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 painmuscle pain Locations: PAGM, Ventral medulla, Dorsal horn

4 SG Lamina I C-fibre Glutamate Lamina V sP PAG, RVM etc Descending pathways Ca 2+ VDCCs BRAIN Dorsal Horn Carbamazapine, lignocaine GABAPENTIN amytriptyline Ketamine OPIOIDS

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

6 Tramadol Weak opioids (cont.) Weak µ agonist Amine uptake inhibiting action:NE and serotonin Dose 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 S trong O pioids agonists: morphine, pethidine,fentanyl, methadone methadone partial agonists :-buprenorphine, pentazocine pentazocine agonist-antagonist :- nalbuphine

8 MorphinePethidine  Bioavailability: 30-60%, due to1 st 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

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

10 Kapanol (20, 50, 100 mg)

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

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 ;11:

13 Narcotic Type 2

14 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 Transdermal narcotics

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17 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

18 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

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

20 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

21 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

22 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

23 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

24 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% or equal to “rescue” dose use  Increase “rescue” dose as baseline dose increases  Treat side effects

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

26 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

27 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

28 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%

29 Equianalgesic Table PO/PR (mg) AnalgesicSC/IV/IM (mg) 30Morphine10 4–8Hydromorphone1.5 20Oxycodone- 20Methadone10

30 Acknowledgement  Assoc. Professor Chutamanee Suttisisang  Assoc. Professor Pongparadee Chaudakestrin  Assist. Professor Penkae Ketuman  Professor Anthony Dickenson