Patient-Controlled Analgesia (PCA) With Ketamine-Morphine (PCA KetaMorph) vs PCA Morphine for Postoperative Analgesia in Idiopathic Scoliosis Surgery - A Randomized Controlled Trial
Phase: NA
Conditions: Adolescent Idiopathic Scoliosis (AIS)
Sponsor: University of Malaya

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TEMPLATE FOR RESEARCH PROPOSAL 
Faculty of Medicine, Universiti Malaya 
_____________________________________________________________________ 
a) Project Title 
Patient-Controlled Analgesia (PCA) with Ketamine–Morphine (PCA KetaMorph) vs PCA 
Morphine for Postoperative Analgesia in Idiopathic Scoliosis Surgery – A Randomized 
Controlled Trial (PCA KetaMorph trial)   
 
b) Team Composition 
Principal Investigator: Siti Nadzrah Binti Yunus, Senior Lecturer (Dr.), Anaesthesiology 
 
Co-Researchers: Name, Designation, Department 
1. Mohd Shahnaz Bin Hasan, Consultant Anaesthesiologist (Professor), Anaesthesiology 
2. Muhammad Faeez bin Mohd Yusoh, Medical Officer (Dr.), Anaesthesiology 
3. Nur Ainina Binti Zulkeplee, Lecturer (Dr.), Anaesthesiology 
4. 
5. 
 
c) Executive Summary (less than 300 words) 
Tip: Executive summary should be written succinctly in paragraphs format. It should include 
information regarding the problem statement, objectives, research methodology, expected 
output/outcomes, and significance/impact of research output 
Posterior spinal fusion (PSF) is the definitive surgical treatment for patients with 
scoliosis. However, the procedure involves extensive tissue dissection, resulting in 
significant postoperative pain. Although patient-controlled analgesia (PCA) with 
intravenous morphine remains the current standard, the large doses required are frequently 
associated with side effects such as nausea, vomiting, pruritus, and sedation [4-6]. These 
complications delay mobilisation, prolong hospital stay, increase healthcare costs, and may 
contribute to opioid tolerance, undermining effective pain control.  
Enhanced Recovery After Surgery (ERAS) protocols strongly promote multimodal 
analgesia, which combines opioid and non-opioid agents to achieve synergistic pain relief 
while minimising opioid exposure. This strategy has been shown to reduce side effects, 
improve recovery, shorten hospital stay, and lower the risk of opioid-related tolerance, 
hyperalgesia, and potential long-term dependence. Despite these advantages, evidence 
for the use of ketamine–morphine PCA in scoliosis surgery remains limited, and 
subanaesthetic ketamine—though effective intraoperatively as an opioid-sparing agent—
remains underutilised in postoperative PCA regimens. Our previous study demonstrated 
that co-administration of subanaesthetic ketamine (0.5 mg/kg) at induction reduced 
postoperative pain sensitivity and hyperalgesia typically associated with high-dose 
remifentanil infusion, a strong opioid analgesic [13]. This finding underscores the potential 
role of ketamine as an opioid-sparing adjunct.  
Building on this, we propose a single-centre, double-blind, randomised controlled 
trial in 114 idiopathic scoliosis patients undergoing elective PSF at University Malaya 
Medical Centre. Participants will be randomised to receive PCA containing ketamine–
morphine (1 mg/mL + 1 mg/mL) or morphine (1 mg/mL) alone, with identical syringes to 
ensure allocation concealment. The primary endpoint is cumulative morphine consumption 
at 48 hours, while secondary outcomes include pain scores, opioid-related side effects, 
time to ambulation, and patient satisfaction.  
This study aims to provide the first Malaysian evidence on an opioid-sparing PCA 
regimen, addressing national ERAS priorities and contributing to global opioid stewardship. 

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d) Research Background and Rationale  
Tip: Introduce the problem at hand including its current burden/challenges, and highlight the need(s) 
for the proposal. Provide a focused literature review with references and highlight current gaps as 
well as scientific rationale for the proposal. State concretely the unique features or the novelty of 
your research proposal. Provide examples of your team's track record in the field or previous/ongoing 
work leading to this proposal (e.g., preliminary data), if available.  
Posterior spinal fusion (PSF) is a surgical procedure and the only effective medical 
treatment for severe idiopathic scoliosis, the most common structural spinal deformity. This 
condition primarily affects adolescents and is characterized by abnormal spinal curvatures 
greater than 50 degrees.  
Due to the extensive nature of the surgery, PSF is recognized as one of the most 
painful pediatric operations. Prospective studies report numeric rating scores (NRS) ≥7/10 
in up to 80% of patients during the first 24 hours, and inadequately treated pain can lead to 
chronic postsurgical pain in as many as 40% of cases [4–6]. This severe pain burden 
necessitates prolonged monitoring and nursing, thereby increasing hospital length of stay 
(LOS).  
Patient-controlled analgesia (PCA) with intravenous morphine is the standard 
approach for managing postoperative pain. It allows patients to decide when and how much 
morphine to receive through an electronic infusion device, giving them direct control over 
their pain relief. PCA is widely used because it is safe and effective, providing on-demand 
analgesia with preset doses and lockout intervals tailored to individual needs, without 
nurse-mediated delays. These safety features ensure adequate pain control while 
preventing overdose, making PCA a reliable and patient-centered method of postoperative 
pain management.  
Our previous study in adolescent idiopathic scoliosis patients at University Malaya 
Medical Centre (UMMC) undergoing PSF demonstrated that wound pain trajectories in the 
first two postoperative weeks were substantial, with morphine consumption peaking at 12 
hours postoperatively, confirming the necessity of PCA morphine in this cohort [7].  The 
high cumulative morphine doses required (30–60 mg in the first 48 h) drive dose- dependent 
nausea, vomiting, pruritus, urinary retention and, most importantly, respiratory depression 
[8]. Efforts to reduce opioid load with non-steroidal anti-inflammatory drugs risk impairing 
bony fusion, while gabapentinoids add dizziness without consistent opioid-sparing benefit 
in children [8]. Our previous study aimed at reducing opioid requirements and optimizing 
analgesia in scoliosis surgery, we investigated perioperative intravenous lignocaine 
infusion. While this approach was safe, it did not reduce postoperative morphine 
consumption [10].  
Global opioid stewardship efforts focus on reducing opioid use while promoting 
safer, multimodal approaches to pain management.  The aim is to reduce opioid-related 
harm such as misuse, dependence, and overdose while still providing effective pain 
management for patients who need it. The key principles therefore include rational 
prescribing by using the lowest effective dose for the shortest possible duration and 
multimodal analgesia by combining opioids with non-opioid medications to minimize opioid 
requirement. In surgery, including spine surgery, opioid stewardship means reducing 
unnecessary opioid exposure through strategies like PCA combinations (e.g., ketamine–
morphine) or by using non-opioid medications like regional anesthesia.   
More importantly, they run counter to the Ministry of Health’s opioid-stewardship 
agenda and the Enhanced Recovery After Surgery (ERAS) objectives, which prioritize safe 
opioid use, early ambulation, and shorter hospital stay.  

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Ketamine is a non-opioid medication that provides pain relief and anesthesia in a 
dose-dependent manner. It helps reduce the need for opioids because it works on different 
receptors than morphine, while still offering effective pain control. By combining ketamine 
with morphine in a PCA regimen, it is possible to achieve effective pain relief while lowering 
overall opioid use, thereby reducing side effects and supporting opioid stewardship goals.   
Our previous research has focused on optimizing analgesia in scoliosis surgery. In 
a UMMC study examining intraoperative opioid exposure, we found that co-administration 
of subanesthetic ketamine (0.5 mg/kg) at induction was able to prevent undesirable 
postoperative hyperalgesia and increased pain sensitivity that are otherwise associated 
with high-dose remifentanil infusion [13]. This finding supports ketamine’s role as an 
NMDA-receptor antagonist in reducing opioid-induced hyperalgesia and highlights its 
potential as an effective opioid-sparing adjunct.  
Therefore, the present study will evaluate whether a ketamine–morphine PCA 
regimen (PCA KetaMorph) can achieve meaningful opioid-sparing effects while maintaining 
effective analgesia. 
 
e) Objective(s) of the Research 
Tip: Objectives should be Specific, Measurable, Achievable, Relevant, and Time-bound (SMART). 
Primary objective 
To determine whether adding ketamine to morphine patient-controlled analgesia (PCA) 
reduces cumulative morphine consumption during the first 48 hours after posterior spinal 
fusion compared with morphine PCA alone.   
Secondary objectives 
1. To compare patient-reported pain intensity (visual analogue scale) at 6, 12, 18, 24, 
30, 36, 42 and 48 hours post-operatively between the two treatment groups. 
2. To evaluate and compare the incidence of opioid-related adverse events (nausea, 
vomiting, pruritus, excessive sedation or respiratory depression) occurring within 48 
hours of surgery. 
3. To compare overall hospital length of stay, time to first flatus and time to first 
ambulation and the proportion of patients who report high satisfaction (Likert score ≥ 4 
/ 5) at discharge in each group. 
 
Objective 
tier 
Specific 
Measurable 
Achievable 
Relevant 
Time-bound 
Primary 
Effect of 
adding 
ketamine to 
PCA on total 
morphine 
usage. 
Percentage 
reduction in 
PCA morphine 
dose (mg) in 
intervention 
arm. 
Sample size (n 
= 113) with 
standardized 
effect size of 
0.55.   
Directly 
addresses 
opioid-
reduction gap 
in PSF 
PCA pump 
summary at 
6-hour 
intervals up 
to 48 h post-
surgery 
Secondary 
(i) 
Effect on 
pain score 
while 
reducing 
opioids 
Mean VAS 
pain score 
difference 
between 
groups 
Self-reported 
pain scores 
every 6 h; target 
≥1-point 
reduction in 
intervention arm 
Ensures 
opioid 
reduction 
does not 
worsen pain 
Pain 
recorded at 6, 
12, 18, 24, 
30, 36, 42 & 
48 h post-
surgery 

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Secondary 
(ii) 
Ketamine 
and opioid-
related 
adverse 
events 
(AEs) 
Incidence of 
nausea, 
vomiting, 
pruritus, 
sedation, 
desaturation, 
psychotropic 
effects 
Daily AE 
assessment by 
researcher plus 
real-time 
reporting by 
ward nurses; 
aim: fewer 
opioid AEs and 
no ketamine 
psychotropic 
events 
Confirms 
safety of 
ketamine 
adjunct 
AEs 
monitored 
continuously 
to 48 h post-
surgery 
Secondary 
(iii) 
Enhance 
recovery 
parameters 
Mean time to 
first flatus, time 
to first 
ambulation 
and hospital 
length of stay 
(LOS) 
LOS SD ≈ 1 day 
from previous 
studies 
Improve time 
to first flatus, 
time to first 
ambulation 
and shorter 
LOS aligns 
with ERAS & 
cost-saving 
aims 
Discharge 
date vs 
surgery date 
Secondary 
(iv) 
Improve 
patient 
satisfaction 
Likert scale 
score on pain 
management 
experience 
Previous 
surveys show > 
70 % baseline 
satisfaction 
Captures 
patient-
centred 
benefit 
Survey on 
day of 
discharge 
 
f) 
Methodology 
i. 
Description of Methodology including study design and research plans. Ideally, researchers 
should demonstrate how the research plans will help to achieve the proposed objectives and 
the feasibility of the project within the stipulated timeline. 
Study design and setting 
Prospective, single-centre, double-blind pilot randomised controlled trial at the 
University Malaya Medical Centre (UMMC). 
 
Study participants 
Inclusion criteria 
1. Aged > 10 years old 
2. Idiopathic scoliosis scheduled for single-stage posterior spinal fusion (PSF). 
3. American Society of Anaesthesiologists (ASA) physical status I–II. 
Exclusion criteria 
1. Known hypersensitivity to morphine, ketamine or formulation excipients. 
2. Hepatic dysfunction (ALT or AST > 2 × upper limit of normal). 
3. Renal impairment (eGFR ≤ 60 mL min⁻¹ 1·73 m⁻²). 
4. Uncontrolled asthma or severe restrictive lung disease. 
5. Cardiac disease or clinically significant arrhythmia. 
6. Epilepsy. 
7. Intellectual disability precluding PCA use. 
8. Chronic opioid therapy or pre-operative pain > 3 months. 
9. Concomitant monoamine-oxidase inhibitor or tricyclic antidepressant 
therapy. 
10. History of severe postoperative delirium. 

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Sample size 
From our previous study (7), the mean ± SD for postoperative PCA morphine usage 
from 0 to 24 hours was 30.84 ± 22.33 mg. We hypothesized that by adding ketamine 
to PCA morphine postoperatively, morphine consumption at 24 hours would be 
reduced by 40% compared with the Usual Care Group. The mean after reduction 
was 18.5 mg, and the calculated G*Power effect size was d ≈ 0.55. The sample size 
for an independent t-test with 80% power and a two-tailed alpha of 0.05 was 102. 
Assuming a 10% dropout rate due to incomplete data, the final sample size was 
calculated as 102 / 0.9 = 113 (~114) patients, which is approximately 57 patients 
per group. 
 
Study intervention, randomisation and blinding 
Informed consent (and assent where appropriate) will be obtained pre- 
operatively. An independent statistician will generate a computerised sequence in 
blocks of four. Sequentially-numbered opaque sealed envelopes (SNOSE; n = 114) 
will assign patients 1:1 to: 
• 
Group A Ketamine–Morphine PCA (K-M) 
• 
Group B Morphine-only PCA (M) 
An Acute Pain Service (APS) nurse not otherwise involved in the study will 
prepare identically labelled 30 mL polypropylene syringes (patient name + study ID 
only). Investigators, ward staff, surgeons and patients will remain blinded. In 
recovery, Group A receives a ketamine–morphine PCA solution (1 mg mL⁻¹ + 1 mg 
mL⁻¹); Group B receives morphine alone (1 mg mL⁻¹). Both devices deliver a 1 mL 
bolus, enforce a five-minute lock-out and cap delivery at 20 mL per four hours, with 
no background infusion. 
 
Anaesthetic protocol 
All patients will fast for 6 hours, with clear fluids allowed up to 2 hours prior to 
surgery. No premedication will be given. TIVA will be administered via target-
controlled infusion (TCI) of remifentanil at 3–5 ng/ml and TCI propofol at 3–5 µg/ml, 
guided by bispectral index readings of 40–60 throughout surgery. After establishing 
baseline neuromonitoring tracing and prior to skin incision, IV Dexmedetomidine 
infusion will be started at a rate of 0.4 mcg/kg/hr; this infusion of IV 
Dexmedetomidine will be discontinued 20 minutes before the end of surgery.   
Mechanical ventilation will be set at 6–8 ml/kg tidal volume and 12–16 breaths 
per minute. Continuous monitoring will include invasive blood pressure, heart rate, 
oxygen saturation, and electrocardiogram.  
Intraoperative analgesia will consist of IV ketamine 0.5 mg/kg administered prior 
to skin incision, IV paracetamol 15 mg/kg, and IV morphine 0.1 mg/kg given 45 
minutes before the end of surgery. Local anaesthetic infiltration with bupivacaine 
0.25% (maximum 2 mg/kg) will be performed by the surgeon prior to wound closure.  
All patients will receive crystalloid infusion at 7 ml/kg/hour, with additional fluid 
boluses (5 ml/kg) if MAP falls below 65 mmHg, heart rate increases by 20%, or urine 
output decreases below 0.5 ml/kg/hour. Intraoperative cell salvage will be used. 
Allogeneic transfusion will be considered if haemoglobin falls below 8 g/dl despite 
completion of cell salvage blood reinfusion, adequate fluid resuscitation, and in 
patients with persistent haemodynamic instability.  

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Postoperatively, patients will be extubated and monitored in the recovery area.  
In the recovery area, pain score will be assessed by the recovery nurse every 5 
minutes. Rescue analgesia of IV Fentanyl 10 mcg/bolus will be administered if pain 
score  ≥ 4. Patient-controlled analgesia (PCA) will be initiated once the patient has 
returned to the ward and continued for up to 48 hours.  
Patients will also receive oral paracetamol 15 mg/kg every 6 hours and oral 
celecoxib 200 mg once or twice daily, in the ward. 
 
Data collection 
Demographics, surgical details and intra-operative drug doses are recorded on 
data collection sheet and transcribed to SPSS. Primary outcome data (cumulative 
morphine use) will be recorded from the PCA pumps at 24 and 48 hours. Secondary 
data comprise pain scores at 6, 12, 24, 36 and 48 hours; opioid-related adverse 
events (nausea, vomiting, pruritus, sedation ≤ RASS -1, or oxygen saturation < 
92%); time to first ambulation; total length of stay; and discharge-day satisfaction 
(five- point Likert scale). Feasibility metrics include recruitment velocity, protocol 
deviations and accuracy of blinding guesses. All SPSS records will be kept in an 
electronic database with two-factor authentication; data are retained for seven years 
before anonymised archiving.  
 
Statistical analysis 
Analyses follow the intention-to-treat principle and use SPSS v26. Distribution 
normality is assessed with the Kolmogorov-Smirnov test. The primary outcome is 
compared by independent-samples t-test or, if non-parametric, the Mann–Whitney 
U test. Repeated pain scores are modelled with linear mixed-effects analysis. 
Incidences of adverse events are compared using χ² or Fisher’s exact tests, and 
time to ambulation is evaluated with Kaplan–Meier curves and log-rank testing. 
Multiple imputation addresses missing data ≥ 5 %. A two-sided p < 0·05 defines 
statistical significance. 
 
Safety 
The investigational ketamine dose (≤ 1 mg kg⁻¹ day⁻¹) is beneath 
psychotomimetic 
thresholds 
and 
within 
formulary 
limits. 
Continuous 
cardiorespiratory and sedation monitoring is maintained for forty-eight hours. A Data 
and Safety Monitoring Board will review unblinded data and may suspend enrolment 
if drug-related serious adverse events occur or if psychotropic or haemodynamic 
serious events exceed 20%. 
 
Ethics and registration 
Approval from the University Malaya Research Ethics Committee, and the trial 
will be registered on ClinicalTrials.gov before the first participant is enrolled, in 
accord with the Declaration of Helsinki and ICH-GCP guidance. 
 
ii. 
Graphical abstract / Flow chart of research activities 
As appended 
 

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iii. 
Gantt chart of research activities 
Year 
2025 
2026 
2027                                                                                 2028 
Month 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
Ju 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
Ju 
A 
S 
O 
N 
D 
J 
Proposal 
Preparation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethics 
application 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training of  
APS nurse 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data 
recruitment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Data 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Manuscript 
preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Submit for 
publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
iv. 
Milestones and Dates (according to the template below) 
Milestone description 
Estimated 
Completion Date 
Cumulative 
Project 
Completion 
Percentage (%) 
 Protocol finalisation 
 1 September 2025 5  
 Ethics approval and clinical trial registration 
31 December 2025 10  
Pharmacy admixture validation and APS staff 
training 
30 January 2026 
15 
First participant enrolled 
2 February 2026 
20 
25% recruitment achieved (n=10) 
1Jun 2026 
35 
50% recruitment achieved (n=20) 
1 August 2026 
50 
75% recruitment achieved (n=30) 
1 December 2026 
65 
Last patient complete 48 h follow up 
1 July 2027 
80 
Data lock and statistical analysis completed 
1 October 2027 
90 
Manuscript submitted to Q1 journal & abstract 
submitted to national meeting 
31 December 2027 95 
Final grant report 
30 january 2028 
100 
  
g) Expected Output/Outcomes 
i. 
Research Publications - number of publications and journal targets 
ii. 
Human Capital Development - number of PhD and/or Masters students (including Clinical 
Masters students) 
iii. 
Intellectual Property (IP)/ Patent 
iv. 
Specific or Potential Applications 
Category 
Target 
Publications 
At least one (1) publication in a Q1/Q2-indexed journal as Corresponding 
Author. 

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Human Capital 
1 Clinical Master student trained as co-author 
1 Research assistant 
IP 
Not applicable 
Clinical 
Application 
Adoption of ketamine–morphine PCA protocol in UMMC Spine Unit 
 
h) Impact Statement (less than 200 words) 
Morphine PCA remains the analgesic mainstay after posterior spinal fusion (PSF) 
in Malaysian adolescents, yet it increases nausea, vomiting, pruritus and delaying 
mobilisation and discharge. These consequences conflict directly with the Ministry of 
Health’s opioid-stewardship drive and with Enhanced Recovery After Surgery (ERAS) 
targets that prioritise early ambulation and shorter length of stay. This study will deliver the  
Malaysian data on a ketamine–morphine PCA regimen, quantifying opioid-reducing, pain 
control and psychotropic or haemodynamic safety in a uniform adolescent cohort. By 
establishing local effect sizes and feasibility parameters, the study will supply the critical 
evidence base required to design a subsequent adequately powered multicentre trial and 
will provide robust, context-specific figures for forthcoming national guideline revisions on 
paediatric perioperative care. Demonstrating safe reduction of opioid exposure has clear 
patient-centred benefits with fewer side-effects and faster recovery in addition to a reduce 
pharmacy expenditure on anti-emetics. Ultimately, the project advances both national 
opioid-stewardship goals and ERAS implementation, with potential to shape practice 
across South-East Asian paediatric spine centres. 
 
i) 
Risk Assessment 
Please provide justification that may cause delays in, or prevent implementation of, 
the project as proposed above; estimate also the degree of risk. 
Major Risks Identified 
Level of Risk 
(Low/ Middle/ 
High) 
Proposed Risk Mitigation Measures 
Recruitment < 2 patients / 
month 
Medium 
Monthly planning with the surgical team 
Psychotropic 
adverse 
event 
Low 
Dose capped; streamline ward protocol and 
discontinuation rule 
Drug-supply interruption 
Low 
Advance purchase 12 month via inpatient 
pharmacy; secondary vendor letter 
 
j) 
Team Narrative (less than 200 words) 
Tip: Describe briefly your team's composition of researchers, their relevant area(s) of expertise and 
their role/contribution to the proposed project 
SNY (PI) is a senior lecturer who provide anaesthesia for spine surgery regularly. SNY 
previously secured a Faculty of Medicine research grant (2020) and has recently published 
on intravenous lignocaine and neuromonitoring in scoliosis surgery. SNY currently has an 
on-going carbohydrate-loading study in AIS which further demonstrates trial-management 
skills. SNY will coordinate all phases of PCA KetaMorph trial, bringing proven expertise in 
data handling and SPSS analysis. 
MSH (scientific advisor) is a senior consultant anaesthetist with > 60 peer-reviewed papers 
and multiple national and international grants. He will refine the protocol, supervise 
recruitment targets, safeguard ICH-GCP compliance and interpret interim data. 

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MFMY (research fellow) is a Clinical Master’s trainee who will manage daily screening, 
consent, data capture and follow-up, while completing GCP certification, strengthening 
future departmental research capacity. 
 
k) References 
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Universiti Malaya Press; 2020. p. 547-8. 
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3. Deepak AS, Ong JY, Choon D, Lee K, Chiu CK, Chan C, Kwan K. The clinical 
effectiveness of a school screening programme for idiopathic scoliosis in Malaysia. Malays 
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