This document discusses opioid analgesic agents and pain transmission. It begins by classifying types of pain and describing pain transmission through A and C nerve fibers and the pain gate theory. Opioid analgesics like morphine work by binding to mu, kappa, and delta opioid receptors in the dorsal horn and brain to close the pain gate and inhibit pain transmission. Side effects include euphoria, nausea, respiratory depression, and constipation. Tolerance can develop with long term use but physical dependence and tolerance do not necessarily indicate addiction. The structure of morphine is also described and how various modifications can increase or decrease its potency.

1. Opioid Analgesic Agents
By,
Dr.P.Dheen Kumar,M.Pharm,Ph.D.,

2. Analgesics
• Medications that relieve pain without causing
loss of consciousness
• Painkillers

3. Classification of Pain
By Onset and Duration
• Acute pain
– Sudden in onset
– Usually subsides once treated
• Chronic pain
– Persistent or recurring
– Often difficult to treat

4. Classification of Pain
• Somatic
• Visceral
• Superficial
• Vascular
• Referred
• Neuropathic
• Phantom
• Cancer
• Psychogenic
• Central

5. Classification of Pain By Source
Vascular pain
• Possibly originates from vascular or
perivascular tissues
Neuropathic pain
• Results from injury to peripheral nerve fibers or
damage to the CNS
Superficial pain
• Originates from skin or mucous membranes

6. Pain Transmission Gate Theory
• Most common and well-described
• Uses the analogy of a gate to describe how
impulses from damaged tissues are sensed
in the brain

7. Pain Transmission
Tissue injury causes the release of:
• Bradykinin
• Histamine
• Potassium
• Prostaglandins
• Serotonin
These substances stimulate nerve endings,
starting the pain process.

8. Pain Transmission
There are two types of nerves stimulated:
• “A” fibers
and
• “C” fibers

9. Pain Transmission
“A” Fibers “C” Fibers
Myelin sheath
Large fiber size
Conduct fast
Inhibit pain
transmission
Sharp and
well-localized
No myelin sheath
Small fiber size
Conduct slowly
Facilitate pain
transmission
Dull and
nonlocalized

10. Pain Transmission
• Types of pain related to proportion of
“A” to “C” fibers in the damaged areas

11. Pain Transmission
• These pain fibers enter the spinal cord
and travel up to the brain.
• The point of spinal cord entry is the
DORSAL HORN.
• The DORSAL HORN is the location
of the “GATE.”

12. Pain Transmission
• This gate regulates the flow of sensory
impulses to the brain.
• Closing the gate stops the impulses.
• If no impulses are transmitted to higher
centers in the brain, there is NO pain
perception.

13. Pain Transmission
• Activation of large “A” fibers CLOSES gate
• Inhibits transmission to brain
– Limits perception ofpain

14. Pain Transmission
• Activation of small “B” fibers OPENS gate
• Allows impulse transmission to brain
– Painperception

15. Pain Transmission
• Gate innervated by nerve fibers from brain,
allowing the brain some control over gate
• Allows brain to:
– Evaluate, identify, and localize the pain
– Control the gate before the gate is open

16. Pain Transmission
“T” cells
• Cells that control the gate have a threshold
• Impulses must overcome threshold to be sent
to the brain

17. Pain Transmission
• Body has endogenous neurotransmitters
– Enkephalins
– Endorphins
• Produced by body to fight pain
• Bind to opioid receptors
• Inhibit transmission of pain by closing gate

18. Pain Transmission
Rubbing a painful area with massage or
liniment stimulates large sensory fibers
• Result:
– GATE closed, recognition of pain REDUCED
– Same pathway used by opiates

19. Opioid Analgesics
• Pain relievers that contain opium,
derived from the opium poppy
or
• chemically related to opium
Narcotics: very strong pain relievers

20. Opioid Analgesics
• codeine sulfate
• meperidine HCl (Demerol)
• methadone HCl (Dolophine)
• morphine sulfate
• propoxyphene HCl

21. Opioid Analgesics
Three classifications based on their actions:
• Agonist
• Agonist-antagonist
• Partial agonist

22. Opioid Analgesics: Site of action
• Large “A” fibers
• Dorsal horn of spinal cord

23. Opioid Analgesics:
Mechanism of Action
• Bind to receptors on inhibitory fibers,
stimulating them
• Prevent stimulation of the GATE
• Prevent pain impulse transmission
to the brain

24. Opioid Analgesics:
Mechanism of Action
Three types of opioid receptors:
• Mu
• Kappa
• Delta

25. Opioid Analgesics: Therapeutic Uses
Main use: to alleviate moderate to severe pain
• Opioids are also used for:
– Cough center suppression
– Treatment of constipation

26. Opioid Analgesics: Side Effects
• Euphoria
• Nausea and vomiting
• Respiratory depression
• Urinary retention
• Diaphoresis and flushing
• Pupil constriction (miosis)
• Constipation

27. Opiate Antagonists
naloxone (Narcan)
naltrexone (Revia)
• Opiate antagonists
• Bind to opiate receptors and prevent a response
Used for complete or partial reversal of
opioid-induced respiratory depression

28. Opiates: Opioid Tolerance
• A common physiologic result of chronic
opioid treatment
• Result: larger dose of opioids are required
to maintain the same level of
analgesia

29. Opiates
• Opioid tolerance and physical dependence
are expected with long-term opioid treatment
and should not be confused with
psychological dependence (addiction).

30. Opiates
• Misunderstanding of these terms leads to
ineffective pain management and contributes
to the problem of undertreatment.

31. Opiates
• Physical dependence on opioids is seen
when the opioid is abruptly discontinued or
when an opioid antagonist is administered.
– Narcotic withdrawal
– Opioid abstinence syndrome

32. Opiates
Narcotic Withdrawal Opioid Abstinence
Syndrome
• Manifested as:
– anxiety, irritability, chills and hot flashes, joint
pain, lacrimation, rhinorrhea, diaphoresis,
nausea, vomiting, abdominal cramps, diarrhea

33. SAR
Modification to Morphine
33

34. 1.
34
Morphine has5 Chiral centers. Onlythe
Levo(-) rotatory isomer is active

35. 2. TheOHgroup in the phenolic ring and basicNitrogen isneeded for
activity and seenin all potent µagonist.
Activity canbe preserved or enhancedby removing other rings.
Changing-OHto just –Hor -OCH3lowers activity asseenwith
codeine
R=C3
substituent
Activityeffect
-H 10XDecrease
-OH morphine
-OCH3
(codeine)
Decrease
35

36. Morphinans
36
Benzomorphine
4-Phenylpiperidines
Fig: Lossof other rings doesn’t effect analgesicactivity.

37. 37
3. The Nitrogen is mostly tertiary with a methyl substitution in
morphine. The size of substituent on Nitrogen dictates
potency and agonist or antagonistactivity.
4. Reduction of 7,8 double bond increases activity
5. Inclusion of Hydroxyl group at14 increases activity
6. Removalof Hydroxyl at 6 increasesactivity
7. Oxidation of Hydroxyl to keto group at 6 increases activity, if
there is also reduction of 7,8 double bond e.g.. hydrocodone
8. Acetylation ofHydroxyl at 6 increases activity
9. Removal of the ether linkage produces compounds called
morphinans that has increasesactivity.

38. 38
Mu Receptor (m)
*Morphine bindsstrongly
*Activation produces analgesia plus side effects
(respiratory depression, euphoria,addiction)
*G-Protein coupled receptor
*m-Receptor subtypes identified which mayallow separation of analgesiafrom
side effects
*m-Receptorsrelated to all sourcesof painstimuli

39. 39
Kappa Receptor ()
*Morphine binds lessstrongly
*Activation produces analgesia plus sedation
*Insignificant side effects
*Potential target for safeanalgesics(compounds acting asagonists at k, antagonists at m
and no activity at the dreceptor).
*G-Protein-coupled receptor
*k Receptors related to non-thermal pain inducedstimuli

40. 40
Delta Receptor ()
* Morphine bindsstrongly
* Receptor for enkephalins
* Activation produces analgesia plus somesideeffects
* G-Protein-linked receptor
* d receptors related to pain induced stimuli from all sources
Sigma Receptor ()
*Activated by some opoid analgesics(e.g. nalorphine)
* Non-analgesic, non-opoid receptor
* Activation produces hallucinogenic effects
* Thought to be responsible for effects of phencyclidine (PCP)(AngelDust)