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 : [email protected]
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
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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