A Randomized Two-parallel Group Controlled Trial Comparing the Effects of 20mg Parecoxib as an Adjunct to 0.75% Ropivacaine in Ultrasound-guided Supraclavicular Block for Upper Limb Surgery
Phase: PHASE3
Conditions: Anesthesia; Functional, Anesthesia
Sponsor: Universiti Sains Malaysia

THE EFFICACY OF PARECOXIB 20MG AS AN ADJUNCT IN 0.75% 
ROPIVACAINE IN SUPRACLAVICULAR BRACHIAL PLEUXS BLOCK FOR 
UPPER LIMB SURGERY 
 
Primary Investigator:  
1) DR VIVEKANANDA GUNASEKARAN  
 
 
 
 
    ( MBBS (Manipal), MMed Anaesthesiology (USM) ) 
 
 
 
 
 
 
Co-investigators: 
 
1) DR MUHAMMAD IRFAN ABDUL JALAL  
    ( MBChB BAO (Queen’s University of Belfast), PhD 
 
 
    (Newcastle University) ) 
 
2) DR WAN MOHD NAZARUDDIN WAN HASSAN 
 
 
 
 
    ( MD (UKM), MMed Anaesthesiology (USM) ) 
 
3) DR RHENDRA HARDY MOHD ZAINI 
    ( MD (USM), MMed Anaesthesiology (USM) ) 
 
4) DR WAN NOR ARIFIN WAN MANSOR 
    ( MD (UIA), MSc Medical Statistics (USM) ) 
 
 
 
 
 
 
 
UNIVERSITI SAINS MALAYSIA 
Date of report: 30th NOVEMBER 2017 
(Minor amendment: 20th  MARCH 2018) 
 
 
 
   NCT ID: To be assigned 

 
ii 
 
 
THE  EFFICACY OF PARECOXIB  20MG AS AN ADJUNCT IN 0.75% 
ROPIVACAINE IN SUPRACLAVICULAR BRACHIAL PLEUXS BLOCK FOR 
UPPER LIMB SURGERY 
ABSTRACT 
Introduction 
Brachial plexus block (BPB) is a critical method in providing anaesthesia for upper limb 
surgery. Parecoxib, a specific COX-2 inhibitor, has the potential as an adjunct for 0.75% 
ropivacaine in supraclavicular BP block setting.  
Objectives 
To investigate whether the efficacy of supraclavicular brachical block is enhanced by the 
addition of 20 mg parecoxib to 0.75% ropivacaine in patients undergoing upper limb 
surgery. 
Methods 
This is a double-blind, active-controlled, parallel group, prospective randomized clinical 
trial conducted between 20th June  and 28th August 2017 involving eighty six (n=86) 
adults whose age were between 18 and 65 years old, with ASA grade I or II and 
undergoing various upper limb surgeries whose durations were between 1 and 4 hours. 
The subjects were block-randomized in 1:1 ratio into two groups; group 1 received 
adjunct IV parecoxib and 0.75% ropivacaine whilst group 2 received 0.75% ropivacaine 
alone. The primary end-points are the duration and onset of sensory and motor block and 
the proportions of complete motor and sensory block at 30 minutes following 
supraclavicular BP block. The significance of the differences in trial endpoints were 
statistically tested using Mann-Whitney and Chi-square tests. 
Results 

 
iii 
 
Eighty six (n=86) subjects were randomised to either group and analysed. There were 
higher durations of sensory and motor blocks in the adjunct parecoxib + ropivacaine 
group compared to the ropivacaine-only groups (sensory block duration: 6.5 hours vs 5.0 
hours, median difference = 1.5 hours, p value <0.001; motor block duration: 4.84 hours 
vs 3.86 hours, median difference = 0.97 hours, p value <0.001). No significant differences 
between the two intervention arms with respect to sensory  (9 minutes vs 9 minutes, 
median difference = 0 minute, p value = 0.511) and motor blockades (17 minutes vs 18 
minutes, median difference = 1 minute, p value = 0.832) onset. Besides, there no 
significant difference in terms of complete sensory and motor blockades at 30 minutes 
post supraclavicular block between parecoxib + ropivacaine and ropivacaine-only groups 
(sensory blockade at 30 minutes: 100% vs 97.7 %, p value = 1.000; motor blockade at 30 
minute = 100% vs 97.7%, p value = 1.000). No adverse events were reported in both 
intervention arms and the trial was not ended prematurely.  
Conclusion 
Adjunct parecoxib significantly enhances the durations of sensory and motor blockades, 
but not their onset and complete sensory and motor block at 30 minutes following 
supraclavicular brachial plexus block. 
(395 words)

 
1 
 
SECTION ONE 
INTRODUCTION 
 
Brachial plexus block (BPB) has enjoyed ubiquitious popularity for upper limb 
surgeries (Raju and Coventry, 2013). It provides sufficient anaesthesia for surgical 
procedures involving upper limbs due to the propinquity of the brachial plexus’ trunks 
and division when they pass the first rib (Gamo et al., 2014). 
There are a few common techniques for BPB and one of the most frequently-
utilised one is supraclavicular BPB (Raju and Coventry, 2013). It is not only an efficient 
mode of anaesthesia intraoperatively, but it is can also provide a quick-onset and dense 
anaesthesia for surgical procedures that involve the proximal mid-humerus down to the 
distal hand with excellent safety profile (Raju and Coventry, 2013; Gamo et al., 2014).  
The supraclavicular block (SCB) is performed above the clavicle and aims at the level of 
the nerve trunks or division of brachial plexus (BP). Other frequently-employed 
alternatives include infraclavicular block, interscalene block and axillary BPB (Raju and 
Coventry, 2013). 
          Nowadays, all techniques for BPB have been widely performed under ultrasound 
(US) guidance and this new modality has been proven to enhance the success rate of BPB 
and lessen the complications involved with BPB; for instance pneumothorax, intraneural 
local anesthetic (LA) injection, nerve injuries etc (Chan et al., 2003; Peterson et al., 
2002). US-guided SCB is aimed to circumferentially disseminate local anaesthetic  (LA) 
agent perineurally, a location that is close to the subclavian artery (Chan et al., 2003).  
There are few adjunct drugs that can be mixed with LA to speed up the onset as 
well as prolong the duration of the block. These drugs can also minimise the potential of 
overdose that may lead to severe and fatal LA toxicity. Parecoxib (Dynastat®) is one of 

 
2 
 
the relatively recently-developed therapeutic agents that are studied at present as an 
adjunct to LA (Liu et al. 2013). It acts by inhibiting the function of the constitutive COX-
2, an isoform of cyclooxygenase (COX) (Liu et al. 2013). 
The aims of the study are to investigate the effect of parecoxib as an adjunct in 
Ropivacaine 0.75% for ultrasound guided SCB. Possible side effects are due to the onset 
of block, duration of block and haemodynamic instability. Prolonged duration of 
anaesthesia was particularly singled out as one of the important end-points to be 
investigated and compared between the recipients of adjunct parecoxib + ropivacaine 
0.75% and single-agent ropivacaine 0.75% (i.e ropivacaine 0.75% only without the 
adjunct parecoxib). 
             There are several studies that have demonstrated that the presence of COX-2 in 
the dorsal horn of spinal cord could regulate spinal nociceptive transmission (Resnick et 
al, 1998; Martin et al., 2007; Li et al., 2009) Furthermore, there are findings from other 
studies that suggested adding a COX-2 antagonist directly on the central or peripheral 
nerve might have a better analgesic effect than intravenously (Yamamoto et al., 1998, 
Kim et al., 2011; Liu et al., 2013). Principally, COX-2 inhibitors reduce inflammation 
and hyperalgesia by reducing prostaglandin production (Yaksh et al., 2001). However, 
the role of COX-2 in the central nervous system is of more importance. Inflammation can 
induce COX-2 production and will lead to prostanoids release that will sensitize the 
peripheral nociceptor terminals and produce localized pain hypersensitivity (Vardeh et 
al., 2009). It is hence thought that the administration of COX-2 antagonist on spinal or 
peripheral nerves may be a more effective mode of pain relief than the intravenous or 
intramuscular route.  
Further details will be discussed in section 2. 
 

 
3 
 
SECTION TWO 
LITERATURE REVIEW 
 
2.1 SUPRACLAVICULAR BRACHIAL PLEXUS BLOCK 
 
Brachial plexus block (BPB) is an indispensable method of providing anaesthesia 
for surgery of the upper limb. The most customarily-used technique is the axillary, 
perivascular approach because it is trivial to perform and the low risk of complications 
associated with this approach. Nevertheless, the brachial plexus blockade may stay 
incomplete because the musculocutaneous and axillary nerves diverge from the brachial 
plexus sheath proximal to the puncture site. 
 
The subclavian perivascular technique which was originally pioneered by Winnie 
and Collins (1964) and the traditional supraclavicular method devised and introduced by 
Kulenkampff and Persky (1928) are the two most commonly utilised methods for BPB in 
the clinical setting. These techniques require needle insertion caudally and perpendicular 
to the brachial plexus. The supraclavicular technique directs the needle toward the first 
rib close to the pleura. This approach provides a greater extent of BP block than the 
axillary approach since it includes the musculocutaneous and the axillary nerve 
blockades, but it possesses a greater risk of serious and potentially fatal complications. 
For instance, the incidence of pneumothorax associated with the traditional Kulenkampff 
technique is between 0.6% and 6.0% (Neal, 2009). Other complications that should also 
be seriously taken into consideration are haematomas attributed to the puncture of a major 
blood vessel and unwanted dissemination of local anaesthetics leading to the paresis of 
stellate ganglion as well as the phrenic (hemidiaphragmatic paresis) and recurrent 
laryngeal nerves (voice hoarseness), hypotension and bradycardia associated with the 
interscalene approach (13 to 24%) (Neal, 2009). 

 
4 
 
 
To boost the success rate and to evade the aforesaid complications, Ting and 
Sivagnanaratnam (1989) developed the use of ultrasonography in the performance of an 
axillary BPB. This approach permits the verification of the cannula localization and 
enables the visualisation of the spread of the local aneaesthetics within the plexus sheath. 
Using this technique, Ting and Sivagnanaratnam reported a 100% success rate without 
any complications (Ting and Sivagnanaratnam, 1989). 
 
In another study by Kapral and others (1994),  the researchers adapted the method 
developed by Ting and Sivagnanratnam and used it for the supraclavicular paravascular 
approach of BPB. The authors investigated the utility and impact of ultrasonic cannula 
guidance for supraclavicular puncture of the brachial plexus sheath against the axillary 
approach in terms of success, rate, onset and the frequency of complications. They found 
that 95% of the subjects in both groups experienced satisfactory analgesia. Nevertheless, 
25% of subjects in the axillary approach group experienced incomplete sensory block 
whilst none of the subjects in the supraclavicular paravascular approach had incomplete 
sensory block. The authors concluded that the ultrasonography-guided approach for the 
supraclavicular block is comparatively as safe as the axillary approach, with a larger 
extent of block than the axillary approach.  
 
Besides, Chan and colleagues (2003) also researched the utility of ultrasound-
guided supraclavicular approach for BPB. The rationale for further researching and 
developing this technique, according to the authors, is that it can be utilised to precisely 
and accurately locate the brachial plexus, hence reducing the procedure-related pain 
associated with imprecise anatomical landmark localisation  based on the trial and error 
approach and potential pneumothorax. The authors observed that in 40 patients who 
received BPB for their elective upper-limb surgeries via this new approach, low pain 
score during their postoperative  care at post-anaesthesia care unit (PACU) (mean score 

 
5 
 
of 0.3 out of 10) and high satisfaction in regard to pain control (median score of 9 out of 
10) were reported. Two failures were recorded which were attributed to subcutaneous 
injection of bupivacaine and partial intravascular local anaesthetic injection which led to 
block failure at 30 minutes post injection. Two study participants experienced 
complications postoperatively which include Horner’s syndrome and transient 
paraesthesia that lasted for less than 48 hours. No incidence of pneumothorax was 
reported. The findings of this study were further corroborated by a subsequent study by 
Chan et al. (2007) who demonstrated that the ultrasound guidance enhanced the success 
rate of axillary BPB (defined as the absence of sensation in upper limb areas supplied by 
the median, ulnar and radial nerves at 30 minutes following axillary BPB) in 188 patients 
who had elective hand surgeries. Apart from that, there were less number of patients in 
the US group who needed supplemental nerve blocks and general anaesthesia in 
comparison to the other group whose subjects underwent axillary BPB guided only by a 
nerve stimulator. The findings of this trial, hence, conclusively showed the superiority of 
this ultrasound-guidance technique over the other alternative methods for BPB. 
 
There are also controversies on whether single injection (SI) ultrasound-guided 
eight-ball corner pocket technique or the triple injection (TI) is superior. Frederickson 
and colleagues (2010) established that the SI is superior to the TI method with respect to 
reducing the procedural time (SI vs TI: 117s vs 158s, p value = 0.002) whilst there were 
significant higher percentages of patients in the SI group experiencing complete motor 
and sensory blockades at 20 minutes post injection than the TI group (the percentages of 
patients experiencing full motor and sensory block at area supplied by radial nerve; SI vs 
TI: 88% vs 55%, p value = 0.02). Even though the SI approach has been established to 
have the best success rate, this method may fall short from adequately anaesthesizing the 
upper part of the brachial plexus, resulting in an incomplete block of the territories 

 
6 
 
innvervated by nerves originated from the upper brachial plexus, such as areas supplied 
by the ulnar nerve ( Frederickson et al., (2009) ). This is further emphasized in a study by 
Thompson and Rorie (1983) who re-evaluated the anatomical aspect of brachial plexus 
sheath utilising dye injections were to assist with the visualisation of the anatomical 
compartments in cadavers. They then extended their study by confirming the multi-
compartmental nature of the brachial plexus sheath anatomy in surgical patients using 
computed tomography (CT) dye studies (Thompson and Rorie, 1983).  They also 
established that an injection into a solitary brachial plexus site did not lead to an ample 
dispersal of the injected dye into all brachial plexus sheath compartments which is formed 
by septae or a tight muscular membrane that restricted the dissemination of local 
anaesthetic agent circumferentially (Thompson and Rorie 1983).  
There are also two other studies who also substantiated the findings of Thompson 
and Rorie (1983) which also proved the existence of septae segregating the brachial 
plexus into a multi-compartmental structure and the authors hypothesised that multiple 
injections is the most sensible approach for brachial plexus blockade (Vester-Andersen 
et al., 1986, Partridge et al., 1987). Nevertheless, those functional anatomical studies 
were only performed on cadaveric specimens and their results were not completely 
convincing to be accurately extrapolated to predict the onset of nerve blockades clinically.  
Nevertheless, according to another study by Arab et al., (2014), the TI technique 
had a more rapid onset and complete block in the first 20 minutes after injection than the 
SI technique. However, there was no difference in terms of the success rate for surgical 
anaesthesia at 30 minutes post injection. However, there were findings in other studies 
that are incongruent with the results obtained by Arab et al., (2014). Tran et al., (2010), 
Tran et al., (2012) and Roy et al., (2012) demonstrated that there are no significant 
advantages in employing the double injection technique for brachial plexus blockade via 

 
7 
 
all kind of approaches (supraclavicular, infraclavicular or axillary) over single injection 
technique. It is worth mentioning, however, that despite the many similarities of Arab et 
al. (2014) study with these three studies, there are differences in the Arab and colleagues 
(2014)’s study design that may make their findings  more relevant and accurate. Firstly, 
the authors employed different sites when giving the injection. Secondly, they only 
focused on 1 type of surgical procedure and thus eliminating any confounders arising 
from the surgical stimulus or location of the surgery. Finally, the authors assessed the 
study outcomes in a different but more accurate fashion in which they chose sensory block 
of the 5 nerves as their primary end point. However, more studies are required to verify 
the findings of Arab et al., (2014) and deliver the final verdict on this never-ending 
controversial issue. 
2.2 ROPIVACAINE: PHARMACOLOGICAL PROPERTIES 
 
Ropivacaine is chemically a long-acting regional anaesthetic of amide group that 
is structurally related to Bupivacaine. In contrast with  Bupivacaine, Ropivacaine is a pure 
S(-) enantiomer, which is a racemate, developed for the purpose of  lessening  potential 
toxicity and enhancing relative sensory and motor blocking properties of other local 
anaesthetic agents. 
 
Before we proceed further, the conceptual underpinning of enantiomers should be 
elucidated first. Enantiomers are chiral molecules that have two dissimilar spatial 
configurations, like the right and left-handed gloves (i.e. one is the mirror image of the 
other), which occur in equivalent quantities in a racemate.  They are both 
pharmacologically active and can be optically distinguished by their effects on the 
rotation of the plane of a polarized light and hence they can be classified into either 
dextrorotatory (clockwise rotation, [R+]) or levorotatory (counterclockwise rotation [S-
]) stereoisomers. The physicochemical properties of the enantiomeric molecules are 

 
8 
 
identical, but the two enantiomers can have substantially different behaviours in terms of 
their affinity for either the pharmacological site of action or the sites that account 
organotoxicity occurrence. The R[+] and S[-] enantiomers of local anaesthetics have been 
demonstrated to possess varied affinity for disparate sodium, potassium and calcium ion 
channels. This may explain the considerable diminution of neuro and cardiotoxicity of 
the S[-] enantiomer when comparison was made with the R[+] enantiomers of the same 
local anaesthetic compounds (Aberg 1972, Luduena et al., 1972). 
 
The progress in chemical technology has made the development of ropivacaine as 
an optically pure S[-] enantiomer from the chiral propivacaine a reality. It is a member of 
the pipecoloxylidides group which is a type of local anaesthetic. It has a propoyl group 
bonded to the nitrogen atom of piperidine, a slight difference to bupivacaine which has a 
butyl group linked to its piperidine group (McClure 1996). 
2.2.1 Pharmacokinetics profiles of ropivacaine 
2.2.1 (a)  Absorption and distribution 
 
The plasma concentration of ropivacaine, like any other local anaesthetic agent, is 
influenced by the vascularity of the injection sites, the total dose amount used and the 
route of administration, the rate of administration and the haemodynamic and circulatory 
condition of the patients (Simpson et al., 2005). When ropivacaine was administered 
either intravenously or as continuous epidural infusion in normal healthy subjects, the 
pharmacokinetic of ropivacaine exhibited a first order linear property which means that 
an increase in the plasma concentration of ropivacaine is proportional to the dose given 
and this effect exists even when ropivacaine is increased up to 80 mg if given 
intravenously (Emanuelsson et al., 1997; Simpson et al., 2005) or up to 3 mg / mL if 
given via continuous epidural infusion (Emanuelsson et al., 1995). If ropivacaine is 
epidurally given, it was observed that ropivacaine dosed at 150 mg is absorbed in entirety 

 
9 
 
from the epidural space in a biphasic fashion. The average half-life of ropivacaine during 
the introductory phase is about 14 minutes, followed by a more protracted phase that has 
a mean distribution t1/2 of approximatelt 4.2 hours (Simpson et al., 2005). 
 
Ropivacaine is extensively bound (94%) to plasma protein, primarily to α1-acid 
glycoprotein (Burm et al., 2000). The total plasma concentration ropivacaine increases 
during the steady epidural infusion of ropivacaine is attributed to a raise in the degree of 
protein binding and the subsequent diminishment in ropivacaine clearance (Burm et al., 
2000). 
 
Ropivacaine quickly travels across the placenta when it is epidurally administered 
during Caesarean section, culminating in almost complete equilibrium of the unbounded 
fraction of ropivacaine in both maternal and foetal plasma (Ala-Kokko et al., 1997). 
Nonetheless, when it comes to ropivacaine’s total plasma concentration, the level of 
unbounded ropivacaine’s total plasma concentration is higher in the maternal than in the 
foetal circulation due to the presence of a more elevated concentration of α1-acid 
glycoprotein-bound ropivacaine in the maternal than foetal plasma (Ala-Kokko et al 
1997). 
2.2.1 (b) Metabolism and excretion 
 
Ropivacaine is largely metabolized in the liver, preferentially by aromatic 
hydroxylation, to 3`-hydroxy-ropivacaine by cytochrome P450 (CYP) 1A2 and N-
dealkylation to 2`,6`-pipecoloxylidide by CYP3A4 (Ekstrom et al., 1996). Ropivacaine 
is primarily excreted by the kidney which is responsible for 86% of  the urinary excretion 
of ropivacaine following a solitary IV dose administration (Lee et al., 1989). The 
mean±SD biological half-life (t1/2 ) of ropivacaine post IV and epidural administration are 
1.8±0.7 hours and 4.2±1.0 hours, respectively. 
 

 
10 
 
2.2.1 (c) Relative potency 
 
A strict association is present between the extent of local anaesthetic’s lipid 
solubility and its toxicological properties and potency. According to the studies which 
measured the minimum local anaesthetic concentration (MLAC), defined as the 
anaesthetic concentration that produces effective analgesia in 50% of patients (EC50), 
ropivacaine exhibits comparable magnitude of potency to bupivacaine at greater doses, 
for instance the dose warranted for peripheral nerve blocks (McGrady and Litchfield 
2004). However, at lower doses (e.g. the doses that are usually given for intrathecal or 
epidural analgesia), ropivacaine is surprisingly observed to be less potent than 
bupivacaine and levobupivacaine (McGrady and Litchfield 2004). Nevertheless, the 
provision of anaesthesia or analgesia to the patients is more clinically pertinent rather 
than worrying about the MLAC and this distinction in anaesthetic potency is commonly 
unnoticeable during the day-to-day clinical practice which involves administering 
ropivacaine at higher doses for routine surgical anaesthesia.  
2.2.1 (d) Tolerability 
 
Ropivacaine is generally well-tolerated in adults irrespective of the administration 
routes. The adverse events associated with reactions to ropivacaine are similar to those 
side effects produced by other amide-based local anaesthetics. In a meta-analysis based 
on the data from disparate but well-designed clinical trials, the adverse events 
experienced by ≥5% of patients who received ropivacaine 0.125-1% via myriad routes of 
administration for surgery, labour pain, Caesarean section, postoperative pain 
management, peripheral nerve block or local infiltration (n=1661) include hypotension 
(32%), nausea (17%), vomiting (7%), bradycardia (6%) and headache (5%) (Simpson et 
al., 2005). These events are attributed to the nerve block received during such procedures 
and the adverse reactions also occurred in similar percentages among 0.25-0.75% 

 
11 
 
bupivacaine recipients (n=1433) (hypotension = 29%, nausea = 14%, vomiting = 6%, 
bradycardia = 5% and headeache = 5%,) given for the same indications. Apart from that, 
when the epidural route is employed for ropivacaine administration prior to surgery, the 
adverse events also occurred in a dose-dependent fashion, a characteristic that was 
similarly observed  among patients who received similar doses of bupivacaine (Simpson 
et al., 2005). 
 
The incidence of ropivacaine-induced cardiovascular symptoms might be 
attributed to age factor. Patients whose age is more than 61 years  and received epidural 
ropivacaine at 1% strength had significantly higher occurrences of bradycardia (58% vs 
15% in patients aged 41-60 years; p value=0.005) and hypotension (74% vs 20%, in 
patients aged between 18 and 40 years; p value=0.002) (Simpson et al., 2002). The 
cardiovascular events can also be linked to ropivacaine toxicity secondary to rapid IV 
injection or massive absorption from peripheral nerve blocks. 
 
Apart from that, ropivacaine is also commonly well-tolerated in paediatric patients 
whose age ranged from 1 month to 15 years and irrespective of the route of administration 
(Bosenberg et al., 2002). The overall incidence of ropivacaine-associated adverse events  
is low, with the most frequent reported adverse events are nausea and/or vomiting. 
Furthermore, foetus and neonates also tolerate ropivacaine well following its use for 
regional anaesthesia in women who underwent Caesarean section or during labour 
(Simpson et al., 2005). The most commonly documented adverse events associated with 
ropivacaine in foetus and neonates are foetal bradycardia (12%), neonatal jaundice (8%) 
and unspecified neonatal complications (7%). These events occurred in similar 
percentages in both ropivacaine and bupivacaine recipients (12%, 8%, and 7%, 
respectively) (Simpson et al., 2005). Moreover, according to a meta-analysis of six 
double-blind trials, ropivacaine did not affect the neonatal neurological and adaptive 

 
12 
 
capacity (NAC) score at 2 and 24 hours post labour. To corroborate this further, the total 
NAC scores were discovered to be significantly greater in neonates whose mothers had 
received ropivacaine rather than bupivacaine (Writer et al., 1998). Accordingly, we can 
conclude that ropivacaine is relatively safer for use in paediatric population than other 
local anaesthetics. 
2.2.2 Pharmacodynamic profiles of ropivacaine 
2.2.2 (a) Mechanisms of action 
 
Ropivacaine causes reversible inhibition of sodium ion influx and thereby blocks 
impulse conduction in nerve fibres (Hansen 2004). This action is potentiated by dose-
dependent inhibition of potassium channels (Kindler et al 2003). Ropivacaine is less 
lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibres. 
As a result, it has selective action on the pain signal transmitted by the A, δ and C nerve 
fibres rather than Aβ nerve, which are more associated with motor function (Rosenberg 
and Heinonen 1983). 
2.2.2 (b)  Drug interactions 
 
Care should be taken when Ropivacaine is used in patients who are also recipients 
of other local anaesthetics which are structurally related to amide-type local anaesthetics, 
since the effects of these drugs are additive. Ropivacaine is metabolised by Cytochrome 
P4501A2 (CYP1A2) into its major metabolite, 3-hydroxy ropivacaine (Arlander et al., 
1998). Thus, potent inhibitors of CYP1A2 such as fluvoxamine, if given concurrently 
with ropivacaine, may interfere with ropivacaine metabolism and this may lead to a raised 
level of plasma ropivacaine concentration (Arlander et al., 1998). As a result, great 
caution is required when ropivacaine is concomitantly given with pharmacological agents 
which are CYP1A2 inhibitors as well. As further examples, possible interactions with 
pharmacological agents, for instance theophylline and imipramine which are also 

 
13 
 
metabolized by CYP1A2 may also occur through competitive inhibition (Jokinen et al., 
2001). 
2.2.2 (c) Adverse effects on CNS and cardiovascular effects 
Cardiotoxicity and neurotoxicity due to unintentional intravascular injection of 
ropivacaine appears to be low. According to a pooled analysis of data from approximately 
3000 patients in 60 clinical studies, the incidence of probable accidental IV injection of 
ropivacaine was 0.2% (six patients) and only one patient experience convulsions 
(Selander et al., 1997). No patient showed symptoms of cardiotoxicity. 
 
It is well known fact that the CNS toxicity occurs before cardiotoxicity for local 
anaesthetic drugs. The signs and symptoms of CNS toxicity are usually excitatory in 
nature such as tremor, muscle twitching, shivering which are produced by the suppression 
of the central inhibitory pathway (Linsey et al., 2014). However, when the plasma 
concentration of local anaesthetic agents further increases, it subsequently causes the 
excitatory pathway of CNS to be blocked and this results in myriads of clinical signs and 
symptoms of CNS suppression, for instance hypoventilation, respiratory depression and 
generalized convulsion (Linsey et al., 2014). 
Besides, when ropivacaine was administered intravenously, the CNS toxic effects 
also occurred earlier than the cardiotoxic symptoms and this happened when the IV 
ropivacaine was infused at a rate of 10mg/min or higher in healthy human subjects. It was 
also demonstrated by Groban 2003 that the dose required for inducing seizure in various 
animal models (rat, dog and sheep) was the highest for ropivacaine in comparison to 
levobupivacaine and bupivacaine. This means that ropivacaine has a lower potential for 
causing CNS toxicity than levobupivacaine and bupivacaine since it requires much higher 
doses than levobupivacaine and bupivacaine to induce convulsion in the animal models 
(Groban, 2003). Such findings were further endorsed by an old study by Knudsen et al. 

 
14 
 
(1997) who showed that 10 to 25% higher dose is required for ropivacaine than 
bupivacaine to cause neurotoxicity. 
With regard to ropivacaine-associated cardiotoxicity, the clinical signs include 
significant changes in cardiac function involving the contractility, conduction time and 
QRS width occurred and the increase in a QRS width was found to be significantly 
smaller with ropivacaine than bupivacaine. Ropivacaine is known to be less lipophilic 
than bupivacaine and together with its stereoselective properties, this contributes to 
ropivacaine having a significantly higher threshold for cardiotoxicity than bupivacaine in 
animals and healthy volunteers (Hansen, 2004; Lefrant et al., 2001). The lower 
lipophilicity of ropivacaine relative to bupivacaine is associated with lesser 
cardiodepressant effects of both ropivacaine isomers than bupivacaine isomers in animal 
studies. The mechanisms of ropivacaine cardiotoxicity are molecularly attributed to three 
main factors; the continuous blockade of the inactive and open sodium ion channels, 
resulting in the increased durations of PR interval and QRS complex which eventually 
causes a high susceptibility to re-entrant arrhythmias (Gristwood 2002). Besides, the 
inhibition of potassium ion channels which causes prolonged QTc interval and the 
amplification of the degree of sodium channel block (Avery 1984) is another factor that 
may mechanistically explain the cardiotoxic effect of ropivacaine. Finally, the effects of 
ropivacaine on the metabolic efficiency of mitochondrial bioenergetics has also been 
proposed as one of the causes of ropivacaine cardiotoxicity (Sztark et al., 1998, Sztark et 
al., 2000). 
2.2.2 (d) Other clinical effects and adverse events 
 
Besides the clinical effects and adverse events described above, it is also known 
that ropivacaine possesses biphasic effect on blood vessels. Ropivacaine induces 
vasoconstriction when it was intradermally injected at a low concentration (0.063 – 0.5%) 

 
15 
 
(Cederholm et al., 1983). On the contrary, vasodilation was observed when higher 
concentration of ropivacaine (1%) was utilised (Cederholm et al., 1983). Consequently, 
ropivacaine is a better alternative to bupivacaine due to its vasoconstrictive effect, when 
used in low dose, causes delays in systemic absorption and subsequent reduction system 
adverse effects. This desirable property can be further enhanced by the addition of 
epinephrine diluted to 1:200000 ratio into a 0.15 to 0.20% ropivacaine solution since this 
will further reduce the peak plasma concentration of ropivacaine (Cmax) and prolong the 
time to peak plasma concentration (Tmax) (Cuvillon et al., 2009). 
 
Ropivacaine has been demonstrated to cause the aggregation of plate in plasma at 
the following cocentrations;  3.75 and 1.88mg/ml (0.375% and 0.188%) which are 
equivalent to the ropivacaine concentrations that  could be normally observed in the 
epidural space during the infusion of ropivacaine  (Porter et al., 2001). Besides, 
ropivacaine also possesses in vitro bacteriostatic activity against Staphylococcus aureus, 
Escherichia coli and Pseudomonas aeruginosa, an effect that is similar to other 
anaesthetic agent (Kampe et al., 2003). 
2.2.3  The roles of ropivacaine in peripheral nerve blocks and upper limb surgery 
 
Peripheral nerve block is utilised for anaesthesia for orthopaedic surgery, and the 
emergence and dissemination of local anaesthetic effect is regulated by the injection 
locality (Hofmann-Kiefer et al., 2002). The authors also discovered that there were no 
significant differences  between ropivacaine (dosed at 7.5 mg/ml) and bupivacaine (dosed 
at 5mg / ml) recipients in terms of the onset and quality of motor and sensory blockades 
when both drugs were administered for BPB via interscalene approach (Hoffman-Kiefer 
et al., 2002). 
Besides, other studies also demonstrated that the concentration of ropivacaine 
employed for long-acting sensory and motor blockades is either 0.5% or 0.75% for 

 
16 
 
axillary, interscalene and subclavian perivascular BPB (Casati et al., 2003; Liisanantti et 
al., 2004). The researchers found that 0.5 – 0.75% ropivacaine produced a similar quality 
of regional anaesthesia as either 0.5% bupivacaine or 0.5% levobupivacaine given as a 
bolus dose of 30 -45 ml (Casati et al., 2003; Liisanantti et al., 2004). Similar findings 
were also established in patients undergoing femoral and sciatic blockades for hallux 
valgus repair where the recipients of 25 ml of 0.75% ropivacaine had a significantly 
quicker onset of sensory  block around the territories supplied by the femoral and sciatic 
nerve (ropivacaine vs bupivacaine: 14 minutes vs 37 minutes, p value = 0.002) and motor 
blockade (ropivacaine vs bupivacaine: 14 minutes vs 51 minutes, p value = 0.001) than 
those receiving 25 ml of 0.5% bupivacaine (Fanelli et al., 1998). Besides, the durations 
of motor blockades at the knee and foot levels were longer in the recipients of ropivacaine 
and bupivacaine when comparison was made with mepivacaine recipients. Finally, 
Fanelli and colleagues (1998) also established that the total duration of analgesia was 
significantly longer in ropivacaine and bupivacaine than in the mepivacaine groups 
(ropivacaine vs bupivacaie vs mepivacaine: 670 minutes vs 880 minutes vs 251 minutes, 
p value = 0.001). Even though ropivacaine recipients had a relatively shorter mean 
duration of motor block at knee level and the total duration of analgesia than bupivacaine 
recipients, these differences were not statistically significant (Fanelli et al,  1998).  
 
With respect to upper limb surgery, there was similar quality of pain relief with 
ropivacaine and bupivacaine in a trial conducted among patients who had interscalene 
block prior to major open surgeries to their shoulders (Borgeat et al., 2001). However, 
the authors observed that the hand strength returned more expeditiously and the degree 
of paraesthesia at the finger level was less in patients receiving 0.2% ropivacaine than in 
those receiving 0.15% bupivacaine (Borgeat et al., 2001). At 24 hours after the 
performance of interscalene block, the hand strength (the primary endpoint) was reduced 

 
17 
 
by 48% in 0.2% ropivacaine recipients and 66% in bupivacaine recipients (p value <0.05) 
(Borgeat et al., 2001). Furthermore, the hand strength was completely recovered for 
subjects in ropivacaine arm at 6 hours following the cessation of ropivacaine  infusion. In 
bupivacaine group, however, there was a protracted recovery of  hand strength since it 
was still reduced by 25%  after the end of bupivacaine administration and the difference 
was significant when comparison was made with the ropivacaine group (Borgeat et al., 
2001). Nevertheless, the results of this study should be taken with a pinch of salt due to 
the controversial use of the non-validated bulb-grip device test as a measurement tool for 
motor strength by the authors.  
In another study conducted locally by Mageswaran and Choy (2010), subjects 
undergoing elective or orthopaedic upper limb surgery were randomized into receiving 
either 0.5% ropivacaine or 0.5% levobupivacaine via infraclavicular brachial plexus 
block. The mean onset for sensory and motor block were significantly higher in 0.5% 
ropivacaine recipients than 0.5 levobupivacaine recipients (sensory block: 13.5 minutes 
vs 11.1 minutes (p value = 0.003), motor block: 19.0 minutes vs 17.1 minutes (p value = 
0.013). However, no statistically-significant difference was found with regard to the 
analgesic efficacy at 6 hours after the surgery. Again, the findings of this study should 
not be taken at face value and hence careful consideration should be exercised before 
recognising the validty of such results since the number of participants allocated in each 
intervention group was small (n = 24 per group). Hence, further studies are required to 
gain further information on the exact benefits of ropivacaine over other anaesthetic agents 
such as bupivacaine for upper limb surgeries. 
2.3 PARECOXIB: PHARMACOLOGICAL PROPERTIES 
The management of moderate-to-severe acute pain involves a prudent utilisation 
of opioids, local anaesthetics, and non-steroidal anti-inflammatory drugs (NSAIDs) (Carr 

 
18 
 
and Goudas 1999). NSAIDs is a group of drugs that function as cyclo-oxygenase (COX) 
inhibitor, an enzyme that is critical for prostaglandins production (Jain 2000). The 
unselective NSAIDs indiscriminately hamper the function of COX-1 and COX-2 (Jain 
2000). 
 COX-1 has “housekeeping” functions which include preserving renal perfusion 
and protecting the gastric mucosal layer against ulceration (Emery 1999). It is 
constitutively expressed and has critical roles in the production of prostaglandin in the 
gastric mucosal layer, platelets and renal blood vessels (Fosslien 1998). On the contrary, 
the blockade of the inducible isoform COX-2 synthesis is believed to be chiefly accounted 
for the NSAIDs' analgesic and anti-inflammatory effects (Bolten 1997, Needleman and 
Isakson 1998).  
 
The development of COX-2-specific oral NSAIDs (e.g. celecoxib and rofecoxib) 
has resulted in a class of theraputic agent that provides effective relief of mild-to-
moderate pain without the gastrointestinal and anti-platelet adverse effects (Jain 2000). 
However, in cases of postoperative nausea and vomiting or where the oral route of 
administration is deemed unsuitable postoperatively, the use of orally-administered 
NSAIDs is hence ill-suited (Carr and Goudas 1999). At present, there are very few 
NSAIDs that are available in parenteral form with ketorolac (Toradol®) is the sole 
exception. Nevertheless, due to being a non-selective COX inhibitor, ketorolac is 
associated with gastrointestinal ulceration, deterioration of kidney function and a 
susceptibilty to raised incidence of perioperative bleeding (McArdle 1999). Besides, 
ketorolac is also contraindicated postoperatively since it may interfere with the wound 
healing process which may result in serious bleeding and other life-threatening post-
surgical complications. 

 
19 
 
 
Parecoxib (Dynastat®) is a COX-2 specific inhibitor which can also be 
administered as an IV or intramuscular injection. It is a prodrug of valdecoxib which was 
chemically designed to overcome the poor solubility of valdecoxib in aqueous solution 
so that it can be administered parenterally (Amabile and Spencer 2004). Structurally, it 
has a sulphonamide moiety. Parecoxib is broken down by carboxylesterase in the liver 
into its active form, valdecoxib (Amabile and Spencer 2004). Valdecoxib, however, is 
metabolized via oxidative process which is catalysed by CYP3A4 and slightly by 
CYP2C9 (Amabile and Spencer 2004). 
There are two postulated mechanisms on how parecoxib modulates nociception. 
Firstly, the blockade of prostaglandin H2 and E2 ,which are subtypes of prostaglandin that 
are synthesised from arachidonic acid, results in the modulation and diminishment of 
nociception by the reduction of the sensory neuron’s electrical excitability and 
bradykinin-associated hyperalgesia (Jain 2000, Amabile and Spencer 2004). Secondly, 
parecoxib may also directly act on the inhibitory or excitatory neurone’s amino acid sites 
(Jain 2000).  In this subchapter, we shall focus our discussion on the pharmacological 
properties of parecoxib to rationalise its use as an adjunct to ropivacaine for BPB. 
2.3.1 Absoprtion, Distribution, Metabolism and Elimination (ADME) 
In normal and healthy individuals, the maximum plasma concentration (Cmax) of 
valdecoxib (the active metabolite of parecoxib) was found 73% lower after the 
administration of 20 mg of IM parecoxib (1 – 1.25 mg/L) than following IV 
administration (3.8-4.7 mg/L) (Gajraj, 2007). The time to Cmax (tmax) was approximately 
5 minutes after IV administration and 20 minutes after intramuscular administration 
(Gajraj 2007). However, the total exposure to valdecoxib (the active form of parecoxib) 
based on the area under the plasma concentration-curve (AUC24h) and the magnitude of 
Cmax for valdecoxib were independent of the routes of administration (Gajraj 2007). 

 
20 
 
Nevertheless, tmax is shorter for valdecoxib after 20 mg of parecoxib was administered 
intravenously (30 minutes) than following IM parecoxib administration (1-2.5 hours) 
(Gajraj 2007).  
 
Parecoxib was also quickly biotransformed to valdecoxib following IV 
administration of 50 mg parecoxib in twelve (n=12) normal individuals (Grossman et al., 
2000).  Grossman and colleagues (2000) established that the t1/2 was 0.69 hours and the 
peak plasma concentration (Cmax) of valdecoxib following the administration of a single 
IV dose of 50 mg parecoxib was 1.02mg/L and this was recorded 0.6 hours following 
parecoxib administration (Ng et al., 2004). If parecoxib is given in a multiple dose regime 
(e.g. 50mg twice daily), the Cmax of valdecoxib was higher (1.40 mg/L  on day 10) with 
the mean valdecoxib plasma concentrations at steady-state (Cav,ss) were attained on the 7th 
day. The area under the concentration-time curve from time 0 to infinity (AUC∞ ) for 
valdecoxib following a single dose of IV parecoxib was 7.80 mg/L per hour and with 
multiple doses, the area under the plasma-concentration time curve at 12 hours (AUC12h)  
was 8.16 mg/L per hour on the 10th day. The t1/2 for valdecoxib was 7.88 hours and 
valdecoxib was the primary compound recovered in the urine within the span of 48 hours 
following parecoxib administration (Ng et al., 2004). 
 
Besides, the mean AUC24 and mean Cmax of valdecoxib was shown to 
proportionately raise with the parecoxib dose (range: 1 to 100 mg) administered as a 
solitary IV dose in 356 patients following dental surgery (the AUC24 is between 0.15 to 
13.61 mg/L per hour; Cmax: 0.026 to 2.16 mg/L) (Daniels et al., 2000). Using 20mg dose 
of parecoxib given intravenously, the authors established that the mean AUC24h and Cmax 
were 2.62 mg/L per hour and 0.45 mg/L, respectively. Besides, the  tmax  remained stable 
(0.5 to 0.9 hours) across all range of IV parecoxib doses (Daniels et al.,2000). 

 
21 
 
 
Parecoxib, in the dose between 1 and 40 mg, is also swiftly biotransformed when 
it is intramuscularly administered. In a study of 56 normal individuals, the t1/2 of parecoxib 
ranged between 0.25 and 0.58 hours (Karim et al., 2000). The Cmax of valdecoxib was 
attained at 1.1 to 3.5 hours after parecoxib was administered and the Cmax and AUC∞ of 
valdecoxib had been found to raise dose-proportionately as the amount of parecoxib doses 
increases. The values for Cmax and AUC∞ were not unfortunately disclosed by the authors. 
Besides, the mean Cmax (0.027 to 0.39 mg / L per hour) of valdecoxib were also found to 
raise in a dose-dependent fashion when parecoxib (dose range: 1 to 20mg) was 
administered as a solitary IM injection to 353 patients with postoperative dental pain 
(Karim et al., 2000). The  median tmax was attained at 1.6 hours post IM parecoxib 
injection. The authors subsequently concluded that the alteration in the plasma 
concentration of valdecoxib is associated with the analgesic duration and onset (Karim et 
al., 2000). 
2.3.2 Potential drug interactions 
 
To evaluate the potential drug interactions between parecoxib and 
pharmacological agents metabolized by CYP3A4, an intravenous infusion of midazolam 
(a commonly-used probe for investigating CYP3A4-mediated drug-drug interactions) 
dosed at 0.07mg/kg over 5 minutes was given to 12 healthy normal and salubrious 
subjects at 1 hour following intravenous administration of parecoxib (40mg) or placebo 
in  a double-blind RCT conducted in a crossover fashion (Ibrahim et al., 2000a). The 
plasma midazolam concentration-time curves were similar for volunteers who had been 
parecoxib-pretreated and those who were in the placebo group. In addition, Cmax, systemic 
clearance and t1/2 for midazolam did not differ significantly between those who were 
pretreated with parecoxib and the individuals who were in the placebo group. 
Furthermore, in another double-blind and crossover RCT, 40 mg of IV parecoxib 

 
22 
 
administered to 12 healthy individuals did not significantly alter the plasma 
concentration-time curve, Cmax , the systemic parecoxib clearance and t1/2 of intravenous 
propofol 2mg/kh  when comparison was made with placebo recipients (Ibrahim et al., 
2000b). 
Apart from that, Parecoxib has also been found to have several other significant 
drug interactions. Compared with placebo, parecoxib (given as 40 mg twice daily for 3 
days followed by a single dose on day 4) did not significantly affect the anti-platelet effect 
of aspirin in response to various aggregants at most time-points (Noveck et al., 2000). 
Platelet aggregation was, on the other hand, lowered in response to arachidonate, ADP or 
collagen in this well-controlled trial.  
 
Besides, in another open-label single centre RCT, eighteen (n=18) normal healthy 
fasted study participants were given a bolus 4000U unfractionated heparin (UFH) 
injection who were then received a heparin infusion at a starting dose of 10 to 14U/kg for 
a minimum duration of 36 hours. The heparin dose was altered to attain an activated 
partial thromboplastin time (aPTT) between 1.5 and 3.0 times the normal baseline value. 
During this period (which is also known as treatment period 1), the aPTT, prothrombin 
time (PT) and platelet counts were routinely monitored until 24 hours had passed after 
the UFH infusion was ceased. Following a 2-day washout period, the treatment period 2 
started during which the study participants  (n=18)  received an IV infusion of 40 mg 
parecoxib twice daily for six consecutive days and a UFH infusion was coadministered 
with parecoxib on day 5 given at the same dose as in treatment period 1 (Noveck et al., 
2001). The results indicate that there were no statistically significant differences in terms 
of the aPTT, platelet counts and PT between those who received both parecoxib and 
heparin in treatment period II and the recipients of heparin alone during treatment period 

 
23 
 
I (Noveck et al., 2001). Hence, parecoxib can be safely coadministed with UFH without 
affecting any coagulation parameters. 
2.3.3 Tolerability and adverse effects 
 
Several adverse events are associated with the intravenously-administered 
parecoxib (20 or 40mg, single dose) compared with intravenous ketorolac (30mg, single 
dose),  single-dose IV morphine sulphate (4mg) or placebo were found in a multi-centre 
double-blind placebo-controlled clinical trial involving 202 female patients with 
moderate to severe pain following abdominal hysterectomy or myomectomy (Langland 
et al., 2000). The most common adverse events occurring in 10% or more patients 
irrespective of treatment are nausea, abdominal pain, headache, abdominal fullness, 
dizziness, back pain, fever, hypoactive bowel sounds, vomiting, tachycardia, somnolence, 
abnormal breath sounds and pruritus. Most adverse events were mild or moderate in 
severity and no statistical significant differences with regard to the proportions of adverse 
events were reported among the intervention groups. Surprisingly, Langland and 
coworkers (2000) found that parecoxib and ketorolac had greater efficacy in controlling 
moderate-to-severe pain than a single-dose morphine sulphate among patinets who had 
undergine abdominal hysterectomies or myomectomies. 
 
In another double-blind placebo-controlled single-centre RCT, 55 patients who 
underwent abdominal hysterectomies or myomectomies were reandomised into one of 
the following intervention arms; normal saline placebo (n=18), 20 mg IV parecoxib 
(n=19) and 40 mg IV parecoxib (n=18) (Tang et al., 2002).  The incidence of adverse 
events reported by these patients were as follows: vomiting  11% (IV 20 mg parecoxib), 
0% (IV 40 mg parecoxib) and 6%  (saline placebo);  pruritus  21% (IV 20 mg parecoxib), 
17% (40 mg IV parecoxib) and 28% (saline placebo); and pyrexia 0% (IV 20 mg 
parecoxib), 11% (IV 40 mg parecoxib) and17% (saline placebo). No other serious adverse 

 
24 
 
events were reported by Tang and colleague (2002). Besides, there were also no 
parecoxib-related adverse events when 20 mg or 40 mg IV parecoxib was administered 
in a double-blind RCT involving 72 female patients experiencing  pain following 
gynaecological surgeries (Kenaan et al., 2001). 
 
With respect to pain control following orthopaedic surgery, Malan et al.,,(2003) 
established that parecoxib, when used concomitantly with PCA morphine, reduced the 
need for PCA morphine and decreased the time for patients on PCA morphine.  Besides, 
Malan and colleagues (2003) also demonstrated that both IV 20 mg (group 2) or 40 mg 
parecoxib (group 3) were well-tolerated amongst all adult patients who had primary or 
revised total hip arthroplasty (n=175), with less number of subjects experiencing 
vomiting, nausea pruritus, tachycardia and pyrexia compared to the placebo group (group 
1)  (Malan et al., 2003). Apart from that, a significantly less number of subjects receiving 
40 mg parecoxib reported pyrexia (p<0.01) and/or emesis (p<0.05) compared to placebo 
(Malan et al., 2003). This evidence hence further confirms the excellent safety profile of 
parecoxib compared to other pain-control medications. 
2.3.4 Pharmacodynamic profiles 
 
As a prodrug, parecoxib undergoes a full and swift bioconversion to valdecoxib 
which is its pharmacologically-active metabolite.  The dose of valdecoxib needed to block 
the activity of COX-2 by half is 0.005μmol / L  and this is much greater higher than the 
half maximal inhibitory dose for COX-1 activity which is 140 μmol/L (Talley et al., 
2000). 
With respect to its analgesic effect, paracoxib’s efficacy has been demonstrated in 
patients with postoperative pain following third molar extraction, gynaecological and 
orthorthopaedic surgery (Barden et al., 2003; Martinez et al., 2007; Mohamad et al., 
2014). The analgesic activity of IV parecoxib can also be conspicuously observed in a 

 
25 
 
murine model of acute inflammation and pain brought about by carrageenan (Talley et 
al., 2000). Talley and co-workers (2000) demonstrated that the IV parecoxib dosed at 30 
mg/kg produced a quick onset of action, resulting in a total reduction of nociceptive 
sensitivity (hyperalgesia) within 1 hour following its administration (Talley et al., 2000). 
The authors also established that a parecoxib dose of 5mg/kg was required to create 
analgesic effects in half of the rats in their murine model. Besides, they also showed that 
a parecoxib dose of 30 mg/kg produce equivalent clinical end-points as ketorolac 
administered in the same dose (Talley et al., 2000). 
 
With regard to its gastrointestinal side effects, Hubbard et al. (2000) established, 
in a double-blind RCT, that normal elderly individuals (aged between 65 and 75 years 
old) who were administered with 40 mg IV parecoxib  twice daily for 7 days (n=31) had 
significantly less susceptibility to gastrointestinal ulceration than those who received 15 
mg IV ketorolac group 4 times a day for 5 days after which they were given placebo for 
2 days (n=31) (0 vs 23% , p<0.05). Moreover, the number of new cases of gastrointestinal 
lesions (both erosions and ulcers) was also significantly less in parecoxib group. Based 
upon endoscopic assessment, Hubbard and colleagues (2000) discovered that there were 
no significant differences in regard to parecoxib-associated gastrointestinal adverse 
events between the parecoxcib and placebo groups (Hubbard et al., 2000). It was also 
established that parecoxib did not inhibit arachidonate-induced platelet aggregation when 
comparison was made with ketorolac (Noveck et al., 2004). In this small open-label, 
single centre, two-treatment period RCT (n = 18), the authors also found that there was 
non-significant alteration of platelet function from baseline when 40 mg parecoxib was 
administered twice daily for 6 consecutive days with an attendant 4000U of 
unfractionated heparin (UFH) given as a bolus on the 5th day which was then followed 
by a UFH infusion with an initial dose of 10-14U/kg for 36 hours. This proves that 

 
26 
 
parecoxib does not cause overt bleeding even when it is concomitantly used with UFH. 
This proves the excellent safety profile of parecoxib compared to other NSAIDs such as 
ketorolac (Noveck et al., 2004). 
2.4 THE ROLE OF PARECOXIB AS AN ADJUNCT TO ROPIVACAINE IN 
BRACHIAL PLEXUS BLOCK (BPB) 
Thus far, there are only two RCTs which investigated the effect of parecoxib as 
an adjunct to ropivacaine in BPB setting. Liu  et al. (2013) conducted a randomized 
controlled trial (RCT) from January 2009 to November 2010 with 150 Chinese patients 
scheduled for elective forearm surgery, using a multiple-nerve stimulation technique. 
Patients were allotted randomly into one of these 3 groups: Group A (n = 50) subjects 
received single-agent 0.25%% ropivacaine for the axillary BPB; Group B (n = 50) 
received 0.25% ropivacaine and 20 mg of adjunct parecoxib on the axillary BPB; and 
subjects in Group C (n = 50) received only 20 mg IV parecoxib. The authors documented  
the sensory and motor blockade duration, and the highest pain score in a 24-hour period 
following elective forearm surgery. 
    
The results indicated that parecoxib, when used as an adjunct to ropivacaine, 
prolonged the motor and sensory block times. However, in those who only received the 
IV parecoxib injection (Group C), such prolongation in sensory and motor block was not 
observed. Liu and co-workers (2013) also found lower mean pain intensity scores in 
Group B  than the Groups A and C subjects. According to the authors,  20 mg parecoxib 
given as an adjunct had significantly lengthened the motor (mean motor block duration: 
371 minutes (group A) vs 509 minutes (group B); mean difference = 138 minutes; 
p < 0.001) and sensory (mean sensory block duration: 439 minutes (group A vs 543 
minutes (group B); mean difference = 104 minutes; p = 0.001) block times when 
comparisons were made with group A. However there were no significant differences 

 
27 
 
with respect to the durations of sensory (mean sensory block duration: 439 minutes (group 
A) vs 457 minutes (group C); mean difference: 18 minutes; p value = 0.300) and motor 
(mean motor block duration: 371 minutes (group A) vs 414 minutes (group C); mean 
difference: 43 minutes;  p value = 0.800) blockades between group A and C. Besides, the 
authors also established that the primary block effectiveness was similar in all three 
groups (96% for group A, B and C). The authors eventually concluded that adjunct 
parecoxib significantly lengthened the duration of axillary brachial plexus blockade and 
lessened postoperative pain in subjects who underwent orthopaedic surgeries to their 
forearms. However, the authors’ findings are still inconclusive due to the small sample 
sizes employed in their trial and the much lower concentration of ropivacaine ( 0.25% 
ropivacaine) that they used in their trial. 
 
There was also another recent study conducted by Cherif and coworkers (2014) in 
Tunisia. They recruited 118 patients who underwent infraclavicular BPB prior to upper 
limb surgeries. The patients were randomized into 3 intervention arms; 1) bupivacaine 
and parecoxib (n=44) (group P), 2) bupivacaine and dexamethasone (n=40) (group D) 
and 3) bupivacaine and saline (n=34) (group C, placebo controls). The authors established 
that parecoxib had significantly hastened the time to onset of motor and sensory blockades 
compared to dexamethasone and saline placebo (mean onset of sensory block: 77.82 
seconds (group P) vs 383.45 seconds (group D) vs 302.94 seconds (groupd C), p value 
<0.05;mean onset of motor block: 120.45 seconds (group P) vs 440.5 seconds (group D) 
vs  316.24 seconds (group C), p value <0.05). However, dexamethasone was found to 
enhance the quality of analgesia in comparison with parecoxib and saline placebo (mean 
Visual Analogue Scale (VAS) score on postoperative day 1: 0.7 (group D) vs 2.68 (group 
P) vs 2.11 (group C), p <0.05; mean time to first analgesic consumption: 2283 minutes 
(group D) vs 1248 minutes (group P) vs 1408 minutes (group C) . Nevertheless, the 

 
28 
 
generalisability of the findings is still implausible due to the small sample size of this 
study, the lack of details on the randomization method and procedure employed by the 
researchers and the lack of controls on confounders that would make the findings 
accidental (spurious) and inauthentic. 
Nonethless, the efficacy of parecoxib (Liu et al., 2013; Cherif et al., 2014) had 
also been substantiated by other safety data for parecoxib obtained from murine models 
and a non-randomized double-blind cross-over trial.  Kim et al. (2011) demonstrated that 
an epidural injection of COX-2 is a beneficial therapeutic alternative in the clincal 
management of pain due to its excellent neurotoxicity profile based on their murine 
model. They also hypothesized that parecoxib might be a suitable alternative to 
corticosteroid for the management of pain associated with herniated discs and other spinal 
pathologies due to its antinoceptive effect on the peripheral and central nervous systems. 
However, since this is just a murine model and did neither incorporate nor investigate the 
possible synergestic effects of ropivacaine and parecoxib on the nociceptive transmission 
and modulation in humans, the findings are still not sufficiently conclusive to effect the 
ubiquitous use of parecoxib in BPB setting. 
Apart from that, Martin et al. (2007) conducted a non-randomized double-blind 
cross-over trial  involving twelve (n=12) normal individuals to investigate the effect of 
IV parecoxib at a dose of 1mg/kg on the electrophysiologic recordings of nociceptive 
flexion reflex (RII). The RII reflex is an objective physiologic index of the spinal 
transmission of nociceptive signals. Their results indicated that parecoxib, when 
compared to placebo, significantly reduced the RII stimulus response curve, suggesting a 
diminishment of the spinal nociceptive signal transmission in. The authors concluded that 
the constitutive COX-2 isoform regulates the spinal nociceptive transmission processes 
and the effect of IV parecoxib on the spinal nociceptive transmission blockade is 

 
29 
 
suggestive of there is no causal relationship between its anti-inflammatory and anti-
nociceptive properties (Martin et al., 2007). Nevertheless, the validity of the study 
findings had also suffered from the study’s sample size, the absence of control subjects 
and the improper randomization technique used in this trial. 
2.5 THE RATIONALE OF THIS STUDY 
There is still a paucity of information concerning the role of parecoxib as an 
adjunct to ropivacaine in supraclavicular BPB, hence creating a gap in clinical knowledge 
(also known as clinical equipoise) with respect to the exact role of adjunct parecoxib in 
supraclavicular BPB setting. The only available details that established the utility of 
adjunct parecoxib in supraclavicular BPB setting are those gained from the small-sized 
trial conducted by Liu et al., (2013) which are only corroborated by safety data obtained 
from the murine model (Kim et al., 2011) and the non-randomized cross-over trial (Martin 
et al., 2007). Furthermore, the usefulness of adjunct parecoxib was only investigated in 
axillary BPB setting and hence its practicality in other approaches of BPB, for example 
supraclavicular BPB, is yet to be properly scrutinised.  Therefore, this clearly warrants a 
new clinical trial to further evaluate the extent of adjunct parecoxib’s utility in other 
clinical setting. 
 
. 
 
 
 
 
 
 
 
 

 
30 
 
2.7  CONCEPTUAL FRAMEWORK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.1: The conceptual framework of the synergestic effects of parecoxib and 
ropivacaine on blocking pain signal transmission resulting in an enhanced onset and 
durations of sensory and motor blockades in BPB. 
 
 
 
 
 
Subjects undergoing upper limb surgeries 
Use of ropivacaine and parecoxib 
Block Na+ ion 
channels 
Block COX-2 
function 
Block central 
nociceptive process 
and modulates 
hyperalgesia 
Block nerve impulse 
generation and 
conduction 
Further reductions in pain signal transmission 
Use of ropivacaine only 
Only blocks Na+ ion channels 
Slower onset and shorter durations 
of sensory and motor blockades 
for brachial plexus block 
Faster onset and longer durations of sensory and 
motor blockades for brachial plexus block 
Only blocks Na+ channels without 
parecoxib effects 
Lesser reductions in pain signal 
transmission 

 
31 
 
SECTION 3 
RESEARCH OBJECTIVES 
3.1 GENERAL OBJECTIVES: 
To investigate the effectiveness of parecoxib 20 mg as an adjunct to ropivacaine 0.75% 
for ultrasound guided supraclavicular block for upper limb surgery. 
3.2 SPECIFIC OBJECTIVES: 
1. To compare the onset of the sensory block between 20mg of parecoxib in 0.75% 
ropivacaine and plain 0.75% ropivacaine. 
2. To compare the onset of the motor block between 20mg of parecoxib in 0.75% 
ropivacaine and plain 0.75% ropivacaine. 
3. To compare  the degrees of sensory and motor block after 30 min between 20mg 
of parecoxib in 0.75% ropivacaine and plain 0.75% ropivacaine. 
4. To compare the duration of the sensory block between 20mg of parecoxib in 
0.75% ropivacaine and plain 0.75% ropivacaine . 
5. To compare the duration of the motor block between 20mg of parecoxib in 
0.75% ropivacaine and plain 0.75% ropivacaine .  
3.3 RESEARCH QUESTIONS 
1. Do subjects receiving 20mg of parecoxib in 0.75% ropivacaine significantly differ 
in terms of the onset of the sensory block when compared to those recipients of 
single-agent 0.75% ropivacaine? 
2. Do recipients of 20mg of parecoxib in 0.75% ropivacaine significantly differ with 
respect to the onset of the motor block when they are compared with those 
recipients of single-agent 0.75% ropivacaine? 

 
32 
 
3. Is there any significant difference between subjects receiving 20mg of parecoxib 
in 0.75% ropivacaine and single agent 0.75% ropivacaine with regard to the 
degrees of sensory and motor block? 
4. Are those receiving 20mg of parecoxib in 0.75% ropivacaine significantly differ 
from the recipients of single-agent 0.75% ropivacaine with respect to the duration 
of sensory block? 
5.  Is there any significance difference in terms of duration of motor block between 
the recipients of 20 mg parecoxib in 20% ropivacaine and those receiving single-
agent 20% ropivacaine? 
3.4 RESEARCH HYPOTHESES 
1. Null hypothesis (H0): There is no significant difference in the onset of the 
sensory block is faster in 20mg of parecoxib in 0.75% ropivacaine in comparison 
to  plain 0.75% ropivacaine. 
2. Null hypothesis (H0): There is no significant difference in the onset of the motor block 
is faster in  20mg of parecoxib in 0.75% ropivacaine in comparison to  plain 
0.75% ropivacaine. 
3. Null hypothesis (H0): There are no significant differences in the degrees of sensory 
and motor block after 30 min is higher in 20mg of parecoxib in 0.75% ropivacaine 
in comparison to  plain 0.75% ropivacaine 
4. Null hypothesis (H0): There is no significant difference in the duration of the sensory 
block in 20mg of parecoxib in 0.75% ropivacaine in comparison to  plain 0.75% 
ropivacaine 
5. Null hypothesis (H0): There is no significant difference in the duration of the motor 
block in 20mg of parecoxib in 0.75% ropivacaine in comparison to  plain 0.75% 
ropivacaine. 

 
33 
 
SECTION 4 
 
RESEARCH METHODOLOGY 
 
4.1 STUDY DESIGN 
 
A prospective, single center, two-parallel group, single (observer)-blinded 
controlled trial involving surgical patients undergoing upper limb surgeries at the HUSM 
surgical theatres. 
4.2 STUDY PERIOD AND PERIOD OF RECRUITMENT 
The total study duration is 10 weeks and the period of patient recruitment is from 20th 
June 2017 till 28th August 2017. 
4.3 TRIAL CENTRE 
Hospital Universiti Sains Malaysia (HUSM) is the main teaching hospital for the 
Eastern Coastal states of Peninisular Malaysia. It is situated in Kubang Kerian, Kelantan 
and handles primary-care referrals from all the states in the eastern region of Peninsular 
Malaysia (Kelantan, Terengganu and Pahang). Hence, it can be considered as one of the 
chief tertiary care centres that dispenses a modern specialty care for nearly a third of the 
whole population in Peninsular Malaysia. 
Annually, HUSM accepts almost 2000 surgical cases, of which nearly 19.65 
percent are elective or semi-emergency surgical patients that require upper limb 
procedures (393 cases). This provides the study investigators ample resources for the 
acquisition of patients that meet the trial criteria which ensures in the accomplishment of 
the intended sample size. 
4.4 REFERENCE AND SOURCE POPULATION 
The reference population is all elective or semi-emergency surgical patients who 
underwent upper-limb surgical procedures and supraclavicular BPB in Kelantan. The 
source population is all elective or semi-emergency surgical patients receiving upper-

 
34 
 
limb surgical procedures and supraclavicular brachial plexus block who resided in Kota 
Bharu. 
4.5 SAMPLING FRAME 
All subjects who fulfilled the eligibility criteria (both inclusion and exclusion) and had 
upper-limb surgical procedures and supraclavicular BPB in the HUSM between 20th June 
2017 and 28th August 2017 were included in the sampling frame. 
4.6 SAMPLING METHOD 
Despite sufficient potential subjects for their recruitment into this trial, convenient 
sampling had to be used due to the time constraint imposed by the urgency for thesis 
submission within the tight submission window (early November). 
4.7 STUDY SUBJECTS 
All patients that fulfilled the eligibility (inclusion and exclusion) criteria and consented 
for study participation. 
4.8 ELIGIBILITY CRITERIA 
4.8.1 Inclusion criteria 
I) Aged between 18 to 70 years old 
II) Subjects with the American Society of Anaesthesiologists (ASA) physical status grade  
1 to 2 
III) The expected duration of surgery was between 1 and 4 hours. 
4.8.2 Exclusion criteria 
I) Subjects who refused to brachical plexus block (BPB) 
II) Known allergies to parecoxib, other NSAIDS and anaesthetic agents. 
III) Pregnancy 
IV) History of prior brachial plexus injury 
V) History of chronic pain that requires long-term use of analgesic medications 

 
35 
 
VI) Coagulopathy 
VII) Systemic infection or local infection at the site of injection 
VII) Known neuropathy for the limb undergoing surgical procedures. 
4.9  OPERATIONAL DEFINITIONS  OF VARIABLES  
a) Independent variables 
i) Age: The age of patients (in years) when BPB was performed. Measured and recorded 
as a strictly positive continuous variable. 
ii) Gender: The gender of a subject. Recorded as a categorical variable with 0 = male 
(the baseline group) and 1 = female. 
iii)  Ethnicity: Subject’s racial origin. Recorded as a categorical variable with 0 = Malay 
(the baseline group), 1 = Chinese, 2 = Indian, 3 = Others (such as Siamese) 
iv) The American Society of Anaesthesiologist (ASA) grades: Recorded as a 
categorical variable with 0 = Grade 1 (the baseline group), 1 = Grade 2. 
v) Weight: The weight of a study participant measured in kilograms measured during he 
pre-surgical assessment. Recorded as a strictly positive continuous variable. 
vi) Intervention groups: Recorded as a categorical variable with 0 = 0.75% Ropivacaine 
only group (the baseline group) and 1 = 0.75% Ropivacaine + adjunct 20 mg parecoxib 
group. 
b) Dependent (outcome) variables 
i) Onset of sensory block: Time required for a decrease of sensation to 30% or less by 
comparison to the contralateral limbs as a reference (Duma et al., 2005). Measured in 
minutes and recorded as a numerical variable. 
ii) Onset of motor block: the time from injection of local anesthetic mixture until a 
reduction in motor power to grade 3 or 4 ensued (Ammar and Mahmoud, 2012). Measured 
in minutes and recorded as a numerical variable. 

 
36 
 
iii) Sensory block duration: The time from injection of local anaesthetic mixture to  
complete recovery  from cold and pain sensation as tested by an alcohol swab and pin 
prick respective in all dermatomes of the brachial plexus (C5-T1). Measured in hours and 
recorded as a continuous variable 
iv) Motor block duration: the time from injection to complete recovery of motor 
function in all nerve dermatomes. Measured in hours and recorded as a continuous 
variable. 
v)  Sensory and motor blockades at 30 minutes: The presence of complete sensory 
(grade 2) and motor (grade 4) blockades at 30 minutes following the BPB institution. 
c) Other relevant clinical variables 
i) Time 1st PCA: The time taken from the end of the surgery until the delivery of the first 
PCA morphine. Measured  and recorded as a strictly positive numerical variable 
ii) Volume PCA: The total volume of PCA morphine administered to the patients after 
surgery until the patient was discharged from the ward. Measured in mls and recorded as 
a numerical variable. 
iii) PCA demand: The total frequency of morphine demand over a period of 24 hours. 
Measured and recorded as a strictly positive numerical count variable. 
iv) Sensory block grades: This was assessed using the a 3-point scale utilised by Crews 
et al. (2002).   There are 3 grades for this variable;  
 Grade 0 = normal sensory response  
 Grade 1 = reduced sensory perception (partial sensory blockade) 
 Grade 2 = no sensation (complete sensory blockade).  
Recorded as 0 = normal (baseline group), 1 = reduced , 2 =  absent.  
v) Motor block grades: The scale used by Borgeat, Ekatodramis and Durmont (2001) 
are employed to grade the magnitude of motor block. This scale has 4 grades: 

 
37 
 
 Grade 1: ability to flex or extend the forearm 
 Grade 2: ability to flex or extend only the wrist and fingers 
 Grade 3: ability to flex or extend only the fingers 
 Grade 4: inability to move the forearm, wrist, and fingers 
Recorded as 0 = Grade 1 (baseline group), 1 = Grade 2, 2 = Grade 3, 3 = Grade 4.  
vi) Surgical sites: The exact location where surgery to the upper limb was carried out. 
Recorded as  1 = Arm, 2 = Forearm, 3 = Hand, 4 = Fingers. 
vii) VRS : The visual rating score (VRS) which was recorded at 1, 2, 4, 12, 24 hours post 
operatively. Its range is between 0 and 10. Recorded as a strictly-positive numerical   
variable.    
viii) Preoperative VRS:  The VRS recorded prior to supraclavicular BPB. 
4.10 STUDY PROTOCOL 
4.10.1 Randomisation method and allocation concealment 
 
After receiving the ethical clearance from USM’s Ethics Committee, the patient 
recruitment for this trial commenced. The study subjects were firstly screened against the 
eligibility criteria and those who met the criteria, informed consents were acquired from 
each one of them. 
 
The study participants were then block-randomized using a block size of 4 with a 
balanced 1:1 allotment ratio without any covariate stratification. This method of 
randomization, instead of the simple randomization technique, was utilized to ensure that 
the number of study participants is equal in both intervention groups. In this case, for 
every block of four study participants, each two of them will be allotted to one 
intervention arm. The block randomization was performed using  permuted block design,  
with the random numbers generated by a random number generator package in Stata 9.0 
(StataCorp, College Station, Texas). This randomization process was performed by an 

 
38 
 
independent third-party statistician (Mr Muhammad Irfan bin Abdul Jalal, Graduate 
Statistician (GradStat), the Royal Statistical Society, UK). 
 
To ensure selection bias was prevented, the allocation sequence was kept inside a 
password-protected STATA 9.0 file which was only accessible to the independent third-
party statistician. The sequence of treatment allotment was only revealed after a study 
participant was properly recruited and subsequently randomized to treatment allotment. 
To prevent ascertainment and performance bias, the study participants and the 
independent assessors (2nd medical officer) were shielded from the knowledge of the type 
of intervention received. However, the intervention was administered by the primary 
investigator (VG) who was not blinded to the kind of intervention received. 
4.10.2 Details of the administered interventions 
The premedication was first prescribed in the morning of the surgery. Upon arrival in 
the OT, all patients were monitored based on the standard anaesthesia monitoring and for 
relevant clinical parameters (baseline blood pressure (BP), saturation pressure of oxygen 
(spO2), electrocardiography (ECG) and heart rate (HR)) which were obtained using the 
electric B30 monitor (Stimuplex D® plus 50mm, B. Braun, Melsungen, Germany) and 
documented before the BPB commenced. Subsequently, IV access of at least 20 G size 
was inserted on the selected hand of study participants. 
Intravenous (IV) loading of Ringer’s Lactate solution (B. Braun, Melsungen, 
Germany) 10 ml/kg was administered before performing the block. Brachial plexus block 
(BPB) was performed in the block corner at the recovery bay. Drugs regime and other 
standard equipment for BPB was prepared and acquired and these include: 
o 5 mls of Lignocaine 2% for skin infiltration 
o 20 mls of Ropivacaine (Naropin®, Astrazeneca) 0.75% + 20mg 
Parecoxib (Dynastat®, Pfizer)(1 mls) ---Group A 

 
39 
 
o 20mls Ropivacaine 0.75%  + 1 ml Normal Saline----Group B. 
o Ultra Sonographic  machine (Mindray® Version M5, Mindray, Shenzen, 
China) with high frequency (10-15MHz) linear probe 
o 50 to 80mm 22 G insulated peripheral nerve block needle. Vygon, 
France 
o 2% chlorhexidine in 70% isopropyl alcohol solution for skin cleaning 
The BPB was implemented by a single operator and assessed by the independent 2nd 
medical officer in-charge who was blinded and oblivious to the treatment administered. 
No peripheral nerve stimulator was employed during the procedure. The detailed 
descriptions of the techniques utilized in the BPB are as follows: 
 The block site will be cleaned and draped. The US probe also was draped for the 
procedure as well. 
 SCB technique: 
o Subjects were positioned semi-recumbent with the head turned to the 
contralateral side with the ipsilateral shoulder slightly elevated with the 
pillow. 
o An exploratory scan was performed in all patients before the block, by 
positioning the probe on a coronal oblique plane above the clavicle.  
o Hypoechoic and pulsating supraclavicular artery was then identified, 
which was lying above the hyper echoic first rib. While maintaining the 
view of the artery, the probe was then angled until both the first rib and 
the pleura were also seen simultaneously. 
o After skin preparation and draping, the probe was next placed in the 
supraclavicular fossa and  subcutaneous infiltration will be given on the 
targeted needle side 

 
40 
 
o The needle was then inserted from lateral to medial direction in the long 
axis of the transducer (in-plane technique).  
o Nineteen (19) ml of 0.75% ropivacaine and 1 ml of 20 mg of parecoxib   
(Group I: parecoxib + ropivacaine) or 19 mls of 0.75% alone plus 1 ml of 
normal saline (Group II:  ropivacaine alone)  was then injected at the 
“corner pocket”.  Adrenaline was not added into any solution. 
o The remaining 5 ml was later injected to a point approximately level with 
the superior/ cephalad aspect of the subclavian artery, but no further than 
1 cm lateral to the artery 
Block performance-related pain was then evaluated immediately after removing the 
needle by asking the patient to verbally quantify the level of pain using a score between 
0 to 10  (0 meaning no pain, 10 meaning excruciating pain). The study participants were 
withdrawn from the trial and rescue medications were given if one of the following 
withdrawal criteria occurred: 
o Patient developed local anaesthetic toxicity (seizure) 
o Patient developed hemodynamically instability bradycardia/hypotension) 
o Patient developed anaphylaxis  
The procedures for the assessment of sensory and motor block are as follows: 
 Assessment of sensory block: 
o Sensory blockade was assessed every 5 minutes up to 30 minutes 
following the completion of administration of intervention. 
o Sensory loss was confirmed by the loss to cold sensation using 10 mls cold 
saline bottle and pinprick sensation using 23G needle in all dermatomes 
supplied by the brachial plexus (C5-T1). 
o Time zero was defined as the time at which LA was completely injected. 

 
41 
 
o Sensory block success was defined as complete pin-prick sensory 
blockade (grade II based on the grading scale employed by Crews et al. 
(2002) ) in all dermatomes of the brachial plexus (C5-T1). 
o The block was considered incomplete if any supplemental local anesthetic 
is needed for complete anesthesia. 
o The block was considered failed if the desired volume did not provide 
complete anesthesia or conversion to general anaesthesia was required 
prior to surgery. 
o General anaesthesia was routinely performed with intravenous induction 
(sedation) agent, short acting opiods and muscle relaxant 
 Assessment of motor block: 
o Motor blockade was also evaluated every 5 minutes up to 30 minutes 
following the completion of administration of intervention. 
o Motor block was assessed by subject’s capability of flexing his / her elbow 
and hand against gravity. This was then graded according to the scale 
utilised by Borgeat, Ekatodramis and Durmont (2001).  
o Motor block success was considered achieved when the motor power was 
reduced to grade 3 or more based on the criteria used by Ammar and 
Mahmoud (2012). 
 Intra-surgical assessment: 
o Requirement of block supplementation, surgical wound infiltration and 
patient requested sedation or general anaesthesia 
o Surgical anaesthesia success was defined as surgery without the 
requirements of block supplementation, general anesthesia (administered 
for incomplete block) or surgical site infiltration 

 
42 
 
o Haemodynamic  monitoring was performed at baseline, after LA injection, 
after 15 min, 30 min, 1 hour of block procedure & after completing 
surgery. 
 Postoperative assessment: 
o Sensory and motor blockade durations were assessed on half-hourly basis 
(up to 12 hours postoperatively), during the post surgical period. 
o Patient-controlled analgesia (PCA) morphine or IV tramadol was given as 
rescue analgesia. 
o Pain scores were assessed using the visual rating scale (VRS) (0-10) where 
pain was evaluated when the patients were resting at 1, 2, 4, 12, 24 hours 
postoperatively. 
o The duration of analgesia (time interval from the completion of local 
anesthetic administration until the first need of rescue analgesia in the 
form of PCA morphine or IV tramadol) and the amount of morphine or 
tramadol consumed during the postoperative 24 hours were also 
documented. 
o Any evidence of complications (e.g., bruises/swelling at the block site, 
chest pain/ breathing difficulty, dysaesthesia/ muscle weakness in the 
operated extremity  not related to the site of operation) were also recorded.  
o Surgeons were alerted to report any neurological  problems not related to 
surgery during the clinical rounds prior to the patients were discharged 
from the hospital. 
o Anaesthetic preferences (one of the following: 1) the BPB; 2) block under 
deep sedation; 3) block under GA). 
o Preferred block for future hand operations was then recorded. 

 
43 
 
4.11 SAMPLE SIZE DETERMINATION 
Sample size calculation was performed using Power & Sample Size (PS®) 
software version 3.1.2 (Dupont and Palmer, Vanderbilt, Nashville, Tenessee, 2014) based 
on the following outcome parameters: 
i) Motor Block Duration –based on Liu et.al, 2013 
We are planning a study of a continuous response variable from independent 
control and experimental subjects with 1 control per experimental subject.In a previous 
study the response within each subject group was normally distributed with a standard 
deviation of 139 minutes (Liu et al. 2013). If the true difference in the experimental and 
control means of motor block time is 138 minutes and assuming the attrition (drop-out) 
rate was 20%,  44 subjects (22 in each intervention arm) were required to reject the null 
hypothesis that the population means of the experimental and control groups are equal. 
The type I (α) and type II (β) were fixed at 0.05 and 0.1, respectively and hence the power 
(1-β) of the study is 0.9. 
ii) Sensory Block Duration – based on Liu et.al, 2013 
We are planing a study of a continuous response variable from  that  required 1 
control per experimental subject (1:1 control-to-experimental unit ratio). In a previous 
study, the response within each subject group was normally distributed with  standard 
deviation of 140 minutes (Liu et al. 2013). If the true difference in the experimental and 
control means of sensory block time is 104 minutes and assuming the attrition (drop-out) 
rate is 20%, we required 39 experimental subjects and 39 control subjects to be able to 
reject the null hypothesis that the population means of the experimental and control 
groups are equal with probability (power, 1 - β) of 0.9.The type 1 error probability (α) 
associated with this test of this null hypothesis is 0.05. 
4.12 ETHICAL ISSUES AND CONSENT ACQUIREMENT PROCESS 

 
44 
 
Since this study involves the use of invasive interventions on human subjects, it 
therefore requires ethical review of study protocol by the institutional review board. To 
meet this requirement, an ethical clearance was sought from USM Human Research 
Ethics Committee, which was obtained on 20th June 2016 (Human Research Ethics 
Committee (HREC) reference number: USM/JEPeM/16010033 ). Besides, this study 
was also conducted in accordance to the principles of ethics on human research that had 
enacted by the Declaration of Helsinki during the 18th World Medical Association 
General Assembly, 1964).  
Voluntary written informed consent was acquired from each study participant. 
They were informed about their rights to withdraw from the study at any stage and for 
any reason without jeopardizing their subsequent medical care. To protect the 
confidentiality and anonymity of each study participant, the names of the subjects were 
not documented in the data collection sheet and each subject received a set of random 
number produced by the Microsoft Excel random number generator for identification 
purposes. Apart from that, the data collection sheet were kept by the principal investigator 
at a secured place and the SPSS file, in which all the research data was stored, was 
password-protected to prevent any accidental or intentional breach of participant’s 
confidentiality. 
To ensure that no subjects were recruited more than the minimum number required to 
significantly demonstrate the difference in the study outcomes between the 20mg 
parecoxib + 0.75% ropivacaine and single-agent 0.75% ropivacaine groups, interim 
analyses were conducted after every 6 subjects recruited. These were done after the 
number of recruited subjects exceeded 20 subjects per group. Any toxicity or 
unanticipated harms associated with the study interventions were recorded and reported 
using JEPeM-USM-FORM 3(G):2014 Adverse Events Report. Opinions from 

 
45 
 
independent study adjudicators which consist of USM ethical review board members 
were sought to determine whether the trial should be stopped prematurely due to obvious 
patterns of benefits or harms observed from the interim analyses. If the trial is deemed to 
be ended prematurely, the date and reason for such early trial termination should be 
notified to the JEPeM committee using JEPeM-USM-FORM 3(E) 2015. 
4.13 STATISTICAL ANALYSIS 
All analysis was implemented using the Statistical Package for Social Science 
(SPSS) for Windows version 20 IBM Corp. Released 2011. IBM SPSS Statistics for 
Windows, Version 20.0. Armonk, NY: IBM Corp) and STATA version 11 (StataCorp. 
2009. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP). 
The data was firstly assessed for any inaccurate data entry and missing data. The 
data was cross-checked with the information in data collection sheet to optimise accuracy 
of data entry. Multiple imputation was then utilised as remedial measures to rectify and 
mitigate the effects of missing data on the accuracy of subsequent analyses. Besides, 
missing data were treated as missing at random (MAR) based upon Rubin’s missing data 
mechanism (Little and Rubin, 2002). 
 Numerical data was then descriptively summarised in mean and standard 
deviation (or median and interquartile range if the data were not normally distributed) 
whilst frequency and percentage were the descriptive summaries for categorical data.  For 
continuous outcome variable, the normality of each outcome variable was then 
subjectively evaluated by histogram with overlying normal distribution curve, box and 
whisker plot and stem and leaf diagram. Besides, Shapiro-Wilks (since the sample size is 
small, i.e. less than 50) was also utilised to provide objective assessments of normality 
assumption. Any significant p-value (p<0.05) indicates that the normality (Gaussian) 
assumption had been violated. These assessments were then further strengthened by the 

 
46 
 
objective evaluation of the normality assumption using Fisher’s coefficient of skewness, 
whose formula is presented as follows: 
Fisher’s coefficient of skewness = Skewness / standard error of skewness 
Any variable that exhibits a Fisher’s coefficient of skewness that is nearly twice 
as large as the standard error of skewness (1.96 x SE) would indicate the presence extreme 
skewness (i.e. more than 1.96 or less than -1.96) and as a result, the normality (Gaussian) 
assumption was assumed to be violated. Besides, the kurtosis (the peakness of the 
distribution) was also examined using the same cut-off (±1.96) to ensure that the peak of 
the distribution conformed to the bell-shaped characteristic of the normal (Gaussian) 
distribution. The final verdict on the normality assumption of a distribution was based 
upon whether such distribution “passed” both objective and subjective evaluations of its 
distributional characteristics. 
For categorical outcomes, either Pearson χ2 or Fisher’s exact test was used to 
assess the significance of association between the intervention arms and the the 
proportions of successful complete sensory block after 30 minutes. For numerical 
outcomes, either independent t-test (with or without adjustment for the violation of 
homogeneity of variance assumption) or Mann-Whitney test was used, depending upon 
whether the normality assumption was violated or not. However, if both normality and 
homogeneity of variance assumptions were violated, the adjusted independent-t test 
(corrected for degree of freedom) was used since it controls type I error rate better than 
the Mann-Whitney U test (Ruxton 2006). 
 The statistical analysis conducted for each objective clinical outcome are given 
on the next page: 
 
 

 
47 
 
Table 4.1: The statistical methods used for each clinical outcome 
Objective parameters 
Statistical analysis 
 
The onset of the sensory block 
Independent t / Mann-Whitney 
testa  
 
The onset of the motor block 
Independent t / Mann-Whitney 
testa  
 
The degree of sensory and motor block 
30 minutes after BPB 
 
  Pearson Chi Square  /  Fisher’s Exact 
testb 
The duration of sensory block 
Independent t / Mann-Whitney 
test  
 
The duration of motor block  
  Pearson Chi Square  /  Fisher’s Exact 
testb 
 
        aNon-parametric analogue of independent-t test. It is used when the normality   
       assumption is violated 
      bUsed when the percentage of cells with expected value of less than 5 is more than  
       20% 
 
The level of significance was set at 0.05 and any p value that was less than 0.05 (p<0.05) 
is considered significant. The analysis was performed in accordance to the intention-to-
treat (ITT) principle. A step-by-step summary of statistical methods employed for the 
analysis of this trial’s data is given by figure 4.1 on the next page. 
 

 
48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4.1: The step-by-step summary of the statistical methods used in this trial. 
 
Data entry and check for inaccurate data 
entry 
Multiple imputation for missing data 
Numerical variables 
Categorical variables 
Descriptive statistics 
 Mean (Standard Deviations) 
 Median (Interquartile range) 
Normality and variance 
homogeneity check 
 Objective tests (Shapiro Wilks 
test, Fisher’s skewness 
coefficient) 
 Subjective tests (Histogram with 
overlying normal curve, Box-
plots) 
 Homogeneity of variance check 
(Levene’s test) 
Descriptive statistics 
 
Counts (Percentages) 
Checking associations 
 Independent t-test (with or without 
Welch’s correct for homogeneity of 
variance assumption violation) 
 Mann-Whitney test (if normality 
assumption is violated but homogeneity 
of variance is fulfilled) 
Checking associations 
 Pearson’s χ2 (if expected count 
<5 is less than 20% of the total 
number of cells in a contingency 
table). 
 Fisher’s exact test (if the above 
assumption is violated) 

 
49 
 
4.14 TRIAL FLOW CHART 
 
                                                                                               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4.2: The flowchart of this study (prepared according to the CONSORT guideline). 
Group A ((Ropivacaine 0.75% +20mg 
Parecoxib)) (n = 43) 
 
Received intervention (n=0) 
 
Subjects withdrawn: 
o Anaphylaxis (n=0) 
o Toxicity (n=0) 
o Haemodynamic instability 
(n=0) 
Group B (Ropivacaine 0.75%.+1mls NS) 
-20mls) (n =43) 
 
Received intervention (n=0) 
 
Subjects withdrawn: 
o Anaphylaxis (n=0) 
o Toxicity (n=0) 
o Haemodynamic instability 
(n=0) 
Post-intervention assessments: 
 Onset of sensory and motor block 
 Duration of sensory and motor block 
 Visual rating score (VRS) for procedure-related pain 
 % of complete block after 30 min 
 % of complete surgical block 
 BP, HR 
 Time of first PCA morphine demand 
Subjects excluded (n=0) 
 Not meeting eligibility criteria (n = 0 
 Decline participation (n=0) 
 Other reasons (n=0) 
Preoperative assessment & screening for 
against eligibility criteria (n=86) 
Enrollment of patients & written consent 
Premedication 
Standard monitoring in the OT (NIBP, spO2, ECG, ETCO2) 
Block randomization 
Statistical analyses 
o Analysed (n = 86) 
o Excluded from analyses (n =0) and reasons (e.g. incomplete data, incorrect data etc) 

 
50 
 
SECTION FIVE 
STUDY RESULTS 
5.1 
THE 
CLINICO-DEMOGRAPHIC 
PROFILES 
OF 
THE 
STUDY 
PARTICIPANTS 
 
On the whole, 86 study participants were included in the analysis. The mean age 
and weight of the participants are similar between the two groups of interventions. Apart 
from that, both intervention groups exhibit similar patterns of VRS pain score, volumes 
of local anaesthetics received, supplemental local anaesthetics received and PCA 
morphine profiles. 
 
With regards to gender and ethnic compositions, both intervention groups, in 
general, demonstrated similar proportions of females, males and each ethnic groups. 
Furthermore, both intervention arms  have also relatively the same proportions of 
participants for each ASA grade. Nevertheless, with respect to the specific surgical sites, 
more study participants in the ropivacaine group had surgeries to their arms whilst more 
patients in the combined parecoxib-and-ropivacaine group had surgeries to their 
forearms. Besides, there are also two missing data in this group. However, it can be safely 
said that proportions of surgical sites are roughly similar in both groups. For further 
information, refer to table 5.1 and figures 5.1-5.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
51 
 
Table 5.1: The clinico-demographic characteristics of study participants (n = 86) 
______________________________________________________________________ 
Parameters               Parecoxib + Ropivacaine (n=43)               Ropivacaine (n=43) 
       
Mean (SD)            n(%)               Mean (SD)          n(%) 
______________________________________________________________________ 
Age 
 
 
       
 43.8 (13.7) 
 
                  46.3 (12.6) 
                                          
 47.5 (26)a                                    51.0 (21.0)a 
 
Weight (kg)                       
60.8 (7.6)                                    61.6 (7.6) 
 
 
 
        
60.0 (13.0)a 
 
 
       60.0 (12.0)a 
 
VRS pain score                     1.0 (0)                                           1.0 (0) 
 
LA volume 
 
          20.0 (0)  
 
 
       20.0 (0) 
 
Supplement LA  
 
0.0 (0)  
 
 
       0.0 (0) 
volume 
 
Time to 1st PCA 
 
0.0 (0)  
 
 
       0.0 (0) 
morphine (hours) 
 
PCA Morphine demand      0.0 (0)  
 
                  0.0 (0) 
within 24 hours  (counts) 
 
 
PCA Morphine given  
0.0 (0)  
 
 
       0.0 (0) 
within 24 hours (counts) 
 
Gender 
Female 
 
 
 
            16 (37.2) 
 
 
 20 (46.5) 
Male  
 
 
 
            27 (62.8) 
 
 
 23 (53.5) 
 
Ethnicity  
 
Malay  
 
 
 
        
42 (97.7) 
 
 
  41 (95.3) 
Chinese 
 
 
 
       
1   (2.3) 
 
 
    1   (2.35) 
Others  
 
 
 
 
0   (0)  
 
                1   (2.35) 
 
Surgical sites  
 
       
 
 
                        
Forearm                                          
 
         14 (32.5)                                   8   (18.6)  
Arm                                                      
         21 (48.9) 
 
       31   (72.1) 
Hand                                                  
         0   (0) 
 
 
         1   (2.3) 
Fingers 
 
 
 
 
         6   (14.0) 
 
         3   (7.0) 
Missing 
 
 
 
 
         2   (4.6)  
 
         0    (0) 
 
ASA grades 
I 
 
 
 
 
 
         7   (16.3) 
 
         6   (14.0) 
II 
 
 
 
 
 
         36 (83.7) 
                    37  (86.0) 
 
Preoperative VRS score 
0.0 (0.0) 
 
 
 
0.0 (0.0)__________ 
aMedian (Interquartile range) 
 
 

 
52 
 
 
 
a) Gender 
 
 
 
b) Ethnicity 
 
Figure 5.1 (a-b): The proportions and percentages of subjects in each intervention arm, 
as stratified by gender and ethnicity of subjects 
 
 

 
53 
 
 
a) ASA grades 
 
 
b) Sensory block 
 
c) Motor block 
 
Figure 5.2 (a-c): The proportions and percentages of ASA grades, sensory and motor 
block status at 30 minutes post BPB as stratified by the intervention arms. 

 
54 
 
 
 
Figure 5.3:  Pie charts detailing the percentages of subjects in each intervention arm as 
stratified by the surgical sites. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
55 
 
5.2 THE STATISTICAL EVALUATIONS OF THE NORMALITY AND 
HOMOGENEITY OF VARIANCES ASSUMPTIONS FOR CONTINUOUS  
OUTCOME VARIABLES 
 
Based on the results presented in table 5.2 and figures 5.4 – 5.9, it can be 
conspicuously observed that all continuous outcome variables have violated the normality 
(Gaussian) assumptions. This claim is corroborated by the significant Shapiro-Wilks test 
results for the all outcome variables and the large values for the a significant proportion 
of Fisher’s coefficients of skewness. Besides, based on the inspection of figures 5.4 – 5.9, 
all of the histograms with the overlying distribution curves do not conform to the bell-
shaped characteristic of normal distributions and exhibit extreme skewness with or 
without “peaked” (leptokurtic) or flat (platykurtic) at the symmetrical point. This fact is 
further augmented by the uneven lengths of box parts of the box plots when comparisons 
were made with their whiskers. All these are tell-tale signs of distributions that have 
violated the characteristics of normal distribution curves. 
 
On the other hand, the homogeneity of variances assumption is deemed fulfilled 
for the majority of continuous outcome variables since the p values for the Levene’s tests 
are not significant. However, for motor block duration, the p value is significant, 
indicating that the homogeneity of variances assumption is not tenable. We can conclude 
for this variable, the variances are inhomogeneous between the two intervention groups 
(i.e there is a heteroscedasticity in the variances). 
 
From these results, we conclude that the appropriate statistical test is Mann 
Whitney test for all continuous outcome variables, except for motor block duration (in 
this case, the Welch’s version of the independent t-test is the most suitable alternative). 
 
 
 

 
56 
 
Table 5.2: The objective statistical tests for the evaluation of the assumption of normality 
 
Parameters 
Shapiro-Wilks test 
Fisher’s Skewness Coefficients 
 
Par+Ropib 
Ropivacaine 
Par+Ropib 
Ropivacaine 
 
Age 
<0.001 
<0.001 
1.04 
-2.58 
 
Weight 
0.019 
0.003 
1.56 
-0.31 
 
Sensory 
block onset 
<0.001 
0.001 
2.61 
2.70 
 
 
Motor block 
onset 
0.001 
<0.001 
-1.01 
-0.84 
 
 
Sensory 
block 
duration 
0.001 
0.001 
1.62 
0.13 
 
 
 
Motor block 
duration 
<0.001 
<0.001 
0.69a 
-1.29 
 
 
aKurtosis (peakness of the distribution) indicates normality assumption is violated. 
bParecoxib + Ropivacaine 
 
Table 5.3: The results of Levene’s tests for assessing the homogeneity of variances 
assumption 
 
Parameters 
F statistics 
p values 
Age 
 
1.239 
0.269 
Weight 
 
0.064 
0.801 
Sensory block onset 
 
0.003 
0.957 
Motor block onset 
 
2.000 
0.161 
Sensory block duration 
 
0.517 
0.474 
Motor block duration 
 
7.564 
0.007 
 

 
57 
 
 
 
 
 
 
 
 
Figure 5.4: The histograms (with the overlying distribution curves) and box plots 
representing the characteristics of distribution for age. 
 
 
 
 

 
58 
 
 
 
 
 
 
 
 
 
 
 
Figure 5.5: The histograms (and the overlying distribution curve) and box plots 
representing the distribution of weights of patients. 
 

 
59 
 
 
 
 
 
 
 
 
Figure 5.6:  The histograms (with the overlying distribution curves) and box plot of the 
time of onset of sensory block as stratified by the intervention arms. The circles and 
numbers represent outliers and outlier’s ID. 
 

 
60 
 
 
 
 
 
 
 
 
 
Figure 5.7: The histograms (with overlying distribution curves) and box plots 
representing the time of onset of motor block as stratified by the intervention groups. 

 
61 
 
 
 
 
 
 
 
 
 
Figure 5.8: The histograms (with the overlying distribution curves) and box plots for 
the duration of sensory block as stratified by the intervention groups. 
 

 
62 
 
 
 
 
 
 
 
 
 
Figure 5.9: The histograms (with the overlying distribution curves) and box plot 
representing the duration of motor block as stratified by the intervention groups. The 
circles and numbers indicate outliers and outlier’s ID, respectively. 
 

 
63 
 
5.3 THE ASSOCIATIONS BETWEEN THE INTERVENTION ARMS AND 
CLINICAL OUTCOMES 
5.3.1 The onset of sensory and motor block 
 
From table 5.4, there are no significant differences between the two intervention 
arms with respect to the sensory and motor block onsets. These are corroborated by the 
small median differences in both clinical outcomes when comparisons are made between 
these two groups. 
5.3.2 The degrees of sensory and motor block 
 
Based on inspection of table 5.5, there are no significant differences with regard 
to the degrees of sensory and motor block at 30 minutes following supraclavicular BPB 
between the two intervention arms (p values of 1 for both outcome parameters). The odds 
ratio cannot even be computed because there are cells with 0 count. 
5.3.3 The durations of sensory and motor block 
 
There are significant differences in terms of the durations of sensory and motor 
block between the intervention arms and the differences are 1.5 hours and almost 1 hour, 
respectively (table 5.4). The evidence against null hypothesis can be considered very 
strong since the p values are less than 0.001 for both clinical outcomes. Hence, the null 
hypothesis of no significant difference can be safely rejected. 
5.3.4 Other clinical parameters 
 
For other clinical parameters, there is no single significant difference observed 
between the intervention groups. Hence, both groups exhibit fairly balanced effects of 
confounders.  

 
64 
 
Table 5.4: The differences between the intervention arms in terms of sensory and motor block onset and durations and other clinical parameters 
(n=86). 
Outcomes 
Intervention arms 
 
Median differences* 
Mann-Whitney 
U statistics 
p values 
Parecoxib + Ropivacaine 
Median (IQR) 
Ropivacaine only 
Median (IQR) 
 
Sensory block onset 
(minutes) 
 
9.00 (2.25) 
9.00 (3.00) 
0 
861.00 
0.577 
Motor block onset 
(minutes) 
 
17.00 (5.00) 
18.00 (6.00) 
-1 
900.50 
0.832 
Sensory block  
duration (hours) 
 
6.50 (2.0) 
5.0 (2.00) 
1.50 
199.00 
<0.001 
Motor block  
duration (hours) 
 
4.84 (0.77)a 
3.86 (0.60)a 
0.97 (0.68, 1.27)b 
6.561 (79.342)c 
<0.001 
Age (years) 
 
47.5 (26) 
51.0 (21.0) 
-3.5 
838.00 
0.455 
Weight (kg) 
 
60.0 (13.0) 
60.0 (12.0) 
0 
809.50 
0.399 
*Parecoxib and Ropivacaine group minus Ropivacaine only group, aMean (SD), bMean difference (95% CI), cIndependent t-test for unequal variance (degree of freedom) 
 
 
 
 

 
65 
 
Table 5.5: The associations between the intervention arms in terms of the degrees of sensory and motor blockade at 30 minutes following 
supraclavicular brachial plexus block and other clinical parameters (n=86). 
Outcomes 
Intervention arms 
 
Odds ratio (95% CI) 
χ2 statistics (df) 
p values 
Parecoxib + Ropivacaine 
n (%) 
Ropivacaine only 
n (%) 
 
Degree of sensory 
block 
Complete block 
Normal sensation 
 
 
 
43 (100) 
0 (0) 
 
 
42 (97.7) 
1   (2.3) 
-a 
Not applicable 
1.000 
Degree 
of 
motor 
block 
Flex / extend forerarm 
(grade I) 
No 
upper 
limb 
movement (grade IV) 
 
 
 
0 (0) 
 
43 (100) 
 
 
1   (2.3) 
 
42 (97.7) 
 
-a 
Not applicable  
1.000 
Gender 
Female 
Male 
 
 
16 (37.2) 
27 (62.8) 
 
20 (46.5) 
23 (53.5) 
Not applicable 
0.764 (1) 
0.382 
Ethnicity 
Malay 
Chinese  
Others 
 
 
42   (97.7) 
1   (2.3) 
                0   (0) 
 
41 (95.3) 
1   (2.35) 
1   (2.35) 
Not applicable 
Not applicable 
1.000 
aCannot be computed due to the presence of 0 cell count 
 

 
66 
 
Table 5.5, continued 
ASA grades 
I 
II 
 
 7  (16.3) 
36 (83.7) 
6   (14.0) 
37 (86.0) 
Not applicable 
0.091 (1) 
0.763 
Sites of surgery 
Forearm 
Arm 
Hand 
Fingers 
Missing 
 
 
 
14 (32.5) 
21 (48.9) 
                 0 (0) 
                 6 (14.0) 
2 (4.6) 
 
          8 (18.6) 
31 (72.1) 
          1 (2.3) 
3 (7.0) 
          0 (0) 
 
Not applicable 
 
Not applicable 
 
0.102 
 
 
 
 
 
 
 
 
 
 

 
67 
 
5.4 THE ADVERSE EVENTS ASSOCIATED WITH ROPIVACAINE AND / OR 
PARECOXIB 
 
No subjects reported any significant and serious side effects associated with 
ropivacaine and parecoxib. The signs and symptoms of side effects that are commonly 
associated with ropivacaine administration such as CNS (seizures, peri-oral numbness, 
paraesthesia, dysaesthesia, tremor, dizziness) and cardiovascular toxicities (hypotension, 
bradycardia and arrythmias) were not reported by any study participant in both 
intervention groups. Besides, no significant side effects related to parecoxib 
administration (gastrointestinal bleeding, anaphylaxis reactions such as swelling, rash and 
breathing difficulties, jaundice, abnormal liver function tests etc.) were experienced by 
the study participants. 
 
The trial was not stopped prematurely and lasted for the whole duration as 
planned. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
68 
 
SECTION SIX 
 
 
DISCUSSION 
 
6.1 
THE 
ANTI-NOCICEPTIVE 
EFFECTS 
OF 
PARECOXIB 
IN 
SUPRACLAVICULAR BRACHIAL PLEXUS BLOCK 
 
In this study, our primary finding is that synergistic combination of ropivacaine 
and parecoxib only prolonged the duration of sensory and motor blockades, not the onset 
of sensory and motor block. This proves that COX-2 inhibitors act centrally and that the 
spinal transmission of nociceptive signals is affected by constitutively-expressed COX-2 
in the central nervous system. More generally, our results indicate that the anti-
inflammatory and antinociceptive effects of COX-2 inhibitors are not necessarily related 
since the dosage we used in this study was well below the dose required for anti-
inflammatory induction. However, the discrepancy between our findings and Liu et al. 
(2013) in terms of the onset of sensory and motor blockades can be attributed to the higher 
concentration of ropivacaine (0.75%) compared to one used by Liu et al. (2013) (0.25% 
ropivacaine). As a result, Liu et a. (2013) reported a significant difference with regard to 
the onset of sensory and motor blockades between 0.25% ropivacaine + parecoxib 
recipients and those who received 0.25 % ropivacaine only. Therefore, our finding adds 
to the current knowledge by demonstrating the attenuation of 20 mg parecoxib’s effect 
when it is used as an adjunct to a higher concentration of ropivacaine. Besides, we also 
generalised the findings and conclusion made by Liu et al. (2013), who only recruited 
subjects who were recipients of axillary brachial plexus blockade, by demonstrating that 
the benefits of adjunct parecoxib can also be extended to patients undergoing BPB via 
supraclavicular approach as well. We also sucessfully managed to control the 
confounding effects of preoperative (baseline) pain scores since both intervention groups 

 
69 
 
exhibited identical mean visual rating scores (VRS). Consequently, the validity of our 
findings is more bona fide than the ones asserted by Liu et al. (2013).  
 
The prolongation of sensory and motor blockades upon the addition of 20 mg 
parecoxib to ropivacaine is still not well-understood. There are several explanations that 
can be put forward to expound these findings. Firstly, the inhibition of COX-2’s action 
will result in a decrease in the production of prostacyclin (a potent vasodilator), whilst 
conserving the synthesis of the vasoconstrictive thromboxane A2. Consequently, 
parecoxib prolonged the duration of anaesthetic action in a similar fashion like the 
vasoconstrictive effect produced by adjunct epinephrine mixed with LA agents for 
infiltrative anaesthesia (Newton et al., 2004). Next, the action of ropivacaine on sodium 
channels might be altered by the addition of parecoxib. Butterworth IV and Strichartz 
(1990) had hypothesized that there were a multitude of LA’s mechanisms of actions for 
spinal and epidural analgesia and one of them was via the reduction of prostacylin and 
prostaglandin production, resulting in a modulated effect of LA on sodium channel 
bloackade. Thirdly, the inhibitory effect of parecoxib on COX-2 may also decrease the 
production of prostanoid centrally, hence reducing the effects of peripheral inflammation 
and the ensuant mechanical hypersensitivity (Samad et al., 2001).  
NSAIDSs have long been considered to have effects on the CNS via COX 
inhibition, as numerous experimental models over the past 15 years have established. The 
findings that both COX isoforms are expressed in the CNS and the fact that central 
nociceptive transmission and pain hypersensitivity secondary to mechanical 
inflammation are modulated by COX-2 following peripheral inflammation lend further 
support to this notion (Choi et al., 2009; Vardeh et al., 2009). These observations question 
the classical perception that  NSAIDs’s antinociceptive effect was solely attributed to 
preventing the sensitization of nociceptor (Sinatra 2002). Nevertheless, the peripheral and 

 
70 
 
central modes of NSAID actions should not be regarded as mutually independent but as 
complementary and possibly synergistic. Furthermore, the fact that COX-2 is also 
constitutively expressed in the CNS hints towards its role in modulating pain induced by 
even the normal physiological processes (Burian and Geisslinger, 2005; Martin et al., 
2007). 
 
Nevertheless, the arguments about the roles of COX-2 enzymes in central pain 
modulation in both normal physiological and pathological settings were far from 
conclusive since they chiefly relied upon the findings obtained from animal models, not 
from experiments or trials involving human subjects. Thus far,  the central effects of 
COX-2-specific inhibitors in humans was solely investigated in the setting of primary and 
secondary hyperalgesia caused by sunburn injury due to exposure to an ultraviolet-B 
(UVB) radiation, the application of electrical stimulation transdermally and skin 
sensitization via capsaicin exposure (Sycha et al., 2005; Koppert et al., 2004; Burns et 
al., 2006). However, the generalisability of the findings obtained from these experimental 
models is still restrictive due to their ancillary methods used to evaluate the intervention’s 
central analgesic effects. Moreover, the findings were also heavily biased since the 
experimental results obtained were contingent upon the types of experimental pain model 
used by the researchers. This may hence cause the negative results reported by  Burns and 
coworkers (2006). 
The primary issue that prevents the researchers from gaining a concrete evidence 
and thus conclusively confirming the authenticity of COX-2-specific inhibitor’s central 
antihyperalgesic effect is that in the majority of  pain states induced by inflammatory 
causes, a mixture of peripheral and central sensitization materalises. As a result,  it is 
indeed laborious to distinguish the peripheral from spinal components of the 
antihyperalgesic effects attributed to COX-2-selective inhibitor. The effect of antidromic 

 
71 
 
electrical stimulation on peripheral sensitization had been negated by the prior work of 
Schmeltz et al. (1996). In fact, Klede et al. (2003) had assuringly established, using an  
anaesthetic strip experiment, that in the setting of electrically-induced mechanical 
hyperalgesia, the origin of such hyperalgesic state is centrally located, not peripherally 
located. The unvarying pain scores obtained prior to and following the exposure to the 
electrical stimuli and the absence of clinically and statistically meaningful decrease in 
axon reflex erythema, which has a peripheral hyperalgesic component, further 
corroborate the belief that COX inhibitors’ peripheral effects did not result in evident 
antihyperalgesic effect (Koppert et al., 2004). 
 
The central release of prostaglandins which results in the creation of hyperalgesic 
state is a fact that has been agreed upon by the scientific community (Vanegas and 
Schaible, 2001). Nevertheless, the involvement of disparate molecular and cellular 
mechanisms in the production of the central hyperalgesic effects induced by 
prostaglandins is still yet to be wholly comprehended. Baba et al. (2001) demonstrated 
that PGE2 has the ability to precisely depolarize the neurons located at spinal dorsal horns 
through the EP2 receptors. Furthermore, the blockade of glycinergic neural signal 
transmission of the inhibitory neurons by PGE2  through blocking the glycine receptor 
that posesses α3 subunit could also be one of the critical mechanisms of inflammatory 
hyperalgesia (Zeilhofer, 2005). Hence, it is highly likely that the addition of parecoxib 
may remove the blockade to the α3 glycine receptor and hence prolonging the duration 
of sensory and motor blockade by improving the glycinergic neural signal transmission. 
6.2 THE MECHANISMS OF ANTI-NOCICEPTIVE EFFECTS OF PARECOXIB 
 
In an in vitro study by Mitchell et al. (1994), the authors, using preparations of 
broken cells and cyclooxygenase enzymes that had been purified, demonstrated that 
acetylsalicylic acid  (ASA*) was only twice more potent than salicylate in terms of COX-

 
72 
 
2 inhibition despite both having identical analgesic profile. The authors then hypothesized 
that the analgesic activities of both ASA and salicylate  might be attributed to their 
predominant action on COX-2 rather than COX-1 since ASA has much superior COX-1 
inhibitory action (i.e. 100 times more potent) to salicylate whilst both of them having 
equianalgesic capacity. Nevertheless, due to the in vivo nature of this experiment, the 
findings should be treated with caution when extrapolating and correlating the results to 
other in vivo  experimental models and clinical studies. 
It is a well-known fact that prostaglandin E2 (PGE2) has the capacity to sensitize 
the peripheral nerve endings to pain (Warner and Mitchell 2004). This is substantiated by 
Svenson and Yaksh (2002) who had explicated in their excellent review article that the 
COX-2 enzyme could be indigenously found in the dorsal and ventral grey matter of the 
spine, dorsal root ganglia and even in the glial cell such as astrocytes. Apart from that, 
Beiche et al. (1998) also confirmed the presence of COX-2 using immunohistochemical 
techniques in the neurons that are located in the whole layers of spinal cord’s lamina, 
especially in its outermost superficial layer. The presence of constitutive COX-2 in the 
neuronal cells of all lamina of the spinal cord may explain for the acute antinociceptive 
effect of the intrathecal administration of COX-2 inhibitors. Furthermore, Pinardi et al. 
(2005), together with the observations made Samad et al. (2001) and Seybold et al. 
(2001), further endorsed the conclusion drawn from the other studies that the COX-2-
induced prostanoid at the spinal level may result in the perpetuation of hyperalgesic state. 
These perhaps partly expound the abolition of hyperalgesic state induced by the substance 
P and the NMDA-mediated nociceptive transmission via cycloxygenase inhibition 
(Malmberg and Yaksh 1992) and carrageenan-induced thermal hyperalgesia by the COX-
2-specific inhibitor that was intrathecally administered (Yaksh et al., 2001). In addition, 
Warner and Mitchell (2004) also stated that the induction of COX-2 expression and hence 

 
73 
 
PGE2 synthesis by the injured cells may in turn result in the neuronal hyperexcitability 
that will cause pain hypersensitivity in the neighbouring uninjured cells. Moreover, 
Ossipov et al. (2004) also established the presence of μ-opioid receptors in the same 
locality (i.e. the outermost laminae of the spinal cord’s dorsal laminae) as COX-2 
inhibitor.  All these facts lend further support to the hypothesis that the combination of 
analgesic or anaesthetic agents with divergent mechanistic profiles may be more effective 
in attenuating acute pain and prolonging the effects of anaesthetic agents (Phillips and 
Currier 2004). The results of these prior research hence corroborated the outcomes of our 
study that the addition of parecoxib to other anaesthetic agents may further reduce the 
sensitization of nerve ending to pain and, in general, reinforce the duration of sensory and 
motor blockades.  
 
Based on the findings obtained from their murine model of abdominal 
constriction, Abacioglu and coworkers (2000) has advocated that the components of the 
L-arginine / nitric oxide (NO) / cGMP cascade may be involved in the transmission of 
nociceptive processes both peripherally and centrally by either a direct effect on the 
nociceptors per se or by the involvement of other related pathways of nociceptive 
processes induced by NO (Abacioglu et al., 2000). Nitric oxide (NO) is involed in the 
antinociceptive activity of morphine and the intrathecal administration of morphine 
modulates spinal antinociception by interacting with the NO-glutamate cascade. In 
contrast, the activity of COX-2 may be stimulated by NO (Dudhgaonkar et al., 2004), 
which in turn seems to be modulated by morphine administered intrathecally. In addition, 
COX-2 and inducible NO synthase are both frequently and simultaneously co-regulated 
(Simmons et al., 2004). 
 
 

 
74 
 
6.3 PARECOXIB-ASSOCIATED TOXICITY AND ADVERSE EVENTS IN 
BRACHIAL PLEXUS BLOCKS 
 
It is also crucial to establish whether injecting parecoxib directly into the brachial 
plexus resulted in neurotoxicity. We found that no recipients of parecoxib during the 
brachial plexus block reported any evidence of neurotoxicity. Our findings corroborated 
the findings of Liu et al. (2013) and Kim et al. (2011).  
 
Liu et al. (2013) followed up the patients for two months after surgery and they 
found out no single episode of paraesthesia was reported by the study participants. As a 
result, the authors believed that their study provides the first direct evidence that 
parecoxib can be safely tolerated when injected into the peripheral nerve or spinal cord. 
Besides, the neurotoxicity of parecoxib administered into the epidural space was 
investigated and no behavioural or histological changes attributed to the neurotoxicity in 
the spinal cords of rats were observed following the administration of parecoxib. 
 
The fact that there is a low incidence of toxicity associated with parecoxib when 
used for brachial plexus block may popularise its use. Besides, due to its opiod-sparing 
effect, Kim et al. (2011) has recommended that parecoxib can be safely combined and 
administered intrathecally with other opioid such as morphine. Hence, the potentially-
fatal side effects of opioids such as death, respiratory depression and thrombosis can be 
avoided. Apart from that, it is also worth mentioned that since parecoxib only acts on 
enzyme system and not on receptors, the risks of tolerance, resistance and addiction will 
be smaller than drugs of opioids class (Wang et al. 1995). 
6.4 LIMITATIONS OF THE STUDY 
The first limitation of this study is the small size employed in this trial. As a result, 
the power of the study might be affected, resulting in the failure of rejecting the null 
hypothesis. However, we have already meticulously calculated the sample size of this 

 
75 
 
study based on the findings of Liu et al. (2013) and the total subject obtained is 
presumably sufficient to provide at least 90% power in rejecting the null hypothesis. 
Nevertheless, the effect size demonstrated by the findings Liu et al. (2013) may be much 
larger than ours and as a result, they required a much smaller sample size to confidently 
reject the null hypothesis. It is highly recommended that a larger sample size should be 
employed if future researchers would endeavour to verify our findings. 
 
The second limitation of our study is much more subtle. It is highly recommended 
that the future statistical analysis of a trial data should be done within the Bayesian 
framework, not solely within the frequentist setting. In this trial, the use of p values as the 
decision rule to determine whether a null hypothesis should be rejected or not may lead 
to incorrect conclusion since p value on itself is not the probability of a null (or studied) 
hypothesis is true (Wasserstein and Lazar, 2016) . P value is actually just an assertion on 
the compatibility of our findings (or data) are with the hypothesis prespecified before the 
p value is obtained and assumed to be true (Wasserstein and Lazar, 2016). Besides, p 
value is also not a measure of effect size since a large p value does not mean that effect 
size is small and clinically negligible  and a small p value represents a large and clinically-
relevant effect size (Wasserstein and Lazar, 2016). Apart from that, p value is also not a 
measure whether a null hypothesis should be accepted or rejected since a small p value is 
not indicative of an evidence against null hypothesis or vice versa. This is because there 
are many other competing hypotheses that may be more compatible with the data than the 
tested null hypothesis (Wasserstein and Lazar, 2016). In fact, a borderline p value, for 
instance p equals 0.049, is just a weak against the null hypothesis and is usually lumped 
together with any p value that is less than 0.05 (Greenland et al., 2016). As a result of this 
statistical fallacy associated with the misinterpretation of p value, the number of positive-
but-irreproducibe findings in trials will start to rise (Halsey et al., 2015).  

 
76 
 
Another drawback of p value is we cannot incorporate the prior information 
obtained from the results previous trial (i.e. from Liu et al., (2013)) with the findings of 
our study to alter our belief on the validity of tested hypotheses. Bayesian statistics 
provides a better tool to address the shortcomings of the frequentist school of statistics 
(Spiegelhalter et al., 2004). In the Bayesian school of thought, the information contained 
in our findings is represented by the likelihood of our data and the prior information (i.e. 
the results obtained from Liu et al., (2013)) is conveyed by the prior distribution. Our 
conclusion on whether to accept a statistical hypothesis will then depend on our posterior 
belief which is an updated prior after mathematically combining it with the likelihood of 
the data in this fashion: 
Prior X Likelihood = Posterior 
However, Bayesian statistics suffered from several drawbacks which hamper its 
ubiquitous use by the scientific community. The obvious disadvantage of using Bayesian 
statistics is, however, the intractable posterior distribution obtained which results in 
statistical methods that  computationally intensive. To compute the posterior distribution 
that represents the researcher’s belief after “seeing” the information in the data and 
integrating it with the prior belief is arduous especially for multi-dimensional cases. The 
only way to solve this problem is to resort to statistical simulation using the Markov Chain 
Monte Carlo (MCMC) method which requires a state-of-the-art computer. 
 
The third limitation of our study is the enrollment criteria we used to screen the 
patients. we excluded the definite pain-related main factors (eg, psychiatric anxiety and 
alcohol abuse) but did not limit other factors that also might affect pain sensation (eg, age 
and sex). If we had stricter enrollment criteria such as restricting the study to one certain 
type of surgical procedure or just in females or males, the findings of our study will be 
more cogent. Fourthly, we also did not evaluate the pain threshold of the study 

 
77 
 
participants since we are not in possesion of any valid apparatus that can establish the 
threshold of heat or pressure-induced pain in humans accurately. We did evaluate the 
preoperative VRS as a surrogate measure for the pain threshold of each study participant 
but we believe this is not an accurate measure of the participants’ pain tolerance. Finally, 
we only employed a single dose of parecoxib (i.e. 20 mg parecoxib) and consequently we 
were not being able to evaluate the association between different doses of parecoxib and 
the trend in the duration and onset of sensory and motor blockade. However, we did 
ascertained that the inclusion of  20 mg parecoxib to ropivacaine increased the duration 
of motor and sensory blockades.  

 
78 
 
SECTION SEVEN 
CONCLUSION 
All in all, our conclusively demonstrated that the addition of parecoxib to 
ropivacaine prolonged the duration of sensory and motor blockades, but not their onset. 
Several mechanisms have been proposed that may explain the differential effects of 
parecoxib on both onset and duration of the blockades. Besides, we also discussed about 
a few limitations of our study and recommended several remedies to improve the designs 
and analyses of future trials addressing the same research question. Contigent upon the 
findings of future studies, a 20 mg adjunct parecoxib will provide better anaesthetic 
effects than a single 0.75% ropivacaine in patients undergoing upper limb surgeries.  
 
 
 

 
79 
 
REFERENCES 
 
Abacioğlu N, Tunçtan B, Akbulut E, Cakici I. Participation of the components of 
L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal 
constriction in the mouse. Life Sciences 2000;67(10):1127-1137. 
 
 
Aberg G. Toxicological and local anaesthetic effects of optically active isomers 
of two  local anaesthetic compounds. Acta Pharmacologica et Toxicologica 
1972;31:273–286. 
 
 
Ala-Kokko TI, Alahuhta S, Jouppila P, Korpi K, Westerling P, Vähäkangas K. 
Feto-maternal distribution of ropivacaine and bupivacaine after epidural 
administration for cesarean section. International Journal of Obstetric 
Anesthesia 1997;6(3):147-52. 
 
 
Amabile CM, Spencer AP. Parecoxib for parenteral analgesia in postsurgical 
patients. Annals of Pharmacotherapy 2004;38(5):882-886. 
 
 
Ammar AS, Mahmoud KM. Ultrasound-guided single injection infraclavicular 
brachial plexus block using bupivacaine alone or combined with 
dexmedetomidine for pain control in upper limb surgery: A prospective 
randomized controlled trial. Saudi J Anaesth. 2012;6(2):109-14.  
      DOI: 10.4103/1658-354X.97021. 
 
 
Arab SA, Alharbi MK, Nada EM, Alrefai DA, Mowafi HA. Ultrasound-guided 
supraclavicular brachial plexus block: single versus triple injection technique 
for upper limb arteriovenous access surgery. Anaesthesia and Analgesia 
2014;118(5):1120-1125. 
 
 
Arcand G, Williams SR, Chouinard P, Boudreault D, Harris P, Ruel M, et al., 
Ultrasound-guided infraclavicular versus supraclavicular block. Anesthesia 
and Analgesia 2005;101(3):886-90. 
 
 
Arlander E, Ekström G, Alm C, Carrillo JA, Bielenstein M, Böttiger Y, Bertilsson 
L, Gustafsson LL. Metabolism of ropivacaine in humans is mediated by 
CYP1A2 and to a minor extent by CYP3A4: an interaction study with 
fluvoxamine and ketoconazole as in vivo inhibitors. Clinical Pharmacology 
and Therapeutics. 1998;64(5):484-491. 
 
 

 
80 
 
Avery P, Redon D, Schaenzer G, Rusy B. The influence of serum potassium on 
the cerebral and cardiac toxicity of bupivacaine and lidocaine. Anesthesiology 
1984;61(2):134-138. 
 
 
Baba H, Kohno T, Moore KA, Woolf CJ. Direct activation of rat spinal dorsal 
horn neurons by prostaglandin E2. Journal of Neuroscience 2001;21(5):1750–
1756. 
 
Barden J, Edwards JE, McQuay HJ,  Moore RA. Oral valdecoxib and injected 
parecoxib for acute postoperative pain: a quantitative systematic review. 
BMC Anesthesiology 2003;3:1. doi:  10.1186/1471-2253-3-1. 
 
 
Beiche F, Klein T, Nusing R, Neuhuber W, Goppelt-Struebe M. Localization of 
cyclooxygenase-2 and prostaglandin E2 receptor EP3 in the rat lumbar spinal 
cord. Journal of Neuroimmunology 1998;89(1-2):26-34.  
 
 
Bolten WW. Scientific rationale for specific inhibition of COX-2. Journal of 
Rheumatology 1998;25(Suppl. 51): 2-7.  
 
 
Borgeat A, Ekatodramis G, Dumont C. An evaluation of the infraclavicular block 
via a modified approach of the Raj technique. Anesth Analg. 2001;93(2):436–
41. 
 
 
Borgeat A, Kalberer F, Jacob H, Ruetsch YA, Gerber C. Patient-controlled 
interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after 
major open shoulder surgery: the effects on hand motor function. Anesthesia 
and Analgesia 2001;92(1):218-223. 
 
 
Bosenberg A, Thomas J, Lopez T, Lybeck A, Huizar K, Larsson LE. The efficacy 
of caudal ropivacaine 1, 2 and 3mg/ ml for postoperative analgesia in children. 
Paediatric Anaesthesia 2002;12(1):53-8. 
 
 
Burian M, Geisslinger G. COX-dependent mechanisms involved in the 
antinociceptive action of NSAIDs at central and peripheral sites. 
Pharmacology and Therapeutics 2005;107(2):139–154. 
 
 
Burm AG, Stienstra R, Brouwer RP, Emanuelsson BM, van Kleef JW. Epidural 
infusion of ropivacaine for postoperative analgesia after major orthopedic 
surgery: Pharmacokinetic evaluation. Anesthesiology 2000;93(2):395-403. 
 
 

 
81 
 
Butterworth IV JF, Strichartz GR. Molecular mechanism of local anesthesia: A 
review. Anesthesiology 1990;72(4):711-734. 
 
 
Burns D, Hill L, Essandoh M, Jarzembowski TM, Schuler HG, Janicki PK. Effect 
of valdecoxib pretreatment on pain and secondary hyperalgesia: a randomized 
controlled trial in healthy volunteers [ISRCTN05282752, NCT00260325]. 
BMC Anesthesiology 2006;6:3. https://doi.org/10.1186/1471-2253-6-3 
 
 
Carr DB, Goudas LC. Acute pain. Lancet 1999;353(9169):2051-8. 
 
 
Casati A, Borghi B, Fanelli G, Montone N, Rotini R, Fraschini G, Vinciguerra F, 
Torri G. Interscalene brachial plexus anesthesia and analgesia for open 
shoulder surgery: a randomized, double-blinded comparison between 
levobupivacaine and ropivacaine. Anesthesia and Analgesia 2003;96(1):253-
259. 
 
 
Cederholm I, Evers H, Löfström JB. Skin blood flow after intradermal injection 
of ropivacaine in various concentrations with and without epinephrine 
evaluated by laser Doppler flowmetry. Regional Anesthesia. 1992;17(6):322-
328. 
 
 
Chan VW, Perlas A, McCartney CJ, Brull R, Xu D, Abbas S. Ultrasound guidance 
improves success rate of axillary brachial plexus. Canadian Journal of 
Anaesthesia 2007; 54(3):176-182. 
 
 
Chan VWS, Perlas A, Rawson R, Odukoya O. Ultrasound-guided supraclavicular 
brachial plexus. Anaesthesia and Analgesia 2003;97(5): 1514-1517. 
 
 
Cherif A, Ben Yedder S, Sebai S, Mendili I, Ben Ahmed I, Barhoumi M. Effects 
of parexocib versus dexamethasone with bupivacaîne by infraclavicular block 
for upper limb surgery: 8AP2-6. European Journal of Anesthesiology 
2014;21(supplement 52):129-130. 
 
 
Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and -2 in 
neuroinflammation: implications for translational research. Trends in 
Pharmacological Sciences 2009; 30(4): 174–181. 
 
 
Crews JC, Weller RS, Moss J, James RL. Levobupivacaine for axillary brachial 
plexus block: a pharmacokinetic and clinical comparison in patients with 
normal renal function or renal disease. Anesth Analg. 2002;95(1):219-23. 
 

 
82 
 
  
Cuvillon P, Nouvellon E, Ripart J, Boyer JC, Dehour L, Mahamat A, et al., A 
comparison of the pharmacodynamics and pharmacokinetics of bupivacaine, 
ropivacaine (with epinephrine) and their equal volume mixtures with 
lidocaine used for femoral and sciatic nerve blocks: a double-blind 
randomized study. Anesthesia Analgesia 2009;108:641–649. 
 
 
Daniels SE, Kuss M, Mehlisch DR, Searls GD. Pharmacokinetic and efficacy 
evaluation of intravenous parecoxib in a postsurgical dental pain model 
[poster]. ASCPT; 2000 Mar; Los Angeles (CA). 
 
 
Duma A, Urbanek B, Sitzwohl C, Kreiger A, Zimpfer M, Kapral S. Clonidine as 
an adjuvant to local anaesthetic axillary brachial plexus block: a randomized, 
controlled 
study. 
Br 
J 
Anaesth. 
2005 
Jan;94(1):112-6. 
DOI: 
10.1093/bja/aei009. 
 
Ekstrom G, Gunnarsson UB. Ropivacaine, a new amide-type local anesthetic 
agent, is metabolized by cytochromes P450 1A and 3A in human liver 
microsomes. Drug Metabolism and Disposition 1996;24(9):955-61. 
 
Emanuelsson BM, Zaric D, Nydahl PA, Axelsson KH. Pharmacokinetics of 
ropivacaine and bupivacaine during 21 hours of continuous epidural infusion 
in healthy male volunteers. Anesthesia and Analgesia 1995;81(6):1163-8. 
 
 
Emanuelsson BM, Persson J, Sandin S, Alm C, Gustafsson LL. Intraindividual 
and interindividual variability in the disposition of the local anesthetic 
ropivacaine in healthy subjects. Therapeutic Drug Monitoring 1997; 
19(2):126-31. 
 
Emery P. Cox-1, Cox-2: so what? Scandinavian Journal of Rheumatology 
1999;28(1):6-9. 
 
Fanelli G, Casati A, Beccaria P, Aldegheri G, Berti M, Tarantino F, Torri G. A 
double-blind comparison of ropivacaine, bupivacaine and mepivacaine during 
sciatic 
and 
femoral 
nerve 
blockade. 
Anesthesia 
and 
Analgesia 
1998;87(3):597-600. 
 
Fosslien E. Adverse effects of nonsteroidal anti-inflammatory drugs on the 
gastrointestinal system. Annals of Clinical and Laboratory Science 1998;28 
(2):67-81. 
 
Frederickson MJ, Ball CM, Dalgleish AJ. Analgesic effectiveness of a continuous 
versus single-injection interscalene block for minor arthroscopic shoulder 
surgery. Regional Anesthesia and Pain Medicine 2010;35(1):28-33. 
 
 

 
83 
 
Frederickson MJ, Patel A, Young S, Chinchanwala S. Speed of onset of ‘corner 
pocket supraclavicular’ and infraclavicular ultrasound guided brachial plexus 
block: a randomized observer-blinded comparison. Anaesthesia 2009;64(7): 
738-744. 
 
 
Gajraj NM. COX-2 inhibitors celecoxib and parecoxib: valuable options for 
postoperative pain management. Current Topics in Medicinal Chemistry 
2007;7(3):235-249. 
 
 
Gamo K, Kuriyama K, Higuchi H, Uesugi A, Nakase T, Hamada M, Kawai H. 
Ultrasound-guided supraclavicular brachial plexus block in upper limb 
surgery: outcomes and patient satisfaction. The bone and joint journal 
2014;96-B(6):795-799. 
 
 
Greenland S, Senn SJ, Rothman KJ, Carlin JB, Poole C, Goodman SN, Altman 
DG. Statistical tests, P values, confidence intervals, and power: a guide to 
misinterpretations. Europen Journal of Epidemiology 2016;31(4):337-50. 
doi: 10.1007/s10654-016-0149-3 
 
 
Gristwood RW. Cardiac and CNS toxicity of levobupivacaine:strengths of 
evidence for advantage of bupivacaine. Drug Safety 2002;25(3):153-163. 
 
 
Groban L. Central nervous system and cardiac effects from long-acting amide 
local anesthetic toxicity in the intact animal model. Regional Anesthesia and 
Pain Medicine 2003;28(1):3-11. 
 
 
Grossman E, Hubbard R, Laurent A. A safety and pharmacokinetic study of 
analgesic doses of parecoxib sodium, a new COX-2 specific inhibitor, in 
healthy subjects [poster no. 653]. Presented at the 19th Annual Scientific 
Meeting of the American Pain Society; 2000 Nov 
 
 
Halsey LG, Curran-Everett D, Vowler SL, Drummond GB. The fickle P value 
generates irreproducible results. Nature Methods 2015;12(3):179-85.  
       doi: 10.1038/nmeth.3288. 
 
 
Hansen TG. Ropivacaine: A pharmacological review. Expert Review of 
Neurotherapeutics 2004;4(5):781-91. 
 
 
Hofmann-Kiefer K, Herbrich C, Seebauer A, Schewender D, Peter K. 
Ropivacaine 7.5mg/ml versus bupivacaine 5 mg /ml for interscalene brachial 

 
84 
 
plexus block – a comparative study. Anesthesia and Intensive Care 
2002;30(3):331-337. 
 
 
Hubbard RC, Kuss ME, LeComte DL, Pan X, Talwalker S, Steven Geis G. An 
endoscopic study of the gastroduodenal effects of SC-69124A, a parenteral 
COX-2-specific inhibitor, in the elderly [abstract]. Gastroenterology 2000 
Apr; 118 Suppl. 2 (Pt 2): 250. 
 
 
Ibrahim A, Karim A, Feldman J, Kharasch E. Effects of parecoxib, a parenteral 
COX-2 specific inhibitor, on the disposition of midazolam [abstract no. 529]. 
Annual Meeting of the American Society of Anesthesiologists, 2000. 
 
 
Jain KK. Evaluation of intravenous parecoxib for the relief of acute post-surgical 
pain..Expert Opinion on Investigational Drugs 2000;9(11):2717-2723. 
 
 
Jokinen MJ, Olkkola KT, Ahonen J, Neuvonen PJ. Effect of rifampin and tobacco 
smoking on the pharmacokinetics of ropivacaine. Clinical Pharmacology and 
Therapeutics 2001;70:344-50. 
 
 
Kampe S, Poetter C, Buzello S, Wenchel HM, Paul M, Kiencke P, Kasper SM. 
Ropivacaine 0.1% with sufentanil 1 microg/mL inhibits in vitro growth of 
Pseudomonas aeruginosa and does not promote multiplication of 
Staphylococcus aureus . Anesthesia and Analgesia 2003;97(2):409–11. 
 
Kapral S, Krafft P, Eibenberger K, Fitzgeral R, Gosch M, Weinstabl C. 
Ultrasound-guided supraclavicular approach for regional anesthesia of the 
brachial plex. Anaesthesia and Analgesia 1994;78(3): 507-513. 
 
 
Karim A, Laurent A, Kuss M, Hubbard R, Qian J, Searle GD et al., Single dose 
tolerability and pharmacokinetics of parecoxib sodium, a COX-2 specific 
inhibitor, following intravenous administration [abstract no. A-944]. Annual 
Meeting of the American Society of Anesthesiologists, 2000. 
 
 
Kenaan CA, Bikhazi GB, Deepika K, Calfa CI, Ortiz K. Analgesic activity and 
safety of parecoxib in post-surgical patients: an interim report [abstract no. 
257]: An Interim Report. Anesthesia and Analgesia 2001;(2S):S257. 
 
 
Kim YH, Lee PB, Park J, Lim YJ, Kim YC, Lee SC, Ahn W. The neurological 
safety of epidural parecoxib in  rats.Neurotoxicology 2011;32:864-870. 
 
 

 
85 
 
Kindler CH, Paul M, Zou H, Liu C, Winegar BD, Gray AT, et al., Amide local 
anaesthetics potently inhibit the human tandem pore domain background K+ 
channel TASK-2 (KCNK5). Journal of Pharmacology and Experimental 
Therapeutics 2003;306(1):84-92. 
 
 
Klede M, Handwerker HO, Schmelz M. Central origin of secondary mechanical 
hyperalgesia. Journal of Neurophysiology 2003;90(1):353–9. 
 
 
Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central 
nervous and cardiovascular effects of i.v. infusions of ropivacaine, 
bupivacaine and placebo in volunteers. British Journal of Anaesthesia 
1997;78(5):507-14. 
 
 
Koppert W, Wehrfritz A, Korber N, Sittl R, Albrecht S, Schuttler J, Schmelz M. 
The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce 
central hyperalgesia in humans. Pain 2004;108:148-153. 
 
 
Kulenkampff  D, Persky MA. Brachial plexus anaesthesia: Its indications, 
technique and dangers. Annals of Surgery 1928;87(6):883-891. 
 
 
Langeland F, Turpin M, Waller P, Kuss ME, LeComte DL, Dhadda SS. A 
comparative analgesic efficacy study of parecoxib, a new COX-2 specific 
inhibitor, in post-gynecological surgery patients. [poster no. 814]. Presented 
at the 19th Annual ScientificMeeting of the American Pain Society; 2000 
Nov. 
 
Lee A, Fagan D, Lamont M, Tucker GT, Halldin M, Scott DB. Disposition 
kinetics of ropivacaine in humans. Anesthesia and Analgesia 1989;69(6):736-
738. 
 
 
Lefrant JY, de La Coussaye JE, Ripart J, Muller L, Lalourcey L, Peray PA, Mazoit 
X, Sassine A, Eledjam JJ. The comparative electrophysiologic and 
hemodynamic effects of a large dose of ropivacaine and bupivacaine in 
anesthetized and ventilated piglets. Anesthesia and Analgesia 2001; 
93(6):1598-605. 
 
 
Liisanantti O, Luukkonen J, Rosenberg PH. High-dose bupivacaine, 
levobupivacaine in axillary brachial plexus block. Acta Anaesthesiologica 
Scandinavica 2004; 48(5):601-606. 
 
 

 
86 
 
Linsey CE, Picard J, Weinberg GL. Local anaesthetic systemic toxicity. 
Continuing Education in Anaesthesia Critical Care and Pain 2014;15(3): 136-
142. 
 
 
Li SQ, Xing YL, Chen WN, Yue SL, Li L, Li WB. Activation of NMDA receptor 
is associated with up-regulation of COX-2 expression in the spinal dorsal horn 
during nociceptive inputs in rats. Neurochemical Research 2009;34(8):1451-
1463. 
 
 
Little RAJ, Rubin DB (2002). Statistical analysis with missing data. 2nd 
edition.John Wiley and Sons; Hoboken, New Jersey. ISBN: 978-0-471-
18386-0 
 
 
Liu X, Zhao X, Lou J, Wang Y, Shen X. Parecoxib added to ropivacaine prolongs 
duration of axillary brachial plexus blockade and relieves postoperative pain. 
Clinical Orthopaedics and Related Research 2013 ;471(2):562-568. 
 
 
Luduena F, Bogado E, Tullar B. Optical isomers of mepivacaine and bupivacaine 
[ENGLISH version]. Archives internationales de pharmacodynamie et de 
thérapie 1972;200:359–369. 
 
 
Mageswaran R, Choy YC. Comparison of 0.5% ropivacaine and 0.5% 
levobupivacaine for infraclavicular brachial plexus. Medical Journal of 
Malaysia 2010;65(4):300-303. 
 
 
Malan TP Jr, Marsh G, Hakki SI, Grossman E, Traylor L, Hubbard RC. Parecoxib 
sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine 
analgesia 
and 
is 
opoid-sparing 
following 
total 
hip 
arthroplasty. 
Anesthesiology 2003;98(4):950-956. 
 
 
Malan TP, Marsh G, Grossman E, et al., Evaluation of the opiod-sparing 
effectiveness of parecoxib sodium, a new COX-2 specific inhibitor, in the 
management of postoperative pain following total hip arthroplasty [abstract 
no. 774]. Journal of Pain and Symptom Management 2001; 2 Suppl. 1: 38. 
 
 
Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or 
substance P receptor blocked by spinal cyclooxygenase inhibition. Science 
1992;257(5074):1276–1279. 
 
Martin F, Fletcher M, Chauvin D, Bouhassira MD. Constitutive cyclooxygenase-
2 is involved in central nociceptive processe in human. Anesthesiology 
2007;106(5):1013-1018. 

 
87 
 
 
 
Martinez V, Belbachir A, Jaber A, Cherif K, Jamal A, Ozier Y, Sessler DI, 
Chauvin M, Fletcher D. The influence of timing of administration on the 
analgesic efficacy of parecoxib in orthopedic surgery. Anesthesia and 
Analgesia 2007; 104(6): 1521–1527. doi:  10.1213/01.ane.0000262039.695 
13.9d 
 
 
McArdle P. Intravenous analgesia. Critical Care Clinics 1999;15(1):89-104. 
 
 
McClure JH. Ropivacaine. British Journal of Anaesthesia 1996;76(2):300-307 
 
 
McGrady E, Litchfield K. Epidural analgesia in labour. Continuing Education in 
Anaesthesia, Critical Care and Pain 2004;4(4):114–7. 
 
 
Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity 
of nonsteroid anti-inflammatory drugs as inbibitors of constitutive and 
inducible cycle-oxygenase, Proceedings of the Natural Academy of Sciences 
USA 1994; 90;24:11693-11697. 
 
 
Mohamad AH, McDonnell NJ, Bloor M, Nathan EA, Paech MJ. Parecoxib and 
paracetamol for pain relief following minor day-stay gynaecological surgery. 
Anaesthesia and Intensive Care 2014;42(1):43-50. 
 
 
Neal JM. Chapter 13:The upper extremity: Somatic blockade. In: Cousins MJ, 
Horlocker TT, Carr DB, Bridenbaugh PO, editors. Cousin’s and 
Birdenbaugh’s Neural Blockade in Clinical Anesthesia and Pain Medicine. 
4th edition. Philadelphia: J.B. Lippincott; 2009. pp. 387–416. 
 
 
Needleman P, Isakson PC. The discovery and function of COX-2. Journal of 
Rheumatology 1997;24 (Suppl. 49): 6-8. 
 
 
Newton DJ, McLeod GA, Khan F, Belch JJF. The effect of adjuvant epinephrine 
concentration on the vasoactivity of the local anesthetics bupivacaine and 
levobupivacaine in human skin. Regional Anesthesia and Pain Medicine 
2004;29(4):307-11. 
 
Ng A, Temple A, Smith G, Emembolu J. Early analgesic effects of parecoxib 
versus ketorolac following laparoscopic sterilization: a randomized controlled 
trial. British Journal of Anaesthesia 2004;92(6):846-849. 
 
 

 
88 
 
Noveck RJ, Hubbard RC. Parecoxib sodium, an injectable COX-2-specific 
inhibitor, does not affect unfractionated heparin-regulated blood coagulation 
parameters. Journal of Clinical Pharmacology 2004;44(5):474-80. 
 
 
Ossipov MH, Lai J, King T, Vanderah TW, Malan TP Jr, Hruby VJ, Porreca F. 
Antinociceptive and nociceptive actions of opioids. Journal of Neurobiology 
2004;61(1):126-48. 
 
 
Partridge BL, Katz J, Benirschke K. Functional anatomy of the brachial plexus 
sheath: implications for anesthesia.  Anesthesiology 1987;66(6):743-747. 
 
 
Peterson MK, Millar FA, Sheppard DG. Editorial 1: Ultrasound-guided nerve 
blocks. British Journal of Anaesthesia 2002;88(5):621-624. 
 
 
Phillips WJ, Currier BL. Analgesic pharmacology: II. Specific analgesics. The 
Journal of American Academy of Orthopaedic Surgeons 2004;12(4):221-33. 
 
 
Porter J, Crowe B, Cahill M, Shorten G. The effects of ropivacaine hydrochloride 
on platelet function: an assessment using platelet function analyser (PFA-
100). Anaesthesia 2001;56(1)-15-18. 
 
 
Raju PKBC, Coventry DM. Ultrasound-guided brachial plexus blocks. 
Continuing Education in Anaesthesia Critical Care and Pain 2014;14(4):185-
191. 
 
 
Resnick DK, Graham SH, Dixon CE, Marion DW. Role of cyclooxygenase-2 in 
acute spinal cord injury. Journal of Neurotrauma 1998;15(12):1005–1013. 
 
 
Rosenberg PH, Heinonen E. Differential sensitivity of A and C nerve fibres to 
long-acting amide local anaesthetics. British Journal of Anaesthesia 
1983;55(2):163-167. 
 
 
Roy M, Nadeau MJ, Côté D, Leveseque S, Dion N, Nicole PC, Turgeon AF. 
Comparison of a single- or double-injection technique for ultrasound-guided 
supraclavicular block: a prospective randomized, blind controlled study. 
Regional Anesthesia and Pain Medicine 2012;37(1):55-59. 
 
Ruxton GD. The unequal variance t-test is an underused alternative to Student’s 
t-test and the Mann-Whitney U test. Behavioral Ecology 2006;17(4):668-690. 
 
 

 
89 
 
Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre 
JV, Woolf CJ. Interleukin-1beta-mediated induction of Cox-2 in the CNS 
contributes to inflammatory pain hypersensitivity. Nature 2001; 410(6827): 
471-475. 
 
 
Schmelz M, Schmidt R, Handwerker HO, Torebjörk HE.. Encoding of burning 
pain from capsaicin-treated human skin in two categories of unmyelinated 
nerve fibres. Brain 2000;123(Part 3):560–71. 
 
 
Selander D, Sjövall J, Waldenlind L. Accidentally I.V. injections of ropivacaine: 
clinical experiences of six cases. Regional anesthesia 1997;22(2):70. 
 
 
Simon MJ, Veering BT, Stienstra R, van Kleef JW, Burm AG. The effects of age 
on neural blockade and hemodynamic changes after epidural anesthesia with 
ropivacaine. Anesthesia and Analgesia 2002;94(5):1325-30. 
 
 
Simpson D, Curran MP, Oldfield V, Keating GM. Ropivacaine: A review of its 
use 
in 
regional 
anaesthesia 
and 
acute 
pain 
management.Drugs 
2005;65(18):2675-717. 
 
 
Sinatra R. Role of COX-2 inhibitors in the evolution of acute pain management. 
Journal of Pain and Symptom Management 2002;24(1 Suppl):S18-27. 
 
 
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials 
and health-care evaluation. 1st edition. Chichester:John Wiley and Son; 2004 
 
ISBN: 978-0471499756. 
 
 
Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid 
cascade in nociceptive processing. Annual Review of Pharmacology and 
Toxicology 2002;42:553–583. 
 
 
Sycha T, Anzenhofer S, Lehr S, Schmetterer L, Chizh B, Eichler HG, Gustorff B. 
Rofecoxib attenuates both primary and secondary inflammatory hyperalgesia: 
a randomized, double blinded, placebo controlled crossover trial in the UV-B 
pain model. Pain. 2005;113(3):316-22. 
 
 
Sztark F, Malgat M, Dabadie P, Mazat JP. Comparison of the effects of 
bupivacaine and ropivacaine one heart cell mitochondrial bioenergetics. 
Anesthesiology 1998; 88(5):1340-1349. 
 
 

 
90 
 
Sztark F, Nouette-Gaulain K, Malgat M, Dabadie P, Mazat JP. Absence of 
stereospecific effects of bupivacaine isomers on heart mitochondrial 
bioenergetics. Anesthesiology 2000;93(2):456-462. 
 
 
Talley JJ, Bertenshaw SR, Brown DL, Carter JS, Graneto MJ, Kellogg MS, 
Koboldt CM, Yuan J, Zhang YY, Seibert K. N-[[(5-methyl-3-phenylisoxazol-
4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent 
and selective inhibitor of COX-2 for parenteral administration. Journal of 
Medicinal Chemistry 2000; 43(9): 1661-3. 
 
 
Tang J, Li S, White PF, Chen X, Wender RH, Quon R, Sloninsky A, Naruse R, 
Kariger R, Webb T, Norel E. Effect of parecoxib, a novel intravenous 
cyclooxygenase type-2 inhibitor, on the postoperative opioid requirement and 
quality of pain control. Anesthesiology 2002;96(6):1305-9. 
 
 
Thompson GE, Rorie DK. Functional anatomy of the brachial plexus sheaths. 
Anesthesiology 1983;59(2):117-122. 
 
 
Ting PL, Sivagnanaratnam V. Ultrasonographic study of the spread of local 
anaesthetic during axilliary brachial plexus block. British Journal of 
Anaesthesia 1989;63(3):326-329. 
 
 
Tran DQ, Bertini P, Zaouter C, Muñoz L, Finlayson RJ. A prospective, 
randomized comparison between single- and double-injection ultrasound-
guided infraclavicular brachial plexus block. Regional Anesthesia and Pain 
Medicine 2010;35(1):16-21. 
 
 
Tran DQ, Pham K, Dugani, Finlayson RJ. A prospective, randomized comparison 
between double-, triple-, and quadruple-injection ultrasound-guided axillary 
brachial 
plexus 
block. 
Regional 
Anesthesia 
and 
Pain 
Medicine 
2012;37(3):248-253. 
 
 
Vanegas H, Schaible HG. Prostaglandins and cyclooxygenases in the spinal cord. 
Progress in Neurobiology 2001;64(4):327–63. 
 
 
Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB, Woolf CJ, FitzGerald 
GA, Samad TA. COX2 in CNS neural cells mediates mechanical 
inflammatory pain hypersensitivity in mice. Journal of Clinical Investigation 
2009;119(2):287–294. 
 
 

 
91 
 
Vester-Andersen T, Husum B, Zaric D, Eriksen C. Perivascular axillary block 
VII: the effect of a supplementary dose of 20 ml mepivacaine 1% with 
adrenaline 
to 
patients 
with 
incomplete 
sensory 
blockade. 
Acta 
Anaesthesiologica Scandinavica. 1986;30(3):231-234. 
 
 
Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors and 
lessons from the clinic. FASEB J 2004;18(7):790-804. 
 
 
Wasserstein RL, Lazar NA. The ASA’s statement on p-values: context, process 
and purpose. The American Statistician 2016;70(2):129-133.  
      doi:10.1080/00031305.2016.1154108 
 
 
Winnie AP, Collins VJ. The subclavian perivascular technique of brachial plexus 
anaesthesia. Anaesthesiology 1964; 25:353-363. 
 
 
Writer WD, Stienstra R, Eddleston JM, Gatt SP, Griffin R, Gutsche BB, et al., 
Neonatal outcomes and mode of delivery after epidural analgesia with 
ropivacaine and bupivacaine: A prospective meta-analysis. British Journal of 
Anaesthesia 1998;81(5):713-7. 
 
 
Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute 
antihyperalgesic action of nonsteroidal, anti-inflammatory drugs and release 
of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal 
cyclooxygenase-2 (COX-2) but not COX-1. Journal of Neuroscience 2001; 
21(16): 5847–5853. 
 
 
Yamamoto T, Sakashita Y. COX-2 inhibitor prevents the development of 
hyperalgesia induced by intrathecal NMDA or AMPA. Neuroreport 
1998;9(17):3869-3873. 
 
 
Zeilhofer HU. The glycinergic control of spinal pain processing. Cellular and 
Molecular Life Sciences 2005;62(18):2027-35. 
 
 

 
 
 
 
 
 
CASE REPORT FORM (CRF) 
 
 
 
DATA COLLECTION SHEET:  
                 EFFECT OF PARECOXIB  20MG AS AN ADJUNCT IN 0.75% ROPIVACAINE TO  
                 ULTRASOUND GUIDED SUPRACLAVICULAR BLOCK FOR UPPER LIMB  
                 SURGERY 
 
 
PRE OP SCREENING: 
INCLUSION CRITERIA 
TICK 
(√ ) 
EXCLUSION CRITERIA 
(X) 
Adult (age 18 to 
60) 
 
Patient refusal for BPB 
 
ASA I to II              
 
 
Known case of allergic to parecoxib 
and local anesthesia 
 
Expected duration of 
surgery 1-4 hours 
 
 
History of previous brachial plexus 
injury 
 
 
 
 
Pregnancy 
 
 
 
 
History of chronic pain, those that 
using chronic analgesic medication 
 
 
 
 
Coagulapathy 
 
 
 
 
Systemic infection or local infection at 
site of injection 
 
 
 
 
History of Ischaemic Heart Disease. 
 
 
 
History of Renal failure 
 
 
 
History of Atopy 
 
 
 
 
 
 
 
 
CASE NO 
GROUP:  
SCB / ICB 

 
 
 
 
 
BACKGROUND DATA  
Date: __________     
Full Surgical Procedure: 
__________________________________________________________  
SITE OF SURGERY 
CODING TICK (√ ) 
Arm 
1 
 
Forearm 
2 
 
Hand 
3 
 
Fingers 
4 
 
 
R/N: _________________________     
Age: __________             Sex: M/F                  Ethnicity: M / C /I /Others  
ASA: I / II  
If ASA II, state the disease/s__________________________  
Height: ________ cm      Weight: _________ kg 
BLOCK TECHNIQUE 
 Size  of the needle: 50 / 80/ 100 mm 
 Depth of skin to superior part of the artery: ___________ cm 
 VRS of procedure-related pain (1 to 10): _____________________ 
 
 Volume of LA given: ___________ ml 
 
 Supplement volume of LA given: _________ ml 
 
 Time of completing LA injection: ___________ 
 
 Time of sensory block onset ( reduce sensation ≤ 25% from contralateral side): 
___________ 
 
 Onset of sensory block: __________ min 
 
 Time of motor block onset ( reduce motor power ≤ 25% from contralateral side): 
___________ 
 
 Onset of motor block: __________ min 
 
 
 Assessment of  sensory block after 30 min: 
 
SENSORY BLOCK 
TICK ( √ ) 
2 (Normal) 
 
1 (partial block/ reduced) 
 
0 (Complete block/ absent) 
 
 
 Assessment of motor block after 30 min: 
CASE NO: 

 
 
 
 
 
 
GRADE 
TICK ( √ ) 
1 ( able to flex or extend the forearm) 
 
2 (able to flex or extend only the wrist 
and fingers) 
 
3 (able to flex or extend only the 
fingers) 
 
4 (unable to move the forearm, wrist, 
and fingers) 
 
 
 
 
              QUALITY OF OPERATIVE CONDITIONS 
QUALITY OF OP 
Please tick (√) 
4 (Excellent/ No complaint from patient) 
 
3 (Good/ Minor complaint with no need for the 
supplemental analgesics) 
 
2 (Moderate/ Complaint that required supplemental 
analgesia) 
 
1(Unsuccessful/ Patient given general anaesthesia) 
 
 
 
                SITE REQUIRED SUPPLEMENT BLOCK 
PATCHY BLOCK SITE 
Please tick (√) 
Ulnar 
 
Median 
 
Musculocutaneous 
 
Radial 
 
 
POST OP ASSESSMENT 
 Time of complete motor function recovery: 
 
 Time of complete cold & pin-prick sensation recovery: 
 
 Duration of sensory block: __________ min 
 
Duration of motor block: ___________ min 
 
 Time of 1st PCA demand: ___________ 
 
 Total of PCA Morphine demand over 24 hours: __________ 
 
 Total of PCA Morphine delivery over 24 hours: _____ 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
COMPLICATIONS (ASSESSMENT AFTER 48 H): 
 
 
COMPLICATIONS 
Please tick (√) 
Bruises/swelling at the block site 
 
Chest pain/ breathing difficulty 
 
Dysaesthesia 
 
Muscle weakness 
 
Seizures 
 
Bradycardia 
 
Hypotension 
 
Others:  
 
 
 
 
ANAESTHETIC PREFERENCES FOR FUTURE HAND OPERATIONS: 
  
ANAEST TECH  PREFERENCE 
Please tick (√) 
Same block 
 
Block under deep sedation 
 
Block under GA 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
CASE NO: 

 
 
 
 
 
PATIENT INFORMATION AND CONSENT FORMS (ENGLISH VERSION) 
 
RESEARCH INFORMATION 
 
 
Research Title:  
 
THE EFFECT OF PARECOXIB 20 MG AS AN ADJUNCT IN 0.75% 
ROPIVACAINE TO ULTRASOUND GUIDED SUPRACLAVICULAR 
BLOCK FOR UPPER LIMB SURGERY. 
 
Researchers: 
 
 
1. Dr Wan Mohd Nazaruddin bin Wan Hassan (Anaesthetist and Senior Lecturer , 
Department of Anaesthesiolgy and Intensive Care Unit, HUSM),  
 
2. Dr Vivekananda Gunasekaran (Medical Officer Anaesthesiolgy, Master Candidate, 
USM), No.MPM 44220 
 
Introduction 
 
You are invited to take part voluntarily in a research  study the comparison of perineural parecoxib in 0.75% 
ropivacaine and plain ropivacaine 0.75% in ultrasound guided supraclavicular brachial plexus block for 
upper limb surgery. 
 
Generally, brachial plexus is a bunch of nerves derived from spinal cord from multiple 
levels into the nerves branches peripherally. It provides movement of the upper limb 
muscles (motor) and also supply the dermatomes (sensory). It can be blocked at certain 
levels throughout its route. For this study, we interested to block the plexus at the level 
of supraclavicular. 
 
It is important to know that this study will benefit both the patient and the doctor: 
i. 
Patient’s peace of mind from any risk from general anesthesia; free from 
interruption of unwanted pain post-operatively; can take orally after the operation; 
can have an early hospital discharge after the operation; and can communicate 
with the surgeon during the surgery. 
ii. 
Doctor (surgeon) can fully focus on the operation since there is no unintentional 
arm movement after the brachial plexus block; the vasodilatation effect of brachial 
plexus block will provide a good surgical field to the surgeon hence optimum 
surgery outcome. 
 
This study is supervised by Dr Wan Mohd Nazaruddin bin Wan Hassan (Anaesthetist and 
Senior Lecturer , Department of Anaesthesiolgy and Intensive Care Unit, HUSM),  
 
The supraclavicular  brachial plexus block will be performed by the researcher, Dr 
Vivekananda Gunasekaran (M.Med. Anesthesiology, HUSM) and other medical officers 
who had skills and previledge in performing brachial plexus block. 
 
Before agreeing to participate in this research study, it is important that you read and 
understand this form.  It describes the purpose, procedures, benefits, risks, discomforts, 
and precautions of the study.  It also describes the alternative procedures that are 
available to you and your right to withdraw from the study at anytime. If you participate, 
you will receive a copy of this form to keep for your records. 
 
Your participation in this study is only during your scheduled elective or emergency 
surgery for upper limbs surgery. Up to 86 patients will be participating. 
 

 
 
 
 
 
Purpose of the Study 
 
The purpose of this study is to determine the effect of adding parecoxib 20 mg in 0.75% ropivacaine in 
comparison to plain ropivacaine 0.75% in ultrasound guided supraclavicular block.Are of interest is 
concentrated mainly at onset of anaesthesia as well as duration of the block wheereby the patient remains 
pain free. 
 
Qualification to Participate 
 
The doctor in charge of this study or a member of the study staff has discussed with you 
the requirements for participation in this study.  It is important that you are completely 
truthful with the doctor and staff about you health history. You should not participate in 
this study if you do not meet all qualifications. 
 
Some of the requirements to be in this study are: 
 
 
You are between the ages of 18 and 65 years old 
 
 
You are scheduled for elective or emegency for upper limbs surgery 
 
 
You must be consented for brachial plexus block (supraclavicular approach) 
 
 
You cannot participate in this study if: 
 
 
You refuse to cooperate or to participate in this study 
 
 
You are allergy to parecoxib  and ropivacaine. 
 
 
You are pregnant or suspected pregnant or breastfeeding 
 
 
You had history of brachial plexus injury 
 
 
You had history of chronic pain that using regular chronic analgesic 
 
 
You have coagulapathy 
 
 
You had systemic infection or local infection at site of injection 
 
 
You have serious chronic heart disease, lungs disease and liver disease 
 
 
You had nerve disease involving the limbs that going for surgery 
 
 
You had join this study before and did not complete the study 
 

 
 
 
 
 
Study Procedures 
 
Patients are  recruited from Operation Theatre (OT) List, scheduled for upper limbs surgery provided by 
Orthopedic or Plastic and Reconstructive Surgery Department, HUSM 
 
No premedication will be prescribed in the morning of the surgery and patients will be randomized using 
simple randomization technique in the morning of the surgery 
 
Block randomization technique 
Two cards written either Group A (parecoxib 20 mg (1ml)+ropivacaine 0.75%(19 ml)) or Group B 
(ropivacaine 0.75% 19 ml + 1 ml NS) will be put inside the opaque envelope (allocation concealment) 
 
A card will be picked up each time by either anaesthesia nurse or second medical officer incharge in the OT 
 
Upon arrival in the OT, patients will be brought to the Recovery Room for the procedure. 
 
All patients will be monitored based on standard anaesthesia monitoring (non invasive BP, pulse oxymetry 
(spO2), electrocardiography (ECG)  
 
Baseline BP, and HR will be documented before the procedures. 
 
IV excess at least 20 G will be inserted on the other hand 
 
IV loading of Ringer’s Lactate solution 10 ml/kg will be given before performing the block. 
 
BPB will be performed in the bock corner at the recovery bay. 
 
Drugs regime for BPB will be prepared, which is: 
 
5 ml of Lignocaine 2% for skin infiltration 
 
            19 mls ropivacaine 0.75% +parecoxib 20 mg (1ml) 
 
Other standard equipments will be used for the block: 
 
Ultra Sonographic  machine Mindray Version M5, Manufactured in China with high frequency (10-
15MHz) linear probe 
 
50 to 80mm 22 G insulated peripheral nerve block needle. Vygon, France 
 
2% chlorhexidine in 70% isopropyl alcohol solution for skin cleaning 
 
Block will be performed by a single operator and 2nd medical officer incharge will be blinded assessor. The 
technique will not use peripheral nerve stimulator.  
 

 
 
 
 
 
 
The block site will be cleaned and draped. The US probe also will be draped for the procedure. 
 
SCB technique will be as below: 
 
Subjects are in the semi-recumbent position with the head turned to the contralateral side and the  
ipsilateral shoulder slightly elevated with the pillow. 
 
An exploratory scan will be performed in all patients before the block, by positioning the probe in a  
coronal oblique plane above the clavicle.  
 
Hypo echoic and pulsating supraclavicular artery will be identified, which is lying above the hyper  
echoic first rib. 
 
While maintaining the view of the artery, the probe is then angled until both the first rib  
and the pleura are also seen simultaneously. 
 
After skin preparation and draping, the probe will be placed in the supraclavicular fossa and  subcutaneous 
infiltration will be given on the targeted needle side 
 
The needle will be inserted from lateral to medial direction in the long axis of the transducer (in-plane 
technique)  
 
15 ml of the LA will be injected at the “corner pocket” , an approximately 1 cm2 area bounded medially by 
the subclavian artery and inferiorly by the first rib 
 
The remaining 5 ml will be injected to a point approximately level with the superior/ cephalad aspect of 
the subclavian artery, but no further than 1 cm lateral to the artery. 
 
Risks 
 
 
 
 
 
 
Based on the study done by Dr Vincent W.S. Chan et al. (2003), ultrasound guidance for 
brachial plexus block can potentially improve success and complication rates. In his 
study, the block was successful after one attempt in 95% of the cases and one well known 
complication,  air in the outer layer of the lungs or pneumothorax, did not occur. 
 
However, the complications of supraclavicular brachial plexus block still can occur (e.g.: 
hematoma, intravascular injection, pneumothorax) but less because the operator is expert and 
routinely done the procedure. The procedure will be stopped if any complication should 
develop and if needed, patient will be observed in “PACU” or “ICU”. To prevent the 
complications, all the safety measures will be complied.   
 
 
 
If there is any new important  information discovered during the period of study which 
could change the consent and to be continue involved in the study, you will be informed 
as soon as possible. 
 
 
Reporting Health Experiences. 
 

 
 
 
 
 
If you have any injury, bad effect, or any other unusual health experience during or after 
this study, make sure that you immediately tell the nurse or Dr Vivekananda Gunasekaran 
0174384585.  You can call at anytime, day or night, to report such health experiences. 
 
 
Other Treatments 
 
You do not have to take part in this study to be treated for your illness or condition. Other 
treatments and therapies for your condition are available, including your current therapy.  
The study doctor can discuss these treatments and treat you. 
 
 
Participation in the Study 
 
Your taking part in this study is entirely voluntary.  You may refuse to take part in the 
study or you may stop participation in the study at anytime, without a penalty or loss of 
benefits to which you are otherwise entitled. Your participation also may be stopped by 
the study doctor or sponsor without your consent. 
 
If you stop being part of this study, the study doctor or one of the staff members will talk 
to you about many medical issues regarding the stopping of your participation. 
 
 
Possible Benefits 
 
Study drug and study procedures will be provided at no cost to you. You may receive 
information about your health from any physical examination and laboratory tests to be 
done in this study. 
 
Although this drug (ropivacaine 0.75% and parecoxib ) is commonly used as part of 
anesthetic treatment, there is no guarantee that you will receive any medical benefit. 
 
 
Investigator’s Payment 
 
The study doctors are not receiving any form of payment from any private sponsor.  
 
 
Questions 
 
If you have any question about this study or your rights, please contact; 
 
Dr Vivekananda Gunasekaran 
Department of Anaethesiology 
USM Health Campus. 
Tel: 0174384585 (HP) 
 
 
 
 
If you have any questions Regarding the Ethical Approval, please contact; 
 
Mr Bazlan Hafidz Mukrim 
Secretary of Research Ethics Committee (Human) 
Clinical Science Research Platform 
USM Health Campus 
No. Tel: 09-767 2354/ 09-767 2362 
Email : bazlan@usm.my/jepem@usm.my 

 
 
 
 
 
Confidentiality 
 
Your medical information will be kept confidential by the study doctor and staff and will 
not be made publicly available unless disclosure is required by law. 
 
Your original medical records may be reviewed by the Ethical Review Board for this study, 
and regulatory authorities for the purpose of verifying clinical trial procedures and/or 
data.  Your medical information may be held and processed on a computer. 
 
By signing this consent form, you authorize the record review, information storage and 
data transfer described above. 
 
 
Signatures 
 
To be entered into the study, you or a legal representative must sign and data the 
signature page. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
Patient Information and Consent Form 
(Signature Page) 
 
Research Title:  
 
THE EFFECT OF PARECOXIB 20 MG AS AN ADJUNCT IN 0.75% 
ROPIVACAINE TO ULTRASOUND GUIDED SUPRACLAVICULAR 
BLOCK FOR UPPER LIMB SURGERY. 
 
 
Researchers: 
 
 
1. Dr Wan Mohd Nazaruddin bin Wan Hassan (Anaesthetist and Senior Lecturer , 
Department of Anaesthesiolgy and Intensive Care Unit, HUSM),  
 
2. Dr Vivekananda Gunasekaran (Medical Officer Anaesthesiolgy, Master Candidate, 
USM), No.MPM 44220 
 
To become a part this study, you or your legal representative must sign this page. By signing this page, I am 
confirming the following:  
 
I have read all of the information in this Patient Info rmation and Consent 
Form including any information regarding the risk in this study and I have 
had time to think about it. 
 
All of my questions have been answered to my satisfaction.  
 
I voluntarily agree to be part of this research study, to follow the study 
procedures, and to provide necessary information to the doctor, nurses, or 
other staff members, as requested. 
 
I may freely choose to stop being a part of this study at anytime.  
 
I have received a copy of this Patient Information and Consent Form to 
keep for myself. 
 
 
 
 
Patient Name (Print or type) 
 
 
 
 
 
Patient 
Initials 
and 
Number 
 
 
 
Patient I.C No. (New)  
 
 
 
 
 
Patient I.C No. (Old) 
 
 
 
 
Signature of Patient or Legal Representative  
 
 
Date (dd/MM/yy) 
(Add 
time 
if 
applicable) 
 
 

 
 
 
 
 
 
Name of Individual  
Conducting Consent Discussion (Print or Type) 
 
 
 
 
 
 
 
 
 
 
Signature of Individual   
 
 
 
 
Date (dd/MM/yy) 
Conducting Consent Discussion 
 
 
 
 
 
 
Name & Signature of Witness  
 
            
 
Date (dd/MM/yy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  
i) 
All subject/patients who are involved in this study will not be covered by insurance. 

 
 
 
 
 
 
 
 
PATIENT INFORMATION AND CONSENT FORMS (MALAY VERSION) 
 
 
 
 
 
 
 
 
 
 
 
LAMPIRAN A 
 
MAKLUMAT KAJIAN 
 
Tajuk Kajian: 
 
KESAN PENGGUNAAN PARECOXIB SEBANYAK 20 MG SEBAGAI AGEN TAMBAHAN KE 
DALAM 0.75% ROPIVACAINE MENGGUNAKAN TEKNIK ULTRASOUND UNTUK 
PEMBIUSAN SUPRAKLAVIKULAR BAGI PEMBEDAHAN TANGAN DAN LENGAN. 
 
 
Nama Penyelidik: 
 
 
3. Dr W Mohd Nazaruddin bin W Hassan (Pakar Bius Neuro dan Pensyarah, Jabatan 
Anestesiologi dan Unit Rawatan Rapi, HUSM), 
 
4. Dr Vivekananda Gunasekaran (Medical Officer Anestesiologi,Master Candidate USM 
      No.MPM 44220 
 
 
Pengenalan 
 
Anda dipelawa untuk menyertai satu  penyelidikan secara sukarela untuk menentukan sama ada 
penambahan ubat Parecoxib ke dalam Ropivacaine 0.75% semasa pembiusan saraf 
(supraklavikular) dapat mempercapatkan kesan pembiusan dan juga manambahkan durasi 
tahan sakit.(pain free duration)         
 
Pada umumnya, otot pergerakan dan deria rasa anggota tangan kanan dan kiri dikawal oleh 
cabang dari saraf tunjang yang dikenali sebagai Brachial Plexus yang berpunca dari leher dan 
berterusan di bawah tulang bahu sehinggalah ke jari jemari. Oleh itu, fungsi saraf Brachial 
Plexus boleh disekat di sepanjang unjurannya dari leher ke jari jemari. Untuk kajian ini, kami 
lebih berminat untuk menyekat fungsi saraf Brachial Plexus di paras atas tulang bahu 
(supraklavikular).  
 
Pentingnya kajian ini dapat dikongsi bersama oleh pesakit dan doktor dari segi: 
i. 
Keselesaan pesakit yang tidak perlu risau risiko pembiusan penuh; tidak perlu risau 
masalah sakit sebaik sahaja selepas pembedahan; boleh makan dan minum selepas 
pembedahan; boleh segera  pulang ke rumah selepas pembedahan; dan berinteraksi 
dengan doktor sewaktu pembedahan; 
ii. 
Doktor bedah dapat memberi tumpuan yang penuh pada bahagian yang perlu dibedah 
kerana anggota tak dapat bergerak selepas pembiusan; hasilnya pembedahan lebih 
optimum.  
 
 
Kajian ini akan diseliai oleh Dr W Nazaruddin b W Hassan (Pakar Bius Neuro dan Pensyarah, 
Jabatan Anestesiologi HUSM). 
Manakala teknik pembiusan akan dijalankan oleh Dr Vivekananda Gunasekaran  (M.Med. 
Anestesiologi HUSM) dan pegawai perubatan yang ada privilegde dan kemahiran melakukan 
pembiusan brachial plexus. 
  
Sebelum anda bersetuju untuk menyertai kajian penyelidikan ini, adalah penting anda membaca 
dan memahami borang ini.  Ia  menghuraikan tujuan, prosedur, manfaat, risiko, ketidakselesan 
dan langkah berjaga-jaga kajian ini. Ia juga menghuraikan prosedur alternatif yang terdapat 
untuk anda dan hak anda untuk menarik diri dari kajian ini pada bila-bila masa. Sekiranya anda 

 
 
 
 
 
menyertai kajian ini, anda akan menerima satu salinan borang ini untuk disimpan sebagai rekod 
anda. 
 
Penyertaan anda di dalam kajian ini adalah sewaktu anda dijadualkan untuk pembedahan 
kecemasan atau elektif. Seramai 86 pesakit akan menyertai kajian ini. 
 
 
 
Tujuan Kajian  
 
Kajian ini bertujuan untuk mengetahui kesan dan manfaat dengan penambahan Parecoxib ke 
dalam Ropivacaine 0.75% dan membandingkannya dengan teknik yang menggunakan 
Ropivacaine 0.75% sahaja.Perkara yang akan dibandingkan adalah jagka masa keberkesanan 
pembiusan dan juga jangka masa yang diambil selepas pembedehan untuk pesakit kembali 
seperti sediakala contohnya mampu untuk menggerakkan tangan.                                                
 
Kelayakan Penyertaan 
 
Doktor yang bertanggungjawab dalam kajian ini atau  salah seorang kakitangan kajian 
telah membincangkan kelayakan untuk menyertai kajian ini dengan anda. Adalah penting 
anda berterus terang dengan doktor dan kakitangan tersebut tentang sejarah kesihatan 
anda. Anda tidak seharusnya menyertai kajian ini sekiranya anda tidak memenuhi semua 
syarat kelayakan. 
 
Beberapa keperluan untuk menyertai kajian ini adalah – 
 
 
 
Anda mesti berumur diantara 18 – 65 tahun. 
 
Anda dijadualkan untuk pembedahan tangan atau lengan samada elektif atau 
kecemasan  
 
Anda mesti memberikan kebenaran bertulis untuk pembiusan Brachial Plexus 
(Supraklavikular) 
 
 
Anda tidak boleh menyertai kajian ini sekiranya – 
 
 
Anda tidak mahu memberikan kerjasama atau tidak mahu mengikuti kajian ini. 
 
Anda alergik pada ubat dexmedetomidine dan ropivacaine. 
 
Anda mengandung atau suspek hamil atau sedang menyusukan anak 
 
Anda ada sejarah kecederaan pada brachial plexus. 
 
Anda ada sejarah sakit kronik yang menggunakan ubat tahan sakit yang kronik 
 
Anda menghidapi “ coagulapathy” 
 
Anda menghidapi jangkitan kuman sistemik atau lokal tempat injeksi  
 
Menghidap penyakit jantung kronik, masalah paru-paru dan penyakit hati kronik. 
 
Anda menghidap penyakit saraf yang menglibatkan tangan yang ingin dibedah 
 
Anda telah mengikuti kajian ini sebelum ini atau tidak memenuhi kriteria kajian 
 
Prosedur-prosedur Kajian 
 
1. 
Pesakit yang dijadualkan untuk pembedahan tangan atau lengan di bawah seliaan Jabatan Orthopedik atau 
Bedah Plastik dan Rekonstruktif HUSM akan dipilih untuk menyertai kajian. 
 
2. 
Premedikasi untuk sedasi tidak diberikan sebelum prosedur dijalankan. 
 
3. 
Pesakit akan dipilih secara rawak menggunakan teknik rawak berblok pada pagi 
pembedahan 
 
4. 
Teknik rawak berblok: 
a. 
Dua kad bertulis kumpulan A (Parecoxib +Ropivacaine 0.75%) atau kumpulan B 
(Ropivacaine 0.75%) akan disimpan dalam sampul surat 

 
 
 
 
 
b. 
Satu kad akan dipilih samada oleh jururawat anesthesia atau pegawai perubatan 
kedua bertugas dalam wad bedah  
 
5. 
Pesakit dibawa ke Ruang Pemulihan untuk prosedur. Tanda-tanda vital diambil dan direkod 
(tekanan darah, kadar denyutan nadi, EKG, SpO2). 
 
6. 
Kanulasi saluran darah melalui intravena dibuat pada lengan yang tidak dioperasi 
menggunakan Branula bersaiz 20G. 
 
7. 
Pembiusan brachial plexus secara supraklavikular dilakukan oleh penyelidik (Dr Vivekanada 
Gunasekaran)atau pegawai perubatan yang ada priviledge dan dibantu oleh seorang lagi 
pegawai perubatan sebagai pemerhati bebas. 
 
8. 
Selepas kulit dibersih dengan ubat pencegah kuman untuk sterilisasi, ubat lidocaine 2% 
sebanyak 2 ml disuntik di kulit untuk pembiusan setempat. 
 
9. 
Dengan menggunakan ultrasound (USG), brachial plexus dikenalpasti dan jarum bersaiz 
22G, 50 mm dimasukkan  
 
10. Ubat Parecoxib 20 mg (1 ml) dan anestetik lokal Ropivacaine 0.75% dimasukkan sebanyak 
19 ml dalam 2 lokasi berlainan pada sarung plexus ( posterior and anterior pocket) untuk 
biius supraklavikular. 
 
11. Selepas prosedur selesai, setelah pesakit sudah berasa kebas dan tidak boleh 
menggerakkan lengan, pesakit ditolak ke Dewan Bedah untuk dioperasi. 
 
12. Jika pesakit mengalami komplikasi dari pembiusan, tindakan resusitasi (ubat, intubasi) akan 
dilakukan dan terkecuali dari kajian.    
 
Risiko 
 
Berdasarkan kajian yang dilakukan oleh Dr Vincent W.S. Chan et al. (2003), pembiusan 
brachial plexus yang dilakukan dengan menggunakan ultrasound mampu mengurangkan 
kadar kegagalan prosedur dan menurunkan kadar komplikasi. Dalam kajian beliau, kadar 
sukses pembiusan brachial plexus dengan hanya sekali suntik adalah 95% dan salah satu 
komplikasi yang boleh berlaku iaitu udara di selaput luar paru-paru atau pneumothorax, tidak 
berlaku. 
 
 
Namun, risiko terjadinya komplikasi pembiusan brachial plexus teknik supraklavikular masih ada 
(contoh: injeksi ke dalam pembuluh darah, perdarahan setempat, pneumothorax) tetapi sangat 
kurang kerana prosedur ini dilakukan oleh doktor yang mahir serta selalu melakukannya. Jika 
berlaku sebarang komplikasi yang tidak diingini, dan jika perlu, pesakit akan ditempatkan 
di “PACU” (Post-op Anesthesia Care Unit) atau “ICU” (Intensive Care Unit). Semua 
langkah keselamatan diikuti dengan teliti untuk mencegah sebarang komplikasi. 
 
  
Jika apa-apa maklumat penting yang baru dijumpai semasa kajian ini yang mungkin 
mengubah persetujuan and untuk terus menyertai kajian ini, anda akan diberitahu 
secepat mungkin. 
 
 
Melaporkan Pengalaman Kesihatan 
 
Jika anda mengalami apa-apa kecederaan, kesan buruk, atau apa-apa pengalaman 
kesihatan yang luarbiasa semasa kajian ini, pastikan anda memberitahu jururawat atau 
Dr Vivekanada Gunasekaran di 0174384585 secepat mungkin. Anda boleh membuat 
panggilan pada bila-bila masa, siang atau malam, untuk melaporkan pengalaman 
sedemikian. 
 
 
Rawatan Lain 
 

 
 
 
 
 
Anda tidak perlu mengambil bahagian dalam kajian ini untuk rawatan bagi penyakit atau 
keadaan anda. Terdapat rawatan dan terapi lain untuk keadaan anda, termasuk rawatan 
anda yang kini. Doktor kajian boleh membincangkan rawatan dan terapi ini dengan anda. 
 
 
Penyertaan Dalam Kajian 
 
Penyertaan anda dalam kajian ini adalah secara sukarela. Anda boleh menolak 
penyertaan dalam kajian ini atau anda boleh menamatkan penyertaan anda dalam kajian 
ini pada bila-bila masa, tanpa sebarang hukuman atau kehilangan sebarang manfaat yang 
sepatutnya diperolehi oleh anda. 
 
Jika anda berhenti menyertai kajian ini, doktor kajian atau salah seorang kakitangan akan 
berbincang dengan anda mengenai apa-apa isu perubatan berkenaan dengan 
pemberhentian penyertaan anda. 
 
 
Kemungkinan Manfaat  
 
Ubat dan prosedur kajian akan diberikan kepada anda tanpa kos.  Anda mungkin 
menerima maklumat tentang kesihatan anda dari apa-apa pemeriksaan fizikal dan ujian 
makmal yang bakal dilakukan dalam kajian ini. 
 
Walaupun ubat ini (Ropivacaine dan Parecoxib ) merupakan ubat yang sering 
digunapakai dalam bidang anestesia, tidak ada jaminan bahawa anda akan menerima apa-
apa manfaat perubatan. 
 
 
Bayaran Doktor (Penyelidikan) 
 
Doktor kajian tidak menerima bayaran daripada mana-mana pihak penaja swasta.  
 
 
Soalan 
 
Sekiranya anda mempunyai sebarang soalan mengenai prosedur kajian ini atau hak-hak 
anda, sila hubungi; 
Dr Vivekananda Gunasekaran 
Pegawai Perubatan Bius, 
Jabatan Anestesiologi dan Rawatan Rapi 
Universiti Sains Malaysia 
Tel: 0174384585 (HP) 
 
 
Sekiranya anda mempunyai sebarang soalan berkaitan kelulusan Etika kajian ini, sila 
hubungi; 
 
 
 
 
Encik Bazlan Hafidz Mukrim 
Setiausaha Jawatankuasa Etika Penyelidikan (Manusia) USM 
Pelantar Penyelidikan Sains Klinikal, USM Kampus Kesihatan. 
No. Tel: 09-767 2354 / 09-767 2362 
Email : bazlan@usm.my/jepem@usm.my 
 
 
Kerahsiaan 
 
Maklumat perubatan anda akan dirahsiakan oleh doktor dan kakitangan kajian dan tidak 
akan dedahkan secara umum melainkan jika ia dikehendaki oleh undang-undang. 
 

 
 
 
 
 
Rekod perubatan anda yang asal mungkin akan dilihat oleh Lembaga Etika kajian ini dan 
pihak berkuasa regulatori untuk tujuan mengesahkan prosedur dan/atau data kajian 
klinikal.  Maklumat perubatan anda mungkin akan disimpan dalam komputer dan diproses 
dengannya. 
 
Dengan menandatangani borang persetujuan ini, anda membenarkan penelitian rekod, 
penyimpanan maklumat dan pemindahan data seperti yang dihuraikan di atas. 
 
 
Tandatangan 
 
Untuk dimasukkan ke dalam kajian ini, anda atau wakil sah anda mesti menandatangani 
serta mencatatkan tarikh halaman tandatangan (Lihat LAMPIRAN 1). 
 

 
 
 
 
 
 
Borang Keizinan Pesakit 
(Halaman Tandatangan) 
  
Tajuk Kajian: 
 
KESAN PENGGUNAAN PARECOXIB SEBANYAK 20 MG SEBAGAI AGEN TAMBAHAN KE 
DALAM 0.75% ROPIVACAINE MENGGUNAKAN TEKNIK ULTRASOUND UNTUK 
PEMBIUSAN SUPRAKLAVIKULAR BAGI PEMBEDAHAN TANGAN DAN LENGAN. 
 
 
Nama Penyelidik: 
 
 
1. Dr W Mohd Nazaruddin bin W Hassan (Pakar Bius Neuro dan Pensyarah, Jabatan 
Anestesiologi dan Unit Rawatan Rapi, HUSM), 
 
5. Dr Vivekananda Gunasekaran (Medical Officer Anestesiologi,Master Candidate USM 
 
No.MPM 442200 
 
Untuk menyertai kajian ini, anda atau wakil sah anda mesti menandatangani mukasurat 
ini.Dengan menandatangani mukasurat ini, saya mengesahkan yang berikut: 
 
 
Saya telah membaca semua maklumat dalam Borang M aklumat 
dan Keizinan Pesakit ini termasuk apa-apa maklumat berkaitan 
risiko yang ada dalam kajian dan saya telah pun diberi masa 
yang mencukupi untuk mempertimbangkan maklumat tersebut.  
 
Semua soalan-soalan saya telah dijawab dengan memuaskan.  
 
Saya, 
secara 
sukarela, 
bersetuju 
menyertai 
kajian 
penyelidikan 
ini, 
mematuhi 
segala 
prosedur 
kajian 
dan 
memberi maklumat yang diperlukan kepada doktor, para 
jururawat dan juga kakitangan lain yang berkaitan apabila 
diminta. 
 
Saya boleh menamatkan penyertaan saya dalam k ajian ini pada 
bila-bila masa. 
 
Saya telah pun menerima satu salinan Borang Maklumat dan 
Keizinan Pesakit untuk simpanan peribadi saya.  
 
 
 
 
Nama Pesakit (Dicetak atau Ditaip) 
 
 
 
Nama Singkatan & No. Pesakit 
 
 
 
 
No. Kad Pengenalan Pesakit (Baru) 
 
 
 
No. K/P (Lama) 
 
 
 
 
Tandatangan Pesakit atau Wakil Sah  
 
 
Tarikh (dd/MM/yy) 
(Masa jika perlu) 
 
 
 
 
 
Nama & Tandatangan  Individu yang Mengendalikan    
Tarikh (dd/MM/yy) 

 
 
 
 
 
Perbincangan Keizinan (Dicetak atau Ditaip) 
 
 
 
 
Nama Saksi dan Tandatangan  
 
 
 
Tarikh (dd/MM/yy) 
 
Nota: 
i) Semua subjek/pesakit yang mengambil bahagian dalam projek penyelidikan ini 
tidak dilindungi insuran.