A Non-inferiority Trial on Pain Relief During Oocyte Retrieval

Study Overview
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Brief Summary
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The objective of the trial is to compare fentanyl and midazolam vs diazepam and pethidine in terms of the pain levels and post-operative side effects of TUGOR

Detailed Description
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In-vitro fertilization / embryo transfer (IVF / ET) is a well-established method to treat various causes of infertility. It involves multiple follicular development, retrieval of oocytes and embryo transfer after fertilization. Egg retrieval at the majority of IVF units is performed through the transvaginal route under ultrasound guidance (TUGOR) [1]. During TUGOR, the needle has to pass through the mucosa in the vaginal vault in order to puncture the follicles in the ovary. The procedures are generally short, lasting about 20-30 minutes but are still painful without anaesthesia or analgesia. Intravenous sedation with or without local anaesthesia is the most widely used method. Conscious sedation is a safe and cost-effective method of providing analgesia and anesthesia for TUGOR. [2] It is easy to administer in cooperative and motivated patients. It has a relatively low risk for adverse effects on oocyte and embryo quality and pregnancy rates. [3] Paracervical block (PCB) in conjunction with conscious sedation during TUGOR was shown to significantly reduce the pain during TUGOR when compared to PCB alone [4]. A Cochrane review on various methods of sedation and analgesia for pain relief during TUGOR has shown no single method or delivery system appeared superior for pregnancy rates and pain relief. [5] Most of the methods seemed to work well and the effect was usually enhanced by addition of another method such as pain relief with paracervical block. [6] The investigators' reproductive centre has recently aligned with the Assisted Reproduction Centre of the University of Hong Kong (HKU). The investigators are using 0.1mg fentanyl and 5mg midazolam intravenously for pain relief in TUGOR at Kwong Wah Hospital (KWH) whereas 5mg diazepam and 25mg pethidine intravenously are being used in HKU. The investigators would like to compare fentanyl and midazolam vs diazepam and pethidine in terms of pain levels and post-operative side effects of TUGOR in this prospective non-inferiority randomized double-blinded trial. The investigators postulate there are no differences in the pain levels between two groups but the postoperative side effects may be different.

Official Title
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A Prospective, Non-inferiority Randomized Double-blinded Trial Comparing Fentanyl and Midazolam vs Diazepam and Pethidine for Pain Relief During Oocyte Retrieval

Conditions
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Infertility

Intervention / Treatment
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* Drug: fentanyl
* Drug: pethidine
* Drug: Diazepam
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: presence of both ovaries; body mass index less than 30 written informed consent and Chinese Exclusion Criteria: IVF cycle converted from ovulation induction or intrauterine insemination cycles; patient requests general anaesthesia for TUGOR; history of drug sensitivity to lignocaine/fentanyl/midazolam/diazepam/pethidine; less than 3 dominant follicles present; dominant follicles present in one ovary only and TUGOR performed on one side only.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A: intravenous fentanyl, midazolam<br>group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval | Drug: fentanyl<br>* arm A receiving iv fentanyl<br>Drug: Midazolam<br>* arm A receiving iv midazolam<br>* Other names: dormicum;|
| Placebo Comparator: B: intravenous pethidine, diazepam<br>group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval | Drug: pethidine<br>* arm B receiving iv pethidine<br>Drug: Diazepam<br>* arm B receiving iv diazepam<br>* Other names: valium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Level During Oocyte Retrieval | The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful | will be assessed within 4 hours of oocyte retrieval | 
| Pain Level After Oocyte Retrieval | The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful | will be assessed within 4 hours of oocyte retrieval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Side Effects by Type | side effects will be scored by yes or no | will be assessed within 4 hours of oocyte retrieval | 
| Patient's Satisfaction on Oocyte Retrieval | satisfaction will be scored from 0-3 (0=excellent, 1=satisfactory, 2=fair, 3=unsatisfactory) | will be assessed within 4 hours of oocyte retrieval | 
| Clinical Pregnancy Rate | presence of intrauterine sac in ultrasound after a positive pregnancy test | will be assessed within ten weeks of oocyte retrieval | 
| Ongoing Pregnancy Rate | positive fetal heart pulsation seen in ultrasound at eight weeks of gestation | will be assessed within ten weeks of oocyte retrieval | 
| Patient's Satisfaction on Pain Relief | satisfaction on pain relief will be scored at 0-10 (10 being most satisfied) | within 4 hours after retrieval | 
| Sedation Level | S = sleeping, easily aroused; 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to stimuli | immediately after retrieval | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fentanyl, midazolam, pethidine, diazepam