The combination of low dose of naloxone and morphine in PCA 10/4 Morning Meeting Yu Chang Yeh.
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Transcript of The combination of low dose of naloxone and morphine in PCA 10/4 Morning Meeting Yu Chang Yeh.
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The combination of low dose of naloxone and morphine in PCA
10/4 Morning Meeting Yu Chang Yeh
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The combination of low dose of naloxone and morphine in PCA
ObjectiveBackgroundsPatient selection and exclusion Standard setup
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The combination of low dose of naloxone and morphine in PCA
Intolerable side effectsLow side effects setupTreatment failure and withdrawal Relevant studies
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Objective
Dose the combination of low does naloxone and morphine in PCA reduce the incidence of side effects and requirement of morphine?
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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
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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
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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/hr20/20/20 --- total 60Gan Anesthesiology 1997;81:77-84
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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 PlaceboGan Anesthesiology 1997;81:77-84Included in Miller Anesthesia
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Backgrounds 5
In animal studyEnhanced release of endogenous opiatesUp-regulation phenomenonWithin 30 minParonis CA J Pharmaol Exp Ther 1991;259:582-9.Yoburn BC J Pharmaol Exp Ther 1986;239: 132-5.
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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
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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
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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.
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NO
NO
<Standard PCA Setup> Drug: 1mg/ml Morphine PCA dose: 2ml Lockout time 10min
Intolerable side effects A. Nausea / Vomiting B. Pruritus C. Urinary retention D. Change in consciousness E. Respiratory depression
Yes
<Adjust PCA Setup> Drug:1mg/ml Morphine+ 2μ g/ml Naloxone PCA dose: 2ml Lockout time 10min
Intolerable side effects A. Nausea / Vomiting B. Pruritus C. Urinary retention D. Change in consciousness E. Respiratory depression F. Increase intensity of pain
Yes
1. Withdrawal 2. Adjunct drugs for side effects
<Inclusion criteria> 1. Age 18-65y/o 2. ASA I – III 3. Surgical procedure < 4hours
<Exclusion criteria> 1. Intraoperative Fentanyl use > 4μ g/kg
2. Post-OP NSAIDs and antiemetics use
Tab 1
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Patients selection
Inclusion criteria1. Age 18-65y/o2. ASA I-III3. Surgical procedure < 5 hrs4. Use PCA for postoperative pain control5. Who suffers form intolerable side effects
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Patient exclusion
1. Intraoperative Fentanyl use 4μg/kg2. Patient with hiatal hernia and esopha
geal reflux symptoms 3. Recent use of antiemetics or antipruri
tic treatment after 4. Recent use of NSAIDs after operation
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Standard PCA Setup
Morphine 1mg/mlPCA dose 2ml Lockout time 10minNo continuous dose
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Intolerable side effects
Nausea and vomitingPruritusUrinary retentionChange in consciousnessRespiratory depression
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Low side effect PCA setup
PCAMorphine 1mg/mlNaloxone 2μg/mlPCA dose 2mlLockout time 10minNo continuous dose
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Treatment failure
Nausea and vomitingPruritusUrinary retentionChange in consciousnessRespiratory depressionIncrease intensity of pain
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Withdrawal
WithdrawalAdjunct drugs for side effects
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Measurements and Evaluation
Evaluation of Pain intensity Pain on exertion – verbal numerical
scale 0-10 Pain at rest – verbal numerical scale
0-10
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Measurements and Evaluation
Evaluation of side effects Nausea –
0 absent 1 mild 2 moderate 3 severe
Vomiting – number of events
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Measurements and Evaluation
Pruritus – 0 absent 1 mild 2 moderate 3 severe
Urinary retention – yes / no
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Measurements and Evaluation
Consciousness – 0 alert 1 sleepy 2 stupor 3 coma
Respiratory depression – respiratory rate
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個案編號:
Low Dose Naloxone in PCA 研究記錄表
姓名 性別 ( )M ( )F 病歷號
Age y/o 身高 cm 體重 kg
ASA 手術日期 手術時間
過去病史 ( ) HT ( )DM ( ) CVA ( ) CAD ( ) Allergy
( ) Asthma ( )COPD ( ) Prior Surgery _______
( ) Others
手術名稱
( )ETGA ( )LMA ( ) IVG
麻醉方式
術中使用 Fentanyl 總劑量 ______ug / kg
Time 靜痛 動痛 BP HR RR 噁心 嘔吐 癢 積尿 意識
PCA開始使用時間 發生副作用時間 改成研究配方時間 Demand Delivery Total 10min 30min 1hr 2hr 4hr 8hr
發生副作用前使用 PCA總劑量 ____ mg 整個療程 PCA用量 ____ mg 評估指數參考依據 (請填數字或文字敘述亦可)
休息時疼痛 疼痛指標 0-10 0 不痛 10最痛
移動時疼痛 疼痛指標 0-10 0 不痛 10最痛
生命徵象 血壓 心跳速率 呼吸速率
意識變化 0 清醒 1 想睡 2 沉睡 3 昏迷
噁心 0 無 1 輕微 2 中等 3 嚴重
嘔吐 請記錄次數
皮膚癢 0 無 1 輕微 2 中等 3 嚴重
尿液積留 0 無 1 有
Tab 2
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Low Dose Naloxone in PCA研究記錄表
姓名 病歷號
開始使用 PCA時間 月 日 時 分
產生副作用時間 月 日 時 分
產生副作用時評估
靜痛 動痛 BP HR RR 意識 噁心 嘔吐 癢 積尿
改成低副作用配方後一小時評估
靜痛 動痛 BP HR RR 意識 噁心 嘔吐 癢 積尿
兩小時後評估
靜痛 動痛 BP HR RR 意識 噁心 嘔吐 癢 積尿
四小時後評估
靜痛 動痛 BP HR RR 意識 噁心 嘔吐 癢 積尿
八小時後評估
靜痛 動痛 BP HR RR 意識 噁心 嘔吐 癢 積尿
評估指數參考依據 (請填數字或文字敘述亦可)
休息時疼痛 疼痛指標 0-10 0 不痛 10最痛
移動時疼痛 疼痛指標 0-10 0 不痛 10最痛
生命徵象 血壓 心跳速率 呼吸速率
意識變化 0 清醒 1 想睡 2 沉睡 3 昏迷
噁心 0 無 1 輕微 2 中等 3 嚴重
嘔吐 請記錄次數
皮膚癢 0 無 1 輕微 2 中等 3 嚴重
尿液積留 0 無 1 有
Tab 3
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TABLE 10–3. Characteristics of Opioid Receptors
Tissue bioassay Guinea pig ileum Mouse vas deferens Rabbit vas deferens
Endogenous ligand Enkephalin Enkephalin Dynorphin
-Endorphin (?)
Exogenous agonist ligand Morphine DPDPE U 50,488
Phenylpiperidines DADLE 1 Butorphanol
DAMGO, DAGO Deltorphin Bremazocine
Antagonist Naloxone Naloxone Naloxone
Naltrexone Naltrindole NorBNI
Cloned (human) Yes Yes Yes
Subtypes 1,2,3 1,2,3 1,2,3
G protein–coupled Yes Yes Yes
Adenylate cyclase Inhibits Inhibits Inhibits
Voltage-dependent calcium channels
Inactivates Inactivates Inactivates
Potassium channel conductance
Increases Increases ?
Actions
Analgesia, sedation, respiratory depression, miosis, bradycardia, nausea, vomiting, decreased gastrointestinal mobility
Supraspinal analgesia Respiratory depression (?)
Spinal analgesia Diuresis Dysphoria Respiratory depression, (weak)
Tab 4
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Fig 1
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Fig 2
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TABLE 10–22. Reported Severe Complications Following Naloxone Administration
AUTHOR NALOXONE DOSE
(IV, mg) COMPLICATION
Azar1068 0.4 Hypertension (270/140)
Estilo1069 0.4 Hypertension (260/140); cerebrovascular accident
Flacke1070 0.4 Pulmonary edema
Tanaka1071 0.4 Hypertension (340/150)
Andree1072 0.4 Cardiac arrest, death
0.4 Cardiac arrest, death
Prough1073 0.1 Pulmonary edema
0.2 (+0.3 IM) Pulmonary edema
Michaelis1074 0.1 Ventricular tachycardia, ventricular fibrillation
0.4 Ventricular fibrillation
Partridge1075 0.08 Pulmonary edema
Taff1076 0.3 Pulmonary edema
Tab 5
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Relevant Studies 1
Naloxone – other applications 1 Septic and hemorrhagic shock Alcoholism Poatanesthetic apnea in infants Primary apnea and periodic breathing as
sociated with hypoxemia Restore flow-resistive load compensation
in patients with COPD
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Relevant Studies 2
Naloxone – other applications 2 May ameliorate the neurologic deficit
following an ischemic or traumatic neurologic insults in animals
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Relevant Studies 3
Other Opioid antagonist Naltrexone Nalmefene
Long acting Equipotent to naloxone Plasma half life 3-10hours Naloxone 64 +/- 12min Morphine 2-7hours
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Relevant Studies 4
Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous PCASaline/ 15ug nalmefene / 25ug nalmefeneDecrease the need for antiemetics and antipruritic medications
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Relevant Studies 5
Lidocaine+Morphine vs Morphine aloneMusic Men and womenNaloxone vs PCEA
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Relevant Studies 6
1999 systemic review Droperidol Clonidine Ondansetron Tropisetron Metoclopramide Hyoscine Promethazine
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Relevant Studies 7
2000 British Journal of AnesthesiaPrevention of postoperative nausea and vomiting by continuous infusion of subhypnotic propofol in female patients receiving intravenous PCAPlacebo, 5, 10, 15, 20, 20 ug/kg/min No symptoms 25%,40%,45%,65%,75%
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Relevant Studies 8
Total fentanyl consumption Placebo, 5, 10, 15, 20, 20 ug/kg/min 413/585/537/514/712 ug
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Thanks for your attention!
Have a nice day!
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Sample size
Null hypothese / one or two sided alternative hypotheseAppropriate statistical testChoose a reasonable effect size (and variability if necessary)Set α,βUse the appropriate tables or formula
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Tab 6
Outcome variables
DichotomousContinusous
Predictor variable
Dichotomous
Chi-square test
T-test
ContinuousT-test Correlation
coefficient
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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
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Example
The efficacy of Salbutamol and ipratropium bromide for the treatment of asthmaFEV1 after 1 week treatmentPrevious study Mean 2liter with S 1literEffective size 0.2liter (10%) Standard effective size 0.2/1 = 0.2
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Example
α= 0.05β= 0.2 (power = 0.8)Look across the Table 394 for each group
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Example
Sample size (per equal-sized group) = 16 / (E/S)2
Try to reduce the sample size Increase E Decrease S