Can common differences in our genes explain why some people are more sensitive to pain than others?
| ISRCTN | ISRCTN16294731 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16294731 |
| Secondary identifying numbers | B3236 |
- Submission date
- 02/11/2021
- Registration date
- 25/11/2021
- Last edited
- 14/01/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Other
Plain English Summary
Background and study aims
We know that genes influence our sensitivity to pain, but we do not have a full understanding of how this happens - which genes are important and why?
Who can participate?
We are recruiting participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who have specific, common, changes in a gene heavily implicated in pain sensitivity call Transient Receptor Potential A1 (TRPA1).
What does the study involve?
We will invite participants to take part, based upon their known genetic information i.e. if they have or do not have these common changes in their TRPA1 gene. We will then carefully determine their pain sensitivity using quantitative sensory testing. This includes determining their heat and cold detection thresholds and pain thresholds, their mechanical detection thresholds, and their mechanical (punctate and pressure) pain thresholds. We will then apply 10% cinnamaldehyde, an activator of TRPA1, to their forearm for 20 minutes, measure any changes in blood flow and then repeat the sensory testing.
What are the possible benefits and risks of participating?
There are some risks associated with participating. Some pain will be experienced, though this will be minimized. The stimuli, particularly the cinnamaldehyde, may cause some redness of the skin which will settle on its own. Any sensations evoked by the cinnamaldehyde can be reduced by gently cooling the affected area.
Where is the study run from?
University of Bristol (UK)
When is the study starting and how long is it expected to run for?
November 2018 to January 2022
Who is funding the study?
Above and Beyond, the University Hospitals Bristol Charity, via their Neurosciences and Mental Health Legacies Call. Grant reference ABL-2019-20-10.
The UK Medical Research Council and Wellcome (Grant ref: 21765/Z/19/Z) and the University of Bristol provide core support for ALSPAC.
Individual team members are supported by the MRC (MC_UU_00011) and the University of Bristol, Wellcome Trust (202802/Z/16/Z) and Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019).
Who is the main contact?
Dr Jim Dunham, james.p.dunham@bristol.ac.uk
Contact information
Scientific
School of Physiology, Pharmacology and Neuroscience
Bristol Anaesthesia, Critical Care and Pain Research
Faculty of Biomedical Sciences
University of Bristol
Biomedical Sciences Building - E27
Tankard's Close
Bristol
BS8 1TD
United Kingdom
 ORCID ID |
0000-0002-1435-5043 |
|---|---|
| james.p.dunham@bristol.ac.uk |
Study information
| Study design | Single centre adaptive recall by genotype study |
|---|---|
| Primary study design | Observational |
| Secondary study design | An adaptive recall by genotype |
| Study setting(s) | Other |
| Study type | Other |
| Participant information sheet | 40614_PIS_v6_09Sep2019.pdf |
| Scientific title | Evaluating the association of TRPA1 gene polymorphisms with pain sensitivity: A protocol for an adaptive recall by genotype study. |
| Study hypothesis | Individuals homozygous for common (MAF>1%) SNPs in TRPA1 will have altered acute pain sensitivity as demonstrated by Quantitative Sensory Testing. |
| Ethics approval(s) | Approved 29/10/2019, ALSPAC Ethics and Law Committee (Children of the 90s, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK; +44 (0)117 331 0010; alspac-ethics@bristol.ac.uk), ref: 94082 |
| Condition | The association of TRPA1 gene polymorphisms with pain sensitivity |
| Intervention | Five TRPA1 SNPs known to introduce missense mutations and with minor allele frequencies of >1% hypothesized to impact TRPA1 function will be investigated. The effect of these five SNPs will be assessed in three groups due to the high linkage disequilibrium between two pairs of minor alleles. QST results from the individuals in these three test groups will be compared to those of a reference group who are homozygous for the major (ancestral) allele at all five SNPs. The results will be subject to planned interim assessments for futility to alter recruitment if there is low probability of success of detecting a phenotype for a given allele until a maximum of 100 participants have been assessed. Heat pain threshold is the primary outcome. The SNPs of interest were rs7819749, rs959976 with rs920829, rs16937976 with rs13268757 (dbSNP build 154, GRCh38) and a control group of individuals homozygous for all five major alleles. Investigators and participants will remain blind to genotype throughout the recruitment and data collection phases of the study. The participants will be assessed using quantitative sensory testing (QST) before and after sensitisation by topical application of 10% cinnamaldehyde (a known activator of TRPA1). QST paradigms are based upon the DFNS protocol, streamlined in line with the primary hypothesis to omit some non-nociceptive assessments. |
| Intervention type | Genetic |
| Primary outcome measure | Measured before and after 20 minute topical application of 10% cinnamaldehyde in ethanol: Heat pain threshold measured using a thermode (Medoc TSA-II, Medoc, Israel, or similar) on the right volar forearm. The temperature of the thermode will change at 1°C per second until the participant reports either detection of temperature change, or detection of pain via a mouse click. The thermode then returns to a neutral temperature of 32°C. The first trial will be discarded as an acclimatisation and then followed by 3 experimental repeats. |
| Secondary outcome measures | Measured before and after 20 minute topical application of 10% cinnamaldehyde in ethanol: 1. CDT, cold detection threshold measured using the same method as the heat threshold with a cooled thermode 2. WDT, warm detection threshold measured using the same method as the heat threshold 3. CPT, cold pain threshold measured using using the same method as the heat threshold with a cooled thermode 4. MDT, mechanical detection threshold 5. MPT, mechanical pain threshold 6. MPS; mechanical pain sensitivity Thresholds for innocuous mechanical stimuli will be assessed using calibrated von Frey filaments (TouchTest; Stoelting, USA) via the method of levels. Mechanical pain thresholds, again via the method of limits, and stimulus response curves will be assessed using calibrated punctate needle stimulators (PinPricks; MRC Systems, Germany). For the stimulus response curve participant numerical pain ratings from 0 (no pain) to 100 (worst imaginable pain), will be assessed 5 times with 7 filaments exerting forces from 8 to 512mN presented in a randomised manner 7. Brush, presence or absence of brush allodynia measured with 5 standardised brush strokes (SenseLab; via MRC Systems, Germany) 8. Pressure, deep pressure pain threshold measured using an algometer (Somedic, Sweden) applied over the muscles of the right volar forearm 9. Axonal flare in response to cinnamaldehyde will be measured using full-field laser perfusion imaging (FLPI) of the target area of skin (moorFLPI-2; Moor Instruments) |
| Overall study start date | 01/11/2018 |
| Overall study end date | 01/01/2022 |
Eligibility
| Participant type(s) | Other |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 100 |
| Participant inclusion criteria | Participants within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who are a regionally representative cross-sectional population aged around 30 years (with a correspondingly relatively low incidence of chronic pain). |
| Participant exclusion criteria | 1. Neurological disorders including peripheral neuropathy 2. Regular use of analgesics 3. Any pain medication taken within 24 hours of QST 4. Pregnancy 5. Acute or Chronic pain conditions 6. Severe anxiety/depression 7. Allergy to cinnamon, mustard, alcohol / chlorhexidine wipes, latex. 8. Use of non-prescribed or recreational drugs (assessed by questionnaire). |
| Recruitment start date | 27/01/2020 |
| Recruitment end date | 31/12/2021 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Bristol
BS8 1TD
United Kingdom
Sponsor information
University/education
Senate House
Tyndall Ave
Bristol
BS8 1TH
England
United Kingdom
| red-office@bristol.ac.uk | |
| Website | http://bristol.ac.uk/ |
"ROR" |
https://ror.org/0524sp257 |
Funders
Funder type
Charity
No information available
Government organisation / Universities (academic only)
- Alternative name(s)
- Universitas Bristolliensis, bristoluniversity, bristoluni
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Wellcome, WT
- Location
- United Kingdom
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/12/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The protocol and data will be published in a high impact peer-reviewed journal. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 6 | 09/09/2019 | 04/11/2021 | No | Yes |
| Protocol (preprint) | 01/12/2020 | 04/11/2021 | No | No | |
| Protocol article | 12/01/2022 | 14/01/2022 | Yes | No |
Additional files
Editorial Notes
14/01/2022: Publication reference added.
26/11/2021: Internal review.
04/11/2021: Trial's existence confirmed by University of Bristol.
