The Importance of Power in Photobiomodulation, a Systematic Review and Meta-analysis of High Intensity Laser Therapy

doi:10.21203/rs.3.rs-4813995/v1

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Systematic Review

The Importance of Power in Photobiomodulation, a Systematic Review and Meta-analysis of High Intensity Laser Therapy

https://doi.org/10.21203/rs.3.rs-4813995/v1

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Low-level light therapy (LLLT; ≤0.5 Watts; W) has advanced to the stage of guideline recommended treatment with payer coverage for treating shallow tissue oral mucositis. However, LLLT often fails in trials treating deeper tissue pathologies due to an inability to penetrate and deliver sufficient therapeutic light. By contrast, Class IV high-intensity laser therapy (HILT; 0.5-80W) typically at 100-fold higher powers has proven successful for treating these same deeper tissue pathologies. To evaluate the range of indications responding favorably to Class IV HILT, we searched PubMed, Google Scholar, and Cochrane databases from 2018 to March 2024 using the keywords "laser" AND "photobiomodulation" OR "therapy" AND "high" AND "patients" NOT "surgical", focusing on controlled trials. Effect sizes were determined using Cohen’s d. Fifty-six identified studies (n=1,486 HILT vs n=1,494 controls) reported zero serious adverse events. HILT reduced pain in 100% of the trials focused on the knee (n=10), spine, shoulder/arm, and wounds with large effect sizes (>90%). Positive outcomes were demonstrated for the hand/wrist (n=5), feet, face/jaw, bone osteoporosis, and endometriosis. Improvements in range of motion (94%; n=16), functional outcomes (84%; n=37), quality of life (80%; n=20), knee cartilage thickness, rotator cuff tear size, and nerve conduction were demonstrated. Larger effect sizes occurred in follow-up measurements made after cessation of treatment (n=18) indicating that benefits were sustained and not merely transient. The average (median, range) power used was 9.5W (10.5, 0.5-30) and the average power density was 9.1W/cm² (8; 1-30). We conclude that Class IV HILT is an exceptionally safe, effective, and increasingly recognized treatment that is in a promising discovery phase of research for an expanding list of indications with deep-tissue pathologies. The medical and payer communities should include HILT as a viable treatment option for indications showing positive outcomes in the published research.

Anesthesiology & Pain Medicine

Optics/Lasers

photobiomodulation

musculoskeletal

pain

knee

arthritis

Since the inception of photobiomodulation therapy (PBMT) over 50 years ago, PBMT has primarily been used to treat shallow tissue pathologies (< 1cm deep) using low-powered light that is less than 500 mW. Numerous therapeutic successes and countless basic science studies have undeniably demonstrated the advantageous properties and clinical benefits of PBMT for a growing range of shallow tissue pathological indications. However, when attempting to treat deeper tissue pathologies, the lower-powered approaches have consistently failed to yield positive results due to the light's inability to penetrate the deeper pathological tissues.^1,2 Over the past two decades, since the first FDA approval of higher-powered coherent laser therapy in the range of 1–80 watts (W), numerous studies investigating higher powers for the treatment of deep tissue pathologies have demonstrated positive outcomes for the same indications.^3–10 This is commonly referred to as high-intensity laser therapy (HILT). The full range of indications that respond positively to HILT is currently in a discovery phase of research and an area of focus for this meta-analysis. Our meta-analysis is accompanied by our review highlighting pioneering firsts in HILT clinical research, both historical and ongoing.

PBMT Discovery, Acceptance, and the General Limitations of LLLT to Treating Shallow Tissue Pathologies Only

PBMT was initially discovered in 1967 when increased hair growth was observed in shaved mice irradiated with red light in an attempt to determine its carcinogenic properties, which it did not.¹¹ Thereafter in the early 1970s, PBMT was then evaluated in clinical settings by Andrew and Adam Mester in patients with recalcitrant non-healing leg ulcers.¹² Treatment with just 10 mW of 630nm wavelength light from a helium neon laser resulted in a remarkable complete recovery in 823 out of 1,018 patients (81.4%), with only 23 patients showing no change.¹³ Almost 74% of patients who had qualified as non-healing for an average of 5.1 years were healed, on average, within 5.5 months of therapy. These impressive outcomes highlight the urgency of using PBMT, particularly considering that the 5-year mortality rate for patients with diabetic and ischemic foot ulcers is higher than that of several cancers, including prostate and breast cancer.¹⁴

The steady rise in recognition of PBMT was accelerated exponentially by the development of the "NASA LED" in the NASA Space Medicine laboratory of Professor Harry Whelan in 1998.¹⁵ This innovative technology made PBMT more affordable, accessible, and energy efficient, thereby making it more widely available for at-home therapies.

By 2020, for the first time in the history of photobiomodulation therapy medicine, clearly therapeutically beneficial outcomes for the treatment of oral mucositis culminated in acceptance at all levels. This ranges from physician consensus-recommended treatment guidelines to recognition by insurance payers using low powers in the range of 25–150 mW to deliver photobiomodulation therapy.^16,17

However, it is important to note that the efficacy of low-level laser therapy (LLLT; low power) in treating oral mucositis is limited to shallow tissue pathologies of less than 2 cm. Evaluation of low-powered PBMT with powers below 500 mW for the treatment of deeper musculoskeletal pathologies have consistently failed to produce positive outcomes.^18–23 Rigorous analysis revealed that LLLT cannot penetrate tissues beyond 2 cm, which is an insufficient depth for delivering therapeutic light intensities to the deeper tissue pathologies occurring in most musculoskeletal arthropathies.^24–26

High Powered Lasers Confer Benefits to Deep Tissue Pathologies

On the other hand, high-intensity laser therapy (HILT; higher power) used in clinical practice can penetrate deeply into tissues to deliver effective levels of photobiomodulation therapy. Research by Morries et al. demonstrated that a 15W laser with a 7 cm² spot size can penetrate 3 cm (1.2 inches) of tissue while maintaining an established therapeutically active power density of approximately 50 mW/cm².²⁴ As a result, the use of an 80W laser enables the delivery of therapeutic doses of PBMT to tissues as deep as 15 cm (6 inches) .^7,27 Multiple independent studies have shown that HILT consistently produces positive outcomes, particularly in the treatment of knee osteoarthritis (1). This approach has the potential to prevent total knee arthroplasty, ultimately saving approximately $29,488 per procedure based on a 2018 cost analysis.²⁸

The FDA class IV device designation encompasses therapeutic lasers since it continues to be generally defined by powers as low as 500mW even though the class IV designation has historically been used to primarily refer to surgical lasers, which use higher powers (e.g., 100-300W) and longer wavelengths (e.g.,10,600nm CO₂ lasers or 2,940nm Er: YAG lasers) than therapeutic lasers. This Surgical laser light is highly absorbed by water to cause flash-boiling, ablation, or carbonization. By contrast, HILT light is not appreciably absorbed by water due to shorter 800-1064nm wavelengths and lower power settings commonly ranging from 2-30W, which impart nondestructive therapeutic cellular activities in a painless fashion.² To make matters even more complicated, a 50W CO₂ surgical laser becomes a therapeutic light when the spot size is defocused to a 10cm².² So, spot size matters as the light spot size can ultimately control whether a light is surgical or therapeutic and this also controls the depth of penetration for a therapeutic light source of fixed wavelength and collimation. Finally, the power density (irradiance; W/cm²) is the most informative parameter for a given wavelength as related to these surgical⌠therapeutic modalities and depths of penetration.

The FDA only recognized clearance for class IV therapy laser devices as recently as 2002.²⁹ Several medical associations have recommended high-powered photobiomodulation therapies. In 2021, The American Academy of Orthopedic Surgeons began recommending laser therapy for the treatment of osteoarthritis of the knee joint.³⁰ The American College of Physicians issued a guideline for treating non-radicular low back pain with PBMT starting in 2017.³¹ The American Physical Therapy Association Orthopedic Section began issuing PBMT treatment recommendations for heel pain plantar fasciitis, neck pain, and Achilles tendinitis.^32–34 The World Health Organization now recommends laser therapy and its photobiomodulation benefits for neck pain.³⁵ The list of recommended treatment indications continues to expand.

Photobiomodulation therapy has been established and accepted at all levels for treating shallow tissue pathologies. However, the most commonly used power settings have been limited to lower powers (≤ 500mW; class III), which have generally failed to produce positive outcomes when treating deep tissue pathologies (> 2 cm). By using high-powered (1-80W) laser PBMT, positive outcomes have been repeatedly achieved due to the ability of high-powered lasers to penetrate depths of up to 15 cm.^24,27,36 More medical professionals in numerous fields of study are becoming aware of the possibilities of using higher-powered laser PBMT to reach deeper tissues.

The primary objective of this meta-analysis was to assess the sum categorical efficacy of high-powered laser PBMT for any categorical indication as published in controlled clinical trials. This includes considering outcome metrics such as pain reduction, range of motion increases, functionality improvements, quality of life improvements, wound closures, neurophysiological measures, or others. The secondary objective was to perform a summary analysis of the optimal laser parameters (power settings, dosages, and wavelengths) and treatment plans used in the currently limited available controlled trials. Accordingly, a suggested summary table of optimal laser parameters and treatment plans is offered at the end of the results section.

Search for Evidence and Article Selection

This study adheres to all PRISMA guidelines and provides the required information accordingly. We conducted a systematic review of the best evidence using Cochrane guidelines. The structured question for this review is displayed in Fig. 1. We searched the most important and appropriate electronic medical databases, including PubMed, Cochrane Library, and Google Scholar. The search terms used were "laser" and ("photobiomodulation" or "therapy") and "high" and "patients," excluding any articles related to surgery, limited to the years 2018 to March 2024, and focused on clinical trials. Articles that were deemed irrelevant to the research objectives were excluded. After collecting the full texts of articles related to the study's objectives, we reviewed the references of these articles and identified additional relevant references for review

Inclusion and Exclusion Criteria

The inclusion criteria were as follows: (1) controlled clinical trial studies, (2) published between 2018 and November 2023, (3) use of higher powered lasers with average power settings > 0.5W, (4) patients with a medical diagnosis, (5) comparison of higher powered lasers versus LLLT or placebo lasers or a common background, and (6) the use of outcome measures such as pain, range of motion, quality of life, cartilage thickness, disability indices, bone density, or gait. The exclusion criteria included (1) fundamental research or studies conducted on animals, (2) controlled trials involving patients without a medical diagnosis, (3) review articles, and (4) articles lacking statistical and clinical data. For publications that only provided information on peak power, frequency, and pulse time, we calculated the average power using the formula³⁷: average power = peak power x hertz frequency x pulse duration.

Statistical Analysis

The significance level was based on reported p scores < 0.05. The statistical method was designed to specifically measure the effect size (ES) attributable to HILT compared to the control group. To evaluate the magnitude of the difference between groups, we determined the effect size of each variable using Cohen's d.^38,39 The standardized mean of group assessments made before and after treatment was divided by the pooled standard deviation.

$$\:ES=\frac{M\:time\:zero-M\:follow\:up}{SD\:pooled}$$

The difference in effect sizes between the HILT and control groups was calculated by subtracting the effect size for each group, which served as a metric for determining the relative efficacy specifically attributable to HILT.⁹

Difference in effect size = ES₁ – ES₂

Interpretation of the effect sizes was based on the values established by Cohen: small effect ≤ 0.2, medium effect 0.2–0.8, and large effect > 0.8.³⁸ Confidence intervals for the difference of 2 means was calculated with assistance from the PEDro calculator.⁴⁰

Power density (W/cm²) is the most important parameter controlling the depth of penetration at a constant wavelength, collimation, and continuous setting, but the power density parameter is often not described in studies. Spot size matters. A PBMT device can become surgical if the spot size is concentrated and vice versa, a surgical carbon dioxide laser can become therapeutic if it is defocused to a larger size.² Since the depth of penetration is a major focus of our meta-analysis, we include a description of the power density throughout our entire report whenever the spot size for the hand piece is described and can be determined in any study.

QUALITATIVE SUMMARY OF INCLUSIVE STUDIES

The meta-analysis included 56 studies that fullfilled the criteria for inclusion. These studies evaluated various outcome measures such as pain, function, quality of life, range of motion, strength, and anatomical structures (Tables 1 and 2). Among these studies, two were triple-blinded, 23 were double-blinded, 23 were single-blinded, 3 were not blinded, and one had an undetermined blinding status. Using the standard p < 0.05 as the probability value, significant reductions in pain were found in 43 out of 47 studies. Additionally, 36 out of 39 arthropathies showed statistically significant reductions in pain.

Table 1

**Summary list of all studies meeting criteria for inclusion in the meta-analysis.** Studies are categorized by target anatomies towards consideration of the relative depth of penetration respectively: knee, spine/back, shoulder/arm, face, hand/wrist, foot, wounds, gynecological, bone, and COVID-19. Single, double, or triple blinded are denoted by numbers 1–3. HILT specific outcomes are described with effective pain reduction, range of motion (ROM) increases, quality of life (QoL) increases, or functional gains after HILT treatment denoted as positive (+) or negative (-) when assessed.
KNEE
Reference	Blinding	HILT Specific Outcomes	<Pain	>ROM	>QoL	>Function
Ahmad¹ Knee Osteoarthritis (Malaysia) 37511894; 2023	2	Pain reduced (NPRS scale) Flexion reduced LLLT had clinically insignificant outcomes	+	+	+	+
Akaltun² Knee Osteoarthritis (Turkey) 33074393 2020	2	Pain reduced (VAS & WOMAC) ROM increased Cartilage thickness increased	+	+		+
Bettancourt³ Knee osteoarthritis (Portugal) J.Arthritis; 2020	1	Pain reduced at EOT and 1mo after cessation	+
Ekici⁴ Knee OA (Turkey) 37743421; 2023	2	Pain reduced Cartilage thickness increased ROM increased	+	+		+
El-Shamy⁵ Hemophilic Arthropathy (Egypt) 27976591; 2018	2	Pain reduced Gait performance improved Functional improvements	+		+	+
El-Shamy⁶ Juvenile Rheumatoid Arthritis Egypt) 30016193; 2018	2	Pain reduced Gate improved (GAITRite)	+			+
Mostafa⁷ Knee Osteoarthritis (Egypt) 34986012; 2022	2	Pain reduced Gate improved (WOMAC)	+			+
Nazari⁸ Knee Osteoarthritis (Iran) 30178432; 2019	3	Pain reduced Stiffness in knee reduced (WOMAC stiffness) ROM increased	+	+		+
Nouri⁹ Patellofemoral Pain Syndrome (Iran) 31360367; 2019	1	Pain reduced Functionality improved	+			+
Samaan¹⁰ Knee Osteoarthritis (Egypt) 35678062; 2022	1	Pain reduced ROM increased Function improved (WOMAC)	+	+		+
Siriratna¹¹ Knee Osteoarthritis (Thailand) 36313402; 2022	1	Pain reduced Functional ability was unchanged (WOMAC)	+			-
Taheri¹² Knee osteoarthritis (Iran) MEJRH-134330; 2024	1	Pain reduced Functional ability improved (WOMAC)	+	+		+
Wibisono¹³ Knee Osteoarthritis 2024	U	Greater increase in balance in the HILT group than LLLT				+

SPINE/BACK
Reference	Blinding	HILT Specific Outcomes	<Pain	>ROM	>QoL	>Function
Abdelbassett¹⁴ Chronic lower back pain (Saudi Arabia & Egypt) 33178306; 2020	2	Pain reduced Disability reduced Lumbar mobility improved ROM increased QoL improved (EroQoL)	+	+	+	+
Abdelmageed¹⁵ Chronic Discogenic Sciatica (Egypt) link; 2022	1	Pain reduced Increased walking distance Increased leg ROM Increased spinal neuron activity Potential recovery from conduction block	+			+
Ahi¹⁶ Myofascial pain syndrome (Turkey) 36538189 2022	1	Pain reduced Disability reduced (NDI) ROM increased QoL improved (SF-36)	+	+	+	+
Chatterjee¹⁷ Peripheral neuropathy, lumbar (India) 31405365; 2019	1	Pain reduced more by HILT	+		+	-
Chen¹⁸ Lumbar disc protrusion (China) 28854500; 2018	1	Pain reduced Disability reduced (ODI) ROM increased	+			-
Gawaan¹⁹ Myofascial pain syndrome post-neck discectomy (Egypt) The Egyptian Journal of Hospital Medicine (2023)	1	Pain reduced Pressure pain threshold increased Neck ROM increased	+	+
Ince²⁰ Neck pain (Turkey) 37204965 ; 2024	1	Pain reduced Cervical ROM increased Disability (NDI) reduced QoL (SF-36) increased	+	+	+	+
Kenareh²¹ Chronic neck pain (Iran) 34733743; 2021	U	Short term pain relief	+			+
Sherif²² Cervical Radiculopathy (Egypt) Medical Journal of Cairo University; 2023	U	Pain was reduced Electrophysiological measures were unchanged	+
Venosa²³ Cervical Spondylosis (Italy) 30443883; 2019	1	Pain reduced ROM increased Disability (NDI) reduced	+	+	+	+
Yilmaz²⁴ Cervical disc herniation (Turkey) 32147037; 2020	1	Pain reduced QoL improved ROM increased	+	+	+

SHOULDER/ARM
Reference	Blinding	HILT Specific Outcomes	<Pain	>ROM	>QoL	>Function
Abdelhakiem²⁵ Hemiplegic shoulder (Egypt) 38538637; 2024	?	Pain reduced, functional ability improved, and handgrip strength increased	+			+
Aceituno-Gómez²⁶ Subacromial impingement (Spain) 30672303; 2019	2	Pain unchanged Disability (CMS score) unchanged	+			-
Atan²⁷ Adhesive capsulitis (frozen shoulder (Turkey) 32808147 2021	2	Pain reduced QoL improved Functional ability (SPADI) unchanged	+		+	-
Elsodany²⁸ Rotator Cuff Tendinopathy (Egypt & Saudi Arabia) 30188253; 2018	1	Pain reduced ROM increased both at EOT & 3mos post-treatment	+	+		+
Karaca²⁹ Lateral sylitis (Turkey) 36117204; 2022	0	Pain reduced Grip strength increased Hand function increased	+			+
Kaydock³⁰ Lateral epicondylitis (Turkey) 32637921; 2020	2	Pain reduced Hand grip strength increased QoL (SF-36) increased Function (QDASH) increased	+		+	+
Korkmaz³¹ Hemiplegic Shoulder Pain (Turkey) 33829317; 2021	2	Pain reduced ROM increased Disability index (SPADI) decreased Motor recovery improved QoL (NHP) improved Functional (FIM) improved Rotator cuff tear size reduced	+	+	+	+
Ordahan³² Adhesive capsulitis (Turkey) 37533657; 2023	2	Pain reduced Disability index (SPADI) decreased	+	-		+
Yilmaz³³ Subacromial Impingement Syndrome (Turkey) 33400012; 2021	2	Pain reduced ROM increased Function (CMS) increased QoL (SF-36) improved Strength increased Daily activity increased	+	+	+	+
Sen³⁴ Lateral epicondylitis (Turkey) 38280938; 2024	0	Pain reduced Disability improvement	+			+
Zaki³⁵ Subacromial impingement syndrome(Iran) 34184965; 2022	1	Pain reduced Function (SPADI) improved Ultrasound (MSKUS) improvements	+			+

FACE
Reference	Blinding	HILT Specific Outcomes	<Pain	>ROM	>QoL	>Function
Abdullatif³⁶ Bell’s Palsy (Egypt) 2022	1	Increased eyebrow raising Increased smiling ability		+		+
Ekici³⁷ Myogenic temporomandibular joint disorder (Turkey) 34174507; 2021	2	Pain reduced ROM increased in jaw Functional disability reduced Improved QoL	+	+		+
Elkallah³⁸ Chronic sinusitis (Egypt) 32904078; 2020	1	Symptomatic improvements (SNOT-22)
Nadershah³⁹ Temporomandibular joint disorder (Saudi Arabia) 31988570; 2020	2	Pain reduced	+
Wu⁴⁰ Bell’s Palsy (China) 37738368; 2023	0	Improved facial grades Improved electrophysiology		+	+	+
HAND/WRIST
Abdel-aal⁴¹ Hand OA in SLE (Egypt) 32638614; 2020	2	Pain reduced Swelling reduced Tenderness reduced Grip strength increased	+			+
Cantero-Tellez⁴² Thumb OA (Spain & USA) 31807782; 2020	3	Pain reduced	+
Ahi⁴³ De Quervain’s Tenosynovitis, thumb (Turkey) 36974441; 2023	2	Pain reduced Hand grip strength increased QoL (SF-36) increased Function (QDASH) increased	+			+
Ezzati⁴⁴ Carpal tunnel syndrome (Iran) 31742366; 2020	2	HILT was superior to LLLT: Pain reduced Electrophysiological measures (CMAP & sensory nerve conduction)	+			+
Chongkriengkrai⁴⁵ de Quervain’s tenosynovitis (Thailand) 37783935; 2023	2	Pain unchanged Hand grip strength unchanged Disability Several AEs	-

FOOT
Reference	Blinding	HILT Specific Outcomes	<Pain	>ROM	>QoL	>Function
Bidoki⁴⁶ Plantar fasciitis (Iran) 38584653; 2024	2	30W 980nm 8J/cm²	+		+	+
Elnagger⁴⁷ Hemophilic A ankle arthropathy (Egypt) 31628558 2020	1	Pain reduced Gait improved	+			+
Naruseviciute⁴⁸ Plantar fasciitis (Lithuania) 32513018; 2020	1	No statistical difference in pain Laser more effective than LLLT in the opinion of participants	+
Ordahan⁴⁹ Plantar fasciitis (Turkey) 29627888; 2018	2	Pain reduced (VAS) Function improved QoL improved (Laser all more than LLLT)	+		+	+
Yesil⁵⁰ Calcaneal spur (Turkey) 31478095; 2019	2	Pain unchanged QoL unchanged Function (FAOS) unchanged Improved pedographic measures	-		-	+
WOUNDS
Lu⁵¹ Chronic Refractory Wounds (China) 34253665; 2021	1	Improvement in Bates-Jensen Wound Assessment Tool (BWAT) Improvement in Pressure Ulcer Scale for Healing
Thabet⁵² Caesarian Healing in diabetic women (Egypt) 29706708; 2018	1	Wound appearance improved	+
GYNECOLOGICAL
Thabet⁵³ Endometriosis (Egypt) 29668354 2018	1	Pain and adhesions reduced Improved QoL	+		+
BONE
Alayat⁵⁴ Osteoporosis (Saudi Arabia) 29068756; 2018	1	Lumbar bone mineral density improved and sustained for 1y
Blinding − 0, unblinded: 1, single-blinded; 2, double-blinded; 3, triple blinded; U - unknown. (+) significantly positive outcome, (-) no apparent benefit, NA - not applicable/not measured. Pain measures are all VAS-based unless noted. ROM - range of motion. QoL - quality of life.

Table 2

**Laser parameters, treatment plan, and study design with follow-up sorted from highest to lowest positive effect size outcomes.** Panels are categorized by knee, spine/back, shoulder/arm, face, hand/wrist, foot, wounds, gynecologic, or bone. Table only includes studies for which effect sizes could be calculated from the available data as statistically presented.
COVID-19
Reference	Blinding	HILT Specific Outcomes	<Lung indices	<ICU admission	>Mortality	>Taste restoration
Shabaan⁵⁵ COVID-19 Loss of taste (ageusia) 37149582; 2023	2	Complete taste restoration after laser 94% vs 61%				+
Vetrici⁵⁶ COVID-19 pneumoniae (Canada)33776469 33776469; 2021	1	Improved lung function Reduced ICU admissions Rapid recovery Reduced mortality N = 10	+	+	+

KNEE

Author

Diagnosis

Reference

Laser

Settings

Treatment

Study Design

Cohen’s d

Effect Size

El-Shamy¹

Juvenile Rheumatoid Arthritis (Egypt)

30016193; 2018

10.5W 52.5W/cm²

120–150µs 10-30Hz

750J/knee/session

HIRO 3.0

3x/wk

4wk

ET ± HILT

EOT

4.6

Nazari²

Knee Osteoarthritis

(Iran) 30178432; 2019

4W spot size? 30Hz

2100J/session

E20780 - laser YAG HT

3x/wk

4wk

ET ± HILT

EOT

4.0

El-Shamy³

Hemophilic Arthropathy

(Egypt) 27976591; 2018

10.5W (52.5W/cm²) 120–150µs 10-30Hz

750J/knee/session

HIRO 3.0

3x/wk

12wk

ET ± HILT

EOT

2.9

Samaan⁴

Knee Osteoarthritis

(Egypt) 35678062; 2022

12W (12W/cm²) 25Hz

300J/analgesic or 3000J/biostimulation BTL6000

2x/wk

2wk

ET ± HILT

EOT

2.4

Bettancourt⁵

Knee osteoarthritis

(Portugal)

J.Arthritis; 2020

30W (30W/cm²)

Pulsed & Continuous

6J and 80J

(BTL industries?)

Every other day

14x total

2wks

HILT v sham

4wk

1.9

Siriratna⁶

Knee Osteoarthritis

(Thailand)

36313402; 2022

1W (0.5W/cm²)

2000Hz

560J/session

Mphi laser device

2-3x/wk

10x total

HILT v sham

EOT

1.8

Ahmad⁷

Knee Osteoarthritis

(Malaysia)

37511894; 2023

5W/cm²

190J pulsed & 3000J CW

BTL-6000

1x/wk

12wks

HILTvLLLT

EOT

1.3

Akaltun⁸

Knee Osteoarthritis

(Turkey) 33074393 2020

12W (12W/cm²2) 25Hz

300J/analgesic session & 3000J/biostimulation session

BTL6000

5X/wk

2wk

±HILT

6wks

1.1

Taheri⁹

Knee osteoarthritis

(Iran) MEJRH-134330; 2024

500J

Lumix CPS

3x/wk

2wk

ET ± HILT

EOT

1.1

Mostafa¹⁰

Knee Osteoarthritis

(Egypt)

34986012; 2022

10.5W

52.5W/cm²

1500mJ/cm²/session

HIRO 3.0

3x/wk

4wk

HILT v Shock Wave Therapy

EOT

1.0

Ekici¹¹

Knee OA

(Turkey)

37743421; 2023

10W & 5W

10W/cm²/Analgesic & 5W/cm²/Biostimulatory

BTL6000

3x/wk

3wk

ET ± HILT

EOT

0.4

Wibisono¹²

Knee OA (Indonesia)

Medico Hospitalia; 2024

10W 2m – analgesic phase

10W 4m – biostimulatory phase

2x/wk

4wk

HILT v LLLT

0.3

Spine/Back

Reference

Laser

Settings

Treatment

Study Design

Cohen’s d

Effect Size

Venosa¹³

Cervical Spondylosis (Italy)

30443883; 2019

10.5W

52.5W/cm²

120–150µs, 10-30Hz

2050J/session

HIRO 3.0

2x/wk

6wks

HILT + ET v US + TENS + ET

4wks

3.3

Sherif¹⁴

Cervical Radiculopathy (Egypt)

Medical Journal of Cairo University; 2023

2W & 4W

980nm 4Hz

840J/session

LevelLaser EZ1

2x/wk

4wks

ET ± HILT

EOT

2.3

Ince¹⁵

Neck pain (Turkey)

37204965 ; 2024

10.5W

52.5W/cm²

120–150µs 10-30Hz

2632J/session

HIRO 3.0

5x/wk

4wks

ET ± HILT

12wks

1.8

Abdelbassett¹⁶

Chronic lower back pain (Saudi Arabia & Egypt)

33178306; 2020

12W

12W/cm²

1200J/session

BTL000

2/wk

12wks

HILT v sham

EOT

1.5

Gawaan¹⁷

Myofascial pain syndrome post-neck discectomy (Egypt)

The Egyptian Journal of Hospital Medicine

(2023)

14W

pulsed

2803J/session

Device Omega

3x/wk

4wk

ET ± HILT

EOT

1.4

Abdelmageed¹⁸

Chronic Discogenic Sciatica (Egypt)

link; 2022

1W/cm2

810nm + 980nm

400J/session

3x/wk

4wks

PT ± HILT

EOT

1.4

Kenareh¹⁹

Chronic neck pain (Iran)

34733743; 2021

10W 3m

Then 7W 7m

1/d 2wks

10x total

HILT v US

1.4

Chen²⁰

Lumbar disc protrusion(China)

28854500; 2018

12W

12W/cm²

7500J/session

BTL600

5x/wk

2wk

±HILT + Spinal decompression

4wks

1.0

Chatterjee²¹

Peripheral neuropathy, lumbar (India)

31405365; 2019

8W 5.3W/cm²

980nm:810nm at 80%:20%

1920J

3x/wk 4wks

1x/wk 8wks

HILT v Sham

+standard of care

0.9

Ahi²²

Myofascial pain syndrome (Turkey)

36538189 2022

8W/cm²

BT6000

2x/wk

4wk

ET + PT ± HILT

EOT

Don’t have raw data, but (+)

Yilmaz²³

Cervical disc herniation (Turkey)

32147037; 2020

8W/cm²

1850J/session

BTL6000

5x/wk

4wk

ET ± HILT

EOT

0.3

SHOULDER/ARM

Reference

Laser

Settings

Treatment

Study Design

Cohen’s d

Effect Size

Karaca²⁴

Lateral epicondylitis

(arthropathy) (Turkey)36117204; 2022

4W and 6W

13-20W/cm2

6J/cm² analgesic & 12J/cm² biostimulation

BTL6000

2x/wk

2wks

PT + ESWT ± HILT

4wks

5.0

Elsodany²⁵

Rotator Cuff Tendinopathy (Egypt & Saudi Arabia) 30188253; 2018

Power? 10.5W?

2050J per session

HIRO 3.0

3x/wk

4wks

ET ± HILT

EOT

4.7

Abdelhakiem²⁶

Hemiplegic shoulder pain after stroke

38538637; 2024

3x 8W 75s 100J

6x 12W 30s

ITO (LAZR-207)

3x/wk

3wks

ET ± HILT

1wk

4.5

Atan²⁷

Adhesive capsulitis (frozen shoulder; (arthropathy) (Turkey)

32808147; 2021

8, 12, 8W

100J/cm²

iLux

5x/wk

3wk

ET ± HILT

3mos

Zaki²⁸

Subacromial impingement syndrome

34184965; 2022

5W/cm²

2050J/session

Zimmer Opton

3x/wk

7 sessions total

LLL-KT, HPL-KT, & sham-KT

Do not have raw data

Ordahan²⁹

Adhesive capsulitis

(Turkey)

37533657; 2023

12W

12W/cm²

10J/cm²/analgesic & 100J/cm²/biostimulatory

BTL6000

5x/wk

3wk

HILT ± stretchin + ET

v LLLT ± stretchin + ET

3wks

1.6

Korkmaz³⁰

Hemiplegic Shoulder Pain

(arthropathy) (Turkey)

33829317; 2021

8W/cm²

300J/analgesic session & 2500J/biostimulatory session

BTL600

3x/wk

3wk

PT ± HILT

EOT

1.3

Yilmaz²³

Subacromial Impingement Syndrome

(arthropathy) (Turkey)

334000012; 2021

10.5W

52.5W/cm²

40Hz

2781J/session

HIRO 3.0

5x/wk

3wks

ET ± HILT

EOT

0.4

Aceituno-Gómez³¹

Subacromial impingement (Spain)

30672303; 2019

12W

pulsed

250J/cm²

iLux Laser device

(Mectronic)

5x/wk

3wk

ET ± HILT

3mos

0.3

Kaydock³²

Lateral epicondylitis

(arthropathy), (Turkey)

32637921; 2020

6W/cm²

6J/cm²/analgesic & 120-150J/cm²/biostimulatory

BTL6000

3x/wk

3wk

HILT v LLLT

EOT

0.4

FACE

Reference

Laser

Settings

Treatment

Study Design

Cohen’s d

Effect Size

Ekici³³

Myogenic temporomandibular joint disorder

(Turkey)

34174507; 2021

10.5W

52.5W/cm²

120–150µs 10-30Hz

1029J/session

HIRO 3.0

1x/wk

15d

HILT v sham

4wk

1.5

Wu³⁴

Bell’s Palsy (China)

37738368; 2023

1W of 808nm + 0.2W of 905nm

3x/wk

72x total

±HILT

1.2

Abdullatif³⁵

Bell’s Palsy

(Egypt) 2022

1,808J/session

HIRO 3.0

1x/wk

4wk

2 sides of face

EOT

Elkallah³⁶

Chronic sinusitis

(Egypt)

32904078; 2020

1W/cm²

810nm & 980nm

150J/sinus

Zimmer Opton Pro

3x/wk

4wk

SMT ± HILT

EOT

Nadershah³⁷

Temporomandibular joint disorder

(Saudi Arabia)

31988570; 2020

2.5W/cm²

300J/treatment

Ezlase 940 device

(Biolase Technology, Inc. California, USA)

Every other day

10d

HILT v sham

EOT

HAND/WRIST

Abdel-aal³⁸

Hand OA in SLE

(Egypt)

32638614; 2020

Power?

2100J/session

HIRO 3.0

3x/wk

8wks

HILT v sham

EOT

1.9

Cantero-Tellez³⁹

Thumb OA

(Spain & USA)

31807782; 2020

1.5W

0.3W/cm²

800 + 970nm

2Hz 50% duty cycle

75J/session

K- Laser, Mod. K1200

3x/wk

4wks

HILT v sham

EOT

1.2

Ahi⁴⁰

De Quervain’s Tenosynovitis, thumb

(Turkey)

36974441; 2023

12W

52.5W/cm²

10J/cm²/analgesic & 120-150J/cm²/biostimulatory

BTL6000

3x/wk

5wk

HILT v sham

EOT

1.0

Ezzati⁴¹

Carpal tunnel syndrome

(Iran)

31742366; 2020

1.6W

808nm

8J or 20J/cm²

5x/2wks

HILT v LLLT

EOT

0.4

Chongkriengkrai⁴²

de Quervain’s tenosynovitis

(Thailand)

37783935; 2023

8W/cm²

80J/analgesic & 800J/biostimulatory

BTL600

3x/wk

3wk

Split + ET + HILT/sham

3wk

-0.9

FOOT

Reference

Laser

Settings

Treatment

Study Design

Cohen’s d

Effect Size

Ordahan⁴³

Plantar fasciitis (Turkey)

29627888; 2018

8W and 6W

First week: 8W 6J/cm2

Next 2 weeks: 6W 120J/cm2

BTL6000

3x/wk

3wks

HILT v LLLT

EOT

2.2

Elnagger⁴⁴

Hemophilic A ankle arthropathy

(Egypt)

31628558

2020

7W/cm²

3000J

BTL600

3x/wk

8x total

PT ± HILT

EOT

0.7

Naruseviciute⁴⁵

Plantar fasciitis (Lithuania)

32513018; 2020

10.5W

52.5W/cm²

120–150µs 10-30Hz

3000J

HIRO 3.0

8x/3wk

PT ± HILT

EOT

0.5

Yesil⁴⁶

Calcaneal spur

(Turkey) 31478095; 2019

10.5W

52.5W/cm²

120–150µs 10-30Hz

1281J/session

HIRO 3.0

5x/wk

3wks

ET + HILT/sham

4wks

0.1

WOUNDS

Lu⁴⁷

Chronic Refractory Wounds; (China)

34253665; 2021

8W/cm²

80J/cm²

BTL6000

3x/wk

3wk

SMT + HILT/sham

EOT

4.2

Thabet⁴⁸

Caesarian Healing in diabetic women; (Egypt)

29706708; 2018

10.5W

52.5W/cm²

120–150µs 10-40Hz

360-540J

HIRO 3.0

SMT + HILT/sham

EOT

0.9

GYNECOLOGICAL

Thabet⁴⁹

Endometriosis (Egypt)

29668354

2018

10.5W

52.5W/cm²

120–150µs 10-40Hz 0.1% duty cycle

1300J

BTL600

3x/wk

8wk

HT ± HILT

EOT

2.2

BONE

Alayat⁵⁰

Osteoporosis (Saudi Arabia)

29068756; 2018

10.5W

52.5W/cm²

120–150µs 10-30Hz

3000J total per session

HIRO 3.0

3x/wk

24 wks

ET ± HILT

EOT

0.5

1064nm wavelengths were used throughout unless noted otherwise under treatment settings. FU-follow-up; ET-exercise therapy; PT-physical therapy; ESWT-extracorporeal shock wave therapy; KT-kinesiology taping; LLL-low level light; HT-hormone therapy; EOT-end of treatment follow-up. SMT-standard medical treatment. Kaydock study was a measure of hand grip strength and Abdel-all was a measure of joint swelling. All other measures were VAS.

Most significantly, no serious adverse events (AEs) were observed in 56 controlled trials. Eight non-serious AEs were reported among a total of 1,486 HILT-treated patients. One patient, a light-skinned female with adhesive capsulitis, experienced a photoallergy.⁴¹ Three non-serious AEs were reported in children with hemophilic arthropathies, but no further details were provided.⁴² Two other patients reported post-HILT pain, and one experienced post-swelling pain in a study treating patients with de Quervain's tenosynovitis (wrist tendon pain).⁴³

The greatest cumulative categorically favorable pain reduction response data was observed with treatment of knee pathologies. Pain was reduced in all 12 out of 12 studies that measured pain (Table 2 and Supplementary Table S1). Eleven out of 12 studies exhibited a large effect size in pain reductions. A thirteenth study demonstrated improvements in balance in patients with osteoarthritis only after treatment with HILT, but not when treated with LLLT.⁴⁴

In a 2020 knees osteoarthritis study, changes in knee cartilage thickness were measured from three different ultrasound aspects at 6 weeks after treatment.⁴⁵ High-powered PBMT resulted in a medium to large effect size in changes in cartilage thickness from all three aspects, according to Cohen's criteria for effect size (|d| < 0.2 = small effect; 0.2 < |d| < 0.8 = medium effect; |d| > 0.8 = large effect.³⁸ Only one study measured changes in tendon (supraspinatus) size before and after treatments.⁴⁶ In this study, treatment of patients with subacromial impingement syndrome with HILT demonstrated an improvement in supraspinatus tendon thickness compared to LLLT or sham laser treatment.

HILT treatment showed significant pain reduction in all 11 spine studies, including non-specific lower back pain, cervical disc herniation, discogenic sciatica, myofascial pain syndrome, cervical radiculopathy, cervical spondylosis, peripheral neuropathy, diabetic neuropathy, and lumbar disc protrusion. In foot indications, 5 out of 6 HILT treatments resulted in statistically significant pain reduction, specifically for plantar fasciitis and ankle arthropathy (Table 1). However, no significant pain reduction was observed for calcaneal spur.

For shoulder or arm-related conditions, HILT treatment led to significant pain reduction in 11 out of 12 studies measuring pain, including rotator cuff injury, tendinopathy, adhesive capsulitis, subacromial impingement, lateral epicondylitis, and hemiplegic shoulder pain. Negative data was obtained in one study focusing on subacromial impingement and one study focusing on lateral epicondylitis. However, the latter lateral epicondylitis study did show positive outcomes in terms of increased hand grip strength and upper limb function (QDASH).

Two studies focused on post-stroke patients with hemiplegic shoulder pain evaluating exercise therapy ± HILT yielded exceptionally large effect size positive outcomes after HILT (ES = 4.5 and 1.3).^47,48 Additionally, HILT not only resulted in significant reduction in shoulder pain but it also decreased rotator cuff tear size. The control group, which did not receive HILT treatment, showed no change in tear size.⁴⁸ Healing was confirmed through ultrasound measurements. Cohen effect sizes for both reduction in tear size and pain measures in the HILT group were large, suggesting that proper healing of the tissue contributed to the significantly greater pain reduction

Non-musculoskeletal studies with large effect sizes (Cohen's > 0.8), included wound healing (chronic refractory and caesarian section), chronic discogenic sciatica (increased nerve activity and pain reduction), endometriosis (pain reduction), and TMJ (mouth opening size also increased; Tables 1 and 2). A positive outcome of lesser effect size was also achieved for osteoporosis with osteopenia.⁴⁹ Bone density measures were made 6 months and 1 year after cessation of treatment. In both cases, there was an increase in bone mineral density in the HILT plus exercise group, but no significant change was observed in the exercise therapy only group.

In musculoskeletal disorders, restricted range of motion (ROM) and loss of cartilage are common. In 15 out of 16 studies assessing ROM, HILT treatment resulted in statistically significant increases in ROM compared to control groups without HILT (Table 1). These studies involved patients with knee osteoarthritis (n = 7), subacromial impingement (n = 2), cervical spondylosis, hemiplegic shoulder pain, neck pain, myofascial pain syndrome post-neck discectomy, rotator cuff tendinopathy, hemophilic arthropathy, and myogenic temporomandibular joint disorder.

Quality of life measures attempt to quantify how debilitating various conditions are to patients’ overall well-being and their basic functional life-skills. HILT treatment demonstrably improved the quality of life (QoL) in 16 out of the 20 studies assessing QoL. Positive QoL outcomes were observed after treatment of patients diagnosed with knee osteoarthritis, subacromial impingement syndrome, endometriosis, plantar fasciitis, hemiplegic shoulder pain, neck pain, adhesive capsulitis (frozen shoulder), chronic lower back pain, cervical disc herniation, cervical spondylosis, lateral epicondylitis, and myogenic temporomandibular joint disorder (Table 1). Functional outcomes or abilities include measurements of physical functions using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scale or the measures of the ability to walk further over 6 minutes as with patients with hemophilic arthropathy.^45,50 HILT increased patient functional abilities in 31 out of 37 studies making functional assessments.

Technical Procedural Aspects

The most used lasers were the BTL-6000 (n = 20 studies) and the HIRO 3.0 (n = 15). The most commonly used wavelength was 1064nm (n = 42), while 4 studies used 810 + 980nm (Zimmer Opton Pro), 2 used 808 + 905nm, 2 used 980nm, 2x 940nm, and three studies used 808nm + 905nm, 800nm + 970nm, or 940nm (Table 2). In 27 out of 29 studies, a biphasic administration method was used to generate positive outcomes. This method involved an initial analgesic mode (lower power) followed by a biostimulatory mode (higher power) in subsequent treatment sessions. The Hilterapia HIRO 3 laser (ASA laser, Arcugnano, Vicenza, Italy) used distinctly different and unique laser settings with both an exceptionally high peak power (3kW) and an exceptionally short pulse (100µs). Studies were primarily conducted in Turkey (n = 16) and Egypt (n = 15), with smaller numbers in Iran (n = 6), Saudi Arabia (n = 4), China (n = 3), and other countries with 2 studies (Thailand, Italy, Spain), or a single study (United States, Lithuania, Thailand, Malaysia, Portugal; Table 2).

QUANTITATIVE SUMMARY OF HILT EFFECT SIZES

Forest plot analysis was used to visually present the comparisons of quantitative effect size outcomes. Figure 2 illustrates the pain (VAS) outcomes of evaluations of HILT, categorized by anatomies that have similar depths of pathology: knees, shoulder/arm, and spine related. Among a total of 9 studies, knee-related pathologies displayed the highest average effect size compared to shoulder/arm (n = 11) and spine-related pathologies (n = 13), with effect sizes of -2.3, -1.85, and − 1.15 respectively. Figure 2 presents both end-of-treatment (EOT) and extended post-cessation of HILT follow-ups for knee-related pathologies.

Most importantly, 17 out of 18 studies, which measured outcomes at extended follow-up times (Supplementary Table S2), revealed that the benefits of pain reduction after the cessation of HILT treatment plans were sustained and not temporary. The average large effect size for pain reduction between groups after treatment cessation was 2.2 ± 1.5 for extended follow-up measures, compared to 2.0 ± 1.7 for end of treatment measures. This summary data demonstrates that HILT does not only provide temporary pain relief. Instead, it has biostimulatory properties and can promote tissue regeneration, leading to sustained positive outcomes in the clinic. It addresses the pathology itself and not merely the symptomatic presentation in the repetitive unlimited fashion characteristic of many pain medications.

HILT is superior to LLLT in Controlled Trials

HILT was found to be superior to LLLT in 7 out of 8 studies, with a statistically significant large effect size (ES) difference compared to LLLT (Table 4; average ES = 1.21 ± 0.76). HILT demonstrated superiority over LLLT in the treatment of knee osteoarthritis (5W/cm² vs 0.4W and 5W vs 78mW), lateral epicondylitis (8W/cm² vs 240mW), adhesive capsulitis (frozen shoulder; 12W/cm² vs 240mW), subacromial impingement (5W/cm² vs 250W/cm²), plantar fasciitis (7W/cm² vs 50mW), and carpal tunnel syndrome (1.6W vs 50mW; power densities are provided as they are more meaningful, when details were provided within studies). One study compared two different HILT parameters (12W/cm² vs 0.8W), but did not use LLLT (< 500mW).⁵¹ Both treatments were equally effective in reducing chronic nonspecific lower back pain in this study.

Optimal Laser Powers Needed Per Categorical Anatomies to the Best We can Determine Based on Limited Available RCT Evidence

To determine optimal power settings to use per respective indications that can be based on the highly limited currently available trial data we used effect size (ES) quantitations to perform the following analysis (Table 2 and summary Table 3). We report the power densities used to achieve the best outcomes per categorical diagnosis when the spot size is described in the study reports.

Table 3

Optimal laser parameters and treatment plans based on summary analysis of the most positive outcomes from RCTs fulfilling criteria for inclusion in our meta-analysis.
Anatomy	Power density	“Dose” (as Joules or Fluence, J/cm²)	Treatment Plan
Knee (arthropathies, injuries)	5-30W/cm2	750-3000J	Daily treatment regimens for at least 2 weeks
Spine/Back (radiculopathies, spondylosis, neck pain, chronic pain, myofascial pain syndrome post-neck discectomy, discogenic sciatica, lumbar disc protrusion)	10-12W/cm2	850-7500J	5x/wk for 2wks or 2x/wk for 4-6wks
Shoulder/arm (lateral epicondylitis, rotator cuff tendinopathy, adhesive capsulitis, frozen shoulder, subacromial impingement syndrome)	5-20W/cm2	2000-2500J	2-3x/wk for ≥2wks
Wound (Chronic Refractory Wounds)	8-10W/cm2	80J+150J/cm2 or 540J	3x/wk for ≥3wks
Hand/wrist (arthropathies, carpal tunnel syndrome, De Quervain’s tenosynovitis)	0.3-12W/cm2	2100J or 150J/cm2	3x/wk for ≥4wks
Foot (plantar fasciitis, ankle arthropathy)	8W/cm2	120J/cm2	3x/wk for 3wks

Table 4

**Summary of HILT vs LLLT studies in this meta-analysis.** Laser parameters and outcomes are shown. All studies used the same treatment plans between groups. Pain reduction, functional (including disability indices), and quality of life (QoL) measures are noted. The superior outcome is labelled for each metric. A blank cell denotes that no measurement was made.
	HILT			LLLT			Superiority
Reference	Power or Power Density	λ (nm)	Dosage	Power or Power Density	λ (nm)	Dosage	Pain reduction	Function	QoL
Abdelbassett⁵¹ Chronic lower back pain (Saudi Arabia & Egypt) 33178306; 2020	12W	1064	1200J	0.8W	850	1200J	Both class IV HILT lasers. Both powers were effective.
Ahmad⁷ Knee Osteoarthritis (Malaysia) 37511894; 2023	5W	1064	400J	0.4W	830	3190J	HILT	HILT	HILT
Ezzati²³ Carpal tunnel syndrome (Iran) 31742366; 2020	1.6W	808	20J/cm²	50mW	860	20J/cm2	HILT	HILT Nerve conduction & Compound muscle action potential
Kaydock²⁰ Lateral epicondylitis (Turkey) 32637921; 2020	8W/cm²	1064	150J/cm²	240mW	904	2.4J/cm2	HILT	HILT SF-36 & QDASH	HILT
Naruseviciute²² Plantar fasciiitis (Lithuania) 32513018; 2020	7W 7W/cm²	1064	3000J	50mW	785	140J	Both groups exhibited reduced pain. There was no untreated control.
Ordahan¹⁰⁶ Adhesive capsulitis (Turkey) 37533657; 2023	12W/cm²	1064	120J/cm²	240mW	904	3J/cm²	HILT
Ordahan²¹ Plantar fasciiitis (Turkey) 29627888; 2018	6W/cm²	1064	150J/cm²	240mW	904	0.16W/cm² 640J/session	HILT	HILT Heel tenderness	HILT Foot and Ankle Outcome Scores
Zaki⁴⁶ Subacromial impingement syndrome 34184965; 2022	4W 5W/cm²	810 + 980	2050J	200mW 250W/cm²	810 + 980	2000J	HILT	HILT

It is important to note that the HIRO 3.0 device utilizes extremely short pulses (120–150µs pulses at frequencies of 10-40Hz), with the light being off for most of the time of each second. Additionally, it operates at exceptionally high peak powers (12kW) with a spot size of 0.2cm². Due to these unique characteristics, the HIRO 3.0 treatment method is fundamentally different from other devices that use continuous or 50% off pulsed settings. Therefore, our focus in this discussion is limited to the studies that utilized continuous or pulsed (50% on/off) settings, rather than HIRO 3.0 micro-pulsing (120–150µs, 10-40Hz).

Knee – 12W at 12W/cm² (52.5W/cm² micro-pulsed)

Twelve studies all yielded positive calculated effect sizes ranging from 4.6 to 0.4, using power settings ranging from 1W to 14W. The study with the greatest measurably positive effect size involved the treatment of children with juvenile rheumatoid arthritis.⁵⁰ However, this study needs to be qualified since it is the only study involving children, and children naturally recover at a greater rate than adults. Additionally, this is a unique and distinct rare form of arthropathy that occurs due to recurrent bleeds inherent in hemophilic arthropathy. As a result, the benefits were reduced in follow-up measures. The laser treatment settings were 10.5 W (50W/cm², 120–150µs, 10-30Hz, 750J per knee per session, HIRO 3.0) three times per week for 4 weeks. In contrast, other studies using non-micro-pulsed settings achieved large effect sizes that improved over time, as measured in extended follow-up measures conducted after the cessation of treatment. These studies used 12W or 30W settings at power densities of 12 W/cm² or 30W/cm².

Spine/Back – 12W at 12W/cm² (10.5W at 52.5W/cm² micro-pulsed)

Eleven studies focused on pathologies of the spine achieved measurably positive outcomes by using power settings ranging from 1W to 14W. The study with the highest effect size (3.3 ES) involved treatments using 10.5W (50W/cm², 1064nm, 120–150µs,10-40Hz, 2050J total, over 30m, HIRO 3.0) for patients with cervical spondylosis.⁵² These treatments were administered twice a week for a duration of 6 weeks.

Shoulder and arm – 6W at 6W/cm²

Thirteen studies focused on the shoulder or arm using powers ranging from 4W to 12W. Effect sizes could be calculated for 8 studies. The most impressive quantitative positive outcome (5.0 ES) was achieved when using 6W (1064nm, BTL6000) to treat patients with lateral epicondylitis.⁵³ Treatment involved an initial 45 seconds of 4W (12W/cm²) to provide analgesia followed by 12 minutes of 6W administration. Only four sessions were conducted over two weeks. The authors did not mention whether the administration was continuous or pulsed. The results of two studies evaluating HILT treatment for de Quervain's tenosynovitis were contrasting and interesting.^43,54 A positive outcome (ES = 1.0) with no adverse events was achieved with a higher power and shorter treatment duration, while a negative outcome occurred with 3 out of 10 subjects experiencing adverse events when using a lower power but for a longer time (10W 100s 250J vs 8W 5min 800J respectively; BTL600 1064nm for both).

Face – 10.5W

Five studies focused on the face, which included two Bell's Palsy studies, two temporomandibular joint disorder studies, and one study on chronic sinusitis. However, only one of these studies provided enough data to calculate the effect size for pain.⁵⁵ The study showed an impressively large effect size (1.5 ES) when the myogenic temporomandibular joint disorder was effectively treated using micropulsed therapy with a power output of 10.5 watts (50W/cm², 120–150µs, 10-30Hz, 1092J/session, HIRO 3.0), administered five times per week for three weeks.

Foot − 8W (24W/cm²)

Six studies focused on the foot – three on plantar fasciitis, one on ankle arthropathy, one on calcaneal spur, and one on diabetic peripheral neuropathy.^{21,22,56–58} These used 7W to 10.5W. These used power settings ranging from 7W to 10.5W. The most positive outcome (2.2 ES) was achieved when using 8W superpulsed (24W/cm²; 1064nm; BTL6000) for just 75 seconds to deliver 150J three times in the first week followed by just 30 second treatments at 6W power to deliver 120 J three time per week for a subsequent 2 weeks.²¹ These were exceptionally short treatment sessions.

Hand – 1.5W (0.3W/cm²; 800 + 970nm)

Five studies focused on the hand and all exhibited measurably positive effect size outcomes, but the power setting was not described for the most impressively positive outcome (1.9 ES) involving treatment of hand osteoarthritis.⁵⁹ Thus, we must defer to the second most impressively positive outcome, which was achieved by treating thumb osteoarthritis with 800nm with 970nm at a power of just 1.5W (2Hz, 50% duty cycle). This treatment was applied over an area of 5cm² for only 45 seconds per session.⁶⁰ The treatment was done three times per week for a period of four weeks.

Wound – 10.5W (50W/cm²)

Just two controlled studies were conducted on wounds, and both yielded positive outcomes. The effect sizes were 4.2 for cesarian healing and 0.9 for chronic refractory wounds.^61,62 The most impressive treatment regimen (10.5W, 25Hz, 1064nm, HIRO 3.0) consisted of three phases: (1) fast scanning across the entire wound for 100-150J, (2) 14 seconds of irradiation focused on 12–14 spots for a total of 160-240J, and (3) the same as the first phase but at a slower scanning pace. Treatments took 8 minutes and were administered three times per week for 8 weeks.

Bone – 10.5W micropulsed (50W/cm²)

There was only one study that examined the effects of HILT on bone mineral density in men with osteopenia or osteoporosis. The study demonstrated a medium effect size (0.5 ES), and most importantly, this effect size was maintained even 1 year after the treatment was stopped (0.4 ES).⁴⁹ The treatment used in this study involved the administration of micropulsed light with an average power of 10.5W (at 50W/cm², 1064nm, 120–150µs, 10-30Hz, 3000J per session using HIRO 3.0) three times per week for a total of 24 weeks.

The objective of this meta-analysis was to evaluate the full range of indications that can benefit from high-powered laser photobiomodulation therapy. The secondary objective was to determine the optimal laser settings and treatment regimens based on the currently available data from randomized controlled trials (RCTs). Pain levels after high-powered laser therapy (HILT) were the most commonly measured outcome, and all studies focused on the knee, spine, shoulder/arm, and wound showed reductions in pain. Most of these reductions were significant, as indicated by the large effect sizes (Tables 1 and 2). Additionally, improvements in range of motion, mobility, quality of life, cartilage growth, rotator cuff tear recovery, and nerve conduction were also demonstrated.

Consistent with our project's hypothesis, all 7 out of 8 studies that directly compared HILT to LLLT showed that higher powered lasers had better outcomes. The only exception was one study where both high and low energy PBMT effectively reduced pain in patients with plantar fasciitis and it is possible this was due to referred pain for which the laser was not focused on the appropriate pathogenic anatomy (discussed below in limitations section; Table 3). Three of these HILT superior studies focused on the shoulder and arm, while the other individual studies focused on the knee, foot, and hand. In a previous double-blind RCT for patients with myofascial pain, LLLT treatment did not reduce pain, whereas a similar study using HILT showed a significant reduction in pain.^63,64 Furthermore, LLLT treatment did not provide any benefits for temporomandibular joint dysfunction (TMJD), while a controlled study using HILT showed that the higher powered approach was especially effective in reducing pain. In summary, based on our meta-analysis spanning the past six years, high-powered laser PBMT consistently produces superior outcomes.

Our findings are in agreement with all prior meta-analyses.^65–69 Overwhelmingly positive outcomes (96%) were observed after comprehensive evaluation of HILT treatment specifically targeting pain (July 2020 to August 2022; n = 31 RCTs).⁶⁹ When treating knee osteoarthritis, HILT + ET outperformed LLLT + ET (≤ December 2019; n = 10 RCTs).⁷ An analysis focused on knee osteoarthritis concluded that HILT effectively alleviates pain (≤ September 2022; n = 9 CTs).⁷⁰ Likewise, an analysis of HILT treatment for neck pain concluded that it effectively reduces pain and improves cervical ROM (≤ March 2022; n = 9 RCTs).⁶⁸ Another analysis comparing HILT to other physical therapy modalities for knee osteoarthritis found that HILT is superior in terms of pain reduction and functional improvement (≤ March 2022; n = 10 RCTs). In line with our observations, an extensive meta-analysis of musculoskeletal outcomes (≤ September 2022; n = 42 RCTs) found large (> 0.8) effect sizes in pain reduction and improved function after HILT treatment.⁶⁵ Overall, it is evident that HILT holds significant potential for transforming the treatment of various musculoskeletal pains, stiffness, and loss of function. However, there are current limitations to implementation including a general lack of physician awareness of the wide-ranging therapeutic utility of HILT and restricted patient access.

Study Limitations

Our study had several limitations. Firstly, other than one study focused on knee arthropathy that used 30 watts⁷¹, the highest-powered laser was only 15 watts for subacromial impingement.⁷² However, there are photobiomodulation therapy lasers in regular clinical practice that use powers as high as 80 watts that have yet to be evaluated in a controlled setting. We could not find any RCTs describing the evaluation of average powers above 30W. Secondly, most of our studies were limited to the 1064nm wavelength without consideration of higher powers using other wavelengths. Most basic PBMT biomedical research has in fact used wavelengths between 650 (red) to 830nm range. This is significant because 810-830nm light is not absorbed by water, thus making this the lowest heat-generating wavelength,⁷³ which enables more tolerable deeper penetrating PBMT at the highest power density settings. Additional limitations include variable study designs, variable follow-up times, failure to report spot size, and small sample sizes.

Another limitation potentially affecting outcomes is the possibility that the laser was not directed towards the source of pathogenesis. For instance, foot pain associated with plantar fasciitis may initially manifest as referred pain originating from tightness in the hips. It is well-known that stretching and strengthening the hips can be beneficial in reducing foot pain.^74,75 Therefore, it is possible that more positive outcomes for plantar fasciitis could be achieved if the laser was directed at the hip. This may increase range of motion and influence the nerves responsible for sending pain signals through the sacrum. Similarly, for other conditions involving referred pain in the extremities, focusing the laser on the spinal cord or central nervous system (CNS) may lead to more positive benefits. This is because all pain signals ultimately pass through these anatomical routes since all pain signals ultimate go through these anatomical routes.

High-powered Laser PBMT Therapeutic Index is Superior to Standard Pain Management Pharmaceuticals (NSAIDs and opioids)

Out of the 1,456 patients treated with HILT in all studies within this meta-analysis, there was not a single serious adverse event reported from our meta-analysis. This safety profile is vastly superior to the pharmacotherapeutics that are commonly used to treat chronic pain conditions. Even more, HILT clearly has the potential to correct the cause of the pain by stimulating tissue regeneration with healing, while pain-relieving pharmacotherapies are generally not designed to address the cause, rather only to address the symptomology. Opioid side effects commonly involve analgesic tolerance, addiction, constipation, nausea, and respiratory depression that can result in death.⁷⁶ In fact, opiate-related overdoses have been among the fastest rising causes of death in America, rising to epidemic proportions over the past 3 decades from 1988 until 2018.^77,78 By 2028, the estimates are that more Americans will have died in the 21st century of drug overdoses than those who died in all of America’s wars over its entire history. Additionally, a 2022 report released by the U.S. Commission on Combating Synthetic Opioid Trafficking estimates that drug overdoses now cost the U.S. approximately $1 trillion every year.⁷⁹ Finally, on Feb. 10, 2022, the CDC issued new guidelines for prescribing opioids that advises doctors to limit new opioid prescriptions and discuss alternative therapies with patients.⁸⁰ By comparison, no serious adverse events have ever been reported let alone deaths, when using high-powered PBMT. High-powered laser PBMT should be considered as an approach that may enable the transition from chronic medication to a tolerable or potentially even painless health status.

When the 100% efficacy observed for studies focused on knees, shoulders/arms, and spine is combined with this level of safety, the combined therapeutic index (toxicity: efficacy) of high-powered PBMT is truly remarkable next to pharmaceutical approaches. Most significantly, these high-powered laser PBMT RCTs are now proven to provide sustained benefits in bio-stimulation of tissue healing with regeneration, unlike pharmaceuticals commonly used to address musculoskeletal disorders, including the chronic use of corticosteroids and NSAIDs, both of which are well-known to disrupt the removal of damaged tissue and the collective wound healing process.^81,82 High-powered PBMT is now poised to take a new position as an effective, non-invasive, and drug-free, alternative therapy treatment for pain relief, inflammation reduction, and accelerated healing.

Optimal Treatment for Stimulating Cartilage /Tendon Growth in the Knee with Osteoarthritis

Knee osteoarthritis (KOA) commonly involves the loss of supporting cartilage with knee replacement surgery often being the usual recourse. One 2020 HILT study in this meta-analysis demonstrated a statistically significant increase in knee cartilage thickness after HILT treatment compared to baseline, indicating that high-intensity laser therapy can stimulate cartilage regeneration.^45,80 Comparing it with a 2017 study that failed to demonstrate increased cartilage suggests that a daily regular treatment regimen is the best approach to increasing the chance for sustained recovery with both sustained reductions in pain and true increases in cartilage growth. Similar powers (12W in positive outcome; 10.5W in negative), wavelengths (both 1064nm), and pulse settings (10Hz in positive outcome and 30Hz in negative) settings were used in both 2020 studies. However a more regular treatment regimen was used in the more successful approach – 5 days per week for 2 weeks compared to just 2 days per week for 6 weeks.⁸³ A more positive pain reduction outcome was observed with time (ES_EOT=0.4 becomes 1.1 by 6 weeks; VAS), correlating with the statistically significant increases in femoral cartilage thickness (ES_{MedialCartilage}=0.7 becomes 1.1 by 6 weeks). In the study by Ekici and Ordahan, no significant change in cartilage thickness was observed when performing treatments at just 5W/cm² biostimulatory power settings 3x/wk for patients with knee osteoarthritis.⁸⁴ Still, the HILT effectively reduced pain in a statistically significant fashion for these patients and this reduction in pain was sustained and apparent at measures made at 3 months post-cessation of treatment. All told, the summary results support that it is best to perform at least daily ≥ 10W/cm² treatment regimens to increase the chance of stimulating cartilage growth with sustained outcomes.

Most impressively, the sizes of partial tear rotator cuff tears (PTRCT) were significantly decreased with a large effect after treating patients with hemiplegic shoulder pain using HILT compared to controls in a study performed by Korkmaz et al., which utilized 8W/cm² administered 3x/wk for 3wks (ES_PTRCT=0.9).⁴⁸ These results clearly indicate that the high-powered laser can stimulate tendon growth. Another study demonstrated that HILT treatment (5W/cm²) effectively reduced inflammation of supraspinatus tendons in patients with subacromial impingement syndrome.⁴⁶

Based on the summary data, knee arthropathies and injuries would appear poised to be the next indication most likely to be recognized in consensus guidelines and paid for by insurance companies. This indication has the greatest current cumulative data with consistently positive outcomes. Not only does knee arthropathy clearly respond favorably to high-powered laser PBMT as concluded from this meta-analysis, but The American Academy of Orthopedic Surgeons (AAOS) now recommends laser therapy in its latest recommendations for the non-arthroplasty treatment of osteoarthritis of the knee joint to “improve pain and function.³⁰ Investigators point out that patients should expect to experience improvements in pain and function with the treatment and significantly, there have been no reports of serious side effects from laser treatment for pain control.⁸⁵ A 2022 meta-analysis focused on laser PBMT for treating KOA reached the same conclusion that summary data indicates high-powered laser PBMT works for relieving pain and stiffness in KOA, especially when combined together with exercise therapy and using higher powers.⁷

Our meta-analysis data supports that high-powered laser photobiomodulation therapy is a consistently effective and exceptionally safe treatment approach for reducing pain and stimulating sustained recovery for a wide range of indications that generally involve musculoskeletal joint-related pathologies, nerve-associated pathologies, wounds, and endometriosis. More controlled trials are needed to further establish consensus guideline treatment recommendations and gain recognition by payers for knee arthropathies and an expanding variety of indications.

Competing Interests

WTP was supported by compensation from Aspen Laser, LLC. CEV is the CEO of Aspen Laser and has issued and pending patents.

Supplementary Materials

Supplementary file contains Table S1 and S2.

Funding Information

WTP was supported by compensation from Aspen Laser, LLC.

Author’s Contributions

CEV and WTP conceived and contributed to the study design. WTP performed analysis. Both authors contributed to, reviewed, and approved the article.

Acknowledgements

We thank and gratefully acknowledge Anthony Murawski and Thomas A. Hertel, MSPT for critical reading, critique, and analysis of the manuscript.

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The authors declare potential competing interests as follows: Both authors were supported by Aspen Lasers, LLC. CEV is the CEO of Aspen Laser and has issued and pending patents.

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The Importance of Power in Photobiomodulation, a Systematic Review and Meta-analysis of High Intensity Laser Therapy

Status:

Version 1

Abstract

Figures

INTRODUCTION

PBMT Discovery, Acceptance, and the General Limitations of LLLT to Treating Shallow Tissue Pathologies Only

High Powered Lasers Confer Benefits to Deep Tissue Pathologies

METHODS

Search for Evidence and Article Selection

Inclusion and Exclusion Criteria

Statistical Analysis

RESULTS

QUALITATIVE SUMMARY OF INCLUSIVE STUDIES

Technical Procedural Aspects

QUANTITATIVE SUMMARY OF HILT EFFECT SIZES

HILT is superior to LLLT in Controlled Trials

Knee – 12W at 12W/cm² (52.5W/cm² micro-pulsed)

Spine/Back – 12W at 12W/cm² (10.5W at 52.5W/cm² micro-pulsed)

Shoulder and arm – 6W at 6W/cm²

Face – 10.5W

Foot − 8W (24W/cm²)

Hand – 1.5W (0.3W/cm²; 800 + 970nm)

Wound – 10.5W (50W/cm²)

Bone – 10.5W micropulsed (50W/cm²)

DISCUSSION

Study Limitations

High-powered Laser PBMT Therapeutic Index is Superior to Standard Pain Management Pharmaceuticals (NSAIDs and opioids)

Optimal Treatment for Stimulating Cartilage /Tendon Growth in the Knee with Osteoarthritis

CONCLUSION

Declarations

Competing Interests

Supplementary Materials

Funding Information

Author’s Contributions

Acknowledgements

References

Additional Declarations

Status:

Version 1

The Importance of Power in Photobiomodulation, a Systematic Review and Meta-analysis of High Intensity Laser Therapy

Status:

Version 1

Abstract

Figures

INTRODUCTION

PBMT Discovery, Acceptance, and the General Limitations of LLLT to Treating Shallow Tissue Pathologies Only

High Powered Lasers Confer Benefits to Deep Tissue Pathologies

METHODS

Search for Evidence and Article Selection

Inclusion and Exclusion Criteria

Statistical Analysis

RESULTS

QUALITATIVE SUMMARY OF INCLUSIVE STUDIES

Technical Procedural Aspects

QUANTITATIVE SUMMARY OF HILT EFFECT SIZES

HILT is superior to LLLT in Controlled Trials

Knee – 12W at 12W/cm2 (52.5W/cm2 micro-pulsed)

Spine/Back – 12W at 12W/cm2 (10.5W at 52.5W/cm2 micro-pulsed)

Shoulder and arm – 6W at 6W/cm2

Face – 10.5W

Foot − 8W (24W/cm2)

Hand – 1.5W (0.3W/cm2; 800 + 970nm)

Wound – 10.5W (50W/cm2)

Bone – 10.5W micropulsed (50W/cm2)

DISCUSSION

Study Limitations

High-powered Laser PBMT Therapeutic Index is Superior to Standard Pain Management Pharmaceuticals (NSAIDs and opioids)

Optimal Treatment for Stimulating Cartilage /Tendon Growth in the Knee with Osteoarthritis

CONCLUSION

Declarations

Competing Interests

Supplementary Materials

Funding Information

Author’s Contributions

Acknowledgements

References

Additional Declarations

Status:

Version 1

Knee – 12W at 12W/cm² (52.5W/cm² micro-pulsed)

Spine/Back – 12W at 12W/cm² (10.5W at 52.5W/cm² micro-pulsed)

Shoulder and arm – 6W at 6W/cm²

Foot − 8W (24W/cm²)

Hand – 1.5W (0.3W/cm²; 800 + 970nm)

Wound – 10.5W (50W/cm²)

Bone – 10.5W micropulsed (50W/cm²)