1. Opioid Analgesics Munir Gharaibeh, MD, PhD, MHPE
Faculty of Medicine, The University of Jordan
April, 2014

2. Munir Gharaibeh MD, PhD, MHPE
Opioid Analgesics
Opioid
Analgesic
Narcotic
Opium: Papaver somniferum
Morphine, Morpheus , -ine
Endorphins
Enkephalins
September 18
Munir Gharaibeh MD, PhD, MHPE

3. Munir Gharaibeh MD, PhD, MHPE
Opioid Analgesics
Dependence(Abuse, Addiction, Habituation):
Psychological (Psychic, Craving, Compulsive)
Physiological (Physical, Adaptive )
Tolerance.
Cross Dependence.
Cross Tolerance.
September 18
Munir Gharaibeh MD, PhD, MHPE

4. Munir Gharaibeh MD, PhD, MHPE
September 18
Munir Gharaibeh MD, PhD, MHPE

5. History of Opium Papaver semniferum 3000 BC Morphine 1806 Heroin 1898
شركة الهند الشرقية
حرب الأفيون
اختراع السيرنج
Morphine Receptors ”Goldstein”

6. Comparison of Analgesics
Opioids
Nonopioids
Efficacy
Strong
Weak
Prototype
Morphine
Aspirin
Pain Relieved
Any Type
Musculoskeletal
Site of Action
Central
Peripheral and Central
Mechanism
Specific Receptors
PG Synthesis
Danger
Tolerance & Dependence
G.I irritation
Anti-inflammatory No
Yes
Antipyretic
Antiplatelets
September 18
Munir Gharaibeh MD, PhD, MHPE

7. Opiate Receptor Effects
Mu1
Mu2
Kappa
Sigma
Delta
Morphine
Bemazocine
N-allylcyclazocine
Morphine,
Leu-enkephalin
Analgesia
No analgesia
Analgesia; excessive heat
Apnea
Tachypnea
Indifference
Sedation
Delirium
Miosis
Mydriasis
Nausea &Vomiting
September 18
Munir Gharaibeh MD, PhD, MHPE

8. Opiate Receptor Effects
Mu1
Mu2
Kappa
Sigma
Delta
Constipation
Urine retention
Diuresis
Pruritus
Temperature increase
Tolerance
Little
tolerance
Cross
No mu cross
Mu cross
September 18
Munir Gharaibeh MD, PhD, MHPE

9. Munir Gharaibeh MD, PhD, MHPE
Opioid Analgesics
Peptides
Alkaloids : Natural
Semi synthetic
Synthetic
September 18
Munir Gharaibeh MD, PhD, MHPE

10. Munir Gharaibeh MD, PhD, MHPE
Opioid Peptides “1970s”
Peptides helped in the understanding of:
Mechanism of actions of opioids.
Placebo effect of drugs.
Acupuncture.
Stimulation induced analgesia.
Regulation of the release of pituitary hormones.
September 18
Munir Gharaibeh MD, PhD, MHPE

11. Opiate Receptor Interactions
September 18
Munir Gharaibeh MD, PhD, MHPE

12. Munir Gharaibeh MD, PhD, MHPE
Sites of Action
Substantia gelatinosa
Periventricular area
Periaqueductal grey
Hypothalamus
Thalamus
Striatum
Limbic System
Nucleus accumbens
September 18
Munir Gharaibeh MD, PhD, MHPE

13. Munir Gharaibeh MD, PhD, MHPE
September 18
Munir Gharaibeh MD, PhD, MHPE

14. Receptor mechanisms of analgesic drugs
The primary afferent neuron originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron.
Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at mu -opioid receptors (MOR) or blocked in the afferent axon by local anesthetics.
Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers, alph 2 agonists.
Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.
September 18
Munir Gharaibeh MD, PhD, MHPE

15. Sites of action of opioid analgesics
Inflamed or damaged peripheral tissues.
Spinal cord.
Thalamus.
September 18
Munir Gharaibeh MD, PhD, MHPE

16. Munir Gharaibeh MD, PhD, MHPE
Brainstem local circuitry underlying the modulating effect of opioids on descending pathways.
The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron.
This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord.
September 18
Munir Gharaibeh MD, PhD, MHPE

17. Opioid analgesic action on the descending inhibitory pathway
Sites of action of opioids on pain-modulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus caeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C).
September 18
Munir Gharaibeh MD, PhD, MHPE

18. Cellular Mechanisms of Action
Inhibit adenylate cyclase, so decrease cAMP.
Inhibit Ca++ entry by decreasing phosphorylation of voltage operating Ca++channels.
Enhance K+ efflux.
The net result is an increase in release of DA, 5HT, nociceptive peptides like substance P, resulting in blockage of nociceptive transmission.
September 18
Munir Gharaibeh MD, PhD, MHPE

19. Depressant Effects of Morphine
Suppression of pain, analgesia.
Drowsiness and decreased mental alertness, sedation
Decreased respiration.
Increased intracranial pressure.
Decreased myocardial oxygen demand.
Suppression of cough, antitussive.
September 18
Munir Gharaibeh MD, PhD, MHPE

20. Depressant Effects of Morphine
Decreased peristalsis.
Inhibition of fluid and electrolyte accumulation in the intestinal lumen.
Decreased gastric acid secretion.
Inhibition of emetic center.
Slight decrease in body temperature.
Decreased release of LH and FSH
September 18
Munir Gharaibeh MD, PhD, MHPE

21. Stimulant Effects of Morphine
Euphoria.
Constriction of pupils, miosis.
Stimulation of chemoreceptor trigger zone.
Increased tone of intestinal smooth muscle.
Increased tone of sphincter of Oddi, increased biliary pressure.
September 18
Munir Gharaibeh MD, PhD, MHPE

22. Stimulant Effects of Morphine
Increased tone of detrusor muscle.
Increased tone of vesical sphincter.
Increased release of prolactin and antidiuretic hormone.
Proconvulsant in overdose.
September 18
Munir Gharaibeh MD, PhD, MHPE

23. Munir Gharaibeh MD, PhD, MHPE
Pharmacokinetics
September 18
Munir Gharaibeh MD, PhD, MHPE

24. Munir Gharaibeh MD, PhD, MHPE
Therapeutic Uses
Acute Pain.
Chronic Pain: but we should try:
Nonopiates
Weaker opiates.
Regular fixed schedule.
Myocardial Infarction.
Obstetric Anesthesia.
Pulmonary Edema:
Relieve anxiety.
Cause peripheral pooling
Constipating Effect.
September 18
Munir Gharaibeh MD, PhD, MHPE

25. Adverse Effects of Opioids
Behavioral restlessness, tremulousness, and hyperactivity.
Respiratory depression.
Nausea and vomiting.
Increased intracranial pressure.
Postural hypotension accentuated by hypovolemia.
Constipation.
Urinary retetion.
Itching and urticaria.
September 18
Munir Gharaibeh MD, PhD, MHPE

26. Munir Gharaibeh MD, PhD, MHPE
Contraindications
Head Injury.
Shock and decreased blood volume.
Chronic Hypoxic Conditions.
September 18
Munir Gharaibeh MD, PhD, MHPE

27. Munir Gharaibeh MD, PhD, MHPE
Tolerance to Opioids
Factors Affecting Development of Tolerance:
Rate of Administration
Dose
Agent used.
September 18
Munir Gharaibeh MD, PhD, MHPE

28. Munir Gharaibeh MD, PhD, MHPE
Tolerance to Opioids
Tolerance develops to almost all actions of opioids, EXCEPT:
Miosis.
Constipation.
Convulsions.
September 18
Munir Gharaibeh MD, PhD, MHPE

29. Munir Gharaibeh MD, PhD, MHPE
Tolerance to Opioids
Exact mechanism of tolerance to opioids is unknown, but it is:
Not metabolic
Not immunologic
Homeostatic
September 18
Munir Gharaibeh MD, PhD, MHPE

30. Munir Gharaibeh MD, PhD, MHPE
September 18
Munir Gharaibeh MD, PhD, MHPE

31. Munir Gharaibeh MD, PhD, MHPE
Opioid Withdrawal
6-12 hr:
Drug seeking (purposive) behavior, non purposive signs, such as restlessness, lacrimation, rhinorrhea, sweating, yawning.
12-24hr:
Restless sleep for several hours (yen) and feeling more miserable than before after awakening; irritability, tremor, dilated pupils, anorexia, gooseflesh skin.
September 18
Munir Gharaibeh MD, PhD, MHPE

32. Munir Gharaibeh MD, PhD, MHPE
Opioid Withdrawal
24-72hr:
Increased intensity of previous signs plus weakness, depression, nausea, vomiting, intestinal cramps, diarrhea, alternate chills and flushes, various aches and pains, increased heart rate and blood pressure, involuntary movements of arms and legs, dehydration and possible electrolyte imbalances.
September 18
Munir Gharaibeh MD, PhD, MHPE

33. Munir Gharaibeh MD, PhD, MHPE
Opioid Withdrawal
Later:
Symptoms of autonomic hyperactivity alternate with brief periods of restless sleep and gradually decrease in intensity until addict feels better in 7-10 days but may still exhibit strong craving for the drug.
Some mild signs may be detectable for up to 6 months.
Delayed growth and development of infants born to addicted mothers may be detected for up to one year.
September 18
Munir Gharaibeh MD, PhD, MHPE

34. Treatment of Opioid Dependence
Suppression of Withdrawal Syndrome
Morphine
Heroin
Methadone
Clonidine
Opioid Substitution:
LAAM
Detoxification:
Gradually decreasing the dose of methadone.
Naloxone
Narcotic Antagonists:
Naltrexone for 2-6 months following detoxification.
September 18
Munir Gharaibeh MD, PhD, MHPE

35. Munir Gharaibeh MD, PhD, MHPE
Opioid Agonists
Morphine
Codeine
Oxycodone
Hydrocodone
Heroin
Meperidine (Pethidine)
Methadone & L  Acetyl Methadone (LAAM)
d- Propoxyphene.
Tramadol
September 18
Munir Gharaibeh MD, PhD, MHPE

36. Comparison of Opioid Agonists
Analgesia
Antitussive
Constipation
Respiratory Depression
Abuse Liability
Morphine
+++ ++
Heroin
++++
Codeine +
+,--
Oxycodone
Meperidine --
+,-
Methadone
D-propoxyphene
September 18
Munir Gharaibeh MD, PhD, MHPE

37. Partial Agonists-Antagonists
Pentazocine.
Buprenorphine.
Nalorphine.
Nalbuphine.
September 18
Munir Gharaibeh MD, PhD, MHPE

38. Munir Gharaibeh MD, PhD, MHPE
Antagonists
Nalorphine
Naloxone
Naltrexone
September 18
Munir Gharaibeh MD, PhD, MHPE

39. Munir Gharaibeh MD, PhD, MHPE
September 18
Munir Gharaibeh MD, PhD, MHPE