ABSTRACT
Objectives
To determine whether pulsed near‐infrared laser irradiation differentially modulates pain thresholds mediated by Aδ‐ and C‐fibers in humans.
Materials and Methods
In this randomized, sham‐controlled, single‐blind, parallel‐group trial, healthy adults received pulsed 830‐nm laser irradiation (peak power 10 W) or sham irradiation applied to the volar forearm. Aδ‐ and C‐fiber–mediated pain thresholds were assessed before and immediately after irradiation using intra‐epidermal electrical stimulation delivered via a concentric bipolar electrode. Linear mixed‐effects models were used to examine group × time interactions for each fiber types.
Results
Significant group‐by‐time interactions were observed for Aδ‐mediated thresholds (p = 0.034) and C‐fiber–mediated thresholds (p = 0.046), indicating differential pre–post changes between the laser and sham groups. Pain thresholds increased following active irradiation in both fiber types, whereas minimal changes were observed after sham irradiation. Between‐group differences in change scores were associated with moderate standardized effect sizes.
Conclusion
Pulsed 830‐nm laser irradiation induces immediate modulation of peripheral nociceptive processing in humans across Aδ‐ and C‐fibers, supporting fiber‐specific modulation of nociceptive processing under controlled experimental conditions.
Clinical Trial Registration
University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR), UMIN000056285.
Keywords: Aδ‐fiber, C‐fiber, intra‐epidermal electrical stimulation, pain threshold, photobiomodulation, pulsed laser irradiation
1. Introduction
Pain perception is mediated by functionally distinct peripheral nociceptive fibers, primarily thinly myelinated Aδ‐fibers and unmyelinated C‐fibers, which differ in conduction velocity, excitability, and perceptual characteristics of pain [1, 2]. Quantitative assessment of these fiber types has contributed to mechanistic understanding of nociception and to evaluation of analgesic interventions.
Photobiomodulation, including low‐level laser therapy, modulates nociceptive processing and produces analgesic effects by influencing peripheral nerve activity. Proposed mechanisms include modulation of mitochondrial function via cytochrome c oxidase activation, increased ATP production, and downstream effects on ion channel activity and neuronal excitability [3, 4]. However, reported effects on pain perception remain inconsistent, largely owing to variability and incomplete reporting of irradiation parameters such as wavelength, output power, pulse structure, and duration [5]. This heterogeneity limits mechanistic interpretation and controlled parameter‐based investigation.
High‐power pulsed laser irradiation has gained attention because short pulse durations combined with high peak power may induce photobiological effects while minimizing thermal tissue damage. Clinical studies of pulsed high‐intensity laser therapy, commonly using Nd:YAG systems at approximately 1064 nm, have reported improvements in pain outcomes compared with placebo or sham irradiation across conditions such as chronic low back pain and knee osteoarthritis [6, 7, 8]. Double‐blind randomized sham‐controlled trials using pulsed laser protocols with peak power in the 10‐W range have also demonstrated analgesic effects in orofacial pain conditions [9]. Nevertheless, most prior studies have relied on subjective pain ratings, and controlled experimental evidence directly quantifying fiber‐specific effects of pulsed laser irradiation remains limited.
The pain threshold of intra‐epidermal nerve terminals (PINT), assessed using intra‐epidermal electrical stimulation, enables selective evaluation of Aδ‐ and C‐fiber‐mediated pain thresholds. Low‐intensity intra‐epidermal electrical stimulation preferentially activates Aδ nociceptors [10], whereas modified stimulation parameters and electrode configurations permit evaluation of C‐fiber‐related responses [11, 12]. This approach has been applied in experimental and clinical settings and is sensitive to changes in peripheral nociceptive function [13].
Given structural and functional differences between Aδ and C fibers, photobiomodulation may influence these fiber types differently. However, fiber‐specific effects of high‐power pulsed laser irradiation on Aδ‐ and C‐fiber‐mediated pain thresholds under controlled conditions have not been established. Therefore, the aim of this randomized controlled trial was to investigate the effects of 10‐W pulsed laser irradiation on Aδ‐ and C‐fiber‐mediated pain thresholds in healthy adults using PINT. The primary outcomes were changes in Aδ‐ and C‐fiber‐mediated pain thresholds assessed by PINT. We hypothesized that pulsed laser irradiation would increase fiber‐specific pain thresholds relative to sham irradiation.
2. Materials and Methods
2.1. Study Design
This study was a randomized, sham‐controlled, parallel‐group trial with a single‐blind design conducted in healthy adults. The study was approved by the Institutional Ethics Committee of Honjo General Hospital (Approval No. 2024020701; approved on February 7, 2024) and conducted in accordance with the Declaration of Helsinki. The trial was prospectively registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR; UMIN000056285). Written informed consent was obtained from all participants before participation.
2.2. Sample Size Calculation
An a priori sample size calculation was performed using G*Power version 3.1 [14, 15]. Because no previous study has examined PINT‐based Aδ‐ and C‐fiber pain thresholds after 10‐W pulsed laser irradiation, the effect size estimate was based on our prior study in healthy adults (Cohen's d = 1.46) [16]. Using a two‐tailed independent‐samples t‐test (difference between two independent means), with α = 0.05 and power (1 − β) = 0.95, the required sample size was 14 participants per group (total n = 28). Although the primary analysis used linear mixed‐effects models, the sample size was estimated using an independent‐groups framework as a conservative approach.
2.3. Participants
Twenty‐eight healthy adult volunteers were recruited for the study. The inclusion criteria were ages of ≥ 18 years and absence of current pain or neurological disorders. The exclusion criteria included a history of chronic pain, peripheral neuropathy, dermatological conditions affecting the forearm, current use of analgesics or neuroactive medications, and prior exposure to laser therapy within the preceding 3 months.
2.4. Randomization and Blinding
Participants were randomly assigned in a 1:1 ratio to the active laser or sham group using a pre‐prepared, stratified random allocation sequence based on a paper‐based lottery system. The allocation sequence was generated in advance, and group assignments were determined by drawing lots at the time of participant enrollment by an investigator. This study employed a single‐blind design in which participants were unaware of group allocation, whereas the investigator administering the laser intervention was not blinded because of technical requirements. Outcome assessments were performed by a different physical therapist; however, the outcome assessor was not blinded to group allocation, which may introduce potential bias.
During sham irradiation, the laser output was set to 0 W and no therapeutic laser light was emitted; however, the guide light remained illuminated. The sham procedure was otherwise identical to the active condition in terms of device appearance, handling, irradiation duration, and sensory cues (including electronic sounds and cooling fan operation) to maintain participant blinding. Outcome assessments were conducted according to a standardized protocol. The flow of participants is presented in Figure 1.
Figure 1.
Flowchart of participants through the randomized, sham‐controlled trial.
2.5. Experimental Procedure
All experiments were conducted in a temperature‐controlled laboratory. Laser irradiation and PINT assessments were performed on one forearm, with the laterality randomly assigned for each participant. Participants were seated with the tested forearm supported in a standardized supinated position, which was maintained during baseline assessment, intervention, and post‐intervention measurements.
After an acclimation period, baseline Aδ‐ and C‐fiber pain thresholds were measured. Participants then received active laser or sham irradiation, followed immediately by repeat pain threshold assessments using identical electrode placement and stimulation procedures. All procedures were performed by licensed physical therapists trained in the study protocol, with a single examiner responsible for all outcome assessments. Adverse events were monitored throughout the study.
2.6. Outcome Measures: Aδ‐ and C‐Fiber Pain Thresholds
Pain thresholds mediated by Aδ and C fibers were assessed using intra‐epidermal electrical stimulation, defined as the pain threshold of intra‐epidermal nerve terminals (PINT). Electrical stimulation was delivered using a peripheral nerve stimulator (PNS‐5100) and a surface stimulation electrode (NM‐983W) (NIHON KOHDEN CORPORATION, Tokyo, Japan). A disposable concentric bipolar electrode was attached to the volar forearm at a standardized site corresponding to the center of the laser irradiation area (Figure 2A). The electrode position was marked to ensure consistent placement before and after irradiation.
Figure 2.
(A) Electrode placement for PINT assessment and (B) laser irradiation sites. (A) The concentric bipolar electrode for PINT assessment was placed on the volar forearm, with the electrode center positioned 1 cm ulnar to the midpoint of a line connecting the center of the wrist crease (a) and the center of the cubital fossa (b). This location corresponded to the center of the laser irradiation area. The electrode was secured with adhesive tape to maintain stable contact. (B) Laser irradiation was applied sequentially to three contiguous sites along the longitudinal axis of the forearm, centered on the electrode placement site (Sites 1–3).
Participants pressed a handheld switch when perceiving the stimulus. Stimulation intensity was gradually decreased from a clearly perceptible level, and the minimal current intensity (mA) consistently detected was defined as the pain threshold. Stimulation parameters were adjusted to preferentially assess Aδ‐ and C‐fiber‐mediated thresholds as previously described [10, 11, 12]. Each threshold was measured three times, and the mean value was used for analysis. All measurements were performed by the same examiner, who was not blinded to group allocation.
The reliability of this protocol was confirmed in a preliminary assessment (n = 14), demonstrating excellent test–retest reliability (ICC [1,1] = 0.95 for Aδ fibers and 0.92 for C fibers). During testing, the device display was positioned outside the participants' view to prevent visual feedback.
2.7. Laser Irradiation Protocol
Pulsed laser irradiation was applied to the volar surface of one forearm using a semiconductor laser device (FINELASER EL‐1000; OG Wellness Technologies Co. Ltd., Okayama, Japan). The laser was operated at a wavelength of 830 nm with a peak output power of 10 W in pulsed mode. The pulse structure consisted of an on time of 20 ms and an off time of 180 ms, corresponding to a duty cycle of 10%. The irradiation area of the probe was 1.5 cm² (aperture diameter: 14 mm). The average output power was 1 W, resulting in a total delivered energy of 300 J over 5 min. Because irradiation was distributed sequentially across three irradiation sites, each site received approximately 100 J, corresponding to a fluence of 66.7 J/cm². The average power density was 0.67 W/cm².
Laser irradiation was delivered to three contiguous sites along the longitudinal axis of the forearm, covering a total length equivalent to approximately three probe diameters, and centered on the PINT electrode placement site (Figure 2B). Irradiation was initiated at the most proximal site and delivered for 10 s. The probe was moved distally by one probe diameter to irradiate the central site for 10 s, followed by irradiation of the distal site for an additional 10 s. After irradiation at the three sites, the probe was returned to the initial proximal site, and this sequence was repeated continuously for a total irradiation time of 5 min.
The laser device was equipped with a contact‐sensitive safety mechanism that allowed laser emission only when the probe tip contacted the skin. Irradiation time was counted only during active laser emission. For the sham condition, the same device and irradiation procedure were applied for the same duration, but the laser output was set to 0 W using a configuration developed in collaboration with the manufacturer, ensuring that no therapeutic laser emission occurred. The device operation sounds, guide light, and display indications were identical to those during active irradiation.
2.8. Statistical Analysis
Data distribution was assessed using the Shapiro–Wilk test. Linear mixed‐effects models (LMMs) were fitted separately for Aδ‐ and C‐fiber pain thresholds, including fixed effects for group (laser vs. sham), time (pre vs. post), and their interaction, with a random intercept for participant to account for intra‐subject correlation. Estimated marginal means were calculated for each group × time combination.
As a supplementary analysis, change scores (post–pre) were calculated, and between‐group differences were examined. Effect sizes (Cohen's d) and corresponding 95% confidence intervals (CIs) were reported to facilitate interpretation beyond p‐values [17]. The use of LMMs for repeated‐measures data is supported by prior methodological literature [18, 19]. Statistical significance was set at p < 0.05. All analyses were performed using SPSS Statistics version 23.0 J (IBM Corp., Armonk, NY, USA).
3. Results
3.1. Participants
Twenty‐eight healthy adults were randomized to the laser (n = 14) or sham group (n = 14). All participants completed the study and were included in the analyses. Baseline characteristics are presented in Table 1. There were no significant between‐group differences in baseline Aδ‐ and C‐fiber pain thresholds. No adverse events or unintended effects were observed in either group during the study.
Table 1.
Participant characteristics at baseline.
| Total (n = 28) | Laser group (n = 14) | Sham group (n = 14) | |
|---|---|---|---|
| Age (years) | 28.6 ± 7.2 | 28.3 ± 6.4 | 28.9 ± 8.2 |
| Height (cm) | 165.4 ± 9.0 | 166.3 ± 10.4 | 164.6 ± 7.6 |
| Weight (kg) | 59.9 ± 7.7 | 61.2 ± 9.0 | 58.5 ± 6.1 |
| Sex, n (male/female) | 15/13 | 8/6 | 7/7 |
| Intervention side, n (right/left) | 14/14 | 7/7 | 7/7 |
| Baseline PINT (mA), Aδ‐fiber | 0.10 ± 0.09 | 0.11 ± 0.11 | 0.09 ± 0.06 |
| Baseline PINT (mA), C‐fiber | 0.38 ± 0.16 | 0.35 ± 0.14 | 0.41 ± 0.18 |
Note: Values are presented as mean ± SD or number of participants.
3.2. Aδ‐Fiber Pain Thresholds
Linear mixed‐effects modeling revealed a significant group × time interaction for Aδ‐fiber pain thresholds (F(1,26) = 4.997, p = 0.034), indicating differential changes between groups. Post‐intervention thresholds increased in the laser group, whereas minimal change was observed in the sham group (Figure 3A). The between‐group difference in change scores corresponded to a moderate effect size (Cohen's d = 0.72; 95% CI, −0.04 to 1.49).
Figure 3.
Changes in (A) Aδ‐fiber and (B) C‐fiber pain thresholds before and after intervention. Estimated marginal means (95% confidence intervals [CIs]) of (A) Aδ‐fiber‐mediated and (B) C‐fiber‐mediated pain thresholds before (Pre) and after (Post) laser or sham irradiation. Linear mixed‐effects models revealed significant group × time interactions for both outcomes (Aδ‐fiber: p = 0.034; C‐fiber: p = 0.046).
3.3. C‐Fiber Pain Thresholds
A significant group × time interaction was also observed for C‐fiber pain thresholds (F(1,26) = 4.411, p = 0.046). Thresholds increased following active irradiation, whereas values in the sham group remained largely unchanged (Figure 3B). The between‐group difference in change scores yielded a moderate‐to‐large effect size (Cohen's d = 0.86; 95% CI, 0.08–1.64).
4. 4. Discussion
4.1. Fiber‐Specific Effects of Pulsed Laser Irradiation
This randomized, sham‐controlled study demonstrated that pulsed laser irradiation produced immediate, fiber‐specific modulation of nociceptive processing in healthy adults. Significant group × time interactions were observed for both Aδ‐ and C‐fiber‐mediated pain thresholds, indicating differential changes between the laser and sham groups. Both fiber types exhibited significant modulation following irradiation, with moderate‐to‐large standardized effect sizes for between‐group differences in change scores. However, confidence intervals were relatively wide, particularly for Aδ‐fiber thresholds, indicating uncertainty in the precision of these estimates. These findings extend previous reports of photobiomodulation‐induced analgesia [20, 21, 22, 23] by providing quantitative, fiber‐specific evidence at the level of peripheral nociceptive input rather than relying solely on subjective pain outcomes.
4.2. Fiber‐Specific Responsiveness of Aδ and C Fibers
Although both Aδ‐ and C‐fiber‐mediated pain thresholds were significantly modulated, the present study was not designed to formally compare the magnitude of effects between fiber types. Therefore, the findings should be interpreted as demonstrating fiber‐specific modulation rather than definitive fiber‐type–dependent differences in responsiveness. Classical and contemporary studies distinguish “fast” pain conveyed by thinly myelinated Aδ fibers from “slow” pain mediated by unmyelinated C fibers, reflecting differences in temporal dynamics and perceptual characteristics of nociception [2, 24]. Experimental evidence further supports non‐equivalent contributions of A and C nociceptors under different stimulus conditions [25]. The observed modulation across both fiber types suggests that pulsed laser irradiation may influence early stages of peripheral nociceptive signaling, although the relative sensitivity of different fiber classes requires further investigation.
Photobiomodulation has been proposed to influence neuronal excitability through modulation of ion channels and mitochondrial signaling pathways [20, 26], potentially altering membrane polarization, action potential initiation, or recovery dynamics. The present findings do not establish a specific biological mechanism, and alternative explanations, including differences in baseline excitability or stimulus–response characteristics between fiber types, cannot be excluded. Rather than providing definitive mechanistic conclusions, the results delineate a reproducible pattern of fiber‐specific responsiveness that identifies peripheral nociceptive fibers as potential targets of photobiomodulation and supports targeted mechanistic investigation in future studies.
4.3. Implications for Heterogeneity in Photobiomodulation Research
A major challenge in the photobiomodulation literature is the heterogeneity of reported analgesic effects, likely reflecting variability in irradiation parameters such as wavelength, output power, pulse structure, duration, and treatment area [5]. Systematic reviews and meta‐analyses have highlighted inconsistent outcomes across clinical studies, even within similar pain conditions [21, 22, 23]. The present study addressed this issue by applying a fixed, high‐peak‐power pulsed protocol and evaluating fiber‐specific pain thresholds within a single experimental framework. By assessing Aδ‐ and C‐fiber‐mediated thresholds under identical irradiation and sham conditions, the findings move beyond global pain outcomes and provide a differentiated perspective on how photobiomodulation may influence peripheral nociceptive processing.
4.4. Methodological Strengths and Analytical Considerations
Several methodological features strengthen internal validity. A high‐quality sham condition was implemented with identical device appearance, handling, auditory cues, and irradiation duration to minimize expectancy effects. Pain thresholds were assessed using intra‐epidermal electrical stimulation, which preferentially activates small‐diameter nociceptive fibers under appropriate stimulation parameters, including selective activation of Aδ fibers and parameter‐dependent evaluation of C‐fiber‐related responses [10, 11, 12, 26]. Linear mixed‐effects models were used for the primary analysis to account for intra‐subject dependence and provide valid inference in repeated‐measures designs, consistent with methodological literature supporting the robustness of mixed‐effects approaches [18, 19].
4.5. Conceptual Overlap Between Photobiomodulation and PINT Assessment
Both photobiomodulation and intra‐epidermal electrical stimulation are thought to influence nociceptive processing through modulation of peripheral neural excitability, including voltage‐dependent ion channel function. Although these mechanisms were not directly assessed, this conceptual overlap supports the use of PINT as a sensitive experimental tool for detecting immediate changes in nociceptive thresholds following photobiomodulation.
4.6. Limitations and Future Directions
This study was conducted in healthy adults and assessed only immediate effects; therefore, the findings may not generalize to clinical pain populations characterized by central sensitization, inflammation, or structural pathology. The results should be interpreted as reflecting modulation of peripheral nociceptive processing rather than direct clinical analgesic efficacy. The single‐blind design represents an additional limitation because experimenter‐related bias cannot be fully excluded, particularly as the outcome assessor was not blinded to group allocation, although the intervention and assessment were performed by different physical therapists. Nevertheless, comprehensive sham procedures were implemented to minimize participant awareness of allocation. In addition, the effectiveness of participant blinding was not formally evaluated (e.g., by assessing participants' guesses of group allocation), which may limit the ability to fully confirm the effectiveness of participant blinding.
A potential limitation also relates to the sample size estimation. Although the study was powered based on a large effect size derived from prior work, the observed effect sizes were smaller than anticipated, resulting in relatively wide confidence intervals. This suggests that the present study may have been underpowered to precisely estimate the true magnitude of the effects. Therefore, while the significant group × time interactions support the presence of a modulatory effect, the magnitude of these effects should be interpreted with caution.
Finally, the temporal evolution and persistence of laser‐induced effects were not examined. Future studies should investigate clinical pain populations, longer‐term and repeated irradiation protocols, and complementary mechanistic measures to clarify how parameter‐specific photobiomodulation influences nociceptive signaling.
5. Conclusion
In summary, the present study demonstrated immediate modulation of both Aδ‐ and C‐fiber‐mediated nociceptive thresholds following pulsed laser irradiation. By combining rigorous sham control, fiber‐specific outcome measures, and conservative statistical modeling, this study provides a controlled experimental framework that may facilitate parameter‐informed investigation of photobiomodulation effects in experimental pain research.
Author Contributions
Nobuyuki Takeuchi conceived and designed the study, supervised the project, performed the statistical analyses, interpreted data, and drafted the manuscript. Masanao Matsumoto and Masaya Tabei were responsible for participant recruitment, laser irradiation procedures, and pain threshold assessments. All authors critically reviewed and revised the manuscript and approved the final version.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We thank OG Wellness Technologies Co. Ltd., Japan, for providing the laser device with a sham irradiation function free of charge for use in this study. The company had no role in the study design, data collection, data analysis, data interpretation, or preparation of the manuscript. This study was supported by JSPS KAKENHI Grant Number JP23K10484.
Data Availability Statement
All data are available upon reasonable request to the corresponding author.
References
- 1. Dubin A. E. and Patapoutian A., “Nociceptors: The Sensors of the Pain Pathway,” Journal of Clinical Investigation 120 (2010): 3760–3772, 10.1172/JCI42843. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Julius D. and Basbaum A. I., “Molecular Mechanisms of Nociception,” Nature 413 (2001): 203–210, 10.1038/35093019. [DOI] [PubMed] [Google Scholar]
- 3. de Freitas L. F. and Hamblin M. R., “Proposed Mechanisms of Photobiomodulation or Low‐Level Light Therapy,” IEEE Journal of Selected Topics in Quantum Electronics 22 (2016): 7000417, 10.1109/JSTQE.2016.2561201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Zhang Z., Zhang Z., Liu P., et al., “The Role of Photobiomodulation to Modulate Ion Channels in the Nervous System: A Systematic Review,” Cellular and Molecular Neurobiology 44 (2024): 79, 10.1007/s10571-024-01513-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Zein R., Selting W., and Hamblin M. R., “Review of Light Parameters And Photobiomodulation Efficacy: Dive Into Complexity,” Journal of Biomedical Optics 23 (2018): 1–17, 10.1117/1.JBO.23.12.120901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Alayat M. S. M., Aly T. H. A., Elsayed A. E. M., and Fadil A. S. M., “Efficacy of Pulsed Nd:YAG Laser in the Treatment of Patients With Knee Osteoarthritis: A Randomized Controlled Trial,” Lasers in Medical Science 32 (2017): 503–511, 10.1007/s10103-017-2141-x. [DOI] [PubMed] [Google Scholar]
- 7. Alayat M. S. M., Atya A. M., Ali M. M. E., and Shosha T. M., “Long‐Term Effect of High‐Intensity Laser Therapy in the Treatment of Patients With Chronic Low Back Pain: A Randomized Blinded Placebo‐Controlled Trial,” Lasers in Medical Science 29 (2014): 1065–1073, 10.1007/s10103-013-1472-5. [DOI] [PubMed] [Google Scholar]
- 8. Thabet A. A. E. M. and Alshehri M. A., “Effect of Pulsed High‐Intensity Laser Therapy on Pain, Adhesions, and Quality of Life in Women Having Endometriosis: A Randomized Controlled Trial,” Photomedicine and Laser Surgery 36 (2018): 363–369, 10.1089/pho.2017.4419. [DOI] [PubMed] [Google Scholar]
- 9. Amanat D., Ebrahimi H., Lavaee F., and Alipour A., “The Adjunct Therapeutic Effect of Lasers with Medication in the Management of Orofacial Pain: Double Blind Randomized Controlled Trial,” Photomedicine and Laser Surgery 31 (2013): 474–479, 10.1089/pho.2013.3555. [DOI] [PubMed] [Google Scholar]
- 10. Mouraux A., Iannetti G. D., and Plaghki L., “Low Intensity Intra‐Epidermal Electrical Stimulation Can Activate Aδ‐Nociceptors Selectively,” Pain 150 (2010): 199–207, 10.1016/j.pain.2010.04.026. [DOI] [PubMed] [Google Scholar]
- 11. Kodaira M., Inui K., and Kakigi R., “Evaluation of Nociceptive Aδ‐ and C‐Fiber Dysfunction With Lidocaine Using Intraepidermal Electrical Stimulation,” Clinical Neurophysiology 125 (2014): 1870–1877, 10.1016/j.clinph.2014.01.009. [DOI] [PubMed] [Google Scholar]
- 12. Motogi J., Kodaira M., Muragaki Y., Inui K., and Kakigi R., “Cortical Responses to C‐Fiber Stimulation by Intra‐Epidermal Electrical Stimulation: An MEG Study,” Neuroscience Letters 570 (2014): 69–74, 10.1016/j.neulet.2014.04.001. [DOI] [PubMed] [Google Scholar]
- 13. Kukidome D., Nishikawa T., Sato M., et al., “Measurement of Small Fibre Pain Threshold Values for the Early Detection of Diabetic Polyneuropathy,” Diabetic Medicine 33 (2016): 62–69, 10.1111/dme.12797. [DOI] [PubMed] [Google Scholar]
- 14. Faul F., Erdfelder E., Buchner A., and Lang A. G., “Statistical Power Analyses Using G*Power 3.1: Tests for Correlation and Regression Analyses,” Behavior Research Methods 41 (2009): 1149–1160, 10.3758/BRM.41.4.1149. [DOI] [PubMed] [Google Scholar]
- 15. Faul F., Erdfelder E., Lang A. G., and Buchner A., “G*Power 3: A Flexible Statistical Power Analysis Program for the Social, Behavioral, and Biomedical Sciences,” Behavior Research Methods 39 (2007): 175–191, 10.3758/bf03193146. [DOI] [PubMed] [Google Scholar]
- 16. Takeuchi N. and Matsumoto M., “Immediate Effect of Pulse Irradiation with a 10‐W Semiconductor Laser on Current Perception Threshold and Current Pain Threshold,” Nippon Laser Igakkaishi 40 (2020): 309–313, in Japanese ( 10.2530/jslsm.jslsm-40_0051. [DOI] [Google Scholar]
- 17. Lakens D., “Calculating and Reporting Effect Sizes to Facilitate Cumulative Science: A Practical Primer for T‐Tests and ANOVAs,” Frontiers in Psychology 4 (2013): 863, 10.3389/fpsyg.2013.00863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Arnau J., Bendayan R., Blanca M. J., and Bono R., “The Effect of Skewness and Kurtosis on the Robustness of Linear Mixed Models,” Behavior Research Methods 45 (2013): 873–879, 10.3758/s13428-012-0306-x. [DOI] [PubMed] [Google Scholar]
- 19. Muhammad L. N., “Guidelines for Repeated Measures Statistical Analysis Approaches With Basic Science Research Considerations,” Journal of Clinical Investigation 133 (2023): e171058, 10.1172/JCI171058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Cheng K., Martin L. F., Slepian M. J., Patwardhan A. M., and Ibrahim M. M., “Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review,” Journal of Pain 22 (2021): 763–777, 10.1016/j.jpain.2021.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Chow R. T., Johnson M. I., Lopes‐Martins R. A., and Bjordal J. M., “Efficacy of Low‐level Laser Therapy in the Management of Neck Pain: A Systematic Review and Meta‐Analysis of Randomised Placebo or Active‐treatment Controlled Trials,” Lancet 374 (2009): 1897–1908, 10.1016/S0140-6736(09)61522-1. [DOI] [PubMed] [Google Scholar]
- 22. Stausholm M. B., Naterstad I. F., Joensen J., et al., “Efficacy of Low‐Level Laser Therapy on Pain and Disability in Knee Osteoarthritis: Systematic Review and Meta‐analysis of Randomised Placebo‐Controlled Trials,” BMJ Open 9 (2019): e031142, 10.1136/bmjopen-2019-031142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Tripodi N., Feehan J., Husaric M., Sidiroglou F., and Apostolopoulos V., “The Effect of Low‐Level Red and Near‐Infrared Photobiomodulation on Pain and Function in Tendinopathy: A Systematic Review and Meta‐Analysis of Randomized Control Trials,” BMC Sports Science, Medicine and Rehabilitation 13 (2021): 91, 10.1186/s13102-021-00306-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Perl E. R., “Ideas About Pain, a Historical View,” Nature Reviews Neuroscience 8 (2007): 71–80, 10.1038/nrn2042. [DOI] [PubMed] [Google Scholar]
- 25. Hsieh M. T., Donaldson L. F., and Lumb B. M., “Differential Contributions of A‐ and C‐Nociceptors to Primary and Secondary Inflammatory Hypersensitivity in the Rat,” Pain 156 (2015): 1074–1083, 10.1097/j.pain.0000000000000151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Motogi J., Sugiyama Y., Laakso I., et al., “Why Intra‐Epidermal Electrical Stimulation Achieves Stimulation of Small Fibres Selectively: A Simulation Study,” Physics in Medicine and Biology 61 (2016): 4479–4490, 10.1088/0031-9155/61/12/4479. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data are available upon reasonable request to the corresponding author.