1. Drugs Used in Management of pain
DR: Asmaa Fady.
MD., MSC, M.B, B.Ch
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2. Learning objectives: Objectives of the lecture:
At the end of this lecture the student should:
Revise how pain is perceived and modulated, emphasizing on neurotransmitters, receptors, channels involved.
Classify drugs used in management of pain.
Expand on pharmacology of opiates, patterns of classification, mechanism of action, indications, ADR,…etc. detailing on morphine as an example.
Compare in brief actions and indications of other opiate agonists and antagonists
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3. Pain
An unpleasant sensory or emotional experience initiated by a harmful (tissue damaging or noxious) stimulus.
The sensory nervous system perception of such stimuli is termed “Nociception”.
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4. اسم ورقم المقرر – Course Name and No.
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5. Periaqueductal Grey Matter Substantia Gelatinosa
Somatosensory Cortex
 Perception of Pain
Cingulate Cortex
 Affective component of Pain
Enkephalines, NE, GABA
Thalamus
PAIN Transmission
& Processing
Periaqueductal Grey Matter
Dorsal Root Ganglion
Pain signals
Substantia Gelatinosa
Substance P- glutamate
Spinal
Cord
Noniceptors
Prostaglandins, Bradykinins, 5HT, Histamine
Stimulus

6. Key mediators of nociception:
Mediators that activate nociceptors (ascending pathway) are:
Bradykinin
Prostaglandins
Substance P
Glutamate
Mediators that act to reduce the perception of and response to pain (descending pathway):
Endorphins (e.g. Enkephalin)
Monoamines (e.g. serotonin, norepinephrine).
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7. Drugs used in management of pain (Analgesics):
Drugs used to treat mild or moderate pain (non opioids)include:
Paracetamol
NSAIDs (e.g. Aspirin, Ibuprofen, naproxen)
Drugs used to treat severe pain are opioids (e.g. morphine)
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8. Drugs used in management of pain:
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9. Pharmacological classification of analgesics
Analgesics :These are drugs that relieve pain without loss of consciousness or other sensations by CNS Effect.
Classification of Analgesics:
A) Central Analgesics = Proper Analgesics:
1- Narcotic (opioid) Analgesics e.g. Morphine.
2- Anti-Pyretic Analgesics (non-steroidal anti- inflammatory drugs = NSAIDs.) e. g. Aspirin.
B) Peripheral Analgesics = Not Proper Analgesics:
a- Nitroglycerine in Anginal pain.
c- Antacids in Peptic ulcer.
d- Antispasmodics e.g. Atropine in colic.
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10. Narcotic (Opioid) Analgesics
These are drugs that relieve pain centrally, but in large dose they cause stupor & drowsiness, & on long use they produce tolerance & dependence.
Classification of Narcotic Analgesics
Opioid Agonists (morphine)
Opioid Antagonists (naloxone)
mixed Opioid Agonists antagonist (Buprenorphine): agonist on kappa & delta , antagonist om mu
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11. Classification of Narcotic Analgesics
A- Opioid Agonists:
I- Natural (Phenanthrene Opium Alkaloids) :
a- Morphine
b- Codeine = methyl morphine.
II- Semisynthetic Morphine (phenanthrene) Derivatives:
a- Di-acetyl-morphine (Heroin).
b- Di-hydro-morphinone
c- Di-hydro-codeinone
III- Synthetic Morphine Substitutes:
a- Meperidine b- Fentanyl
c- Methadone d- tramadol
B- Mixed Agonist-Antagonist Narcotic Analgesics:
a- Pentazocine b- Buprenorphine
c- Nalbuphine d- Butorphanol
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12. opioids
Derived from the dried milky juice  exuded by incised seed capsules of a species of poppy, Papaver somniferum,
Mimic action of endogenous
opioids; Endorphins.
Act on endogenous opioid
receptors mu, delta, kappa,
sigma
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13. Morphine -pharmacokinetics
1- Absorption: a- well absorbed Orally, But 1st pass hepatic metabolism. b- Better absorbed after S.C. & I.M. injections. c- In shock (Slow Diluted I.V. injection). 2- Distribution: All over the body & passes B.B.B.& Placental Barrier: a- During pregnancy (Addiction of Fetus). b- During labor Neonatal asphyxia
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14. Morphine -pharmacokinetics
3- Metabolism:
a- Extensive Hepatic First Pass Metabolism.
b- Conjugated with Glucuronic acid (Deficient in extremities of age) and converted into:
- Morphine-6-Glucuronide More Active than Morphine.
- Morphine-3-Glucuronide Inactive.
4- Excretion:
a- Saliva.
b- Stomach Stomach wash in all cases of poisoning.
c- Bile Enterohepatic circulation.
d- Milk Affect suckling baby.
e- Urine Major route of excretion.
5- t ½ : (2 – 3 hours) & Duration of action (6 – 8 hours).
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15. Morphine –pharmacodynamics mechanism of action
Morphine stimulates specific Opioid = Opiate receptors in CNS & Periphery. Types of Opiate (Opioid) Receptors: (CNS_ Smooth ms) 1- Mu (1 & 2): Analgesia (Spinal & Supra-spinal), Euphoria, Sedation, Dependence, inhibition of R.C., Miosis & Constipation. 2-Kappa (1, 2 & 3): بس أضعفAnalgesia (Spinal & Supra-spinal), Dysphoria, Less inhibition of R.C. & Less Miosis. 3- Delta (1 & 2): Analgesia (Spinal mainly) & Constipation. 4- Sigma: Dysphoria & Hallucination. 
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16. Morphine –pharmacodynamics mechanism of action
Mechanism of Opiate (Opioid) Receptors:
1- They are membrane receptors coupled to Gi-protein:
2- Inhibit Adenylate cyclase Decrease cAMP.
3- Open K+-Channel (postsynaptic) Hyperpolarization.
4- Block Ca2+-Channel (presynaptic) Decrease Release of transmitters & mediators.
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17. Pharmacological Actions of Morphine
1- CNS: depression & stimulation of certain parts:
1-Analgesia all types of pain except itching
1-Euphoria
2-Narcosis
2-Excitation in some females & Animals
R.C. : Hypoventilation & Hypoxia
3- 3rd Cranial nerve Miosis (PPP)
4- Cough center : Antitussive
4- Vagal center (CIC) Bradycardia
5- V.M.C. : Hypotension
5- C.T.Z. (Small dose) Nausea & vomiting
6- H.R.C. : Hypothermia
6- A.D.H.
7- Hormones: ACTH, FSH & LH.
8- Lowers seizure threshold Epilepsy
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18. Analgesic effect of Morphine:
a- Effective in all types of pain especially Deep visceral pain.
b- Not effective in itching. Morphine is a Histamine- releaser.
c- Morphine affects pain perception & integration:
- Inhibits Release of Substance-P & Glutamate in Substantia gelatenosa Inhibits pain transmission.
- Sensory cortex Inhibits Pain perception.
- Frontal cortex Alters psychological reaction to pain Indifference.
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19. Pharmacological Actions of Morphine
2- A. N. S.: Sympathetic (inhibit VMC) & Parasympathetic (stimulate CIC). 3- Eye Miosis Pin Point Pupil (PPP) 4-C. V. S. Bradycardia & Hypotension a- Inhibit VMC & Stimulate Vagal center (CIC) b- Direct Venodilator effect. c- Release of Histamine V.D.
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20. Pharmacological Actions of Morphine
5- Respiratory System: - Depresses R.C. - Depresses Cough center Central Antitussive. - Histamine release Bronchospasm especially in susceptible asthmatic patients. 6- Smooth muscle Spasmogenic effect (except Bv). 7- G. I. T. : contract circular muscle and relax longitudinal ms. a- Spasmogenic decreases Propulsive peristalsis & increases Segmental contraction Constipation b- Decrease All secretions (except salivary).
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21. Pharmacological Actions of Morphine
8- Biliary Tract Spasmogenic Spasm of biliary duct &Sphincter of Oddi Increase Intrabiliary pressure.
- Avoid after cholecystectomy.
- In biliary colic Add Atropine to Morphine
9- Urinary Tract Spasmogenic Spasm of Ureter In renal colic Add Atropine to Morphine.
Spasm of sphincters Retention of Urine
Oliguria Increased A.D.H.
10- Uterus: No effect but Morphine passes placental barrier Neonatal asphyxia.
11- Skin: Histamine release Itching
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22. Therapeutic Uses of Morphine
1- Pain : Analgesic in Severe Visceral Pain except itching. a- Cardiac pain e.g. Myocardial infarction b- Cancer pain especially in terminal stages c- Colic: Add Atropine in Biliary & Renal colic. d- Bone Fractures (Except Skull, Morphine is contraindicated in Head injury). e- Postoperative: Except Biliary. 2- pulmonary Edema due to Acute Left Ventricular Failure: a- Venodilator. b- Sedation c- Slow respiration. 3- Primary Neurogenic shock. 4- Preanesthetic medication.
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23. Contraindications of Morphine:
1- Head injury: a- Miosis Interfere with proper diagnosis. 2- Increased Intra-cranial tension. 3- Epilepsy. 4- Respiratory diseases e.g. Asthma & C.O.P.D. 5- Acute abdomen: Morphine Interfere with proper diagnosis. 6- Pregnancy & Labor. 7- Liver disease (Deficient metabolism) 8- Extremities of age (Deficient metabolism) 10- Alone in biliary & renal colic. 11- Allergy to morphine.
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24. Adverse Effects of Morphine:
1- Interfere with proper diagnosis of Head injury & Acute abdomen. 2- Inhibition of Respiration 3- P.P.P. (pin point pupil) 4- Nausea & Vomiting 5- Bronchospasm 6- Constipation 7- Retention of urine 8- Neonatal asphyxia 9- Itching 10- Tolerance (all effects except miosis & constipation) 11- Acute Morphine Poisoning. 12- chronic Toxicity (addiction)
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25. Acute Morphine Poisoning
a- Manifestations:
Coma + PPP + Hypoventilation, Hypoxia, Hypotension & Hypothermia.
b- Cause of Death :
Respiratory Failure.
c- Treatment:
- Artificial respiration.
- Stomach wash in Every case even after parenteral poisoning.
Use K-Permanganate + Charcoal + MgSO4.
Specific Morphine Antagonists e.g. Naloxone (0.4 mg I.V.).
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26. Opioid antidote (antagonist): naloxone
Pure antagonist. More selective on mu receptors.
Therapeutic uses:
a- Acute Morphine poisoning ( 0.4 mg I.V.) to be repeated due to Short t ½ = 1 hour
b- Opioid-induced Neonatal asphyxia Mother (IM) or Neonate (Intraumbilical).
c- Diagnosis of Opioid addiction S.C Withdrawal manifestations e.g. Mydriasis
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27. Other Opioids: Methadone
1- As potent as Morphine. 2- Longer t ½ = 1 – 2 days Less withdrawal manifestations. 3- Local anesthetic effect. 4- Uses: a- Analgesic in Severe visceral pain e.g. Terminal cancer. b- To substitute Morphine & Heroin during their withdrawaL.
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28. Other opiods: Meperidine ( Pethidine)
Synthetic
Strong agonist : Morphine-Like + Atropine- Like
( No P.P.P. may cause Mydriasis, No Constipation, No Narcosis (No Hypnosis).
Uses:
1- Severe Visceral pain e.g. Myocardial infarction.
2- Alone in Biliary & Renal colic. (single use is allowed)
3- Pre-anesthetic medication (Better than Morphine).
4- Obstetric Analgesia.
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29. Other Opioids: Fentanyl
1-Synthetic drug Derivative of Meperidine. 2- Strong Mu receptor Agonist Strong Analgesic 80 Times > Morphine 3- High Lipid solubility: I.V. Rapid Onset + Short duration 4- Used as I.V. Anesthesia: but induce vomiting if used alone. 5- Used In cancer pain as transdermal patches. 6- Adverse Effects (Vomiting, Marked inhibition of R.C. & increase Muscle tone & Truncal rigidity)
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30. Other Opioids: Codeine (Methyl-Morphine)
Phenanthrene Opium Alkaloid.
Therapeutic Uses:
a- Antitussive (15-30 mg at bed time) in Dry useless cough & Dangerous cough e.g. Postoperative.
b- Analgesic (10 mg) in Mild & Moderate visceral pain + Aspirin & Paracetamol.
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