Investigating Composite Biomarkers for Pain Catastrophizing

Pain is a complex, multidimensional, and subjective experience; and although, investigators use a single word "pain", to describe our perception, multiple mechanisms contribute to the generation and maintenance of pain. To help diagnosing and improving pain management, there is a need for developing tools. These tools may include measurements of substances, or biomarkers, in the blood; e.g. small molecules called microRNA and proteins. In these experiments, the investigators would like to investigate how the psychological response to stress and pain alters the impulses in the brain and the content of microRNA and proteins in the blood. The future aim is to identify patients in high risk of developing and maintaining chronic pain and to be able to treat chronic pain efficiently.

Study Overview

• Status: Recruiting
• Conditions: Pain, Acute
• Intervention / Treatment: Drug: hypertonic saline; Drug: isotonic saline

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laura Petrini, PhD; Phone Number: 0045 99409826; Email: lap@hst.aau.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9220
    • Recruiting
    • Aalborg University
    • Contact: Silvia Lo Vecchio; Phone Number: +4521397785; Email: slv@hst.aau.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy men and women in the age 18-80 years
• Speak and understand English

Exclusion Criteria:

• Acute and chronic pain
• Pregnancy or breastfeeding
• Drug addiction defined as the use of cannabis, opioids or other drugs
• Present or previous history of neurological, dermatological, immunological, musculoskeletal, cardiac disorder or mental illnesses that may affect the results (e.g. Neuropathy, muscular pain in the upper extremities, etc.)
• Focal and generalized seizure
• Surgery or any other therapy for epilepsy
• Present or previous AEDs (anti-epileptic drugs) administration
• Present or previous use of epileptic devices (<1 year prior the enrolment)
• Lack of ability to cooperate
• Current use of medications that may affect the trial, such as antipsychotics and pain killers as well as systemic or topical steroids and anti-inflammatory drugs.
• Skin diseases
• Consumption of alcohol or painkillers 24 hours before the study days and between these
• Participation in other trials within 1 week of study entry (4 weeks in the case of pharmaceutical trials)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: isotonic saline	Drug: isotonic saline; The site of injections will be determined by palpation of the contracted First Dorsal Interosseus (FDI) muscle. The skin will be cleaned with alcohol before injection. A bolus injection of 0.2 mL isotonic saline (9 mg/mL) will be administered to the FDI muscle as control.
Experimental: hypertonic saline	Drug: hypertonic saline; The site of injections will be determined by palpation of the contracted First Dorsal Interosseus (FDI) muscle. The skin will be cleaned with alcohol before injection. A bolus injection of hypertonic saline (7% NaCl) will be administered to the FDI muscle using a 1 mL syringe with a disposable needle (27G), and 30 the volume of the bolus will be 0.2 mL .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oscillations of the main electroencephalogram (EEG) frequency	Electroencephalographic (EEG) recording will be performed placing a 64-electrodes cap over the scalp according to the 10-20 international system. Oscillations of the main EEG frequency bands (delta, alpha, beta, gamma) from the frontal and parietal lobes will be detected and correlated to the individual pain rate as well as the dimensions of the psychological questionnaires.	10 minutes of recording before isotonic/hypertonic injection
Oscillations of the main electroencephalogram (EEG) frequency	Electroencephalographic (EEG) recording will be performed placing a 64-electrodes cap over the scalp according to the 10-20 international system. Oscillations of the main EEG frequency bands (delta, alpha, beta, gamma) from the frontal and parietal lobes will be detected and correlated to the individual pain rate as well as the dimensions of the psychological questionnaires.	10 minutes of recording after isotonic/hypertonic injection
Perturbation of the electroencephalogram (EEG) rhythms	Electroencephalographic (EEG) recording will be performed placing a 64-electrodes cap over the scalp according to the 10-20 international system. Perturbation of the above-mentioned EEG rhythms will be measured in response to the hypertonic/isotonic saline injection and compared to a resting state baseline recording.	10 minutes of recording before isotonic/hypertonic injection
Perturbation of the electroencephalogram (EEG) rhythms	Electroencephalographic (EEG) recording will be performed placing a 64-electrodes cap over the scalp according to the 10-20 international system. Perturbation of the above-mentioned EEG rhythms will be measured in response to the hypertonic/isotonic saline injection and compared to a resting state baseline recording.	10 minutes of recording after isotonic/hypertonic injection
Collection of blood samples	Whole blood samples (5 mL per each time point, a total of 20 mL per subject) will be collected into SST™ II Advance Serum Separation Tubes containing anticoagulant EDTA.	time 0 (baseline)
Collection of blood samples	Whole blood samples (5 mL per each time point, a total of 20 mL per subject) will be collected into SST™ II Advance Serum Separation Tubes containing anticoagulant EDTA.	Time 1 (3 hours)
Collection of blood samples	Whole blood samples (5 mL per each time point, a total of 20 mL per subject) will be collected into SST™ II Advance Serum Separation Tubes containing anticoagulant EDTA.	time 2 (24 hours)
Collection of blood samples	Whole blood samples (5 mL per each time point, a total of 20 mL per subject) will be collected into SST™ II Advance Serum Separation Tubes containing anticoagulant EDTA.	time 3 (48 hours)
Collection of blood samples	Whole blood samples (5 mL per each time point, a total of 20 mL per subject) will be collected into SST™ II Advance Serum Separation Tubes containing anticoagulant EDTA.	time 4 (72 hours)
MicroRNAs (miRNAs) expression analysis	From the blood samples previously collected, miRNA will be isolated for a subsequent miRNA library preparation. Subsequently, extracted miRNA will be reversely transcribed, and cDNA will be used for total miRNAs sequencing.	time 0 (baseline)
MicroRNAs (miRNAs) expression analysis	From the blood samples previously collected, miRNA will be isolated for a subsequent miRNA library preparation. Subsequently, extracted miRNA will be reversely transcribed, and cDNA will be used for total miRNAs sequencing.	time 1 (3 hours)
MicroRNAs (miRNAs) expression analysis	From the blood samples previously collected, miRNA will be isolated for a subsequent miRNA library preparation. Subsequently, extracted miRNA will be reversely transcribed, and cDNA will be used for total miRNAs sequencing.	time 2 (24 hours)
MicroRNAs (miRNAs) expression analysis	From the blood samples previously collected, miRNA will be isolated for a subsequent miRNA library preparation. Subsequently, extracted miRNA will be reversely transcribed, and cDNA will be used for total miRNAs sequencing.	time 3 (48 hours)
MicroRNAs (miRNAs) expression analysis	From the blood samples previously collected, miRNA will be isolated for a subsequent miRNA library preparation. Subsequently, extracted miRNA will be reversely transcribed, and cDNA will be used for total miRNAs sequencing.	time 4 (72 hours)
Proteome analysis	From the blood samples previously collected, the protein concentration will be determined. Protein sequencing will be done using mass spectrometers.	time 0 (baseline)
Proteome analysis	From the blood samples previously collected, the protein concentration will be determined. Protein sequencing will be done using mass spectrometers.	time 1(3 hours)
Proteome analysis	From the blood samples previously collected, the protein concentration will be determined. Protein sequencing will be done using mass spectrometers.	time 2 (24 hours)
Proteome analysis	From the blood samples previously collected, the protein concentration will be determined. Protein sequencing will be done using mass spectrometers.	time 3 (48 hours)
Proteome analysis	From the blood samples previously collected, the protein concentration will be determined. Protein sequencing will be done using mass spectrometers.	time 4 (72 hours)
Metabolome analysis	From the blood samples previously collected. Metabolites will be investigated and identified by a 4D feature finding using Metaboscape.	time 0 (baseline)
Metabolome analysis	From the blood samples previously collected. Metabolites will be investigated and identified by a 4D feature finding using Metaboscape.	time 1(3 hours)
Metabolome analysis	From the blood samples previously collected. Metabolites will be investigated and identified by a 4D feature finding using Metaboscape.	time 2 (24 hours)
Metabolome analysis	From the blood samples previously collected. Metabolites will be investigated and identified by a 4D feature finding using Metaboscape.	time 3 (48 hours)
Metabolome analysis	From the blood samples previously collected. Metabolites will be investigated and identified by a 4D feature finding using Metaboscape.	time 4 (72 hours)
Plasma cortisol levels measurement	From the blood samples previously collected, plasma levels of cortisol will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 0 (baseline)
Plasma cortisol levels measurements	From the blood samples previously collected, plasma levels of cortisol will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 1(3 hours)
Plasma cortisol levels measurements	From the blood samples previously collected, plasma levels of cortisol will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 2 (24 hours)
Plasma cortisol levels measurements	From the blood samples previously collected, plasma levels of cortisol will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 3 (48 hours)
Plasma cortisol levels measurements	From the blood samples previously collected, plasma levels of cortisol will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 4 (72 hours)
Plasma Interleukin-6 (IL-6) levels measurements	From the blood samples previously collected, plasma levels of IL-6 will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 0 (baseline)
Plasma Interleukin-6 levels measurements	From the blood samples previously collected, plasma levels of IL-6 will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 1(3 hours)
Plasma Interleukin-6 levels measurements	From the blood samples previously collected, plasma levels of IL-6 will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 2 (24 hours)
Plasma Interleukin-6 levels measurements	From the blood samples previously collected, plasma levels of IL-6 will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 3 (48 hours)
Plasma Interleukin-6 levels measurements	From the blood samples previously collected, plasma levels of IL-6 will be evaluated through enzyme-linked immunosorbent assay (ELISA).	time 4 (72 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measuring Pain using VAS	The subject will rate the pain intensity continuously for 20 minutes and VAS will start from zero (0), representing no pain, and will end at one hundred (100) representing worst pain imaginable.	20 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Catastrophizing Scale (PCS) questionnaire	The PCS assesses negative and exaggerated coping concerning anticipated or experienced painful stimuli. Thirteen items have to be answered on a 5-points Likert-type scale from 0 (non at all) to 4 (all the time).	time 0 (baseline)
Positive and Negative Affect Schedule (PANAS) questionnaire	The PANAS measures positive affects (PA) dimensions ( "the extent to which a person feels active, enthusiastic, and alert") and negative affects (NA) dimensions (a condition of "general distress and unpleasable engagement"). Twenty words are associated with the subject's current feelings and have to be rated on a 5-points Likert-type scale from 1 (non at all) to 5 (extremely).	time 0 (baseline)
Reinforcement Sensitivity Theory - Personality Questionnaire (RST-PQ).	The RST-PQ contains the following subscales: Fight-Flight-Freeze System (FFFS, 10 items), related to active avoidance of adverse stimuli;; Behavioral Inhibition System (BIS, 23 items), related to anxiety and passive avoidance of adverse stimuli;; Behavioral Approach System (BAS, 32 items), it reflects reward interest, reward reactivity, impulsivity. In total, 65 items have to be answered on a 4-points Likert-type scale, from 1 (non at all) to 4 (highly).	time 0 (baseline)
State-Trait Anxiety Inventory - Form Y (STAI-Y)	The STAI-Y questionnaire measures two types of anxiety, the state and the trait anxiety, as well as the severity of the overall anxiety level. The questionnaire is divided into two sections of 20 items each to be rated on a 4-points Likert-type scale from 1 (non at all) to 4 (very much).	time 0 (baseline)
Heart rate assessment	An electrocardiogram (ECG) will be recorded with a standard 3-lead montage (one electrode on each wrist and the third on the left ankle)	time 0 (baseline)

Collaborators and Investigators

• Sponsor: Aalborg University
• Investigators: Principal Investigator: Laura Petrini, PhD, Aalborg University

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 16, 2021
• First Submitted That Met QC Criteria: March 5, 2021
• First Posted (Actual): March 8, 2021

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain
• Other Study ID Numbers: N-20200095

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No