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OPIOIDS - Pharmacology

OPIOIDS - Pharmacology. Opioids. Transmitters : Endogenous opioid peptides Enkephalins (m & d receptors) Dynorphins (κ receptors) Endorphins Actions Opioids stimulate axons of inhibitory interneurons Peripheral inflammation: Sensitivity to opioids in spinal cord is increased

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OPIOIDS - Pharmacology

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  1. OPIOIDS - Pharmacology

  2. Opioids • Transmitters: Endogenous opioid peptides • Enkephalins (m & d receptors) • Dynorphins (κ receptors) • Endorphins • Actions • Opioids stimulate axons of inhibitory interneurons • Peripheral inflammation: Sensitivity to opioids in spinal cord is increased • Peripheral neuropathic pain: Sensitivity to opioids is greatly reduced

  3. Pain Modulation: Central mechanisms • Gate control • Aβ axons stimulate inhibitory interneuron • Activity in central projection neuron is reduced • Opiate-induced analgesia • μ Receptor :Agonists: Morphine; Antagonist: CTAP • Reduces acute pain & hyperalgesia in most models • δ Receptor :Agonist: SNC80 , Antagonist: Naltrindole • Reduces acute pain & hyperalgesia in inflam. pain models • May have fewer side effects (Constipation, respiratory depression, physical dependence) than μ-agonists • κ Receptor : Agonist: U50,488 • No effect on chronic muscle pain • Locations: PAGM, Ventral medulla, Dorsal horn

  4. BRAIN PAG, RVM etc Descending pathways Lamina V OPIOIDS amytriptyline Carbamazapine, lignocaine SG C-fibre Glutamate sP Lamina I Ketamine Ca2+ VDCCs GABAPENTIN Dorsal Horn

  5. Weak opioids Codeine Weak m agonist, methbolize to morphine (30%) Dose 30-60 mg oral q 4-6 hrs Side effects : constipation/ itching/ nausea/ vomiting Available as: TWC(15) TWC(30) Codeine (15, 30 mg)

  6. Weak opioids (cont.) Tramadol Weak µ agonist • Amine uptake inhibiting action:NE and serotonin • Dose 50-100 mg oral q 6 hrs • Anticholinergic side effects: tachycardia, nausea, vomiting,voiding difficulty, sweating • Available as IR, ER (Tramal) and combination ( Ultracet® (Tramadol& paracetamol)

  7. Strong Opioids agonists: morphine, pethidine,fentanyl, methadone partial agonists :-buprenorphine, pentazocine agonist-antagonist :- nalbuphine

  8. Bioavailability: 30-60%, due to1st part metabolism Immediate release: 3-4 hr Extended release:12-24 h Metabolize to M6G (agonist), M3G (neurotoxicity), may accumulate in renal failure Only parenteral route in TH Faster onset, short duration (2-3 hr) No more effective than morphine at treating biliary or renal pain High addictive potential (rush and stimulant effect) More CNS toxicity (i.e. seizures, delirium due to nor-pethidine metabolite Should not be used any more Morphine Pethidine

  9. MST, MS Contin (10, 30, 60 mg)

  10. Kapanol (20, 50, 100 mg)

  11. Oral morphine solution Rama, Siriraj, Songkhla 2mg/ml -stability, convenience, dosage Fentanyl lollipop Fentanyl buccal tablet Immediate release opioid

  12. Methadone • Cheap and available for opioid maintenance • Racemic of L and R –isoform, theoretically support NMDA and mu-receptor mechanism • Variable half life, extended with long term use • Use as third line, for switching in refractory case • Start at lower dose, then slowly titrate • Study recommends to switch from morphine to methadone in 3-day (one third reduction and substitution with equianalgesic dose (4 to 1- 6 to 1 ratio), followed by a one week titration Fredheim OM, Eur J Pain. 2007 ;11:599-604.

  13. Narcotic Type 2

  14. Transdermal narcotics • Fentanyl TTS (Durogesic®/ D-Trans® ) • 12, 25, 50, 100 µgm/patch • onset : 6-12 hrs, change patch q 3 days • Should not use for acute pain due to delay onset • Indications • Terminal cancer pts. who are not able to eat • Cancer of the head and neck region • Pts. who develop severe side effects of oral narcotics • Pts. who consume very high dose oral narcotics

  15. Opioid Therapy and Chemical Dependency • Risk of addiction: Evolving view • Acute pain: Very unlikely • Cancer pain: Very unlikely • Chronic noncancer pain: Surveys of patients without abuse or psychopathology show rare addiction Surveys that include patients with abuse or psychopathology show mixed results

  16. Opioid Therapy: Drug Selection • Immediate-release preparations • Used mainly • For acute pain • For dose finding during initial treatment of chronic pain • For “rescue” dosing • Can be used for long-term management in select patients

  17. Opioid Therapy: Drug Selection • Immediate-release preparations • Combination products • Acetaminophen, aspirin, or ibuprofen combined with codeine, hydrocodone, dihydrocodeine • Single-entity drugs, eg, morphine • Tramadol

  18. Opioid Therapy: Drug Selection • Extended-release preparations • Preferred because of improved treatment adherence and the likelihood of reduced risk in those with addictive disease • Morphine, oxycodone, fentanyl, hydromorphone, codeine, tramadol, buprenorphine • Adjust dose q 2–3 d

  19. Opioid Therapy: Drug Selection • Role of methadone • Another useful long-acting drug • Unique pharmacology when commercially available as the racemic mixture • Potency greater than expected based on single-dose studies • When used for pain: multiple daily doses, steady-state in 1 to several weeks

  20. Opioid Selection:Poor Choices for Chronic Pain • Meperidine • Poor absorption and toxic metabolite • Propoxyphene • Poor efficacy and toxic metabolite • Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, dezocine) • Compete with agonists  withdrawal • Analgesic ceiling effect

  21. Opioid Therapy: Routes of Administration • Oral and transdermal—preferred • Oral transmucosal—available for fentanyl and used for breakthrough pain • Rectal route—limited use • Parenteral—SQ and IV preferred and feasible for long-term therapy • Intraspinal—intrathecal generally preferred for long-term use

  22. Opioid Therapy: Guidelines • Consider use of a long-acting drug and a “rescue” drug—usually 5%–15% of the total daily dose • Baseline dose increases: 25%–100% orequal to “rescue” dose use • Increase “rescue” dose as baseline dose increases • Treat side effects

  23. Opioid Therapy: Side Effects • Common • Constipation • Somnolence, mental clouding • Less common • Nausea – Sweating • Myoclonus – Amenorrhea • Itch – Sexual dysfunction • Urinary retention – Headache

  24. Opioid Responsiveness • Opioid dose titration over time is critical to successful opioid therapy • Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects occur • No maximal or “correct” dose • Responsiveness of an individual patient to a specific drug cannot be determined unless dose was increased to treatment-limiting toxicity

  25. Poor Opioid Responsiveness • If dose escalation  adverse effects • Better side-effect management • Pharmacologic strategy to lower opioid requirement • Spinal route of administration • Add nonopioid or adjuvant analgesic • “Opioid rotation” • Nonpharmacologic strategy to lower opioid requirement

  26. Opioid Rotation • Based on large intraindividual variation in response to different opioids • Reduce equianalgesic dose by 25%–50% with provisos: • Reduce less if pain severe • Reduce more if medically frail • Reduce less if same drug by different route • Reduce fentanyl less • Reduce methadone more: 75%–90%

  27. Equianalgesic Table PO/PR (mg)AnalgesicSC/IV/IM (mg) 30 Morphine 10 4–8 Hydromorphone 1.5 20 Oxycodone - 20 Methadone 10

  28. Acknowledgement • Assoc. Professor Chutamanee Suttisisang • Assoc. Professor Pongparadee Chaudakestrin • Assist. Professor Penkae Ketuman • Professor Anthony Dickenson

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