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

Not yet recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Estimated)

2000

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

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

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
Intervention / Treatment
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

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

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

Erasme University Hospital

Investigators

  • 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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 2, 2026

Primary Completion (Estimated)

May 31, 2028

Study Completion (Estimated)

June 30, 2028

Study Registration Dates

First Submitted

August 10, 2026

First Submitted That Met QC Criteria

August 10, 2026

First Posted (Actual)

August 13, 2026

Study Record Updates

Last Update Posted (Actual)

August 13, 2026

Last Update Submitted That Met QC Criteria

August 10, 2026

Last Verified

August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID 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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