Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized controlled trial.

This study aimed to provide preliminary evidence for the efficacy of invasive laser acupuncture (ILA) for chronic non-specific low back pain (CNLBP). This was a single-center, randomized, patient and assessor-blinded, placebo-controlled, parallel-arm, clinical trial with a 1:1:1 allocation ratio that included a full analysis set. Forty-five participants with CNLBP were randomly assigned to the control group (sham laser), 650 group (650 nm-wavelength ILA), or 830 group (830 nm-wavelength ILA) (n = 15/group). All participants received ILA for 10 min, followed by electroacupuncture for 10 min on the same day. The treatment was performed once per day, twice per week for 4 weeks at bilateral BL23, BL24, BL25, and GB30. The primary outcome was the among-group difference of changes in the visual analog scale (VAS) scores at intervention endpoint (week 4). The secondary outcomes were the among-group difference of changes in VAS at 4 weeks after intervention completion (week 8), those in the Korean version of the Oswestry Disability Index (ODI) and the European Quality of Life Five-Dimension- Five-Level (EQ-5D-5L) at intervention endpoint (week 4) and 4 weeks after intervention completion (week 8). The VAS scores of the 650 group decreased significantly compared with those of the control group (p = 0.047; week 4 vs. week 0). The ODI scores of the 650 group (p = 0.018, week 4 vs. week 0; p = 0.006, week 8 vs. week 0) and 830 group (p = 0.014, week 4 vs. week 0) decreased significantly compared with those of the control group. There was no adverse event related to ILA and no significant difference in changes in vital signs among the three groups. The 650 group showed significant improvements in pain intensity and functional disability. The 830 group showed significant improvements in functional disability. Therefore, ILA therapy at 650 nm and 830 nm wavelengths can be used to treat CNLBP.

Introduction

Chronic non-specific low back pain (CNLBP) is a common health problem; it is considered to be a multifactorial disorder comprising interactions of musculoskeletal pain and psychosocial factors [1,2]. CNLBP is defined as pain and discomfort localized in the lumbosacral region with no specific underlying pathological causes that persists for more than 3 months [3,4]. Functional limitations and consequent disability caused by CNLBP not only affect daily activities and quality of life but also increase health care expenditures [5].

The guidelines for CNLBP recommend treatment comprising the use of non-steroidal anti-inflammatory drugs, antidepressants, exercise therapy, and psychosocial interventions [6,7]. Acupuncture has been used for the treatment of CNLBP mainly by those who practice complementary and alternative medicine [8]. However, the recommendations for acupuncture are inconsistent. Of eight treatment guidelines, only four recommend the use of acupuncture [6].

Laser acupuncture (LA) (the use of a low-level laser [LLL]) to stimulate acupoints) is considered a safe treatment modality because of its painless and noninvasive nature [9]. LA is primarily used to treat arthralgia or musculoskeletal pain; however, some studies have investigated its efficacy for treating CNLBP [10,11]. The efficacy of LLL therapy (LLLT), including LA for CNLBP, has not been established. A Cochrane report [12] concluded that there were insufficient data to draw firm conclusions on the clinical effect of LLLT for low back pain (LBP). There is a need for further methodologically rigorous randomized controlled trials (RCTs) to evaluate the effects of LLLT. Several systematic reviews and meta-analyses [13-15] have suggested that LLLT including LA may have a significant positive effect on reducing pain. However, there is still a lack of high quality evidence supporting its efficacy. Rigorously blinded trials are needed to confirm the efficacy of LLLT for CNLBP and identify the optimal LLLT parameters. Several studies have reported that LA did not show significant effects compared with sham laser for patients with LBP [16-18]. The methods of LLLT used in previous studies were noninvasive and there was no study on invasive laser [12-18].

Noninvasive LA is applied to the skin at acupoints using a laser-emitting device that can be used as an alternative to needles. Invasive LA (ILA) involves the simultaneous application of invasive acupuncture treatment at acupoints and focused laser irradiation using a laser machine connected to an acupuncture needle consisting of an optical fiber-coupled laser diode [19]. Previous studies have shown that ILA has significant effects on neuropathic pain [20,21] and osteoarthritis [22] in rat models. However, clinical evidence obtained from rigorous RCTs regarding the efficacy and safety of ILA for CNLBP is lacking. Therefore, we conducted this pilot study to obtain basic data regarding the efficacy of ILA for CNLBP by comparing the efficacy of ILA at different wavelengths.

Materials and methods

This study adhered to the standard protocol items of the Recommendations for Interventional Trials (SPIRIT) statements [23] and Consolidated Standards of Reporting Trials (CONSORT) guidelines [24]. The detailed methods of this study have been disclosed in a previous publication [19].

Study design

This study was a prospective, patient and assessor-blinded, parallel-arm, single-center (Dongshin University Gwangju Korean Medicine Hospital, Republic of Korea) RCT with a 1:1:1 allocation ratio. A total of 45 participants who met the inclusion criteria were randomly allocated to the control group (sham laser; n = 15), 650 group (650 nm-wavelength ILA; n = 15), or 830 group (830 nm-wavelength ILA; n = 15). The participants received ILA for 10 min followed by electroacupuncture (EA) for 10 min on the same day. The treatment was performed once per day, twice per week, for 4 weeks at bilateral Shenshu (BL23), Qihaishu (BL24), Dachangshu (BL25), and Huantiao (GB30) points.

Outcome measurements were determined at baseline (week 0), 4 weeks after the first intervention (week 4; end of the intervention), and 4 weeks after the completion of the intervention (week 8). The study design is summarized in Table 1.

Table 1

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.

	STUDY PERIOD
	Enrolment	Allocation	Post-allocation					Close-out
TIMEPOINT	Screening		Visit1-2	Visit3-4	Visit5-6	Visit7	Visit8	Visit9
	Week		1	2	3	4	4	8
ENROLMENT
Informed consent	X
Sociodemographic profile	X
Medical history	X
Vital signs	X	X	X	X	X	X	X	X
Inclusion/exclusioncriteria	X
Allocation		X
VAS	X
INTERVENTIONS
ILA(sham, 650 nm, 830 nm)			X	X	X	X	X
EA			X	X	X	X	X
ASSESSMENTS
Change of medical history			X	X	X	X	X	X
Safety assessment			X	X	X	X	X	X
VAS			X				X	X
Scores for ODI,			X				X	X
EQ-5D-5L			X				X	X

ILA, invasive laser acupuncture; EA, electroacupuncture; VAS, visual analog scale; ODI, Korean version of the Oswestry Disability Index; EQ-5D-5L, European Quality of Life Five Dimension Five Level Scale.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki. The study protocol (version 1.2) was approved by the Institutional Review Board (IRB) of Dongshin University Gwangju Korean Medicine Hospital (approval no: DSGOH-2019-004; approval date: April 17, 2020) before the trial began. This trial was registered at the Clinical Research Information Service (cris.nih.go.kr; registration number: KCT0004610; registration date: January 7, 2020). The purpose and potential risks of this study were fully explained to all participants, and all participants provided written informed consent before participating in the study.

Participant recruitment

We recruited participants at Dongshin University Gwangju Korean Medicine Hospital in the Republic of Korea between May 12, 2020 and September 17, 2020. The clinical research coordinator (CRC) continuously monitored the medical conditions of the enrolled participants to maximize adherence to the intervention protocols.

Participation

The inclusion criteria were as follows: age between 19 and 70 years; presence of CNLBP for at least the previous 3 months; score of ≥40 points on a 100 mm visual analog scale (VAS) for pain at the time of screening; fluency in Korean language adequate for reliable completion of all study assessments; and voluntary provision of informed consent.

The exclusion criteria were as follows: radicular pain or progressive neurological deficits; diagnosis of a serious spinal pathology (cancer, recent vertebral fracture, spinal infection, or inflammatory spondylitis); presence of a serious chronic disease (cancer; severe cardiovascular, cerebrovascular, liver, or kidney disease; or diabetic neuropathy); history of treatment for alcohol/drug dependency or mental illness (schizophrenia, dementia, or epilepsy) during the 6 months preceding enrollment; LBP not caused by a spinal or soft tissue disease (trauma, ankylosing spondylitis, fibromyalgia, rheumatoid arthritis, or gout); presence of contradictions for LA or EA, such as blood clotting abnormalities (hemophilia), severe skin disease in the lumbar region, presence of metallic devices in the lumbar spine, or presence of electronic medical devices (pacemaker); previous lumbar spinal surgery within 1year or scheduled procedures during the study period; pregnancy or planning to become pregnant; and concurrent participation in other clinical trials.

The dropout criteria were as follows: <75% compliance with the protocol procedures; incidence of serious adverse events (AEs); reluctance to continue participation in the trial; incomplete data that could influence the results; and large protocol error or significant deviation in implementation.

Randomization and blinding

After acquiring written informed consent and completing baseline measurements, the 45 enrolled participants were assigned serial numbers generated using SPSS version 21 (IBM Corp., Armonk, NY, USA) and randomly allocated to one of the three study groups (n = 15 per group). The serial number codes were inserted in opaque envelopes that were sealed and stored in a double-locked cabinet.

We adopted a patient and assessor-blinded trial procedure. Real laser and sham laser had no differences in appearance, feel, or sound. During the course of this clinical trial, the assessor did not contact any participant at any point of time other than the time of assessment. Hence, participants and assessor remained blinded to the treatment allocation until study completion. A statistician with no conflicts of interest performed the analysis. However, because of the nature of ILA treatment, investigators could not be blinded. The CRC generated the allocation sequence, enrolled the participants, and assigned them to groups.

Intervention

The participants received treatment once per day, twice per week, for 4 weeks. The treatment was administered by Korean physicians who were licensed to administer treatment and had 6 years of formal university training to practice Korean medicine. ILA and EA treatment were performed using a medical device (Ellise; Wontech Co. Ltd., Daejeon, Republic of Korea) capable of laser irradiation and electrical stimulation. It is composed of a main body consisting of a laser output device and an electrical stimulator, a sterile, stainless steel, disposable acupuncture needle (external diameter, 0.3 mm; inner diameter, 0.15 mm; length, 30 mm) in which an optical fiber is inserted, optical fiber-coupled laser diode (650 nm used the InGaAIP; 830 nm used the GaAIAs) and an electrical stimulus clip. The parameters of the ILA are 20 mW for power, 12 J/point for energy dose, 63.69 W/cm2 for power density, and 38216.56 J/cm2 for energy density. With the participants in the prone position, the needles were vertically inserted in bilateral Shenshu (BL23), Qihaishu (BL24), Dachangshu (BL25), and Huantiao (GB30) points [25,26]. The depths of insertion were between 9 mm and 30 mm, depending on the location of the needle [27]. Noninvasive LA is applied to the skin at acupoints. In contrast, the ILA used in our study was irradiated at the tip of the acupuncture needle under the skin. Manual stimulation was not performed. The participants received ILA (control group, sham laser; 650 group, 650 nm-wavelength laser; 830 group, 830 nm-wavelength laser) for 10 min, followed by EA for 10 min on the same day. The control group underwent the same procedures as the ILA group, but the laser was not turned on. No differences in observations, feelings, or sounds were observed among the three groups during the procedure. Hence, all participants were blinded to the group selection. During the study period, the participants were allowed to continue routine management regimens and existing medications. However, they were not permitted to engage in other treatments to ameliorate CNLBP symptoms.

Outcome measurements

Primary outcome was the among-group difference of changes in VAS at intervention endpoint (week 4). The secondary outcomes were the among-group difference of changes in VAS at 4 weeks after intervention completion (week 8) and those in the Korean version of the Oswestry Disability Index (ODI) and the European Quality of Life Five-Dimension-Five-Level (EQ-5D-5L) at intervention endpoint (week 4), and 4 weeks after intervention completion (week 8).

The VAS is a 10 cm-long straight line marked at each end with the anchor labels “no pain” and “worst pain imaginable” [28]. It is the most frequently used instrument for measuring the pain intensity of LBP [29].

The ODI is one of the most commonly used scales to assess disability related to LBP [30]. The validated Korean version of the ODI, which excludes items regarding the sexual life of the individual from the original ODI, contains nine questions about daily activities, including inventories of pain intensity, personal care, lifting, walking, sitting, standing, sleeping, social life, and traveling. Each question is rated using a scale of 0 to 5, with a higher score indicating severe pain-related disability [31].

The validated Korean version of the European Quality of Life Five-Dimension (EQ-5D) is a generic instrument used to measure health-related quality of life, including five dimensions pertaining to mobility, self-care, usual daily activities, pain and discomfort, and anxiety and depression [32]. The European Quality of Life Five-Dimension- Five-Level (EQ-5D-5L) is a new version of the EQ-5D scale that includes five levels of severity for each of the five EQ-5D dimensions. Each dimension is scored using a scale of 1 to 5 [33].

Sample size calculation

Because of the lack of adequate preliminary studies and limited research funds, study period, and recruitment opportunities, we adopted a pilot study design. The appropriate sample size for two-arm or three-arm pilot studies is more than 12 [34,35]. Considering a dropout rate of 20%, we assigned 15 participants to each group (total of 45 participants).

Because our study was a pilot study, the sample size was insufficient to determine the effectiveness of ILA for CNLBP. Our study provides preliminary evidence for the efficacy and safety of ILA for CNLBP, and the results can be used to estimate the appropriate sample size needed for future confirmative RCTs of the efficacy and safety of ILA for CNLBP.

Statistical analyses

With IRB approval, the statistical analyses were revised during the study. We performed a full analysis set to assess efficacy, and missing values were implemented by the last observation carried forward method. To reduce the risk of bias, a statistician who was not involved in this clinical trial analyzed the final data using SPSS version 20.0 software (SPSS Inc., Chicago, IL, USA) and two-sided significance tests with a 5% significance level. Continuous variables are presented as the mean and standard deviation (SD) or median, first, and third quartiles and categorical variables are presented as the number or percentage.

Baseline characteristics were collected and compared using One-way analysis of variance (ANOVA), the Kruskal-Wallis test or chi-squared (χ2) test. Within-group differences in all outcome values of the three groups were compared using a repeated-measures ANOVA or Friedman test. Difference in changes in all outcome values among three groups (week 4 vs. week 0 and week 8 vs. week 0) were compared using ANOVA or the Kruskal-Wallis test. Differences in changes in the outcome values between two groups (week 4 vs. week 0 and week 8 vs. week 0; significant changes observed in ANOVA or the Kruskal-Wallis test) were compared using a Scheffe post hoc test or Mann-Whitney U test. For safety evaluation, incidence of adverse events (AEs) among the three groups were compared using chi-squared (χ2) test and difference in changes in vital signs at 4 weeks after the first intervention (week 4 vs. week 0) were compared among the three groups using ANOVA. Subanalyses and interim analyses were not performed.

Results

Participants

We recruited participants between May 11, 2020 and November 5, 2020. During the study period, 388 patients were assessed for eligibility and 343 were excluded. Forty-five patients were included in this study and randomly assigned to the control group (n = 15), 650 group (n = 15), or 830 group (n = 15). Three participants in the control group did not complete the treatment. Two participants in the 830 group did not complete treatment. The data of 45 patients with CNLBP were used for the final analysis (Fig 1).

Fig 1

CONSORT 2010 flow diagram.

Baseline characteristics

The baseline demographic characteristics of the patients in the three groups are presented in Table 2. No significant differences in baseline demographic characteristics or study variables were detected among the three groups (p>0.05) (Table 2).

Table 2

Homogeneity tests for baseline demographic characteristics and study variables for 45 patients with chronic non-specific low back pain.

Dependent Variables	control Group(n = 15)	650 Group(n = 15)	830 Group(n = 15)	F or χ2(p)
	M (SD)or m(Q1, Q3)m (Q1, Q3)or n (%)	M (SD)or m(Q1, Q3)	M (SD)or m(Q1, Q3)
Age (y)	59.73(6.03)	57.60(6.85)	54.40(12.19)	45.89(0.178) *
Sex (Female)	13 (86.7%)	9 (60.0%)	9 (60.0%)	3.32 (0.190) *
Education(years)	12.67 (4.64)	12.40 (3.29)	13.33 (3.70)	10.99 (0.810) *
Height(cm)	159.75 (5.65)	162.39 (6.01)	161.57 (6.20)	0.77 (0.470) †
Weight(kg)	62.39 (10.86)	70.43 (9.86)	65.23 (11.03)	2.22 (0.121) †
VAS	50.47 (9.38)	55.07 (17.58)	49.60 (12.96)	0.69 (0.508) ††
ODI	9 (7, 11)	11 (9, 17)	11 (8, 13)	3.35 (0.187)¥
EQ-5D-5L	8 (6, 9)	9 (8, 11)	8 (7, 9)	4.85 (0.088)¥

M, Mean; SD, standard deviation; m, median; Q1, first quartiles; Q3, third quartiles.

*, x-test;

†, One-way ANOVA test;

¥, Kruskal-Wallis test.

Efficacy evaluation

After 4 weeks of intervention, we observed significant improvements in the control group (changes in VAS scores), 650 group (changes in VAS, ODI, and EQ-5D-5L scores), and 830 group (changes in VAS, ODI, and EQ-5D-5L scores) (Table 3).

Table 3

Changes in outcome measures after treatment completion in the three groups.

Groups	Dependent Variables	Week 0	Week 4	Week 8	χ²(p)
		(M±SD) orm(Q1,Q3)	(M±SD) orm(Q1,Q3)	(M±SD) orm(Q1,Q3)
Control group (n = 15)	VAS	50.47±9.38	36.20±19.06	34.13±20.65	8.28(0.001) †
	ODI	9 (7,11)	7 (5,11)	8 (7,11)	1.66(0.436) ǂ
	EQ-5D-5L	8 (6,9)	7 (5,9)	8 (5,9)	2.80(0.247) ǂ
650 group (n = 15)	VAS	55.07 ±17.58	23.13 ±11.43	26.53 ±23.92	15.91(<0.001) †
	ODI	11 (9,17)	7 (7,8)	5 (3,11)	19.26(<0.001) ǂ
	EQ-5D-5L	9 (8,11)	7 (6,8)	7 (5,9)	12.50(0.002) ǂ
830 group (n = 15)	VAS	49.60 ±12.96	28.60 ±14.95	25.27 ±15.60	21.41(<0.001) †
	ODI	11 (8,13)	5 (3,7)	6 (4,7)	16.61(<0.001) ǂ
	EQ-5D-5L	8 (7,9)	7 (5,7)	7 (6,7)	12.84(0.002) ǂ

M, Mean; SD, standard deviation; m, median; Q1, first quartiles; Q3, third quartiles.

†, One-way Repeated-measures ANOVA test;

ǂ, Friedman test.

We observed a significant difference in changes in VAS scores (p = 0.047; week 4 vs. week 0), and ODI scores (p = 0.019, week 4 vs. week 0; p = 0.019, week 8 vs. week 0) among three groups. The VAS scores of the 650 group significantly decreased compared with those of the control group (p = 0.047; week 4 vs. week 0) (Table 4).

Table 4

Difference in changes in VAS scores among three groups (n = 45).

Dependent Vatiables	Group	Deference(w4-w0)	F (p)post hoc test (Scheffe)	Deference(w8-w0)	F (p)post hoc test (Scheffe)
		(M±SD)		(M±SD)
VAS	Controla	-14.27±17.17	3.29 (0.047) †a<b	-16.33±20.12	1.37 (0.274) †
	650b	-31.93±21.94		-28.53±24.37
	830c	-21.00±17.56		-24.33±17.17

M, Mean; SD, standard deviation;

†, One-way ANOVA test.

Additionally, the ODI scores of the 650 group (p = 0.018, week 4 vs. week 0; p = 0.006, week 8 vs. week 0) and 830 group (p = 0.014, week 4 vs. week 0) significantly decreased compared with those of the control group (Table 5).

Table 5

Difference in changes in ODI and EQ-5D-5L scores among three groups (n = 45).

Dependent Vatiables	Group	Deference(w4-w0)	F (p)	Deference(w8-w0)	F (p)
		m(Q1, Q3)	Z(p)	m(Q1, Q3)	Z(p)
ODI ǂ	Controla	-1 (-4, 1)	7.90 (0.019)¥	-1 (-4, 2)	7.91 (0.019) ¥
	650b	-5 (-10, -1)		-6 (-8, -2)
	830c	-5 (-7, -1)	a vs b-2.37 (0.018) Ŧa vs c-2.46 (0.014) Ŧ	-4 (-8, -2)	a vs b-2.73 (0.006) Ŧa vs c-1.98 (0.047) Ŧ
EQ-5D-5L ǂ	Controla	-1 (-2, 2)	3.11 (0.211)¥	-1 (-2, 2)	5.78 (0.058)¥
	650b	-2 (-4, 0)		-2 (-4, -1)
	830c	-1 (-3, 0)		-1 (-3, 0)

m, median; Q1, first quartiles; Q3, third quartiles;

¥, Kruskal-Wallis test;

Ŧ, Mann-Whitney U test P<0.025 (Bonferoni correction).

Safety evaluation

For safety evaluation, the incidence of AEs and difference in changes in vital signs at 4 weeks after the first intervention (week 4) were compared among the three groups. AEs that occurred during this study were recorded in a case report form after evaluating their relationship with the intervention. Two AEs related to the intervention occurred in the control group. One was a subcutaneous hematoma and the other was nausea. Both patients recovered without treatment. No serious AEs were observed during this study. There were no significant treatment-induced changes in vital signs, except for some temperature changes in the 650 group. However, the decrease of temperature in the 650 group was within the normal ranges for temperature (Table 6).

Table 6

Changes in vital signs (Week4 vs. Week0) after treatment completion within the three groups.

Groups	Dependent Variables	Week 0(M±SD)	Week 4(M±SD)	Deference(w4-w0)(M±SD)	t(p)#
Control group (n = 15)	Systoric BP	124.13±11.96	121.47±14.22	-2.67±9.13	1.13(0.277)
	Diastoric BP	82.13±8.42	81.80±10.97	0.33±9.04	0.14(0.889)
	Pulse	73.60±13.02	74.80±13.07	1.20±7.44	-0.63(0.625)
	Respiration	20.00±0.00	20.00±0.00	0.00±0.00	-0.00(1.00)
	Temperature	36.59±0.30	36.52±0.35	-0.07±0.28	1.02(0.326)
650 group (n = 15)	Systoric BP	125.60±12.44	123.53±16.78	-2.07±11.03	0.73(0.480)
	Diastoric BP	79.93±8.64	81.00±12.25	1.07±9.54	-0.43(0.671)
	Pulse	75.67±5.61	77.13±10.21	1.47±8.44	-0.67(0.512)
	Respiration	20.13±0.52	20.00±0.00	-0.13±0.52	1.00(0.334)
	Temperature	36.84±0.21	36.64±0.37	-0.20±0.33	2.37(0.033)
830 group (n = 15)	Systoric BP	120.73±12.12	122.20±16.43	1.47±11.54	-0.49(0.630)
	Diastoric BP	81.40±7.63	78.53±9.13	-2.87±8.15	1.36(0.195)
	Pulse	74.67±11.68	75.27±11.02	0.60±10.68	-0.22(0.831)
	Respiration	19.87±0.52	20.00±0.00	0.13±0.52	-1.00(0.334)
	Temperature	36.66±0.27	36.71±0.32	0.05±0.24	-0.87(0.401)

M, Mean; SD, standard deviation; BP, blood pressure;

#, paired t- test.

There were no significant differences in changes in vital signs among the three groups (Table 7).

Table 7

Difference in changes in vital signs (Week4 vs. Week0) among three groups.

	Control group		650 group	830 group
Systoric BP difference (M±SD)	-2.67±9.13		-2.07±11.03	1.47±11.54
F(p) †	0.66 (0.520)
Diastoric BP difference (M±SD)	-0.33±9.04		1.07±9.54	-2.87±8.15
F(p) †	0.75(0.480)
Pulse difference (M±SD)	1.20±7.44		1.47±8.44	0.60±10.68
F(p) †	0.04(0.964)
Respiration difference (M±SD)	0.00±0.00	-0.13±0.52		0.13±0.52
F(p) †	1.50 (0.235)
Temperature difference (M±SD)	-0.07±0.28	-0.20±0.33		0.05±0.24
F(p) †	2.99(0.061)

M, Mean; SD, standard deviation;

†, One-way ANOVA test.

Discussion

Although LA has been used to treat CNLBP, the efficacy and optimal treatment method of LA for CNLBP remain controversial because of insufficient evidence. To the best of our knowledge, this is the first RCT to investigate the efficacy of ILA and the effects of different ILA wavelengths on pain intensity, disability related to LBP, and quality of life of patients with CNLBP. Our study results could provide a basis for developing an optimal LA treatment method for CNLBP.

Our study had several main findings. First, the 650 group exhibited a significant improvement in the VAS score compared with the control group at the intervention endpoint. Second, the 650 and 830 groups exhibited significant improvements in the ODI scores compared with the control group at the intervention endpoint. Third, the 650 group exhibited significant improvements in the ODI scores compared with the control group at 4 weeks after intervention completion. Fourth, there was no adverse event related to ILA and no significant difference in changes in vital signs among the three groups. Fifth, we observed significant improvements in the control group (changes in VAS scores), 650 group (changes in VAS, ODI, and EQ-5D-5L scores), and 830 group (changes in VAS, ODI, and EQ-5D-5L scores).

ILA at 650 nm resulted in significant improvements in pain intensity and disability related to pain, and ILA at 830 nm resulted in significant improvements in disability related to pain for patients with CNLBP.

There are several reasons for our results. First, the analgesic effects of LLLT may have influenced the results. LLLT, also known as photobiomodulation, uses red or near-infrared light to stimulate tissue healing and regeneration. Cytochrome c oxidase in the mitochondria and light-/heat-gated ion channels are primary chromophores; both of these lead to the generation of reactive oxygen species that can activate transcription factors, which may act as exercise mimetics [36]. Multiple mechanisms underlie LLLT analgesia. Experimental evidence has suggestedthat laser irradiation induces peripheral neural blockade, suppresses central synaptic activity, modulates neurotransmitters, reduces muscle spasm and interstitial edema, and exerts anti-inflammatory effects [37]. A recent systematic review and meta-analysis of LLLT (including LA) for CNLBP reported that LLLT has a significant positive effect on reducing pain and improving functional disability and rarely produces severe AEs [15]. Second, the nature of the ILA may have affected the results. Noncollimated light scatters and is reflected at the superficial skin layers, which limits energy penetration through the skin. Because the acupuncture meridians and their acupoints are thought to exist in the myofascial layer of the body, the low energy penetration of light-emitting diode devices theoretically fails to stimulate acupoints [38]. However, ILA can compensate for light scatter and enhance energy penetration because the laser is irradiated at the tip of the acupuncture needle inserted under the skin. During a previous study, 660 nm laser irradiation of the skin did not result in significant pain reduction for patients with LBP [18]. Third, the laser parameters and dosage may have affected the results. The power density and wavelength affect the level of light penetration and scattering. The power density of a laser, defined as the laser energy supplied per area (W/cm2), influences the depth of energy penetration. Higher energy density results in deeper energy transmission [38]. Light wavelengths from 650 to 900 nm penetrate the skin the most. With a well-focused laser beam, red wavelengths (approximately 648 nm) can penetrate 2 to 4 cm beneath the skin surface, and infrared wavelengths (approximately 810 nm) can penetrate up to 6 cm beneath the skin [38].

Our study had some limitations. First, because of limited research funds, study period, and recruitment opportunities, we adopted a pilot study design. The sample size was not sufficient to investigate the efficacy and safety of ILA for CLBP; therefore, this may have led to bias in the results. Second, we did not use the various laser parameters or dosages typically used as treatment of CNLBP. Different wavelengths, power outputs, and energy doses affect the level of light penetration and scattering. There are various laser parameters and dosages for treating CNLBP [10,12]. However, the laser parameters and dosages used during this study are limited. Therefore, further studies investigating effective laser parameters and dosages should be performed. Third, we adopted a patient and assessor-blinded approach because the characteristics of acupuncture application make investigator-blinding impossible.

Conclusions

ILA at 650 nm led to significant reductions in pain intensity and improvements in pain-related functional disability with CNLBP. ILA at 830 nm led to a significant improvement in pain-related functional disability for patients with CNLBP. Our results suggest that ILA therapy at 650 nm and 830 nm can be used to treat CNLBP. However, because our study was a pilot clinical trial with a small sample size, further rigorously designed clinical studies with a larger sample size are needed to validate these results.

The appearance and components of Ellise.

(DOCX)

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Invasive laser acupuncture procedure and electroacupuncture procedure.

(DOCX)

Click here for additional data file.

Data.

(DOCX)

Click here for additional data file.

CONSORT checklist.

(DOC)

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Study protocol.

(PDF)

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23 Mar 2022

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**********

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Reviewer #1: This is an interesting study. The research project is well prepared and provided.

I have got only a few remarks:

-in Introduction section please describe the power and level of evidence in literature instead of boring and general principles. The analyses of quality of published RCTs so far would be useful. You can describe the PEDro or/and GRADE value of published articles. Please create the table with characteristics of RCTs like in systematic review. You can present Cochrane (if it is possible) reports and metaanalyses/systematic reviews from this area. Generally, the reader would like to read about reasearch status of this area, and what is new in your study. Why it is innovative?

-please enclose a few photos connected with laser app. It would be helpful

Reviewer #2: Thank you for the opportunity to review this interesting topic.

I do have several concerns:

Effects or efficacy? The authors used 'Effects' in the title and then used 'efficacy' in most parts of the paper. They are two different things; please clarify.

However, How was the 'safety' data collected? It was not detailed.

Blinding: patient blind? Single blind? What about the assessor? How did they blind the patients was not clear.

The intervention regime was not clear: All participants received laser acupuncture for 10 min once per day and electroacupuncture for 10 min once per day (twice per week on separate days) for 4 weeks at …; this is very unclear.

ILA and EA were performed with a medical device …. Please provide details of this device.

ILA intervention was not clear; the LA and ILA were used interchangeably. Please provide details of the ILA device.

How did you calculate the energy dose? 12 J/point? 12x8 points? 96 J in total? Where is the recommendation of such dosage?

I am not comfortable with each group having the electroacupuncture for 10 min once per day; the therapeutic effect may be from electroacupuncture, needling, LA, or LLLT since the author declared that the sham group also had significant improvements in the control group changes in VAS scores …

Laser acupuncture and ILA are used interchangeably;

Keywords should have up to 6 keywords and avoid the ones already in the title.

Language editing: there are many misspellings for example, line 53, Comprisinginteractions? Fig.1 words were cut off in half

The authors failed to give due diligence; as such, the report is rather poor in quality.

Reviewer #3: A three arm randomized-control pilot clinical trial aimed to preliminary evaluate the efficacy of two wavelengths of invasive laser acupuncture (ILA) to treat low back pain (CNLBP). The VAS scores of the participants receiving 650-nm wavelength ILA decrease significantly compared to the control group. The ODI scores for both the 650 and 830 wavelength groups decreased significantly compared to the control group.

Minor revisions:

1- Perhaps the abstract should be modified to indicate that the trial aimed to provide preliminary evidence for the efficacy of ILA for CNPBP.

2- Line 190: Clarify what the statisticians were blinded from.

3- If the data is normally distributed provide the mean and standard deviation. However, if the data is not normally distributed, summarize using median, first and third quartiles.

4- Table 3: Define M.

5- Tables: Remove the columns labeled Significant.

6- P-values never equal zero; express small p-values as < 0.001.

7- Table 4: State the type of summary statistics provided in parentheses. Perhaps the label is partially obscured due to formatting of the document.

8- If an interaction effect is significant, provide an interpretation of the results, but do not test main effects because the tests for main effects are uninteresting in light of significant interactions. If interaction effects are non-significant, drop the interaction effects from the model and test the main effects. Determining which results to present when testing interactions is often a multi-step process.

9- Cite the statistical software used for the analysis.

**********

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Reviewer #1: Yes: Jakub Taradaj

Reviewer #2: No

Reviewer #3: No

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16 Apr 2022

Reviewer #1: This is an interesting study. The research project is well prepared and provided.

I have got only a few remarks:

-in Introduction section please describe the power and level of evidence in literature instead of boring and general principles. The analyses of quality of published RCTs so far would be useful. You can describe the PEDro or/and GRADE value of published articles. Please create the table with characteristics of RCTs like in systematic review. You can present Cochrane (if it is possible) reports and metaanalyses/systematic reviews from this area. Generally, the reader would like to read about reasearch status of this area, and what is new in your study. Why it is innovative?

Response: Thank you for your valuable comments. In accordance with your suggestion, we have attached a consort checklist as the S2 appendix to indicate reporting quality of our manuscript. We presented the conclusion of Cochrane report and several systematic review/meta-analyses on the efficacy of LLLT for chronic non-specific low back pain to describe the power and level of evidence in literature as follows : “The efficacy of LLL therapy (LLLT), including LA for CNLBP, has not been established. A Cochrane report [12] concluded that there were insufficient data to draw firm conclusions on the clinical effect of LLLT for low back pain (LBP). There is a need for further methodologically rigorous randomized controlled trials (RCTs) to evaluate the effects of LLLT. Several systematic reviews and meta-analyses [13-15] have suggested that LLLT including LA may have a significant positive effect on reducing pain. However, there is still a lack of high quality evidence supporting its efficacy. Rigorously blinded trials are needed to confirm the efficacy of LLLT for CNLBP and identify the optimal LLLT parameters. Several studies have reported that LA did not show significant effects compared with sham laser for patients with LBP [16-18]. The methods of LLLT used in previous studies were noninvasive and there was no study on invasive laser [12-18]. on pages 3-4, lines 65-76.

-please enclose a few photos connected with laser app. It would be helpful

Response: Thank you for your comments. Per your suggestion, we have attached photos of the appearance and components of Ellise, invasive laser acupuncture (ILA) procedure, and electroacupuncture procedure as S1 Fig and S2 Fig.

Reviewer #2: Thank you for the opportunity to review this interesting topic.

I do have several concerns:

Effects or efficacy? The authors used 'Effects' in the title and then used 'efficacy' in most parts of the paper. They are two different things; please clarify.

Response: We apologize for the confusion. We have revised the title as follows : “Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized, controlled trial” on pages 1, lines 1-2.

However, How was the 'safety' data collected? It was not detailed.

Response: We apologize for not being detailed in our description of safety evaluation. We inserted the pertinent sentences in the statistical analyses and safety evaluation subsection as follows : “For safety evaluation, incidence of adverse events (AEs) among the three groups were compared using chi-squared (χ2) test and difference in changes in vital signs at 4 weeks after the first intervention (week 0 vs. week 4) were compared among the three groups using ANOVA.” on page 12, lines 238-241.

“For safety evaluation, the incidence of AEs and difference in changes in vital signs at 4 weeks after the first intervention (week 4) were compared among the three groups. AEs that occurred during this study were recorded in a case report form after evaluating their relationship with the intervention. Two AEs related to the intervention occurred in the control group. One was a subcutaneous hematoma and the other was nausea. Both patients recovered without treatment. No serious AEs were observed during this study. There were no significant treatment-induced changes in vital signs except for some temperature changes in the 650 group. However, the decrease of temperature in the 650 group was within the normal ranges for temperature (Table 6). There were no significant differences in changes in vital signs among the three groups (Table 7)” on page 16-18, line 291-306.

We have inserted the changes in vital signs within the three groups and difference in changes in vital sign among the three groups as Table 6 and Table 7.

Blinding: patient blind? Single blind? What about the assessor? How did they blind the patients was not clear.

Response: Thank you for your query. We apologize for the confusion. We adopted a patient and assessor-blinded trial procedure. We revised Randomization and Blinding subsection as follows: “We adopted a patient and assessor-blinded trial procedure. Real laser and sham laser had no differences in appearance, feel, or sound. During the course of this clinical trial, the assessor did not contact any participant at any point of time other than the time of assessment. Hence, participants and assessor remained blinded to the treatment allocation until study completion. A statistician with no conflicts of interest performed the analysis. However, because of the nature of ILA treatment, investigators could not be blinded.”

on page 8, line 156-161.

We described the patient blinding method in the intervention subsection as follows : “The control group underwent the same procedures as the ILA group, but the laser was not turned on. No differences in observations, feelings, or sounds were observed among the three groups during the procedure. Hence, all participants were blinded to the group selection.” on page 9, line 182-185.

The intervention regime was not clear: All participants received laser acupuncture for 10 min once per day and electroacupuncture for 10 min once per day (twice per week on separate days) for 4 weeks at …; this is very unclear.

Response: We apologize for not clearly describing the intervention regime. We revised this sentence for more clarity as follows : “ All participants received laser acupuncture for 10 min, followed by electroacupuncture for 10 min on the same day. The treatment was performed once per day, twice per week for 4 weeks at bilateral BL23, BL24, BL25, and GB30.” on page 2, line 31-34.

ILA and EA were performed with a medical device …. Please provide details of this device.

Response: Thank you for your comments. To provide details of a medical device, we attached photos of the appearance and components of Ellise, invasive laser acupuncture(ILA) procedure and electroacupuncture procedure as S1 Fig and S2 Fig, and we have revised the intervention subsection to provide details of a medical device as follows : “ILA and EA treatment were performed using a medical device ( Ellise; Wontech Co. Ltd., Daejeon, Republic of Korea) capable of laser irradiation and electrical stimulation. It is composed of a main body consisting of a laser output device and an electrical stimulator, a sterile, stainless steel, disposable acupuncture needle (external diameter, 0.3 mm; inner diameter, 0.15 mm; length, 30 mm) in which an optical fiber is inserted, optical fiber-coupled laser diode (650 nm used the InGaAIP; 830 nm used the GaAIAs) and an electrical stimulus clip. The parameters of the ILA are 20 mW for power, 12 J/point for energy dose, 63.69 W/cm2 for power density, and 38216.56 J/cm2 for energy density. on page 9, lines 167-175.

ILA intervention was not clear; the LA and ILA were used interchangeably. Please provide details of the ILA device.

Response: Thank you for your comments. LA used in RCT for CNLBP is noninvasive. LA is applied to the skin at acupoints using a laser-emitting device that can be used as an alternative to acupuncture needles [1-7]. The laser beams irradiated to the skin are scattered and reflected at the superficial skin layers, which limits energy penetration through the skin. In contrast, ILA used in our study is irradiated at the tip of the acupuncture needle under the skin. Thus, ILA can compensate for light scatter and enhance energy penetration.

We inserted the pertinent sentences in the intervention subsection as follows : “Noninvasive LA is applied to the skin at acupoints. In contrast, the ILA used in our study was irradiated at the tip of the acupuncture needle under the skin.” on page 9, line 178-180.

For a detailed description of the ILA device, please see the answer to the above questions.

How did you calculate the energy dose? 12 J/point? 12x8 points? 96 J in total? Where is the recommendation of such dosage?

Response: Thank you for your query. The following physical formula was used to calculate the dose [2]: Energy dose (J) = Watts (W) ⅹseconds (secs); Power density (W/cm2) = Watts/area of acupuncture needle tip (cm2); Energy density (J/ cm2) = Watts (W) ⅹseconds (secs)/ area of acupuncture needle tip (cm2)

The parameters of the ILA used in our study are as follows:

- Energy dose : 12(J) = 0.02 (W) ⅹ 600 (secs)

- Power density : 63.69 W/cm2 = 0.02 (W) / 3.14 ⅹ 0.01 ⅹ 0.01(cm2)

- Energy density : 38216.56 J/cm2 = 0.02 (W) ⅹ 600 (secs)/ 3.14 ⅹ 0.01 ⅹ 0.01(cm2)

The energy dose used in our study was 12 J/point and 96 J (12 ⅹ 8 points) in total.

There is no energy dose of recommended LLLT used in CNLBP treatment. The energy dose used in RCTs that investigated the efficacy of LLLT including LA for CNLBP varied to 0.2 – 1873.8 J/point [4]. A recent systematic review and meta-analysis suggested that the energy dose of LLLT for CNLBP was recommended to be 4 J or more per point [8].

I am not comfortable with each group having the electroacupuncture for 10 min once per day; the therapeutic effect may be from electroacupuncture, needling, LA, or LLLT since the author declared that the sham group also had significant improvements in the control group changes in VAS scores …

Response: Thank you for your comments. We understand your concern that electroacupuncture treatment would have affected the results of our study. When we designed this study, we thought that all participants in our study should receive the minimal treatment for CNLBP. Thus, we adopted electroacupuncture as the basic treatment. Exercise, massage, hot fomentation, and soft cupping were performed in both groups as basic treatment in the previous RCTs that investigated the efficacy of LLLT for CNLBP [1-4].

Laser acupuncture and ILA are used interchangeably;

Response: Thank you for your comments. LA is noninvasive. LA is applied to the skin at acupoints using a laser-emitting device that can be used as an alternative to acupuncture needles. In contrast, ILA used in our study is irradiated at the tip of the acupuncture needle under skin. Ellise, a medical device used in our study, is only able to perform ILA using a sterile, stainless steel, disposable acupuncture needle in which an optical fiber is inserted. The acupuncture needles were vertically inserted in acupoints and then laser was irradiated at the tip of the acupuncture needle under skin. We have attached photos of the invasive laser acupuncture (ILA) procedure as S2 Fig to describe the ILA procedure in detail.

Keywords should have up to 6 keywords and avoid the ones already in the title.

Response: Thank you for your comments. In accordance with your advice, we have revised the keywords as follows : “low back pain, 650 nm low level laser, 830 nm low level laser, pain intensity, visual analog scale, clinical trial”

Language editing: there are many misspellings for example, line 53, Comprisinginteractions? Fig.1 words were cut off in half

The authors failed to give due diligence; as such, the report is rather poor in quality.

Response: We appreciate your pertinent observations. Based on your observations, we have carefully rechecked the revised manuscript for further grammar and spelling errors. We have had our manuscript re-edited by a professional English language editing service to ensure that the text is free from any spelling and grammar errors. The edit was performed by editors at Editage, a division of Cactus Communications.

Reviewer #3: A three arm randomized-control pilot clinical trial aimed to preliminary evaluate the efficacy of two wavelengths of invasive laser acupuncture (ILA) to treat low back pain (CNLBP). The VAS scores of the participants receiving 650-nm wavelength ILA decrease significantly compared to the control group. The ODI scores for both the 650 and 830 wavelength groups decreased significantly compared to the control group.

Minor revisions:

1- Perhaps the abstract should be modified to indicate that the trial aimed to provide preliminary evidence for the efficacy of ILA for CNLBP.

Response: Thank you for your comments. In accordance with your suggestion, we inserted the following sentence into the abstract section: “ This study aimed to provide preliminary evidence for the efficacy of invasive laser acupuncture (ILA) for chronic non-specific low back pain (CNLBP).” on page 2, line 26-27.

2- Line 190: Clarify what the statisticians were blinded from.

Response: We apologize for the confusion. We revised “Analyses were performed by blinded biostatisticians” to “To reduce risk of bias, a statistician who was not involved in this clinical trial analyzed the final data.” on page 11, line 226-227.

3- If the data is normally distributed provide the mean and standard deviation. However, if the data is not normally distributed, summarize using median, first and third quartiles.

Response: Thank you for pointing this out. VAS data is normally distributed, while ODI and EQ-5D-5L data are not normally distributed. Therefore, based on your advice, we provided VAS and vital signs data as mean and standard deviation, and ODI and EQ-5D-5L data as median, first, and third quartiles in tables 2, 3, 4, 5, 6, and 7.

4- Table 3: Define M.

Response: We apologize for the confusion. We have provided mean as M and median as m to prevent confusion and we have defined M and m below the table 2, 3, 4, 5, 6, and 7.

5- Tables: Remove the columns labeled Significant.

Response: Thank you for your comments. We revised Table 4 that analyzed interaction between time and group to Table 4, which compared changes in the VAS scores among three groups.

6- P-values never equal zero; express small p-values as < 0.001.

Response: Thank you for your comments. According to your advice, we expressed small p-values as < 0.001 in Table 3.

7- Table 4: State the type of summary statistics provided in parentheses. Perhaps the label is partially obscured due to formatting of the document.

Response: Thank you for your comments. We revised Table 4, which analyzed interaction between time and group to Table 4, which compared changes in the VAS scores among three groups.

8- If an interaction effect is significant, provide an interpretation of the results, but do not test main effects because the tests for main effects are uninteresting in light of significant interactions. If interaction effects are non-significant, drop the interaction effects from the model and test the main effects. Determining which results to present when testing interactions is often a multi-step process.

Response: We appreciate your valuable suggestions. The purpose of our study was to investigate the efficacy of ILA on pain reduction in CNLBP. Therefore, the primary outcome was the among-group difference of changes in VAS at 4 weeks after the first intervention (week 4). The interaction between time and group of VAS was not significant. Based on your suggestions, we have revised Table 4, which analyzed interaction between time and group to Table 4, which compared changes in VAS scores among the three groups.

9- Cite the statistical software used for the analysis.

Response: Thank you for your comments. We have cited the statistical software used for the analyses in the statistical analyses subsection as follows : “To reduce risk of bias, a statistician who was not involved in this clinical trial analyzed the final data using SPSS version 20.0 software (SPSS Inc., Chicago, IL, USA) and two-sided significance tests with a 5% significance level.” on page 11, line 226-228.

Reference

1. Yousefi-Nooraie R, Schonstein E, Heidari K, Rashidian A, Pennick V, Akbari-Kamrani M, et al. Low level laser therapy for nonspecific low-back pain. Cochrane Database Syst Rev. 2008;2: CD005107. doi: 10.1002/14651858.CD005107.pub4.

2. Glazov G, Yelland M, Emery J. Low-level laser therapy for chronic non-specific low back pain: a meta-analysis of randomised controlled trials. Acupunct Med. 2016;34: 328-341. doi: 10.1136/acupmed-2015-011036.

3. Huang Z, Ma J, Chen J, Shen B, Pei F, Kraus VB. The effectiveness of low-level laser therapy for nonspecific chronic low back pain: a systematic review and meta-analysis. Arthritis Res Ther. 2015;17: 360. doi: 10.1186/s13075-015-0882-0.

4. Yeum H, Hong Y, Nam D. Low-level laser therapy including laser acupuncture for non-specific chronic low back pain: systematic review and meta-analysis. J Acupunct Res. 2021;38: 8-19. doi: 10.13045/jar.2020.00283.

5. Glazov G, Yelland M, Emery J. Low-dose laser acupuncture for non-specific chronic low back pain: a double-blind randomised controlled trial. Acupunct Med. 2014;32: 116-123. doi: 10.1136/acupmed-2013-010456.

6. Glazov G, Schattner P, Lopez D, Shandley K. Laser acupuncture for chronic non-specific low back pain: a controlled clinical trial. Acupunct Med. 2009;27: 94-100. doi: 10.1136/aim.2009.000521.

7. Shin JY, Ku B, Kim JU, Lee YJ, Kang JH, Heo H, et al. Short-term effect of laser acupuncture on lower back pain: a randomized, placebo-controlled, double-blind trial. Evid Based Complement Alternat Med. 2015;2015: 808425. doi: 10.1155/2015/808425.

8. Yeum H, Hong Y, Nam D. Effective low-level laser therapy including laser acupuncture treatment conditions for non-specific chronic low back pain: systematic review and meta-analysis. J Acupunct Res. 2021;38: 85-95. doi: 10.13045/jar.2020.00311.

Submitted filename: Response_to_Reviewer-PLOS_ONE-resub.docx

Click here for additional data file.

12 May 2022

14 May 2022

We are very grateful for the constructive comments and the opportunity to revise our manuscript.

Point-by-point responses to the reviewers’ comments are provided below. The corresponding changes have been highlighted in the revised manuscript with track changes.

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The paper reads much clearer after the revision.

A few minor changes are required:

page 11, line 220: the first word 'efficacy' should be 'effectiveness':

"Because our study was a pilot study, the sample size was insufficient to determine the efficacy of ILA for CNLBP.".

Response. Thank you for your comments. In accordance with your suggestion, We revised ‘efficacy’ to ‘effectiveness’

Table 3 needs editing; some words are cut in half. Same as Table 7.

Response. Thank you for your comments. In accordance with your suggestion,we edited Table 3 and 7.

Table 6, there should be a gap between 'group' and (n=15).

Response. Thank you for your comments. In accordance with your suggestion,we edited Table 6.

In figure 1, the first letter should be F, not f.

Response. Thank you for your comments. In accordance with your suggestion,we revised the figure 1.

Submitted filename: (second) response to reviewer-PLOS ONE.docx

Click here for additional data file.

18 May 2022

Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized, controlled trial

PONE-D-22-02875R2

Dear Dr. Kim,

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Additional Editor Comments (optional):

The authors have addressed all the reviewers' comments.

Reviewers' comments:

20 May 2022

PONE-D-22-02875R2

Efficacy of invasive laser acupuncture in treating chronic non-specific low back pain: A randomized controlled trial

Dear Dr. Kim:

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