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MORPHINE: New Findings of an Old Drug By Amnuay Thithapandha, Ph.D. Professor, Office of Academic Affairs

MORPHINE: New Findings of an Old Drug By Amnuay Thithapandha, Ph.D. Professor, Office of Academic Affairs Faculty of Medicine Ramathibodi Hospital Mahidol University. Among the remedies which it has pleased Almighty God to give to man

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MORPHINE: New Findings of an Old Drug By Amnuay Thithapandha, Ph.D. Professor, Office of Academic Affairs

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  1. MORPHINE: New Findings of an Old Drug By Amnuay Thithapandha, Ph.D. Professor, Office of Academic Affairs Faculty of Medicine Ramathibodi Hospital Mahidol University

  2. Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium. Sydenham (1680)

  3. In 1806, F. Serturner (a German pharmacist) reported the isolation of a pure substance from opium that he named MORPHINE, after Morpheus (Greek god of dreams)

  4. CONFUSING TERMINOLOGY Narcotic ( Greek = stupor ) ---- used only in a legal context Opioid--- any substance (synthetic or semisynthetic) that has morphine-like effects Opiate--- a substance derived from opium and has morphine-like effects

  5. MAIN USES OF MORPHINE • SEVERE PAIN • POST-OPERATIVE • TRAUMATIC • CANCER PAIN (terminal) • BURN PAIN • TO INTERRUPT THE PAIN CYCLE • Remember : “Severe Pain Can Kill” • (F.J. Brescia et al., J Clinical Oncol 10 : 149, 1992; • G.K. Groulay & D.A. Cherry, Clin J Pain 7:347,1991 )

  6. MORPHINE : KINETICS ORAL BIOAVAILABILITY = 20 % HALF – LIFE ( PO, IM ,SC , IV ) = 2 – 3 h CONJUGATED IN LIVER & EXCRETED VIA KIDNEY ( 90 % OR MORE ) M6G = Active metabolite (9X) M3G = Toxic metabolite • IN PATIENTS WITH DEHYDRATION, RENAL FAILURE OR HEPATIC INSUFFICIENCY  REDUCE DOSE  INCREASE DOSING INTERNVAL  USE ONLY PRN IF OLIGURIA OR ANURIA IS PRESENT

  7. ADVERSE EFFECTS OF MORPHINE COMMON : N+V, DROWSINESS (initial) DELIRIUM (CONFUSION) COMMON : CONSTIPATION (on- going) SEDATION OCCASIONAL : DRY MOUTH URINARY RETENTION PRURITIS HALLUCINATION RESPIRATORY DEPRESSION

  8. CH3 N 1 2 3 6 4 5 0 OH HO UGT2B7 UGT1A1 UGT2B7 • M3G M6G • MAJOR METABOLITE POTENT m-AGONIST • WEAK m -ANTAGONIST(x 9 MORPHINE) • ADRS UGT = UDP - GLUCURONOSYLTRANSFERASE

  9. INTRAVENOUS M6G: PHARMACOKINETICS Renal Function Normal Impaired Creatinine clearance (ml/min) 84 19 M6G clearance (ml/min) 89 26 Volume of distribution (L) 14.7 16.4 Elimination half-life(h) 1.9 7.4 AUC (nmol/L.h) 370 1319 BW=70 kg; Dose= 1 mg AUC from zero to infinity R. Osborne et al., Lancet,April 9,1988

  10. M6G (0.5 mg, IV) 100 Cancer pain N = 5 x ± SEIV OVER 5 MIN R. Osborne et alLancet, April 9, 1988 80 60 VAS 40 20 TIME (h) 4 1 2 3 5 6 7 8

  11. 100 M6G M 80 M3G 60 CSF M6G (ng/ml) 40 SENSITIVE (4) 20 INSENSITIVE (6) 10 20 30 60 100 140 180 M (10 mg, IV)

  12. MAJOR EFFECTS OF MORPHINE METABOLITES M3G (m-antagonist) M6G (m-agonist) • SEDATION • ANALGESIA • CONSTIPATION • RESPIRATORY DEPRESSION • DELIRIUM • HALLUCINATION • INCOHERENCE • TREMOR M UGT1A1 UGT2B7 UGT2B7 M6G M3G TOXICITY

  13. Case: MORPHINE REACTIONS Sirima Triamruktakul,a 45-year-old woman weighing 56 Kg, was admitted to the emergency room because of low back pain. The pain intensity was such that she could not mobilize and felt desperate. She was given a small dose of morphine (5 mg, IM) but did not obtain any pain relief even at 1 hour after the drug administration. In fact, she manifested signs of tremor and hallucination which became apparent at only half an hour after the opioid. Diazepam(5 mg, IV) was needed to ameliorate these adverse reactions.

  14. Case: MORPHINE REACTIONS (CONT) Three months later she was readmitted with the same complaint. Morphine (5 mg, IM) was tried on her again with the same signs of its adverse reactions. Blood samples were taken serially from 0.5,1,2,3,4,6 and 8 hours. When morphine and its metabolites were analyzed, it was found that she could make little M6G but an unusually large M3G profile was noted.

  15. 45 yr

  16. UGT 2B7 1 2 3 4 5 6 (736) (149) (132) (220) (721) bp (88) Promoter 1816 816 CAU TAU GAC GCC His Tyr Asp Ala

  17. GENETIC ANOMALIES UNDERLINE THE CAUSE OF SEVERE ADVERSE REACTIONS TO MORPHINE PATIENT DISEASE M3G ADRSGENETIC CAUSE M6G Appendicitis 10:1 N + V Point mutation in exon 2,6 Burn 25:1 Delirium Point mutation in + Tremor exon 2,6 Renal stone 30:1 Tremor Insertion of an extra + Hallucination TA in the promoter; Point mutation in exon 6 Low back pain 40:1 N + V Gene deletion + Hallucination + Seizure The M3G:M6G ratio was obtained from AUC 0.5-8h after morphine (5 mg, IM).

  18. AUCa0 M3G 10.0 8.4 M6G AUCa0 40.4 3.4 9.2 12.8 15.6 Hallucination n+v NORMAL M3G/M6G RATIOS ARE 3-5 35.2 Xanthopsia M UGT1A1 UGT2BT UGT2BT M3G M6G

  19. Nose itching and pruritis caused by morphine are due to histamine release and are antagonized by hydroxyzine or naloxone. In the presence of the antagonist, however, plasma histamine level in the sensitive individuals remains elevated. A.Thithapandha, Toxicol. Appl.Pharmacol., 2007(in press)

  20. * 5 MORPHINE-INDUCED HISTAMINE RELEASE IN SENSITIVE PATIENTS 4 8 3 PLASMA CONC (ng/ml) * P < 0.05 * 2 1 10 20 0 INSENSITIVE CONTROL SENSITIVE

  21. MORPHINE (Base, pKa= 7.9) NALOXONE M – OPIOID RECEPTOR MAST CELL HISTAMINE ANALGESIA HYDROXYZINE ITCHING

  22. No patient should ever wish for death because of a physician’s reluctance to use adequate amounts of effective opioids. Gutstein and Akil (Goodman & Gilman, 11thedition, 2006)

  23. Thank You for your attention

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