A Novel Two-Step Dosing Induction Strategy (The Propofol Challenge Test) to Minimize Propofol Injection Pain (PROTECT)

August 10, 2026 updated by: Erasme University Hospital

A Novel Two-Step Dosing Induction Strategy (The Propofol Challenge Test) to Minimize Propofol Injection Pain: A Time-block-Allocated Comparative Effectiveness Study

Propofol is the most widely used intravenous hypnotic agent for the induction of general anesthesia owing to its rapid onset and short duration of action. Despite its favorable pharmacokinetics and widespread use, a notable drawback persists: the incidence of pain on injection. Statistics on the matter are widely variable, but some estimates indicate that the incidence of pain with propofol injection is around 70%1.

To date, no studies have systematically evaluated whether dividing the induction dose of propofol-starting with a small sub-induction bolus (e.g., 20 mg) followed by the remainder-can reduce pain perception.

We hypothesize that a two-step administration of propofol-consisting of a small initial dose followed by the remaining dose-may serve as a nociceptive preconditioning stimulus and reduce postoperative patient-recalled injection pain compared to standard single-bolus administration.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

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Intervention / Treatment

Intervention / Treatment

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Detailed Description

Background and Rationale Propofol is the most widely used intravenous hypnotic agent for the induction of general anesthesia owing to its rapid onset and short duration of action. Despite its favorable pharmacokinetics and widespread use, a notable drawback persists: the incidence of pain on injection. Statistics on the matter are widely variable, but some estimates indicate that the incidence of pain with propofol injection is around 70%1.

The mechanism behind propofol-induced injection pain is multifactorial. Propofol, an alkylphenol, directly irritates the venous endothelium upon contact. In addition, it activates the kallikrein-kinin system, leading to the release of bradykinin and other proinflammatory mediators, which increase vascular permeability and sensitize peripheral nociceptors. While various methods-such as pretreatment with lidocaine-have shown efficacy in reducing this discomfort, a substantial proportion of patients still report moderate to severe pain during administration.

To date, no studies have systematically evaluated whether dividing the induction dose of propofol-starting with a small sub-induction bolus (e.g., 20 mg) followed by the remainder-can reduce pain perception. The rationale for this approach draws on a parallel from thermos-sensory experience: gradual immersion in cold water is often less painful than immediate full-body exposure. Anecdotal and physiological evidence suggests that incremental exposure to a noxious stimulus allows for short-term adaptive responses, reducing the subjective intensity of the experience. On a mechanistic level, this effect may involve both peripheral and central nervous system plasticity. A small initial dose of propofol may serve as a moderate nociceptive stimulus that activates endogenous inhibitory pathways-such as descending modulation from the periaqueductal gray and rostroventral medulla-which dampen the transmission of subsequent pain signals. This phenomenon, known as homotopic or heterotopic noxious conditioning stimulation (HNCS) or preconditioning-induced hypoalgesia, relies on dynamic modulation of nociceptive input at spinal and supraspinal levels.

We hypothesize that a two-step administration of propofol-consisting of a small initial dose followed by the remaining dose-may serve as a nociceptive preconditioning stimulus and reduce postoperative patient-recalled injection pain compared to standard single-bolus administration.

Sample size:

The sample size was calculated to detect a clinically meaningful difference in the incidence of injection pain between the two groups in the proposed PROTECT trial. We plan to conduct an interim analysis at the midpoint of data collection (around 4 months) to assess conditional power based on the observed effect size. At that point, we will simulate 1,000 completed trials using the interim data to estimate conditional power. If conditional power is <10%, we would consider stopping the study early for futility. Conversely, if we observe strong early evidence of efficacy, we may stop early using a conservative O'Brien-Fleming boundary (interim p < 0.005, final p < 0.048). Assuming an incidence of pain of 10% in the control group and 5% in the intervention group (absolute difference of 5%) and using a two-sided chi-square test to compare independent proportions with alpha = 0.048 (adjusted for the interim look), we estimate that 880 participants (440 per group) would be required to detect this difference with 80% power. We propose enrolling 1,000 patients to allow for potential dropout.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
2000

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

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Study Contact

Study Contact

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Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adults ≥18 years old.
  • Undergoing non cardiac surgery under general anesthesia.
  • Receiving propofol for induction.
  • No midazolam premedication
  • 20g IV Catheter below the antecubital fossa used for induction of anesthesia

Exclusion Criteria:

  • Emergency surgery.
  • Inability to communicate (language or cognitive impairment).
  • Pre-induction IV analgesia administration or patients under preoperatively
  • Patient with dementia, Alzheimer or other uncontrolled psychiatric diseases that would impact their ability to willingly participate

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Single bolus injection
Patient will receive their propofol induction dose in a single bolus injection.
Other: Bolus injection
During Months 1, 3, 5 and 7 patients will receive a full single bolus of propofol
Experimental: Fractionned injection
Patients will receive 20 mg of propofol followed by the remaining dose of propofol 30-40 seconds later.
Other: Fractionned onjection
During Months 2, 4, 6 and 8 patients will receive the same total dose but delivered in two sequential injections: an initial subdose (e.g., 20 mg), followed by the remainder of the dose after a brief interval (e.g., 30 seconds).

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Pain on injection
Time Frame: 6 hour
To compare the incidence of postoperative patient-recalled injection pain compared to standard single-bolus administration.
6 hour

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Intensity of pain
Time Frame: 6 hours
The intensity of remembered pain (Visual analog scale 0-10)
6 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Erasme University Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Alexandre Joosten, MD, PhD, Department of Anesthesiology & Perioperative Medecine, Ronald Reagan Medical Center, University of California Los Angeles, USA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 2, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 31, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 30, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 10, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 10, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 13, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 13, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 10, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HUB20260364

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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