Chronic PainCAIRNCT06127693
Childhood Adversity, Inflammatory Reactivity and Persistent Pain
An observational study of Chronic Pain and Central Sensitisation, run by University of Cape Town at 1 site in South Africa.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Chronic Pain, Central Sensitisation, Immune Response
- What is being tested?
- Tetravalent Influenza Vaccine and High-frequency electrical stimulation
- Type of treatment
- Vaccines, Lifestyle or therapy programme
- How many people
- 101 participants
- Where
- 1 siteSouth Africa
- Study dates
- 21 Jun 2022to 20 Sep 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- Between the ages of 18 and 65 years old.
Who cannot join
- 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,
Show all 17Show fewer
- 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),
- Smoking habit,
- Febrile illness in the preceding 4 weeks.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Roles of Childhood Adversity and Inflammatory Reactivity in Promoting Pain and Fatigue After Provocation
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:
Read more
- Does participant-reported childhood adversity predict levels of IL-6 and TNF-α after in vitro provocation of whole blood using endotoxin?
- 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)?
- 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?
For this study, the investigators will recruit and enrol 96 healthy human adults (18 - 65 years old) with a range of adverse experiences during childhood. Participants will attend 2 study sessions during which the investigators will take a sample of blood, assess pressure pain threshold before and after cold water immersion, assess heart rate variability, and assess the surface area of secondary skin hypersensitivity after electrical stimulation. At the end of the first session, participants will receive the influenza vaccination.
Read the detailed description
Background
Adverse experiences during childhood (childhood adversity) are associated with an increased risk of persistent pain and fatigue in adulthood. While the physiological relationships that link childhood adversity, persistent pain, and fatigue are unclear, all three factors are each associated with heightened innate immune and neural responses in adulthood. As such, neuroimmune interactions could underlie the relationship between childhood adversity, persistent pain, and fatigue, although the balance between the immune and neural influences likely varies across individuals.The investigators hypothesise that childhood adversity influences persistent pain and fatigue by priming: 1) immune, 2) neural, or 3) both systems, within an individual. Although previous studies have examined either immune or neural processes representing vulnerability to persistent pain and fatigue, the investigators are not aware of any study that has investigated both systems in the same cohort.
Methods
96 healthy adult humans with a range of childhood adversity history will undergo psychophysical testing before and after in vivo neural provocation (high frequency electrical stimulation) and, separately, immune provocation (influenza vaccine). Study proxies for vulnerability to persistent pain are surface area of secondary skin hypersensitivity induced by neural provocation and change in conditioned pain modulation after immune provocation; the proxy for vulnerability to fatigue is heart rate variability 24h after immune provocation. Immune responsiveness is represented by IL-6 and TNF-α levels in supernatant after in vitro lipopolysaccharide provocation of whole blood. The investigators hypothesise that levels of IL-6 and TNF-α after in vitro immune provocation will be positively associated with the area of secondary skin hypersensitivity after in vivo neural provocation, and negatively associated with conditioned pain modulation after in vivo immune provocation.
- Being tested
- Tetravalent Influenza Vaccine, High-frequency electrical stimulation
- Keywords
- Secondary hyperalgesia, Pain, Innate immune response, Adverse childhood experiences, Conditioned pain modulation
- Medical subject headings
- Chronic Pain, Hyperalgesia, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tetravalent Influenza VaccineDrug
Also called flu vaccine
All participants will receive the tetravalent influenza vaccine
High-frequency electrical stimulationBehavioural
All participants will receive High-frequency electrical stimulation
| Study group | Role | What they receive |
|---|---|---|
| Mild childhood adversity (control) | Score of 25-36 on the Childhood Trauma Questionnaire-short form. Receives: Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation | |
| Moderate childhood adversity | Score of 37-67 on the Childhood Trauma Questionnaire-short form. Receives: Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation | |
| Severe childhood adversity | Score of >67 on the Childhood Trauma Questionnaire-short form. Receives: Drug: Tetravalent Influenza Vaccine; Behavioral: High-frequency electrical stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline
Provoked inflammatory response
Mean z-scores of IL-6 and TNF-alpha levels
Measured: Baseline
Secondary hypersensitivity (surface area)
Surface area of secondary hypersensitivity induced by high-frequency electrical stimulation
Measured: 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)
Measured: 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).
Measured: Baseline and 24 hours after the influenza vaccine (immune provocation).
Secondary outcomes (5)
Heart rate variability
Using 3-lead ECG and Biopac System
Measured: Baseline, 40 minutes after the high-frequency electrical stimulation (neural provocation), and 24 hours after the influenza vaccine (immune provocation).
N-back test
Assessing working memory
Measured: Baseline and 24 hours after the influenza vaccine (immune provocation).
6-minute walk test
Assessing physical exertion and recovery
Measured: Baseline and 24 hours after the influenza vaccine (immune provocation).
Secondary hypersensitivity (magnitude)
Change in ratings on the Sensation and Pain Rating Scale to punctate mechanical stimulation. 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).
Measured: 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
Change in ratings on the Sensation and Pain Rating Scale to punctate mechanical stimulation. 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).
Measured: Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Nov 2023
- Study start21 Jun 2022
- Primary completion20 Sep 2023
- Study completion20 Sep 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 101 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cape Town
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Victoria Madden, University of Cape Town
- Investigators
- Victoria J Madden, PhD, Principal investigator, University of Cape Town
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06127693
- Sponsor's protocol ID
- HREC REF 560/2021
- Acronym
- CAIR
- Status last verified
- Nov 2023
- First submitted
- 31 Oct 2023
- Last updated
- 13 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The data management plan complies with the South African Protection of Personal Information Act (POPIA) of 2013. All coded data (from the screening, enrolment and data collection phases) will be stored in a password-protected Google Drive folder, under the governance of the PI. Additionally, the back-up external hard drives will be stored in a secure location.
Publications
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.
PubMed 40372281
Study at a glance
From the registry record, last updated by the sponsor on 13 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Roles of Childhood Adversity and Inflammatory Reactivity in Promoting Pain and Fatigue After Provocation
- ClinicalTrials.gov ID
- NCT06127693
- Acronym / sponsor ID
- CAIR / HREC REF 560/2021
- Keywords
- Secondary hyperalgesia, Pain, Innate immune response, Adverse childhood experiences, Conditioned pain modulation
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 101 participants (actual)
- Lead sponsor
- University of Cape TownUniversity, hospital or other
- Study start
- 21 Jun 2022 (actual)
- Primary completion
- 20 Sep 2023 (actual)
- Study completion
- 20 Sep 2023 (actual)
- First posted
- 13 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Does participant-reported childhood adversity predict levels of IL-6 and TNF-α after in vitro provocation of whole blood using endotoxin?
- 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)?
- 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?
For this study, the investigators will recruit and enrol 96 healthy human adults (18 - 65 years old) with a range of adverse experiences during childhood. Participants will attend 2 study sessions during which the investigators will take a sample of blood, assess pressure pain threshold before and after cold water immersion, assess heart rate variability, and assess the surface area of secondary skin hypersensitivity after electrical stimulation. At the end of the first session, participants will receive the influenza vaccination.
Detailed description
Background
Adverse experiences during childhood (childhood adversity) are associated with an increased risk of persistent pain and fatigue in adulthood. While the physiological relationships that link childhood adversity, persistent pain, and fatigue are unclear, all three factors are each associated with heightened innate immune and neural responses in adulthood. As such, neuroimmune interactions could underlie the relationship between childhood adversity, persistent pain, and fatigue, although the balance between the immune and neural influences likely varies across individuals.The investigators hypothesise that childhood adversity influences persistent pain and fatigue by priming: 1) immune, 2) neural, or 3) both systems, within an individual. Although previous studies have examined either immune or neural processes representing vulnerability to persistent pain and fatigue, the investigators are not aware of any study that has investigated both systems in the same cohort.
Methods
96 healthy adult humans with a range of childhood adversity history will undergo psychophysical testing before and after in vivo neural provocation (high frequency electrical stimulation) and, separately, immune provocation (influenza vaccine). Study proxies for vulnerability to persistent pain are surface area of secondary skin hypersensitivity induced by neural provocation and change in conditioned pain modulation after immune provocation; the proxy for vulnerability to fatigue is heart rate variability 24h after immune provocation. Immune responsiveness is represented by IL-6 and TNF-α levels in supernatant after in vitro lipopolysaccharide provocation of whole blood. The investigators hypothesise that levels of IL-6 and TNF-α after in vitro immune provocation will be positively associated with the area of secondary skin hypersensitivity after in vivo neural provocation, and negatively associated with conditioned pain modulation after in vivo immune provocation.
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Mild childhood adversity (control) | – | Drug: Tetravalent Influenza Vaccine, Behavioral: High-frequency electrical stimulationScore of 25-36 on the Childhood Trauma Questionnaire-short form. |
| Moderate childhood adversity | – | Drug: Tetravalent Influenza Vaccine, Behavioral: High-frequency electrical stimulationScore of 37-67 on the Childhood Trauma Questionnaire-short form. |
| Severe childhood adversity | – | Drug: Tetravalent Influenza Vaccine, Behavioral: High-frequency electrical stimulationScore of >67 on the Childhood Trauma Questionnaire-short form. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (1 listed)
- Between the ages of 18 and 65 years old.
Key exclusion criteria (17 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tetravalent Influenza VaccineAlso: flu vaccineAll participants will receive the tetravalent influenza vaccine | Drug | Mild childhood adversity (control), Moderate childhood adversity, Severe childhood adversity |
| High-frequency electrical stimulationAll participants will receive High-frequency electrical stimulation | Behavioural | Mild childhood adversity (control), Moderate childhood adversity, Severe childhood adversity |
Primary outcome
Childhood Trauma Questionnaire-Short form
Time frame: Baseline
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).
Provoked inflammatory response
Time frame: Baseline
Mean z-scores of IL-6 and TNF-alpha levels
Secondary hypersensitivity (surface area)
Time frame: 30 minutes, 45 minutes and 60 minutes after the high-frequency electrical stimulation (neural provocation)
Surface area of secondary hypersensitivity induced by high-frequency electrical stimulation
Conditioned pain modulation
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
Change in pressure pain threshold (test stimulus) after cold water immersion (conditioning stimulus)
Temporal summation
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
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).
5 secondary outcomes
Heart rate variability
Time frame: Baseline, 40 minutes after the high-frequency electrical stimulation (neural provocation), and 24 hours after the influenza vaccine (immune provocation).
N-back test
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
6-minute walk test
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
Secondary hypersensitivity (magnitude)
Time frame: 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
Time frame: Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Nov 2023.
- Derived from this study: PubMed 40372281Bedwell 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.
- Individual participant dataSharing planned: Yes. The data management plan complies with the South African Protection of Personal Information Act (POPIA) of 2013. All coded data (from the screening, enrolment and data collection phases) will be stored in a password-protected Google Drive folder, under the governance of the PI. Additionally, the back-up external hard drives will be stored in a secure location.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Victoria J Madden, PhD principal investigator
University of Cape Town
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Chronic Pain and Central Sensitisation, run by University of Cape Town at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Childhood Trauma Questionnaire-Short form (time frame: Baseline). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06127693, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Nov 2023.