Update Pain Management

1. Update Pain Management Presenter : DrNorlidaBintiSuhaimi Moderator : Dr Wan Rohaidah

2. Outline presentation… • Intravenous Paracetamol • PCA Oxynorm • Bupenorphine patch • Perioperative lignocaine infusion

3. Intravenous Paracetamol

4. “A Fatal Accident Inquiry in Scotland in 2011 concluded that a young adult died from liver failure due to an overdose of paracetamol. The Sheriff found ‘there was, at the time of the death, a prevailing culture of assumed familiarity with the administration of IV paracetamol, a familiarity derived from the common use of oral paracetamol’. The patient, who weighed 35kg, died nine days after receiving paracetamol 1g IV on a sustained and regular basis.”

5. Introduction… • IV paracetamol was licensed in the UK in 2004 and is used routinely in anaestheticpractice. • Paracetamol is frequently used for perioperative analgesia, alone or in combination with an opioid. • Clinical studies have shown that paracetamolhas potent analgesics and reduce opioid consumption.

6. IV Paracetamol - therapeutic indications… • for the short-term treatment of moderate pain - especially following surgery • for the short-term treatment of fever • when administration by IV route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible.

7. IV Paracetamol – contraindications… • in patients with hypersensitivity to paracetamol • in cases of severe hepatocellular insufficiency.

8. Precautions for use: IV Paracetamolshould be used with caution in cases of: • hepatocellular insufficiency • severe renal insufficiency (creatinine clearance ≤ 30 mL/min) • chronic alcoholism • chronic malnutrition (low reserves of hepatic gluthatione)

9. IV Paracetamol – clinical pharmacology… • Paracetamol has essentially no effect on cyclo-oxygenase in vitro – but it has been classified as a NSAID because of its moderate analgesic and antipyretic properties. • The drug is not associated with the increased incidence of platelet dysfunction, gastritis, and renal toxicity that are sometimes associated with NSAIDs

10. MOA • Unclear • it is thought to exert its analgesic activity by inhibiting the synthesis of prostaglandins in the CNS (central acting) and peripherally blocking pain impulse generation. • In addition, it has been proposed that acetaminophen has a serotonergic (5-HT) mechanism and a cannabinoid agonism mechanism, which may contribute to its analgesic effect.

11. It has been proposed that its antipyretic actions are due to : - inhibition of the hypothalamic heat- regulating center, - inhibition of prostaglandin synthesis within the central nervous system , by inhibition of COX-3 (a COX – 1 ) variant. - cannabinoid agonism.

12. Pharmacokinetics and Pharmacodynamics. • The pharmacokinetics of intravenous acetaminophen have been described in several studies, and the serum therapeutic level required to produce an analgesic effect is 16 mcg/mL in adults and 10 mcg/mL in children.

13. IV PCM has a faster onset and results in more predictable pharmacokinetic than oral or rectal PCM formulations • provides onset of pain relief within five to 10 minutes after administration.

14. mean IV C max (maximum plasma concentration of drug) was nearly twice that observed with oral administration and nearly four times that observed with rectal administration. • The lag time after oral administration is 20-30 min • The lag time after rectal administration often exceeds 1 hour

15. A major benefit is that IV PCM may be administered before or during surgery, permitting the initiation of effective analgesic therapy in the early phase of the postoperative period. • When patients are able to tolerate oral intake, they may be switched from IV to oral PCM to maintain the predictable analgesia established by the IV route.

16. Distribution: • The volume of distribution of paracetamol is approximately 1 L/kg. • Oral bioavailability 80% • Paracetamol is not extensively bound to plasma proteins(10%) • Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg/mL) were observed in the Cerebro Spinal Fluid as and from the 20th minute following infusion.

17. Paracetamol metabolized by the liver mainly to glucuronide conjugates but also sulphate and cysteine conjugates • These are actively excreted in the urine, only small fraction being excreted unchanged. • N- acetyl-p-amino-benzoquinoneimine is a highly toxic metabolite of paracetamol that produced in small amount in therapeutic doses. • It is rapidly conjugated with hepatic glutathione to render it harmless

18. Following toxic dose – gluthatione is exhausted, NAPQI accumulates – then free to form covalent bonds with sulphydryl groups on hepatocytes resulting cell death and centrilobular hepatic necrosis • Treatment: - with oral methionine(enhances gluthatione synthesis) and/or oral or IV acetylcysteine which is hydrolysed to a precursor of glutathione

19. IV Paracetamol - Presentation

20. Composition: • One ml contains 10mg paracetamol • One 50 ml vial contains 500mg paracetamol • One 100 ml vial contains 1000mg paracetamol

21. The 100 ml vial or 100 ml bag is restricted to adults, adolescents and children weighing more than 33 kg. • The 50 ml vial is adapted to infants, toddlers and children weighing less than 33 kg.

22. Recommended dose of IV paracetamol…

23. IV Paracetamol : administration… • IV Paracetamolshould be given by infusion over 15 minutes • minimum dose interval should not be less than four hours (six hours in patients with renal impairment).

24. Once the vacuum seal of the glass vial has been penetrated, the dose of IV must be administered within 6 hours. • IV Paracetamolis a single-use vial, and the unused portion must be discarded. • To prevent the possibility of an air embolism, it is important to observe the end of the infusion

25. can also be diluted in a 0.9% sodium chloride solution or 5% glucose solution • Use the diluted solution within the hour following its preparation (infusion time included).

26. NON–WEIGHT-BASED DOSING: • For 1000 mg (10 mg/mL) doses, deliver from the bottle Use aseptic technique to prepare the vial and IV line

27. Insert a vented IV set into upright vial; open vent

28. Hang bottle; adjust flow for 15-minute infusion • Monitor the end of the infusion in order to prevent the possibility of an air embolism

29. WEIGHT-BASED DOSING: For extracted doses <1000 mg (10 mg/mL), deliver from separate container • For small-volume pediatric doses up to 60 mL • Using aseptic technique, withdraw appropriate dose from vial and into a syringe as above • Administer over 15 minutes using a syringe pump

30. Since introduction, there have been concerns about accidental overdose of IV paracetamol due to errors in drug prescription and administration, particularly in children, small adults, the elderly, alcoholics and those with pre-existing hepatocellular insufficiency.

31. Reported errors include: - incorrect dose in adults with high or low body mass index; - accidental overdose in children associated with use of 100ml- vials; - 10-fold drug calculation errors; - confusion between dose volume in millilitres and dose of drug in milligrams; - errors when setting up infusion pumps; - and duplication of doses between the ward and the operating theatre or recovery.

32. SALG recommendations… • IV paracetamolshould be prescribed carefully, according to the weight, age and co-morbidities of the patient. The upper dose limit for each single dose and in each 24-hour period should not be exceeded. • 50ml vials of IV paracetamol should be used for patients less than 33kg. In infants and small children, doses should be measured accurately using a syringe.

33. Enquiry about recent paracetamol ingestion should form part of routine pre-operative assessment. • All doses of paracetamol administered in the operating theatre should be recorded on the drug administration chart and in the anaesthetic record.

34. Advice should be sought from the local poisons information service in all cases of overdose of intravenous paracetamol. • Treatment with acetylcysteine is suggested following a single dose greater than 60mg/kg. • IV paracetamol remains under intensive monitoring by the MHRA. • All suspected adverse reactions to IV paracetamol should be reported to the Yellow Card Scheme and discussed with the local poisons information service.

35. PCA OxyNorm

37. Oxycodone is a semi-synthetic derivatives, full opioid agonist with no antagonist properties. • It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. • Oxycodone is similar to morphine in its action. - The therapeutic effect is mainly analgesic, anxiolytic and sedative.

38. Oxynorm… • belongs to a group of medicines called strong analgesics • Indication: * commonly used as an analgesic in moderate to severe acute pain * also used in moderate to severe cancer pain, and sometimes in chronic non-cancer pain

39. Opiod receptor classification… Reseptor type Location Action when stimulated µ receptor *brain especially - analgesia areas involved - physical with sensory & dependence motor perception - resp depression and integration - reduced peristalsis - Abundant in - euphoria preaqueductal grey. - meiosis *Spinal cord δ receptor * brain - Analgesia - anti depressant - physical dependence

40. Reseptor type Location Action when stimulated Ƙ receptor * Brain - Spinal analgesia * Spinal cord - Sedation - Meiosis NOP receptor * Brain - Anxiety ( nociceptin * spinal cord - Depression Orphanin FQ - Affect learning Peptide receptor and memory - Most recently - involved in identified tolerance

41. Other pharmacological effects of oxycodone : - respiratory depression, antitussive, bronchospasm - smooth muscle (constipation, reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi and transient elevations in serum amylase) - nausea and vomiting : CTZ stimulation via 5- HT3 and dopamine receptors - cardiovascular system (release of histamine and/or peripheral vasodilatation, possibly causing pruritus, flushing, sweating and/or orthostatic hypotension).

42. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. - Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

43. Pharmacokinetics… • Absorption - 40% to 85% bioavailability after oral administration - presence of methoxy group at C3 position of the phenanthrene structure protects drug against glucuronide conjugation, and hence first pass effect -100% bioavailability after iv administration

44. Distribution: • Distributed to skeletal muscle, liver, intestinal tract, lungs, spleen and brain. - tissues with mu, kappa and delta opiod receptors • Pka 8.5. at pH 7.4, 7.4% unionized Vd 2-6 L/kg 45% protein binding

45. Metabolism & Elimination: • Oxycodone has an elimination half-life of approximately 3 hours • metabolisedprincipally in the liver to noroxycodone and oxymorphone. • Oxymorphonehas some analgesic activity but present in plasma in low concentrations and is not considered to contribute to oxycodone’s pharmacological effect. • CYP3A4 and CYP2D6 are involved in the formation of noroxycodone and oxymorphone, respectively. • Metabolites mainly excreted in urine and sweat, accumulates in patients with renal impairement.

46. PCA oxynorm : administration… • Concentration: Oxycodone hydrochloride 10 mg/ml • Dilute to 1 mg/ml in 0.9% saline, 5% dextrose or water for injections. • Setting: * Bolus doses : 0.03 mg/kg (e.g. 1-2mg per 70 kg) * lock-out time : minimum 5 minutes. * Background infusion : nil * Four hour dose limit : 30 mg

47. Discontinuation of PCA... • PCA should be discontinued when minimal use is required and the patient is able to tolerate oral analgesia • Full explanation and reassurance must be given to the patient. • Ensure that adequate analgesia is prescribed. • Continue regular pain assessment after the pain control system has been discontinued and act accordingly.

48. Transferring patients between oral and parenteral oxycodone… • The dose should be based on the following ratio: 2 mg of oral oxycodone is equivalent to 1 mg of parenteral oxycodone. • It must be emphasized that this is a guide to the dose required. • Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

49. Buprenorphine patch

50. BUPRENORPHINE… • is a semisynthetic, highly lipophilic derivative of the opium alkaloid thebain • approximately 25-50 times as potent as morphine, usual dose ~ 0.3-0.6 mg • Buprenorphine is a partial agonist .has high affinity for, but low intrinsic activity at, mu receptors. • however, its maximal opioid effects are less than that of full agonists, and reach a ceiling where higher doses do not result in increasing effect. • produces analgesia and other effects similar to morphine, including CVS