Randomized Controlled Trial of Transcutaneous Electrical Nerve Stimulation for Pain Relief During Transvaginal Oocyte Retrieval Using Conscious Sedation
Phase: NA
Conditions: Transcutaneous Electric Nerve Stimulation, Oocyte Retrieval
Sponsor: The University of Hong Kong

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STUDY PROTOCOL 
 
1. General Information  
Protocol: Randomized controlled trial of transcutaneous electrical nerve 
stimulation for pain relief during transvaginal oocyte retrieval using 
conscious sedation 
 
Principal investigator:  
Name: Professor NG Hung Yu Ernest 
Title: Clinical Professor 
Address: Room 533, 5/F, Block K, Department of Obstetrics and Gynaecology, 
Queen Mary Hospital.  
Telephone number: 2255 3406 
Email: nghye@hku.hk 
 
Co-investigators:  
Dr Wong Ho Yan Queenie 
Honorary Assistant Professor, Department of Obstetrics and Gynaecology, the 
University of Hong Kong 
 
Dr. YUNG Shuk Fei Sofie 
Clinical Assistant Professor, Department of Obstetrics and Gynaecology, the 
University of Hong Kong 
 
Dr. KO Ka Yee Jennifer 
Associate Consultant, Department of Obstetrics and Gynaecology, Queen 
Mary Hospital 
 
Dr. LI Hang Wun Raymond 
Associate Professor, Department of Obstetrics and Gynaecology, the 
University of Hong Kong 
 
2. Background 
Oocyte retrieval under the transvaginal ultrasound guidance is an essential 
part of in-vitro fertilization. It involves passing an aspiration needle into the 
pelvic cavity through the vaginal mucosa and puncturing the ovarian cortex 
to reach the ovarian follicles. Despite being less invasive when compared 
with retrieval through laparoscopy in the old days, it is still a painful 
procedure.  Different methods of pain relief have been used. The most 
commonly used modalities are conscious sedation with analgesia with or 
without paracervical block1-3, patient-controlled conscious sedation and 
analgesia4, spinal anaesthesia and general anaesthesia.  
 
The best type of analgesia has not been established. A Cochrane review in 
2013 by Kwan et al5 on pain relief for women undergoing oocyte retrieval for 
assisted reproduction conclude that the current evidence from 21 
randomized controlled trial did not support one particular method over 
another. The concurrent use of more than one method of sedation and pain 
relief resulted in better pain relief than a single modality alone.   

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The pain relief method used should be safe, effective and with minimal side-
effects. Transcutaneous electical nerve stimulation is an non-pharmacological 
and non-invasive pain relief  for nocieptive, neuropathic and musculoskeletal 
pain involving delivering pulsed electric current across skin6. It reduces 
labour pain and postpone the use of pharmacological angelsia in labouring 
women7. It has also been reported for reducing pain and increasing patients’ 
satisfaction when used in office hysteroscopy without sedation8. It has not 
been studied as a pain relief method for oocyte retrieval in assisted 
reproduction.  
 
This randomized double-blinded control trial aims to compare the pain levels 
experienced by the women using the standard conscious sedation and those 
who had TENS in addition to conscious sedation. The hypothesis is that there 
will be less pain in women with both conscious sedation and TENS.  
 
Reference : 
1. E.H.Y Ng, O.S Tang, D.K.C Chui, P.C Ho.A prospective, randomized, double 
blind and placebo controlled study to assess the efficacy of paracervical block 
in the pain relief during egg collection. Hum Reprod, 14 (1999), pp. 2783-
2787 
 
2. E.H.Y Ng, O.S Tang, D.K.C Chui, P.C Ho. A comparison of two different 
doses of lignocaine used in paracervical block during egg collection in an in-
vitro fertilization programme. Hum Reprod, 15 (2000), pp. 2148-2151 
 
3. E.H. Ng, D.K. Chui, O.S. Tang, P.C. Ho. Paracervical block with and without 
conscious sedation: a comparison of the pain levels during egg collection and 
the postoperative side effects. Fertil Steril, 75 (2001), pp. 711-717 
 
4. Lier, M. C., Douwenga, W. M., Yilmaz, F., Schats, R., Hompes, P. G., Boer, 
C. and Mijatovic, V. (2015), Patient-Controlled Remifentanil Analgesia as 
Alternative for Pethidine with Midazolam During Oocyte Retrieval in 
IVF/ICSI Procedures: A Randomized Controlled Trial. Pain Pract, 15: 487–
495. doi:10.1111/papr.12189 
 
5. Kwan I,  Bhattacharya S, Knox F, McNiel A. Pain relief for women 
undergoing oocyte retrieval for assisted reproduction. Chochrane Database 
Syst Rev 2013:1CD004829. 
 
6. Johnson 
M. Watson 
T. Transcutaneous 
electrical 
nerve 
stimulation, Electrotherapy: 
Evidence-based 
Practice. , 2008 
Edinburgh 
Churchill Livingstone (pg. 253 -96) 
 
7. Santana LS et al. Transcutaneous electrical nerve stimulation (TENS) reduces 
pain and postpones the need for pharmacological analgesia during labour: a 
randomised 
trial. 
J 
Physiother. 2016 
Jan;62(1):29-34. 
doi:10.1016/j.jphys.2015.11.002. Epub 2015 Dec 11. 
 

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8. Lison F, et al. Transcutaneous Nerve Stimulation for Pain Relief During 
Office Hysteroscopy: A Randomized Controlled Trial. JF Lisón et al. Obstet 
Gynecol 129 (2), 363-370. 2 2017. 
 
3. Trial objectives and purpose 
To evaluate if TENS is effective in reducing pain during transvaginal oocyte 
retrieval using conscious sedation 
 
4. Trial design 
This is a randomized, double-blinded placebo-controlled trial. Women who 
are eligible will be recruited and randomized into one of two groups.  
a. Treatment group: conscious sedation with 25 mg IV pethidine and 5mg IV 
diazepam and active TENS 
b. Placebo group: conscious sedation with 25 mg IV pethidine and 5mg IV 
diazepam and placebo TENS 
 
5. Selection and withdrawal of subjects 
 
5.1 Inclusion Criteria Women who undergo transvaginal oocyte retrieval who 
is aged 18 or above will be recruited.  
 
5.2 Exclusion Criteria 
Women will be excluded from the study if 
• There is only one ovary 
• Oocyte retrieval performed on one ovary only 
• There are less than three follicles >=16mm in diameter 
• Allergic to pethidine or midazolam 
• Previous experience with TENS 
• Skin damage or allergy at site of TENS pads application 
• History of pacemaker insertion 
 
5.3 Subject withdrawal criteria 
Participation in the study is totally voluntary. The subjects can withdraw 
from the study at any time and they will receive standard medical care. 
Their participation may be discontinued in case of severe side effects 
during the procedure. 
 
5.4 Criteria for exclusion from secondary analysis 
None 
 
6. Treatment of subjects 
Women who are indicated to undergo IVF in our center will be assessed for 
eligibility for the study. Written consent will be obtained from those who 
agreed to join the study.  
 
Randomization  
Eligible women recruited will be randomized according to a computer-
generated randomization list prepared by a designated research staff into 
one of the two groups on the day of oocyte retrieval:  

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1. Patient with both conscious sedation and active TENS 
2. Patient with conscious sedation and placebo TENS 
 
Blinding 
Both the women and the physician performing the procedure will be blinded 
from the group allocation.  
 
Checking of effectiveness of blinding will be done by asking the patient and 
the physician after the procedure as to which group they think the women is 
in.  
 
The procedure 
Women will receive ovarian stimulation according to the departmental 
Standard Operating Procedures. Ovarian stimulation will be monitored by 
ultrasound. Human chorionic gonodotrophin or an agonist (decapepty) will 
be given when the dominant follicle is at least 18mm and there are three 
more follicles of at least 16mm. Oocyte retrieval will then be arranged 36 
hours later. 
 
Prior to oocyte retrieval, two sets of self-adhesive electrodes will be placed 
on the women back on each side of the spine at T10 to S4 level. Instructions 
on how to titrate the TENS amplitude to the desired level that gives a strong 
non-painful electrical paraesthesia will be given to the women by the 
research nurse who is unaware of the group allocation. TENS therapy will 
start 5 minutes before the procedure and stop 5 minutes after the removal of 
oocyte aspiration needle.  The TENS machine used in the study will be the  
Endomed 482 that delivers biphasic pulsed currents using pulse duration of 
400 µs  and pulse frequencies between 80-100 pulses s−. The women in the 
treatment group will be given a TENS machine with electrodes emitting 
impulses while those in the placebo group will be given a TENS machine with 
electrodes that is not emitting any impulses.  
 
The woman lies on the operative bed in a lithotomy position. 25mg Pethidine 
and 5mg Diazepam will be given intravenously. The blood pressure and pulse 
of the woman are checked after the drug administration and the oxygen 
saturation is monitored continuously throughout the procedure. 10ml 1% 
lignocaine is injected to the paracervical region by the operating surgeon 
with a 21-gauge needle after cleansing the vagina and cervix with 
chlorhexidine. Under transvaginal ultrasound guidance, a 16-gauge ovum 
aspiration needle is introduced. Aspiration of follicles is performed with a 
suction pressure of 100 mmHg. 
 
Assessment of pain level 
The women will be asked to rate the pain according to a 100mm linear visual 
analogue scale. They will be asked to rate the pain level related to insertion of 
an intravenous cannula and the anticipated pain level of the retrieval.  
 
 

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Then women will be asked to rate  
1. The maximum vaginal pain during the procedure 
2. The maximum abdominal pain during the procedure 
3. Pain immediately after the procedure before they leave the operating room 
4. Pain at 1 hour after the procedure 
 
Patient’s satisfaction towards pain relief will be assessed before discharge. 
They will be rated as 5, ‘excellent’; 4, ‘satisfactory’; 3, ‘fair’; 2,’not very 
satisfactory’ and 1, ‘totally unsatisfactory’.  
 
Collection of data 
Apart from the pain score, patient’s satisfaction level, occurrence of side 
effects, patient’s characteristics including age, body mass index, blood 
pressure, heart rate, past history of dysmenorrhea, chronic pelvic pain, mood 
disorders will be recorded. The duration of procedure, number of follicle 
aspirated and experience of surgeons will be documented.  
 
Follow-up 
No routine follow-up visits will be arranged solely for the study unless 
considered necessary by the investigators.  
 
7. Assessment of outcome 
The primary outcome will be the pain level during oocyte retrieval 
experienced by patient. 
 
Secondary outcomes include side effects and satisfaction of patient.  
 
8. Assessment of safety 
The use of Pethidine and midazolam has been widely used and proven to be 
safe. They are the standard medications used in our unit for conscious 
sedation. Oxygen saturation, heart rate of the patient will be monitored 
throughout the procedure. Blood pressure will be measured before and after 
the procedure.  
 
TENS is a non-invasive and non-pharmacological pain relief method. The side 
effects are minimal including possible allergy to the skin pads, soreness in 
case of overuse and having an unpleasant sensation if the energy is set too 
high. The intensity of the TENS machine will be controlled by the patients 
thus minimizing the possibility of unpleasant sensation.  
 
9. Statistics 
Sample size calculation 
According to our previous study, the pain level of the retrieval using 
conscious sedation alone was 23.0 ± 21.0 (mean ± SD) on a 100-point visual 
analogue scale. Effect size is estimated based on recommendations for a 
minimum clinically relevant change of 10 mm on a 0–100 mm VAS for pain. 
Assuming the pain level is reduced from 23.0 to 13.0 on a 100-point visual 
analogue scale following TENS, the sample size required would be 70 in each 

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treatment arm to give a test of significance of 0.05 and a power of 0.8 
(Sigmastat, Jandel Scientific, U.S.A.). A total of 160 subjects or 80 subjects in 
each treatment group are needed if we anticipated a dropout rate of 10% 
 
Statistical analysis 
Demographic features between the two groups will be compared. 
Comparison of categorical variables between groups will be done using X2 –
test. For continuous variables, the Student’s t-test and Mann-Whitney U-test 
will be used for parametric and non-parametric data, respectively. All 
statistical analyses will be performed using the Statistical Program for Social 
Sciences, SPSS and MedCalc software.  
 
 
10. Direct access to source data / documents 
The investigators permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspections, providing direct access to source data/documents. 
 
 
11. Quality control and quality assurance 
Patients will be managed by the clinicians who have appropriate experience 
in performing transvaginal oocyte retrieval.  
 
12. Ethics 
Ethics approval for the current study will be obtained from the joint 
Institutional Review Board of the University of Hong Kong and Queen Mary 
Hospital. Written consent will be obtained from recruited subjects. Their 
participation is totally voluntary. They can withdraw from the study at any 
time. 
 
 
13. Data Handling and record keeping 
All data will be stored in locked computer files that are accessible only to the 
investigators and research staffs involved in the study. The principal 
investigator will be responsible for data management including data coding, 
monitoring and verification. 
 
 
14. Financing and insurance 
The study will be financed by the Department of Obstetrics and Gynaecology, 
the University of Hong Kong. 
 
 
15. Publication policy 
The findings of this study will be submitted for consideration for publication 
in peer-reviewed scientific journal. 
 
 
 
 

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16. Supplements 
The study will be conducted in compliance with the Declaration of Helsinki 
and Good Clinical Practice (ICH-GCP). 
 
 
17. We certify that the information given is complete and accurate to the best of 
our knowledge.