Transdermal Microneedle Lignocaine Delivery Versus EMLA Patch for Topical Analgesia Before Venepuncture Procedure To Adults in Clinical Setting
Phase: PHASE1
Conditions: Glaucoma, Cataract, Ophthalmological Disorder
Sponsor: Universiti Kebangsaan Malaysia Medical Centre

1 
 
 
Research Protocol 
Transdermal microneedle lignocaine delivery versus 
EMLA patch for topical analgesia before venepuncture 
procedure to adults in a clinic setting 
 
Date of Document: 17th June 2024 (version 3.0)-revised 
 
PRINCIPAL INVESTIGATOR: Professor Dr Cheah Fook Choe 
 
CO-INVESTIGATORS: Professor Dr Azrul Azlan Hamzah 
Professor Dr Mae-Lynn Catherine Bastion 
Dr Muhammad Irfan Abdul Jalal 
Dr Lam Chen Shen 
Ms. Chua Xin Yun 
 
COLLABORATORS: Dr Goh Chee Seong 
 

2 
 
CHAPTER 1 
 INTRODUCTION 
 
1.1 Transdermal Drug Delivery (TDD) 
Venepuncture is one of the most commonly encountered invasive medical procedures that 
causes significant traumatic pain experience and stress to the hospitalised patients. The anxiety 
and apprehension toward needle puncture may be exacerbated in patients with chronic 
conditions who require frequent  venepuncture. This in long term may affect their emotional 
well-being and eventually deter them from seeking future medical attention.  
With the current advances in medical science and technology, healthcare is continually 
improving with innovative approach to holistically deliver treatment to the patients efficiently 
and effectively. Local anaesthesia prior to venepuncture is regarded as a modern approach that 
fits with the Good Clinical Practice (GCP) framework in providing a quality standard of care 
to the hospitalised patients. More recently, the emergence of transdermal drug delivery system 
(TDDS) has been valued for its invention as a less invasive alternative in facilitating effective 
drug administration. 
The conventional drug-delivery route through hypodermic needle injection and topical cream 
are the most common strategy for systemic drug delivery through the skin surface. However, 
both methods are having their inherent downsides. The greatest challenge associated with 
hypodermic needle use is the pain, stress, and even needle phobia caused by its invasiveness 
which leads to lower patient compliance and acceptability.1,2 On the other hand, the topical 
drug delivery with formulated cream (e.g. lignocaine cream) would be a more attractive 
alternative route of administration since it is painless and can be self-administered by the 
patients themselves. Nonetheless, as the drugs must passively diffuse across the skin, its onset 
of action and efficacy might be affected by its limited bioavailability at the site of action.3 Such 
delayed or substandard drug efficacy would thus be impractical and unsuitable for widespread 
and convenient use in the modern-day fast-paced clinical setting.  
Besides, previous researches have investigated various state-of-the-art TDDS alternatives such 
as iontophoresis (induction of electrical current to drive electrostatic diffusion of charged 
anaesthetic permeants through the skin layers), sonophoresis (generation of low-frequency 
ultrasound that facilitates the penetration of drugs), electroporation (formation of 
microchannels upon electric pulse to increase permeability), magnetophoresis (utilisation of 
magnetic field), thermophoresis (short thermal exposure to ablate the skin surface for better 
diffusion of drugs), and the jet injection (controlled compression of gas or spring to deliver 
anaesthetic drug into targeted skin layer).4–6 However, these myriad strategies of enhancing 
transdermal drug delivery are hampered by several design pitfalls and undesirable adverse 
reactions such as second-degree burns, cross-contamination risk, limited absorption for drugs 
of large molecular size and others.1 Hence, a more revolutionary approach is required to 
circumvent the issues above. 
 
1.2 Skin Structure and Transdermal Drug Delivery (TDD) 
Human skin is the most readily accessible and largest organ in the human body which covers 
and area of 1.5 - 2.0m2 and accounts for 16% of the total body weight of an adult.1,7 The primary 
role of human skin is to serve as a barrier that protects the human body against the relatively 

3 
 
hostile external environment. However, such organised barrier function has also led to a poor 
permeation of the applied topical drug across the skin layer, hence impairing effective drug 
delivery and onset of action. 
The skin is histologically classified into 3 main compartments: (1) the outermost epidermis, (2) 
the middle dermal layer, and (3) the innermost hypodermis.1,8,9 The avascular layer of 
epidermis predominantly consists of keratinocytes (~95% of total cell in epidermis) which are 
the non-viable constituents of the outermost stratum corneum (SC) and the viable cutaneous 
sublayers underneath the SC. Several sublayers of the viable epidermis, i.e. stratum basale, 
stratum spinosum, stratum granulosum, and stratum lucidum are collectively 50-100 μm thick 
and are adjoint together by tonofibrils. On the whole, the whole skin epidermal layer is 50-150 
μm thick.10  
The epidermis is partitioned from the deeper dermal layer by an undulating epidermal-dermal 
junction. Dermis is the thickest substructure of the skin (2-3 mm thick) and it is primarily 
composed with collagen and elastin fibres that confer it the strength and elasticity.11 The 
papillary and reticular layers of the dermis house the blood vessels, nerves, lymphatic vessels, 
skin appendages, and the connective tissues.8,9 Lying underneath it is the innermost hypodermis 
or the subcutaneous layer, which is an elastic layer that is mainly constituted of the adipose 
tissues, blood vessels and nerve endings.9 Figure 1 illustrated the structure and composition of the 
human skin. 
 
 
 
Figure 1. Human skin structure and composition. The skin is mainly comprised of 3 layers, 
i.e. epidermis, dermis, and hypodermis with different structural elements that reside within 
distinct anatomical positions. Figure courtesy: Tomáš Kebert &amp; umimeto.org - Own work, CC BY-SA 4.0 
 
In the context of TDD, the stratum corneum (SC) is the primary mechanical barrier that limits 
the uptake rate of the topically applied drugs. The SC, made up of multilayered dead 
corneocytes scattered throughout a lipid-rich matrix, is principally a lipophilic nature by its 
barrier properties and which will exhibit a selective permeability for the penetration of 
relatively lipophilic molecules into deeper layers of the skin.12 Therefore, drugs that are rather 

4 
 
lipophobic or high in molecular weight are relatively impeded for its effective systemic 
delivery. Apart from that, the underlying epidermal-dermal junction would be the secondary 
factor conferring the resistance on the molecular transportation of drug molecules across the 
epidermal layer into dermis.13 Only the drug molecules that managed to get through the SC and 
the papillary dermis will effectively reach the systemic circulation to exert its systemic 
effects.14  
The sophisticated structure of the skin has also been implicated as the main barrier to ensuring 
an optimal bioavailability of the drugs delivered using TDDS. Previous study reported that the 
only 10-20% the total drug in a topical preparation successfully permeated across the skin 
layers.15a On the contrary, the high bioavailability of the drugs (90-100% of the total drug) has 
been touted as the main advantage of hypodermic needle.15 However, its invasive and pain-
inducing nature again limits its widespread usage.15 Hence, a novel TDD system is required to 
overcome the aforementioned design limitations.  
15a) Prausnitz MR, Langer R. Transdermal drug delivery. Nature biotechnology. 2008;26(11):1261-8. 
 
 

5 
 
CHAPTER 2 
 LITERATURE REVIEW 
 
2.1 Emergence of Microneedle and its Applications 
With the advent of the microfabrication technology, a revolutionary solution of effective 
transdermal drug delivery has been introduced with the use of microneedle (MN) patch. MN is 
a medical device that is composed of tiny micron-sized needles aligned in out-of-plane 
protruded arrays that can be impregnated with bioactive drug substances.16 These micron-sized 
needles create multiple transdermal microchannels when they puncture through the cutaneous 
stratum corneum. Consequently,  this innovative means of drug delivery enhances 
transcutaneous drug absorption, resulting in a faster onset of therapeutic action.15  
MN offers several superior clinically-relevant benefits. The most significant advantage of MN 
is it minimises the pain experienced by the patients by preventing nociceptor stimulation during 
venepuncture. Further, the MN design could also be tailored for the intended therapeutic agent 
delivery.15 Besides, MN can also be readily self-administered by the patients without the expert 
assistance from the healthcare professionals.15,16 With regard to needle breakage issue 
associated with the conventional hypodermic needle usage, the dissolvable MN is  potentially 
attractive in circumventing such a design imperfection. Furthermore, dissolving MN would 
also minimise the biohazard wastage compared to the conventional metal-based hypodermic 
needles.17 
Maltose, a natural non-cytotoxic carbohydrate is one of the most common constituents utilised 
in MN fabrication due to its excellent biodegradability profile and quick dissolution within 
minutes of administration.18,19 With a well-recognised safety record, maltose is also widely 
used for various pharmaceutical formulations with its proven safety and efficacy track record 
upon clinical application.20 Among MN types, dissolvable MN is a type of biodegradable 
microneedle patch that can be encapsulated with pharmaceuticals for transdermal drug 
delivery. Dissolving drug-embedded microneedle patch allows a continuous dissolution of 
drugs into the targeted skin layer upon its insertion onto the skin surface.21 Such drug 
administration strategy could also be described as a ‘poke-and-release’ drug delivery system.21 
To date, the scientific endeavours investigating the effects of dissolving microneedles on 
delivering anaesthetics for the adult patients who requires regular blood transfusion by their 
clinical conditions are scarce. So far, only three prior studies evaluated the efficacy of 
microneedles for alleviating pain in adult patients undergoing routine vein-puncturing 
procedures. Rzhevskiy et al. (2022) demonstrated in a clinical trial investigating the efficacy 
of lidocaine delivered via a hollow microneedle (MicronJet600) prior to peripheral venous 
cannulation. They showed a significant 11-fold VAS score reduction in adults undergoing 
routine peripheral venous cannulation when 2% lidocaine was intradermally administered 
using MicronJet600 compared to no anaesthetic pretreatment (mean VAS score: 3.6 (MJ+L 
combination) vs 39.7 (placebo); Cohen’s d: -.43 (95% CI -48, -3.9)) .22 In addition, Ornelas et 
al. (2016) conducted a randomised, single-blinded, parallel-group clinical trial to evaluate the 
effect of microneedle pre-treatment in hastening the onset of cutaneously-applied 4% lidocaine 
cream. They demonstrated that the microneedle-assisted 4% lidocaine delivery had shortened 
the application time from 60 to 30 minutes and significantly minimised the pain induced by 

6 
 
needle lancet at 30 mins  compared to sham patch (VAS score (mean ± SD):  microneedle: 4 
± 1.3 mm; sham: 14.4 ± 3.8 mm).23 In contrast, Gupta et al. (2012) compared the efficacy of 
lidocaine injections administered by hollow borosilicate-glass microneedle with the 
conventional hypodermic needle in 15 healthy adults. They established that both lidocaine 
delivery systems produce similar local anaesthetic effects (p > 0.05) across all time points, but 
the hollow microneedle recipients reported significantly better dermal analgesic effects 
compared to the recipients of conventional hypodermic needles24  
Based on these findings, the utility of microneedles is promising for effective anaesthetic 
delivery and pain amelioration. However, the validity of the aforementioned evidence may be 
limited by several methodological shortcomings. For instance,  the efficacy of transdermal 
microneedle in alleviating venepuncture-related pain has not been investigated in a clinical trial 
setting. Besides, Ornelas et al’s RCT was limited to only male population, a significant 
methodological weakness that hampers the generalisability of the results to the whole 
population23. Apart from that, Gupta et al. (2012) stated that the hollow borosilicate-glass 
microneedle prototype suffers from undesirable lidocaine leakage when it was applied on their 
subjects24. Therefore, further investigations are necessary to improve the microneedle design 
so that the local anaesthetic delivery can be further optimised for convenient application in 
adults who undergo frequent routine clinical procedures venepuncture. 
To our knowledge, the efficacy of lignocaine-impregnated microneedle for local anaesthetic 
delivery has not been studied. Hence, the safety, tolerability and pharmacodynamic property 
of lignocaine-embedded microneedle warrant further investigation. Therefore, our trial is 
designed to provide the answers to such scientific lacunae. 
 
2.2 The general pharmacological properties of lignocaine 
Lignocaine, in its solid state, possesses a crystalline and colourless structure that is dissolvable 
into a hydrochloric salt form.25 It possesses anti-arrhythmic and anti-nociceptive properties 
mediated through voltage-gated sodium and potassium channel blockade.26  
It is primarily bound to α-acid glycoprotein (AAG) (approximately 50%) and to lesser extent, 
albumin (around 25%).27-28 Diseases such as myocardial infarction and cirrhosis and other 
factors, for instance smoking and age, will influence the serum AAG concentration levels 
which in turn will affect the fraction of free plasma lignocaine concentration.29-32 By contrast, 
an increase in the AAG level will reduce the amount of unbound, active lignocaine in the 
plasma, resulting in a reduction of its pharmacological effects at a specific plasma lignocaine 
concentration.33 The volume of distribution at steady state, Vss, in normal adults is 1.32 (SD 
0.27) L/kg whilst the Vss in chronic heart failure (CHF), chronic liver impairment and chronic 
renal failure (CRF) patients  are 0.88 L/kg, 2.31 L/kg and 1.2 L/kg, respectively.34-35  
 
 

7 
 
Lignocaine has a high degree of hepatic extraction ratio (62%-81%).36 Hence, factors affecting 
hepatic blood flow such as metoprolol-mediated reduction in hepatic blood flow, congestive 
heart failure and acute myocardial infarction will influence the biotransformation rate of 
lignocaine.37-38 Apart from that, lignocaine is metabolized by CYP3A4, CYP3A5 and CYP1A2 
through consecutive deethylation steps.39-40 Therefore, concurrent administration of CYP1A2 
and CYP3A4 inhibitors such as amiodarone, fluvoxamine, erythromycin and others causes 
mild-to-major elevations of serum lignocaine concentrations.41-43 Lignocaine dosage reduction 
by up to 60% is thus warranted when a CYP1A2 inhibitor (e.g. fluvoxamine) is concomitantly 
administered with lignocaine.44  
Lignocaine 
has 
two 
major 
metabolites; 
monoethylglycinexylidide 
(MEGX) 
and 
glycinexylidide (GX).45 MEGX is responsible for both lignocaine’s therapeutic and toxic 
effects whilst GX primarily causes lignocaine-associated toxicity.46-47 Lignocaine is mainly 
eliminated via hepatic metabolism and the clearance rate ranges from 0.72 (SD 0.15) L/hr/kg 
in healthy adults34 to 0.25 L/hr/kg in patients with Child-Pugh class C hepatic impairment.48  
The main adverse events (AEs) associated with toxic level of serum lignocaine affect two major 
organ systems; the central nervous system (CNS) and cardiovascular system (CVS). In the 
former, the major AEs are confusion, slurring of speech, paraesthesia around the lips and 
tongue, diplopia, tremor, seizures whilst sinus bradycardia, sinus arrest and disturbances in 
atrioventricular conduction are the major AEs in the latter.49 The toxic effects of lignocaine 
will appear when serum lignocaine concentration exceeds 5 mg/L and convulsion occurs when 
it exceeds 10 mg/L.50 Despite being associated with the development of nasal adenomas and 
tumours in murine models, lignocaine is not associated with cancer development in humans.50-
51  
In 1999, the US Food and Drug Administration (FDA) has approved the lidocaine 5% patch 
(Lidoderm®, Endo Pharmaceuticals Inc, Malvern, USA) for the treatment of postherpetic 
neuralgia.52 Henceforth, it has been extensively investigated for the treatment of other medical 
conditions such as low back pain, postoperative pain control, rib fractures and for the 
prevention of venepuncture or injection-related pain in paediatric patients.53-56 However, in a 
recent meta-analysis by Bai et al., the 5% topical lidocaine patch was ineffective as an adjunct 
for the management of acute and postoperative pain since no significant differences were found 
in terms of the mean pain intensity scores, duration of hospital stay and the postoperative opioid 
consumption between the 5% topical lidocaine patch and placebo recipients.57 Hence, a new 
transdermal drug delivery system that can transcutaneously deliver lignocaine more effectively 
is required, especially in the context of alleviating pain associated with routine vein-puncturing 
procedures, namely venepuncture or intravenous cannulation. 
2.3 Dermato-pharmacokinetics (DPK) and mathematical modelling of microneedle-assisted topical 
anaesthetic delivery 
The dermal bioavailability of transdermally-delivered local anaesthetic agents should be accurately 
quantified in order to precisely evaluate their pharmacodynamic interactions with the cutaneous 
nociceptors. However, the quantification procedure is fraught with significant methodological 
challenges. Recently, Pensado et al. demonstrated that the minimally invasive stratum corneum (SC) 
sampling was only adequately-powered to detect a 50% difference in the mean uptake and clearance 
parameters and pharmacodynamic response characteristics (measured using the area above the 
blanching effect curve (AAEC)) between two different doses of Betnovate® (0.1% w/w BMV) cream 

8 
 
applied on the anterior aspects of forearms of 12 individuals, whilst a larger sample size was required 
to detect a smaller effect size (20% difference) for the two applied doses.58 In contrast, the skin 
blanching technique produced more highly variable results and therefore was relatively 
indiscriminative to the two different Betnovate® cream doses.58  Other techniques that have been 
proposed for dermato-pharmacokinetic (DPK) assessments of topical drugs, such as the in vitro Franz 
Diffusion Cell, ex vivo tape stripping, in-vivo micro-dialysis and suction blister techniques and confocal 
laser microscopy are also laden with serious methodological shortcomings (i.e. invasive procedure, 
absence of sensitive methods to analyze the analyte’s concentration, technical variations in the tape 
removal).59 Consequently, the DPK properties of topically-delivered local anaesthetics could not be 
accurately evaluated, which is the principal reason why our research will focus more on  the TDD 
system’s safety profile evaluation through the quantification of the amount of lignocaine or 5% EMLA 
dermal patch entering the systemic circulation (classical bioavailability). 
For an infinite dose of a given local anaesthetic agent, the quantity of penetrant or permeant that has 
reached the receptor chamber at time t, Q(t), can be represented by the following mathematical 
relationship:60 
Q(t) = A * p * h * c* [𝐷∗
𝑡
ℎ2 −
1
6 −
2
𝛱2 ∑
(−1)𝑛
𝑛2
∞
𝑛=1
∗𝑒
(−𝐷∗𝑛2∗𝛱2∗𝑡
ℎ2
)]      (Equation 2.1) 
where A is the skin’s surface area that is available for drug molecule diffusion; p is the coefficient of 
partition between the donor vehicle and the homogenous membrane; h is the thickness of the 
membrane (path length traversed by the drug molecules); C is the permeant’s concentration in the 
donor solution; * is the multiplication symbol and D is the coefficient of diffusion for the permeant in 
the membrane. From equation 2.1, it can be clearly observed that the delivery of active drug 
molecules is proportionally related to the skin’s surface area. As a result, a topically-applied local 
anaesthetic must be correctly applied to the intended cutaneous surface area to ensure optimal 
absorption and delivery of the anaesthetic drug molecules to the target site action site (i.e. skin 
nociceptors).  
From equation 2.1, we can also deduce that decreasing h will also increase Q(t). Since microneedles 
puncture through the skin’s SC layer, this reduces h and thus increases Q(t). We, therefore, 
hypothesized that the increased quantity of local anaesthetic agents (penetrant) at the skin 
nociceptors (receptor chamber) will also enhance the analgesic property of the local anaesthetic 
agents, resulting in a faster onset of action and subsequent greater pain reduction. Our postulate is 
further corroborated by Ronnander et al. who demonstrated that a change in the dermal 
concentration of sumatriptan delivered via dissolvable polyvinylpyrrolidone (PVP) microneedle with 
respect to time can be mathematically modelled using:61-62 
𝑑𝑐
𝑑𝑡 = −(𝐾𝐿𝑐) +  4 (
𝑘𝐷𝑡𝑎𝑛 𝜃
𝜌∗𝑐𝑜𝑠 𝜃) ℎ2 [
𝛽𝜌−𝑐
𝑣0+𝑣𝑐,0−𝑣𝑐] [𝑐𝑠−(
1−𝛽
𝛽) 𝑐],                (Equation 2.2) 
where KL is the constant of elimination; c is the drug concentration in the skin layer, kD is the constant 
for the rate of dissolution of a drug matrix (in cm/h),  𝜌 is the drug matrix’s density (or the 
microneedle’s density (in g/cm3)) , θ is the half angle (in degree) at the dissolvable microneedle’s apex 
(or microneedle’s height-length ratio), h is the height of the dissolvable microneedle, β is the fraction 
of drug mass in the microneedle, 𝑣0 + 𝑣𝑐,0 −𝑣𝑐 is the sum of the initial volume of the skin layer (cm3) 
and the initial volume of the microneedle (cm3) minus the volume of microneedle at the time when c 

9 
 
is measured (cm3) and cs is the solubility of matrix polymer in a solvent (e.g. water, measured in g/cm3). 
Using the Fick’s second law of diffusion, equation 2.2 could be rewritten as62-63: 
𝛿𝑐
𝛿𝑡 =  𝐷
𝛿2𝑐
𝛿𝑦2 +  4(
𝑘𝐷𝑡𝑎𝑛 𝜃
𝜌∗𝑐𝑜𝑠 𝜃)ℎ2 [
𝛽𝜌−𝑐
𝑣0+𝑣𝑐,0−𝑣𝑐] [𝑐𝑠−(
1−𝛽
𝛽) 𝑐] ,                  (Equation 2.3) 
where D is the diffusion coefficient or diffusivity (cm2/h) and 
𝛿2𝑐
𝛿𝑦2  is the curvature of the 
concentration profile at a specific point (x-position) in space. The first term on the right-hand side of 
equation 2.2 denotes the diffusion of the drug across the cutaneous layers and the second term 
represents the estimate of drug released from its encapsulating polymer via dissolution.62 
From equations 2.2 and 2.3, we could again conjecture that the concentration of a drug in the skin is 
dependent upon the drug loading (β), and the height of the dissolvable microneedle (h).61-64 By 
increasing the height of the microneedle, the stratum corneal layer can be bypassed and the local 
anaesthetics can hence be rapidly delivered at the intended site of action (skin nociceptors). 
Therefore, we believe a lignocaine-embedded microneedle patch design may enhance the lignocaine’s 
onset of action via a similar mechanism. 
58. 
Pensado A, McGrogan A, White KAJ, Bunge AL, Guy RH, Delgado-Charro MB. Assessment of 
dermal bioavailability: predicting the input function for topical glucocorticoids using stratum 
corneum sampling. Drug Deliv Transl Res. 2022 Apr;12(4):851-861. doi: 10.1007/s13346-021-
01064-8.  
59.  
Supe S, Takudage P. Methods for evaluating penetration of drug into the skin: A review. Skin 
Res Technol. 2021 May;27(3):299-308. doi: 10.1111/srt.12968.  
60.  
Finnin B, Walters KA, Franz TJ. Chapter 5: In Vitro Skin Permeation Technology. In: Benson 
HAE, Watkinson AC. Transdermal and Topical Drug Deliver: Principles and Practice. Hoboken, 
NJ; Wiley: 2012. p.99. 
61.  
Ronnander P, Simon L, Spilgies H, Koch A. Modelling the in-vitro dissolution and release of 
sumatriptan succinate from polyvinylpyrrolidone-based microneedles. Eur J Pharm Sci. 2018 
Dec 1;125:54-63. doi: 10.1016/j.ejps.2018.09.010.. 
62. 
 Ronnander P, Simon L, Koch A. Experimental and mathematical study of the transdermal 
delivery of sumatriptan succinate from polyvinylpyrrolidone-based microneedles. Eur J 
Pharm Biopharm. 2020 Jan;146:32-40. doi: 10.1016/j.ejpb.2019.11.007.  
63.  
Ita, K. Microneedles. London, UK; Academic Press: 2022. p.163. 
64.  
Yadav PR, Han T, Olatunji O, Pattanayek SK, Das DB. Mathematical Modelling, Simulation 
and Optimisation of Microneedles for Transdermal Drug Delivery: Trends and Progress. 
Pharmaceutics. 2020 Jul 22;12(8):693. doi: 10.3390/pharmaceutics12080693.  
 
2.3 Justifications of study 
Based on our brief review of literature, we have then pointed out three problem statements in 
bridging the knowledge gaps from previous research with the highlighted significance of our 
current study.  
I) The safety profile of transdermally-delivered lignocaine that is directly embedded within the 
matrix of dissolvable microneedle in the adult patients requiring venepuncture during routine 

10 
 
clinical settings have not been robustly and exhaustively tested in previous studies. This study 
aims to evaluate the safety and tolerability of lignocaine-embedded microneedle in this cohort 
of patients. The microneedle patch was designed and used (without impregnated drugs) in a 
previous project approved by this committee among paediatric thalassaemia patients. This trial 
protocol has been published in clinicaltrials.org and also in Journal of Clinical Medicine 2022, Sep 
8;11(18):5291. doi: 10.3390/jcm11185291. The safety profile was good with side effects showing 
that out of 19 patients studied, none reported any serious adverse reactions (SARs) or sudden 
unexpected serious adverse reactions (SUSARs) to the microneedle, with only one case complained 
of mild itchiness at the patch site. 
II) The pharmacokinetic properties of lignocaine that is directly delivered transdermally 
through embedment within dissolvable microneedle’s matrix have not been investigated in the 
previous study. Therefore, a subset of this study patients will provide the preliminary 
pharmacokinetic data for lignocaine delivered via such administration route which will indicate 
the extent of absorption of lignocaine, if any at all, into the systemic circulation. Animal study 
in rats showed no scarring and complete healing after microneedle patching, and blood plasma 
lidocaine was subtherapeutic level, below 0.4ng/mL and diminished to almost nil after 150 
minutes.  
 

11 
 
 
Hence, our current research is looking forward to providing the answers in response to the 
problem statements above as well as to highlight the potential of lignocaine-impregnated 
microneedle for its clinical application in topical anaesthetic administration and management. 
To summarize the foundations of our research, the conceptual framework of this research is 
shown in Section 2.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

12 
 
2.4 
 Conceptual Framework 
 
 
 
 
 
 
 
 
 
Lignocaine applied to skin diffuse and 
penetrate through the skin layers 
Microneedle (MN) aids in transdermal 
delivery of lignocaine drug  
Lignocaine is applied to promote 
anaesthetic effect for alleviating pain in 
venepuncture  
Lignocaine-embedded MN speeds up 
the onset of anaesthesia with higher 
analgesic intensity  
Lower VAS score and algesimeter 
readings in the group receiving 
lignocaine-impregnated MN after 30 
minutes of administration 
Improved pain perception in the regular 
practice of venepuncture 
Better treatment compliance and 
patient acceptance in healthcare 
Distribution of lignocaine under the skin 
promotes its anaesthetic effects for pain 
alleviation 
Pharmacokinetic study of Lignocaine 
absorption into the systemic circulation 
from the administration site  
Interpret the pharmacokinetic data if 
the lignocaine is absorbed and 
distributed in the circulation 
Establish a reliable platform of safety 
anaesthetic delivery with drug 
embedded microneedle  
Adult patients who require venepuncture  for 
blood investigations 
Pharmacodynamic component 
Pharmacokinetic component 
 

13 
 
CHAPTER 3  
OBJECTIVES 
3.1 General Objective 
To assess the safety and efficacy of lignocaine-embedded microneedles as a means of pain-
reduction in adult patients requiring routine venepuncture procedure. 
 
3.2 Specific Objectives 
1. To evaluate the safety profile of lignocaine-embedded microneedle patch as a means of pain 
reduction in adult patients requiring routine vein-puncturing procedures 
2. To assess the pharmacokinetic (PK) parameters of lignocaine in the systemic circulation 
when the transdermal lignocaine delivery is enhanced through microneedle usage. 
3. To compare the efficacy of lignocaine-embedded microneedle patch with standard 5% 
EMLA dermal patch for pain reduction during venepuncture procedure based on mean changes 
in VAS scores and skin algesimeter index (pharmacodynamic (PD) study). 
 
3.3 Research Questions 
1. What is the safety profile of lignocaine-embedded microneedle patch used for pain reduction 
in adult patients requiring routine vein-puncturing procedures? 
2. What are the values of PK parameters (AUCinf, AUCt, Cmax, t1/2, volume of distributions (Vd) 
and clearance) for the lignocaine constituent in adult patients receiving lignocaine-embedded 
microneedles for routine vein-puncturing procedures? 
3. Are there differences between lignocaine-embedded microneedle patch and standard 5% 
EMLA dermal patch for pain reduction during venepuncture procedure based on mean changes 
in VAS scores and skin algesimeter index? 
 
 
 

14 
 
3.4 Research Hypotheses 
1. H0: The proportion of participants experiencing adverse event is not significantly different  
           from 0. 
 
    H1: The proportion of participants experiencing adverse event is not significantly different  
           from 0. 
 
2. H0: The values of PK parameters for the lignocaine constituent in adult patients receiving  
           lignocaine-embedded microneedles are not bioequivalent with the values of PK  
           parameters for the lignocaine constituent in adult participants receiving lignocaine  
           through the standard topical route. 
 
    H1: The values of PK parameters for the lignocaine constituent in adult patients receiving  
           lignocaine-embedded microneedles are bioequivalent with the values of PK parameters 
           for the lignocaine constituent in adult participants receiving lignocaine through the  
           standard topical route. 
 
3. H0: There are no differences in mean changes in VAS scores and skin algesimeter index   
 
between the trial participants receiving lignocaine-embedded microneedle patch and 
 
standard 5% EMLA dermal patch. 
    H1: There are significant differences in mean changes in VAS scores and skin algesimeter 
 
index between the trial participants receiving lignocaine-embedded microneedle patch 
 
and standard 5% EMLA dermal patch.  
 
 
 

15 
 
CHAPTER 4 
 METHODOLOGY 
4.1 Study Design 
This study can be divided into two distinct stages: 
a) Stage 1: Non-randomized single-centre open-label single group clinical trial to primarily 
assess the safety and tolerability of lignocaine-impregnated microneedle in adult patients 
undergoing routine vein-puncturing related procedures (pharmacokinetic (PK) study).  
b) Stage 2: A randomized single centre double blind two parallel group active controlled 
clinical trial to assess the efficacy of lignocaine-impregnated microneedle compared to 5%  
EMLA dermal patch (Pharmacodynamic (PD) study). 
 
4.2 Study Location 
The study will be carried out at the Ophthalmology Outpatient Clinic, Hospital Canselor 
Tuanku Muhriz (HCTM), UKM, Bandar Tun Razak.  
 
4.3 Study Period 
1st December 2022 – 30th November 2024 (24 months) 
 
4.4 Eligibility Criteria 
The inclusion and exclusion criteria of the study participants are as follows: 
 
4.4.1 Inclusion Criteria 
I) Patients aged 18 years old and above 
II) Patients requiring venepuncture for blood investigations before ophthalmological 
procedures 
 
4.4.2 Exclusion Criteria 
I) Patient with a previous history of sensitization or allergy to lignocaine. 
II) Patient with a previous history of allergy to materials used in the study i.e., plaster, 
electrodes, maltose, Polyvinyl Alcohol (PVA), and Polyethylene Terephthalate (PET) 
III) Patient exposed to analgesic usage within 24 hours prior to the procedure 
IV) Generalized skin disorder/ rash 
V) Agitated/ fretful / uncooperative patient 

16 
 
VI) Uncommunicative/deaf/mute 
VII) Patients on hypnotics, or chronic pain relief medications 
VIII) Patients with psychiatric conditions or cognitive impairment 
IX) Patients with hepatic impairment 
 X) Patients who are on CYP450 3A4, 3A5 or 1A2-inducing or inhibiting drugs (erythromycin, 
ciprofloxacin, amiodarone etc.) or pharmacotherapeutic agents that affect hepatic blood flow 
(metoprolol) since both may affect the metabolism of lignocaine.  
XI) Failed first/single attempt at venepuncture after the application of the MN patch. 
 
4.5 Reference Population 
All adult patients undergoing vein-puncturing procedures at the Ophthalmology Outpatient 
Clinic in Malaysia. 
 
4.6 Source Population 
All adult patients undergoing  venepuncture at the Ophthalmology Outpatient Clinic, Hospital 
Canselor Tuanku Muhriz (HCTM), UKM, Bandar Tun Razak. 
 
4.7 Sampling Frame 
All adult patients undergoing venepuncture at the Ophthalmology Outpatient Clinic, Hospital 
Canselor Tuanku Muhriz (HCTM), UKM, Bandar Tun Razak and fulfil the eligibility criteria. 
 
4.8 Study Subjects 
All adult patients undergoing  venepuncture at the Ophthalmology Outpatient Clinic, Hospital 
Canselor Tuanku Muhriz (HCTM), UKM, Bandar Tun Razak, fulfil the eligibility criteria and 
consent to trial participation. 
 
4.9 Sampling Method 
Stratified random sampling, a type of probability sampling method, will be used for both stages 
of the trial since the sample size required (section 4.9) is smaller than the whole pool of 
participants. Since differential pain experience has been shown in females and male adults58, 
the stratification variable is the gender of the participants to ensure that our study sample 
contains an equal number of female and male adults and is representative of patient population. 
  
4.10 Sample Size Calculation 

17 
 
4.10.1 Pharmacokinetic (PK) study 
Due to the paucity of prior information, formal sample size calculation for stage 1 
(pharmacokinetic (PK)) study based on power analysis cannot be carried out. Based on 
recommendations by Ogungbenro and Aarons (2010) and Julious (2012), the sample size is set 
at 20 subjects each for the PK study59-60. Even though, it is recommended that the sample size 
can be minimally set at 12 subjects for a single-group pilot pharmacodynamic trial (Julious, 
2012), the sample size is increased to 20 subjects since based on Julious 2012’s results (Figure 
3 of Julious 2012), the statistical asymptote is reached when the sample size is at least 20 
subjects59. Hence, the addition of another subject will result in only non-substantial gain in the 
precision of the parameter estimates when the sample size of 20 participants is reached.   
 
4.10.2 Pharmacodynamic (PD) Study 
For stage II of the trial, the sample size was calculated using Power and Sample Size (PS) 
Program version 3.1.6 (Vanderbilt University, Nashville, Tennessee, USA; 2018). The 
standard deviation (SD) of the VAS score of 2.1 were obtained from a prior study and this is 
for patients who received 5% EMLA.61 We consider a 1-point VAS difference between the 
intervention group as the minimum detectable difference (MTD) and type I error and study 
power (1- β) were fixed at 0.05 and 0.80, respectively. The ratio of controls to cases is fixed at 
1:1 ratio. Based on these parameter values, the calculated sample size is 70 participants per 
group. 
After accounting for a 10% drop-out rate, the final sample size is 77 participants per group 
(ntotal= 154 participants) for this stage of trial. 
 
4.11 Physical Description of the Lignocaine-Embedded Microneedle  
Currently, we are able to manually produce some microneedle array patches (MAP) in a lab 
scale quantity. Different designed parameters MAP has been used for initial test on animal skin 
and also human skin. In this project, two major parts will be carried out. First, we will design 
a semi-auto machine to fabricate MAP. Refine parameters will be adapted from previous 
designs for the fabricate of the drug impregnated microneedles. Second, we will carry out a 
clinical trial for testing on the real implementation and application of the fabricated MAP. The 
details for each session are discussed as below 
 
Part I: Preparation of Biodegradable Drug Impregnated Microneedle Array Patch 
In a previous project, few parameters such as base plate size, number of microneedles per unit 
area, height etc. that have been determined and optimized. They will be used as a guideline for 
the design of new microneedle fabrication machine for better microneedle fabrication. With a 
new fabrication machine, we will be able to have a small-scale production to achieve a pre-
commercialization technology readiness.  
In this part, we will focus on the fabrication and implementation of biodegradable microneedle 
array patch. Sugar compounds such as sucrose, trehalose, and maltose have experimented as 

18 
 
biodegradable matrix materials for microneedles. In particular, maltose itself is a carbohydrate 
that is widely-acknowledged as a generally recognized safe excipient material for drug 
delivery. MAP fabricated from maltose generally demonstrate strong mechanical properties, 
and as such can facilitate perforation of skin and formation of micro-channels for transdermal 
drug delivery. Besides, for enabling the function as dissolvable MAP, maltose can rapidly 
dissolve in the dermal regions within minutes under body temperature, and is thus able to 
deliver therapeutic compounds such as proteins and peptides rapidly, safely and in an 
environmentally-friendly manner. The MAP that we propose as a prototype will consist of two 
basic but essential structures, i.e. the microneedles and the substrate (baseplate). This special 
design allows the microneedles to be separated from the substrate once the MAP is applied 
onto the skin. While the substrates can be readily disposed of after being peeled off from the 
skin, the microneedles and the therapeutic loads that they carry would stay on the skin and 
continue to dissolve and release drugs in a predetermined and sustained manner. Furthermore, 
as the microneedle is only 150 µm in length, thus, maximum penetration would only reach 
epidermis-dermis intersection. There is no possibility of the microneedles reaching the blood 
vessels, due to the limited length of the microneedles. Therefore, the drug distribution will 
follow a topical mode of distribution. No systemic distribution of drug is expected. 
A. Preparation of microneedle matrix mix for the dissolving microneedle 
 
I. 
To prepare the calcium ion cross-linked alginate/sugar (Ca2+/Alg-sugar) composites, 
sodium alginate powder is firstly dissolved in DI water at a weight ratio of 1:4 with the stir 
in a water bath at 60 °C until to gain the homogeneous solution. 
II. 
And then, the 15% (w/w) CaCl2 solution is added slowly with rapid mixing to cross-link 
alginate (CaCl2/Cross-linked alginate weight ratio = 1:10). 
III. 
To enhance the mechanical properties of composite microneedles, 15% (w/w) maltose 
monohydrate or any carbohydrate equivalents is added simultaneously into the sodium 
alginate solution to form precursor for preparation of paste for the fabrication of drug-
loaded microneedles and baseplate (substrate): 
 
 
 
 
 
 
 
 
 
 
B. Fabrication of mould as a microneedle stamp used to fabricate negative mould 
with polydimethylsiloxane (PDMS) via the moulding technique  
 
 
 
Sodium alginate 
powder 
Di-ionized water 
Sodium alginate powder 
was measured 
CaCl2 solution 
Cross-linked alginate  
Alginate and maltose in the ratio of 
1:4 maintained at an elevated 
temperature of 60C for forming an ion 
cross-linked composite 
15% (w/w) CaCl2 solution is 
added slowly with rapid mixing 
to cross-link alginate 
(CaCl2/Cross-linked alginate 
weight ratio = 1:10). 
Figure 1: The microneedle composite will be prepared based on the above-mentioned steps 

19 
 
 
A mould will be fabricated based in this fabrication process. The moulds for different sizes, 
shape and physical scales of microneedles will be designed.  
 
I. 
In the previous lab-scale fabrication, the pyramidal microneedle patch is fabricated 
using polymethyl methacrylate (PMMA) and used as the male mould. In this project, 
we will use a more solid and hard materials such as metal for the male mould.  
II. 
Subsequently, reversed mould (which is the female mould for the microneedle 
fabrication) is fabricated. To do so, a PDMS mixture is blended and added to a dust-
free master structure, followed by centrifugation (4000 rpm, 30 min, 25°C, centrifuge 
and application of vacuum (200 mbar, 30 min, 25°C, vacuum drying oven) to remove 
air bubbles.  
III. 
After curing at 100°C for 5 h, the female mould is obtained, which can be used to 
produce microneedles made of sugar compounds (such as maltose).  
IV. 
The above processes are to prepare reverse mould with different physical parameters to 
test for the suitability and conformity of the mould for fixing onto the semi-auto 
fabrication machine. After that, the designs have the highest aptness will be used. The 
parameters will be adapted into a 3D printer for small scale produce of these female 
moulds.  
 
 
 
 
 
 
 
 
C. Semi-auto machine for the fabication of dissolving microneedle array patch 
 
Figure 2: Moulds with different sizes, shapes and physical parameters will be designed and 
prepared  
A(i) 
A(ii) 
A(iii) 
 
 
Female mould with the best parameters will be used as standard for small –scale production of the 
mould with different design and physical parameters used for microneedle fabrication 
A(iv) 
 

20 
 
With the use of MAP-fabrication machine,  
I. 
A two-step casting process will be used to fabricate Ca2+/Alg-sugar composite 
microneedles. Firstly, the microneedle matrix loaded with therapeutic protein or drug 
is poured onto the centrifuged by a refrigerated centrifuge at 10000 rpm in 20 °C for 10 
min to fill up the porous container of microneedle mould to form a thicker pre-casting 
microneedle baseplate. 
II. 
Then, the preformed drug (lignocaine)-loaded microneedle preforming plate will be 
loaded to the machine and go through stamping, forming hardening to become a final 
microneedle array patch as shown in a schematic diagram in Figure 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The microneedle patch is made in a prototype lab in Alnair Incorporated, Tokyo, Japan, 
which is the collaborator in this study. 
The microneedles were individually heat treated at 120°C for sanitation before packaging. 
 
 
Preformed drug loaded microneedle 
preforming plate will be loaded to the 
machine and go through stamping, forming 
hardening to become a final microneedle 
array patch 
Sugar compounds such as sucrose, trehalose, and 
maltose will be used to mixed to the dedicated 
drug/s and the mixture will go through a centrifuge 
process in a perforated container to form a thicker 
pre-casting microneedle baseplate 
Figure 3: The microneedle matrix composite will have filled into a porous container to form 
a pre-casted microneedle plate, the plate will be used to form microneedle tips and baseplate 
after a series of stamping, forming, hardening processes. 
 

21 
 
4.12 Trial Conduct 
4.12.1 Pharmacokinetic (PK) Study Conducts 
Therefore, for this project, we will conduct a subproject as Phase 1 trial to assess the safety and 
tolerability of 12.5mg lignocaine-embedded microneedle on a small number of adult patients 
(20 patients; 10 males and 10 females) without hepatic or renal dysfunction. All participants of 
this phase I will be cataract patients who will be recruited from the HCTM ophthalmology 
outpatient clinic. Pre-treatment fasting is not required for all participants.   
On the day of the study, each potential participant will be screened for study eligibility based 
on our pre-specified inclusion and exclusion criteria. An interim abridged medical history will 
be taken from each participant and their list of medications will be reviewed. Vital signs 
(systolic and diastolic blood pressures, oral temperature, pulse and respiratory rates) will be 
taken and targeted clinical examinations will be performed by the medical officers to assess 
the overall health of the participants. 
First, an intravenous cannula will be placed at the dorsum of the hand and the routine bloods 
taken for investigations plus approximately 3.0 ml venous blood samples will then be 
withdrawn at t=0. Then the 12.5mg lignocaine-impregnated microneedles will be applied to 
the antecubital fossa, after which blood will be drawn from the earlier inserted intravenous 
cannula at t=30, 60, 90, 120, 180 minutes and collected into separate 3.5-ml of plastic blood 
collection tube with accelerator & separator gel (BD™, New Jersey, USA). Heparinized saline 
will be periodically infused to ensure that the cannula lumen remains patent throughout the 
sampling periods. The blood samples will then be sent to Jabatan Kimia Malaysia for 
lignocaine concentration measurements using the validated methodology of Gas 
Chromatography Nitrogen Phosphorus Detector (GC-NPD). 
In comparing against the 12.5mg lignocaine-embedded microneedle, a similar approach as 
above to test the systemic absorption of EMLA will be studied in a group of another 20 patients 
but utilising the method employed in the previous paediatric trial, i.e. 5% EMLA cream 1 ftu 
enhanced by microneedle patch (JEP-2021-578; published protocol – J. Clin. Med. 2022, 11, 
5291. https://doi.org/10.3390/jcm11185291).   
 
a) Determining Serum Lignocaine Concentration using Gas Chromatography-Nitrogen 
Phosphorus Detector (GC-NPD): A Brief Protocol 
One (1) mL of the blood will be taken from the collection tube and alkalinized with NaOH 
solution of pH 12. The internal standard, Methaqualone and the organic solvent, Chlorobutane 
will then be added to the mixture. The mixture will be subsequently mixed using a roller mixer 
and centrifuged to extract the organic the layer which will be then concentrated. from the 
partition. A clean-up solution, hexane-ethanol, will be then added to the sample mixture which 
will be again vortexed and centrifuged. The bottom organic layer will be then moved into 
another tube and it will be evaporated to complete dryness under nitrogen gas flow in room 
temperature. The residue will be subsequently reconstituted using absolute ethanol prior to 
loading into the GC-NPD system.  
Lignocaine in the blood matrix will be spiked based on the level below or within the range in 
the therapeutic level. Besides, the response of the drug in the gas chromatography (i.e. the 

22 
 
resolution and the peak of in GC) will be taken into consideration. In normal practice, 
lignocaine at the amount of 0.5 parts per million (ppm) will be spiked and a lower amount of 
lignocaine (0.3 ppm) will be used for quality control, which are based on previous 
recommendations by Winek et al (Lignocaine: Therapeutic: 1.5-5.0 ppm; Toxic: 7-20 ppm; 
Lethal:>25 ppm)62. For calibration, a 1-point calibration to estimate serum lignocaine 
concentration will be used. A series of 1-point calibration will also be carried out whenever 
serum lignocaine concentration exceeds the therapeutic range. 
 
b) Post-intervention Monitoring and Pharmacokinetics Data Analysis 
The participants will be allowed to return home after the last blood sample is taken at t=180. 
The participants will be further monitored for any adverse events (AEs) such as redness, pain, 
itchiness, blistering, etc (local reactions) and light-headedness, euphoria, tinnitus, diplopia etc. 
(systemic reactions), serious adverse events (SAEs) and suspected unexpected serious adverse 
reactions (SUSARs) for up to 48 hours via telephone calls. 
The pharmacokinetic data will be first summarized in mean / standard deviation or median / 
interquartile range for continuous data and count and percentage for categorical data. The 
pharmacokinetic parameters (AUCinf, AUCt, Cmax, Cmin, tmax, t1/2, volume of distribution (Vd), 
Clearance (Cl)) of lignocaine will be evaluated using blood samples obtained at times t=0, 30, 
60, 90, 120, and 180 minutes after the application of lignocaine-impregnated MN patch. The 
intraindividual and interindividual variations of the pharmacokinetic parameters will be 
evaluated using coefficient of variation (CV) and these will be classified as low (CV≤10%), 
moderate (CV ≈ 25%) and high (CV>40%).63 The pharmacokinetic data will be analysed using 
the non-linear mixed effect models based on two-compartmental model which will be 
implemented on NONMEM® version VI (Icon Development Solutions, Ellicott City, 
Maryland, USA). The influence of clinically relevant covariates such as participant’s age, 
gender, BMI and others on pharmacokinetic parameters will be evaluated in a stepwise fashion. 
First-order conditional likelihood (FOCE INTER on NONMEM) will be used to fit the data 
and model selection will be dependent upon the likelihood ratio test, the estimates of 
pharmacokinetic parameters and their 95% confidence intervals and goodness-of fit measures. 
 
4.12.2 Pharmacodynamic (PD) Study Conduct 
a) Randomization Procedure and Blinding (Masking) of Trial Participants 
For random allocation, block randomization procedure with varying block size (permuted 
block) will be utilized to guarantee that both intervention groups will have an equal number of 
trial participants. This will be carried out by the trial statistician using the R package, blockrand 
version 1.50 which will be implemented on R platform.64 The list of generated random numbers 
will be used to allocate the study participants to either intervention or control branch. The 
allocation sequence generated will be kept in a password-protected document that is only 
accessible to the statistician to maintain allocation concealment. To further ensure the adequacy 
of allocation concealment, randomisation code will not be revealed until the potential trial 
participants have been definitively enrolled into the trial, which will be after all baseline 
measurements are made and all eligibility criteria are deemed fulfilled by the study recruiters. 

23 
 
In addition, allocation concealment is further safeguarded by ensuring identity of the allotted 
treatment is only revealed to the interventionist (i.e. the person who will be administering the 
intervention) via secured telephone calls (central randomization). Consecutive recruitments 
will be made until the final intended sample size is achieved. 
 
For this study, the outcome assessors and care providers (may be the same individual) will be 
masked to the identity of interventions (single blinding / single masking). Only the statistician 
and interventionist/procedurist will be unmasked to the study interventions. Furthermore, 
unique ID code to indicate each treatment sequence assignment will be generated and utilised 
to ensure that the unintentional / intentional unmasking of one trial participant will not 
compromise the integrity of blinding for the rest of study participants. The primary unblinded 
trial persons (subjects, the statistician and the procedurist/interventionist) are instructed not to 
divulge the identity of the allotted treatments to other blinded trial personnel. The success of 
blinding will be determined by asking the blinded trial persons to guess the identity of 
interventions received and then compare the results obtained with what would be anticipated 
by chance. Blinding indices such as James’ Blinding Index or Bang’s blinding Index could also 
be calculated to objectively assess whether blinding has been successfully achieved in this 
trial.65,66  
 
b) Administration of Lignocaine-embedded Microneedle (intervention) and EMLA 
(control) patches 
Prior to the administration of intervention/control, relevant clinic-demographic profiles (age, 
gender, ethnicity, anthropometric measurements, presence of comorbidities,) will be recorded 
and entered in the case report forms (CRFs) that are specifically designed for this study. This 
research study uses lignocaine embedded microneedles. The comparison of pharmacodynamic 
properties (i.e. efficacy) between 12.5 mg lignocaine delivered through direct embedment 
within the microneedle matrix and standard 5% EMLA dermal patch containing 1 finger-tip- 
unit (FTU=0.5g) of 12.5mg lignocaine and 12.5mg prilocaine will be assessed via VAS score 
and skin algesimeter index for the pain induced by venepuncture.  
The window period given to lignocaine for it to be effective will be based on the usual clinical 
practice observation where it is usually applied for 30 minutes prior to venepuncture. The 
rationale behind it is due to logistical issues and for the day care's operational convenience. 
Nevertheless, in a busy clinical setting, the application time is sometimes shortened to 15 
minutes for a slight anaesthetic effect.  Thus, we postulate that, with the aid of microneedle, 
the time to onset of action for lignocaine could be greatly reduced resulting in a much more 
reduced pain sensation when the clinical assessment is carried out 30 minutes after treatment 
application. 
The administrator of interventions (procedurist) will identify and draw a grid of 1cm × 1cm at 
the antecubital fossa, which will serve as an ideal site for venepuncture. The procedurist will 
then apply the lignocaine-impregnated microneedle patch.  After a 30-minute application time, 
the attending medical officer will perform venepuncture using a 21-gauge (G) hypodermic 
needle inserted into the vein beneath the analgised patch. 
For the participants allotted to the standard 5% EMLA dermal patch, 1 FTU of 5% EMLA 
cream will be applied and covered with a piece of adhesive to form a dermal patch. This will 

24 
 
be applied for 30 minutes similarly on the antecubital fossa. This application delivers an 
equivalent of 12.5mg lignocaine and 12.5mg prilocaine.  
During the trial day, the participants will not be allowed to take any analgesic medications 
(NSAID, Opioids, Paracetamol) since they will modulate the level of pain experienced by the 
participants due to the received interventions. Other medications and concomitant care will be 
permitted during the trial. 
 
c) Pain Assessment 
The study participants will first be guided on the operating manual for a 10-points, 100mm 
VAS pain score by an outcome assessor. The participants will be presented with a ruler that 
contains 100-mm slots with “No Pain” written on the left side and “Worst Pain” on the opposite 
right side. The study participants will then be asked to move and place the slider in the slot that 
accurately describes his/her pain at the following time points: 1) within 5 minutes after 
application of lignocaine-impregnated MN patch and before venepuncture (baseline VAS 
score); 2) within 5 minutes after venepuncture. The investigator/outcome assessor, who is 
blinded to the subject intervention arm will record the location of the slot where the slider is 
placed in millimetres (mm), clearly printed on the ruler’s reverse side and this will be the 
participant’s VAS score. Throughout the process, there will be a trained investigator standing 
by to assist the verification of the pain scale and to aid the participants who require additional 
assistance. 
For a subset of randomly selected patients, before applying MN patch and EMLA Cream, the 
patients will be attached with the PainMonitor™ (Med-Storm Innovation AS, Oslo, Norway) 
device whereby the electrodes will be attached to the hypothenar eminence of the opposite hand 
not receiving the venepuncture. The procedurist will set up this machine and application before 
the interventions are commenced. The skin conductance peaks (in microSiemens (μS) and the 
skin algesimeter index (in microSiemens per second (μS/s)) will be recorded by the outcome 
assessor who will be blinded to the subject intervention arm. Those parameters indicate the 
skin’s sympathetic nerve block induced by the topical anaesthetic. The measurement time 
points start from the point of intervention and the recordings continued for at least 15 seconds. 
 
4.12.3 Clinical Data Collection 
All study personnel (i.e. interventionist/procedurist, investigator/outcome assessors, healthcare 
providers) will receive training (e.g. use of open ended questions when assessing VAS pain 
score and adverse events related to interventions) in VAS measurement, administration of 
lignocaine-embedded MN patch prior to trial commencement to standardise data collection, 
enhance data quality and reduce data inconsistency and measurement variability.  
All data collected will be checked for data quality using double data entry practice and checking 
for sensible data range and format (e.g. integer for the number of adverse events experienced 
within 24 hour of intervention). All paper-based CRFs will be stored in locked cabinets that 
are only accessible to the principal investigators, data manager and statistician and these will 
be maintained for 5 years after the trial ends. For quality control, periodic random check on a 
subset of CRFs will be carried out. 

25 
 
All data recorded on paper-based CRFs which will then be transcribed into an SPSS 
spreadsheet in an .sav extension at the central site conducted by statistician-trained data entry 
personnel. This will then be converted into a Stata-friendly file format (dta extension) to aid 
statistical analysis. The dataset will be password-protected and is only accessible to the 
principal study researchers and statistician to prevent any intended or unintended breach of 
patient confidentiality. Backup datasets will be stored in a password-protected thumb drives 
and cloud storage (GoogleDrive) that are again only accessible to the principal study 
investigators and statistician. The password for all datasets will be regularly changed to ensure 
maximum prevention against any data breach. 
 
4.12.4 Interventional Safety Assessment 
We define adverse events (AE) as "an abnormal sign, symptom, laboratory test, syndromic 
combination of such abnormalities, untoward or unplanned occurrence (e.g. accident), or any 
unexpected deterioration of concurrent illness".67 For serious AE (SAE), this is defined as 
"adverse events that result in the following outcomes: 1) death; 2) life-threatening AEs; 3) 
inpatient hospitalization or prolongation of existing hospitalization; 4) a persistence of 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly or birth defect.68  
We classify the likelihood of AEs / SAEs (unrelated, possible, probable, definite) based on 
Naranjo et al. classification.69 All AE/SAE will be recorded and graded based on the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5 and US FDA's Toxicity Grading 
Scale Healthy Adults and Adolescents Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. All AEs or SAEs can be classified into local skin reaction (pain, erythema, ecchymosis, 
swelling, itchiness, tenderness) or systemic reaction (fever, irritability, tiredness, anorexia, 
vomiting, tachycardia, seizure, hypotension). 
All AEs will be recorded on the CRFs. The detailed characteristics, the time and dates of onset 
and disappearance, and severity of AEs will be included in the CRFs. The study investigators 
will assess each participant experiencing AEs and they will receive appropriate treatments 
accordingly. The relationships between AEs and lignocaine-embedded microneedles will be 
evaluated by the investigators and classified as either unrelated, possible, probable or definite 
based on Naranjo et al. classification. AEs are considered as unexpected AEs when the AEs 
are not previously observed and not reported in the Investigator’s Brochure or standard 
lignocaine package insert. Any incidence of AEs or SAEs classified as possibly, probably and 
definitely linked to lignocaine-embedded microneedles will be monitored until the AEs/SAEs 
resolution is complete or the Investigator deem that the AEs or SAEs have become stable or 
irrevocable. 
All AEs of grade 3 and above will be reported to the JEPUKM within 5 business days. All 
SAEs (including Serious Unexpected Suspected Adverse Events (SUSARs)) will be reported 
within 24 hours of occurrence (expedited reporting) to the JEPUKM. If AEs / SAEs occur or 
are still ongoing by the end of the study period, the study participants will still be continuously 
followed up until complete resolution of AEs / SAEs which will take the following form: 1) 
additional participant visit to the trial centre / hospital; 2) telephone calls to the subjects; 3) 
additional reporting in the form of letters from the treating physicians. 

26 
 
Participant enrolment, intervention allocation and administration will be stopped if one of the 
following occurs (study halting criteria): 
a) Death related to lignocaine-impregnated MN patch  
b) Any participant experiences bronchospasm, laryngospasms or anaphylaxis within 24 hours 
post lignocaine-impregnated MN patch  
c) Any SAE related to lignocaine-impregnated MN patch  
d) Any AE of grade 3 and above or any SAE that cannot obviously be implicated on other 
causes 
e) Any study participant who develops abscess, ulceration or erosion at the site(s) of lignocaine-
impregnated MN patch  
To ensure the independence of safety monitoring, all recorded safety data will be reviewed by 
JEPUKM which functions as an independent Data Safety Monitoring Board (DSMB) for our 
trial. 
 
4.13 Operational Definitions of Study Variables 
a) Independent variables 
 
i) Age: The age of a study participant at the first study visit. The variable will be measured in 
years and month and modelled as a continuous numerical variable and will not be categorised 
into separate age groups. 
 
ii) Gender: A categorical variable that will be recorded in the SPSS data frame as 0 = female 
(base category) and 1 = male. Missing data shall be recorded as 999 
 
iii) Ethnicity: A categorical variable that will be recorded in the SPSS data frame as 0 = Malay 
(base category); 1 = Chinese; 2 = Indian; and 3 = Other ethnicity. Missing data shall be recorded 
as 999. 
 
iv) Body mass index (BMI): A continuous numerical variable that is calculated using the 
standard body mass index formula; BMI = kg / m2. This variable will be categorised according 
to a widely used BMI classification70-71: 
<18.5= underweight (SPSS code: -1) 
 18.5-24.9= normal BMI (SPSS code: 0; base category) 
25.0-29.9= Overweight (SPSS code: +1) 
≥30 = Obese (SPSS code: +2) 
 
The categorized variable will then be used as a predictor variable for statistical modelling 
purposes. Missing data will be recorded as 999 in the SPSS spreadsheet. 
 
 
 

27 
 
v) Intervention groups: A categorical variable representing the types of interventions 
received by the study participants in each study visit. This variable will be recorded in the 
SPSS data frame as 0 = 5% EMLA dermal patch only group (control, base category, 30 
minutes); 1 = Lignocaine-Embedded Microneedle Patch (30 minutes) 
 
vi) Baseline VAS score: A continuous numerical variable that will be measured before the 
administration of intervention. This will be used as a predictor variable to control the 
confounding effect of heterogenous baseline VAS scores among study participants. Missing 
data will be recorded as 999 in the SPSS spreadsheet. 
 
vii) Baseline pain score obtained via PainMonitor™ device: A continuous numerical 
variable that will be measured before the administration of intervention. This will be used as 
a predictor variable to control the confounding effect of heterogenous baseline VAS scores 
among study participants. Missing data will be recorded as 999 in the SPSS spreadsheet. 
 
 
b) Dependent (outcome variables) 
 
i) VAS score (30-minutes post intervention application): A continuous numerical variable 
that will be measured during each visit; 30 minutes after lignocaine-embedded microneedle or 
5% EMLA application. Missing data will be recorded as 999 in the SPSS spreadsheet. 
 
ii) Pain score from PainMonitor™ device (30-minutes post intervention application): A 
continuous numerical variable that will be measured during each visit: 30 minutes after either 
lignocaine-embedded microneedle or 5% EMLA application. Missing data will be recorded as 
999 in the SPPS spreadsheet. 
 
 
 

28 
 
4.14 Ethical Issues 
Voluntary written informed consent will be obtained from each study participant. This study 
will be conducted in accordance with the principles of ethics in human research as stipulated 
by the Declaration of Helsinki (18th World Medical Association General Assembly, 1964), the 
Good Clinical Practice (GCP) guidelines, and ISO14155:2020 Clinical Investigation for 
Medical Devices for Human Subjects. Ethical approval will be obtained from the UKM 
Research Ethics Committee (Human) (JEPUKM). 
All research participants will sign informed consent forms prior to their study participation. 
The participants will be made aware that their participation is completely voluntary and they 
can withdraw from the study at any time point. The research participants will also be notified 
that their decisions to withdraw from the study will not jeopardise their current or subsequent 
treatments and healthcare services received. To ensure the confidentiality of patient 
information, each participant will be assigned an anonymous research ID code that will be used 
for data storage and analysis. The data will solely be made available to the research team 
members and access to the storage may only be granted by the principal investigators. 
To aid the transparency of reporting, the trial will be registered at the Clinical Trials Registry 
(https://clinicaltrials.gov/) and the Malaysian National Medical Research Registry (NMRR) 
(https://nmrr.gov.my/). The full trial protocol will be made available in the same trial registries 
and prepared according to the Consolidated Standards of Reporting Trials (CONSORT) 
guideline for parallel design and the 2013 Standard Protocol Items: Recommendations for 
Interventional Trials (SPIRIT) statement. Any future protocol modifications will be submitted 
first to the JEPUKM for approval and the list of protocol changes will be made available to the 
public via both the Clinical Trials and NMRR registries. 
The trial data with study participant identification numbers removed (Hospital RN, Identity 
Card (IC) numbers, subject’s identification number (SIDNO) will be made available to the 
public via Harvard Dataverse repository for research data (https://dataverse.harvard.edu) to 
ensure the transparent dissemination of study findings and adherence to recommendations 
made by leading medical journal editors for the future publication of this research. 
 
 

29 
 
4.15 Statistical Analysis 
Data analysis will be performed using Statistical Package for Social Science (SPSS™) (IBM 
Corp. Released 2020. IBM Statistics for Windows, Version 27.0, Armonk, NY: IB Corp) and 
STATA™ version 15 (StatCorp. 2017. Stata Statistical Software: Release 15. College Station, 
Texas: StataCorp LP). Our primary analysis will be based on the intention-to-treat (ITT) 
principle by which all trial participants will be analysed according to their original intended 
treatment assignment. For missing observations, we will use the multiple imputation method 
to fill in the missing data, assuming the missing at random (MAR) mechanism. To check the 
robustness of the results, we will also conduct sensitivity analysis by comparing the results 
obtained using complete case analysis (i.e. including patients with complete observations) with 
full case (i.e. patients with complete and imputed observations for missing data) analysis. 
The differences in terms of the outcomes measures between the groups will be statistically 
assessed using an independent t-test if the parametric assumption is met (i.e. the data are 
normally distributed) or the Mann-Whitney test if the data are non-normally distributed.  To 
control and adjust the effects of confounding variables such as baseline pain scores, body mass 
index (BMI), gender of the patients, multiple linear regression analysis will be used. Variable 
selection will be based on a mixture of strategies: 1) stepwise regression based on Akaike 
Information Criterion (AIC), Bayesian Information Criterion (BIC); 2) purposeful selection of 
covariates; 3) clinical domain knowledge.  Effect modification will be assessed by creating and 
assessing the significance of the statistical interaction terms. The goodness of fit of the model 
will be evaluated using the coefficient of multiple determination, R2. 
Model assumptions (linearity, independence, normality, and homoscedasticity of residuals) 
will be assessed using a studentised residual vs predicted values scatter plots and Durbin 
Watson statistics. Box-Cox transformation with carefully selected exponent (lambda) will be 
employed in the presence of skewness in the outcome variables. The presence of influential 
observations will be suspected in the presence of large leverage (extreme value in the x space) 
and residual values (extreme value in the y space) for any outlying observations. This will be 
further confirmed using influential diagnostic measures such as Cook's distance72, dfFITS and 
dfBeta.73 The significance threshold will be set at 0.05 and 95% confidence intervals will be 
presented for each effect estimate. 
 
 
 
 
 
 
 
 
 

30 
 
TRIAL WORKFLOW 
Participant recruitment and screening based on the trial’s 
eligibility criteria from ophthalmology clinic (n =) 
Informed consent from each eligible trial participant 
Study Subjects (n=) 
Participant excluded for not 
meeting eligibility criteria (n=) 
Participant excluded due to: 
Missing data (n=) 
Study withdrawal (n=) 
Serum lignocaine assay 
error (n=) 
Phase I trial 
(n=) 
Blood sampling at t=0,30,60, 
90, 120, 180 minutes. 
Serum lignocaine concentration quantification 
using GC-NPD to be conducted at the 
Malaysian Chemistry Department 
Analysis of pharmacokinetic parameters (AUC0-, 
Cmax, Tmax,T1/2, Vd, Clearance) using NONMEM 
Final number of participants 
included for data analysis (n=) 
Briefing of participants, Baseline assessment for 
VAS score and skin algesimeter index 
Lignocaine-embedded 
MN application and 
wait for 30 minutes 
(window period) 
Venepuncture procedure. Then, post-intervention VAS score 
and skin algesimeter index assessments. 
Publication of trial results and end of project report submission to JEPEM, UKM 
Final number of 
participants included for 
data analysis (n=) 
Statistical analysis using SPSS 
Figure 1: Anticipated trial workflow based on the 2010 CONSORT statement flowchart 
Participant excluded for not 
consenting to trial participation (n=) 
5% EMLA patch 
(n=) 
Lignocaine-
embedded MN patch 
(n=) 
5% EMLA dermal 
patch application and 
wait for 30 minutes 
(window period) 
Final number of 
participants included for 
data analysis (n=) 
Phase II trial 
(n=) 

31 
 
GANTT CHART 
 
Project activities 
Timeline 
2022 
2023 
2024 
11 12 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Research 
application for 
ethics approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial subject 
recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum assays for 
lignocaine levels 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analyses and 
interpretation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data presentation, 
Manuscript 
preparation, Final 
project report, 
and Publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of project 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

32 
 
BUDGET 
No. 
Description 
Unit price (RM) 
Quantity 
Price (RM) 
1 
PROFESSIONAL SERVICE 
  
 
  
1.1 
Lignocaine quantitation assay with GC-NPD 
125 sample 
120 
15000  00 
 
 
 
 
Total 
  
 
15000  
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

33 
 
REFERENCES  
1. 
Alkilani AZ, McCrudden MT, Donnelly RF. Transdermal Drug Delivery: Innovative 
Pharmaceutical Developments Based on Disruption of the Barrier Properties of the 
stratum corneum. Pharmaceutics. 2015;7(4):438-70. doi: 10.3390/pharmaceutics7040 
438.  
2. 
Jeong WY, Kwon M, Choi HE, Kim KS. Recent advances in transdermal drug delivery 
systems: a review. Biomater Res. 2021;25(1):24. doi: 10.1186/s40824-021-00226-6.  
3. 
Lee BM, Lee C, Lahiji SF, Jung UW, Chung G, Jung H. Dissolving Microneedles for 
Rapid and Painless Local Anesthesia. Pharmaceutics. 2020;12(4):366. doi: 
10.3390/pharmaceutics12040366. 
4. 
Murthy SN, Sammeta SM, Bowers C. Magnetophoresis for enhancing transdermal drug 
delivery: Mechanistic studies and patch design. J Control Release. 2010;148(2):197-
203. doi: 10.1016/j.jconrel.2010.08.015.  
5. 
Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a low-dose lidocaine 
iontophoresis system for topical anesthesia in adults and children: a randomized, 
controlled trial. Clin Ther. 2004;26(7):1110-9. doi: 10.1016/s0149-2918(04)90183-x.  
6. 
Kim TY, Jung DI, Kim YI, Yang JH, Shin SC. Anesthetic effects of lidocaine 
hydrochloride gel using low frequency ultrasound of 0.5 MHz. J Pharm Pharm Sci. 
2007;10(1):1-8. 
7. 
Benson HAE, Grice JE, Mohammed Y, Namjoshi S, Roberts MS. Topical and 
Transdermal Drug Delivery: From Simple Potions to Smart Technologies. Curr Drug 
Deliv. 2019;16(5):444-460. doi: 10.2174/1567201816666190201143457. 
8. 
Yousef H, Alhajj M, Sharma S. Anatomy, Skin (Integument), Epidermis. [Updated 2021 
Nov 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-
. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470464/ 
9. 
Ali S, Shabbir M, Shahid N. The structure of skin and transdermal drug delivery system 
- A review. Research Journal of Pharmacy and Technology. 2015; 8(2):103-109. doi: 
0.5958/0974-360X.2015.00019.0 
10. 
Duarah S, Sharma M, Wen J. Recent advances in microneedle-based drug delivery: 
Special emphasis on its use in paediatric population. Eur J Pharm Biopharm. 
2019;136:48-69. doi: 10.1016/j.ejpb.2019.01.005.  
11. 
Liu X, Kruger P, Maibach H, Colditz PB, Roberts MS. Using skin for drug delivery and 
diagnosis in the critically ill. Adv Drug Deliv Rev. 2014 ;77:40-9. doi: 
10.1016/j.addr.2014.10.004.  
12. 
Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery 
systems: current and future prospects. Drug Deliv. 2006;13(3):175-87. doi: 
10.1080/10717540500455975. 
13. 
Andrews SN, Jeong E, Prausnitz MR. Transdermal delivery of molecules is limited by 
full epidermis, not just stratum corneum. Pharm Res. 2013;30(4):1099-109. doi: 
10.1007/s11095-012-0946-7.  
14. 
Ita K. Transdermal Delivery of Drugs with Microneedles-Potential and Challenges. 
Pharmaceutics. 2015;7(3):90-105. doi: 10.3390/pharmaceutics7030090.  

34 
 
15. 
Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, Dua K. 
Microneedles: A smart approach and increasing potential for transdermal drug delivery 
system. Biomed Pharmacother. 2019;109:1249-1258. doi: 10.1016/j.biopha.2018.10. 
078.  
16. 
Li J, Zeng M, Shan H, Tong C. Microneedle Patches as Drug and Vaccine Delivery 
Platform. Curr Med Chem. 2017;24(22):2413-2422. doi: 10.2174/092986732466617 
0526124053.  
17. 
Xu J, Xu D, Xuan X, He H. Advances of Microneedles in Biomedical Applications. 
Molecules. 2021;26(19):5912. doi: 10.3390/molecules26195912.  
18. 
Zhang Y, Jiang G, Yu W, Liu D, Xu B. Microneedles fabricated from alginate and 
maltose for transdermal delivery of insulin on diabetic rats. Mater Sci Eng C Mater Biol 
Appl. 2018;85:18-26. doi: 10.1016/j.msec.2017.12.006.   
19. 
Larrañeta E, Lutton REM, Woolfson  AD, Donnelly RF. Microneedle arrays as 
transdermal and intradermal drug delivery systems: Materials science, manufacture and 
commercial development. Materials Science and Engineering R: Reports. 2016;104:1-
32.  https://doi.org/10.1016/j.mser.2016.03.001. 
20. 
Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for 
transdermal delivery. Pharm Res. 2008;25(1):104-13. doi: 10.1007/s11095-007-9350-0.  
21. 
Sartawi Z, Blackshields C, Faisal W. Dissolving microneedles: Applications and 
growing 
therapeutic 
potential. 
J 
Control 
Release. 
2022;348:186-205. 
doi: 
10.1016/j.jconrel.2022.05.045. 
22. 
Rzhevskiy A, Popov A, Pavlov C, Anissimov Y, Zvyagin A, Levin Y, Kochba E. 
Intradermal injection of lidocaine with a microneedle device to provide rapid local 
anaesthesia for peripheral intravenous cannulation: A randomised open-label placebo-
controlled 
clinical 
trial. 
PLoS 
One. 
2022;17(1):e0261641. 
doi: 
10.1371/journal.pone.0261641.  
23. 
Ornelas J, Foolad N, Shi V, Burney W, Sivamani RK. Effect of Microneedle 
Pretreatment on Topical Anesthesia: A Randomized Clinical Trial. JAMA Dermatol. 
2016;152(4):476-7. doi: 10.1001/jamadermatol.2015.5544.  
24. 
Gupta J, Denson DD, Felner EI, Prausnitz MR. Rapid local anesthesia in humans using 
minimally 
invasive 
microneedles. 
Clin 
J 
Pain. 
2012;28(2):129-35. 
doi: 
10.1097/AJP.0b013e318225dbe9.  
25. 
Lidocaine Hydrochloride and Epinephrine Injection USP [Package Insert]. Quebec, 
Canada: Pfizer Canada ULC; 2006. 
26. 
Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ 
currents by local anesthetics in the dorsal horn neurons of the spinal cord. 
Anesthesiology. 1998;88(1):172-9. doi: 10.1097/00000542-199801000-00025. 
27. 
Edwards DJ, Lalka D, Cerra F, Slaughter RL. Alpha1-acid glycoprotein concentration 
and protein binding in trauma. Clin Pharmacol Ther. 1982;31(1):62-7. doi: 
10.1038/clpt.1982.10. 
 
 

35 
 
28. 
Tesseromatis C, Kotsiou A, Tsagataki M, Tigka E, Vovou J, Alevizou A, Perisanidis C, 
Saranteas T, Karakitsos D, Karabinis A, Kostopanagiotou G. In vitro binding of 
lidocaine to liver tissue under the influence of propranolol: another mechanism of 
interaction? 
Eur 
J 
Drug 
Metab 
Pharmacokinet. 
2007;32(4):213-7. 
doi: 
10.1007/BF03191006. 
29. 
Routledge PA, Stargel WW, Wagner GS, Shand DG. Increased alpha-1-acid 
glycoprotein and lidocaine disposition in myocardial infarction. Ann Intern Med. 
1980;93(5):701-4. doi: 10.7326/0003-4819-93-5-701.  
30. 
Barry M, Keeling PW, Weir D, Feely J. Severity of cirrhosis and the relationship of 
alpha 1-acid glycoprotein concentration to plasma protein binding of lidocaine. Clin 
Pharmacol Ther. 1990;47(3):366-70. doi: 10.1038/clpt.1990.41.  
31.  
McNamara PJ, Slaughter RL, Visco JP, Elwood CM, Siegel JH, Lalka D. Effect of 
smoking on binding of lidocaine to human serum proteins. J Pharm Sci. 1980;69(6):749-
51. doi: 10.1002/jps.2600690646.  
32.  
Lerman J, Strong HA, LeDez KM, Swartz J, Rieder MJ, Burrows FA. Effects of age on 
the serum concentration of alpha 1-acid glycoprotein and the binding of lidocaine in 
pediatric 
patients. 
Clin 
Pharmacol 
Ther. 
1989;46(2):219-25. 
doi: 
10.1038/clpt.1989.129. 
33. 
Routledge PA, Shand DG, Barchowsky A, Wagner G, Stargel WW. Relationship 
between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction. 
Clin Pharmacol Ther. 1981;30(2):154-7. doi: 10.1038/clpt.1981.141. 
34. 
Burm AG, de Boer AG, van Kleef JW, Vermeulen NP, de Leede LG, Spierdijk J, 
Breimer DD. Pharmacokinetics of lidocaine and bupivacaine and stable isotope labelled 
analogues: a study in healthy volunteers. Biopharm Drug Dispos. 1988;9(1):85-95. doi: 
10.1002/bod.2510090109.  
35.  
Thomson PD, Melmon KL, Richardson JA, Cohn K, Steinbrunn W, Cudihee R, 
Rowland M. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and 
renal failure in humans. Ann Intern Med. 1973;78(4):499-508. doi: 10.7326/0003-4819-
78-4-499. 
36. 
Huet PM, Lelorier J, Pomier G, Marleau D. Bioavailability of lidocaine in normal 
volunteers and cirrhotic patients. Clin Pharmacol Ther. 1979;25(2):229-30. 
37. 
Bauer LA, Horn JR, Maxon MS, Easterling TR, Shen DD, Strandness DE Jr. Effect of 
metoprolol and verapamil administered separately and concurrently after single doses 
on liver blood flow and drug disposition. J Clin Pharmacol. 2000;40(5):533-43. doi: 
10.1177/00912700022009152.  
38.  
Prescott LF, Adjepon-Yamoah KK, Talbot RG. Impaired Lignocaine metabolism in 
patients with myocardial infarction and cardiac failure. Br Med J. 1976;1(6015):939-41. 
doi: 10.1136/bmj.1.6015.939. 
39. 
Wang JS, Backman JT, Taavitsainen P, Neuvonen PJ, Kivistö KT. Involvement of 
CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. 
Drug Metab Dispos. 2000;28(8):959-65.  
 
 

36 
 
40.  
Huang W, Lin YS, McConn DJ 2nd, Calamia JC, Totah RA, Isoherranen N, Glodowski 
M, Thummel KE. Evidence of significant contribution from CYP3A5 to hepatic drug 
metabolism. Drug Metab Dispos. 2004;32(12):1434-45. doi: 10.1124/dmd.104.001313. 
41. 
Ha HR, Candinas R, Stieger B, Meyer UA, Follath F. Interaction between amiodarone 
and lidocaine. J Cardiovasc Pharmacol. 1996;28(4):533-9. doi: 10.1097/00005344-
199610000-00009.  
42.  
Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of fluvoxamine and erythromycin on 
the pharmacokinetics of oral lidocaine. Basic Clin Pharmacol Toxicol. 2006;99(2):168-
72. doi: 10.1111/j.1742-7843.2006.pto_482.x.   
43.  
Olkkola KT, Isohanni MH, Hamunen K, Neuvonen PJ. The effect of erythromycin and 
fluvoxamine on the pharmacokinetics of intravenous lidocaine. Anesth Analg. 
2005;100(5):1352-1356. doi: 10.1213/01.ANE.0000148123.79437.F9 
44. 
Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P. Cytochrome P450 
1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. 
Clin Pharmacol Ther. 2004;75(1):80-8. doi: 10.1016/j.clpt.2003.09.007. 
45. 
Narang PK, Crouthamel WG, Carliner NH, Fisher ML. Lidocaine and its active 
metabolites. Clin Pharmacol Ther. 1978;24(6):654-62. doi: 10.1002/cpt1978246654. 
46. 
Thomson AH, Elliott HL, Kelman AW, Meredith PA, Whiting B. The pharmacokinetics 
and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet 
Biopharm. 1987;15(2):101-15. doi: 10.1007/BF01062338.  
47.   Strong JM, Mayfield DE, Atkinson AJ Jr, Burris BC, Raymon F, Webster LT Jr. 
Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide. Clin 
Pharmacol Ther. 1975;17(2):184-94. doi: 10.1002/cpt1975172184. 
48 
Wójcicki J, Kozłowski K, Droździk M, Wójcicki M. Lidocaine elimination in patients 
with liver cirrhosis. Acta Pol Pharm. 2002;59(4):321-4. 
49. 
Rademaker AW, Kellen J, Tam YK, Wyse DG. Character of adverse effects of 
prophylactic lidocaine in the coronary care unit. Clin Pharmacol Ther. 1986;40(1):71-
80. doi: 10.1038/clpt.1986.141. 
50. 
Weinberg L, Peake B, Tan C, Nikfarjam M. Pharmacokinetics and Pharmacodynamics 
of Lignocaine: A Review. World Journal of Anesthesiology. 2015;4(2):17-29. doi: 
0.5313/wja.v4.i2.17. 
51. 
Kirkland DJ, Sheil ML, Streicker MA, Johnson GE. A weight of evidence assessment 
of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to 
safety of lidocaine exposure. Regul Toxicol Pharmacol. 2021;119:104838. doi: 
10.1016/j.yrtph.2020.104838. 
52. 
Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of 
postherpetic neuralgia. Drugs. 2004;64(9):937-47. doi: 10.2165/00003495-200464090-
00002.  
53. 
Gimbel J, Linn R, Hale M, Nicholson B. Lidocaine patch treatment in patients with low 
back pain: results of an open-label, nonrandomized pilot study. American Journal of 
Therapeutics. 2005;12(4):311-9. doi: 10.1097/01.mjt.0000164828.57392.ba.  
 
 

37 
 
54. 
Sun Y, Li T, Wang N, Yun Y, Gan TJ. Perioperative systemic lidocaine for postoperative 
analgesia and recovery after abdominal surgery: a meta-analysis of randomized 
controlled 
trials. 
Dis 
Colon 
Rectum. 
2012;55(11):1183-94. 
doi: 
10.1097/DCR.0b013e318259bcd8. Erratum in: Dis Colon Rectum. 2013;52(2):271.  
55.  
Zink KA, Mayberry JC, Peck EG, Schreiber MA. Lidocaine patches reduce pain in 
trauma 
patients 
with 
rib 
fractures. 
Am 
Surg. 
2011;77(4):438-42. 
doi: 
10.1177/000313481107700419.  
56.  
Kim CH, Yoon JU, Lee HJ, Shin SW, Yoon JY, Byeon GJ. Availability of a 5% 
lidocaine patch used prophylactically for venipuncture- or injection-related pain in 
children. J Anesth. 2012;26(4):552-5. doi: 10.1007/s00540-012-1360-3. 
57. 
Bai Y, Miller T, Tan M, Law LS, Gan TJ. Lidocaine patch for acute pain management: 
a meta-analysis of prospective controlled trials. Curr Med Res Opin. 2015 
Mar;31(3):575-81. doi: 10.1185/03007995.2014.973484. 
58. 
Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and 
experimental findings. Br J Anaesth. 2013 Jul;111(1):52-8. doi: 10.1093/bja/aet127. 
59. 
Ogungbenro K, Aarons L. How many subjects are necessary for population 
pharmacokinetic experiments? Confidence interval approach. Eur J Clin Pharmacol. 
2008;64(7):705-13. doi: 10.1007/s00228-008-0493-7.  
  
60. 
Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical 
Statistics: The Journal of Applied Statistics in the Pharmaceutical Industry. 
2005;4(4):287-91.  
61. 
Yamamoto LG, Boychuk RB. A blinded, randomized, paired, placebo-controlled trial 
of 20-minute EMLA cream to reduce the pain of peripheral i.v. cannulation in the ED. 
Am J Emerg Med. 1998 Nov;16(7):634-6. doi: 10.1016/s0735-6757(98)90163-2.  
62. 
Winek CL, Wahba WW, Winek CL Jr, Balzer TW. Drug and chemical blood-level data 
2001. Forensic Sci Int. 2001;122(2-3):107-23. doi: 10.1016/s0379-0738(01)00483-2.  
63. 
Rowland,\ M, Tozer TN. Clinical pharmacokinetics and pharmacodynamics: Concepts 
and Applications. 4th edition. Philadelphia: Lippincott Williams and Wilkins; 2011. 
64. 
Greg Snow. blockrand: Randomization for Block Random Clinical Trials. R Package 
version 1.5. 2022. https://CRAN.R-project.org/package=blockrand 
65. 
James KE, Bloch DA, Lee KK, Kraemer HC, Fuller RK. An index for assessing 
blindness in a multi-centre clinical trial: disulfiram for alcohol cessation--a VA 
cooperative study. Stat Med. 1996 Jul 15;15(13):1421-34.  
66. 
Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 
2004 Apr;25(2):143-56. doi: 10.1016/j.cct.2003.10.016. PMID: 15020033. 
67. 
Aronson JK. Medication errors: what they are, how they happen, and how to avoid them. 
QJM. 2009;102(8):513-21. doi: 10.1093/qjmed/hcp052.  
68. 
Code of Federal Regulation, Title 21, Section 312.32 (21CFR312.32). (2020). 
Accessible from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch. 
cfm?fr=312.32. Date of access: 05 / 06 / 2022. 
 
 

38 
 
69. 
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq 
C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. 
Clin Pharmacol Ther. 1981;30(2):239-45. doi: 10.1038/clpt.1981.154.  
70. 
Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden 
associated with overweight and obesity. JAMA. 1999;282(16):1523-9. doi: 
10.1001/jama.282.16.1523.  
71. 
Obesity: preventing and managing the global epidemic. Report of a WHO consultation. 
World Health Organ Tech Rep Ser. 2000;894:i-xii, 1-253.  
72. 
Cook RD. Detection of Influential Observation in Linear Regression. Technometrics. 
1997;19(1):15–18. https://doi.org/10.2307/1268249 
73.  
Belsley DA, Kuh E, Welsch RE. Regression diagnostics: Identifying influential data and 
sources of collinearity. New York: Wiley; 1980. 
74. 
Muhammad Irfan Abdul Jalal , Kai Shen Ooi , Kai Cheong Foo et al. Transdermal 
Maltose-Based Microneedle Patch as Adjunct to Enhance Topical Anesthetic before 
Intravenous Cannulation of Pediatric Thalassemic Patients Receiving Blood 
Transfusion: A Randomized Controlled Trial Protocol J Clin Med 2022 Sep 
8;11(18):5291. doi: 10.3390/jcm11185291. 
75.     EMLA Cream 5% (5g pack). Summary of product characteristics. 
https://www.medicines.org.uk/emc/product/871/smpc/print 
 
 
 
 
 
 

39 
 

40 
 
APPENDIX A: PATIENT INFORMATION SHEET AND CONSENT FORM 
(ENGLISH VERSION) 
 
PATIENT INFORMATION SHEET 
 
Research Title: Transdermal microneedle lignocaine delivery versus EMLA patch for topical 
analgesia before venepuncture procedure to adults in a clinic setting 
 
 
Introduction:  
 
You are invited to participate in a clinical research study. Before participating in this study, it 
is crucial that you read thoroughly and understand the information provided in this sheet, 
whereby the study will be verbally explained to you, and you will be allowed to ask questions. 
After you are adequately satisfied that you understand this study and you wish to take part 
or continue to participate in this study, you must sign this informed consent form. You will be 
given a copy of these patient information sheet and consent forms to take home with you. 
 
Purpose of Study: 
Vein-puncturing procedures elicits much pain and is regarded as the most frequently 
traumatic experience encountered among patients in the regular practice of the health care 
settings. Such pain may be reduced by applying topical anaesthetic drugs. For example, 
lignocaine cream is a non-invasive and convenient approach of administering anaesthesia to 
the body skin surface. The usual recommended duration of time taken for lignocaine cream 
to work is around 30 minutes. However, in a busy clinical setting, the time is often shortened 
to 15 minutes for a slight anaesthetic effect. As such, a transdermal drug delivery system 
(TDDS), the microneedle, has been introduced as an alternative to enhance the delivery of 
topical anaesthesia by puncturing the skin at a very superficial level to create multiple tiny 
tracts for faster action of anaesthetic drug absorption. The microneedle patch is a prototype 
device that is still being tested and not registered. It contains multiple micron-sized needles 
made of sugar (maltose) that will dissolve into the skin and subsequently achieve the 
objective of delivering the anaesthetic drugs. As such, our current research study aims to 
determine the safety and tolerability of lignocaine-embedded microneedle patch for patients 
requiring frequent venepuncture. Besides, this research also aims to obtain preliminary 
information on the efficacy of lignocaine-embedded microneedle in reducing pain associated 
with venepuncture. 
 
What will the study involve? 
For this research, you will be participating in either one of the following components of the 
trial: i) blood levels of lignocaine over 3hours or ii) lignocaine-microneedle versus EMLA patch. 
It is emphasised that you do not get to choose which group you will be in if you agree to 
participate. We use a selection system that the project investigators are abiding to. 
 
 
 
 

41 
 
i) Blood level of drug study over 3 hours 
In this study, you are will undergo a venepuncture for blood collection during an outpatient 
visit at the Ophthalmology Clinic, HCTM. A medical doctor will perform an intravenous 
cannulation on the back of your right hands (dorsal side) that is intended for blood collection. 
Subsequently, you will be receiving a topical anaesthetic administration via lignocaine-
embedded microneedle which will be applied on the skin surface of the back of your left hand. 
This will result in the numbness to that particular region of the hand. A small amount of blood 
(about 3 mLs each time) samples will then be collected from the cannula at six time points 
(time, t= 0, 30, 60, 90, 120, and 180 minutes) which will be sent to the laboratory for 
determining the level of lignocaine in your blood. In total, you are expected to be at the clinic 
for 3 hours, which is the average time taken for a normal visit to the eye clinic. 
 
ii) Lignocaine-microneedle versus EMLA patch  
 
If you are selected as a participant of this part of the research, you will first undergo a routine 
clinical examination on the trial day. You may be chosen to rate your baseline pain score using 
a ruler-styled scoring system (VAS) and a pain monitoring device. The lignocaine-embedded 
microneedle or EMLA patch, depending on which group you will be allotted to, will be 
introduced on the identified surface of the back of your hand. After 30 minutes, venepuncture 
will be performed by a trained medical officer.  You will be then asked to evaluate the degree 
of your pain using the VAS score. You will also have a pain monitoring device attached to your 
palm for measurement purposes. You will then be monitored for one hour following the 
procedure to identify whether you experience any adverse effects associated with the 
lignocaine-microneedle application. 
 
Risks: 
This investigation possesses minimal risk to participants and is unlikely to cause side effects. 
Although topical skin anaesthetics are applied, you may still feel some pain from the needle/s, 
although this will be much reduced. Topical lignocaine is a widely used drug and little adverse 
reactions have been reported. Nevertheless, the possible side effects reported from the 
lignocaine application include: 
 
• pallor 
• redness 
• alterations in temperature sensation over the application area 
 
With regards to EMLA patch, special precautions are advised in G6PD deficient individuals 
who may be at increased risk for developing symptoms as a result of methaemoglobin rise in 
blood causing temporarily a bluish tinge to the skin and decreased oxygen in the blood. If you 
are G6PD deficient, please inform us about this condition prior to the study. 
Additional risks associated with microneedle application might include possible mild-to-
moderate irritation, especially in those with sensitive skin, such as 
 
• redness 
• swelling 
• itching 
• blistering 

42 
 
Adverse side-effects reporting is part of the outcomes of this study, but If you encounter any 
problems or side effects experienced during the study, we will be giving you medications to 
reduce the side effects accordingly.  
 
Benefits: 
The information collected from this clinical study may contribute to the advancement of 
medical knowledge on the safety and efficacy of dissolving microneedle in delivering local 
anaesthetic agents, which will benefit patients in the future. 
 
Do you have to take part? 
Your participation in this study is absolute voluntarily. Your medical care will not be affected 
if you decide not to participate in this study. You will still have the usual standard of care 
according to the day-care protocol. 
 
If you agree to participate, you will be asked to sign the “Informed Consent Form”. You will 
be given a copy of the informed consent form and this patient information sheet. Should you 
decide to participate, you cannot decide which group you will be assigned to, but you are still 
free to withdraw from the study at any time without giving a reason or penalty. If you decide 
to cease from participating in this study, you must inform your study investigator and no new 
data will be further collected from you. The researcher may also remove your participation 
from the study for various reasons. In this event, you will not lose your rights as a patient and 
will still receive the usual standard of care.    
 
Data & Confidentiality: 
Participant’s confidentiality will be maintained throughout the investigation. Your personal 
data well be anonymized as your identity be always kept confidential. Data collected and 
entered into the Case Report Form will remain as the governed property of UKM. In the event 
of any publication generated from this study, your identity will be remained confidential to 
the public. 
 
By signing the Informed Consent Form attached, you (or your legally acceptable 
representative, if relevant) are authorizing such access to your study records. 
 
Payment and compensation: 
You do not have to pay, nor will you be paid to participate in this study. You do have to pay 
for the usual hospital charges. 
 
 
 

43 
 
Whom can I ask about the study? 
If you have any questions about this study or your rights, please contact: 
 
Principal Investigator: 
Prof. Dr Cheah Fook Choe 
 
 
 
 
Department of Paediatrics 
 
 
 
 
UKM Medical Centre 
 
 
 
 
Phone Number : 03-9145 5391  
 
Co-investigator 
 
Prof Dr Mae-Lyn Catherine Bastion 
 
 
 
 
Department of Ophthalmology 
 
 
 
 
UKM Medical Centre 
 
 
 
 
Phone Number: 03-9145 5983 
 
 
 
 
 
Dr Lam Chenshen 
Department of Ophthalmology 
 
 
 
 
UKM Medical Centre  
 
 
 
No. Telefon: 03-8921 6520 
 
Signatures 
To be selected into this study, you must sign and date the signature page [ATTACHMENT A] 

44 
 
ATTACHMENT A 
 
Patient/Subject Information and Consent Form 
(Signature Page) 
 
Research Title: Transdermal microneedle lignocaine delivery versus EMLA patch for topical analgesia before 
venepuncture procedure to adults in a clinic setting 
 
 
Researcher's Name: Prof. Dr Cheah Fook Choe, Prof. Dr Mae-Lyn Catherine Bastion, Dr Lam Chen Shen 
 
To become a part of this study, you must sign this page. By signing this page, I am confirming the following: 
• 
I have read and understand all the information in this Patient Information Sheet and Consent Form, including 
any information  regarding the risk stated in this study and I, have given sufficient time to consider about this 
study. 
• 
All of my questions have been answered to my satisfaction. 
• 
Hereby, 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 any time. 
• 
I have received a copy of this Patient Information Sheet and Consent Form to keep for myself. 
 
 
 
 
Patient Name (Print or type) 
     Patient Initials and Number 
 
 
 
Patient I.C No. (New) 
 
 
 
Signature of Patient 
              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

45 
 
 APPENDIX C: CASE REPORT FORM (CRF) 
 
CASE REPORT FORM 
 
Research title: Transdermal microneedle lignocaine delivery versus EMLA patch for topical analgesia before  
  venepuncture procedure to adults in a clinic setting 
 
Research Investigators: Professors Dr Cheah Fook Choe, Mae-Lynn Catherine Bastion, Dr Lam CS. 
 
 
 
Kod Rawak: 
Randomisation code 
 
A. MAKLUMAT SUBJEK 
SUBJECT’S DETAIL 
 
Nama Subjek : 
 
Subject’s name 
 
 
Usia / Age 
: 
 
tahun / years ________ bulan / months 
 
No. Pend / RN  : 
 
 
No. telefon 
: 
Telefon bimbit  : 
Handphone  
 
 
 
Telephone no. 
 
 
 
 
 
 
 
 
 
Telefon rumah   : 
Home 
 
 
 
 
 
 
 
 
 
 
Tarikh lahir 
: 
 
/  
/  
Date of birth 
 
 
 
 
 
 
 
 
 
 
 
Tarikh keizinan: 
 
/  
/  
Date of consent 
 
 
 
 
 
 
 
Jantina   : 
 
Lelaki 
 
Perempuan 
Gender 
 
Male 
 
Female 
 
 
Kaum : 
 
 
Melayu 
 
Cina 
 
 
India 
Ethnicity 
 
Malay 
 
Chinese 
 
Indian 
 
 
Lain-lain, silanyatakan: 
 
Sticker Pesakit 
ID Subjek: 
 
 
 
 
 
 
Tarikh: 
 
 
/  
 
/  
 
Subject ID 
 
Date 
Hari 
Day 
Bulan 
Month 
Tahun 
Year 

46 
 
Others, please specify 
 
B. SEJARAH PENYAKIT KELUARGA 
FAMILY HISTORY OF ILLNESS 
 
Adakah sesiapa ahli keluarga yang dijangkit penyakit yang ketara dalam sejarah penyakit mereka: 
Has any of the family members having any significant disease in their history of illness. 
 
Darjahpertama 
 
Ya 
Tidak 
First degree 
 
 
 
 
 
 
 
Bapa 
 
 
Father 
 
 
 
 
 
 
Ibu 
 
 
 
Mother 
 
 
 
 
 
 
Adik-beradik  
 
 
Siblings 
 
 
 
 
 
 
 
Lain-lain:  
Others 
 
 
 
 
 
Jika Ya, sila nyatakan jenis penyakit yang terlibat dan umur ketika 
diagnosis:  
If Yes, please specify the types of diseases and age at diagnosis: 
 
 
 
 
 

47 
 
C. KAJIAN SEJARAH PERUBATAN / PENGAMBILAN UBAT BERKAITAN 
REVIEW OF MEDICAL HISTORY / MEDICATIONS CHECKLIST 
 
Sejarah perubatan yang berkaitan: 
Relevant medical history 
 
Kencing Manis 
 
: 
 
Diabetes 
 
Darah Tinggi 
 
: 
 
Hypertension 
 
Penyakit Buah Pinggang : 
 
Kidney disease 
 
Penyakit Autoimun 
: 
 
Autoimmune disease 
 
Penyakit Hati 
 
: 
 
Hepatic diseases 
 
Lain-lain  
 
: 
Others 
 
 
 
Pengambilan ubat berkaitan (sila nyatakan nama ubat, tujuan perubatan, dos dan cara pengambilan) 
Medications (please specify the name, indications, dosage and administration frequency) 
 
Nama 
Tujuan 
Dos 
Cara pengambilan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Senarai semak ubat-ubat 
Medication checklist 
Erythromycin 
 
Ciprofloxacin 
 
Amiodarone 
 
Beta-adrenergic blockers 
(timolol eyedrops, metoprolol etc) 
 
 
 
 

48 
 
 
Adakah pesakit pernah mengalami alahan/ kesan sampingan yang teruk daripada mana-mana ubat? 
Has subject ever experienced any allergy or adverse event from any medications? 
 
 
Ya *  
 
 
Tidak  
 
 
Yes 
 
 
 
No 
 
*Jika ‘Ya’, sila nyatakan jenis ubat yang terlibat: 
If yes, please specify the type of medication 
 
 
Sila nyatakan jenis diagnosis MATA dan pembedahan MATA yang dirancangkan: 
Please specify the type of ocular diagnosis and the planned operation  
 
Diagnosis: 
 
Tarikh: 
 
  
Mata 
 
Pembedahan / Surgery: 
 
Phacoemulsification: 
 
Kiri 
         Kanan 
 
 
 
 
 
 
 
ECCE: 
 
 
 
Trabeculectomy: 
 
 
 
Glaucoma drainage device: 
 
 
 
Pars plana vitrectomy: 
 
 
 
Corneal transplant: 
 
 
 
Lain-lain/ Others: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

49 
 
D. DATA KLINIKAL 
CLINICAL DATA 
 
Pengukuran antropometri: 
Anthropometric measurement 
 
1. Berat  
: 
kg 
 
Weight 
 
2. Tinggi  
: 
cm 
 
Height 
 
3. Indeks Jisim Tubuh (BMI) 
: 
kg/𝑚2 
 
Body mass index 
 
Tanda-tanda vital 
Vital signs 
       Untuk kegunaan jika diperlukan 
                To be applied if needed 
Unit 
Unit 
  Lawatan klinik 
Clinic visit 
    PK Study 
 
 
    Tarikh/ Date: 
     __ / __ / __ 
Tarikh/Date: 
__ / __ / __ 
Blood Sample (Y/N) 
Volume (mL) 
Tekanan Sistolik 
Systolic pressure 
mmHg 
 Time: 0 min 
Tekanan Diastolik 
Diastolic pressure 
mmHg 
 Time: 30 mins 
Nadi 
Heart rate 
bpm 
 Time: 60 mins 
Paras gula 
Dextrostix 
mmol/L 
 Time: 90 mins 
Skala kesakitan 
(VAS) 
Pain scale (VAS) 
 Time: 120 mins 
Skala Kesakitan 
(Pain Monitor) 
Pain score 
(Pain Monitor) 
 
 
 Time: 180 mins 
  Samples sent to  
  Jabatan Kimia 
 Date: 
   
 Time: 
 Tandatangan dan nama ringkas  
 pemeriksa 
Initials and name of examiner 
 
 

50 
 
LOG PENJEJEKAN KESAN SAMPINGAN / ADVERSE EFFECTS TRACKING LOG 
 
No. 
Date 
reported 
Adverse event 
description 
Start 
date 
End 
date 
Ongoing 
(Yes or No) 
Outcome1 
Severity 
/ grade2 
Serious 
(Yes or No) 
AE 
treatment3 
Expected 
(Yes or No) 
Intervention 
Attribution / 
Relatedness4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scales: 
Outcome1 
Severity / grade2 
AE treatment3 
Intervention Attribution / 
Relatedness4 
0- Fatal 
1- Not recovered / Not resolved 
2- Recovered w/sequelae 
3- Recovered w/o sequelae 
4- Recovering / Resolving 
0- Mild 
1- Moderate 
2- Severe 
3- Life-threatening 
4- Death / Fatal 
0- None 
1- Medication(s) 
2- Medication TX 
0- Definite 
1- Probable 
2- Possible 
3- Unrelated 
4- Not applicable 
(did not receive intervention) 
 
Verified by (Prior to data entry): 
 
Signature: 
 
Name: 
Date: