Precision Medicine for Nociception, Sngception and Proprioception.

Study Overview
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Brief Summary
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Precision medicine is defined as an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person by the Precision Medicine Initiative. Patients have different response to different treatment modalities, and sore/pain medicine is no exception. In our experience, low-level laser (LLL), ultrasound, and prolotherapy can reduce sore /pain through different genetic pathway. Whether the therapeutic effect is controlled by the genetic variants of those sore /pain related genes or not, is still in debate. The aims of this study are (1) To set up next generation sequencing (NGS)-based approach to find genetic variants which can determine the response of sng/pain treatment modalities and the phenotype of idiopathic scoliosis. (2) To find possible metabolomics and proteomic markers of sng/pain. (3) To determine the algorithm of precision medicine for sng/pain control via the genetic markers. Investigators will recruit 80 myofascial pain participant and 80 idiopathic scoliosis participant from Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital Bei-Hu Branch in 2023 and 2025. The myofascial pain participant participants will receive LLL, ultrasound, and prolotherapy, and the therapeutic effect will be recorded. The clinical trial will evaluate the Sng / pain (VAS) and muscle tone of the idiopathic scoliosis participant. The blood and urine samples from the first, the second, and the third visits will be analyzed by next generation sequencing, and mass spectrometry to find the possible biomarker in 2024 and 2025. Investigators expect to develop the individualized treatment plan by means of these biomarkers. Hopefully, the results will be widely applied in the field of sore /pain medicine.

Detailed Description
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Precision medicine is defined as an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person by the Precision Medicine Initiative. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage by the International Association for the Study of Pain (IASP).Traditionally, soreness, or sng, is also included as one of the pain sensation. Recently, the investigators defined sngception as acid and/or soreness sensation in the somatosensory system, and revealed that analgesia in muscle is through substance P and Tac1. According to the clinical outcome, some patients responded to physical agents well, and some preferred injections. The genetic variants of the above-mentioned genes might be the determining factors of differential therapeutic effects. However, it took about 4-8 weeks for a patient to switch from one treatment option to another one. If the investigators can determine the optimal treatment modality by genetic biomarkers, the treatment course and total expanse will decrease a lot. The investigators hypothesize that the genetic variants of the proposed genes (TRPV1, ASIC1a, ASIC3, Tac1, COMT, TCL1A, POMC, RGS4, ASIC2, ASIC4, TRPA1, NK1R, G2A, GPR4, OGR1, TDAG8, TASK1, TASK2, TASK3, TREK1, P2X2, P2X3, P2X5, TRPV4, KCNK1, NTSR1, NTSR2, CaV3.2, Nav1.1, Piezo1, and Piezo2, Runx3 or Egr3, endothelin converting enzyme-like 1 (ECEL1), myosin heavy chain genes MYH3 and MYH8, myosin-binding protein C gene, MYBPC1, and TNNI2, TNNT3 and TPM2 that encode the muscle regulatory proteins troponin I, troponin T and beta-tropomyosin) could be the prognostic biomarkers of sng/pain treatments or proprioceptive function. 1.Specific Aims To set up next generation sequencing (NGS)-based approach to find genetic variants which can determine the response of sng/pain treatment modalities and the phenotype of idiopathic scoliosis. To find possible metabolomics and proteomic markers of sng/pain. To determine the algorithm of precision medicine for sng/pain control via the genetic markers. 2.In the past years, our team had some achievements to justify the search of genetic variants for development of a new sore/pain treatment algorithm. Analgesia of LLLT is through TRPV1. Analgesia by therapeutic ultrasound is through ASIC3. Dextrose injection decreased chronic muscle pain through ASIC1a. Biomarker for sng/pain in fibromyalgia. 3.Study design (1) Participants from cohort A-Myofascial pain syndrome: The investigators will recruit 80 participant from National Taiwan University Hospital and its Branch hospital. B. Clinical trail design: After obtaining the informed consent, the basic demographic data, including age, gender, job, education level, and past medical history of eligible participant are collected. The eligible participant first received LLLT with a 685-nm wavelength and an output of 30 mW at energy densities of 8 J/cm2 at trigger point of upper trapezius muscle. The pre- and post-treatment VAS-pain and VAS-sng are collected for LLLT phenotype determination, respectively. Then, they are conveniently assigned into two groups (40 subjects in each group): A. therapeutic ultrasound group; B. prolotherapy group. Group A receives therapeutic ultrasound. Group B receives hypertonic prolotherapy at perimysium of upper trapezius muscle. No other medication or physical modality was given to avoid efficacy interference in both groups. The recruited participant receive evaluation before and after injection, and 2-week after injection. The primary outcome is VAS-pain and VAS-sng. The secondary outcomes are pain threshold, muscle tone, and SF-36. Venous blood and urine samples were collected at first visit and 2-week visit, respectively. The buffy coat is separated after centrifugation, and stored as well. The urine samples were aliquoted and stored at -80 ºC in a locked freezer for future analysis. Rescue therapy (cross-over treatment): If the participant does not satisfy with their first round treatment and the improvement of VAS is less than 10, then they are eligible to receive the rescue therapy-the treatment in the other group. And they will return to clinic for another 2 weeks. The outcome variables will be collected in the 3rd visit as well. (2) Participants from cohort B-idiopathic scoliosis: The investigators will recruit 80 participant from National Taiwan University Hospital and its Branch hospital, and Taichung Veteran Hospital. B. Clinical Trail design: After obtaining the informed consent, the basic demographic data, including age, gender, job, education level, physical activity level, and past medical history of eligible participant are collected. The recruited participant receive evaluation for once only. The collected parameters include Cobb's angle, spine rotational angle, VAS-pain and VAS-sng, strength and tone of paraspinal muscle, and SF-36. Venous blood and urine samples were also collected. Data analyses will be performed as previously described. Briefly, the raw sequencing data will be aligned to the reference human genome (Feb. 2009, GRCh37/hg19) using BWA-MEM. The investigators will use Picard to perform necessary data conversion, sorting and indexing. The main variant calling process, for both single nucleotide variants and indels, will be operated with the GATK software package. Structural variants will also be identified. The investigators will apply ANNOVAR to appropriately annotate the genetic variants; this include at least gene annotation, amino acid change annotation, SIFT scores, PolyPhen2 score, dbSNP identifiers, 1000 Genome Project allele frequencies, gnomAD allele frequencies and ClinVar database with variant clinical significance. The investigators will then use IGV to view the mapping and annotation of sequences on a graphic interface. The allele frequencies of variants of interest will be compared between different groups of participants. The investigators will look for possible rare variants with very strong effects (the single-gene model) as well as relatively common variants with moderate to strong effects (the complex phenotype model).

Official Title
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Precision Medicine for Nociception, Sngception and Proprioception.

Conditions
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Pain, Chronic, Rehabilitation, Pain, Shoulder, Idiopathic Scoliosis

Intervention / Treatment
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* Device: LASER
* Device: Ultrasound
* Drug: Prolotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.Cohort A: (1) Age between 20-100 years old. (2) VAS>=30 or VAS>=30 at 4 kg pressure (3) Diagnosed as myofascial pain syndrome patients and willing to receive treatment (including LLLT, therapeutic ultrasound, and local dextrose injection therapy) 2. Cohort B: Age between 13-65 years old. Diagnosed as idiopathic scoliosis The diagnosis of scoliosis was confirmed by antero-posterior plain Xray with Cobbs angle larger than 10 degrees. Exclusion Criteria: 1.Cohort A: Those having active infection, malignancy, and hematological diseases were excluded. The patients had received local injection at upper trapezius within 6 months are also excluded. 2.Cohort B: Those having active infection, malignancy, and hematological diseases were excluded. Those having specific etiologies of scoliosis, including congenital scoliosis due to malformation or faulty segmentation of the vertebrae and neuromuscular scoliosis due to muscular imbalance, syndromic scoliosis or degenerative scoliosis. Pregnancy.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Cohort A-Myofascial pain syndrome The eligible patients first received LLLT with a 685-nm wavelength and an output of 30 mW at energy densities of 8 J/cm2 at trigger point of upper trapezius muscle. Then, they are conveniently assigned into two groups (40 subjects in each group): A. therapeutic ultrasound group; B. prolotherapy group. The same physician (the principal investigator) injects all patients to avoid inter-physician variability. Rescue therapy (cross-over treatment): If the participant does not satisfy with their first round treatment and the improvement of VAS is less than 10, then they are eligible to receive the rescue therapy-the treatment in the other group. Cohort B-idiopathic scoliosis: The recruited patients receive evaluation for once only. The collected parameters include Cobb's angle, spine rotational angle, VAS-pain and VAS-sng (visual analogue scale), pain threshold, strength and tone of paraspinal muscle, and SF-36.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort A-A.therapeutic ultrasound group<br>Participants: Age between 20-100 years old who diagnosed as myofascial pain syndrome patients and willing to receive treatment. Intervention: Group A (A) receives 1 MHz therapeutic ultrasound for 5 min at a frequency of 2-3 times per week at the painful upper trapezius muscle. | Device: LASER<br>* LLLT with a 685-nm wavelength and an output of 30 mW (BTL-5000 Laser, BTL, Stevenage, UK) at energy densities of 8 J/cm2 at trigger point of upper trapezius muscle.<br>Device: Ultrasound<br>* 1 MHz therapeutic ultrasound for 5 min at a frequency of 4-6 times two week at the painful upper trapezius muscle.<br>* Other names: Therapeutic ultrasound;Drug: Prolotherapy<br>* Hypertonic prolotherapy at perimysium of upper trapezius muscle. The injectant is 5ml 5% dextrose solution.<br>* Other names: Hypertonic prolotherapy;|
| Active Comparator: Cohort A-B.prolotherapy group<br>Participants: Age between 20-100 years old who diagnosed as myofascial pain syndrome patients and willing to receive treatment. Intervention: Group B receives hypertonic prolotherapy at perimysium of upper trapezius muscle. The injectant is 5ml 5% dextrose solution. | Device: LASER<br>* LLLT with a 685-nm wavelength and an output of 30 mW (BTL-5000 Laser, BTL, Stevenage, UK) at energy densities of 8 J/cm2 at trigger point of upper trapezius muscle.<br>Device: Ultrasound<br>* 1 MHz therapeutic ultrasound for 5 min at a frequency of 4-6 times two week at the painful upper trapezius muscle.<br>* Other names: Therapeutic ultrasound;Drug: Prolotherapy<br>* Hypertonic prolotherapy at perimysium of upper trapezius muscle. The injectant is 5ml 5% dextrose solution.<br>* Other names: Hypertonic prolotherapy;|
| No Intervention: Cohort B<br>Participants: Age between 13-65 years old who diagnosed as idiopathic scoliosis The diagnosis of scoliosis was confirmed by antero-posterior plain Xray with Cobbs angle larger than 10 degrees. Intervention: None | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scale (VAS) | Visual Analogue Scale (VAS) anchor the patient's mark, providing a range of scores from 0-100. score 0 means 'no pain' and score 100 means 'pain worst'. VAS have been recommended: no pain (0 point), mild pain(10-40 point), moderate pain (50-70 point ), and severe pain (80-100 point). | Baseline Visual Analogue Scale. | 
| Visual Analogue Scale (VAS) | Visual Analogue Scale (VAS) anchor the patient's mark, providing a range of scores from 0-100. score 0 means 'no pain' and score 100 means 'pain worst'. VAS have been recommended: no pain (0 point), mild pain(10-40 point), moderate pain (50-70 point ), and severe pain (80-100 point). | Only cohort A: Change from Baseline Visual Analogue Scale at 2 weeks. | 
| Visual Analogue Scale (VAS) | Visual Analogue Scale (VAS) anchor the patient's mark, providing a range of scores from 0-100. score 0 means 'no pain' and score 100 means 'pain worst'. VAS have been recommended: no pain (0 point), mild pain(10-40 point), moderate pain (50-70 point ), and severe pain (80-100 point). | Only cohort A: Change from Baseline Visual Analogue Scale at 4 weeks (if crossover) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myoton-Muscle tone | Muscle tone means state of muscle tension, which unit is Natural oscillation frequency [Hz]. This higher or lower value meaning is uncertainty. The range was from 10 to 30 Hz. | Cohort A: Baseline, week 2, week 4 (if crossover); Cohort B: Baseline | 
| Myoton- Dynamic stiffness | Muscle tone means muscle biomechanical properties, which unit is N/m. This higher or lower value meaning is uncertainty. The range was from 100 to 600 Hz. | Cohort A: Baseline, week 2, week 4 (if crossover); Cohort B: Baseline | 
| Pain thresholds | The item evaluate by SBMEDIC Algometer. The investigators used a device to press the participant's upper trapezius muscle until the subject call uncomfortable and then recorded the value. The investigators catch mean by three times. Pain thresholds range from 0 to 800 Kpa. Low thresholds means higher pain sensitivity (Pain tolerance) or muscle inflammation. | Cohort A: Baseline, week 2, week 4 (if crossover); Cohort B: Baseline | 
| SF-36 | Quality of life (36-Item Short Form Survey) | Cohort A: Baseline, week 2, week 4 (if crossover); Cohort B: Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sng / Pain, Precision medicine, Next generation sequencing, Proprioception, Prolotherapy