Opioid Analgesics

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

2. Opioid Analgesics • Opioid • Analgesic • Narcotic • Opium: Papaversomniferum • Morphine, Morpheus , -ine • Endorphins • Enkephalins Munir Gharaibeh MD, PhD, MHPE

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

4. Munir Gharaibeh MD, PhD, MHPE

5. History of Opium Papaversemniferum 3000 BC Morphine 1806 Heroin 1898 شركة الهند الشرقية 1600 حرب الأفيون 1839-1842 اختراع السيرنج 1853 Morphine Receptors ”Goldstein” 1973

6. Comparison of Analgesics Munir Gharaibeh MD, PhD, MHPE

7. Opiate Receptor Effects Munir Gharaibeh MD, PhD, MHPE

8. Opiate Receptor Effects Munir Gharaibeh MD, PhD, MHPE

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

10. 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. Munir Gharaibeh MD, PhD, MHPE

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

12. Sites of Action • Substantiagelatinosa • Periventricular area • Periaqueductal grey • Hypothalamus • Thalamus • Striatum • Limbic System • Nucleus accumbens Munir Gharaibeh MD, PhD, MHPE

13. 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. Munir Gharaibeh MD, PhD, MHPE

15. Sites of action of opioidanalgesics • Inflamed or damaged peripheral tissues. • Spinal cord. • Thalamus. Munir Gharaibeh MD, PhD, MHPE

16. 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. 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). Munir Gharaibeh MD, PhD, MHPE

18. Cellular Mechanisms of Action • Inhibit adenylatecyclase, 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. 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. 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 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. 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. Munir Gharaibeh MD, PhD, MHPE

23. Pharmacokinetics Munir Gharaibeh MD, PhD, MHPE

24. 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. 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. Munir Gharaibeh MD, PhD, MHPE

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

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

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

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

30. Munir Gharaibeh MD, PhD, MHPE

31. 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. Munir Gharaibeh MD, PhD, MHPE

32. 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. Munir Gharaibeh MD, PhD, MHPE

33. 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. Munir Gharaibeh MD, PhD, MHPE

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

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

36. Comparison of Opioid Agonists Munir Gharaibeh MD, PhD, MHPE

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

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

39. Munir Gharaibeh MD, PhD, MHPE