Childhood Adversity, Inflammatory Reactivity and Persistent Pain

NCT06127693 | Completed

• 1 other identifier: HREC REF 560/2021
• Study Type: observational
• Target: 101
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this observational study is to investigate how adverse experiences during childhood are linked to people experiencing persistent pain and fatigue in adulthood. The questions the investigators aim to answer are:

1. 1.Does participant-reported childhood adversity predict levels of IL-6 and TNF-α after in vitro provocation of whole blood using endotoxin?
2. 2.Do levels of IL-6 and TNF-α after in vitro immune provocation using endotoxin predict vulnerability to persistent pain and fatigue after in vivo immune provocation (tetravalent influenza vaccine)?
3. 3.Do levels of IL-6 and TNF-α after in vitro immune provocation using endotoxin predict vulnerability to persistent pain and fatigue after in vivo neural provocation?

Conditions

Chronic Pain; Central Sensitisation; Immune Response; Adverse Childhood Experiences

Keywords

Secondary hyperalgesia; Pain; Innate immune response; Adverse childhood experiences; Conditioned pain modulation

Outcome Measures

Primary Outcomes (5)

• Childhood Trauma Questionnaire-Short form

  The Childhood Trauma Questionnaire-Short form uses 28 statements to probe five domains: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Participants rate the extent to which each of the 28 possible situations was true during their childhood and adolescence, on a 5-point Likert scale ranging from "never true" to "very often true". The total score is computed by summing scores across forward- and reverse-coded items and a separate denial score that is obtained using three of the items. A higher score indicates more childhood adversities (i.e. worse outcome). The investigators will use the total score on the Childhood Trauma Questionnaire-Short to recruit specifically for a varied range in childhood adversity history and enrol participants into three similarly sized groups: 1) minimal childhood adversity (control) (score 25-36), 2) moderate childhood adversity (score 37-67), and 3) severe childhood adversity (score \> 67).

  Baseline

• Provoked inflammatory response

  Mean z-scores of IL-6 and TNF-alpha levels

  Baseline

• Secondary hypersensitivity (surface area)

  Surface area of secondary hypersensitivity induced by high-frequency electrical stimulation

  30 minutes, 45 minutes and 60 minutes after the high-frequency electrical stimulation (neural provocation)

• Conditioned pain modulation

  Change in pressure pain threshold (test stimulus) after cold water immersion (conditioning stimulus)

  Baseline and 24 hours after the influenza vaccine (immune provocation).

• Temporal summation

  Mechanical stimuli will be provided from a 256mN von Frey Filament. Participants will provide ratings to mechanical stimuli using the Sensation and Pain Rating Scale. The Sensation and Pain Rating Scale has a 'non-painful' range, on the left of the scale, ranging from -50 - "no sensation" to 0 - "the exact point at which what you feel transitions to pain". The 'painful' range, on the right of the scale, ranges from 0 to +50 - "most intense pain you can imagine". A lower score means less intense sensation/pain (i.e. better outcome) and a higher score means more intense sensation/pain (i.e. worse outcome).

  Baseline and 24 hours after the influenza vaccine (immune provocation).

Secondary Outcomes (5)

• Heart rate variability

  Baseline, 40 minutes after the high-frequency electrical stimulation (neural provocation), and 24 hours after the influenza vaccine (immune provocation).

• N-back test

  Baseline and 24 hours after the influenza vaccine (immune provocation).

• 6-minute walk test

  Baseline and 24 hours after the influenza vaccine (immune provocation).

• Secondary hypersensitivity (magnitude)

  Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation).

• Static and dynamic light touch, and single electrical stimulation

  Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation)

Study Arms (3)

Mild childhood adversity (control)

Score of 25-36 on the Childhood Trauma Questionnaire-short form.

Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation

Moderate childhood adversity

Score of 37-67 on the Childhood Trauma Questionnaire-short form.

Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation

Severe childhood adversity

Score of \>67 on the Childhood Trauma Questionnaire-short form.

Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation

Interventions

Tetravalent Influenza Vaccine DRUG

All participants will receive the tetravalent influenza vaccine

Also known as: flu vaccine

Mild childhood adversity (control); Moderate childhood adversity; Severe childhood adversity

High-frequency electrical stimulation BEHAVIORAL

All participants will receive High-frequency electrical stimulation

Mild childhood adversity (control); Moderate childhood adversity; Severe childhood adversity

Eligibility Criteria

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

Study Population

The investigators will recruit healthy adult volunteers (≥18 and ≤ 65 years old) with a range of childhood trauma. All interested volunteers will complete the Childhood Trauma Questionnaire-Short form. The investigators will use the total score on the questionnaire to recruit specifically for a varied range in childhood adversity history and enrol participants into three similarly sized groups: 1) minimal childhood adversity (control) (score 25-36), 2) low-moderate childhood adversity (score 37-67), and 3) severe childhood adversity (score \> 67). The investigators will enrol volunteers into each group using a 'first to qualify, book, and attend the testing sessions' approach, with the goal of achieving similar group sizes. Some groups may fill up faster than others.

You may qualify if:

• Between the ages of 18 and 65 years old.

You may not qualify if:

• Incompetence to consent and participate, e.g. acute psychosis or high suicide risk.
• Pregnancy,
• Electrical implants (e.g. pace-maker),
• Metal implants in the forearm,
• Tattoos on the forearm,
• Any visible injury or open wounds in the forearm,
• Known history of allergic reactions to vaccines,
• Has received the current season's influenza vaccine,
• Chronic pain (pain on most days for the past 3 months),
• Diabetes Mellitus,
• Peripheral vascular disease,
• Sensory impairment in the forearm, shoulder and lower back,
• Use of medication that could later skin sensitivity (e.g. analgesic medication, immune modulators, topical medical creams),
• Cardiovascular disorders,
• Medication that alters immune function (e.g. NSAIDs, steroids),

Sponsors & Collaborators

• University of Cape Town: lead

Study Sites (1)

University of Cape Town

Cape Town, Western Cape, 7701, South Africa

Location

Related Publications (1)

• Bedwell GJ, Mqadi L, Kamerman P, Hutchinson MR, Parker R, Madden VJ. Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception. Pain. 2025 Nov 1;166(11):e590-e605. doi: 10.1097/j.pain.0000000000003658. Epub 2025 May 15.

  PMID: 40372281 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Blood plasma

MeSH Terms

Conditions

Chronic Pain; Hyperalgesia; Pain

Interventions

Influenza Vaccines

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Viral Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Victoria J Madden, PhD

  University of Cape Town

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 31, 2023
• First Posted: November 13, 2023
• Study Start: June 21, 2022
• Primary Completion: September 20, 2023
• Study Completion: September 20, 2023
• Last Updated: November 13, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: In keeping with open science, and following a final assessment to eliminate the possibility of reverse identification of any participant, all coded data will be made publicly available via a public repository (e.g GitHub) at study completion.

Locations

ZA (1)