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

The combination of low dose of naloxone and morphine in PCA

10/4 Morning Meeting Yu Chang Yeh


ObjectiveBackgroundsPatient selection and exclusion Standard setup


Intolerable side effectsLow side effects setupTreatment failure and withdrawal Relevant studies

Objective

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

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

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

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

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

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.

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

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

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.

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

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

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

Standard PCA Setup

Morphine 1mg/mlPCA dose 2ml Lockout time 10minNo continuous dose

Intolerable side effects

Nausea and vomitingPruritusUrinary retentionChange in consciousnessRespiratory depression

Low side effect PCA setup

PCAMorphine 1mg/mlNaloxone 2μg/mlPCA dose 2mlLockout time 10minNo continuous dose

Treatment failure

Nausea and vomitingPruritusUrinary retentionChange in consciousnessRespiratory depressionIncrease intensity of pain

Withdrawal

WithdrawalAdjunct drugs for side effects

Measurements and Evaluation

Evaluation of Pain intensity Pain on exertion – verbal numerical

scale 0-10 Pain at rest – verbal numerical scale

0-10


Evaluation of side effects Nausea –

0 absent 1 mild 2 moderate 3 severe

Vomiting – number of events


Pruritus – 0 absent 1 mild 2 moderate 3 severe

Urinary retention – yes / no


Consciousness – 0 alert 1 sleepy 2 stupor 3 coma

Respiratory depression – respiratory rate

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

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


兩小時後評估


四小時後評估


八小時後評估


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

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

Fig 1

Fig 2

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

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

Relevant Studies 2

Naloxone – other applications 2 May ameliorate the neurologic deficit

following an ischemic or traumatic neurologic insults in animals

Relevant Studies 3

Other Opioid antagonist Naltrexone Nalmefene

Long acting Equipotent to naloxone Plasma half life 3-10hours Naloxone 64 +/- 12min Morphine 2-7hours

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

Relevant Studies 5

Lidocaine+Morphine vs Morphine aloneMusic Men and womenNaloxone vs PCEA

Relevant Studies 6

1999 systemic review Droperidol Clonidine Ondansetron Tropisetron Metoclopramide Hyoscine Promethazine

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%

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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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

Tab 6

Outcome variables

DichotomousContinusous

Predictor variable

Dichotomous

Chi-square test

T-test

ContinuousT-test Correlation

coefficient

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

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

Example

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

Example

Sample size (per equal-sized group) = 16 / (E/S)2

Try to reduce the sample size Increase E Decrease S

Documents

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