A Non-inferiority Trial on Pain Relief During Oocyte Retrieval

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

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

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Drug: fentanyl; Drug: Midazolam; Drug: pethidine; Drug: Diazepam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Kwong Wah Hospital
• Collaborators: The University of Hong Kong; Queen Mary Hospital, Hong Kong
• Investigators: Principal Investigator: Shui Fan Lai, Kwong Wah Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: June 17, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (Estimate): July 10, 2015

Study Record Updates

• Last Update Posted (Actual): March 5, 2019
• Last Update Submitted That Met QC Criteria: February 11, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: midazolam; fentanyl; diazepam; pethidine
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antiemetics; Gastrointestinal Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Neuromuscular Agents; Muscle Relaxants, Central; Fentanyl; Midazolam; Diazepam; Meperidine
• Other Study ID Numbers: KW/FR-15-021(83-22)