Clinical trial NCT04539249
Conditions: Acute Post-operative Pain Following Caesarean Section
Sponsor: Olakunle Ifeoluwa Makinde
Start date: 2020-11-04; Completion date: 2021-03-31
Enrollment: 324 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background: Multimodal analgesia; a combination of opioid and non-opioid analgesics, for management of acute post-operative pain significantly reduces the incidence of adverse effects associated with liberal post-operative opioid use including sedation, respiratory depression, constipation, ileus, urinary retention, delayed recovery, addiction etc. However, opioid addiction remains a worsening public health problem and have followed administration of opioid analgesics for post-operative pain and subsequent chronic use in many addicts; especially the opioid naive. Caesarean section is a commonly performed surgery and is a common source of first exposure to opioids in women. Trend in post-operative analgesia is moving towards opioid-free (multimodal) analgesia; a combination of non-opioid and adjuvant analgesics. Magnesium sulphate is an adjuvant analgesic. When administered peri-operatively, it has been reported to prolong the duration of spinal anaesthesia, decrease post-operative pain and opioid use without adverse effect.

Aim: To determine the effectiveness and safety of a combination of peri-operative intravenous magnesium sulphate, intravenous paracetamol, and post-operative rectal diclofenac as opioid-free, multimodal analgesia for management of acute post-operative pain after a caesarean section.

Null Hypothesis: Combination of intravenous magnesium sulphate, intravenous paracetamol, and rectal diclofenac as analgesia regimen for acute post-operative pain after a caesarean section is not as effective and safe as a routine opioid-based multimodal analgesia regimen used in the study setting.

Alternate Hypothesis: Combination of intravenous magnesium sulphate, intravenous paracetamol, and rectal diclofenac as analgesia regimen for acute post-operative pain after a caesarean section is as effective and safe as a routine opioid-based multimodal analgesia regimen used in the study setting.

Materials and Methods: A randomized clinical trial, comparing a combination of peri-operative intravenous magnesium sulphate, intravenous paracetamol, and post-operative rectal diclofenac with an opioid-based multimodal regimen as control. Eligible patients will be consecutively selected from among women booked for caesarean section at the Federal Medical Centre, Yenagoa. Control group will receive a combination of post-operative intramuscular pentazocine, intravenous paracetamol and rectal diclofenac. Pain intensity will be determined in both groups and compared. Need for rescue opioid analgesic will be determined in both groups and compared. Incidence of any adverse event in both groups will be determined.

Detailed description:

Arms: arm 1: Combination of intravenous magnesium sulphate, intravenous paracetamol and rectal diclofenac arm 2: Combination of intramuscular pentazocine, intravenous paracetamol and rectal diclofenac
Interventions: intervention 1: Magnesium sulphate intervention 2: Pentazocine
Intervention descriptions: intervention 1: 1g of paracetamol as an I.V infusion and 4g of magnesium sulphate as an I.V. bolus preoperatively. Continuous infusion of 1g/hr of magnesium sulphate intraoperatively and for the first 2 hours post-operatively. Further post-operatively, 100 mg of suppository diclofenac 12 hourly, intravenous paracetamol 1g 6 hourly, both over 24 hours.

N.B: Intramuscular pentazocine 30 mg (45 mg if patient is \> 70 kg) will be used as rescue analgesia as needed (that is, only on patients' request for further analgesia or following an assessment of moderate to severe pain despite the planned analgesic regimen) at least 4 hourly during the first 24 hours after caesarean section. intervention 2: Post-operatively, suppository diclofenac 100mg 12 hourly, intramuscular pentazocine 30 mg (45 mg if patient is \> 70 kg) 6 hourly, intravenous paracetamol 1g 6 hourly, all for 24 hours.

N.B: Intramuscular pentazocine 30 mg (45 mg if patient is \> 70 kg) will be used as rescue analgesia as needed (that is, only on patients' request for further analgesia or following an assessment of moderate to severe pain despite the planned analgesic regimen) at least 4 hourly during the first 24 hours after caesarean section.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
SINGLE-CENTRE, RANDOMIZED, CLINICAL TRIAL OF OPIOID-FREE 
ANALGESIA VERSUS ROUTINE OPIOID-BASED ANALGESIA REGIMEN FOR THE 
MANAGEMENT OF ACUTE POST-OPERATIVE PAIN FOLLOWING CAESAREAN 
SECTION 
 
ClinicalTrials.gov 
NCT04539249 
 
Date: October 12, 2020. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


INTRODUCTION 
Background And Rationale 
Traditionally, opioid analgesics have been the mainstay of analgesic management of acute post-
operative pain due to their effectiveness.1 However, liberal administration of opioid analgesics to 
achieve optimum pain control is associated with various side effects including respiratory 
depression, sedation (with associated impairment of mother and child bonding, delayed initiation 
of breastfeeding, reduced ambulation and increased risk of thromboembolism), post-operative 
nausea and vomiting (PONV), constipation, ileus, pruritus, urinary retention, opioid-induced 
hyperalgesia (OIH), opioid tolerance, dependence and addiction.1-3 Kehlet and Dahl in the early 
1990s recommended balanced analgesia or a multimodal approach to the management of acute 
post-operative pain and paved way for the “multimodal movement”.4 This was premised on a 
previous work by Kehlet that established that a single analgesic drug or technique cannot achieve 
optimal acute post-operative pain relief that allows normal function without significant side 
effects.5  
Apart from combination of drugs, multimodal analgesia also employs different routes for the 
administration of analgesic agents, and has brought to the fore the roles of non-opioid analgesics, 
co-analgesics/adjuvant analgesics, peripheral nerve blocks and wound infiltration in the 
management of acute postoperative pain.6-8 Multimodal analgesia has successfully achieved 
control of post-operative pain and reduction in opioid related side effects, however, addiction, 
disability and deaths arising from opioid exposure and abuse have reached disturbing rates. 
Chronic opioid use and opioid use disorder is associated with intraoperative and post-operative 
opioid use, especially in previously opioid naive patients.3,9-11 Eighty percent of surgical patients 
receive opioids as a fundamental agent for pain relief.12 A systematic review reported an incidence 
of opioid use disorder following opioid prescription for pain as high as 34%.13 Caesarean section 
is a commonly performed surgery and is a common source of initial exposure to opioids in women 
of reproductive age.9  
The morbidity and mortality associated with opioid abuse has become of public health importance. 
Incidence of opioid abuse and related death is alarmingly high in the United States of America 
(USA),14-16 and on the rise in Canada,17 Australia,18 and in England and Wales.19 About 560 deaths 
were recorded in Colorado, USA in 2017 and 47,600 deaths same year in the whole of the USA 
from opioid overdose.16 Canada recorded 2,861 apparent opioid-related deaths in 2016,17 and 
1,045 Australians died from opioid overdose in 2016.18 Nigeria is also experiencing an 
unprecedented degree of opioid abuse especially of codeine and tramadol.20-22  
As a result, the trend in management of post-operative pain is moving towards avoidance of 
opioids. This is currently driving multimodal analgesia beyond being combinations of one opioid 
and one non-opioid, or one opioid and two non-opioids, towards a combination of non-opioid and 
adjuvant analgesics.23 Opioid-free analgesia; a multimodal analgesia technique that combines non-
opioid and adjuvant analgesics on a regular scheduled basis, with the use of opioids limited to 
rescue analgesia only if required, has a potential to tackle the fast rising and spreading opioid 
crises.24,25 Opioid-free analgesia also utilizes the principle of preventive analgesia; multimodal 
analgesia coverage starting pre-operatively and continued intraoperatively and post-operatively, 
to limit the intensity of post-operative pain through prevention of primary and secondary 
hyperalgesia, from nociceptive stimuli induced by surgical tissue injury.26 Non-opioid analgesics, 


adjuvant analgesics and techniques that have been studied for management of post-operative pain 
include paracetamol, NSAIDs (e.g. diclofenac, ketorolac, and ibuprofen), ketamine hydrochloride, 
magnesium sulphate, gabapentin, pregabalin, clonidine, dexmedetomidine, and bupivacaine, 
ropivacaine; for peripheral nerve block and wound infiltration.7,8  
Successful reductions in the peri-operative opioid consumption by up to 70% with implementation 
of opioid-free analgesia regimens have been documented.27-29 Paracetamol and a NSAID are 
considered basic components of a standard opioid-free analgesia regimen because apart from being 
safe, cheap and readily available, they offer superior analgesia and reduction of opioid 
consumption by their synergistic effect.30 The effectiveness and opioid sparing effect of combined 
diclofenac suppository and intravenous paracetamol for post-operative pain after caesarean section 
is known and documented.31  
A notable previous effort towards an opioid-free analgesia regimen for the management of acute 
post-operative pain was made by the Procedure Specific Postoperative Pain Management 
(PROSPECT) working group.23 The PROSPECT working group is made up of surgeons and 
anaesthesiologists with procedure-specific management of post-operative pain as part of their aim. 
PROSPECT recommendations are based on consensus after undertaking systematic reviews of 
literature and reviews are updated as new data becomes available. Based on a systematic review 
performed until 2014, PROSPECT recommendation for caesarean section combines oral 
gabapentinoid preoperatively, neuraxial anaesthesia + intravenous paracetamol + intravenous 
NSAID + transversus abdominis plane block or iliohypogastric/ilioinguinal block or wound 
infiltration with local anaesthetic intraoperatively, then intravenous paracetamol + intravenous 
NSAID ± continuous wound infiltration with local anaesthetic, while systemic opioid is limited to 
rescue analgesic (if required) post-operatively.32 
Some drawbacks to this PROSPECT recommendation for caesarean section are that abdominal 
wall block techniques are not yet commonly practiced by obstetricians, the role of some of the 
techniques is still debatable33,34 and the combination of routes of administration and techniques 
recommended is in our opinion cumbersome and invasive. It is noteworthy that the PROSPECT 
recommendation only reflects how opioid-free analgesia can be achieved in principle and no 
multimodal peri-operative analgesia regimen can be considered sacrosanct at least at present.8 
While efforts towards solving the ongoing opioid addiction crisis by addressing the contribution 
of peri-operative administration of opioids continue, in resource-limited settings especially, a 
readily available, less cumbersome, cheap and effective opioid-free analgesia regimen which can 
obviate or at least reduce peri-operative opioid consumption and can give a comparable degree of 
analgesia to opioid-based analgesia is necessary. 
This study sets out to determine the effectiveness and safety of a combination of peri-operative 
intravenous magnesium sulphate, intravenous paracetamol, and post-operative rectal diclofenac as 
opioid-free, multimodal analgesia for management of acute post-operative pain after a caesarean 
section. Studies have shown that administration of magnesium sulphate in the peri-operative period 
prolongs the duration of spinal anaesthesia and decreases post-operative pain and opioid use 
without side effect.35-40 Our goal for presenting our protocol for this study is so that it may be 
replicated in other settings and possibly modified for future studies. In addition, if this study finds 
that peri-operative intravenous magnesium sulphate, intravenous paracetamol, and post-operative 
rectal diclofenac significantly reduces post-operative opioid consumption and is as effective and 


safe as the opioid-based analgesia regimen compared, it will help reduce opioid prescription for 
women undergoing a caesarean section and join the efforts towards solving the ongoing opioid 
addiction crisis.   
OBJECTIVES 
General Objective 
To determine the effectiveness; primarily, and the safety of a combination of peri-operative 
intravenous magnesium sulphate, intravenous paracetamol, and post-operative rectal diclofenac as 
opioid-free multimodal analgesia regimen for the management of acute post-operative pain, in 
women undergoing caesarean section.  
Specific Objectives  
• To determine current pain intensity in the first 24 hours after a caesarean section using the 
numerical rating scale for pain (NRS). 
• To compare pain intensity in opioid-free analgesia treated women to that in opioid-based 
analgesia treated women. 
• To determine and compare the need for rescue opioid analgesic among opioid-free 
analgesia treated women and opioid-based analgesia treated women. 
• To determine adverse events associated with the opioid-free analgesia regimen. 
• To determine the prevalence of opioid-related adverse events in opioid treated patients. 
 
RESEARCH QUESTION AND HYPOTHESES  
Research Question 
This study sought to answer the question below.  
Will peri-operative administration of intravenous magnesium sulphate, intravenous paracetamol, 
and post-operative rectal diclofenac (a) obviate or at least reduce peri-operative opioid 
consumption (b) be as effective and safe, as a routine opioid-based multimodal analgesia regimen 
in the management of acute post-operative pain in women undergoing caesarean section?  
Study hypothesis 
Null Hypothesis: Combination of intravenous magnesium sulphate, intravenous paracetamol, and 
rectal diclofenac as analgesia regimen for acute post-operative pain after a caesarean section is not 
as effective and safe as a routine opioid-based multimodal analgesia regimen used in the study 
setting. 
Alternative Hypothesis: Combination of intravenous magnesium sulphate, intravenous 
paracetamol, and rectal diclofenac as analgesia regimen for acute post-operative pain after a 
caesarean section is as effective and safe as a routine opioid-based multimodal analgesia regimen 
used in the study setting. 
 
 
 
 
 
 


METHODS: TRIAL DESIGN, PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
Trial Design 
Single-centre, non-inferiority, parallel, randomized, controlled, clinical trial with balanced 
randomization [1:1] into two arms.  
Study Setting 
This study will be conducted in the department of Obstetrics and Gynaecology of the Federal 
Medical Centre, Yenagoa, Bayelsa State, Nigeria. The hospital is a tertiary level health facility, 
with its main facility situated in Yenagoa, the capital of Bayelsa State, and an annex at Otuoke; a 
town in Ogbia local government area of Bayelsa State. The hospital receives patients directly, and 
serves as a referral hospital to all the primary and secondary level health facilities in the State, to 
private hospitals in Yenagoa and its environs, and also to the State-owned university teaching 
hospital. Bayelsa State has a population of about 1,700,000 people. The hospital records an average 
of 1800 deliveries annually. Unpublished data from the facility during the study period showed a 
hospital level caesarean section rate of 30.8%.  
Study Population 
The study population will be pregnant women who had caesarean section at the Federal Medical 
Centre, Yenagoa, Bayelsa State during the study period.  
Eligibility criteria 
Eligibility will be determined through relevant information obtained from case folders and history 
obtained from the women. Table 1 shows the eligibility criteria for the study.  
Table 1: Eligibility criteria 
Inclusion Criteria:  
1. Pregnant women booked for elective, 
scheduled and urgent caesarean section 
at 
the 
Federal 
Medical 
Centre, 
Yenagoa, Bayelsa State during the 
study period. 
2. Pregnant women who give consent to 
participate in the study. 
Exclusion Criteria: 
1. Pregnant women with active peptic 
ulcer disease, active liver disease, 
hepatic failure, and renal failure.  
2. Pregnant women with previous history 
of ischaemic heart disease/myocardial 
infarction, 
heart 
failure, 
venous 
thrombosis and stroke. 
3. Hypersensitivity 
to 
pentazocine, 
paracetamol, diclofenac or magnesium 
sulphate. 
4. Pregnant women with history of non-
medical use (abuse) of opioids.   
5. Pregnant 
women 
on 
magnesium 
sulphate or have a clinical indication to 
receive magnesium sulphate. 
6. Pregnant 
women 
booked 
for 
emergency caesarean section (because 
the urgency may not allow time for 
adequate patient counseling before 
recruitment). 


7. Pregnant women booked for caesarean 
section under general anaesthesia or 
epidural anaesthesia. 
8. Pregnant women who can neither 
communicate in English nor colloquial 
English. 
 
Trial team recruitment and care team education 
Research assistants were recruited and trained for the study. The research assistants who will assess 
pain intensity in the women were trained by a consultant anaesthetist. Part of their training was to 
resist the temptation to disbelieve the women’s expression and self-report of pain. Cooperation by 
doctors, anaesthetists and surgical nurses during this study was ensured by prior presentation of 
the study to the Obstetrics and Gynaecology department and the relevant anaesthesia and surgical 
nursing units of the hospital. Interventions for groups A and B and instructions to anaesthetists 
were also printed out boldly and pasted on the wall of the theatre in a conspicuous manner. 
Intervention 
After preloading, all the women will receive spinal anaesthesia with 2 ml [10 mg] of hyperbaric 
0.5% bupivacaine (Marcaine®- Aspen Pharma Trading Limited, Ireland) into the subarachnoid 
space, and patients will be laid supine immediately. This fixed dose of bupivacaine was chosen 
instead of height and weight-adjusted dose to make the protocol easy to follow for the anaesthetists. 
It is backed by evidence from a randomized controlled trial showing that a fixed dose of 10 mg of 
hyperbaric 0.5% bupivacaine had similar results to height and weight-adjusted dose in spinal 
anaesthesia for caesarean section41 
Participants in intervention arm A will receive a combination of peri-operative intravenous 
magnesium sulphate (ANCALIMA®- LIFESCIENCES LTD, India), intravenous paracetamol 
(THERMODOL®-Unosource Pharma, India), and post-operative rectal diclofenac (LOFENAC®- 
BLISS GVS PHARMA LTD, India) as follows: 1g of intravenous paracetamol as an infusion 
slowly over 15 minutes, then 4g of a 20% solution of magnesium sulphate as an intravenous bolus 
slowly over 10 minutes preoperatively; during preloading for spinal anaesthesia. Thereafter, 
continuous infusion of 1g/hr of a 20% solution of magnesium sulphate will be delivered with a 
syringe pump intraoperatively (commenced at the time of skin incision) until the first 2 hours post-
operatively. Post-operatively; immediately after wound dressing and patient cleaning, 100 mg of 
suppository diclofenac will be administered. Intravenous paracetamol 1g will be continued 6-
hourly and suppository diclofenac 100 mg continued 12-hourly, both over 24 hours post-
operatively.  
Participants in intervention arm B will receive a combination of intramuscular pentazocine 
(ZOPENT®- GREENLIFE PHARMACEUTICALS LTD, Nigeria), intravenous paracetamol 
(THERMODOL®-Unosource Pharma, India) and rectal diclofenac (LOFENAC®- BLISS GVS 
PHARMA LTD, India) as follows: 100 mg suppository diclofenac post-operatively immediately 
after wound dressing and patient cleaning. Thereafter, intramuscular pentazocine 30 mg (45 mg if 
patient is > 70 kg) and intravenous paracetamol 1g will be commenced and administered 6-hourly. 
Suppository diclofenac 100 mg will be continued 12-hourly, all for 24 hours post-operatively. 


Rescue analgesia will be allowed in this study outside the prescribed analgesia regimen for both 
arms of the study if needed. Intramuscular pentazocine 30 mg (45 mg if patient was > 70 kg) will 
be used as rescue analgesia. It will be administered only on patients’ expression of moderate to 
severe pain or following an assessment of moderate to severe pain by ward nurses/research 
assistants, despite the planned analgesia regimen for both arms of the study. 
There will be no blinding at this stage of the study. Thus, the participants, the researcher, the 
research assistants who will be involved in administration of the peri-operative analgesics and the 
research assistants and nurses who will be involved in administration of the post-operative 
analgesics will be aware of the allocated arm. 
Primary Outcome Measures 
The primary outcome measures to be evaluated are post-operative pain scores following caesarean 
section at 4, 8 and 24 hours post-operative and post-operative pentazocine use, pentazocine use as 
rescue analgesia, frequency of pentazocine use and cumulative dose of pentazocine used during 
the first 24 hours post-operative.  
Secondary Outcome Measures 
The secondary outcome measures to be evaluated are incidences of magnesium-related adverse 
effects including hypersensitivity reaction, respiratory depression, bradycardia, hypotension, 
nausea and vomiting, lightheadedness, presyncope, and any other adverse event recorded from the 
time of first administration of peri-operative analgesia to 2 hours postoperative. Others are the 
Apgar scores of the neonates at the first and fifth minutes after birth and incidences of opioid-
related adverse effects including constipation, ileus, pruritus, urinary retention and any other 
adverse event recorded during the first 24 hours post-operative.  
Participant Timeline 
This trial is planned to commence in November, 2020. All measurements will be taken during the 
intervention phase. There will be no follow-up phase.  
Figure 1 is a flow diagram of the steps to be taken to conduct this study. 
 
 


 
 
 
Figure 1: Study flow diagram 


Sample Size Calculation 
Sample size was determined using the formula for sample size determination for non-inferiority 
clinical trials42; n = 2 (Z1-α + Z1-β) 2 x SD2 / d2; where n is the minimum sample size. Giving a 
level of significance (α) of 0.05 and power (1 – β) of 80%, then Z1-α is the standard normal deviate 
at 95% confidence interval (1.96) and Z1-β is the standard normal deviate for power of 80% in 
this study (0.84). SD is the standard deviation of the pain intensity after caesarean section (primary 
outcome measure) in a study done in Brazil and reported as 2.2,43 and d (non-inferiority limit) = 
1.3, as derived from a previous study.44   
Therefore, n = 2 (1.96 + 0.842) 2 x 2.22 / 1.32 = 44.97; approximately 45. Using an attrition rate 
of 10%, this minimum sample size was increased by 5 (10% of 45). Fifty women will be selected 
into each arm of this study, giving a total sample size of 100. 
Recruitment 
Participants will be enrolled into the study in order of appearance, based on their eligibility and 
willingness to participate in the study (consecutive recruitment). All women being prepared for 
urgent, scheduled or elective caesarean section will be met by the researcher or trained assistant in 
the antenatal ward or labour ward. After the researcher or a trained research assistant has explained 
the aim and processes of the study and its benefits to eligible women in simple and clear terms, 
and an assurance of safety is given, participants who express an understanding of the study and 
show willingness to participate will be given the consent form for the study to sign.  
METHODS: ASSIGNMENT OF INTERVENTIONS 
Allocation Sequence Generation 
Participants were allocated to receive either an opioid-free multimodal analgesia regimen in the 
intervention arm A (experimental) or a routine opioid-based multimodal analgesia regimen in the 
intervention arm B (control). Using the WINPEPI software for randomization, a random and 
balanced allocation [1:1] of numbers 1 to 100 to letters A and B was conducted by the 
Researcher. 
Allocation Concealment Mechanism 
Identical and opaque envelopes were labelled outwardly using serial numbers from 1 to 100. The 
envelopes had cards inscribed with letter A or B concealed within them according to the 
randomly assigned letter to each number from 1 to 100. They were then sealed and sequentially 
arranged.   
Implementation 
As each eligible woman are received into the theatre for a caesarean section, a research assistant 
will pick an envelope according to the sequence. The letter inscribed on the card in the envelope 
will be announced and shown to the researcher, anaesthetist and peri-operative nurse (A = 
experimental arm and B = control arm). The serial number / identification number on the envelope 
selected will be attached to the case folder, operation note and other documents for the study. 
Blinding (masking) 
The research assistants who will assess the post-operative pain intensities (primary outcome 
measure) and that who will be responsible for data entry will be blinded in this study.  
 


METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
Data Collection Methods 
The weight and height of the women will be measured and recorded with other biodata of 
interest. The respiratory rate, pulse rate and blood pressure of the women will be measured using 
patient monitor on admission to the theatre and noted. The lowest values of these parameters 
from the time of first administration of peri-operative analgesia to 2 hours post-operative will be 
obtained from the anaesthesia chart.  Any adverse event during this period will also be recorded. 
The Apgar scores of the neonates at the first and fifth minutes after birth will be recorded. Forms 
will be provided on the ward to record any opioid-related adverse event and any other adverse 
event occurring during the first 24 hours post-operative. Hypotension for the purpose of the 
study is defined as a systolic blood pressure < 90 mmHg and/or a diastolic blood pressure < 60 
mmHg. Bradycardia is defined as a pulse rate < 60 beats per minute and respiratory depression 
as a respiratory rate < 12 cycles per minute.  
Pain assessment for this study will rely on the women’s self-reporting of pain intensity and such 
reports will be recorded exactly as stated by the women. Trained and blinded research assistants 
will assess the post-operative pain intensities of the women at 4, 8 and 24 hours after the surgery 
using the Numerical Rating Scale (NRS) for pain (they are house officers who will be rotating 
through other postings other than obstetrics and gynaecology at the time of the study). It will be 
ensured that all the trial documents are concealed in an opaque envelope during their visits to the 
ward.  
At 48 hours post-operative, the researcher will obtain records of pentazocine use during the first 
24 hours after caesarean section from the drug chart of the women using a purpose designed 
proforma. This will include the frequency of pentazocine administration and the cumulative dose 
of pentazocine administered during the first 24 hours post-operative. Forms and proformas to be 
used during the study are shown in appendix 1 – 5.  
Data Management 
The envelopes containing the trial documents will be retrieved by the researcher at 48 hours 
post-operative for each participant. A Microsoft excel spreadsheet template designed to capture 
all the participant information and assessment obtained in the study was saved electronically by a 
blinded research assistant responsible for data entry. The retrieved envelopes will be sent to this 
research assistant for data entry into the excel spreadsheet on weekly basis. During weekly data 
entry, participants will be identified by the serial number / identification number on the envelope 
and trial documents. At the completion of the study, the allocation information (A or B) for each 
participant will be disclosed to the research assistant for inclusion in the data by matching with 
the serial number / identification number previously entered. The completed data will thereafter 
be sent to the data analyst.  
Data Monitoring  
As part of the protocol of the research ethics committee of our institution for internal audit of 
clinical trials, a research auditor will be appointed to inspect the study materials and occasionally 
observe the study procedure. Adverse events or serious adverse events will be reported to the 
office of the research ethics committee of the Federal Medical Centre, Yenagoa at intervals. 
Filled study forms and proforma that will be collated will first be sent to the office of the 
research auditor, where they will be assessed for substantial compliance with the protocol for the 
study. 


Statistical Methods 
An intention-to-treat (ITT) analysis will be performed as the primary analysis for the study. 
Statistical analysis of the data obtained from the study will be done using Statistical Package for 
Social Sciences (SPSS) version 22. Frequencies and percentages of categorical data will be 
determined. Mean and standard deviation of numerical data will also be determined. Continuous 
data like pain score, age, weight and dose of pentazocine used will be assessed for normality 
using the Shapiro-Wilk statistical analysis test. Normally distributed data will be compared 
between experimental and control groups using Student ‘t’ test. Non-normally distributed data 
will be compared using a Mann-Whitney U test. Chi-square test of proportions will be used to 
compare categorical data like age-range, ethnicity, parity, pentazocine use, frequency of 
pentazocine use between experimental and control groups. A p-value < 0.05 will be considered 
significant statistically. If there are statistically significant differences in covariates like age, age-
range, ethnicity, parity and weight between the experimental and control groups, a multivariate 
analysis will be carried out to determine associations with the outcome measures. A clinically 
relevant difference in mean pain score of NRS < 1.3 will be the basis for non-inferiority of 
experimental group to control group.   
Ethical Considerations 
The study protocol was approved by the institutional review board in the study centre on August 
17, 2020 and updated on October 12, 2020.  
Other ethical considerations for the study include voluntary participation, informed consent, 
respectful care, confidentiality, beneficence, non-maleficence and safety of researchers. Steps to 
be taken to address these ethical issues are elaborated in Table 2. 
Table 2: Ethical considerations 
Voluntary Participation, Informed Consent, Respectful Care and Confidentiality 
After an explanation of the aims and processes of this study to an eligible pregnant woman in 
simple and clear terms, she reserves the right to voluntarily participate in the study and to give 
a written informed consent. She also reserves the right to withdraw from the study at any stage 
if she so wishes. Data obtained from this study will be anonymized to ensure the 
confidentiality of participants.   
Contents of such counseling included: 
1. The procedure to be followed in the study, 
2. The benefits to the individual, 
3. The discomforts and risks that are reasonably expected, 
4. The options of therapy, 
5. The willingness of the investigator to answer questions, 
6. The right to refuse or to withdraw from the study without prejudice. 
The language of communication will be English language, but where the patient does not 
understand English language, she will be communicated to in colloquial English. 


Every woman will be treated with fairness, equity and a sense of human dignity, irrespective 
of the age, socioeconomic circumstance, ethnic or religious lineage. 
Beneficence 
1. If this study suggests that a combination of intravenous magnesium sulphate, 
intravenous paracetamol and rectal diclofenac as preventive, opioid-free, multimodal 
analgesia for acute post-operative pain after caesarean section is as effective and safe 
as the routine opioid-based multimodal analgesia regimen used at Federal Medical 
Centre, Yenagoa, 
then,  
I. 
Pregnant women who participated would have contributed to efforts needed to 
address opioid abuse and addiction attributable to peri-operative administration 
of opioids.  
II. 
Pregnant women who participated in the experimental arm would also have had 
the opportunity to avoid repeated administration of opioids peri-operatively 
thus prevent abuse and associated sequelae. 
2. The cost of all analgesics administered for control of acute post-operative pain after 
caesarean section was taken off the participants in the study and born by the 
investigator. 
Non-Maleficence 
The participants in this study will not be subjected to harm in any way. Drugs to be used in 
this study are drugs with already known side effects and established safety profiles. Drugs 
with the same batch number were sourced from reliable drug companies with reputation. Any 
patient with contraindication to administration of any of the drugs will be excluded the study. 
Calcium gluconate/calcium chloride and naloxone; antidotes for magnesium toxicity and 
opioid-induced respiratory depression respectively, will be made available during the study, 
although these complications are rarely encountered from clinical experience with the use of 
these drugs within the stipulated dose range. Emergency drugs to manage hypersensitivity 
reactions (should they occur despite precautionary measures taken) will be made available.  
Safety of Researchers 
Appropriate Infection Prevention and Control (IPC) measures will be ensured during the 
course of the research. Research assistants engaged in the study were given a refresher course 
on the use of personal protective equipment and safe administration of parenteral medications. 
 
Availability of Data and Materials 
Study materials to be used are attached as appendices to this protocol. Once the data analysis for 
the study described in this protocol is complete, the datasets analysed will be available from the 
corresponding author on reasonable request from 3 months after publication of results.  
 


Dissemination of Results 
At the results stage of the study, the protocol and results will be submitted to clinicaltrials.gov as 
required. Study results will be published in a peer-reviewed, open access journal. The authors will 
also seek to present the study in professional scientific conferences. 
DISCUSSION  
To the best of our knowledge, no study has specifically assessed the effectiveness and safety of a 
combination of peri-operative intravenous magnesium sulphate, intravenous paracetamol, and 
post-operative rectal diclofenac as opioid-free analgesia for management of acute post-operative 
pain after a caesarean section. Similar to the PROSPECT recommendation, our study protocol 
adopted the use of intravenous paracetamol and intravenous NSAID as baseline analgesics. We 
chose to introduce magnesium sulphate as part of our opioid-free multimodal analgesia regimen 
because of its adjuvant analgesic effect established from studies that found that administration of 
magnesium sulphate in the peri-operative period decreases post-operative pain and opioid use 
without side effect.35-40 We also relied on the preventive analgesic effect of administration of 
intravenous paracetamol and intravenous magnesium sulphate before surgical incision, continued 
intraoperatively and post-operatively. Our regimen is less cumbersome and less invasive compared 
to use of abdominal wall block techniques. In addition, magnesium sulphate is a familiar drug to 
the obstetrician, readily available and affordable in most settings where comprehensive emergency 
obstetric care is offered, easy to administer and it has been well tolerated clinically.  
After the commencement of our study by this protocol, the PROSPECT recommendation for 
caesarean section was updated by December, 2020, following an updated systematic review of 
literatures on post caesarean section analgesia between May, 2014 and October, 2020.45 The new 
recommendation saw the addition of intraoperative intravenous dexamethasone, specific mention 
of use of Joel-Cohen incision and abdominal binders under surgical technique and use of 
transcutaneous electrical nerve stimulation as an adjuvant postoperatively (Grade A 
recommendations).46 Preoperative oral gabapentinoid was replaced with oral paracetamol.46 Part 
of the limitations of studies used by PROSPECT in making its recommendation are that the 
majority of the analgesic intervention was not evaluated against a multimodal analgesic regimen; 
most of the RCTs assessed a single-analgesic intervention against opioid monotherapy and 
placebo, and that the studies were only in women undergoing planned caesarean section.45,47 These 
issues have been addressed already in the protocol for our own study, in that, magnesium sulphate 
was evaluated as part of an opioid-free analgesia regimen against a routine opioid-based 
multimodal analgesia regimen used in the study setting, and our study included women undergoing 
urgent caesarean section.  
The RCT design of our study gives it strength while the subjectivity of the perception, expression 
and assessment of pain was a limitation. The intensity of pain cannot be perfectly compared 
between one person and the other, neither can it be objectively measured. In addition, this being a 
single-centred study limits the generalizability of the findings to other populations. 
Conclusion 
We have described our protocol for a randomized, controlled, single-centred clinical trial to 
determine the effectiveness and safety of a combination of peri-operative intravenous magnesium 
sulphate and intravenous paracetamol, plus post-operative rectal diclofenac as opioid-free, 
multimodal analgesia for management of acute post-operative pain after a caesarean section. Our 


goal for presenting our protocol for this study is so that it may be replicated in other settings, 
possibly modified for future studies and ultimately join the efforts towards solving the ongoing 
opioid addiction crisis. 
 
 
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Appendix 1: Proforma for biodata and study consent form 
 
 
 
 


Appendix 2: Proforma for theatre/recovery room vital signs and adverse event 
 


Appendix 3: Proforma for adverse event that may occur on the ward 
 
OPIOID-FREE ANALGESIA FOR THE MANAGEMENT OF ACUTE POST-
OPERATIVE PAIN FOLLOWING CAESAREAN SECTION. 
(OFAAPPCS TRIAL) 
WARD ADVERSE EVENT FORM 
 
PATIENT’S IDENTIFICATION NUMBER:    FMCY/O&G/OFAAPPCS/2020/_______ 
SECTION ONE: ANY INCIDENCE OF THE FOLLOWING EVENT? 
 (Tick as appropriate) 
Drug 
given 
I.V MgSO4 
 
I.M Pentazocine 
I.V Paracetamol 
Supp. Diclofenac 
• 
Hypersensitivity reaction (not related to blood transfusion) 
 
• 
Respiratory depression  
 
• 
Bradycardia  
 
• 
Hypotension 
 
• 
Vomiting 
 
• 
Light-headedness/Presyncope 
 
• 
Constipation 
 
• 
Ileus 
 
• 
Pruritus 
 
• 
Urinary retention 
 
    SECTION TWO: ANY OTHER CLINICALLY SIGNIFICANT ADVERSE EVENT? 
(Tick and write as appropriate) 
• 
NO 
 
• 
YES 
 
• 
If Yes, Please 
give details. 
 


Appendix 4: Proforma for pain score 
 
 
 
 
 
 


Appendix 5: Proforma for pentazocine use