EFEK ANTINOSISEPTIF PREGABALIN PADA PENDERITA PASCABEDAH HISTEREKTOMI

THE ANTINOCICEPTIVE EFFECTS OF PREGABALIN ON POST-OPERATIVE HYSTERECTOMY PATIENT

Hermanus J Lalenoh1, A Husni Tanra2, Irawan Yusuf3

1 Bagian Anestesiologi, Fakultas Kedokteran, Universitas Sam Ratulangi Manado, 2 Bagian Anestesiologi, Fakultas Kedokteran, Universitas Hasanuddin Makassar,

3 Bagian Fisiologi, Fakultas Kedokteran, Universitas Hasanuddin Makassar.

Alamat Korespondensi:

dr Hermanus J Lalenoh

Bagian Anestesiologi – Fakultas Kedokteran

Universitas Sam Ratulangi

Manado

HP : 08124401700, 082191851020

E-mail : dr.h.j.lalenoh@gmail.com

2 ABSTRACT

It is important to put attention on the post operative pain as the effective management of pain will decrease the morbidity and mortality, accelerating mobilization and reduce the duration of hospitalization. This study aims to determine the effects of Pregabalin as anti-nociceptive on the blood concentration of glutamate and substance-P in hysterectomy post-operative patients. This research is an experimental study, with randomized controlled clinical trial in which patients were randomly divided into two groups. The number of patients included in this study was 52 women (age 20-50) who underwent hysterectomy surgery. They were divided into group I (n = 26), orally administered Pregabalin 3 mg/Kg of body weight; and group II (n = 26), orally administered Placebo , both were given an hour before surgery. All patients had general anaesthetic, which is the premedication with sulfas atropine and fentanyl injection, induction with propofol injection, and maintenance of anesthesia with N2O: O2, isoflurane and atracurium injection. Patients were intubated and controlled breathing. Pre-operative and after surgery the levels of pain experienced by patients were assessed at 0-hour, 1-hour, 8-hours and 24-hours post-operative, by rating the VAS, blood pressure and heart rate. The examination for levels of glutamate and substance-P in the blood was performed pre-operative, prior to administration of pregabalin and 1-hour post-operative. The amount of morphine injections was monitored until 24-hours post-operative. The results showed a significant increase in the level of pain (VAS), blood pressure, heart rate and the amount of post-operative morphine consumption in the group of patients who were given placebo, compared with the group of patients who were given pregabalin. In pregabalin group, the levels of glutamate and substance-P in blood remained constant or decreased after the surgery. Whereas in placebo group, the levels of glutamate and substance-P in blood increased after the surgery. As the conclusion the pregabalin has antinociceptive effects and can be used as preemptive analgesia.

Keyword: glutamate, substance-P, post-operative pain

PREFACE

Post operative pain is one of the problem from the patient ongoing an operative

procedure. It is important to put attention in order to reduce the morbidity & mortality rate,

early mobilization and reduce the length of stay. The pain consists of the acute and chronic

one. One of the acute pain i.e. the nociceptive pain is the pain caused by nociception as the

result of tissue injury. Post operative pain is one of the acute pain induced by tissue injury and

inflammation (Dellemijn, 2006). This process increase the sensitivity of the peripheral and

central nerves manifested as the feel of pain. Zahn reported 50-70% post operative pain

patients are not treated well (Pogatzki et al, 2007). Drug of choice for post operative pain is

the Non Steroid Anti Inflammatory Drugs. In fact, the post operative pain is hard to eliminate

with NSAIDs only and additional of narcotic analgetic (morphine, pethidine & fentanyl) is

required. Nowadays the preemptive technique (drugs intake before surgery for post operative

pain) is well known (Woolf et al, 1993).

Pregabalin & gabapentine are first known as the anticonvulsant drugs and used as

antiepileptic (Seib et al, 2006), but later these drugs also effective for neuropathic pain (post-

herpetic neuralgia and diabetic neuropathy). Later, the pregabalin & gabapentine are used for

nociceptive pain and post operative inflammation pain. Fassoulki in his study found that the

induction of gabapentine reduce the using of analgetic after mastectomy (Fassoulki, 2005).

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Dirks also found the same result, after giving gabapentine per oral one hour before surgery

(Dirks, 2002). Turan also found that gabapentine will reduce the need of analgesia after

surgery (Turan, 2004). Dahl reported the role of pregabalin and gabapentine for post operative

pain, but further study is advised (Dahl, 2004). Seib found that gabapentine is ideally used for

chronic neuropathic pain only (Seib et al, 2006). Bartholdy did not find the difference using

the morphine within the group with gabapentine and without gabapentine for post operative

pain (Bartholdy et al, 2006).

In contrary, Bromley reported the preemptive analgesia i.e. giving analgetic via oral

one hour before surgery for cure the post operative pain. The drug of choice for this technique

is pregabalin, due to the good pharmacokinetic compared with gabapentine. They found that

the pregabalin will reduce the necessity of morphine post operative and it is also will reduce

the side effects of analgesia agents post operative (Bromley, 2006).

Pregabalin has the structure that is similar with gamma aminobutyric acid (GABA) but

work through the presynaptic cannal Ca2+, inhibit Ca2+ into the cell. This condition will

suppress the production of glutamate and substance-P from pre-synaptic and will reduce the

sensitization and hyperalgesia (Brett, 1998; Eutamene, 2000 ., Mao, 2000). Antihyperalgesia

in this case is caused by the inhibition of glutamate and substance-P neurotransmitters by

pregabalin. The hyperalgesia is also found in neuropathic and post operative pain. Therefore,

it is considered the use of pregabalin for reduce hyperalgesia in post operative care, due to its

anti nociceptive and reduce the perception of post operative pain. This study is aimed to

figure out antinociceptive effect of pregabalin to the level of glutamate and substance-P in

blood and post operative pain.

MATERIAL & METHOD

Location & Methodolgy

The sample of this study are the patients with hysterectomy procedure with anesthesia,

in the central surgery installation of Prof. Dr. R. D. Kandou Hospital, Manado, Indonesia

from January to May 2012. This study is an interventional, with randomized controlled trial

clinical test. The sample taken are 52 patient, divided into 2 groups randomly, 26 with

pregabalin and the control group with placebo.

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Sample & Population

Target Population in this study are adult patients with operative procedure with

anesthesia in the central surgery installation of Prof. Dr. R. D. Kandou Hospital, Manado,

Indonesia. Achieved Population in this study are adult patients with operative procedure with

anesthesia in healthy condition unless for the operative procedure from January to May 2012.

The sample are taken with consecutive sampling. The chosen sample are women patient with

hysterectomy et cause uterine myoma with anesthesia, age 35 – 50 years old, with ASA 1 and

ASA 2.

Data Sampling

All samples are organized based on the surgical procedure and divided into two groups

randomly with random number table. The intervention in this study is the double mask. Both

groups consist of the control group and the group with intervention. The blood sample is

taken from all the patient for glutamate and substance P level before giving the drugs.

Group with pregabalin : One hour before surgery the patient is given pregabalin 150

mg orally, and 30 minutes before surgery the patient is given the injection of sulfas atropine

0,01 mg/kg/day and fentanyl 0,1 ug/kg intramuscular. Control group :One hour before surgery

the patient is given placebo (glucose in capsule) orally, and 30 minutes before surgery the

patient is given the injection of sulfas atropine 0,01 mg/kg/day and fentanyl 0,1 ug/kg

intramuscular. The pregabalin used here is Lyrica (Pfizer), in capsule 150 mgs.

Post operatively both groups are given the injection of morphine intravenously with

PCA infuser. The level of pain is observed during 24 hours since the end of surgical

procedure, using the Visual Analog Scale (VAS) for the pain effect on the cardiovascular

system, the amount of morphine consumption with PCA infuser, the side effect of morphine

(nausea, vomitus) and the side effect of pregabalin (drowsy & dizziness).

The assessment for both groups are the systolic & diastolic blood pressure and heart

rate before surgery, immediately after surgery, 1 hour, 8 hours & 24 hours after surgery; level

of pain with Visual Analog Scale immediately after surgery, 1 hour, 8 hours & 24 hours after

surgery; the amount of morphine used for 24 hours with PCA infuser and level of glutamate

and substance-P in blood before surgery (before giving the pregabalin or placebo) and 1 hours

after surgery. The examination of glutamate and substance-P level is with ELISA kit (USCN,

Wuhan ElAab Science Co.Ltd. Cat No.E0393h). Observation of side effects of pregabalin and

morphine immediately after surgery, 1 hour, 8 hours & 24 hours after surgery.

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Data Analysis

The independent T-test is used for the homogeneity test between two groups basic on

age, weight, height, duration of surgery, fentanyl and isoflurane consumption, while the Mann

Whitney-U Test is used for the movement of systolic and diastolic blood pressure, heart rate,

glutamate and substance P level and the amount of morphine consumption during

observation. Chi Square Test is used for the analysis for the variability of systolic and

diastolic blood pressure, heart rate, glutamate and substance P level between two groups.

Spearman Correlation Test is used for analyze the correlation of variability of pain level with

systolic blood pressure, diastolic blood pressure, heart rate, glutamate and substance-P level

and the amount of morphine consumption.

RESULT

This study observed 52 patients randomly consist of two groups with the individual

variation spread evenly between two groups. The result of homogeneity test based on the age,

weight, height, duration of surgery, fentanyl and isoflurane consumption. The variable of age

between two groups are the same (36-48 year) with the mean of the pregabalin group is 41,7

year and 40,7 year on the control group. The analysis independent t-test shows the p = 0,240

(p>0,05). The mean of weight on the pregabalin group is 54,6 kgs and the control group is

54,9 kgs with p = 0,861 (p>0,05). The mean of height on the pregabalin group is 158,8 cm

and the control group is 157,9 cm with p=0,390 (p>0,05). The mean of surgery duration on

the pregabalin group is 114,6 minutes and the control group is 109 minutes with p=0,118

(p>0,05). The mean of fentanyl consumption on the pregabalin group is 86,5 g and the

control group is 82,7 g with p=0,557 (p>0,05). The mean of isoflurane consumption on the

pregabalin group is 1,04 vol% and the control group is 1,08 vol% with p=0,657 (p>0,05).

Therefore, the variation of age, weight, height, duration of surgery, fentanyl and isoflurane

consumption between two groups show no significant differences and regarded as homogene.

Level of Pain (VAS)

The visual analog scale (VAS) is used to observe the level of pain from the patient

before surgery, early after surgery, 1 hour after surgery, 8 hour after surgery & 24 hour after

surgery (see table 1 & graphic 1). From the data we can see that there is no difference

between two groups for before surgery pain. On the pregabalin group the early after surgery

pain is found on the median VAS 50 mm while the control group is 60 mm with p = 0,000 (p

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< 0,05). On the 1 hour after surgery pain, the pregabalin group is in the median of VAS 40

mm and control group is 55 mm with p = 0,000 (p<0,05). On the 8 hour after surgery pain, the

pregabalin group is in the median of VAS 40 mm and control group is 50 mm with p = 0,000

(p<0,05). On the 24 hour after surgery pain, the pregabalin group is in the median of VAS 20

mm and the control group is 30 mm with p = 0,003 (p<0,05).

The VAS score after surgery is slightly increase on both groups, while on the control

group the raising point is higher than the pregabalin group. The variation of VAS between the

two groups is analyzed with Mann Whitney-U test and shows a significant difference

(p<0,05) between the control group and the pregabalin group on the 1 hour after surgery pain,

8 hour after surgery pain and 24 hour after surgery pain.

Blood Pressure

The dynamic analysis of systolic blood pressure is measured on both groups before

surgery, early after surgery, 1 hour after surgery, 8 hour after surgery and 24 hour after

surgery. Data shows that before surgery the median systolic blood pressure on the pregabalin

group is 120 mmHg while the control group is 130 mmHg with p = 0,001 (p < 0,05). Early

after surgery the median systolic blood pressure on the pregabalin group is 127,5 mmHg

while on the control group is 130 mmHg with p = 0,891 (p>0,05). On the 1 hour after surgery,

the median systolic blood pressure on the pregabalin group is 130 mmHg while on the control

group is 140 mmHg with p = 0,000 (p<0,05). Eight hour after surgery, the median systolic

blood pressure on the pregabalin group is 120 mmHg, and the control group is 137,5 mmHg

with p = 0,000 (p<0,05). On the 24 hour after surgery, the median systolic blood pressure on

the pregabalin group is 115 mmHg and the control group is 120 mmHg with p = 0,000

(p<0,05). The median systolic blood pressure for all time of observation is slightly higher on

the control group compare with the pregabalin group.

The Mann Whitney-U Analysis Test shows the significant difference of systolic blood

pressure (p<0,05) between two groups before surgery, 1 , 8 and 24 hour after surgery. From

the data we can see that early after surgery on the control group, the systolic blood pressure

remain Stabile on 12 from 26 patients (46,15%) and increasing on 14 from 26 patients

(53,84%). On the pregabalin group the stabile systolic blood pressure is found on 18 from 26

patients (69,23%) and increasing on 8 from 26 patients (30,76%). One hour after surgery the

Stabile systolic blood pressure is 6 from 26 patients (23,07%) and increasing on 20 from 26

patients (76,92%) on the control group, while on the pregabalin group the Stabile systolic

blood pressure is found on 17 from 26 patients (65,38%) and increasing on 9 from 26 patients

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(34,61%). Eight hour after surgery on the control group, the stabile systolic blood pressure is

8 from 26 patients (30,76%) and the increasing systolic blood pressure is 18 from 26 patients

(69,23%), while on the pregabalin group the stabile systolic blood pressure is 24 from 26

patients (92,30%) and increasing on 2 from 26 patients (7,69%). On the 24 hour after surgery

of the control group, the stabile systolic blood pressure is found on 24 from 26 patients

(92,30%) and increasing on 2 from 26 patients (7,69%).

On the pregabalin group, the stabile systolic blood pressure is found on 26 from 26

patients (100%) and no increasing systolic blood pressure (0%). The general monitoring on

these data show that there is a increasing of systolic blood pressure after surgery. The

accumulation of increasing systolic blood pressure is higher on the control group compare

with the pregabalin group. The Chi Square test shows the significant increasing of systolic

blood pressure (p<0,05) on 1 hour and 8 hour after surgery on both groups. From the data the

median diastolic blood pressure before surgery on the pregabalin group is 80 mmHg and the

control group is 80 mmHg with p = 0,500 (p>0,05).

The median diastolic blood pressure early after surgery on the pregabalin group is 80

mmHg and the control group is 90 mmHg with p = 0,001 (p<0,05). The median diastolic

blood pressure 1 hour after surgery on the pregabalin group is 80 mmHg and control group is

90 mmHg with p=0,000 (p<0,05). On the 8 hour after surgery, the median diastolic blood

pressure on the pregabalin group is 80 mmHg while the control group is 90 mmHg with p =

0,000 (p<0,05). The median diastolic blood pressure 24 hour after surgery on the pregabalin

group is 80 mmHg and the control group is 80 mmHg with p = 0,137 (p>0,05).

The general evaluation from early after surgery until 8 hour after surgery shows higher

diastolic blood pressure on the control group compare with the pregabalin group. The Mann

Whitney-U test shows significant diference (p<0,05) between the contrl group and pregabalin

group during the observation early after surgery, 1 hour and 8 hour after surgery. From the

data shows that early after surgery, the Stabile diastolic blood pressure on the control group is

found on 10 out of 26 patients (38,46%) and the increasing diastolic blood pressure is found

on 16 out of 26 patients (61,53%) and on the pregabalin group the Stabile diastolic blood

pressure is found on 11 out of 26 patients (42,30%), increasing diastolic blood pressure is

found on 11 out of 26 patients (42,30%) and decreasing diastolic blood pressure is found on 4

out of 26 patients (15,38%).

One hour after surgery on the control group, the Stabile diastolic blood pressure is

found on 2 out of 26 patients (7,69%) and increasing on 24 out of 26 patients (92,30%) and on

the pregabalin group the Stabile diastolic blood pressure is found on 15 out of 26 patients

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(57,69%) and increasing diastolic blood pressure is found on 11 out of 26 patients (42,30%).

Eight hour after surgery on the control group the Stabile diastolic blood pressure is found on 8

out of 26 patients (30,76%) and increasing on 18 out of 26 patients (69,23%), while on the

pregabalin group the Stabile diastolic blood pressure is found on 20 out of 26 patients

(76,92%) and increasing on 6 from 26 patients (23,07%). On the 24 hour after surgery on the

control group, the Stabile diastolic blood pressure is found on 18 out of 26 patients (69,23%),

increasing on 6 out of 26 patients (23,07%) and decreasing on 2 out of 26 patients (7,69%),

while on the pregabalin group the Stabile diastolic blood pressure is found on 21 out of 26

patients (80,76%), increasing on 3 out of 26 patients (11,53%) and decreasing on 2 out of 26

patients (7,69%). On the general assessment, the increasing of diastolic blood pressure on the

control group is higher than the pregabalin group. The Chi Square Test shows significant

difference (p<0,05) on 1 hour and 8 hour after surgery only.

Heart Rate

From the analysis, we found that on the pregabalin group the median heart rate is 80

x/m while on the control group is 80 x/m with p = 0,959 (p>0,05). Early after surgery on the

pregabalin group the median heart rate is 88 x/m and 93 x/m on the control group with p =

0,001 (p<0,05). One hour after surgery, on the pregabalin group the median heart rate is 88

x/m and 96 x/m on the control group with p = 0,000 (p<0,05). On the monitoring 8 hour after

surgery, the median heart rate in pregabalin group is 84 x/m and control group is 94 x/m with

p=0,000 (p<0,05). On 24 hour after surgery, the median heart rate in pregabalin group is 81

x/m and 80 x/m on the control group with p=0,740 (p>0,05). The overall assessment of the

median heart rate on the control group is higher than the pregabalin group. The Mann

Whitney-U Analysis Test result shows significant difference (p<0,05) between two groups on

the monitoring early after surgery, 1 hour and 8 hour after surgery.

From the data, early after surgery on the control group, the stabile heart rate is 8 out of

26 patients (30,76%) and increasing heart rate on 18 out of 26 patients (69,23%) and on the

pregabalin group, the Stabile heart rate is 16 out of 26 patients (61,53%) and increasing heart

rate on 10 out of 26 patients (38,46%). One hour after surgery on the control group, the

Stabile heart rate is 3 out of 26 patients (11,53%) and increasing on 23 out of 26 patients

(88,46%), and on the pregabalin group the Stabile heart rate is 15 out of 26 patients (57,69%)

and increasing on 11 out of 26 patients (42,30%). On the analysis 8 hour after surgery on the

control group, the Stabile heart rate is 9 out of 26 patients (34,61%) and increasing on 17 out

of 26 patients (65,38%) while on the pregabalin group the Stabile heart rate is 23 out of 26

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patients (88,46%) and increasing on 3 out of 26 patients (11,53%). On the analysis 24 hour

after surgery on the control group, the Stabile heart rate is 24 out of 26 patients (92,30%) and

increasing on 2 out of 26 patients (7,69%), while on the pregabalin group the Stabile heart

rate is 24 out of 26 patients (92,30%) and increasing on 2 out of 26 patients (7,69%). On the

general analysis between the two groups, the increasing heart rate was found higher on the

control group rather than the pregabalin group. The Chi Square Test result shows significant

difference of raising heart rate level (p<0,05) early after surgery, 1 hour and 8 hour after

surgery.

Level of Neurotransmitter

In order to observe the dynamic response of neurotransmitters, we did the examination

of serum glutamate and substance-P before surgery and 1 hour after surgery. The dynamic

analysis result of serum glutamate level on both groups can be seen on table 2 and graphic 1.

From this data, we can see that the glutamate level before surgery on the pregabalin group is

vary between 2 – 114 pg/ml with median 23,5 pg/ml, while on the control group is vary

between 8 – 95 pg/ml with median 39,5 pg/ml and p=0,093 (p>0,05). One hour after surgery

on the pregabalin group the glutamate level is vary between 1 – 92,8 pg/ml with median 22,6

pg/ml and the control group is vary between 10,8 – 118,9 pg/ml with median 67,6 pg/ml with

p = 0,000 (p<0,05). On the observation before surgery and 1 hour after surgery, the median

level of glutamate on the control group is higher than the pregabalin group.

The Mann Whitney-U Analysis Test result shows significant difference of serum

glutamate level (p<0,05) on the observation 1 hour after surgery between two groups. From

the data showed, 1 hour after surgery on the control group increasing on 25 out of 26 patients

(96,15%) and decreasing on 1 out of 26 patients (3,84%), while on the pregabalin group the

serum glutamate level increasing on 4 out of 26 patients (15,38%) and decreasing on 22 out

of 26 patients (84,61%). The result of X2 test of duration of observation shows significant

difference on raising level of glutamate production (p<0,05) 1 hour after surgery on the

control group compare with the pregabalin group. In conclusion, the pregabalin inhibit the

raising of glutamate production 1 hour after surgery.

From the data, the level of substance-P before surgery on the pregabalin group is vary

between 11-185 pg/ml with median 48,5 pg/ml, while on the control group is vary between 6-

154 pg/ml with median 60,5 pg/ml and p = 0,510 (p>0,05). One hour after surgery on the

pregabalin group, the substance-P level is vary between 2,3 – 173,5 pg/ml with median 19,3

pg/ml while on the control group is vary between 23,6 – 205,6 pg/ml with median 59,6 pg/ml

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and p = 0,000 (p<0,05). On the observation before surgery and 1 hour after surgery, the

median level of substance-P in control group is higher than the pregabalin group. The Mann

Whitney-U Analysis Test shows significant difference of substance-P level (p<0,05) between

control group and pregabalin group 1 hour after surgery.

We can see that 1 hour after surgery on the control group the level of substance-P

increases on 20 out of 26 patients (76,92%) and decreases on 6 out of 26 patients (23,07%),

while on the pregabalin group, the level of substance-P increases on 5 out of 26 patients

(19,23%) and decreases on 21 out of 26 patients (80,76%). The X2 test result shows

significant difference of raising substance-P level (p<0,05) 1 hour after surgery on control

group compare with pregabalin group. In conclusion, pregabalin decreases the produce of

substance-P 1 hour after surgery.

Morphine Consumption

In order to observe the level of pain from the patient, it is important to assess the

consumption of morphine used with PCA in 24 hours. From the data, the use of morphine

during 24 hours in pregabalin group is vary between 5 – 10 mg with median is 7 mg, while on

the control group is vary between 6 – 15 mg with median 10 mg and p = 0,000 (p<0,05). The

Mann Whitney-U Test result shows significant of number of morphine used for injection

(p<0,05) in 24 hour after surgery between the control group and pregabalin group.

Relationship of VAS, Vital Sign & Neurotransmitter Level

The relationship of level of pain (VAS) with blood pressure, heart rate, glutamate

level, substance-P level and morphine consumption is done by the correlation test. We found

that the change of post operative pain (VAS) is related significantly (p<0,05) to the variation

of systolic blood pressure, diastolic blood pressure, heart rate, glutamate level, substance-P

level and number of morphine used in 24 hour after surgery.

Comparison of Glutamate Level & Substance-P Level

The comparison of serum glutamate and substance-P level in 1 hour after surgery

between two groups can be seen on table 2&3. As the conclusion, the production of glutamate

and substance-P is different significantly on pregabalin group compared with control group.

From graphic 5 & 6, the giving of preemptive pregabalin cause the level of glutamate after

surgery is constant, while the level of substance-P decreases. Therefore, as a conclusion the

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giving of preemptive pregabalin will inhibit the production of glutamate and substance-P on

the neuron 1 hour after surgery.

DISCUSSION

In this study we found lower level of pain from patient given preemptive pregabalin

compared with patient without preemptive pregabalin. The VAS level in the control group is

higher than the group with preemptive pregabalin. The Whitney-U Analysis Test result shows

significant difference (p<0,05) between two groups early after surgery, 1 hour, 8 hour and 24

hour after surgery. This result proves that the preemptive pregabalin is quite effective to

reduce to post operative pain.

This study is in contrary with the study of Bartholdy that proves the difference level of

pain between patient with and without pregabalin (Bartholdy, 2006). This study is appropriate

with the study of Bromley that give pregabalin 1 hour before surgery and proves that

pregabalin reduces the level of post operative pain (Bromley, 2006).

The tissue injury caused by surgery and peripheral sensitization with several chemical

mediators produced will induce the neuroendocrine response i.e. sympathoadrenal activities

with several effects : increasing of heart rate and blood pressure. The perception of pain from

the patient after surgery stimulates the activation of sympathetic nerves (increasing of heart

rate and blood pressure). In this study we find that the systolic and diastolic blood pressure

after surgery increase higher on the control group compared with the pregabalin group. On the

statistic study, there is a significant difference between two groups 1 hour and 8 hour after

surgery.

The heart rate also increase higher on the control group. On the statistic study, there is

a significant difference of heart rate between two groups early after surgery, 1 hour and 8 hour

after surgery. This study is correspond with the study of Hong (2008) that showed the

increasing of blood pressure and heart rate is higher on the control group 1 hour - 4 hour after

surgery. The increasing of the hemodynamic parameter (blood pressure & heart rate) describe

the sensation of pain from the patient. Tissue injury and inflammation reaction caused by

surgical procedure will induced peripheral sensitization.

On the next step, through the transmission the noxious impulse from peripheral

nociceptor will be passed through to the first order neuron (presynaptic neuron). In this

presynaptic neuron, the impulse will induce Ca2+ into the cell through Ca2+ cannal. This

condition will caused the release of several neurotransmitters (glutamate & substance-P) from

presynaptic neuron end into the second order neuron (postsynaptic) that will induce the

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sensation of pain. Therefore, the post operative pain is highly related with the increasing level

of glutamate and substance-P in blood. In this study, the level of glutamate and substance-P

after surgery increase significantly on the control group compared with the pregabalin group.

The statistic study also shows significant difference of glutamate and substance-P level

(p<0,05) in both groups.

Post operatively each patient will be given morphine injection through PCA and in

this study we find that there is raising level of morphine consumption on the control group.

From the statistic study there is a significant difference the using of morphine from the

control group that is higher than the pregabalin group in 24 hour (p<0,05). This study is

correspond with the study of Dirks (2002) and Turan (2004) that proved the number of

morphine used as analgesic decrease on the patients given gabapentin orally 1 hour before

surgery.

From the Spearman correlation test, there is a significant relationship (p<0,05)

between the level of pain (VAS) and the variation of systolic blood pressure, diastolic blood

pressure, heart rate, glutamate level, substance-P level and the consumption of morphine.

There is significant difference on the increasing level of glutamate and substance-P in blood

after surgery on the control group compared with the pregabalin group. On the graphic 5 & 6,

we can see the preemptive pregabalin will increase the level of glutamate after surgery, but in

contrary it decreases the level of substance-P. In other words, the preemptive pregabalin will

reduce the level of pain from the patients.

CONCLUSION & SUGGESTION

Preemptive pregabalin will induce the antinociceptive effect to the post operative

patient i.e. decreasing of pain level, proven by the VAS score, systolic blood pressure,

diastolic blood pressure, heart rate and abating use of morphine in 24 hour after surgery.

Preemptive pregabalin will inhibit the production of glutamate and substance-P on the first

neuron in the posterior cornu of the spinal cord 1 hour after surgery. The transmission of pain

to the second neuron in the posterior cornu of the spinal cord will decrease and so the

perception of pain. The Substance-P is more responsive than glutamate in term of the effect of

pregabalin. For the further study, it is better to evaluate the level of glutamate and substance-P

8 hour and 24 hour after surgery and it is also important to evaluate the level of COX-2 in

blood in order to find out the relationship with glutamate and substance-P level. It is

important to consider the preemptive pregabalin before surgery for the patient ongoing a

surgical procedure in order to reduce the need of post operative analgesic agents.

13 REFFERENCE

Bartholdy,J., Hilsted,K. (2006). Effect of gabapentin on morphine demand and after laparoscopic sterilization using Filshie clips. BMC Anesth. 6 :12.

Brett,P.,Chaplan,S., Sakamoto., Yaksh,T.L. (1998). Characterization of the effects of gabapentin and 3-Isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia. Anesth. 88 : 196-205.

Bromley,L. (2006). Pre-emptive analgesia and protective premedication. Bio Pha. 60: 336 – 340.

Dahl,J.B. (2004). Protective premedication : an option with gabapentin and related drugs. Acta Anaesthesiol Scand . 48 : 1130 - 1136.

Dellemijn,P.L.I. (2006). Recent developments in the understanding of . pain: Recent advances in multidisciplinary pain management, Dutch Foundation Post Graduate Medical Courses in Indonesia. 5-10 .

Dirks,J., Fredensborg,B.B. (2002). A randomized study of the effects of single dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesth. 97 : 3: 560 - 564.

Eutamene,H., Coelho,A.M. (2000). Antinociceptive effect of pregabalin in septic shock induced rectal hypersensitivity in rats. The Journal of Pharmacology and Experimental Therapeutics. 295 : 1 : 162 - 167.

Fassoulaki,A., Triga,A. (2005). Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 101 : 1427 - 1432.

Hong, J.Y. 2008. The effect of preemptive epidural analgesia on postoperative pain and white blood cell response in laparascopic hysterectomy. Korean J Anesthesiol. 48 (6) : 521 – 525.

Mao,J., Chen,L. (2000). Gabapentin in pain management. Anesth Analg. 9 1 : 680 - 687.

Pogatzki,E., Zahn,P. (2007). Postoperative pain, clinical implications of basic research. Journal Home . 21 : 1 : 3-13.

Seib,R.K., Paul,J.E. (2006). Preoperative gabapentin for postoperative analgesia. Can J Anaesth. 53 : 5 : 461 – 469.

Turan,A., Karamanhoglu,B. (2004). The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg. 98 : 1370 – 1373.

Woolf,C.J., Chong,M.S. (1993). Pre-emptive analgesia, treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg . 77 : 362 – 374 .

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Table 1. VAS variation on both groups during observation

Duration of Observation V AS (mm)

P value Pregabalin Group (n=26) Control Group (n=26)

Min - Max Median Min - Max Median

Before surgery 0 – 20 0 0 – 20 0 P > 0,05

Early after surgery 30 – 60 50 50 – 75 60 p = 0,000*

1hr after surgery 30 – 50 40 40 – 75 55 p = 0,000*

8hr after surgery 30 – 50 40 40 – 60 50 p = 0,000*

24hr after surgery 20 – 40 20 20 – 40 30 p = 0,003* Data are shown in minimal, maximal and mean value, deviation standard & probability were tested with Mann Whitney-U test, p < 0,05 is significant. P value < 0,05.

Table 2. Glutamate level alteration between two groups

Duration of Observation Glutamate Level (pg/ml)

P value Pregabalin Group (n=26) Control Group (n=26)

Min - Max Median Min - Max Median

Before Surgery 2 - 114 23,5 8 – 95 39,5 p = 0,093

1hr After Surgery 1 - 92,8 22,6 10,8 -118,9 67,6 p = 0,000* Data are shown in minimal, maximal and mean value, deviation standard & probability were tested with Mann Whitney-U test, p < 0,05 is significant. P value < 0,05.

Table 3. Substance-P level alteration between two groups

Duration of Observation Substance-P Level (pg/ml)

P value Pregabalin Group (n=26) Control Group (n=26)

Min – Max Median Min - Max Median

Before Surgery 11 – 185 48,5 6 – 154 60,5 p = 0,510

1hr After Surgery 2,3 – 173,5 19,3 23,6 -205,6 59,6 p = 0,000* Data are shown in minimal, maximal and mean value, deviation standard & probability were tested with Mann Whitney-U test, p < 0,05 is significant. P value < 0,05.

15

Graphic 1. Glutamate level alteration between two groups

p < 0,05 with Mann Whitney-U Test.

Graphic 2. The Substance-P alteration between two groups

p < 0,05 with Mann Whitney-U Test.

Before Surgery 1 Hour After Surgery

Glu

tam

ate

Lev

el (p

g/m

l)

Pregabalin Group Control Group

Before Surgery 1 Hour After Surgery

Subs

tanc

e=P

Lev

el (p

g/m

l)

Pregabalin Group Control Group