Evaluation of a New Pain Management Regime for Oocyte Pick-Up During Fertility Treatment

The primary objective of this study is to demonstrate that a single pre-procedure dose of sublingual sufentanil 30 µg reduces intra-procedural pain during oocyte pick-up compared with the standard midazolam-based regimen, as measured by repeated Visual Analog Scale scores (0–100 mm) recorded every two minutes throughout the procedure. This comparison is clinically relevant for optimizing pain management in women undergoing in vitro fertilization or assisted reproductive technology procedures, where adequate analgesia is essential for patient comfort and procedural success.

The secondary objectives include:

• To compare time to readiness for discharge after oocyte pick-up between study arms.
• To compare patient satisfaction with pain management at approximately 24 hours post-procedure using the APS-POQ-R questionnaire.
• To compare rescue analgesic use during oocyte pick-up and within 24 hours post-procedure.
• To compare adverse events, including oxygen desaturation, respiratory depression, nausea, vomiting, and excessive sedation between arms.
• To explore procedure and fertility outputs, including number of oocytes retrieved and early clinical pregnancy rate if measured.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted exclusively of **female adults** undergoing **in vitro fertilization** or **assisted reproductive technology** with planned **transvaginal oocyte pick-up**. Participants were required to have **ASA physical status** I–III, indicating a range from healthy individuals to those with mild to moderate systemic disease. The trial population was selected based on the ability to provide informed consent and comply with study procedures, including pain ratings during the oocyte retrieval procedure and 24-hour follow-up assessments. Participants were required to meet institutional safety thresholds for ambulatory oocyte pick-up procedures, including specific airway assessment parameters, **body mass index** limitations, and comorbidity considerations as defined by site standard operating procedures. The trial addressed **acute procedural pain** associated with oocyte retrieval in women undergoing fertility treatment.

This clinical trial evaluates a new pain management regimen for women undergoing oocyte pick-up during in vitro fertilization or assisted reproductive technology procedures. The study is designed as a randomized, controlled trial comparing the efficacy of a single pre-procedure dose of sublingual sufentanil 30 micrograms (Dzuveo) with a standard midazolam-based regimen in reducing intra-procedural pain. The trial qualifies as a low-intervention clinical trial under Article 2(3) of Regulation (EU) No 536/2014, as all medicinal products are authorized in the European Union and European Economic Area and are administered according to their Summaries of Product Characteristics and routine peri-procedural care protocols. The study is categorized as Phase IV, investigating authorized medicinal products used within their approved indications and in accordance with evidence-based practice. The trial involves no additional invasive diagnostic procedures beyond standard care, and the additional burden to participants is limited to pain assessments during the procedure and completion of a 24-hour follow-up questionnaire.

The primary objective of the trial is to demonstrate that sublingual sufentanil 30 micrograms administered before the procedure reduces intra-procedural pain during oocyte pick-up compared with the standard midazolam-based regimen. Pain intensity is measured using repeated Visual Analogue Scale scores (0 to 100 millimeters) recorded every two minutes throughout the procedure, from the first puncture until completion. The primary derived measure will be determined according to the statistical analysis plan and may include mean, median, or area under the curve of Visual Analogue Scale scores over time. Secondary objectives include assessment of patient satisfaction with pain management at approximately 24 hours post-procedure using the Revised American Pain Society Patient Outcome Questionnaire, post-procedural Visual Analogue Scale pain scores at arrival in recovery, 30 minutes, one hour, and discharge, rescue analgesic use at home within 24 hours, incidence of nausea and vomiting at multiple time points, respiratory depression and other adverse events during and immediately after the procedure, vaginal bleeding patterns, recovery metrics including time to discharge and procedure duration, and hormonal and fertility markers including estradiol, follicle-stimulating hormone, luteinizing hormone, progesterone, follicle count, human chorionic gonadotropin at two weeks post-embryo transfer, and clinical pregnancy at approximately seven weeks.

Eligible participants are female adults undergoing in vitro fertilization or assisted reproductive technology with a planned transvaginal oocyte pick-up at the study site. Participants must be able to provide informed consent and comply with study procedures, including pain ratings during oocyte pick-up and 24-hour follow-up. Inclusion criteria require American Society of Anesthesiologists physical status classification I to III under institutional oocyte pick-up sedation and analgesia pathways, and participants must meet institutional safety thresholds for ambulatory oocyte pick-up, including airway assessment, body mass index limits, and comorbidity considerations as per site standard operating procedures. The trial utilizes several medicinal products with defined roles: Dzuveo 30 micrograms sublingual tablet containing sufentanil administered sublingually serves as the test product; Midazolam Viatris 5 milligrams per milliliter solution for injection containing midazolam administered intramuscularly serves as the comparator; and auxiliary medicinal products include Dafalgan Forte 1 gram film-coated tablets containing paracetamol administered orally, Xanax 0.5 milligrams tablets containing alprazolam administered orally, Linisol 2 percent solution for injection containing lidocaine hydrochloride monohydrate administered by infiltration, and Voltaren Retard 75 milligrams prolonged-release tablets containing diclofenac sodium administered orally. Maximum daily doses are established for each product: paracetamol 4000 milligrams, alprazolam 0.5 milligrams, midazolam 5 milligrams, lidocaine 200 milligrams, sufentanil 30 micrograms, and diclofenac sodium 150 milligrams, with a maximum treatment period of one day for all products.

The estimated recruitment start date is January 1, 2026, with an estimated trial end date of December 31, 2026, indicating an overall trial duration of approximately 12 months. Participant involvement begins with a screening and inclusion visit conducted approximately two days before the scheduled oocyte pick-up procedure, during which informed consent is obtained, eligibility criteria are verified, and baseline assessments including hormonal markers (estradiol, follicle-stimulating hormone, luteinizing hormone, progesterone) and follicle count are recorded. On the day of the oocyte pick-up procedure, participants are randomized to receive either sublingual sufentanil or intramuscular midazolam premedication according to the assigned treatment arm. During the procedure, Visual Analogue Scale pain scores are recorded every two minutes from the first puncture until completion, and standard peri-procedural monitoring includes oxygen saturation, respiratory rate, blood pressure, and heart rate. Immediate post-procedural assessments are conducted in the recovery area at arrival (T0), 30 minutes, one hour, and at discharge, recording Visual Analogue Scale pain scores, vital signs, incidence of nausea and vomiting, vaginal bleeding patterns, and any adverse events. Recovery metrics including time to discharge, procedure duration, number of oocytes retrieved, and operator experience level are documented. A follow-up assessment is conducted at approximately 24 hours post-procedure via telephone or questionnaire to evaluate patient satisfaction with pain management using the Revised American Pain Society Patient Outcome Questionnaire, rescue analgesic use at home (type and amount), and delayed adverse events including nausea and vomiting. Additional fertility outcome assessments include measurement of human chorionic gonadotropin at two weeks post-embryo transfer and clinical pregnancy confirmation at approximately seven weeks gestation for participants who undergo embryo transfer. The expected length of participant involvement from screening to the final follow-up assessment is approximately eight to nine weeks, depending on individual treatment timelines and pregnancy outcomes.

Early termination from the study may occur under several conditions. Participants may voluntarily withdraw consent at any time without providing a reason and without prejudice to their ongoing clinical care. The investigator may discontinue a participant if continuation poses a safety risk, if the participant experiences a serious adverse event requiring alternative management, if the participant fails to comply with study procedures including pain assessments or follow-up visits, or if the oocyte pick-up procedure is cancelled or significantly modified from the planned protocol. Administrative reasons for early termination include termination of the entire trial by the sponsor or regulatory authorities, protocol violations that compromise data integrity or participant safety, or loss to follow-up despite reasonable attempts to contact the participant. All participants who discontinue early will be followed for safety as clinically indicated, and available data collected up to the point of discontinuation will be included in the analysis according to the statistical analysis plan.

The experimental medication in this clinical trial is Dzuveo, which contains sufentanil as the active substance. The product is formulated as a sublingual tablet with a strength of 30 micrograms. The medication is administered via the sublingual route, with a maximum daily dose of 30 micrograms and a maximum total dose of 30 micrograms. The maximum treatment period is 1 day. Dzuveo holds marketing authorization in the European Union under the authorization number EU/1/18/1284/001 and is manufactured by Laboratoire Aguettant.

The comparator treatment utilized in this study is Midazolam Viatris, which contains midazolam as the active pharmaceutical ingredient. This product is supplied as a solution for injection at a concentration of 5 mg/ml. The route of administration is intramuscular, with a maximum daily dose of 5 mg and a maximum total dose of 5 mg. The maximum treatment period is 1 day. This product is marketed in Belgium under authorization number BE339385 and is manufactured by Viatris GX.

Several auxiliary medications are employed in this clinical trial to support the pain management protocol. Paracetamol is administered as Dafalgan Forte 1 g film-coated tablets via the oral route. The maximum daily dose is 4000 mg, with a maximum total dose of 4000 mg over a treatment period of 1 day. This product is authorized in Belgium under number BE259551 and manufactured by UPSA SAS.

Alprazolam is provided as Xanax 0.5 mg tablets for oral administration. The maximum daily dose is 0.5 mg, with a maximum total dose of 0.5 mg over 1 day. This product holds Belgian marketing authorization number BE120933 and is manufactured by Viatris Healthcare.

Lidocaine hydrochloride monohydrate is administered as Linisol 2% solution for injection via the infiltration route. The maximum daily dose is 200 mg, with a maximum total dose of 200 mg over a treatment period of 1 day. This product is authorized in Belgium under number BE166704 and manufactured by B.Braun Melsungen AG.

Diclofenac sodium is supplied as Voltaren Retard 75 mg prolonged-release tablets for oral administration. The maximum daily dose is 150 mg, with a maximum total dose of 150 mg over 1 day. This product holds Belgian marketing authorization number BE165471 and is manufactured by Novartis Pharma N.V.

The primary endpoint for efficacy assessment is overall intra-procedural pain intensity during oocyte pick-up, measured using the Visual Analogue Scale (VAS) ranging from 0 to 100 mm. VAS scores will be recorded every 2 minutes from the first puncture until completion of the procedure. The primary derived measure will be determined according to the Statistical Analysis Plan and may include mean or median VAS scores or VAS area under the curve over time.

Secondary endpoints include patient satisfaction with pain management assessed approximately 24 hours post-procedure using the APS-POQ-R instrument. Post-procedure VAS pain scores will be collected at multiple timepoints: at arrival in recovery (T0), at 30 minutes, at 1 hour, and at discharge. Rescue analgesic use at home within 24 hours, including type and amount, will be documented. The incidence of nausea and vomiting will be evaluated at pre-procedure, immediate post-procedure, 30 minutes, 1 hour, discharge, and at 24 hours. Respiratory depression and other adverse events during and immediately after the procedure will be monitored through oxygen saturation (SpO₂), respiratory rate, and clinical observation. Vaginal bleeding will be assessed as usual, less than usual, or more than usual. Recovery metrics will include time to discharge, procedure duration, number of oocytes retrieved, and operator experience level. Hormonal and fertility markers will be measured, including estradiol, FSH, LH, progesterone, and follicle count obtained 2 days pre-procedure, HCG at 2 weeks post-embryo transfer, and clinical pregnancy at approximately 7 weeks.