1. Pain ,opiate analgesics and antagonists
Dr. Israa

2. Mechanism of pain and nociception
Polymodal nociceptors are the main type of peripheral sensory neuron that responds to noxious stimuli; the majority are non-myelinated C fibers whose endings respond to thermal, mechanical and chemical stimuli.
Chemical stimuli causing pain includes:
Bradykinin
Protons
ATP
Vanilloids (e.g. Capsaicin)

3. Stimuli to these receptors (agonist) open cation channels and causing membrane depolarization and action potential initiation .
Theses receptors are sensitized by prostaglandins which explain the analgesic effect of NSAIDs.
Nociceptive fibers terminate in the superficial fibers of the dorsal horn, forming synaptic connection with transmission neurons running to the thalamus

4. Transmission in the dorsal horn is subjective to various modulatory influence, constituting the “gate control mechanism”
Descending pathways from the midbrain and brain stem exert strong inhibitory effect on dorsal horn transmission.
The descending inhibition is mediated mainly by enkephalin, 5-HT from NRM (Neuclus Raphi Magnus) and noradrenaline which is released from the locus coeruleus .

5. Opioids analgesics causes analgesia partly by inhibiting transmission in the dorsal horn, partly by activating the descending pathways, partly by inhibiting excitation of the sensory nerve terminals in the periphery
C-fiber activity facilitates transmission through the dorsal horn through substance P receptors and NMDA receptors.

7. OPIOID ANALGESICS (NARCOTIC ANALGESICS)
Analgesia: Relief of pain without loss of consciousness.
Opium: Natural extract from Poppy plant used for social and medicinal purpose for thousands of years to produce euphoria, analgesia, sleep and to prevent diarrhea
Opioid drugs: natural + synthetic morphine-like drugs.

8. Opioids analgesics and antagonists
Strong agonists includes:
Alfentanil
Fentanyl
Heroin
Mepridine
Methadone
Morphine
Oxycodone
Remifentanil
Sufentanil.
Moderate agonists includes:
Codeine
Propoxyphene.

9. Mixed Agonists and Antagonists
Pentazocine
Nalbuphine
Butorphanol
Buprenorphine
Opioid Antagonists
Naloxone
Naltrexone
Nalmephine

10. Opioid receptors
The opioid agonists act at specific receptor sites to produce their pharmacological effects.
Opioid Receptors are:
μ (μ1, μ 2)
қ (қ1, қ2, қ3)
δ (δ1, δ2)

11. They are four endogenous opioid-like substances: (which also stimulate opioid receptors)
[Met]enkephalin: Tyr-Gly-Gly-Phe-Met
[Leu]enkephalin: Tyr-Gly-Gly-Phe-Leu
Beta Endorphin: a 31 amino acid peptide with [Met]enkephalin at N-terminal sequence
Dynorphin: a 17 amino acid peptide with [Leu]enkephalin at N-terminal sequence

12. Endogenous Opioid Peptides (Opiopeptins)
Families
Precursors
Peptides
Enkephalins
Proenkephalins
(also known as proenkephalin A)
Met-enkephalin
Leu-enkephalin
Endorphins
Pro-opiomelonocortin
(POMC)
MSH*
ACTH*
β-Lipoprotein*
β-Endorphin
Dynorphins
Prodynorphin
(also known as proenkephalin B)
Dynorphin A Dynorphin B
α-Neoendorphin
Β-Neoendorphin
* Non-opioid peptides

13. Opioid Receptors and their Prototypic Ligands
Receptor type
Representative Ligands
Endogenous
Exogenous
Mu (μ)
(μ1, μ2)
Β-endorphin
Morphine
Delta (δ)
(δ1, δ2)
Met-enkephalin
Etorphine
Kappa (κ)
(κ1, κ2, κ3)
Dynorphin A
Ethyl-keto-cycla-zocine

14. Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors
Drug
Receptor type
Mu - μ
Kappa - κ
Delta - δ
Agonists
Morphine
+++ +
Codeine
Methadone
Meperidine
Fentanyl
Sufentanyl
Partial and Mixed Agonists
Buprenorphine PA
Antagonist (−)
Pentazocine
Antagonist (---)
Antagonists
Nalaxone and Naltrexone
Antagonist (−−−)
Antagonist (−−)
Endogenous Peptides
Met-enkephalin ++
Beta-endorphin
Dynorphin A

15. Three genes have been identified which code for opioid peptides
• Beta endorphin and ACTH
• Enkephalins
• Dynorphins
These neuropeptides are released by stress and appear to modulate the release of other neurotransmitters.

16. Mechanism of Action of opioids
Morphine binds opioid receptors and thus impairs the normal sensory pathways through:
Blockade of calcium channels which leads to decreased release of substance P and glutamate from the 1st neuron of the sensory pathway (in substantia gelatinosa in spinal cord).
Decreased c-AMP which leads to opening of K-channels and hyperpolarization of the 2nd neuron of the sensory pathway.

17. Mechanism of Action of Opioids

19. Effects due to μ-receptor stimulation:
Supraspinal, spinal & peripheral analgesia
Euphoria
Respiratory depression
Miosis
Decreased GIT motility,
Sedation
Physical dependence.
B. Effects due to қ-receptor stimulation:
Spinal and peripheral analgesia,
Dysphoria
Sedation
Respiratory depression (less)
Miosis (less)
Decrease GIT motility
Physical dependence

20. C. Effects due to δ-receptor stimulation:
Spinal analgesia
Respiratory depression
Decrease GIT motility .
They are not true opioid receptors only some opioids react with them .

21. I. Morphine
Effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver.
Metabolism involves glucuronide formation, the product of which is excreted in the urine.

22. A. Effects of morphine
1. Central Nervous System Effects
Morphine has mixed depressant and stimulatory actions on the CNS.
- Depressant effects predominate in man.
- Excitatory effects predominate in cats and
horses.

23. a) Analgesia:
Drowsiness is common
Continuous dull pain relieved more effectively than sharp intermittent pain
Most patients indicate that they can still feel the pain, but that it no longer bothers them
Morphine is an agonist at μ and қ opioid receptors.

24. b) Euphoria and sedation
It is mainly due to activation of μ-receptor
c) Emesis
Morphine directly stimulates the chemoreceptor trigger zone, usually transient and disappear with repeated administration .
d) Antianxiety
e) Miosis (pinpoint pupil).
It is due to stimulation of the Edenger- Westphal nucleus of the oculomotor nerve .

25. f) Cough reflex is inhibited:
This action, surprisingly, does not correlate closely with analgesic and respiratory depressant effect of opiates, and its mechanism of action at receptor level is unclear
Chemical modification (Codiene and Pholcodiene ) the antitussive effect can occur at sub- analgesic dose.

26. g) Respiration depression:
Due to a direct effect on the brain stem respiratory center.
Death from narcotic overdose is nearly always due to respiratory arrest.
It occur at therapeutic doses but not accompanied with cardiac center depression in contrast to other CNS depressant like general anesthetic agents.

27. h) Other effects:
Morphine is a basic drug causes the release of histamine causes the body to feel warm and the face, nose to itch, bronchoconstriction and hypotension .
It also abolishes hunger
It dilate the cerebral vessels and increase intracranial pressure

28. 2. Cardiovascular Effects
Postural orthostatic hypotension due primarily to decreased V.M.C. activity leading to peripheral vasodilation, which may be also due in part to histamine release.
In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.

29. 3. Endocrine Effects
Increases prolactin secretion
Increases vasopressin (ADH) secretion (oliguria).
Decreases pituitary gonadotropin (LH & FSH) secretion.
Decreases stress induced ACTH secretion.

30. 4. Gastrointestinal Effects
It decrease the motility and increase the tone of the intestinal circular muscle and the tone of the anal sphincter , it also causes contraction of the gallbladder and constriction of the biliary sphincter.
Constipation (tolerance does not develop to this effect).
Diphenoxylate and Loperamide can be used in the treatment of diarrhea.
They decrease GIT motility and peristalsis

31. 5. Genitourinary Effects
Morphine prolong the second stage of labor by decreasing the strength, duration and frequency of uterine contraction
Inhibit urinary bladder voiding reflex (sometimes catheterization may be required in some cases )

32. B. Adverse Reactions
Generally direct extensions of their pharmacological actions.
Respiratory depression, apnea
Nausea and vomiting
Dizziness, orthostatic hypotension, edema
Mental clouding, drowsiness
Constipation, ileus
Biliary spasm (colic)
Dry mouth
Urine retention, urinary hesitancy
Hypersensitivity reactions (contact dermatitis, urticaria)
Immunosuppression (recurrent infections)

33. C. Precautions
Respiratory depression, particularly in the newborn and patients with COPD
Orthostatic hypotension
Histamine release (asthma)
Drug interactions (with other CNS depressants)
Tolerance and cross tolerance to other opioids
Benign prostatic hyperplasia(may precipitate urine retention
Dependence (psychological & physical)
Liver disease (accumulation of the drug)
Increase intracranial pressure and head injury (it enhances cerebral ischemia)

34. D. Therapeutic uses: - Analgesia: myocardial infarction, terminal cancer, surgery, obstetrical procedures - Dyspnea due to pulmonary edema - Severe diarrhea.

35. II. Other Opioid (Narcotic) Analgesics
A. Heroin (diacetyl morphine)
μ- agonist
Heroin is more lipid soluble than morphine and about 2½ times more potent
It enters the CNS more readily
It is a schedule I drug and is not used clinically, but it is a drug of abuse.

36. B. Codeine From opium or synthesized by methylation of morphine
Has a much better oral /parenteral absorption ratio than morphine.
Effective for mild to moderate pain, cough, diarrhea.
Metabolized in part to morphine by O-demethylation.
μ- receptor agonist.
Has a more potent histamine-releasing action than morphine.
Dependence liability of codeine is less than that of morphine, .
It is 1/12 as potent as morphine

37. C. Dextromethorphan:
Excellent oral antitussive
No analgesic effect
No GI effects
No respiratory depression

38. D. Meperidine (Pethidine)
Produces analgesia, sedation, euphoria and respiratory depression.
Less potent than morphine, mg meperidine equals 10 mg morphine.
Shorter duration of action than morphine (2-4 hrs).
Meperidine has greater excitatory activity than does morphine and toxicity may lead to convulsions.
Meperidine appears to have weak atropine-like activity.
It does not constrict the pupils to the same extent as morphine.

39. Does not cause as much constipation as morphine
Purely synthetic μ- agonist
Not an effective antitussive agent.
less effect in uterine contraction commonly employed in obstetrics also causes less urine retention
Adverse reactions to Meperidine
Respiratory depression
Tremors
Delirium and possible convulsions
Dry mouth
Severe reaction if given with MAOI, consists of excitement, hyperthermia and convulsions; it is due to accumulation of pethidine (norpethidine) metabolite but the details are still unclear.

40. E. Fentanyl
μ- agonist, related chemically to meperidine.
Approximately 80 times more potent than morphine, main use in anesthesia .
Duration of action very short (t1/2 = 20 min).
Can be given IM, IV, transdemally or via patient controlled infusion system and may be given intrathecally.
Often used during cardiac surgery because of its negligible effect on the myocardial contractility.

41. F. Sufentanil
A synthetic opioid related to fentanyl.
About 7 times more potent than fentanyl.
Has a slightly more rapid onset of action than fentanyl.

42. G. Methadone
Pharmacology and analgesic potency similar to morphine; μ- receptor agonist.
Very effective following oral administration.
Longer duration of action than morphine due to plasma protein binding (t1/2 approximately 25 hrs).
Used in methadone maintenance programs for treatment of opioid addicts and for opiate withdrawal syndrome (it reduces the physical abstinence syndrome) make it possible to wean the addict from opioids.

43. H. Propoxyphene
A methadone analog.
Used orally to relieve mild to moderate pain, it is weak analgesic; often combined with Paracetamol.
Has a low addiction potential
The most common adverse effects are: dizziness, drowsiness, and nausea and vomiting.
CNS depression is additive with other CNS depressants (alcohol and sedatives).
Can cause cardio- toxicity and pulmonary edema which can not reversed by naloxone

44. III. Mixed Narcotic Agonists/Antagonists
These drugs produce analgesia, but have a lower potential for abuse and do not produce as much respiratory depression.

45. A. Pentazocine
μ agonist (analgesia) and - қ- antagonist (less respiratory depression).
Orally, it has about the same analgesic potency as codeine.
Adverse reactions: Nausea, vomiting, dizziness, dysphoria, nightmares & visual hallucinations.
Rarely used nowadays

46. B. Nalbuphine
Resembles pentazocine pharmacologically.
Like morphine, nalbuphine reduces myocardial oxygen demand. May be of value following acute myocardial infarction due to both its analgesic properties and reduced myocardial oxygen demand.
Most frequent side effect is sedation.
Less propensity to produce psychotomimetic side effects

47. Resembles pentazocine pharmacologically.
C. Butorphanol
Resembles pentazocine pharmacologically.
3.5 to 7 times more potent than morphine.
Not available for oral administration
They exhibit ceiling of respiratory depression effect
"ceiling effect" for respiratory depression, meaning that once dosages increase past a certain level, no increase in respiratory depression is seen. Therefore, these drugs are theoretically safer than drugs that do not exhibit this property.

48. D. Buprenorphine
A partial agonist at μ-receptor.
200 times more potent than morphine.
Low potential abuse, but can precipitate withdrawal in addicts
In naive persons it acts like morphine
Major use is office-based detoxification of opioids
Causes less sedation, respiratory depression and hypotension even in high doses.

49. IV. Opiate Antagonists
Opiate antagonists have no agonist properties. They are utilized to reverse opiate induced respiratory depression and to prevent drug abuse.
A. Naloxone (Narcan)
Pure opiate antagonist at all opioid receptors
Given parenterally -Short duration of action (1-4 h)
Can precipitate withdrawal in addicts.

50. B. Naltrexone
Oral pure opioid antagonist
Long duration of action
Contraindicated in liver disease
Used in late stages of opioid addiction treatment ( also in treatment of alcoholism).
C. Nalmephine
Long-acting parenteral opioid antagonist.