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Comparison of Intra-Peritoneal Instillation of Bupivacaine and Morphine Hydrochloride versus Bupivacaine and Magnesium Sulfate for Post-Operative Pain Relief after Laparoscopic Cholecystectomy, A Randomized Double-Blind Comparison Study

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2018
Vol.4 No.1:6
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Research Article
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
DOI: 10.21767/2471-982X.100023
Wael Sadaqa*,
Obaida Weld Ali,
Aida Alkaissi,
Khaled Demyati,
Abdelkarim Barqawi,
Muhammad Jaber,
Muhammad Milhim,
Arab Ramadan,
Iyad Maqbool and
Waleed Rimawi
An-Najah Naonal University, Nablus,
Palesnian Territory, Israel
Corresponding author: Wael Sadaqa
w.sadaqa@najah.edu
Senior consultant-Anesthesia and intensive
care, Head of anesthesia and SICU, An-Najah
Naonal University, Nablus, Palesnian
Territory, Israel.
Tel: 00970599782246
Citation: Sadaqa W, Ali OW, Alkaissi
A, Demya K, Barqawi A, et al. (2018)
Comparison of Intra-Peritoneal
Insllaon of Bupivacaine and Morphine
Hydrochloride versus Bupivacaine and
Magnesium Sulfate for Post-Operave Pain
Relief aer Laparoscopic Cholecystectomy,
A Randomized Double-Blind Comparison
Study. Int J Anesth Pain Med. Vol.4 No.1:6
Comparison of Intra-Peritoneal
Insllaon of Bupivacaine and Morphine
Hydrochloride versus Bupivacaine and
Magnesium Sulfate for Post-Operave Pain
Relief aer Laparoscopic Cholecystectomy, A
Randomized Double-Blind Comparison Study
Abstract
Background: Surgical and laparoscopic techniques are two dierent methods for
the removal of gall bladder. Today, laparoscopic cholecystectomy is a preferred
method for short-term hospitalizaon and early return to funcon related to
minimal invasive surgical technique. However, paents sll complain of signicant
postoperave pain, secondary inammaon of the diaphragm and the nocicepve
genus of the annoying membrane's peritoneum.
Mulmodal analgesia is necessary for managing pain aer laparoscopic
cholecystectomy. Magnesium sulfate is a new emerging medicaon for the
management of acute pain. There are no previous reports to compare the analgesic
eect of intraperitoneal insllaon of bupivacaine plus morphine hydrochloride
and bupivacaine plus magnesium sulfate for postoperave pain aer laparoscopic
cholecystectomy.
Aim: The purpose of this study is to compare the analgesic eect of intraperitoneal
insllaon of bupivacaine plus morphine hydrochloride versus bupivacaine plus
magnesium sulfate in paents undergoing laparoscopic cholecystectomy under
general anesthesia for beer pain relief and less opioid consumpon during the
rst 24 hours.
Methods: Following the approval of the Instuonal Review Board of An-Najah
Naonal University and wrien informed consent from paents undergoing
laparoscopic cholecystectomy, hundred paents between 18 and 60 years old,
American Society of Anesthesiologist (ASA) Grades I and II, were randomized to
one of the following groups by the sealed envelope: (Mo group) (n=50) receiving
intraperitoneal insllaon of 30 ml 0.25% bupivacaine and 3 mg morphine and
(Mg group) (n=50) receiving intraperitoneal insllaon of 0.25% bupivacaine plus
50 mg/kg magnesium sulfate to a total volume of 30 ml. Medicaons were given
aer peritoneal wash and suconing through intraperitoneal insllaon. A drug
soluon is prepared by a doctor who does not parcipate in the study. All paents
received the same anesthesia method, general anesthesia was administered.
The inducon protocol was standard for all paents. Paents were monitored for
electrocardiogram (ECG), heart rate, blood oxygenaon (SpO2%) and noninvasive
blood pressure (NIBP). Postoperave pain was evaluated using visual analog
scale (pain score of 0-10). The parcipants were evaluated for 24 hours aer the
operaon with the registraon of abdominal pain. The postoperave pain outcome
was reported at 0 and 30 min, 1, 4, 8, 12, 16 and 24 hours. The cut-o value for
VAS is 4 for indicaon of rescue medicaon. At VAS 4, rescue analgesics were
administered on request (20 mg of pethidine) intravenously in Post Anesthec
Care Unit (PACU) and 50 mg intramuscularly in the surgical ward.
2018
Vol.4 No.1:6
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International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
Introducon
A symptomac gallstone disease is one of the prevailing
problems seen in clinical pracce [1]. Surgical removal of the
gall bladder can be done laparoscopic or open cholecystectomy
[2]. Laparoscopic cholecystectomy (LC) aords dierent
accomplishment compared to open cholecystectomy, and it is
the accepted gallstone treatment approach, as it contributes
minimum bowel guidance, culminang in hasty return to funcon
and reduce the length of stay at the hospital [3].
Similar to all surgical procedures, paents have compelling
postoperave pain; the paents experience severe abdominal
and throat pain at the start of the postoperave period and
crave pain relief aer laparoscopic surgery [4-8]. Progressive
manner to further reduce this pain are the subject of many on-
going studies. Intraoperave and postoperave techniques for
diminishing postoperave pain have been expressed [1]. Beer
control of postoperave pain can benet L.C. as a procedure for
day care and avert further complicaons. On-going pracce for
many instuons, including ours, is to release the paent on the
rst postoperave day [1].
In the United States, over 73 million surgical procedures are
executed on paents annually. Up to 75% of these paents
struggle with postoperave pain, which may have a decisive eect
Results: Paents' characteriscs of age, gender and BMI were comparable in the
two groups. There was no signicant dierence between the groups regarding the
duraon of the surgery. The demographic parameters (age, gender and BMI) have
no eect on the mean of VAS (p value>0.05). There are signicant dierences
between Mo and Mg groups in the total VAS score (p value<0.05). In the Mo group,
the mean of total VAS (2.09) was signicantly lower than the mean of total VAS in
the Mg group (2.71); which means that paents in the Mo group had signicantly
less intensity of pain than paents in the Mg group (p=0.006).
There is a signicant dierence between the number (percent) of paents
complaining of moderate to severe postoperave pain in Mo group 15/50 (30%)
compared to Mg group 25/50 (50%) (p=0.0423). When esmang the size of
the treatment eect of morphine hydrochloride plus bupivacaine, found that
the relave risk reducon of moderate to severe pain postoperavely is 0.40.
There is also a signicant dierence between the number (percent) of paents
complained of drowsiness in Mo Group 7/50 (14%) compared to Mg group 18/50
(36%) (p=0.0115). There are no signicant dierences between the two study
groups regarding nausea, voming, dizziness and urinary retenon.
Paents in Mo group consume less rescue analgesic dose M (± SD) (64.29
mg+22.04) compared to paents in Mg group M (± SD) (74.40 mg+25.67) without
signicant relaonship between both doses (p-value=0.163). Blood pressure,
heart rate and oxygen saturaon were examined as hemodynamic parameters.
The result showed that no signicant relaonship between these parameters and
VAS (p-value>0.05).
Conclusion: Intraperitoneal insllaon of combinaon of bupivacaine with
morphine hydrochloride is superior to bupivacaine plus magnesium sulfate to
reduce the intensity and incidence of postoperave pain in paents undergoing
laparoscopic cholecystectomy surgery without signicant increase of side eects.
This peripheral eect of opioid provides a new approach to pain relief that can
have major clinical benets.
Recommendaon: Based on the results of this study, it is recommended
to consider the intraperitoneal insllaon of morphine hydrochloride with
bupivacaine as a standard applicaon for laparoscopic cholecystectomy surgery
to reduce postoperave pain.
Keywords: Bupivacaine; Intra-peritoneal insllaon; Laparoscopic
cholecystectomy; Magnesium sulphate; Morphine hydrochloride; Rescue
analgesia; Post-operave pain.
Received: February 26, 2018; Accepted: April 20, 2018; Published: April 30, 2018
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© Under License of Creative Commons Attribution 3.0 License
Vol.4 No.1:6
2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
the impact of intraperitoneal local anesthesia for pain alleviaon
aer laparoscopic surgery. Combinaons of intraperitoneal
bupivacaine with morphine have been studied formerly [30]. The
results were demonstrated that paents with combinaons of
intraperitoneal bupivacaine and morphine may promote pain
relief and fewer opioid consumpon during the rst 24 hours,
compared with only the bupivacaine group.
Combinaons of intraperitoneal bupivacaine with magnesium
sulfate have been examined for the treatment of acute pain in
L.C. [31]. The results exhibited that intraperitoneal insllaon of
bupivacaine plus magnesium sulfate grants excellent analgesia in
the immediate postoperave period aer laparoscopic surgery.
There are no prior reports to compare the analgesic eect
of intraperitoneal insllaon of bupivacaine plus morphine
hydrochloride and bupivacaine plus magnesium sulphate for
postoperave pain aer laparoscopic cholecystectomy. The
purpose of this study is therefore to compare the analgesic eect
of intraperitoneal insllaon of bupivacaine plus morphine
hydrochloride versus bupivacaine plus magnesium sulfate to
provide eecve postoperave pain relief in paents undergoing
L.C. under general anesthesia.
Background
Chronological development of surgical
technique of cholecystectomy
Jean-Louis Pet, inventor of gallbladder surgery in 1733 proposed
ousng gallbladder and drainage of the gall bladder, thus
creang stula in paents with empyema which he protably
implemented in 1743 [32]. Marion Simms operated the rst
cholecystectomy of a 45-year-old woman with obstrucve
jaundice 1878 [33]. Mouret from France performed the rst
human L.C. On the day of March 1987, when he concluded a
gynecological laparoscopy on a woman who also complained
from symptomac gallstones, he shied his laparoscope to the
sub-hepac area. When he found a somewhat free and smooth
gall bladder, he determined to remove the laparoscopic instead
of opening. He implemented the procedure protably and the
paent recovered without complexity [34].
There are three components of pain aer laparoscopic surgery:
1. Visceral pain trunks from the expanding of the intra-
abdominal cavity and peritoneal inammaon.
2. Shoulder pain is the consequence of phrenic nerve
irritaon precipitated by enduring carbon dioxide in the
abdominal cavity.
3. Parietal pain as a result of surgical incision which is lower
in intensity by cause of its small size [35].
Pain
Denion of pain: Pain aer laparoscopy can be moderate or
on rehabilitaon me [9]. Acute postoperave pain alleviaon is
important for paent sasfacon and me for discharge, which
will promote results and lower healthcare expenditure [10]. Pain
can be visceral due to peritoneal irritability induced by oang
carbon dioxide in the abdomen, chest pain due to irritaon of
diaphragm and lesser oenmes parietal abdominal pain can
evolve when disturb the abdominal wall [11].
Dierent treatments have been proposed to treat pain aer
laparoscopy. The note of peritoneal inammaon aer carbon
dioxide, pneumoperitoneum, contributes to a legimate
framework for the pracce of non-steroidal an-inammatory
drugs (NSAIDs) [12-17]. Nonetheless, treatment of post
laparoscopic pain with NSAID revenues quesonable outcomes.
Presently, the common treatment for acute postoperave pain
is the pracce of systemic opioids [10]. Opioids are not apart
from complicaons [18]. Drowsiness, nausea, voming, urinary
retenon are all side eects of opioids. These side eects can
preeminent to longer stay and deprived paent outcomes [18].
Alternately, the handling of IV-acetaminophen is postoperavely
expanding [19,20]. This pracce restraints post-operave usage
of opioids and lessens opioid produced side eects [21]. Bringing
up rear, the usage of IV-acetaminophen should be ulized with
discreon in some paents, such as hypovolemia pernent
to dehydraon or blood loss, chronic malnutrion and severe
renal deterioraon. Further, IV acetaminophen is inconsistent in
paents with severe hepac devastaon [19,20].
The performance of injecng local anesthecs into the dierent
layers of the surgical secon (sore) is a familiar pracce in general
anesthesia of surgical cases [22]. Operaons with local anesthecs
have connued to increase in popularity since the mid 1990's
[23]. It is legimately inexpensive, technically uncomplicated,
and may probably diminish postoperave embarrassment [24].
Perioperave localizaon anesthesia (LIA) is one of the ulmate
techniques for accomplish these scopes [25-27]. LIA to the
surgery site is a simple way and has demonstrated an immense
impact on the abdomen, chest and plasc surgical seng.
Literally, it is an extensively used analgesic technique in the last
years. In this technique, a soluon is used that encompasses
long-term local anesthesia in combinaon with opioids, NSAIDs
or steroids [27,28].The eects of LIA may dier depending on the
type of surgical procedure, type and dosage of local anesthesia,
ancillary addion to local anesthesia, injecon in the incision or
whole wound [29].
There are two fundamental methods of local anesthec wound
seng: The rst is a precauonary model that administers
anesthesia pre-operavely. The second model administers
anesthecs immediately before surgical terminaon at the end
of surgery [10]. Currently, peripheral usage of local anesthecs
for postoperave pain administraon has become a favoured
method of laparoscopic surgery. Many reports are accessible on
2018
Vol.4 No.1:6
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International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
severe for part of paents. Progressively, the nature of pain
aer laparoscopy diverges signicantly from that observed aer
laparotomy. In fact, laparotomy primarily results in parietal
pain (abdominal wall); paents ascribe more of visceral pain
aer operave laparoscopy [36]. Shoulder pain aributes
to diaphragmac irritability subsequently of carbon dioxide;
pneumoperitoneum is a usual postoperave observaon aer
laparoscopy (35% to 60%) [14,37].
Visceral pain tales for the greater dislike experienced in the recent
postoperave period. Intensity diminishes quickly aer the rst
24 hours postoperavely. Although visceral pain progresses
aer L.C. is not impressed by mobilizaon, cough increments
its intensity. Indeed the mobilizaon test only enforced the
contracon of the abdominal muscles and did not comprise the
movement of the intra-abdominal viscera. In opposion, cough
harvest a brusque displacement of the liver and hence results
in smulaon of the inamed cholecystectomy wound. Parietal
pain is lesser intense than visceral pain by cause of the small
abdominal cuts and the bordered damage to the abdominal
wall. For the same apprehension, and in contrast to pain aer
laparotomy, parietal pain aer L.C. requires intense abdominal
muscle contracon to be incremented and consequently
aggravated only by cough but not bygone mobilizaon. Shoulder
pain, insignicant during the rst postoperave hours, then
increases to develop into the main trouble on the second day
post-operavely [38].
Shoulder pain that is conngent to the diaphragm's irritaon is the
major trouble in paents undergoing gynecological laparoscopy.
It is reasonable to propose that bupivacaine conducted in the
sub-diaphragmac area blocks nocicepve input engendered in
the inamed diaphragmac peritoneum. Aer L.C. Visceral pain
is prevalent, while shoulder pain is impercepble. An anatomic
intraperitoneal ow (or ux) advance local anesthesia to the
sub-membrane area [39,40] and aside from the cholecystectomy
wound. Therefore, pain convinced in this wound is not blocked,
although local anesthesia is conducted in its immediate
proximity. Correspondingly, local anesthesia aer intraperitoneal
administraon may not accomplish adequate local concentraon
to block nocicepve entrance from the abdominal wall. Finally,
shoulder pain, ignored in early postoperave period, can be
actually ignored by paents who, consequently, will not observe
any reducon aer intraperitoneal bupivacaine [38].
Pathophysiology of post-operave pain: Promptly enlarge
gastrointesnal tract can be accompanied with damage of blood
vessels, traumac clench of nerves and discharge of inammatory
mediators. The lengthened exist of shoulder pain [36,41,42]
suggest agitaon of the phrenic nerve. This pain is most common
aer laparotomy [43] and both laparotomy and laparoscopy are
accompanied with constant pneumoperitoneum, somemes for
3 days. There is a stascally signicant relaonship between the
width of the gas bubble and pain score [44] and this pain can
be diminished by aspiraon of the gas under the diaphragm [42]
with "acve aspiraon" is reduplicated sucon and manipulaon
[45] using a gas discharge or by applying local anesthesia under
the diaphragm under direct vision [46,47] or by a sub-frenic
catheter [48]. Peritoneal inammaon or the existence of gas is
perhaps also the root of the upper abdominal pain aer lower
abdominal surgery or aer diagnosc laparoscopy. This may also
ending for a minimum 3 days [41]. The usage of nitrous oxide
instead of carbon dioxide for peritoneal insuaon cannot be
pledged for the intra-abdominal explosions reported [49], but it
negavely reversal the incidence and severity of postoperave
pain or nausea and voming [50,51].
Pharmacodynamic and pharmacokinec of the
study drugs
The juscaon for choosing the intraperitoneal route is to
block the visceral aerence signal and possibly adjust visceral
nocicepon and give analgesia. Local anesthecs hinder
nocicepon by inuencing nerve membrane associated proteins
and by hindering the discharge and acon of prostaglandins
and other agents that animate or smulate the nociceptors and
devote to inammaon [52]. Nonetheless, absorpon from large
peritoneal surface may happen, which may be another analgesic
mechanism [30]. Bupivacaine is preferred in the current study
because of its eciency and long-term ecacy acvity. The half-
life of bupivacaine is between 5 hrs and 16 hrs [30].
By employing intraperitoneal local anesthesia (IPLA) it may
be conceivable to regulate peritoneal and visceral signalling
to the brain, by that alleviate the metabolic eect of visceral
surgery. There is a barricade of free aerent nerve endings in
the abdomen. Systemic penetraon of local anesthesia from the
abdominal cavity can also play a role in diminished nocicepon.
Local anesthecs have an-inammatory impacts and the
mechanism of these impacts can be prostaglandin antagonism,
hinder of leukocyte migraon and lysosomal enzyme discharge [30].
Morphine hydrochloride: Morphine is a denite mu receptor
agonist and the most hydrophilic opioid in clinical usage. The
hydrophilic quality concludes in reluctant passage athwart
membranes like the intesnal mucosa and the blood brain barrier.
The analgesic reacon is quiet even if given intravenously. Bio-
availability is largely decreased when given orally or rectally and
with relevant individual variances [53]. Morphine is metabolized
in the liver by unicaon to morphine 3-and morphine-6-
glucuronide [54-56]. Metabolites are eliminated through the
kidneys [57,58].
Common side eects associated with morphine use include:
Gastrointesnal side eects. These include nausea, voming,
stomach cramps and conspaon. Shrink pupils-Morphine
can account pupils to compress and emerge pointed in size.
Respiratory depression-The breathing mechanism can be
depressed due to limited blood oxygen levels. In healthy people,
when blood oxygen declines and blood carbon dioxide goes up,
respiratory drive increment. However, morphine debilitates this
drive in the brain [59].
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© Under License of Creative Commons Attribution 3.0 License
Vol.4 No.1:6
2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
Start doses advance to euphoria but at larger doses unpleasant
symptoms such as hallucinaons, delirium, dizziness and
confusion appear. There may be some headache and memory
loss. Biliary colic and consequent severe abdominal pain are
common in the overdose of morphine. With high doses, muscle
rigidity and abnormal movement of limbs and muscles called
myoclonus can confessed [59].
Magnesium sulphate: Magnesium is the fourth most familiar
caon in the body. It has relevant physiological roles in enzymac
acvaon of energy metabolism and protein synthesis [60].
Magnesium has also been demonstrated to have an-nocicepve
eects in animals and human models of chronic pain [61,62].
The analgesic tracts of magnesium are basically regarded to the
antagonism of the N-methyl-D-aspartate (NMDA) receptor and
the control of calcium inux in cells [61,63,64]. This analgesic
eect was rst demonstrated in humans in 1996 when magnesium
was given intravenously during the perioperave period [62]. It
has been suggested to reduce post-operave analgesic needs
[65,66].
Bupivacain: Bupivacaine is the determined local anesthec in
caudal, epidural and vertebral anesthesia and is most oen used
clinically to handle with acute and chronic pain [67].
Further to blocking Na- channels, bupivacaine inuences the
acvity of many other channels, counng NMDA receptors. It
is crucial that bupivacaine hinders NMDA receptor-mediated
synapc transmission in spinal dorsal horns, an area gravely
involved in centralized sensizaon [67]. Rising concentraons
of bupivacaine decreased GluN2 subunit channel transparency
and pH-independent ways by incremenng the average period of
closures and diminishing median me for openings [67].
Aim and Objecves
The purpose of this study is to compare the analgesic eect
of intraperitoneal insllaon of bupivacaine plus morphine
hydrochloride versus bupivacaine plus magnesium sulfate to
provide eecve postoperave pain relief in paents undergoing
L.C. under general anesthesia.
Problem Statement
Postoperave pain is one of the greater prevalent
problems aer L.C. Diminishing of postoperave pain
increases funconal recovery, decreased hospitalizaon
and postoperave morbidity.
There are three sorts of pain aer L.C: Incisional, visceral
and shoulder pain. The pain is caused by many factors and
is a mulmodal pathway, so pain relief is important [68].
The pain of laparoscopic procedures is basically visceral
in its origin. Factors that are extensive for this pain may
be regarded to surgical procedures, CO2 insuaon and
intra-abdominal pressure culvate during laparoscopic
procedure. Higher insuaon pressure should be
prevented as they can signicantly increment the severity
of postoperave pain [68].
Sub-phrenic and shoulder pain aer laparoscopic
procedures debut to derive from diaphragmac and
phrenic nerve irritaon due to insuated CO2. This pain
contributes to aggravate by ambulaon and may end
many days aer surgery. Remaining insuang gas can
also increment the intensity of post-laparoscopic pain.
Accordingly, the abdomen should be acvely vented at
the end of the laparoscopic procedure [68].
Opioids are the groundwork of post-operave pain
monitoring; high dose opioids have many side eects such
as respiratory depression, ileus, nausea and voming.
Any other way the devaluaon of opioid dose would
increments the degree of postoperave pain in paents.
Some complicaons can be prevented when diminishing
postoperave pain in L.C, for example limited respiratory
eort and inability to adequately cure secreon, leading
to a reducon in funconal residual capacity, early airway
closure, segment or lobar collapse, retenon of secreon
which can generate bronchopneumonia [69].
Signicance of the Study
Surgical procedures are accompanied with ssue destrucon and
the majority of paents treated will experience some degree of
pain aer surgery. Many paents complain from moderate or
severe pain aer surgery. Research has demonstrated that poorly
handled pain management can have both acute and chronic
adverse eects. Peripheral acon of opioid especially in inamed
ssue administer support for the existence of peripheral opioid
receptors and provides a new accession to pain management that
can have major clinical advantages. Yet there is stac argument
and local anesthesia insllaon has not proved to be an ulmate
method [70].
Magnesium sulfate is adjuvant that antagonizes calcium similar
to the NMDA receptor antagonists [66,71]. Magnesium and
Bupivacaine award both safe and cheap medicines to decrease
postoperave pain and analgesic consumpon and have been
used as eecve adjuvants for postoperave pain handled [72].
Postoperave recovery may be protracted by postoperave pain
and complicaons may happen more periodically [73]. According
to our knowledge, no data have been published about the
incidence of postoperave pain or the eect of post-operave
pain management in Palesne. The ulmate vision is to improve
postoperave pain management to the point where pain aer
surgery can be prevented and surgery becomes "painless".
Literature Review
Postoperave pain management planning should begin during
the preoperave period. There are several studies that deal
with the monitoring and control of pain aer L.C. and compare
the eect of wound seng with marcaine and opioids, such as
morphine, as compared to magnesium sulphate for postoperave
analgesia [74].
Addion of opioid to local anesthecs results in beer
2018
Vol.4 No.1:6
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International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
postoperave analgesia and reduces opioid demand aer
surgery as described in a study by Chander et al. [75]. The same
study shows that unbearable cut pain decreased when adding
fentanyl as opioid to bupivacaine and decreased analgesic
postoperave consumpon [75]. Tverosky et al. [76] determined
that wound adjustment provides good postoperave analgesia,
which facilitates a fast and even recovery. Local anesthecs are
potent long-term and act through several mechanisms including
inhibion of the eects of prostaglandins, inhibion of migraon
of leukocytes and reduce of vascular permeability.
The results of the study conducted by Upadya et al. [77] included
a total of 60 paents ASA I and II planned for L.C. included, group
I received 2 mg/kg 0.5% bupivacaine as a local intraperitoneal
applicaon and group II paents received 1 g of paracetamol
every 6 hours. Postoperavely, paents were assessed for pain
using Visual Analog Scale (VAS), Visual Rang Scale (VRS), and
Shoulder pain. The total number of paents required to save
analgesia (R.A.) and possible side eects was noted, the authors
show that intraperitoneal and intra-incisional insllaon of 0.5%
bupivacaine gives lower visual analogue scale up to 4 hours.
Postoperavely.
On the other hand, Eldaba et al. [78] studied local anesthesia
with magnesium sulfate aer caesarean secon, a total of 120
paents, ASA I-II was recruited for Caesarean secon. At the end
of the operaon, the wound was inltrated connuously at a rate
of 5 ml/h for 24 hours postoperavely with one of the following
soluons: 0.25% bupivacaine, a mixture of 0.125% bupivacaine
and 5% magnesium sulfate or normal saline (0.9%). Total opioid
consumpon, VAS in rest and movement, the occurrence of opioid
adverse events and signs of ulceraon were evaluated during the
study period (24 hours aer surgery). Remaining pain, surgical
wound infecon, need for addional anbioc treatment and
wound healing failed; and showed that the connuous wound
infusion with local anesthesia alone reduced opioid needs by
approximately 37%. At the same me, connuous wound infusion
with a mixture of local anesthesia and magnesium sulphate
reduces opioid demand by approximately 75% compared to
placebo. Opioid-saving eect reduced postoperave nausea and
voming, sedaon and urinary retenon.
Research Queson
Is there a preference for a group of drugs on the other, which
is intraperitoneal insllaon of bupivacaine plus morphine
hydrochloride and bupivacaine plus magnesium sulfate to reduce
postoperave pain in paents undergoing laparoscopic surgery?
Research Hypothesis
There is a signicant dierence at a level of 0.05 related to
the intensity of post-operave pain between intraperitoneal
insllaon of bupivacaine (marcaine®) plus magnesium sulfate
group and bupivacaine (marcaine®) plus morphine hydrochloride
group in paents undergoing laparoscopic surgery.
There is a signicant dierence at a level of 0.05 related to the
consumpon of rescue medicaon that is Pethidine between
intraperitoneal insllaon of bupivacaine (marcaine®) plus
magnesium sulfate group and bupivacaine (marcaine®) plus
morphine group in paents undergoing laparoscopic surgery.
Study Design
A prospecve, randomized, double blind
comparison study:
Allocaon: Randomized.
Endpoint Classicaon: Safety/Ecacy Study.
Primary Purpose: Observaon.
Sites and sengs
The parcipants were taken from AN- Najah naonal university
Hospital, Nablus, Palesne. AN- Najah naonal university Hospital
was selected due to availability of high quality technologies, which
not available in any other hospital in west bank of Palesne, and
because of the An- Najah naonal university Hospital is a central
high advance hospital and covers the North region of West bank,
Palesne. The other hospital at Isshari Arab hospital in Ramallah
city, which is high level of technological progress.
Sample and sampling
The sample of the study was clients from the sengs which are
determined, the parcipants were chosen randomly, aer having
the permissions to conduct the study and assuring condenality.
The inclusion subjects
Ages 18 and 60 years
Male and female
ASA I-II
The exclusion subjects
Paent with hepac or renal dysfuncon
Use of opioid during 24 hrs prior to the study
Treatment with steroids prior to surgery.
Drug or alcohol abuse
Allergy to any of the study drug,
Chronic pain syndrome as a result of neurological disease
Sample size calculaon
A formula (i.e. Pocock's sample size formula) is used Sample size
was predened by power analysis depending on the likelihood
that the decision rule would lead to the conclusion that the pain
occurred in the control group (these data were taken from the
previous study) [78] and the incidence of pain in the treatment
groups would dier. The error (a) was set to 0.05 which is the
risk of making Type I errors, and (b) Power (1-type II error) was
set to 0.85. Minimum standard error=1. According to the ecacy
analysis, 50 paents were recommended in each group.
A formula (i.e. Pocock's sample size formula) that can be directly
applied for comparison of proporons P1 and P2 in two equally
7
© Under License of Creative Commons Attribution 3.0 License
Vol.4 No.1:6
2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
sized groups:
2
2)84.096.1(
)70.0-30.0(
]0.70)-(1 0.70 + 0.30)-0.30(1[ +=n
Where:
n: Required sample size
P1: Esmated proporon of study outcome in the exposed group
(i.e. combinaon therapy) (P1=0.30).
P2: Esmated proporon of study outcome in the unexposed
group (placebo therapy) (P2=0.70).
α: Level of stascal signicance
Zα/2: Represents the desired level of stascal signicance
(typically 1.96 for α=0.05)
Zβ: Represents the desired power (typically 0.84 for 80% power)
2
2
[0.30(1-0.30) + 0.70 (1-0.70)](1.96 0.84)
(0.30-0.70)
n= +
2
2
[0.30(0.70) + 0.70 (0.30)] (2.8)
(0.40)
n=
[0.21 + 0.21] (7.84)
0.16
n=
[0.42] (7.84)
0.16
n=
n≈ 50 paents
Thus, a total of 100 paents (50 for each group) should be
targeted for recruitment into the study
Randomizaon and blindness
Randomizaon was done through opaque and well-sealed
envelopes. The sequence generaon was done with a computer.
The number was printed on envelopes and the group was
wrien on the card together with the serial number. When the
paents arrived opened envelopes to see the group that would
be assigned.
Blindness: Paents, healthcare providers included in paent
care, as collected and analyzed data, were not aware of the
distribuon of the treatment group.
Methods and Intervenon Plan
A total of 100 paents, ASA I and II between the ages of 18
and 60, planned for laparoscopic surgery were included
in a randomized prospecve double-blind study aer
approval by the IRB and wrien informed consent.
The study inclusion criteria included the use of opioid for
24 hours. Pre-study, drug or alcohol abuse and allergy
to any of the study medicaons, chronic pain syndrome
where pain evaluaon was assessed unreliable due to
neurological disease or treatment with steroids prior to
surgery.
All paents received the same anesthec technique.
General anesthesia is administered. The inducon
protocol was standard for all paents. Paents are
monitored for electrocardiogram (ECG), heart rate (H.R.),
oxygen saturaon (Sa O2), noninvasive blood pressure
(NIBP) and end-dal CO2 (ETCO2). 18-gauge intravenous
cannula was inserted into a suitable vein on the dorsum
of non-dominant hand. During the intraoperave period.
All paents receive ring lactate at a rate of 7 ml/kg/h.
The paents are pre-oxygenated at 5 liters/min 100% O2
for 3 to 5 minutes. Anesthesia is induced by intravenous
administraon of fentanyl (2 μg/kg), propofol (2 mg/kg)
and to facilitate the endotracheal intubaon recuronium
(1 mg/kg). Anesthesia is maintained with a mixture
of air and oxygen 50%/50%, sevourane 1%-2% and
recuronium supplementaon is recorded. The venlaon
is adjusted to maintain ETCO2 between 35 mmHg and
40 mmHg. Paents are placed in trendelenburg posion
during laparoscopy, intra-abdominal pressure maintained
between 12 mmHg and 14 mmHg.
Standard laparoscopic cholecystectomy with 4-port
technique was performed. All operaons were performed
by a team of surgeons who have experience of laparoscopic
surgery.
Randomizaon was done through opaque and well-sealed
envelopes. The sequence generaon was done with a
computer. The number was printed on envelopes and the
group was wrien on the card together with the serial
number. When the paents arrived opened envelopes to
see the group that would be assigned. A drug soluon is
prepared by a doctor who did not parcipate in the study,
and drugs are lled in pre-coded syringes and given to the
surgeon.
Paents were also blinded for the administered drug. The
drugs were delivered in the same size syringe and the
same color by the surgeon. Nurses evaluang paents for
parameters in the post-anesthesia Care Unit (PACU) and
at the surgical ward are not aware of the treatment where
the paent was randomized
Mo group, 30 ml 0.25% bupivacaine and 3 mg morphine
intraperitoneal were received at the site of surgery via the
navel port with paent in a trendelenburg posion (aer
peritoneal washing and sucon).
Mg group, 30 ml 0.25% bupivacaine was received and 50
mg/kg magnesium sulfate was introduced in the same
paern as in the Mo group.
Co2 was then evacuated from the peritoneal cavity and
skin incision was sutured.
2
2
2
21
2211 )(
)-( )]-1()-1([
ZZ
PP PPPP
n
2018
Vol.4 No.1:6
8
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International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
Variable denions
Dependent variable
Dose of rescue analgesic in PACU and in the surgical ward
as connuous variable.
VAS degree in the PACU as connuous variable.
VAS degree in the surgical ward as connuous variable.
Adverse events (nausea, voming, drowsiness, dizziness,
urine retenon).
Independent variable
Intra-Peritoneal Insllaon of Bupivacaine and Morphine
Hydrochloride
Intra-Peritoneal Insllaon Bupivacaine and Magnesium
Sulfate
Age.
Gender.
Duraon of surgery.
Follow up of the paent
Usually the cut o value of VAS is 4 for rescue medicaon
indicaon. When VAS 4, rescue analgesic was
administered. Before inducon of anesthesia paents are
instructed how to use a 10 cm VAS (VAS-0 with end-point
labelled “no pain” and 10 to “worst conceivable pain”).
The degree of postoperave pain is assessed at 0, 1/2, 1,
4, 8, 12, 16, 24 hrs using the VAS score.
R.A. was administered on request, 20 mg of pethidine
intravenously in the recovery room and 50 mg
intramuscularly in the ward if needed. The number of
paents requiring rescue analgesia was recorded in each
group.
Paents evaluated for 24 hours post-operavely with
recording of abdominal pain using the standard 10 cm
VAS. The post-operave pain score reported at 0 and 30
minutes, then at 1, 4, 8, 12, 16 and 24 hours using the VAS
score.
The me of arrival in the post-operave recovery room
is dened as zero hr. post-operavely. Postoperavely, A
trained nurse assessed pain and analgesic consumpon.
If VAS is ≥4, 20 mg pethidine is administered as R.A. unl
paent felt comfortable or VAS<3. All adverse eects
including nausea voming and dizziness are recorded
during 24 hours postoperavely.
Total dose of pethidine requirement measured and
recorded in specied data sheet during next 24 hrs.
Postoperave monitoring included noninvasive BP, HR
and pulse and respiraon were recorded.
The following parameters are evaluated in all study
groups:
The incidence and severity of postoperave pain for 24
hrs (the severity of postoperave pain measured at 0. 0.5,
1, 2, 4, 6, 8, 12, 16 and 24 hrs. postoperavely, using VAS
pain score.
(1) Total dose of analgesia.
(2) Postoperave complicaons (nausea, voming, urine
retenon, drowsiness, dizziness).
(3) Postoperave hemodynamics (HR, BP).
Nausea is treated with metoclopramide (10 mg) i.v.
Morrow assessment of nausea and
emesis
If the voming frequency is twice or higher and/or the paent did
his nausea ≥ on Likert type scale (0-6), it is an indicaon to give
anemec (Pramin® 10 mg i.v.). Nausea was scored by a Lickert-
type scale, which is called MANE (Morrow Assessment of Nausea
and Emesis) [79]. This scale (0-6) was used in daily clinical pracce
on the post anesthec care unit (PACU) at our hospital. Symptom
severity is rated on the scale (0-6) to answer the queson “How
would you describe your nausea at its worst” from 0=none,
1=very mild, 2=mild, 3=moderate, 4=severe, 5=very severe and,
6=intolerable. MANE has been clinically validated and a test-
retest reliability coecient has been determined [79].
Rescue analgesia
Pethidine, like R.A., was administered on request, 20 mg I.V. in
PACU and 50 mg I.M. in the surgical ward as needed. The number
of paents requiring rescue analgesia was recorded in each
group.
Stascal Analysis
For stascal analysis, SPSS version 20.0 is used. The parametric
variables are presented as mean ± SD or frequency (%) and
analyzed by student t-test; Stascal analysis is performed
with an ANOVA test. Non-parametric variables are analyzed by
Chi-Square. P<0.05 was considered as stascally signicant.
Pearson Correlaon between Age and total VAS in Mo and Mg
groups was used.
Ethical Consideraon
This study was conducted in accordance with the Helsinki
declaraon. Individual consent forms were obtained for all
parcipants.
Instuonal Review Board (IRB) approval of An-Najah
Naonal University is obtained.
Consent was obtained from the paent prior to
parcipaon.
Condenality and voluntary parcipaon to all
parcipants were insured
A detailed explanaon of the purpose and objecves of
the study was given to all paents.
9
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Vol.4 No.1:6
2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
Results
The purpose of the current study was to compare intraperitoneal
insllaon of bupivacaine and morphine hydrochloride versus
bupivacaine and magnesium sulfate for postoperave pain relief
aer L.C. 100 paents, ASA I & II, 18-60 years old were recruited
in the study.
Paent characteriscs regarding age, gender and BMI were
comparable in the two groups. There was no signicant dierence
between the groups regarding duraon of surgery Table 1. The
results in Table 2 show that there are no signicant relaonships
between the age and the total VAS in both study Mo and Mg
groups (P values>0.05). The Pearson correlaon coecient in Mo
group was (-0.112) and (-0.052) in Mg group. The results in Table
3 show that there are no signicant dierences between Males
and Females in the Total VAS score in both study Mo and Mg
groups (P values>0.05). In Mo group, the mean of total VAS was
(1.86) for males and (2.18) for females (p=0.328). In Mg group,
the mean of total VAS was (2.45) for males and (2.81) for females
(p=0.253).
The results in Table 4 show that there are no signicant
dierences between BMI groups in the Total VAS score in both
study Mo and Mg groups (P values>0.05). In Mo group, the mean
of total VAS was (2.38) for BMI group (35-39.9), (2.13) for BMI
group (<=24.9), (1.98) for BMI group (25-29.9), (1.83) for BMI
group (30-34.9) (p=0.738). In Mg group, the mean of total VAS
was (3.63) for BMI group (35-39.9), (3.06) for BMI group (<=24.9),
(2.72) for BMI group (25-29.9), (2.43) for BMI group (30-34.9)
(p=0.167).
The results in Table 5 show that there are signicant dierences
between Mo and Mg groups in the total VAS score (P value<0.05).
In Mo group, the mean of total VAS was (2.09) which is signicantly
lower than the mean of total VAS in Mg group (2.71); which means
that paents in Mo group signicantly had less intensity of pain
than paents in Mg group (p=0.006). The results in Table 6 show
that there are signicant dierences between Mo and Mg groups
in the VAS score only at the rst (1/2 hr.) In Mg group, the mean
of VAS at (1/2 hr.) was (2.8) which is signicantly higher than the
mean VAS at (1/2 hr.) in Mo group (1.78) (p=0.016) Figure 1.
The results in Table 7 show that there is no signicant dierence
between Mo and Mg groups in the total R.A. (P value>0.05).
In Mo group, the mean of total R.A. was (64.29) which is not
signicantly dier from the mean of total R.A.in Mg group (74.40)
(p=0.163).
Age and Total VAS Mo Mg
Pearson Correlaon -0.112 -0.052
Sig. (2-tailed) 0.602 0.807
Table 1 Pearson correlaon between Age and total VAS.
Total VAS Mo Mg
Gender M+S.D t(P-value) M+S.D t(P-value)
Male 1.86+0.75 -0.893(0.382) 2.45+0.81 -1.172(0.253)
Female 2.18+0.83 2.81+0.66
Table 2 Independent samples t test results between gender and total vas.
Total VAS Mo Mg
BMI M+S.D F(P-value) M+S.D F(P-value)
<=24.9 2.13+1.94
0.423(0.738)
3.06+0.44
1.871(0.167)
25-29.9 1.98+0.75 2.72+0.7
30-34.9 1.83+0.36 2.43+0.53
35-39.9 2.38+0.92 3.63+1.41
Total 2.04+0.79 2.71+0.72
Table 3 One way anova test results between bmi and total vas.
Total VAS Mo Mg
Type of Surgery M+S.D t(P-value) M+S.D t(P-value)
Elecve 2.11+0.84 0.681(0.503) 2.71+0.76 -0.042(0.967)
Acute 1.88+0.63 2.72+0.62
Table 4 Independent samples t test results between type of surgery and
total vas.
Total VAS M+S.D t(P-value)
Type of inltraon
Mo 2.09+0.81 -2.882(0.006)
Mg 2.71+0.71
Table 5 Independent samples t test results between type of inltraon
and total vas.
Type of inltraon Mo Mg t(P-value)
VAS(hr) M+S.D M+S.D
03.33+1.58 4.08+1.85 -1.518(0.136)
01-Feb 1.78+1.28 2.8+1.53 -2.491(0.016)
1 1.78+1.57 2.24+1.42 -1.061(0.294)
41.79+1.18 2.56+1.76 -1.789(0.08)
82.48+1.47 3.36+2.1 -1.671(0.102)
12 2.26+1.89 2.56+1.19 -0.662(0.511)
16 1.65+1.43 2.48+1.66 -1.841(0.072)
24 1.33+0.7 1.6+0.76 -1.271(0.21)
Table 6 Independent samples t test results between type of inltraon
and total vas through me.
Flow chart detailing the study.Figure 1
2018
Vol.4 No.1:6
10
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International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
The results in Table 8 show that there are no signicant dierences
between the number of paents in Mo and Mg groups in the
Total R.A. at dierent mes 30 min, 1, 4, 8, 12 and 24 hours (P
value>0.05). The number of paents who were requested rescue
medicaon in Mo group at 16 hr. 2(4%) is signicantly less than
in Mo group 12(24%) (p=0.0041). The results in Table 9 show that
there are no signicant dierences between Mo and Mg groups
in the SBP through me (all P values>0.05). In Mo group, the
mean of total SBP was (123.34) which is not signicantly dier
from the mean of total SBP in Mg group (123.45) (p=0.971). The
results in Table 10 show that there are no signicant dierences
between Mo and Mg groups in the DBP through me (all P
values>0.05). In Mo group, the mean of total DBP was (78.04)
which is not signicantly dier from the mean of total DBP in Mg
group (78.58) (p=0.79).
The results in Table 11 show that there are no signicant
dierences between Mo and Mg groups in the HR through me
(all P values>0.05). In Mo group, the mean of total HR was (81.35)
which is not signicantly dier from the mean of total HR in Mg
group (83.51) (p=0.36). The results in Table 12 show that there
are no signicant dierences between Mo and Mg groups in the
SpO2 through me (all P values>0.05). Mo group, the mean of
total SpO2 was (97.85) which is not signicantly dier from the
mean of total SaO2 in Mg group (98.05) (p=0.553). The results
in Table 13 show that there is signicant negave relaonship
between DBP and total VAS in Mg group (P value=0.033<0.05),
the Pearson correlaon coecient was (-0.428). In Mo group,
there is no signicant relaonship. The results also show that
there is signicant negave relaonship between SaO2 saturaon
and total VAS in Mo group (P value=0.009<0.05), the Pearson
correlaon coecient was (-0.518). In mg group, there is no
signicant relaonship.
Total rescue analgesia M+S.D t(P-value)
Type of inltraon
Mo 64.29+22.04 -1.419(0.163)
Mg 74.40+25.67
Table 7 The mean of total rescue analgesia within 24 hours.
Total Rescue
Analgesia (hr)
Value of
Pethidine Dose
(mg)
Mo Frequency
no. of paent (%)
Mg Frequency
no. of paent (%)
1/2 20 0 2(4%)
150 2(4%) 6(12%)
4 50 4(8%) 10(20%)
8 50 16(32%) 18(36%)
12 50 14(28%) 10(20%)
16 50 2(4%) 12(24%)
24 50 0 0
Table 8 Frequencies of total rescue analgesia through type of inltraon
and me.
Hemodynamic Mo Mg t(P-value)
Systolic blood pressure M+S.D M+S.D
0125.64+13.6 127.12+13.74 -0.383(0.704)
1/2 124.32+12.96 125.72+10.71 -0.416(0.679)
1 121.8+11.82 121.72+10.93 0.025(0.98)
4124.8+10.32 123.16+11.33 0.535(0.595)
8122.96+10.91 124.28+11.47 -0.417(0.679)
12 122.64+11.28 123.32+9.88 -0.227(0.822)
16 123+9.93 121.4+11.84 0.518(0.607)
24 121.56+9.06 120.84+10.98 0.253(0.802)
Tot 123.34+10.21 123.45+10.45 -0.036(0.971)
Table 9 Independent samples t test results between type of inltraon
and total sbp through me.
Hemodynamic Diastolic
blood pressure (hr)
Mo Mg t(P-value)
M+S.D M+S.D
078.72+8.34 80.04+9.34 -0.527(0.601)
1/2 78.88+7.13 79.48+8.03 -0.28(0.781)
1 77.28+6.83 77.92+7.99 -0.304(0.762)
478.76+7.15 79.2+8.33 -0.2(0.842)
878.52+7.7 78.64+8.84 -0.051(0.959)
12 77.6+7.82 78.12+8.25 -0.229(0.82)
16 77.84+6.16 77.4+9.44 0.195(0.846)
24 76.68+6.33 77.84+8.71 -0.539(0.593)
Tot 78.04+6.52 78.58+7.82 -0.268(0.79)
Table 10 Independent samples t test results between type of inltraon
and total dbp through me.
Hemodynamic
Heart Rate (hr)
Mo mg t(P-value)
M+S.D M+S.D
082.8+9.62 84.88+10.1 -0.745(0.46)
1/2 81.88+9.76 82.92+11.78 -0.34(0.735)
1 80.64+9.7 84.6+9.55 -1.454(0.152)
482.04+7.93 84.2+10.5 -0.82(0.416)
480.08+7.71 82.92+10.69 -1.077(0.287)
12 81.92+7.69 83.76+9 -0.777(0.441)
16 81.16+9.81 82.72+9.9 -0.56(0.578)
24 80.24+8.48 82.08+9.74 -0.712(0.48)
Tot 81.35+7.61 83.51+8.91 -0.924(0.36)
Table 11 Independent samples t test results between type of inltraon
and total hr through me.
Hemodynamic
Sa O2
Mo Mg t(P-value)
M+S.D M+S.D
097.4+1.71 97.48+2.73 -0.124(0.902)
1/2 97.24+1.61 97.68+0.99 -1.162(0.251)
1 98+1.85 97.88+1.2 0.272(0.787)
498+1.71 98.52+1.16 -1.26(0.214)
898.08+1.66 98.56+1.33 -1.131(0.264)
12 98+1.71 98.16+1.11 -0.393(0.696)
16 98+2.02 98.08+1.63 -0.154(0.878)
24 98.08+1.61 98.04+1.21 0.1(0.921)
Tot 97.85+1.42 98.05+0.88 -0.597(0.553)
Table 12 Independent samples t test results between type of inltraon
and total o2s through me.
11
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2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
From the other hand, the results show that there are no signicant
relaonships between SBP, HR and the Total VAS in both study
Mo and Mg groups (P values>0.05). The results in Table 14 show
that there are no signicant relaonships between Postoperave
complicaons and total R.A. in both study Mo and Mg groups (all
P values>0.05). Regarding nausea, in Mo group, the mean of total
rescue analgesia was (70) for paents who hadn't nausea and
(62.5) for paents who had nausea (p=0.521). In Mg group, the
mean of total R.A. was (53.33) for paents who hadn't nausea
and (77.27) for paents who had Nausea (p=0.132).
Regarding voming, in Mo group, the mean of total R.A. was
(61.67) for paents who hadn't voming and (67.78) for paents
who had voming (p=0.543). In Mg group, the mean of total R.A.
was (72.73) for paents who hadn't voming and (75.71) for
paents who had voming (0.78).
Regarding urine retenon, in Mo group, the mean of total R.A.
was (64.29) for paents who hadn't urine retenon and there
were no paents who had urine retenon (p=˃0.05). In Mg
group, the mean of total R.A. was (74.58) for paents who hadn't
urine retenon and (70) for paents who had urine retenon
(p=0.865).
Regarding drowsiness, in Mo group, the mean of total R.A. was
(61.43) for paents who hadn't drowsiness and (70) for paents
who had drowsiness (p=0.415). In Mg group, the mean of total
R.A. was (67.14) for paents who hadn't drowsiness and (77.22)
for paents who had drowsiness (p=0.389).
Finally, there were no paents who had dizziness or other
postoperave complicaons in both groups. The results in the
Table 15 show that there is a signicant dierence between
the number (percent) of paents complaining of moderate to
severe postoperave pain in Mo group 15/50 (30%) compared
to Mg group 25/50 (50%) (p=0.0423). There is also a signicant
dierence between the number (percent) of paents who
complained of drowsiness in Mo Group 7/50 (14%) compared
to 18/50 (36%) in Mg group (p=0.0115). There are no signicant
dierences between the two study groups regarding nausea,
voming, dizziness and urinary retenon Figure 2. The results
of the Table 16 show that there are no signicant relaonships
Tot SBP
Total VAS Mo Mg
Pearson Correlaon 0.247 -0.335
Sig. (2-tailed) 0.245 0.101
Tot DBP
Pearson Correlaon 0.236 -0.428
Sig. (2-tailed) 0.267 0.033
Tot HR
Pearson Correlaon -0.025 0.055
Sig. (2-tailed) 0.908 0.792
Tot Sa O2
Pearson Correlaon -0.518 -0.204
Sig. (2-tailed) 0.009 0.328
Table 13 Pearson correlaon between postoperave hemodynamic
variables and total vas.
Tot RA Mo Mg
variable
(n1,n2) M (mg)+S.D t(P-value) M(mg)+S.D t(P-value)
nausea
No(10,6) 70+35.36 0.655(0.521) 53.33+28.87 -1.56(0.132)
Yes(32,44) 62.5+17.32 77.27+24.53
voming
No(24,22) 61.67+28.87 -0.619(0.543) 72.73+32.89 -0.283(0.78)
Yes(18,28) 67.78+6.67 75.71+19.5
urine retenon
No(42,48) 64.29+22.04 ----- 74.58+26.21 0.171(0.865)
Yes(0,2) ----- 70+0
drowsiness
No(28,14) 61.43+26.85 -0.834(0.415) 67.14+23.6 -0.877(0.389)
Yes(14,36) 70+0 77.22+26.53
dizziness
No(42,50) 64.29+22.04 ----- 74.4+25.67 -----
Yes(0,0) ----- -----
others
No(42,50) 64.29+22.04 ----- 74.4+25.67 -----
Yes(0,0) ----- -----
Table 14 independent samples t test results between postoperave
complicaons and total rescue analgesia.
Total VAS Mo Mg
Abdominal drain
le at the end M+S.D t(P-value) M+S.D t(P-value)
Yes 2.36+0.77 2.597(0.016) 2.79+0.77 0.785(0.44)
No 1.55+0.61 2.55+0.57
Table 15 Independent samples t test results between the abdominal
drain le at the end and total vas.
Flow chart detailing the study.Figure 2
Total VAS Mo Mg
Duraon of Surgery
Pearson Correlaon 0.202 -0.14
Sig. (2-tailed) 0.368 0.506
Table 16 Pearson correlaon between duraon of surgery and total vas.
between duraon of surgery and the total VAS in both study
groups (P values>0.05).
2018
Vol.4 No.1:6
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Discussion
Incidence and intensity of post-operave pain
As the cause of postoperave pain in paents undergoing
laparoscopic surgery is mulfactorial, mulmodal analgesia is
necessary to counter postoperave pain. In the current study, at
the end of laparoscopic cholecystectomy surgery, 100 paents
were randomized to one of the following groups: Mo group
receiving intraperitoneal insllaon of 30 ml 0.25% bupivacaine
plus 3 mg morphine hydrochloride and MG group receiving
intraperitoneal insllaon of 30 ml 0.25% bupivacaine plus 50 mg/
kg magnesium sulfate. The results in the current study show that
morphine hydrochloride plus bupivacaine signicantly reduces
the incidence and intensity of postoperave pain compared to
magnesium sulfate plus bupivacaine.
The results show that there are signicant dierences between
Mo and Mg groups in the total VAS score (P value<0.05). In
the Mo group, the mean of total VAS (2.09) was signicantly
lower than the mean of total VAS in the Mg group (2.71); which
means that paents in the Mo group signicantly had less
intensity of pain than paents in the Mg group (p=0.006). This
means that bupivacaine plus morphine hydrochloride is more
eecve in reducing the intensity of postoperave pain than
magnesium sulfate plus bupivacaine. The raonale for selecng
the intraperitoneal pathway is to block the visceral aerence
signal and potenally modifying visceral nocicepon. Local
anesthecs inhibit nocicepon by aecng nerve membrane
associated proteins and by inhibing the release and acon
of prostaglandins and other agents that sensize or smulate
nociceptors and contribute to inammaon [52]. However,
absorpon from large peritoneal surface can also occur, which
may be a further mechanism of analgesia. We chose bupivacaine
for our study because of its long-term eecvity. The half-life of
bupivacaine is between 5 hours and 16 hours.
The result of the current study is in accordance with the study
by Bena et al. [30] Showed that addion of 3 mg of morphine to
30 ml of 0.25% bupivacaine further enhanced the eecveness
of intraperitoneal bupivacaine in the reducon of postoperave
pain aer laparoscopic cholecystectomy surgery [30]. On the
other hand, the result of the current study is in violaon of
Shoebi et al. [80] study that shown when magnesium sulfate is
added to bupivacaine, improves intraperitoneal analgesic eect
in postoperave period without any unwanted eects [80].
Magnesium sulfate is used in most studies to improve pain relief
quality with fewer demands on post-operave analgesics. [72,81-
83]. Since magnesium reduces intracellular calcium inux and also
antagonizes the N-methyl-D-aspartate (NMDA) receptor, which
reduces postoperave pain, it is useful for reducing somac and
visceral pain and also reducing the opioid analgesic requirements
[84-86].
For the incidence of postoperave pain, there were signicantly
fewer frequency (percentage) of paents in Mo group 15
(30%) complaining of moderate to severe pain postoperavely
compared to 25 (50%) paents in the Mg group (p=0.0423). This
result is consistent with the study performed by Bina et al. [30]
As shown, the group of bupivacaine plus morphine hydrochloride
had beer pain relief than the control group at all-me intervals
and this dierence was also stascally signicant (P<0.05) [30].
The study claries that morphine hydrochloride with bupivacaine
reduces the incidence of postoperave pain. The result of this
study complies with the study conducted by Hernandez et al.
[35] examined intraperitoneal applicaon of bupivacaine plus
morphine for pain relief aer laparoscopic surgery and reported
that the combinaon is eecve in reducing pain during the rst
6 hours [87-90]. In our study when calculang the size of the
treatment eect of morphine hydrochloride plus bupivacaine, it
was found that the relave risk reducon of moderate to severe
pain postoperavely is 0.40.
On the other hand, a study on the eect of intraperitoneal
insllaon of opioid showed that morphine was ineecve when
given as analgesia. The authors speculated that this may be
because the intact peritoneum prevents the entry of hydrophilic
morphine molecules and blocks their access to the neural
receptors. Inammaon interferes with the peritoneal barrier and,
consequently, the access of opioid agonists to the sensory neurons is
facilitated to produce only analgesia in swelling ssue [52].
The results of the current study are not in line with Maharjan et
al. [31] study conducted in 60 paents undergoing laparoscopic
cholecystectomy. Paents were randomized to one of the
following groups: the bupivacaine group received intraperitoneal
insllaon of 30 ml 0.25% bupivacaine and magnesium sulfate
group receiving intraperitoneal insllaon or 0.25% bupivacaine
plus 50 mg/kg magnesium sulfate to a total volume of 30 ml [91-
93]. Postoperave pain was evaluated using visual analog scale.
The me period for the rst analgesia required was noted and
rescue analgesics were given as tramadol 50 mg intravenously
and as needed. Paents receiving intraperitoneal bupivacaine
plus magnesium sulfate at the end of surgery had beer pain
relief during the rst 24 hours. The authors concluded that the
combinaon of bupivacaine and magnesium sulfate in abdominal
cavity by laparoscopic surgery gives paents beer analgesics
and less analgesics during the rst 24 hours compared to the
bupivacaine group alone.
The requirements for analgesic rescue
medicaon
The results in the current study show that there is no signicant
dierence between Mo and Mg groups in Total Rescue Analyze
(p-value>0.05). In the Mo group, the mean of total R.A. was
(64.29 mg) which does not dier signicantly from the mean of
total rescue analgesia in the Mg group (74.40 mg). There is only
a signicant dierence between the Mo and Mg groups at 16
hours postoperavely in favour of the Mo group. Compared to
a previous study by Bina et al. [30] Comparison of the analgesic
requirements showed that a number of paents receiving rescue
analgesia were signicantly lower in bupivacaine and morphine
groups compared to bupivacaine and placebo group.
13
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Vol.4 No.1:6
2018
International Journal of Anesthesiology & Pain Medicine
ISSN 2471-982X
Adverse eects
Regarding adverse eects, there were no signicant dierences
between the study groups regarding nausea, voming, dizziness,
urinary retenon and were distributed equally in both groups but
there is a signicant dierence between the groups associated
with drowsiness. There are signicantly lower number of
drowsiness in the Mo group 7/50 (14%) compared with the Mg
group 18/50 (36%) (p=0.0115). The authors of the current study
speculated that increased number of paents with drowsiness
in the Mg group could be as a result of the mean (SD) of rescue
medicaon, which is pethidine 74.40 mg ± 25.67 which is higher
than in Mo group 64 mg, 29 mg ± 22.04, This may have caused
drowsiness in the Mg group. The current results are consistent
with [30] results regarding adverse eects, only nausea and/or
voming was present in 10 of 90 paents and was distributed
equally in all groups. Bina et al. [30] also explained that there
was no itching, excessive sedaon or dryness of the bupivacaine
plus morphine group. The authors speculated that this could
be explained because the dose of morphine used in the
intraperitoneal insllaon was signicantly less to cause systemic
side eects. The dose of morphine used was 2 mg morphine
added to 0.25% bupivacaine 30 ml.
Hemodynamic parameters
Regarding hemodynamic parameters, the results in the current
study show that there is signicant negave correlaon between
DBP and total VAS in the Mg group (P=0.033). In the Mo Group
there is no signicant relaonship. And the results also show
that there is a signicant negave correlaon between SpO2 and
total VAS in Mo group (P value=0.009). In the Mg group there
is no signicant relaonship. These results were not clinically
signicant. On the other hand, the results show that there are no
signicant relaonships between both SBP, HR and total VAS in
both study Mo and Mg groups (P-values>0.05). Compared to Bina
et al. [30] important parameters such as HR, BP and SpO2 were
idened as important paent comfort indicators as the values
correlated well with VAS scores.
Conclusion
Intraperitoneal insllaon of combinaon of bupivacaine
with morphine hydrochloride is superior to bupivacaine plus
magnesium sulfate to reduce the intensity and incidence
of postoperave pain in paents undergoing laparoscopic
cholecystectomy surgery without signicant increase of side
eects. This peripheral eect of opioid provides a new approach
to pain relief that can have major clinical benets.
Recommendaons
Based on the results of this study, it is recommended to consider
the intraperitoneal insllaon of morphine hydrochloride
with bupivacaine as a standard applicaon for laparoscopic
cholecystectomy surgery to reduce postoperave pain.
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... In a human study, intraperitoneal injections of morphine and bupivacaine were performed after gallbladder resection to control pain, which ultimately produced appropriate analgesia (Hernandez-Palazon et al., 2003;Schulte-Steinberg et al., 1995). In a similar operation, a combination of bupivacaine and morphine was used to induce analgesia in one group, and bupivacaine and magnesium sulfate were used intraperitoneally in another group, revealing that the use of the combination drug had a better analgesic effect (Sadaqa et al., 2018). ...
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Background: This study was designed to evaluate the analgesic efficacy of intraperitoneal magnesium sulphate or ketamine added to bupivacaine in patients undergoing laparoscopic cholecystectomy. Methods: The study included 80 female patients and a standardized general anaesthetic including fentanyl, thiopentone, N2O, isoflurane, and vecuronium for muscle relaxation. At the end of surgery 50 ml of the studied solution were injected intraperitoneally under both copulae of diaphragm guided by the surgical camera. Patients were randomly allocated into one of four equal groups (n = 20 each), according to the composition of the intraperitoneal solution: normal saline 0.9% in the control group (Group C), bupivacaine 0.25% (Group B), 30 mg/kg magnesium sulphate in bupivacaine 0.25% (Group MB), and 1 mg/kg ketamine in bupivacaine 0.25% (Group KB). The following parameters were evaluated in all studied groups: 1) time to first request of analgesia (time between extubation and first analgesic dose); 2) postoperative shoulder and arm pain for 24 hours; and 3) the amount of postoperative patient-controlled analgesia (PCA) morphine consumed in 0-6 h, 6-12 h, 12-18 h, 18-24 h, and 0-24 h following extubation. Results: Time to first request of analgesia in groups C, B, MB, and KB were 15.33 (5.1) min, 35.23 (4.8) min, 130.34 (6.8) min and 132.13 (5.9) min, respectively, with significantly longer duration (P < 0.05) in groups MB and KB compared to either group C or group B. Dose of intravenous PCA morphine consumed at 0-6 h, 6-12 h, 12-18 h, 18-24 h, and 0-24 h following extubation were significantly lower in groups MB and KB compared to either group C or group B (P < 0.05). The incidence and severity of shoulder pain were significantly reduced in groups MB and KB (P < 0.05). Conclusion: Intraperitoneal co-administration of either magnesium sulphate or ketamine with bupivacaine 0.25% at the end of surgery is effective in reducing postoperative shoulder pain and analgesic requirement following laparoscopic cholecystectomy.