Session-Order Sensitivity of TS and OA in a Capsaicin Crossover Model

NCT07625475 | Completed

• 2 other identifiers: GUELPH-REB-19-06-003REB #19-06-003
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Temporal summation (TS) and offset analgesia (OA) are widely used psychophysical endpoints in pain research that index different components of central nociceptive processing. While crossover designs are commonly used in experimental pain studies to reduce between-participant variability, the design-stability of these endpoints under repeated testing during experimental sensitisation is not well characterised. This study compared the design-stability of mechanical TS (Sumscore) and offset analgesia magnitude (OffA) in a two-period, vehicle-controlled crossover trial of capsaicin-evoked secondary hyperalgesia in healthy adults. The primary aim was methodological: to determine whether session-order effects differ between TS and OffA when these are used as outcome measures in two-period crossover designs of capsaicin-induced central sensitisation. Topical capsaicin was used as a reversible experimental intervention to create a controlled, transient state of secondary hyperalgesia rather than as a therapeutic intervention. The study informs endpoint selection in future quantitative sensory testing (QST) crossover trials.

Conditions

Hyperalgesia; Pain Perception; Central Nervous System Sensitization; Pain Threshold

Keywords

temporal summation; offset analgesia; topical capsaicin; secondary hyperalgesia; quantitative sensory testing (QST); crossover trial; session-order effect; central sensitisation

Outcome Measures

Primary Outcomes (2)

• Mechanical temporal summation (Sumscore)

  Sumscore is a summed pinprick temporal-summation response computed from a train of 16 repeated 256 mN pinprick stimuli delivered perpendicularly to the skin at 1 Hz, paced by a metronome. Pain ratings (NPRS 0-10) immediately after each stimulus were summed (Clouse et al., 2021). The primary Sumscore endpoint was pre-specified as the average of the lateral and inferior testing sites at the lateral elbow, expressed as a baseline-normalised ratio.

  Baseline and 10, 20, 30, and 40 min post-intervention (within each of two sessions, separated by a minimum 1-week washout)

• Offset analgesia magnitude (OffA)

  OffA was measured during a three-phase stepped-stimulus thermal protocol (32-45-46-45-32°C; T1/T2/T3 phases) using a 32 x 32 mm Peltier contact thermode (TSA-II NeuroSensory Analyzer, Medoc AMS). Continuous pain ratings were collected via CoVAS (0-100) at 10 Hz. OA magnitude was quantified as peak minus nadir CoVAS during the 46°C hold and the subsequent 45°C phase. The primary OffA endpoint was pre-specified as the duration-averaged value across three thermal hold durations (5, 10, and 15 s at 46°C), expressed as a baseline-normalised ratio.

  Baseline and 10, 20, 30, and 40 min post-intervention (within each of two sessions, separated by a minimum 1-week washout)

Secondary Outcomes (2)

• Within-session temporal stability (ICC(2,1)) of Sumscore and OffA

  10, 20, 30, and 40 minutes post-intervention

• Differential design-sensitivity (Measure × Intervention × Period interaction)

  10, 20, 30, and 40 minutes post-intervention, across two crossover periods separated by a minimum 1-week washout.

Study Arms (2)

Arm 1: Sequence A-to-B (Capsaicin first)

EXPERIMENTAL

Participants received topical 0.075% capsaicin (Zostrix) cream (5 mL) in Period 1, followed by topical inert (Lubriderm) vehicle (5 mL) in Period 2. Periods were separated by a minimum 1-week washout. n = 6.

Drug: Topical 0.075% capsaicin cream (Zostrix); Other: Topical vehicle lotion (Lubriderm)

Arm 2: Sequence B-to-A (Vehicle first)

ACTIVE COMPARATOR

Participants received topical inert (Lubriderm) vehicle (5 mL) in Period 1, followed by topical 0.075% capsaicin (Zostrix) cream (5 mL) in Period 2. Periods were separated by a minimum 1-week washout. n = 10.

Drug: Topical 0.075% capsaicin cream (Zostrix); Other: Topical vehicle lotion (Lubriderm)

Interventions

Topical 0.075% capsaicin cream (Zostrix) DRUG

5 mL of 0.075% capsaicin cream (Zostrix; Hi-Tech Pharmacal, Amityville, NY, USA) applied to a 5 x 10 cm target region on the lateral elbow and to bilateral C5-C6 cervicothoracic dermatomes (total 15 mL). The cream was massaged into the skin by a gloved investigator until no residue was visible. Used as an experimental probe to evoke transient, reversible secondary hyperalgesia; not under therapeutic evaluation.

Arm 1: Sequence A-to-B (Capsaicin first); Arm 2: Sequence B-to-A (Vehicle first)

Topical vehicle lotion (Lubriderm) OTHER

5 mL of inert vehicle lotion (Lubriderm; Johnson \& Johnson, Montgomery, NJ, USA) applied to the same dermatomes as the capsaicin condition (total 15 mL), using the identical preparation and massage technique. Matched to the capsaicin cream for colour and texture.

Arm 1: Sequence A-to-B (Capsaicin first); Arm 2: Sequence B-to-A (Vehicle first)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adult volunteers (≥18 years of age)
• Able to provide written informed consent in English

You may not qualify if:

• Current or chronic pain
• Neurological disease
• Skin conditions or sensitivity over the test sites to capsaicin
• Contraindications to thermal stimulation of the skin
• Musculoskeletal conditions that could alter somatosensory processing
• Use of analgesic medications within 24 hours prior to each session
• Use of caffeine within 24 hours prior to each session
• Use of alcohol within 24 hours prior to each session

Sponsors & Collaborators

• University of Guelph: lead

Study Sites (1)

Human Health Sciences, University of Guelph

Guelph, Ontario, N1G2W1, Canada

Location

Related Publications (3)

• Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ. 2019 Jul 31;366:l4378. doi: 10.1136/bmj.l4378.

  PMID: 31366597 BACKGROUND

• Clouse JA, et al. The reliability of a temporal summation Sumscore. (2021)

  BACKGROUND

• Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol. 2002 Apr;87(4):2205-8. doi: 10.1152/jn.00730.2001.

  PMID: 11929939 BACKGROUND

MeSH Terms

Conditions

Hyperalgesia

Interventions

Capsaicin

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Polyunsaturated Alkamides; Amides; Organic Chemicals; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: By design, participants, the investigator who applied the creams and collected the outcome data, and the data analyst were blinded to allocation. The randomisation sequence was computer-generated by a research assistant not involved in testing and concealed in sequentially sealed, opaque envelopes; capsaicin and vehicle creams were matched for colour and texture and dispensed in unlabelled containers. Because topical 0.075% capsaicin can produce perceptible burning and visible erythema, participant and investigator blinding may have been incompletely maintained. Participant allocation guesses were collected and investigator awareness of allocation was not formally assessed. The data analyst remained blinded through data lock and application of pre-specified exclusion criteria, and was unblinded only after the analysis dataset was finalised.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Two-period crossover. Participants were randomised in a 1:1 intended allocation (actual 6:10) to one of two sequences (capsaicin-first or vehicle-first). Sessions were separated by a minimum 1-week washout.

Study Record Dates

• First Submitted: May 22, 2026
• First Posted: June 4, 2026
• Study Start: May 1, 2024
• Primary Completion: April 30, 2025
• Study Completion: April 30, 2025
• Last Updated: June 4, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: On request following publication of the primary manuscript.
• Access Criteria: Reasonable request to the corresponding author for non-commercial research use, subject to a data-use agreement consistent with University of Guelph data-sharing policy.

Locations

CA (1)