Opiod Analgesics

• Analgesics- substance that relieves

pain
• Narcotic analgesics are drugs that
can relief pain without causing
narcosis (loss of consciousness)
 Uses
• Choice of drugs for managing chronic pain as
with cancer or RA
• Used as inducing agent (fentanyl) or analgesic
supplement with General anesthetics
• They have clinical use as anti-diarrheal and
antitussive eg Loperamide and
Dextromorphan
• Some opioids such as methadone and
buprenorphine are used to counter addiction of
more potent opioids such as heroin
• Opium - is a Greek word meaning “juice,” or the
extract of seeds from the poppy Papaver
somniferum
• Morphine was the first Narcotic analgesic isolated
from opium which contains over twenty distinct
alkaloids
• Opiates – synthetic/natural compounds both
structurally and pharmacologically similar to
Morphine
• Opiods – synthetic/natural compounds not
structurally but only pharmacologically similar to
Morphine
 Pain and its types
• Pain is an uncomfortable/unpleasant physical
or psychological sensation in the body.
• Pain is a good thing. It warn us of something
damaging our body so we take proper medical
care
• However, constant pain can reduce quality of
life
 Pain has a psychological side .
Once you accept pain, it may not be painful
anymore
• Acute pain : sharp, short term pain
– Surgery, Broken bones, Burns, Sprain, Labor
It is cured if the caused of the pain is removed
or treated
• Chronic pain: dull, long term pain
– Cancer, arthritis, chronic back pain and knee pain,
Migraine
Pain exists for months even when the injury is
healed. Cause not well understood
 How do we feel pain?
• Pain receptors or Nociceptors are found on the free nerve
endings of primary sensory fibers that detect unpleasant
stimuli and pass the information to CNS to be interpreted as
pain
• They are distributed all over the body (skin, muscles, joints,
internal organs but not brain)
• When tissue gets damaged by certain (mechanical, thermal or
chemical) stimuli, it releases inflammatory mediators (eg
bradykinin, serotonin, prostaglandins, cytokines, and H+)
which can activate primary nociceptors
• When these neurons reach the spinal cord, they pass the pain
signal to 2ndary sensory fibers located around the spinal cord
where key NT is substance P.
• The 2ndary sensory fibers transmits information to brain
where it is interpreted as pain.
 Ways to relieve Pain
• GA – affect chemical component of neuro
transmission ( GABA n NMDA receptor)
• LA – block electrical component of neuro
transmission (VG Na+ channel) (especially for
pain)
• NSAIDS – Block local pain messenger such as
prostaglandin
• Opiods- block both chemical and electrical
component of nerve transmission
Except NSAIDS all three are CNS depressents
 Analgesic receptors
• Body has mechanism to naturally relief pain
• There are three types in brain and spinal cord
• µ (mu) --> most widely occurring and target
of most drugs
• Κ (kappa) --> lack respiratory depressing effect
and can counter analgesic effect of µ agonist
• δ (delta) --> reduced GIT motility, respiratory
depression, convulsant effect limited clinical
use
• Only µ and Κ have clinical use
 Mechanism of action
• Opiod analgesic agonize opiod receptors µ,κ and δ
which are G-protein couples receptors. This leads
to a series of event which ultimately block neuronal
pain transmission by:
1. Inhibition of activation of voltage gated Ca+2 channels
which depresses NT release
2. Increases K+ conductance outside the cell to cause
hyper polarization of cell thus reducing it’s excitability
3. Inhibtion of adenyl cyclase
(adenyl cyclase--> cAMP --> PKA --> phosphorylation of
ion channels --> increase chances of channel opening)
Three effects of opiod receptors
 Opioids - Classification
1. Natural Opium Alkaloids: Morphine and Codeine
2. Semi-synthetic: Buprenorphine, Oxycodone, Diacetylmorphine(Heroin)
3. Synthetic Opioids:
• 4-Phenylpiperidines: Loperamide and Fentanyl and Meperidine
• Diphenylpropylamine derivatives: Loperamide and Methdone
• Benzomorphans: Pentazocine, Phenazocine
• Morphinan : Levorphanol and Butorphanol

4. Endogenous opioid : natural pain relieving peptides of the body,

such as endorphins, enkephalins and dynorphins
5. Miscellaneous : Tramadol, Meptazinol
 SAR
Modification to Morphine
1. Morphine has 5 Chiral centers. Only
the Levo(-) rotatory isomer is active
2. The OH group in the phenolic ring and basic
Nitrogen is needed for activity and seen in all
potent µ agonist.
Activity can be preserved or enhanced by
removing other rings
Changing -OH to just –H or -OCH3 lowers
activity as seen with codeine

R= C3 Activity effect
substituent
-H 10X Decrease
-OH morphine
-OCH3 Decrease
(codeine)
 Morphinans
Benzomorphine

4-Phenylpiperidines

Fig: Loss of other rings doesn’t effect analgesic activity.

How many chiral centres?
3. The Nitrogen is mostly tertiary with a methyl
substitution in morphine. The size of
substituent on Nitrogen dictates potency and
agonist or antagonist activity.
a) Increasing size from methyl (ie 1 C) to 3 or 5
carbon (especially with double bonds or
small cyclic/aromatic rings) results in
antagonist activity
b) Still larger substitution restores agonist
activity in more potent form
•If R = 3-5 carbons then µ antagonist effect
(more valid if presence of double bond or Small carbo-cyclic ring)
•If R = > 5 carbon (in chain or ring ) then increased µ agonist effect
R= Nitrogen effect
subtituent
CH2CH=CH2 Becomes µ antagonist
(3 C with
double bond)

CH2CH2Ph µ agonist (10X more potent than

(Total 8 C) morphine)
4. Reduction of 7,8 double bond increases
activity
5. Inclusion of Hydroxyl group at 14 increases
activity

Activity
Activity
increases
increases

7,8 Reduction of double bond

OH at C14
to single bond
6. Removal of Hydroxyl at 6 increases activity
7. Oxidation of Hydroxyl to keto group at 6 increases activity, if
there is also reduction of 7,8 double bond eg hydrocodone
8. Acetylation of Hydroxyl at 6 increases activity

R= C6 substituent Effect in activity

H increase
=O (keto) Decreases
=O (keto) with 7,8 redcution (change Increases (10X more potent than
double bond to single) morphine

H3CC=O (acetyl) Increase

9. Removal of the ether linkage produces
compounds called morphinans that has
increases activity

No ether linkage

Activity increases

Levorphanol (10X potent than morphine)

 Morphine
• It is a naturally occurring analgesic alkaloid extracted from
opium of poppy plant
• Modification to it’s structure has resulted more potent
compound
• Used in chronic pain management
• It’s 3-O-glucoronidation metabolite is inactive
• But it’s 6-O-glucoronidation form is active and thus
does
reduction is needed in case of renal damage (coz it’s rate of
clearance is reduced)
• It is potent enough that it’s 60mg oral dose has analgesic effect
equal to parental administration
• MOA: agonizes µ receptor which depresses pain signals by
• inhibiting VGCC and prevent release of Neurotransmitters
 Codeine

• It is weak µ agonist formed by modification of 3OH

in morphine into H3CO. This results in loss of activity.
Thus codeine is used in moderate to mild pain only.
• It s metabolic product is morphine and thus abused
by addicts.
• The does requires to produce analgesia after
parental dose causes release of histamine that in
turn causes allergic responses. Thus not used
parenterally
• Use limited as antitussive drug
Heroin

• It is 3,6-diacetyl derivative of morphine

• By itself is a weak U agonist but the diacetyl form
increases its lipophilicity and enhances its
penetration into brain
• Also it metabolic product, 6 acetyl morphine, is more
active than morphine
• These two factors make it more potent than
morphine but it’s use it limited by extreme addiction
to it (more potent = more addictive)
Meperidine

• It is a 4-Phenylpiperidines based derivative of

morphine
• A weak µ agonist, 1/10th as potent as
morphine
• Doesn’t inhibit cough
• rapid onset of action but high 1st pass
metabolism
• Thus used in obstetrics, where given in small does
to mother it won’t cause respiratory depression
to the newborn
Fentany
l
• It is a 4-(Phenylpropionamido)piperidines
based derivative of morphine
• It is about 80 times more potent than
morphine
• It Does not cause histamine release on IV
injection (ie no skin inflammation)
• It Inhibits p-glycoprotein mediated efflux of
digoxin (ie increases conc of digoxin in blood)
Buprenorphine

• It has a mixed Agonist/antagonist effect

• It produces 50% analgesic effect about 20-50
times than morphine but can NEVER produce
100% effect
• Potent Partial agonist of µ and κ receptor but
antagonizes δ receptors
• Advantage of less severe respiratory depression
and less incidence of tolerance or addiction
• Used to block effects of high dose of heroin
Pentazocine

•A mixed agonist/antagonist effect

(µ antagonist and κ agonist)
• weak analgesic effect - 1/6 as potent
as morphine
• Since it is a κ agonist it produces dysphoric effects
and also increases blood pressure and heart rate
• Abused drug – when injected with
tripelennamine (an antihistaminic) it increases
euphoric effect and decreases dysphoric
effect
Tramado
l
• not a true opiod analgesic
• (+) isomer has activity 1/3800 that of morphine!
• (-) isomer blocks norepinephrine and serotonin
(excitatory NT) reuptake and thus show some
analgesic activity. But the effect is weak
• It’s metabolite is active and 1/35 as effective as
morphine.
• Non-addictive, no respiratory depression or
constipation
• Used with other analgesic for synergistic
Naloxon
e
• It is a strong opiod antagonist
• High affinity for µ but low affinity for κ and δ
• It is used as a emergency drug to counteract life-
threatening depression of the CNS and
respiratory system due to morphine or heroine
overdose
• It itself is not anxiolytic but can potentiate the
subtherapeutic dose of the anxiolytic drug
busiprone (ie less does of busiprone can be given)
Preparation of Morphine from Poppy plant
1. 10-15 kg of raw opium plant is boiled with 115 kg of water.
The opium alkaloids are eventually extracted into the
boiling water

2. calcium hydroxide, Ca(OH)2, is added to the solution. This

converts the water insoluble morphine into the water
soluble calcium morphenate. Codeine is slightly water
soluble and gets carried over with the calcium morphenate
in the liquid.
The other opium alkaloids are neither water soluble nor
react with the lime to form soluble calcium salts.
They are filtered off and now there is only morphine
salt and
codeine in the solution
4. The clear liquid is filtered and reheated and
Ammonium chloride (NH4Cl) is added to adjust the
alkalinity to a pH of 8 to 9, and the solution is then
allowed to cool. Within one or two hours the salt
form of morphine turns into insoluble neutral form
and precipitate out of the solution

5.The solution is filtered and the residue

containing the morphine is dried in the sun.
When dry, the crude morphine base is a coffee-
colored powder.
Approximately 13 kg of opium, from one hectare of
opium poppies, are needed to produce 1.3 kg of
morphine
1) Morphine + Ca(OH)2 = calcium morpheate

2) Calcium morpheate + NH4Cl = CaCl2 + NH3 + neutral morphine

 Physical dependence/Addiction to
narcotics
• All forms of drug addiction are driven by
stimulation of brain’s self-reward system
• Self reward system refers to activity of
neurotransmitter Dopamine(DA) which has
euphoric effect (intense feelings of happiness,
excitement, and joy)
• Any Drug that concentrate DA in the synapse
by
– stimulate DA release,
– Inhibit DA reuptake or
– Inhibit DA degradation have addition potential
• µ agonist stimulate release of DA, ie causes
euphoria, whereas κ agonist prevent DA
release ie causes dsyphoria (this effect limited
its clinical use)
• Cocaine prevents reuptake of Dopamine at the
synapse and thus prolong the duration and
intensity of reward response
• But the self reward system is self-limiting ie after
prolonged or repeated activation feedback mechanism
blocks the euphoric effect. Thus the effect lasts for
a short while but with opiods, the euphoric effect is
very intense. This short but intense feeling of
happiness is termed as “euphoric rush” and is very
addictive.
• Drugs that slowly distribute to the brain have less
addiction potential because the feedback system can
respond quickly
• Only fast distributing drugs, that are potent too, are
successful to cause a “euphoric rush”
• Distribution into the brain is governed by the
lipophilicity and thus abused drugs are very lipophillic
to allow quick distribution and quick action.
• Also route of administration is lungs or IV to cause
quick distribution (thus oral dosage has less addiction
 Tolerenc
e
• Tolerance means the need for higher doses to
produce same level of effect
• When an agonist binds to µ receptor,
– G second messenger proteins are activated
– and adenyl cyclase are inhibited
• On continuous binding, tolerance develops
due to
– Decreases synthesis of G protein subunits
– upregulation of adenyl cyclase to compensate the
decreases cellular levels of cAMP.
 Withdrawal
• Stopping intake of opiods produces unwanted
physiological effects called withdrawal symptoms
• Within 24 hrs following effects are seen
– muscle aches, restlessness, anxiety, lacrimation (eyes
tearing up) runny nose, excessive sweating, inability
to sleep
• After 24 hrs more intense effects are seen
– Diarrhea, high BP, nausea, vomiting rapid, heart beat
• Cells resist opiod mediated decrease in adenyl
cyclase by upregulating (increases
production) adenyl cyclase.
• If opiods are withdrawn, this upregulated
adenyl cyclase in turn generates more cAMP.
• This increased cellular levels of cAMP causes
many abnormal effects
 Revision
• Body has pain receptors that recognize pain
stimuli

• But Opiod analgesics don’t work by blocking

these pain receptors
• Body also has opiod receptors (anti- pain
receptors)

• Opiod drugs bind to them and strengthen

their anti pain functions (ie they agonize opiod
receptors)
• Blocking pain receptors can also produce
analgesic effect but…..

• …….No analgesic drugs exist that block pain

receptors
• The reason for addictive nature of opiods is
not because they help manage pain

• But because they cause euphoria through

stimulation of dopamine
• There are 3 opiod receptors: µ (mu), κ (kappa),
δ (delta)
• Most clinical analgesic bind to µ

• κ has dysphoric (extreme depression) effect

• δ has high respiratory and convulsive effects

• µ agonist promotes dopamine release that
causes addiction

• κ agonist blocks dopamine release leading

to extreme depression that can cause
suicidal tendency

• δ agonist do not exist

seems like we are stuck with addictive

analgesics!!!
 Mixed agonist/antagonist
Q) How can some opiod drugs be both an
agonist and antagonist at same time?
Ans. There is not 1 but 3 opiod receptors.
It is possible to Agonize at one opiod receptor
and Antagonize another opiod receptor
Eg Buprenorphine is agonist of µ and κ receptor
but antagonizes δ receptors
Q) Are people addicted to opiod
analgesics for their pain managing
effects?
Ans) No. Opiod drugs potentiate the
effects of dopamine at the synapse.
Dopamine is a neurotransmitter that can
induce euphoria which is an intense feeling
of happiness, excitement, and joy. The
addiction is for this euphoric effect.
 Q) Why do addicts prefer IV or
inhalation than oral route?
Ans) With oral route, there is 1st pass
metabolism and slow absorption. Thus the
drug does not accumulate in brain quickly or
at enough concentration to produce the level
of euphoric rush that other routes can do
because they bypass 1st pass metabolism and
directly put drug in blood.
Q) What are the two important characteristics of
drugs that cause addiction?
i) Their receptors must be involved in
potentiating dopamine effects at the synapse
ii) They must have access to the brain ie must
be lipophillic enough to cross the BBB
Q) Heroine is only 1/10th as potent as morphine.
So why do addict prefer heroine than more
potent morphine?
Two reasons
• Heroine is more lipophilic than morphine ie
quicker BBB penetration
• It’s metabolite is more potent than
morphine
• These two factors work together to provide a
intense and quick occuring ‘euphoric rush’
that addicts seek
 HOMEWORK
Rank potency of these compounds
 Future of analgesics : addiction free age

• Recycling opiod receptors

• +Naloxone TLR4 receptors
• Nav1.7 receptors
• P2X receptors
• Glial cells
• Snail cone venom
• Opiorphin
 Recycling opiod targets
• κ agonists that don’t penetrate the brain but
act on peripheral NS don’t cause dysphoria
and are a promising approach since they have
no addiction potential

• Ref : Clin J Pain Volume 26, Number 1, January

2010 Supplement
 +Naloxone and morphine

• + Naloxlone has no activity on opiod receptors

• Research indicates that cause of opiod
addiction involves other receptors beyond
opiods
• It antagonizes toll-like receptor 4 (TLR4)
• Given together with morphine, it has shown
to reduce addiction of morphine without
interfering it’s analgesic activity
• Ref: J Neurosci. 2012 August 15; 32(33): 11187–11200
 P2X7 receptors

• P2X receptors are ATP-gated ion channels

whose roles is in pain following nerve damage
and inflammation.
• Inhibiting a subtype, P2X7 seems to cure
– tactile allodynia (pain caused by touch)
– chronic inflammatory pain in animal model
 Role of Glial cells in pain signalling
• Glial cells are non-neuronal cells that maintain
homeostasis, form myelin, and provide support
and protection for neurons in the brain and
peripheral nervous system
• Neuroscience currently identifies four main
functions of glial cells:
• To surround neurons and hold them in
place
• To supply nutrients and oxygen to neurons
• To insulate one neuron from another
• To destroy pathogens and remove dead
neurons.
• They also have function in glutaminergic and
dopaminergic release pathways

• If morphine can be given with drugs like

AV411, that block glial cells, then no side
effects of morphine can be seen
• Systemically active human opiorphin,which protects
enkephalins from degradation, is a potent yet non-
addictive analgesic without drug tolerance effects

• Ref: J Physiol Pharmacol. 2010 Aug;61(4):483-90.

 What is obstacle in new analgesic
drugs research?
 Bad interpretation from animal models
A 2013 research found Oreo biscuits were more
addictive than cocaine in rats!
 drugs did not penetrate correct compartment
in man
 Invalid target
 Inappropriate patient population for
mechanism
 Animal based study of anti-inflammatory effect

First Induce inflamation

Then give drug n check if

Inflamation is reduced or not
 Effective drugs for Neuropathic pain
Neuropathic pain chronic pain due to damaged
nerves it is described as sensation of burning,
stabbing, shooting or like an electric shock.
NSAIDS are useless in this case
Useful drugs are
• Pregabalin – anticonvulsant
• Amitriplline – tricyclic
antidepressants
• Duloxetine – antidepressant