This document summarizes opioid analgesics. It discusses the classification of opioid analgesics as natural alkaloids like morphine and codeine, semisynthetic drugs, and synthetic opioids. It describes the structures and actions of various opioid analgesics like morphine, codeine, fentanyl, methadone, and antagonists like naloxone. It also discusses the modes of action of opioid analgesics through opioid receptor subtypes and their effects in reducing neurotransmitter release.

1. OPIOID ANALGESICS
Dr. Anshu Dudhe
Professor,
Nagpur college of Pharmacy, Nagpur

2. NARCOTIC ANALGESICS
AGENTS/OPIOID ANALGESICS
 Analgesia (Pain): It is an illdefined, unpleasant
sensation usually evoked by an external or internal
noxious stimulus.
 Analgesics: These are the drugs tht selectively
relives the pain by acting in CNS or on peripheral
pain mechanism, without significantly altering
consciousness. These are divided into two group
 Opioids/Narcotic/Morphine like Analgesics: Opioid
analgesics are basically opium like alkaloid
obtained from poppy (Papaver somniferum)
capsules.
 Non-opioids/Non-narcotic/ Asprin like Analgesics

3. OPIOID ANALGESICS
 Opium: The dark brown resinous material
obtained from poppy (Papaver sominiferum). It
contain two types of alkaloids.
 Phenenthrene derivatives: Morphine (10% in
opium), Codeine (0.5% in opium), Thebain (0.2%
in opium),
 Benzoisoquinoline derivative: Papaverine (1%),
Noscapine (6%)
 The natural or synthetic agent that was derived
from morphine was termed as opioids or opiatcs..

4.  They are often known as norcotic analgesics due
to their ability to produce drug dependence.
 The other actions which are associated with
narcotic analgesics are sedation and constipation.
In therapeutic doses morphine sometimes
produce nausea or vomiting.
 The related compound apomorphine is a
powerful emetic agent

5. OPIOID RECEPTORS:
 Morphine and other opioids exert their actions by
interacting with specific receptors present on
neurones in the CNS and in peripheral tissues.
The opioid receptors are divided into three types
(μ, κ, δ);
 Opioid ligand can interact with different opioid
receptor can agoinst, parital agonists or
competitive antagonist. Morphine is agoinst on μ,
δ and k (Kappa) receptor but its affinity for μ
receptor is much higher than other two δ and k.

6. Receptor Subtypes Location Agonist
(strong)
weak
(wa)/partialAgo
nist
(pa)/moderate
(Ma)
Antagonist Function
mu (μ) μ1, μ2, μ3
Brain ( Cortex,
Thalamus),
Spinal Cord,
peripheral senso
ry neurons,
intestinal tract
Morphi
ne, beta
Endorp
hine ,
Dynorphin
A,B (Wa),
Buprenorphi
ne &
ButorPhanol(
Pa)
Nalaxon
e,
Naltrexo
ne,
Nalorph
ine
μ1:analgesia
physical
dependence
μ2: respiratory
depression
miosis
euphoria
reduced GI mot
ility
physical
dependence
μ3:possible vaso
dilation
delta (δ) δ1,δ2
Brain (deep
cortex, Olfactory
Bulb),
peripheral senso
ry neurons,
Met/Le
u
Enkeph
aline,
beta
Endorp
hine
Pentazocine
(Pa),
Buprenorph
ine (pa),
Morphine
(Wa)
Nalaxon
e,
Naltrexo
ne
(weak
Antagon
ist)
Analgesia,
Antidepressa
nt effects
Convulsant
effects
physical
dependence
kappa (κ) κ1, κ2, κ3
Brain (
Hypothalamus,
), Spinal Cord,
peripheral senso
Dynorph
in A,B,
ketocycl
azine
Pentazocine
(Ma)
Nalaxone
(Moderate
)
Naltrexone
analgesia
Anticonvulsant
depression
dissociative/hall
ucinogenic effect
diuresis

7. CLASSIFICATION OF OPIOID ANALGESICS
 Natural Opium Alkaloid: Morphine, Codeine
 Semisynthetic : DiacetylMorphine,Pholcodeine,
Hydromorphone,oxymorphone, Oxycodone
 Synthetic Opiates:
 Morphinans: Levorphanol, Butorphanol
 Bezomorphans:Pentazocine
 Phenylpiperidines:Pethidine,Fentanyl
 Diphenylpropylamine-Methadone
 Endogenous opioids: Endorphin, Enkephalins,
Dynorphins
 Mixed Agonist-Antagonist: Buprenorphine (μ agonist,
Kappa Antagonist) ,Butorphanol ((μ antagonist, Kappa
agonist),Pentazocine (Kappa agonist)
 Opioid Antagonist: Naloxane, Naltrexone,

8. O
N
OH
HO
CH3
Morphine

9. Fentanyl

10. STRUCTURE ACTIVITY
RELATIONSHIP
 Morphine is a prototype µ-selective opioid agent.
 Structure is composed of 5 fused rings & has 5 chiral
center haring stereochemistry (5R, 6S, 9R, 13S &
14R)
 Morphine shows both (d) & (l) form out of which l-
morphine is naturally occurring & having analgesic
property while d-morphine is devoid of analgesic
activity.
O
N
OH
HO
CH3
Morphine

11.  In morphine, the ring A & basic nitrogen are
important feature for analgesic property.
 Conversion 3-OH to 3-methoxy group gives
codeine and decrease activity up to 15% of
Morphine.

12.  Conversion 6-OH to 6-methoxy group gives
heterocodeine and increases 6 fold activity of
Morphine.
O
N
OCH3
HO
CH3
Heterocodeine

13.  Esterification of 3 & 6-OH group gives compound
more active than morphine.
 eg: Diacetyl morphine (Heroin) is 2 times active
than morphine.
Heroin
O
NCH3
OCOCH3
H3COCO

14.  The double bond present at 7th & 8th position is
not play an active role is analgesic property.
Dihydromorphine and its derivatives have high
potency but decreased duration of action
O
N
OH
RO
CH3
R = H Dihydromorphine
R = CH3 Dihydrocodeine

15.  Oxidation of 6-OH gives ketones and decrease
actvity.
O
N
O
RO
CH3
R = H Dihydromorphinone
R = CH3 Dihydrocodeinone

16.  Incorporation of an azido group at C-6 shows
increased potency about 40-45 times.
Azidomorphine
O
N
N3
HO
CH3

17.  Removal of 4,5-epoxide bridge from morphine
structure generates a new category of drugs
called morphinans having higher potency than
morphine.
Levorphanal
NCH3
HO

18.  Introduction of 14-OH substituent gave
compound several time more potent as analgesic
as compared to parent compound. e.g.
Oxymorphone.

19.  In case when a morphine molecule lacks the both
epoxide ring & C ring to produce benzomorphans,
which again retains analgesic properties.

20.  Replacement of N-CH3 by N-C2H5 resulted in
only slight fall in analgesic response. More
hydrophobic groups such as propyl, pentyl, hexyl
and phenyl ethyl gave on decrease in activity. N-
Allyl morphine has powerful antagonistic
activity.

21. MORPHINE
 Morphine is principal alkaloid in opium and is widely
used till date.
 Morphine is still obtained from opium as the
laboratory synthesis of morphine is difficult. Codeine
is other alkaloid occurring in opium its amount is too
small to be commercial importance. Thus it is
commercially prepared from morphine by methylating
phenolic OH group at 3 position. Morphine is
powerful analgesic and narcotic. It depress CNS and
it also decresases gastric motility. It increases smooth
muscles tone.
 Morphine is used for symptomatic relief of moderate
to severe pain especially that associated with cancer
and for post operative pain. It is used as hypnotic,
suppression of cough and relief of anxiety. Morphine
is also used in the treatment of diarrhea.

22. CODEINE
 Codeine has less addiction property than
morphine probably due to decreased potency.
 Approximately 5% of codeine is metabolized to
morphine via O-demethylation. The enzyme
responsible for the O-demethylation of codeine is
cytochrome P450 (CYP) 2D6. Codeine is used a
weak analgesic (1/10 as Morphine.
 it is used in the form of syrup as codeine
phosphate for the relief of cough and as a tablet
for relief of mild to moderate pain.

23. MEPERIDINE HYDROCHLORIDE
(PETHIDINE)
 Meperidine was found to have low potency at the
receptor compared with morphine (0.2%)
.Meperidine is used for antispasmodic activity.
Meperidine quickly penetrates the blood-brain
barrier and thus has a quick onset of activity and
a high abuse potential.
 Pethidine is an opioid pain-relief medicine
Pethidine is now less frequently used because
newer, safer opioids are available. Pethidine is
sometimes to used to reduce labour pain in
childbirth.

24. ANILERDINE
 Anileridine is a synthetic opioid and strong
analgesic medication. It is a narcotic pain
reliever used to treat moderate to severe pain.

25. DIPHENOXYLATE HYDROCHLORIDE
 Diphenoxylate is a centrally active opioid drug of
the phenylpiperidine series that is used as a
combination drug with atropine for the treatment
of diarrhea as an antidiarrhoeal agents. it acts by
slowing intestinal contractions.

26. LOPERAMIDE HYDROCHLORIDE
 Loperamide is a medicine to treat diarrhoea. It can
help with short-term diarrhoea or irritable bowel
syndrome (IBS). It is sufficiently lipophilic to cross
the blood-brain barrier, yet it displays no CNS-opioid
effects.

27. FENTANYL CITRATE
Fentanyl injection is used to relieve severe pain during and
after surgery. synthetic opioid, approved for treating severe
pain, typically advanced cancer pain. It is 50 to 100 times
more potent than morphine. It is prescribed in the form of
transdermal patches.

28. SYNTHESIS OF FENTANYL
H2
C N O + H2N
H2
C N N
Hydrogenation
1-benzylpiperidin-4-one aniline
H2
C N
H
N
(C2H5CO)2O
H2
C N N
COC2H5

29. SYNTHESIS OF FENTANYL
HN N
C O C 2H 5
C H 2C H 2C l
-HCl
N N
C O C 2H 5
H 2
C

30. METHADONE HYDROCHLORIDE*
 Methadone oral tablet is a prescription
medication used to treat pain. Methadone is a
synthetic opioid approved for analgesic therapy and
for the maintenance and treatment of opioid
addiction.
 It is available as racemic mixture out of which, R-
enantiomer is more potent than the S-enantiomer.
Methadone is a µ-receptor agonist

31. SYNTHESIS OF METADONE

32. PROPOXYPHENE HYDROCHLORIDE
 Propoxyphene is a derivative of methadone and is
an enantiomerically pure ester
 It is used for for mild or moderate pain, usually
give in combination with either aspirin or
paracetamol.

33. PENTAZOCINE
 Pentazocine injection is used to relieve moderate to
severe pain. It may also be used before surgery or
with a general anesthetic . Pentazocine belongs to the
group of medicines called narcotic analgesics (pain
medicines). It acts on the central nervous system
(CNS) to relieve pain.

34. LEVORPHANOL TARTARATE
 Levorphanol is used to relieve pain severe
enough to require opioid treatment and. It
belongs to the group of medicines called narcotic
analgesics (pain medicines). It acts on the central
nervous system (CNS) to relieve pain.

35. MODE OF ACTION OF OPIOID ANALGESICS
 All 3 types of opioid receptors (μ, κ, δ) show their
action by G-protein coupled receptors located
mostly on prejunctional neurones.
 They generally produces inhibitory modulation
by decreasing release of the junctional
transmitters (NA, DA,5-HT,GABA and
Glutamate)

36.  Opioid receptor activation reduces intracellular
cAMP formation and opens K+ channels (mainly
through μ and δ receptors) or suppresses voltage
gated N type Ca2+ channels (mainly κ receptor).
These actions result in neuronal
hyperpolarization and reduced availability of
intracellular Ca2+ → decreased neurotransmitter
release by CNS and myenteric neurones

38. NARCOTIC ANTAGONISTS
 These are the agents which clinically cancel or
reverse most of the action of the opioid drugs.
They are used therapeutically in the treatment of
the overdose with opioids. These are classified as
 CLASSIFICATION
 Agonist-antagonists (κ analgesics)
 Nalorphine, Pentazocine, Butorphanol,
Levallorphan
 Partial/weak μ agonist + κ antagonist
 Buprenorphine
 Pure antagonists
 Naloxone, Naltrexone, Nalmefene

39. NALORPHINE
O
N
OH
HO
CH2
Nalorphine has a strong µ-receptor antagonistic property whereas moderate κ-receptor
agonistic property. It is mixed opioid agonist–antagonist
It antagonized the depressant action of morphine and other opioids but not those of
barbiturates and other non-opioids. It was introduced in 1954 and was used as an
antidote to reverse opioid overdose and in a challenge test to
determine opioid dependence.
Nalorphine is not used clinically because of dysphoric and psychotomimetic effects.

40. LEVALLORPHAN
 It has mixed agonist antagonist properties. It has
a strong µ-receptor antagonistic property
whereas moderate κ-receptor agonistic property..
Treatment of respiratory depression due to
Narcotic overdose.
O
N
HO
CH2

41. NALOXONE
 Naloxone is a pure antagonist at all opioid
receptor subtypes. Structurally, it resembles
oxymorphone except that the methyl group on
the nitrogen is replaced by an allyl group.
 It is used to reverse the respiratory depressant
effects of opioid overdoses. However, it blocks μ
receptors at much lower doses than those needed
to block κ or δ receptors.
O
N
HO
CH2
O
OH