenothaizine
 Naltrexone
Same effect of Naloxone except it is used orally so
.can't use it if for person with acute toxicity
.Long duration of action
Single dose block action of heroin effects for 24 hours,
Patient get no euphoric effect from heroin so person
)gets off heroin )negative reinforcement
Used for emergency treatment, once stabilized, give
. patient Naltrexone
.Approved for use by the FDA
.Also used for treatment of alcoholism