Myofascial pain syndrome (MPS) commonly occurs in individuals with various repetitive strain injuries
[1]
[2]
. Epidemiological studies show that MPS is a widespread issue, with prevalence rates ranging from 30% to 85% among those with musculoskeletal disorders
[3]
. Clinically, MPS is marked by soft tissue pain and involvement of skeletal muscles, presenting as tender nodules and taut muscle bands known as myofascial trigger points (MTrPs)
[4]
-
[8]
. MTrPs are hyperirritable spots in the muscles that can trigger pain. These points are often associated with palpable nodules and tight muscle bands; applying pressure to these areas can worsen pain, cause local muscle twitching, and lead to referred pain
[7]
[8]
. Diagnostic criteria for MPS vary and are frequently updated. In China, diagnosis requires meeting five primary criteria and at least one secondary criterion, while in the United States, meeting four criteria is usually sufficient
[9]
. These variations in criteria can sometimes lead to misdiagnosis or underdiagnosis
[3]
[10]
. Nevertheless, precise identification of trigger points is essential for effective diagnosis and treatment
[9]
[11]
. Current treatment options for MPS include pharmacotherapy (e.g., non-steroidal anti-inflammatory drugs [NSAIDs] and muscle relaxants)
[3]
[12]
, physical therapy (such as massage, stretching, and strengthening exercises)
[3]
, trigger point injections, dry needling, and cognitive behavioral therapy (CBT)
[13]
-
[19]
. Despite the standardization of pain management approaches, existing treatments have notable limitations. NSAIDs, muscle relaxants, and antidepressants can have side effects affecting the gastrointestinal, hepatic, and renal systems
[3]
[20]
[21]
. Additionally, long and often ineffective treatments, along with high costs, can place substantial economic and time burdens on patients. Emerging therapies, like stem cell therapy, face challenges due to limited clinical evidence, high costs, technical complexities, and potential risks
[22]
.
Recent research highlights the growing evidence supporting the use of hyaluronan (HA) and its fragments in managing pain, including inflammatory pain such as shoulder and neck pain, neuropathic pain from herpes zoster, chronic wound pain, cancer pain, and pain from bone metastases
[23]
-
[25]
. Specifically, the 35 kDa low molecular weight hyaluronan fragment (HA35), obtained through the enzymatic cleavage of high molecular weight HA with recombinant human sperm or bovine testicular hyaluronidase, has shown considerable promise
[26]
[27]
. Clinical studies by Xu have demonstrated that a single local injection of HA35 into the nerve trunk significantly reduces inflammation-related shoulder and neck pain
[23]
. Additionally, research suggests that HA35 may alleviate pain by inhibiting TRPV1 ion channel activation and blocking Ca2+ influx
[28]
[29]
. A study involving 98 patients with MPS indicated that the condition most commonly affects the back, followed by the neck and shoulder, with a typical duration of less than one year
[9]
. Based on these findings, we have designed a proof-of-concept clinical study to evaluate the therapeutic efficacy of HA35 trigger point injections for MPS-related pain. This study aims to assess the effects of a 15-day HA35 injection regimen in patients with back pain from MPS and to explore the feasibility of using trigger points as diagnostic markers for MPS through follow-up observations extending up to three months.
2. Materials and Methods2.1. Study Design and Participants
This study was a prospective, single-center, single-arm, open-label clinical trial conducted from May 2023 to September 2024. It was approved by the Ethics Committee of Meltes MED Orthoplastic Hospital (Approval Number: MMOH20230502) and adhered to the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines. Informed consent was obtained from all participants, and the study was registered with the ClinicalTrials.gov database (NCT06444035), organized by the National Institutes of Health (NIH).
Participants were recruited from Meltes MED Orthoplastic Hospital, either seeking treatment or referred for severe pain lasting three months or longer. The inclusion criteria were: individuals aged 18-65 years, either male or female; primary complaint of back pain; presence of taut muscle bands with severe point tenderness upon palpation; pain exacerbated by cold weather or fatigue; limited range of motion in back extension; patient-reported pain of 3 or higher on the Numerical Rating Scale (NRS) (where 0 denotes no pain and 10 represents the worst imaginable pain); and a satisfactory mental status allowing for independent pain assessment and treatment cooperation, with signed written consent.
Exclusion criteria included: history of severe trauma with permanent musculoskeletal dysfunction; specific spinal disorders such as rheumatoid arthritis, ankylosing spondylitis, or osteoporosis; diagnosed psychiatric disorders; refusal to provide written consent; pregnant or breastfeeding women, or those of childbearing potential; and current or recent participation (within the past 30 days) in experimental treatments or device trials.
2.2. Study Treatment
Before the trial commenced, the attending physician thoroughly explained the study procedures to the participants. This research involves administering HA35 injection. The samples used in the study were sourced from NAKHIA IMPEX, a pharmaceutical company based in Ulaanbaatar, Mongolia. The recombinant human hyaluronidase PH20
[19]
[20]
is employed to cleave high-molecular-weight HA (from Bloomage Biotech) into the 35 kDa fragment, referred to as HA35 (B-HA injection, Registration Number L20200708MP07707; Ministry of Health), which is utilized for treating pain-related conditions.
2.3. Study Procedure
Participants received subcutaneous injections of HA35 solution (100 mg/5mL/day) at the designated pain points and surrounding areas on the back for 15 consecutive days. During the treatment period, participants were permitted to continue taking oral pain medications, and comparisons were made between pre- and post-treatment dosages and intervals to assess the efficacy of the injections. Participants were required to self-report their pain levels daily throughout the injection period. The Numerical Rating Scale (NRS) was employed at various time points after treatment to compare pain relief effects with baseline values. Additionally, follow-up assessments were conducted via telephone and in-person visits every four weeks post-treatment, using the Global Pain Scale (GPS)
[30]
[31]
to evaluate overall pain relief. Patient satisfaction with the treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4)
[32]
-
[34]
.
2.4. Outcome Measures
Pain Assessment: The Numerical Pain Rating Scale (NPRS) is widely used in clinical settings to evaluate pain intensity, employing an 11-point scale ranging from 0 (no pain) to 10 (worst imaginable pain) to quantify pain severity
[35]
[36]
. Investigators will assess back pain before and after treatment from three dimensions: current pain, average pain, and maximum pain. This assessment will be conducted using the following questions: “How intense is your pain right now?” (current pain), “How intense has your average pain been today?” (average pain), and “What was the worst pain you experienced today?” (maximum pain).
Overall Pain Assessment During and After Injection Treatment: The GPS, developed by Gentile et al. in 2011, is a multidimensional tool designed to evaluate pain over the past week. It encompasses four dimensions: pain, feelings, clinical outcomes, and activities
[30]
[31]
. The GPS was validated using Classical Test Theory (CTT) and Item Response Theory (IRT) and comprises 20 items, each rated on a 0 - 10 scale. The total score is obtained by summing the item scores and dividing by 2, with higher scores reflecting greater pain intensity and impact.
Treatment Satisfaction Survey: The TSQM 1.4, developed by Atkinson et al. in 2004, assesses patient satisfaction with medication over the preceding 2 to 3 weeks or since the last dose
[32]
-
[34]
. It includes four subscales with a total of 14 questions: Effectiveness (Questions 1 - 3), Side Effects (Questions 4 - 8), Convenience (Questions 9 - 11), and Global Satisfaction (Questions 12 - 14). Each subscale is scored on a 0 - 100 scale, with higher scores indicating greater satisfaction.
2.5. Safety and Adverse Events
The safety of HA35 will be evaluated by comparing laboratory results from patients before and after treatment. Any adverse effects observed by investigators or reported by patients during the treatment, such as redness, itching, or pain at the injection site, will be documented.
2.6. Statistical Analysis
Statistical analyses were conducted using GraphPad Prism software (Version 9.3.1, San Diego, CA, USA). Quantitative data are presented as mean ± standard deviation (SD). Comparisons between two groups were performed using a paired Student’s t-test
[27]
. A p-value > 0.05 was considered not statistically significant (denoted as “ns”); p < 0.05 was deemed statistically significant (denoted as “*”); p < 0.01 indicated more significant results (denoted as “**”); and p < 0.0001 was regarded as highly significant (denoted as “****”)
[27]
. Effect sizes (ES) were calculated to assess clinical significance, defined as the mean change from baseline divided by the standard deviation of the change. Clinical significance was categorized according to Cohen’s ES thresholds: ES < 0.2, negligible; ES ≥ 0.2 to <0.5, small; ES ≥ 0.5 to <0.8, moderate; and ES > 0.8, large
[37]
.
3. Results3.1. Patient Demographics and Baseline Characteristics
A total of 12 patients diagnosed with back MPS accompanied by trigger points were initially enrolled in this study. However, 2 patients chose not to participate, resulting in 10 patients who completed the 15-day injection regimen and the subsequent 3-month follow-up according to the informed consent protocol. All 10 patients were included in the final data analysis (see
Figure 1
). The demographic characteristics of the participants are summarized in
Table 1
. The cohort consisted of 6 females and 4 males, with an average age of 52 years and a mean BMI of 24.90. Employment included 3 individuals in clerical positions, 5 in manual labor, and 2 as athletes. The average duration of pain among the participants was 4 months, with a range from 1 month to 1 year.
Figure 1. Flow-chart.
<xref ref-type="bibr" rid="scirp.138788-"></xref>Table 1. Basic characteristics of participants with back pain.
Characteristic
N = 10
Percentage %
Gender
Male
4
40%
Female
6
60%
Age, Mean ± SD
52.70 ± 8.19
-
BMI, Mean ± SD
24.90 ± 2.07
-
Occupation
Manual Laborers
5
50%
Office Workers
3
30%
Athlete
2
20%
Pain duration
1 - 3 months
3
30%
3 - 6 months
6
60%
7 - 12months
1
10%
More than 12 months
0
0%
Average pain time, Mean ± SD
4.30 ± 3.20
-
Causes of MPS
Invasion of Wind-Cold
0
0%
Chronic Strain
5
50%
Muscle and Fascia Damage or Trauma
2
20%
Prolonged Poor Posture
3
30%
Previous Treatment Methods
Physical Therapy Only, e.g., Acupuncture
4
40%
Medication Only, e.g., Anti-inflammatory and Analgesics
10
100%
Surgery Only
0
0%
Combined Treatment
5
50%
3.2. Primary Outcome Measures
Table 2
presents the NPRS scores for the 10 patients before treatment, during the injection period (at days 1, 3, 5, and 15), and after completing the injections (at days 30, 60, and 90). The patients rated both their current pain and the most severe pain experienced each day. The results, as illustrated in
Figure 2
, show a significant reduction in pain scores post-treatment (P < 0.0001). After just one day of injection therapy, current pain and strongest pain decreased by 50% and 40%, respectively. By the end of the 15 injections, pain relief exceeded 80%, with the scores dropping from a baseline of 6.9 ± 1.8 to 1.1 ± 1.0 (Mean ± SD, P < 0.0001). Follow-up scores revealed that patients maintained low pain levels over 30, 60, and 90 days (NPRS30days = 0.8 ± 1.1, NPRS60days = 0.5 ± 0.7, NPRS90days = 0.6 ± 0.8), with some participants reporting complete pain resolution (NPRS = 0).
3.3. Secondary Outcome Measures
Table 3
shows the GPS scores, indicating significant changes across the four dimensions of pain, feeling, clinical outcomes, and activity before and after treatment (P < 0.0001). After 15 injections, the overall score decreased by approximately 80%, mirroring the trend observed in the primary outcome measures. Post-injection scores continued to decline, stabilizing around a mean of 2.2 at 60 days. The basic pain and the impact of pain on daily life had essentially disappeared.
<xref ref-type="bibr" rid="scirp.138788-"></xref>Table 2. NPRS scores before and after the treatment.
NPRS pain
After treatment
(days)
Patient
One
Two
Three
Four
Five
Six
Seven
Eight
Nine
Ten
Current pain
0
6
7
8
6
7
9
10
4
5
7
1
4
5
6
3
5
4
5
1
2
3
3
2
4
5
2
2
4
3
1
2
3
5
1
3
3
1
2
3
2
0
1
2
15
0
1
1
1
1
2
3
0
0
2
30
0
0
2
0
0
2
3
0
0
1
60
0
0
1
0
0
1
2
0
0
1
90
0
0
1
0
0
2
2
0
0
1
Strongest pain
0
8
9
8
6
8
9
10
5
5
8
1
4
5
6
4
5
5
6
2
3
4
3
3
5
5
3
3
4
3
3
2
4
5
2
3
4
2
2
3
2
0
2
3
15
1
1
1
1
1
2
3
1
1
2
30
1
1
2
0
1
2
3
0
0
2
60
1
1
2
0
1
1
2
0
0
1
90
0
0
2
0
0
2
3
0
0
1
Figure 2. Average values of current pain and strongest pain before and after treatment in all patients.
<xref ref-type="bibr" rid="scirp.138788-"></xref>Table 3. Percentage and number of patients improvement in the pain scores.
Patient
After treatment (days)
0
15
30
60
90
One
52.5
9.5
3.5
2.5
2.5
Two
51
8
4
2
1
Three
56
9
5
2
2
Four
53
8.5
3
1
1
Five
60
15.5
3.5
1.5
2
Six
62
14
9.5
2.5
2.5
Seven
75
19.5
13
4.5
4
Eight
51
10
2.5
2
3
Nine
50.5
11
2
2
3
Ten
51.5
9.5
4.5
2
2
Mean ± SD
56.3 ± 7.7
11.5 ± 3.7
5.1 ± 3.5
2.2 ± 0.9
2.3 ± 0.9
P-value
-
0.0001
0.0001
0.0001
0.0001
Comparison of TSQM scores before and after HA35 injection treatment revealed high levels of treatment satisfaction among participants, as demonstrated by significant improvements in both statistical significance and effect size, as shown in
Table 4
, which provides details on the Treatment Satisfaction Questionnaire for Medication (TSQM), and in
Figure 3
, which illustrates the average TSQM scores for the four total items. As shown in
Table 4
, the TSQM1.4 item scores increased from a range of 1.3 - 3.1 to 3.8 - 6.0, corresponding to a percentage score increase from 27 - 40 to 58.1 - 81.4 (
Figure 3
). As illustrated in
Figure 3
, the highest satisfaction was reported in the areas of side effects (86.0, P < 0.0001, ES > 0.8), effectiveness (81.4, P < 0.0001, ES > 0.8), and overall satisfaction (82.9, P < 0.0001, ES > 0.8). The internal consistency of TSQM1.4 was confirmed by Cronbach’s alpha coefficients above 0.76 across all subscales, indicating reliability
[27]
.
Figure 3. Average TSQM scores for the four total items.
4. Discussion
In this study, we report for the first time the efficacy of the low-molecular-weight hyaluronan fragment HA35 in treating MPS. The etiology of MPS has long been a topic of interest in the medical community. Some research suggests that the pain associated with MPS may result from the stimulation of sensory nerves by algogenic substances within an inflammatory environment, as well as from nerve compression by edematous tissues
[3]
[38]
. Alternative theories propose that impaired blood circulation and the accumulation of metabolic by-products due to prolonged static activity may trigger referred pain and allodynia by activating peripheral nerve endings
[1]
[4]
-
[10]
. Nonetheless, the majority of research has concentrated on MTrPs, which are considered the “gold standard” for diagnosing MPS. The detection of MTrPs using a three-point method is essential for the clinical diagnosis and management of MPS
[39]
. In our study, the enrolled patients, comprising three office workers, three manual laborers, and two athletes, all demonstrated MTrPs. Their pain durations ranged from 1 month to 1 year, and they had previously received various physical therapies, including acupuncture and massage, alongside pain medication. Despite these treatments, as indicated by the TSQM results in
Table 4
, patients generally reported dissatisfaction, with baseline scores significantly below 50%. Following HA35 injection therapy, substantial pain relief was observed, as illustrated in
Figure 2
and
Table 2
. After just one injection, both current pain and maximum pain scores on the NPRS showed significant reductions, with 60% of patients experiencing more than 50% improvement in pain; however, only three patients achieved more than 50% improvement in maximum pain. By the third injection, 80% of patients reported over 50% improvement in current pain, and 70% showed similar improvement in maximum pain. After five injections, all patients experienced more than 50% improvement in both current and maximum pain. Follow-up data indicated that post-treatment pain remained stable within the low range of 0-3 on the NPRS. Some participants reported pain relief as early as 20-60 minutes post-injection, suggesting that HA35 may offer rapid analgesic effects due to its tissue permeability. Imaging studies using Life’s iQID demonstrated that 125I-labeled HA35 appeared in the spleen and lymph nodes within 5 minutes of injection into the hind limb of mice
[27]
.
Myofascial pain, if untreated, can lead to significant physical discomfort and adversely affect daily activities, social interactions, and emotional well-being
[3]
. Hence, accurate diagnosis and effective treatment are essential. Research on long-lived naked mole rats, which possess high concentrations of hyaluronan and its fragments, has shown they remain cancer-free throughout their lives and exhibit a reduced incidence of inflammation-related diseases
[40]
[41]
. Preliminary clinical studies have suggested that HA35 may be effective in treating lung cancer pain, with improvements observed in patients’ facial expressions, mood, and comfort following treatment. Additionally, cytological research indicates that HA35 promotes the migration of neutrophils and mononuclear cells. Combined with iQID imaging, these findings suggest that HA35 may alleviate inflammation by enhancing lymphocyte migration and lymphatic circulation
[26]
. In our study, the GPS scores at three different time points before and after treatment highlighted significant impacts of pain on patients’ daily lives, including fear, depression, exhaustion, sleep quality, ability to work independently, overall physical sensations, shopping, and interpersonal relationships. Following 15 HA35 injections, 80% of patients demonstrated notable improvements in these areas, with no recurrence of pain during the follow-up period; rather, patients’ overall conditions continued to improve. This suggests that HA35 can effectively alleviate chronic myofascial pain with lasting therapeutic benefits. The efficacy and satisfaction with HA35 treatment are further illustrated by the TSQM scores in
Figure 3
, which show high overall satisfaction with HA35 injections for chronic MPS within 90 days post-treatment. The effect sizes (ES) for side effects, effectiveness, and overall satisfaction were close to 0.9, indicating significant correlations. Throughout the treatment and follow-up period, no adverse reactions or side effects were reported
[23]
[24]
[42]
. Moreover, patients who were using pain medications prior to treatment either reduced or discontinued their use afterward. The TSQM scores in
Figure 3
demonstrate that the side effects score reached 86.0 (P < 0.0001), reflecting a significant reduction in the side effects experienced by patients during previous treatments, which had been a major concern beyond achieving effective pain relief.
The primary limitation of this study is the small sample size, which may affect the generalizability of the results. However, as a proof-of-concept experiment, this study aimed to preliminarily validate the efficacy and safety of HA35 injections in treating MPS, providing a valuable reference for MPS diagnosis and pain management. The study met the expected primary and secondary outcomes.
5. Conclusion
MTrPs are the hallmark indicators for diagnosing MPS. The 35 kDa hyaluronan fragment HA35 effectively relieves back myofascial pain and provides sustained therapeutic benefits over an extended period post-treatment.
Supplementary Materials
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Author Contributions
E.P. and D.T.: conceptualization; validation, investigation; formal analysis; writing—original draft; writing—review and editing; visualization. Z.M.: investigation; formal analysis; validation. X.J.: investigation; formal analysis; validation；writing—original draft; writing—review and editing. T.G.: project administration; supervision; formal analysis. M.H.: conceptualization; writing—review and editing; project administration; funding acquisition; supervision; validation; formal analysis. D.E.: conceptualization; project administration; funding acquisition; investigation; formal analysis; validation; supervision; writing—original draft; writing—review and editing. All authors have read and agreed to the published version of the manuscript.
The study was conducted in accordance with the Ethics Committee of Meltes MED Orthoplastic Hospital (approval number MMOH20230502).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available in the article.
Acknowledgements
The authors extend their sincere appreciation to all the patients who participated in this study.
References
Bodine, N. (2023) An Overview of Myofascial Pain Syndrome with a Focus on Trigger Point Injection. The Nurse Practitioner, 48, 18-25. >https://doi.org/10.1097/01.npr.0000000000000110
Saxena, A., Chansoria, M., Tomar, G. and Kumar, A. (2015) Myofascial Pain Syndrome: An Overview. Journal of Pain & Palliative Care Pharmacotherapy, 29, 16-21. >https://doi.org/10.3109/15360288.2014.997853
Cao, Q., Peng, B., Wang, L., Huang, Y., Jia, D., Jiang, H., et al. (2021) Expert Consensus on the Diagnosis and Treatment of Myofascial Pain Syndrome. World Journal of Clinical Cases, 9, 2077-2089. >https://doi.org/10.12998/wjcc.v9.i9.2077
Bron, C., de Gast, A., Dommerholt, J., Stegenga, B., Wensing, M. and Oostendorp, R.A. (2011) Treatment of Myofascial Trigger Points in Patients with Chronic Shoulder Pain: A Randomized, Controlled Trial. BMC Medicine, 9, Article No. 8. >https://doi.org/10.1186/1741-7015-9-8
Bron, C. and Dommerholt, J.D. (2012) Etiology of Myofascial Trigger Points. Current Pain and Headache Reports, 16, 439-444. >https://doi.org/10.1007/s11916-012-0289-4
Fernández-de-las-Peñas, C. and Dommerholt, J. (2017) International Consensus on Diagnostic Criteria and Clinical Considerations of Myofascial Trigger Points: A Delphi Study. Pain Medicine, 19, 142-150. >https://doi.org/10.1093/pm/pnx207
Jin, F., Guo, Y., Wang, Z., Badughaish, A., Pan, X., Zhang, L., et al. (2020) The Pathophysiological Nature of Sarcomeres in Trigger Points in Patients with Myofascial Pain Syndrome: A Preliminary Study. European Journal of Pain, 24, 1968-1978. >https://doi.org/10.1002/ejp.1647
Rivers, W.E., Garrigues, D., Graciosa, J. and Harden, R.N. (2015) Signs and Symptoms of Myofascial Pain: An International Survey of Pain Management Providers and Proposed Preliminary Set of Diagnostic Criteria. Pain Medicine, 16, 1794-1805. >https://doi.org/10.1111/pme.12780
Gao, W.W., Zou, D.S., Wang, W.C., Li, S.L., Chen, H.L., Huang, P.C., Cao, F.L. and Guo, X.L. (2017) Research Progress of Myofascial Pain Syndrome. Chinese Journal of Pain Medicine, 23, 455-458.
Ma, Y., Bu, H., Jia, J.R. and Zhang, X. (2012) Progress of Research on Acupuncture at Trigger Point for Myofascial Pain Syndrome. Chinese Acupuncture&Moxibustion, 32, 573-576.
Mayoral del Moral, O., Torres Lacomba, M., Russell, I.J., Sánchez Méndez, Ó. and Sánchez Sánchez, B. (2017) Validity and Reliability of Clinical Examination in the Diagnosis of Myofascial Pain Syndrome and Myofascial Trigger Points in Upper Quarter Muscles. Pain Medicine, 19, 2039-2050. >https://doi.org/10.1093/pm/pnx315
Inturrisi, C.E. (2002) Clinical Pharmacology of Opioids for Pain. The Clinical Journal of Pain, 18, S3-S13. >https://doi.org/10.1097/00002508-200207001-00002
Dach, F. and Ferreira, K.S. (2023) Treating Myofascial Pain with Dry Needling: A Systematic Review for the Best Evidence-Based Practices in Low Back Pain. Arquivos de Neuro-Psiquiatria, 81, 1169-1178. >https://doi.org/10.1055/s-0043-1777731
Lara-Palomo, I.C., Gil-Martínez, E., Antequera-Soler, E., Castro-Sánchez, A.M., Fernández-Sánchez, M. and García-López, H. (2022) Electrical Dry Needling versus Conventional Physiotherapy in the Treatment of Active and Latent Myofascial Trigger Points in Patients with Nonspecific Chronic Low Back Pain. Trials, 23, Article No. 238. >https://doi.org/10.1186/s13063-022-06179-y
Zhang, Y., Lao, L., Chen, H. and Ceballos, R. (2012) Acupuncture Use among American Adults: What Acupuncture Practitioners Can Learn from National Health Interview Survey 2007? Evidence-Based Complementary and Alternative Medicine, 2012, Article ID: 710750. >https://doi.org/10.1155/2012/710750
Wang, G., Gao, Q., Li, J., Tian, Y. and Hou, J. (2016) Impact of Needle Diameter on Long-Term Dry Needling Treatment of Chronic Lumbar Myofascial Pain Syndrome. American Journal of Physical Medicine & Rehabilitation, 95, 483-494. >https://doi.org/10.1097/phm.0000000000000401
Li, X., Wang, R., Xing, X., Shi, X., Tian, J., Zhang, J., Ge, L., Li, L. and Yang, K. (2017) Acupuncture for Myofascial Pain Syndrome: A Network Meta-Analysis of 33 Randomized Controlled Trials. Pain Physician, 20, E883-E902.
Tough, E.A., White, A.R., Cummings, T.M., Richards, S.H. and Campbell, J.L. (2009) Acupuncture and Dry Needling in the Management of Myofascial Trigger Point Pain: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. European Journal of Pain, 13, 3-10. >https://doi.org/10.1016/j.ejpain.2008.02.006
Choi, Y., Jung, S., Lee, C.H. and Lee, S. (2014) Additional Effects of Transcranial Direct-Current Stimulation and Trigger-Point Injection for Treatment of Myofascial Pain Syndrome: A Pilot Study with Randomized, Single-Blinded Trial. The Journal of Alternative and Complementary Medicine, 20, 698-704. >https://doi.org/10.1089/acm.2013.0243
Moore, N., Duong, M., Gulmez, S.E., Blin, P. and Droz, C. (2019) Pharmacoepidemiology of Non-Steroidal Anti-Inflammatory Drugs. Therapies, 74, 271-277. >https://doi.org/10.1016/j.therap.2018.11.002
Harirforoosh, S., Asghar, W. and Jamali, F. (2014) Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications. Journal of Pharmacy & Pharmaceutical Sciences, 16, 821-847. >https://doi.org/10.18433/j3vw2f
Padda, J., Khalid, K., Zubair, U., Al Hennawi, H., Yadav, J., Almanie, A.H., et al. (2021) Stem Cell Therapy and Its Significance in Pain Management. Cureus, 13, e17258. >https://doi.org/10.7759/cureus.17258
Xu, F., Treger, D., Ma, X., Jia, X., Shofaro, J.H., Ganbaatar, T., et al. (2024) Local Injection of a Freshly Manufactured 35 kDa Hyaluronan Fragment Reduces Neuropathic and Inflammatory Pain: A Clinical Study. European Journal of Inflammation, 22, 1-9. >https://doi.org/10.1177/1721727x241258268
Treger, D., Zhang, L., Jia, X., Hui, J.H., Gantumur, M., Hui, M., et al. (2024) A Clinical Study of the Local Injection of a Freshly Manufactured 35 kDa Hyaluronan Fragment for Treating Chronic Wounds. International Wound Journal, 21, e14906. >https://doi.org/10.1111/iwj.14906
Zhang, Z., Jia, X., Treger, D. and Hui, M. (2024) Low Molecular Weight 35 kDa Hyaluronan Fragment HA35 in the Treatment of Bone Metastasis Pain: A Case Report. Medicine, 103, e39145. >https://doi.org/10.1097/md.0000000000039145
Jia, X., Shi, M., Wang, Q., Hui, J., Shofaro, J.H., Erkhembayar, R., et al. (2023) Anti-inflammatory Effects of the 35kda Hyaluronic Acid Fragment (B-HA/HA35). Journal of Inflammation Research, 16, 209-224. >https://doi.org/10.2147/jir.s393495
Gantumur, M., Jia, X., Hui, J.H., Barber, C., Wan, L., Furenlid, L.R., et al. (2024) Characterization, Bioactivity, and Biodistribution of 35 kDa Hyaluronan Fragment. Life, 14, Article 97. >https://doi.org/10.3390/life14010097
Caires, R., Luis, E., Taberner, F.J., Fernandez-Ballester, G., Ferrer-Montiel, A., Balazs, E.A., et al. (2015) Hyaluronan Modulates TRPV1 Channel Opening, Reducing Peripheral Nociceptor Activity and Pain. Nature Communications, 6, Article No. 8095. >https://doi.org/10.1038/ncomms9095
de la Peña, E., Gomis, A., Ferrer-Montiel, A. and Belmonte, C. (2015) TRPV1 Channel Modulation by Hyaluronan Reduces Pain. Channels, 10, 81-82. >https://doi.org/10.1080/19336950.2015.1109300
Chen, H., Wang, X., Bai, T., Cui, H., Shi, S., Li, Y., et al. (2024) Reliability, Validity, and Simplification of the Chinese Version of the Global Pain Scale in Patients with Rheumatoid Arthritis. BMC Nursing, 23, Article No. 20. >https://doi.org/10.1186/s12912-023-01664-4
Heiberg Agerbeck, A., Martiny, F.H.J., Jauernik, C.P., Due Bruun, K., Rahbek, O.J., Bissenbakker, K.H., et al. (2021) Validity of Current Assessment Tools Aiming to Measure the Affective Component of Pain: A Systematic Review. Patient Related Outcome Measures, 12, 213-226. >https://doi.org/10.2147/prom.s304950
Liberato, A.C.S., São João, T.M., Jannuzzi, F.F., Landaas, E.J., Wongchareon, K. and Rodrigues, R.C.M. (2020) Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4): Ceiling and Floor Effects, Reliability, and Known-Group Validity in Brazilian Outpatients with Hypertension. Value in Health Regional Issues, 23, 150-156. >https://doi.org/10.1016/j.vhri.2020.07.578
Atkinson, M.J., Sinha, A., Hass, S.L., Colman, S.S., Kumar, R.N., Brod, M., et al. (2004) Validation of a General Measure of Treatment Satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), Using a National Panel Study of Chronic Disease. Health and Quality of Life Outcomes, 2, Article No. 12. >https://doi.org/10.1186/1477-7525-2-12
Xue, Q., Long, H., Lin, J., Du, D., Zhou, J., Chen, J., et al. (2021) Quality of Life and Treatment Satisfaction with Pharmacological Interventions in Chinese Adults with Chronic Pain Due to Osteoarthritis. BMC Musculoskeletal Disorders, 22, Article No. 178. >https://doi.org/10.1186/s12891-021-04012-2
Yao, M., Xu, B., Li, Z., Zhu, S., Tian, Z., Li, D., et al. (2020) A Comparison between the Low Back Pain Scales for Patients with Lumbar Disc Herniation: Validity, Reliability, and Responsiveness. Health and Quality of Life Outcomes, 18, Article No. 175. >https://doi.org/10.1186/s12955-020-01403-2
Zapata, K.A., Wang-Price, S.S., Sucato, D.J., Thompson, M., Trudelle-Jackson, E. and Lovelace-Chandler, V. (2015) Spinal Stabilization Exercise Effectiveness for Low Back Pain in Adolescent Idiopathic Scoliosis. Pediatric Physical Therapy, 27, 396-402. >https://doi.org/10.1097/pep.0000000000000174
Serdar, C.C., Cihan, M., Yücel, D. and Serdar, M.A. (2021) Sample Size, Power and Effect Size Revisited: Simplified and Practical Approaches in Pre-Clinical, Clinical and Laboratory Studies. Biochemia Medica, 31, 27-53. >https://doi.org/10.11613/bm.2021.010502
Galasso, A., Urits, I., An, D., Nguyen, D., Borchart, M., Yazdi, C., et al. (2020) A Comprehensive Review of the Treatment and Management of Myofascial Pain Syndrome. Current Pain and Headache Reports, 24, Article No. 43. >https://doi.org/10.1007/s11916-020-00877-5
Shah, J.P., Thaker, N., Heimur, J., Aredo, J.V., Sikdar, S. and Gerber, L. (2015) Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective. PM&R, 7, 746-761. >https://doi.org/10.1016/j.pmrj.2015.01.024
Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., et al. (2013) High-Molecular-Mass Hyaluronan Mediates the Cancer Resistance of the Naked Mole Rat. Nature, 499, 346-349. >https://doi.org/10.1038/nature12234
Zhang, Z., Tian, X., Lu, J.Y., Boit, K., Ablaeva, J., Zakusilo, F.T., et al. (2023) Increased Hyaluronan by Naked Mole-Rat Has2 Improves Healthspan in Mice. Nature, 621, 196-205. >https://doi.org/10.1038/s41586-023-06463-0
Bellar, A., Kessler, S.P., Obery, D.R., Sangwan, N., Welch, N., Nagy, L.E., et al. (2019) Safety of Hyaluronan 35 in Healthy Human Subjects: A Pilot Study. Nutrients, 11, Article 1135. >https://doi.org/10.3390/nu11051135