Background and Objective:

m-Cresol has been used since 1980 to limit bacterial growth in parenteral medications.
Although it is generally considered safe, evidence for local side effects has appeared in
case reports and a clinical trial where changing the preservative led to a disappearance
of local discomfort. This suggests that the preservative itself, rather than the active
drug or the pH of the solution, may be responsible for a pain sensation. The objective of
this study is to systematically evaluate if subcutaneous injection of m-Cresol at
clinically relevant concentrations causes pain in humans.

Study Design:

This is a randomized, double-blind, placebo-controlled, 3-period crossover trial in
healthy volunteers (n=18). To ensure an unbiased assessment and control for potential
order effects, a Williams balanced design is utilized for the randomization of treatment
sequences.

Methodology:

Familiarization: Participants first receive an unblinded injection of control solution to
become accustomed to the experimental procedure and the numerical pain rating scale.

Interventions: Subjects receive three randomized, double-blind 300 µl subcutaneous
injections at different spots on a belly fold, separated by at least 3 cm. The treatments
include:

1. m-Cresol at 0.1%

2. m-Cresol at 0.25%

3. Control solution. Pain Assessment: For each injection, pain intensity is recorded
every 5 seconds using a numerical pain rating scale (0-100) until no pain is
reported for 30 consecutive seconds. The pain caused by the needle insertion itself
is rated separately before the injection begins to serve as a covariate for the
statistical analysis.

Statistical Analysis:

The primary endpoint is the Area Under the Curve (AUC) of the subjective pain ratings
over time. Comparisons will be made between the different m-Cresol concentrations and the
vehicle control using a linear mixed model to test the primary hypotheses.