1. The combination of low dose of naloxone and morphine in PCA 10/4 Morning Meeting Yu Chang Yeh

2. The combination of low dose of naloxone and morphine in PCA Objective Backgrounds Patient selection and exclusion Standard setup

3. The combination of low dose of naloxone and morphine in PCA Intolerable side effects Low side effects setup Treatment failure and withdrawal Relevant studies

4. Objective Dose the combination of low does naloxone and morphine in PCA reduce the incidence of side effects and requirement of morphine?

5. Backgrounds 1 Without antiemetic drugs, the incidence of nausea was on average 43%, of vomiting was 55%, and of any emetic event was 67%.(1) Tramer MR, Walder B. Efficacy and adverse effects of prophylactic antiemetics during patient-controlled analgesia therapy: a quantitative systematic review. Anesth Analg 1999;88:1354-61

6. Backgrounds 2 Pruritus 55% Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997;81:77-84

7. Backgrounds 3 Low dose naloxone infusion (0.25ug/kg/hr) was effective in reducing the incidence of nausea, vomiting, and pruritus. It also deceased opioid requirements. Placebo/ 0.25ug/kg/hr/ 1ug/kg/hr 20/20/20 --- total 60 Gan Anesthesiology 1997;81:77-84

8. Backgrounds 4 1ug/kg/hr decreases opioid-related side effects but seemed to attenuate the pain relief provided by morphine. 64.7+/- 33mg vs 59.1 +/- 27.4mg in Placebo Gan Anesthesiology 1997;81:77-84 Included in Miller Anesthesia

9. Backgrounds 5 In animal study Enhanced release of endogenous opiates Up-regulation phenomenon Within 30 min Paronis CA J Pharmaol Exp Ther 1991;259:582-9. Yoburn BC J Pharmaol Exp Ther 1986;239: 132-5.

10. Backgrounds 6 But …… Direct combination of naloxone and morphine in PCA does not decrease opioid requirements or morphine- related side effects in the postoperative period. Cepeda MS, Africano JM, Manrique AM, Fragoso W, Carr DB. Pain 2002;96:73- 79

11. Backgrounds 7 Systemic reviews suggest that prophylaxis does not work very well, that there is a finite risk of adverse drug reactions with most antiemetic intervention, ant the treatment may be more cost effective than prophylaxis. Tramer MR. A rational approach to the control of postoperative nausea and vomiting: Acta Anesth Scand 2001;45:14-19

12. Backgrounds 8 We try to find out an optimal combination ratio of naloxone and morphine in PCA to reduce the severity of side effects related with PCA morphine. Only patients suffered form intolerable side effects were enrolled in our study.

13. Tab 1

14. Patients selection Inclusion criteria 1. Age 18-65y/o 2. ASA I-III 3. Surgical procedure < 5 hrs 4. Use PCA for postoperative pain control 5. Who suffers form intolerable side effects

15. Patient exclusion 1. Intraoperative Fentanyl use 4μg/kg 2. Patient with hiatal hernia and esophageal reflux symptoms 3. Recent use of antiemetics or antipruritic treatment after 4. Recent use of NSAIDs after operation

16. Standard PCA Setup Morphine 1mg/ml PCA dose 2ml Lockout time 10min No continuous dose

17. Intolerable side effects Nausea and vomiting Pruritus Urinary retention Change in consciousness Respiratory depression

18. Low side effect PCA setup PCA Morphine 1mg/ml Naloxone 2μg/ml PCA dose 2ml Lockout time 10min No continuous dose

19. Treatment failure Nausea and vomiting Pruritus Urinary retention Change in consciousness Respiratory depression Increase intensity of pain

20. Withdrawal Adjunct drugs for side effects

21. Measurements and Evaluation Evaluation of Pain intensity Pain on exertion – verbal numerical scale 0-10 Pain at rest – verbal numerical scale 0-10

22. Measurements and Evaluation Evaluation of side effects Nausea –  0 absent  1 mild  2 moderate  3 severe Vomiting –  number of events

23. Measurements and Evaluation Pruritus – 0 absent 1 mild 2 moderate 3 severe Urinary retention – yes / no

24. Measurements and Evaluation Consciousness – 0 alert 1 sleepy 2 stupor 3 coma Respiratory depression – respiratory rate

25. Tab 2

26. Tab 3

27. Tab 4

28. Fig 1

29. Fig 2

30. Tab 5

31. Relevant Studies 1 Naloxone – other applications 1 Septic and hemorrhagic shock Alcoholism Poatanesthetic apnea in infants Primary apnea and periodic breathing associated with hypoxemia Restore flow-resistive load compensation in patients with COPD

32. Relevant Studies 2 Naloxone – other applications 2 May ameliorate the neurologic deficit following an ischemic or traumatic neurologic insults in animals

33. Relevant Studies 3 Other Opioid antagonist Naltrexone Nalmefene  Long acting  Equipotent to naloxone  Plasma half life 3-10hours  Naloxone 64 +/- 12min  Morphine 2-7hours

34. Relevant Studies 4 Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous PCA Saline/ 15ug nalmefene / 25ug nalmefene Decrease the need for antiemetics and antipruritic medications

35. Relevant Studies 5 Lidocaine+Morphine vs Morphine alone Music Men and women Naloxone vs PCEA

36. Relevant Studies 6 1999 systemic review Droperidol Clonidine Ondansetron Tropisetron Metoclopramide Hyoscine Promethazine

37. Relevant Studies 7 2000 British Journal of Anesthesia Prevention of postoperative nausea and vomiting by continuous infusion of subhypnotic propofol in female patients receiving intravenous PCA, 20 Placebo, 5, 10, 15, 20 ug/kg/min No symptoms 25%,40%,45%,65%,75%

38. Relevant Studies 8 Total fentanyl consumption, 20 Placebo, 5, 10, 15, 20 ug/kg/min 413/585/537/514/712 ug

39. Thanks for your attention! Have a nice day!

40. Sample size Null hypothese / one or two sided alternative hypothese Appropriate statistical test Choose a reasonable effect size (and variability if necessary) Set α,β Use the appropriate tables or formula

41. Tab 6 Outcome variables Dichotomous Continusous Predictor variable Dichotomous Chi-square testT-test Continuous T-testCorrelation coefficient

42. E/S Effect Size (E) The difference in the mean value of the outcome variable between the study group Standard deviation(S) The variability of the outcome variables Standard effective size (E/S) For most study 0.1-0.5

43. Example The efficacy of Salbutamol and ipratropium bromide for the treatment of asthma FEV1 after 1 week treatment Previous study Mean 2liter with S 1liter Effective size 0.2liter (10%) Standard effective size 0.2/1 = 0.2

44. Example α= 0.05 β= 0.2 (power = 0.8) Look across the Table 394 for each group

45. Example Sample size (per equal-sized group) = 16 / (E/S) 2 Try to reduce the sample size Increase E Decrease S