Morphine & fentanyl nida

MORPHINE , FENTANYL ,OPIOID RECEPTORS,

1. MORPHINE & FENTANYL DR NIDA FATIMA JAWAHARLAL NEHRU MEDICAL COLLEGE ALIGARH

2. Opioid Receptors Mu, Delta, Kappa All pure agonists act at Mu receptor Opioid receptors act on CNS: cortex, thalamus, periaquaductal gray, spinal cord & Peripheral neurons Inflammed tissue & Immune cells Respiratory and GI tract

3. MORPHINE Morphine - white , crystalline powder. µ- opioid receptor agonist.

4. Synonyms: Morphine: Astramorph ®, Duramorph ®, Infumorph ®, Kadian®,Morphine Sulfate ®, MSIR®, MS- Contin ®, Oramorph SR®, Roxanol ®

5. Source: Morphine is a naturally occurring substance extracted from the seedpod of the poppy plant, Papavar somniferum . Morphine concentration in opium can range from 4-21 %.

6. HISTORY About 1806, a german youth, Frederich Serturner isolated the primary active ingredient in opium. He tested the new drug on his friends at 10 times the modern recommended dose! ‑Active agent was 10x more potent than opium ‑He named it morphium after morphius , the god of dreams!!!

7. DRUG- MORPHINE Drug Class: Narcotic analgesic ( schedule II) prescription forms: Injectable (0.5-25 mg/ mL strength); oral solutions (2-20 mg/ mL ); immediate and controlled release tablets and capsules (15-200 mg); and suppositories (5-30 mg).

8. Pharmacokinetics Orally -absorbed very slowly, Extensive first pass metabolism - 20%- 40% of bio-availability. Duration of action – ( 3 – 6 hours) Distribution is wide ;concentration in liver, spleen and kidney is greater than plasma. Morphine freely crosses placenta. Plasma half life 3hours (1-5 hrs). 30% is plasma protein bound

9. Metabolism The primary site metabolism is liver, where it undergoes rapid glucuronidation . However, extrahepatic metabolism up to 30% of its total clearance. Morphine-6-glucuronide (m6g), as potent as morphine. M6G has a half-life of approximately 1-2 hours.

10. USES Morphine is used medicinally – R elief of moderate to severe pain in both acute and chronic management. pre-operative sedation and to facilitate the induction of anesthesia . For long-term treatment of terminally ill , pain ridden patients

11. Route of Administration Oral (capsule, syrups, tablets ) Intravenous Intramuscular Subcutaneous Epidural Administration Intrathecal administration.

12. Dosage Oral: Short-acting oral dose-severe, chronic pain in Adults: 10 to 30 mg 4 hrly . I.M/S.C : 5 to 20 mg (usually 10 mg), 4 hrly I.V : initial dose 4 mg to 10 mg slowly over 4-5 min 4hrly. Daily dose range 12-120mg. Pediatric : I.V-0.025–0.1 mg/kg. S.C- 0.1-0.2mg/kg

13. Epidural Adult Dosage 5 mg in lumbar region -pain relief up to 24 hrs Incremental doses 1-2 mg. Max 10 mg/24 hr For continuous infusion an initial dose of 2 to 4 mg/24 hours is recommended INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF EPIDURAL DOSAGE .

14. Intra- thecal Adult Dosage A single injection of 0.2 to 1 mg pain relief for up to 24 hours. A constant intravenous infusion of naloxone hydrochloride, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.

15. Side effects M iosis O rthostatic hypotension R espiratory depression P ain suppression/ P ruritus H istamine release/ h ormonal release I ncreased intracranial tension. N ausea E uphoria S edation

16. Contraindications respiratory depression, hypersensitivity, paralytic ileus , and delayed gastric emptying, Obstructive airway disease, acute hepatic disease, MAO Inhibitor administration, pregnancy, lactation and in children.

17. Interactions Morphine will not be effective in people taking naltrexone . It can increase the sedative effect of alcohol, Increase the risk of respiratory depression when used with MAO inhibitors and cimetidine . It antagonises the effects of diuretics.

18. FENTANYL a potent, synthetic opioid analgesic with a rapid onset and short duration of action. a strong agonist at the μ- opioid receptors.

19. HISTORY Fentanyl first synthesized by Paul Janssen in 1960 by assaying analogues of the structurally related drug pethidine for opioid activity. Historically, used to treat breakthrough pain and is commonly used in pre-procedures as a pain reliever as well as an anesthetic in combination with a benzodiazepine.

20. In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch, Actiq lollipop and Fentora buccal through, sublingual spray

21. Fentanyl Onset: 1-2 minutes IV/IO 8 minutes IM Peak: 3-5 minutes IV route Less predictable IM route Duration: 30-60 minutes IV 1-2 hours IM Duration of respiratory depressant effect of fentanyl may be longer than the analgesic effect

22. Metabolism Hepatic, primarily by CYP3A4 Metabolized to 3-glucuronide metabolites No analgesic properties CSF doses often exceed doses of parent compound (rats) Cause neuroexcitation 6-glucuronide has analgesic properties

23. Medical uses Fentanyl has a therapeutic index of 270 . Intravenous fentanyl is often used for anesthesia (often used along with a hypnotic agent like propofol ) and analgesia. along with local anesthetic for neuraxial administration (epidural or intrathecal or spinal).

24. In combination with benzodiazepine, like midazolam , - procedural sedation for endoscopy, cardiac catheterization, oral surgery, etc. Management of chronic pain including cancer pain. In children intranasal fentanyl is useful for the treatment of moderate and severe pain.

25. Fentanyl patch Takes 12 hours for onset of analgesia Need adequate subcutaneous tissue for absorption Work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours. Takes 24 hours to reach maximum effect Suitable for stable pain only

26. Patches Durogesic / duragesic / matrifen Dosage is based on the size of the patch. Dosage change after six days on patch Change patch every 72 hours Transdermal absorption rate is constant at a constant skin temperature

27. Lozenges Fentanyl lozenges ( Actiq ) are a solid formulation of fentanyl citrate as lollipop that dissolves slowly in the mouth for transmucosal absorption. Effective in treating breakthrough cancer pain It is most effective within 15 minutes.

28. Rate of absorption depends on: Body temperature, skin type, amount of body fat, and placement of the patch Under normal circumstances, the patch will reach its full effect within 12 to 24 hours

29. About 25% of the drug is absorbed through the oral mucosa, resulting in a fast onset of action, and the rest is swallowed and absorbed in the small intestine, acting more slowly. extensive first-pass metabolism, leading to an oral bioavailability of about 33% and 50% when used correctly (25% via the mouth mucosa and 25% via the gut).

30. Adverse effects Most common side-effects (> 10% of patients). CVS: Bradycardia , edema CNS: depression, confusion, dizziness, drowsiness, fatigue, headache, sedation Endocrine & metabolic: Dehydration Gastrointestinal: Constipation, nausea, vomiting, xerostomia

31. Local: Application-site reaction erythema Neuromuscular & skeletal: Chest wall rigidity (high dose I.V.), muscle rigidity, weakness Ocular: Miosis Respiratory: Dyspnea , respiratory depression Miscellaneous: Diaphoresis

32. less frequent (3 to 10% of patients) abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), dyspnea (shortness of breath), apnea , hypoventilation, urinary retention

33. Fentanyl -associated with aphasia fentanyl tends to induce less nausea, as well as less histamine mediated itching, in relation to morphine. Fentanyl - prolonged respiratory depression than other opioid analgesics.

34. Dosage Surgery: Premedication: I.M., slow I.V.: 50-100 mcg/dose (1-2mcg/kg) 30-60 minutes prior to surgery Adjunct to regional anesthesia : Slow I.V.: 25-100 mcg/dose (0.5-2mcg/kg) over 1-2 minutes.

35. Adjunct to general anesthesia : Slow I.V.: Low dose: 0.5-2 mcg/kg/dose depending on the indication. Moderate dose: Initial: 2-20 mcg/kg/dose; Maintenance (bolus or infusion): 1-2 mcg/kg/hour. High dose: 20-50 mcg/kg/dose.

36. Pain management Adults: I.V.Bolus:1-2 mcg/kg or 25-100µg/dose; infusion @ 1-2 µg/kg/hour or 25-200 µg/hr . Severe: I.M, I.V.: 50-100 µg/dose every 1-2 hours as needed.

37. Patient-controlled analgesia (PCA) Usual concentration: 10 mcg/ mL Demand dose: Usual: 20 mcg; range: 10-50 mcg Lockout interval: 5-8 minutes Usual basal rate: ≤50 mcg/hour

38. Critically-ill patients: Slow I.V.: 25-35 mcg or 0.35-0.5 mcg/kg every 30-60 minutes as needed Continuous infusion: 50-700 mcg/hour (based on ~70 kg patient) or 0.7-10 mcg/kg/hour

39. Intrathecal fentanyl Must be preservative-free. Single dose: 5-25 mcg/dose- relief up to 6 hours. Continuous infusion: Not recommended For chronic cancer pain, infusion of very small doses may be practical (American Pain Society, 2008).

40. Epidural fentanyl Must be preservative-free. Single dose: 25-100 µg/dose-relief up to 8 hrs Continuous infusion: 25-100 mcg/hour

41. Pain relief (IV) 1–2 mcg/kg Pain relief (Intranasal) 2 mcg/kg Premedication 10–15 mcg/kg ( Actiq PO) Anesthetic adjunct (IV) 1–5 mcg/kg Maintenance infusion2–4 mcg/kg/h Main anesthetic (IV) 50–100 mcg/kg Pediatric Dosage

42. Opioid withdrawal

43. Acute action Analgesia Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Reduced sex drive Flushed and warm skin Withdrawal signs Pain and irritability Hyperventilation Dysphoria and depression Restlessness and insomnia Fearfulness and hostility Increased blood pressure Diarrhea Pupillary dilation Hyperthermia Lacrimation , runny nose Spontaneous ejaculation Chilliness & “gooseflesh”

44. Opioid Tolerant " Opioid -tolerant" patients-who are taking at least: Oral morphine 60 mg/day, or Transdermal fentanyl 25 mcg/hour, or Oral oxycodone 30 mg/day, or Oral hydromorphone 8 mg/day, or Oral oxymorphone 25 mg/day, or Equianalgesic dose of any opioid for at least 1 wk

45. Opioid Induced Neurotoxicity Neuroexcitability - agitation, confusion, myoclonus , hallucinations and seizures Predisposing Factors: High opioid doses & Prolonged opioid use Recent rapid dose escalation Dehydration & Renal failure & Advanced age Other psychoactive drugs

46. Management of OIN Rehydration Treat concurrent causes of delirium e.g. UTI, pneumonia Reduce dose if pain controlled Switch to a different opioid

47. Thanks!!!