0363 Cold Laser and High-Power Laser Therapies (2)

Cold Laser and High-Power Laser Therapies - Medical Clinical Policy Bulletins | Aetna of 95

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Cold Laser and High-Power LaserTherapies

5/26/2021

Policy History

Last Review

05/21/2021

Effective: 11/09/1999

Next

Review: 03/24/2022

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0363

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Aetna considers low-level laser therapy medically necessary

for prevention of oral mucositis in persons undergoing cancer

treatment associated with increased risk of oral mucositis,

including chemotherapy and/or radiotherapy, and/or

hematopoietic stem cell transplantation.

Aetna considers cold laser therapy (also known as low-level

laser therapy or class III laser), high-power laser therapy (class

IV therapeutic laser), low-level laser therapy using dynamic

photonic and dynamic thermokinetic energies experimental

and investigational for the following indications (not an all-

inclusive list) because there is inadequate evidence of the

effectiveness of cold laser therapy and high-power laser

therapy for these indications:

◾ Achilles tendinopathy

◾ Alzheimer's disease

◾ Bone regeneration/bone healing

◾ Breast implant capsular contracture

◾ Burning mouth syndrome


https://www.aetna.com/


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◾ Cardio-protection following myocardial infarction

◾ Carpal tunnel syndrome

◾ Colorectal cancer

◾ Dementia

◾ Dental pain

◾ Dentin hypersensitivity

◾ Depression

◾ Elbow disorders

◾ Fibromyalgia

◾ Hair loss (including alopecia areata and androgenic

alopecia)

◾ Head and neck cancer

◾ Heart failure

◾ Herpes labialis

◾ Hypothyroidism induced by autoimmune thyroiditis

◾ Inferior alveolar nerve and lingual nerve injuries

◾ Keratosis pilaris

◾ Knee osteoarthritis

◾ Lymphedema

◾ Melasma

◾ Musculoskeletal dysfunction

◾ Myofascial pain syndrome

◾ Neurological dysfunctions

◾ Neuropathic orofacial pain (e.g., burning mouth

syndrome, occipital neuralgia, and trigeminal neuralgia)

◾ Obesity

◾ Oral lichen planus

◾ Oral ulcers in chronic graft-versus-host disease

◾ Pain relief (e.g. acute and chronic low back pain/neck

pain, orthodontic pain, neuropathic pain, shoulder pain)

◾ Parkinson's disease

◾ Patella-femoral pain syndrome

◾ Pemphigus vulgaris

◾ Peri-implant mucositis

◾ Peri-odontitis

◾ Physical therapy (including rehabilitation following

carpal tunnel release)




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◾ Recurrent aphthous stomatitis/ulcers

◾ Rheumatoid arthritis

◾ Shoulder impingement syndrome

◾ Skin burn

◾ Stroke

◾ Temporomandibular joint disorders

◾ Tendon repair

◾ Tinnitus

◾ Traumatic brain injury

◾ Wound healing (including diabetic ulcers, following

hammertoe surgery, gingival healing, and pressure

ulcers).

See also CPB 0604 - Infrared Therapy

(../600_699/0604.html).

Background

Low Level Laser Therapy

Low level laser therapy (LLLT), also known as "cold" laser

therapy, refers to a wide variety of procedures involving

several laser types and treatment methods. LLLT uses red

beam or near infrared nonthermal lasers with a wavelength

between 600 and 1000 nanometers and from five to 500

milliwatts. In contrast, lasers used for surgery typically use 300

watts. When applied, the lasers penetrate the surface of the

skin without a heating (burning) effect, produce no sensation

and do not damage the skin. It is believed that due to the low

skin absorption and no side effects, the laser light can

penetrate deeply into tissues and can reach the site of

damage or injury.

Low-energy lasers (also known as cold lasers or class III

lasers) have been promoted as an effective way to produce

analgesia and accelerate healing of a variety of clinical




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conditions. By definition, low energy laser therapy uses

irradiation intensities that induce minimal temperature

elevation (not more than 0.1 to 0.5°C), if any. For practical

purposes, this restricts treatment energies to a few J/cm2 and

laser powers to 500 mW or less.

Despite these constraints, a wide variety of types of lasers,

treatment schedules, and techniques have been used.

Consequently, apparently conflicting results from studies of

low-intensity lasers may not be in conflict, and may represent

fundamental, but poorly understood, differences in treatment

approaches.

LLLT may be administered by a physician, physical therapist,

occupational therapist or Doctor of Chiropractic (DC) in a

physician’s office or other outpatient setting and requires no

sedation or anesthesia. It is theorized that LLLT may cause a

biostimulatory healing effect for the treatment of a range of

conditions, including arthritis, chronic pain commonly

associated with carpal tunnel syndrome, tissue injuries (eg,

tendinopathy, tendonitis) and severe wounds.

Examples of LLLT devices include Acculaser Pro4,Axiom

BioLaser LLLT Series-3, Bioptron 2, Luminex LL Laser

System, MicroLight 830, RianCorp LTU-904, Thor DDII 830

CL3 Laser System, Thor DDII IR Lamp System and

TerraQuant. The TerraQuant device uses a combination of a

"super pulsed" laser, pulsed infrared, red light and static

magnetic field, which is purported to accelerate pain relief.

Although the results from large, uncontrolled, open trials of

low-energy lasers in inducing wound healing have shown

benefit, controlled trials have shown little or no benefit. The

analgesic effects of low-energy lasers have been most

intensely studied in rheumatoid arthritis. Recent well-

designed, controlled studies have found no benefit from low-

energy lasers in relieving pain in rheumatoid arthritis or other

musculoskeletal conditions. Furthermore, although positive




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effects were found in some earlier studies, it was not clear that

the pain relief achieved was large enough to have either

clinical significance or to replace conventional therapies.

Published systematic reviews of the evidence have concluded

that there is a lack of adequate evidence of effectiveness of

cold laser therapy for treatment of chronic wounds (e.g.,

Schneider and Hailey, 1999; Cullum and Petherick, 2007;

Flemming and Cullum, 1999; Samson et al, 2004; Simon et al,

2004; Wang, 2004; Nelson and Jones, 2006), arthritis

(Brosseau et al, 2007; Brosseau et al, 2005; Marks and de

Palma, 1999; Puett and Griffin, 1994; Wang, 2004),

tuberculosis (Vlassov et al, 2006; Ziganshina and Garner,

2005), tinnitus (Waddell, 2004), pain (Gross et al, 1998; van

der Heijden et al, 2002; Binder, 2002; Speed, 2006; Green et

al, 2003), smoking cessation (White et al, 2006), epicondylitis

(Chapell et al, 2002), Achilles tendinitis (McLauchlan et al,

2001), plantar heel pain (Crawford and Thomson, 2003;

Landorf and Menz, 2007), back pain (Yousefi-Nooraie et al,

2008), and other musculoskeletal disorders (de Bie et al, 1998;

Abdulwadud, 2001; Ohio BWC, 2004; Wang, 2004).

Systematic evidence reviews have also concluded that low-

energy laser therapy (e.g., Microlight 830, Microlight

Corporation of America, Missouri City, TX) is ineffective in

treating carpal tunnel syndrome (Gerritsen et al, 2002;

O'Connor et al, 2003; Ohio BWC, 2004; Wang, 2004; CTAF,

2006).

A recent study (Hirschl et al, 2004) evaluated the effectiveness

of low-level laser therapy in patients with primary Raynaud's

phenomenon (n = 48). Laser and sham therapy each were

applied 5 days a week for 3 weeks. The authors found that low-

level laser therapy reduced the frequency and severity of

Raynaud attacks. The findings of this study were interesting

but need to be validated by further investigation with more

patients and follow-up.




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Kreisler et al (2004) assessed the effect of low-level laser

application on post-operative pain after endodontic surgery in

a double-blind, randomized clinical study. A total of 52 healthy

adults undergoing endodontic surgery were included into the

study. After suturing, 26 patients had the operation site

treated with an 809 nm-GaAlAs-laser at a power output of 50

mW and an irradiation time of 150 seconds. Laser treatment

was simulated in another 26 patients. Patients were instructed

to evaluate their post-operative pain on 7 days following

surgery by means of a visual analogue scale. The results

revealed that the pain level in the laser-treated group was

lower than in the placebo group throughout the 7 day follow-up

period. The differences, however, were significant only on the

first post-operative day. The authors stated that low-level laser

therapy can be beneficial for the reduction of post-operative

pain. However, its clinical effectiveness and applicability with

regard to endodontic surgery need further investigation,

especially in terms of the optimal energy dosage and the

number of laser treatments needed after surgery.

In a randomized controlled study, Bingol et al (2005) examined

the effect of low-power gallium-arsenide laser treatment on the

patients with shoulder pain. A total of 40 patients with

shoulder pain and complied with the selection criteria were

included in the study. They were randomly assigned into 2

groups: (i) laser treatment (n = 20), and (ii) control (n = 20).

In group (i), patients were given laser treatment and an

exercise protocol for 10 sessions during a period of 2 weeks.

In group (ii), placebo laser and the same exercise protocol

was given for the same period. Patients were evaluated

according to the parameters of pain, palpation sensitivity,

algometric sensitivity, and shoulder joint range of motion

before and after treatment. Analysis of measurement results

within each group showed a significant post-treatment

improvement for some active and passive movements in both

groups, and also for algometric sensitivity in group (i) (p < 0.05

to 0.01). Post-treatment palpation sensitivity values showed




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improvement in 17 patients (85 %) for group (i) and 6 patients

(30 %) for group (ii). Comparison between 2 groups showed

superior results (p < 0.01 and p < 0.001) in group (i) for the

parameters of passive extension and palpation sensitivity but

no significant difference for other parameters. These

researchers concluded that this study have shown better

results in palpation sensitivity and passive extension, but no

significant improvement in pain, active range of motion, and

algometric sensitivity in laser treatment group compared to the

control group in the patients with shoulder pain.

Markovic and Todorovic (2007) compared the effectiveness of

dexamethasone and low-power laser (LPL) after surgical

removal of impacted lower third molars under local anesthesia

(2 % lidocaine / epinephrine). A total of 120 healthy patients

were divided into 4 groups of 30 each: (i) group 1 received

LPL irradiation immediately after operation (energy output

4 J/cm2 with constant power density of 50 mW, wavelength

637 nm); (ii) group 2 also received intra-muscular (i.m.)

injection of 4 mg dexamethasone (Dexason) into the

internal pterygoid muscle; (iii) group 3 received LPL

irradiation supplemented by systemic dexamethasone, 4

mg i.m. in the deltoid region, followed by 4 mg of

dexamethasone intra-orally 6 hours post-operatively; and

(iv) control group received only the usual post-operative

recommendations (i.e., cold packs, soft diet, etc.). Low-

power laser irradiation with local use of dexamethasone (group

2) resulted in a statistically significant reduction of post

operative edema in comparison to the other groups. No

adverse effects of the procedure or medication were

observed. The authors concluded that LPL irradiation after

lower third molar surgery can be recommended to minimize

swelling. The effect is enhanced by simultaneous local intra-

muscular use of dexamethasone. The drawbacks of this study

were 2-fold: (i) the effects of LPL, if any, was confounded by

the simultaneous use of dexamethasone, and (ii) while the

combination of LPL and dexamethasone achieved a




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statistical significant reduction in edema, its clinical benefit

is unclear.

Stergioulas (2007) compared the effectiveness of a protocol of

combination of laser with plyometric exercises and a protocol

of placebo laser with the same program, in the treatment of

tennis elbow. A total of 50 patients were randomized into 2

groups: (i) group A (n = 25) was treated with a 904 nm Ga-As

laser, frequency 50 Hz, intensity 40 mW and energy density

2.4 J/cm(2), plus plyometric exercises, and (ii) group B (n =

25) that received placebo laser plus the same plyometric

exercises. During 8 weeks of therapy, patients of the 2 groups

received 12 sessions of laser or placebo, 2 sessions per week

(weeks 1 to 4) and 1 session per week (weeks 5 to 8). Pain at

rest, at palpation on the lateral epicondyle, during resisted

wrist extension, middle finger test, and strength testing was

evaluated using visual analog scale (VAS). Also, the grip

strength, the range of motion (ROM) and weight test were

evaluated. Parameters were determined before treatment, at

the end of the 8th week course of treatment (week 8), and 8th

(week 8) after the end of treatment. Relative to group B, group

A had (i) a significant decrease of pain at rest at the end of 8

weeks of the treatment (p < 0.005) and at the end of

following up period (p < 0.05), (ii) a significant decrease in

pain at palpation and pain on isometric testing at 8 weeks

of treatment (p < 0.05), and at 8 weeks follow-up (p <

0.001), (iii) a significant decrease in pain during middle

finger test at the end of 8 weeks of treatment (p < 0.01),

and at the end of the follow-up period (p < 0.05), (iv) a

significant decrease of pain during grip strength testing at 8

weeks of treatment (p < 0.05), and at 8 weeks follow-up (p <

0.001), (v) a significant increase in the wrist ROM at 8 weeks

follow-up (p < 0.01), (vi) an increase in grip strength at 8

weeks of treatment (p < 0.05) and at 8 weeks follow-up (p <

0.01), and (vii) a significant increase in weight-test at 8

weeks of treatment (p < 0.05) and at 8 weeks follow-up (p <

0.005). The authors concluded that these findings suggested




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that the combination of laser with plyometric exercises was

more effective treatment than placebo laser with the same

plyometric exercises at the end of the treatment as well as at

the follow-up. Moreover, they stated that future studies are

needed to establish the relative and absolute effectiveness of

the above protocol.

Kaviani and colleagues (2006) examined the effects of low-

level laser therapy (LLLT) in the treatment of post-mastectomy

lymphedema. A total of 11 women with unilateral post-

mastectomy lymphedema were enrolled in a double-blind

controlled trial. Patients were randomly assigned to laser and

sham groups and received laser or placebo irradiation (Ga-As

laser device with a wavelength of 890 nm and fluence of 1.5

J/cm2) over the arm and axillary areas. Changes in patients'

limb circumference, pain score, ROM, heaviness of the

affected limb, and desire to continue the treatment were

measured before the treatment and at follow-up sessions

(weeks 3, 9, 12, 18, and 22) and were compared to pre-

treatment values. Results showed that of the 11 enrolled

patients, 8 completed the treatment sessions. Reduction in

limb circumference was detected in both groups, although it

was more pronounced in the laser group up to the end of 22nd

week. Desire to continue treatment at each session and

baseline score in the laser group was greater than in the sham

group in all sessions. Pain reduction in the laser group was

more than in the sham group except for the weeks 3 and 9.

No substantial differences were seen in other 2 parameters

between the 2 treatment groups. The authors concluded that

despite the encouraging results, further studies of the effects

of LLLT in management of post-mastectomy lymphedema

should be undertaken to determine the optimal physiological

and physical parameters to obtain the most effective clinical

response.

In a systematic review of common conservative therapies for

arm lymphoedema secondary to breast cancer treatment,

Moseley et al (2007) stated that secondary arm lymphoedema




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is a chronic and distressing condition which affects a

significant number of women who undergo breast cancer

treatment. A number of health professional and patient

instigated conservative therapies have been developed to help

with this condition, but their comparative benefits are not

clearly known. This systematic review undertook a broad

investigation of commonly instigated conservative therapies for

secondary arm lymphoedema including; complex physical

therapy, manual lymphatic drainage, pneumatic pumps, oral

pharmaceuticals, LLLT, compression bandaging and

garments, limb exercises and limb elevation. It was found that

the more intensive and health professional based therapies,

such as complex physical therapy, manual lymphatic drainage,

pneumatic pump and laser therapy generally yielded the

greater volume reductions, whilst self-instigated therapies

such as compression garment wear, exercises and limb

elevation yielded smaller reductions. All conservative

therapies produced improvements in subjective arm symptoms

and quality of life issues, where these were measured.

Despite the identified benefits, there is still the need for large

scale, high level clinical trials in this area.

Information on lymphedema from the BC Cancer Agency

(2007) notes that laser therapy "may or may not work but need

[s] further study."

Carrasco et al (2009) noted that limited studies have

demonstrated that LLLT may have a therapeutic effect on the

treatment of myofascial pain syndrome (MPS). In this study,

60 patients with MPS and having 1 active trigger point in the

anterior masseter and anterior temporal muscles were

selected and assigned randomly to 6 groups (n = 10 in each

group): Groups I to Ill were treated with GaAIAS (780 nm)

laser, applied in continuous mode and in a meticulous way,

twice-weekly, for 4 weeks. Energy was set to 25 J/cm2, 60

J/cm2 and 105 J/cm2, respectively. Groups IV to VI were

treated with placebo applications, simulating the same

parameters as the treated groups. Pain scores were assessed




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just before, then immediately after the 4th application,

immediately after the 8th application, at 15 days and 1 month

following treatment. A significant pain reduction was observed

over time (p < 0.001). The analgesic effect of the LLLT was

similar to the placebo groups. The authors stated that using

the parameters described in this experiment, LLLT was

effective in reducing pain experienced by patients with MPS.

Thus, it was not possible to establish a treatment protocol.

Yelden and colleagues (2009) examined the effectiveness

LLLT in addition to exercise program on shoulder function in

subacromial impingement syndrome (SAIS). A total of 67

patients with SAIS were randomly assigned to either a group

that received laser (n = 34) or a group that received placebo

laser (n = 26). Pain, functional assessment, disability and

muscle strength of shoulder were assessed before and after a

3-week rehabilitation program. Besides laser or placebo laser,

superficial cold and progressive exercise program were

administered to both groups, 5 days a week, for 3 weeks. A

progressive exercise program that was done twice-daily under

supervision in clinic and at home was given to the patients.

After the treatment, all outcome measurements had shown

significant improvement except muscle strength in both the

groups. When the parameters of the improvement were

compared, there were no significant differences between the 2

groups after treatment. The authors concluded that there is no

fundamental difference between LLLT and placebo LLLT when

they are supplementing an exercise program for rehabilitation

of patients with shoulder impingement syndrome.

In a prospective, randomized double-blind study, Teggi et al

(2009) examined the effectiveness of LLLT for tinnitus. A total

of 60 outpatients with tinnitus presenting sensorineural hearing

loss in the affected ear were included in the study. They were

randomly divided into 2 groups: (i) active laser therapy 20

mins a day for 3 months with a 650-nm, 5-mW soft laser

(group L), and (ii) control group with dummy device, which




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duplicated all aspects of active laser therapy except for the

activation of the laser beam. One subject in both groups

dropped out due to an increase in tinnitus loudness. Two

more patients in each group ceased to comply with the

protocol due to familiar problems. Main outcome measure was

the Tinnitus Handicap Inventory (THI); no statistical difference

was detected between the 2 groups in the THI total score (p =

0.97), and its functional (p = 0.89), emotional (p = 0.89) and

catastrophic (p = 0.89) subscales. Moreover, a VAS for self-

perceived loudness of the tinnitus showed no difference

between the groups (p = 0.69). Regarding psychoacoustic

parameters, the minimum masking level showed no difference

(p = 0.42), while loudness expressed in sensation level

exhibited lower values in the treatment group (p = 0.0127).

Subjects in the treatment group also reported a decreased

rate of hyper-acusis (p = 0.02). No changes were detected in

the audiometric threshold in both groups. The authors

concluded that soft laser therapy demonstrated no efficacy as

a therapeutic measure for tinnitus.

A systematic evidence review by Chow et al (2009) concluded

that lowLLLT reduced pain immediately after treatment in

acute neck pain, and up to 22 weeks after completion of

treatment, in patients with chronic neck pain. The authors

included randomized controlled trials (RCTs) or quasi-RCTs of

LLLT, for participants aged 16 or over with acute or chronic

neck pain, were eligible for inclusion. Sixteen RCTs (n = 820

participants) met inclusion criteria, with sample sizes ranging

from 20 to 90 participants. The authors reported significant

effects of LLLT on acute and chronic neck pain. An evaluation

of the systematic evidence review by Chow et al by the Centre

for Reviews and Dissemination (2009) found that, although

suitable methods were employed to reduce the risks of

reviewer error and bias for the processes of study selection

and data extraction, the authors did not report on whether

such methods were used to assess study quality, which was

assessed using the Jadad scale. The CRD also found that




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this did not assess methods of allocation concealment, so the

risk on investigator bias affecting trial results could not be

ruled out. Furthermore, no information was provided on the

actual levels of withdrawals and drop-outs. The CRD also

found that all trials included in this systematic review had

relatively small sample sizes and information was not provided

on whether treatment groups (in individual trials) were

comparable at baseline for likely confounders. The CRD

noted that the authors of the systematic review acknowledged

the considerable clinical heterogeneity in laser treatment

parameters, but this also seemed apparent with regard to the

sites treated, diagnoses, frequencies of treatment, and uses of

cointerventions; it is therefore questionable whether meta-

analysis was the most appropriate method of synthesis. The

CRD concluded: "Although many aspects of this review were

well-conducted, the considerable clinical heterogeneity seen,

coupled with uncertainty regarding possible bias in the small

trials included, mean the authors' conclusions should be

interpreted with a degree of caution."

In a a randomized, double-blind, placebo-controlled study, Ay

and colleagues (2010) compared the effectiveness of LLLT on

pain and functional capacity in patients with acute and chronic

low back pain caused by lumbar disk herniation (LDH). A total

of 40 patients with acute (26 females/14 males) and 40

patients with chronic (20 females/20 males) low back pain

caused by LDH were included in the study. Patients were

randomly allocated into 4 groups: (i) group 1 (acute LDH, n =

20) received hot-pack + laser therapy; (ii) group 2 (chronic

LDH, n = 20) received hot-pack + laser therapy; (iii) group 3

(acute LDH, n = 20) received hot-pack + placebo laser

therapy, and (iv) group 4 (chronic LDH, n = 20) received hot-

pack + placebo laser therapy, for 15 sessions during 3

weeks. Assessment parameters included pain, patients'

global assessment, physician's global assessment, and

functional capacity. Pain was evaluated by VAS. Patients'

and physician's global assessment were also measured with




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VAS. Modified Schober test and flexion and lateral flexion

measures were used in the evaluation of ROM of lumbar

spine. Roland Disability Questionnaire (RDQ) and Modified

Oswestry Disability Questionnaire (MODQ) were used in the

functional evaluation. Measurements were done before and

after 3 weeks of treatment. After the treatment, there were

statistically significant improvements in pain severity, patients'

and physician's global assessment, ROM, RDQ scores, and

MODQ scores in all groups (p < 0.05). However, no significant

differences were detected between 4 treatment groups with

respect to all outcome parameters (p > 0.05). There were no

differences between laser and placebo laser treatments on

pain severity and functional capacity in patients with acute and

chronic low back pain caused by LDH.

In a randomized double-blind controlled trial, Meireles and

associates (2010) assessed the effectiveness of LLLT on pain

reduction and improvement in function in the hands of patients

with rheumatoid arthritis. A total of 82 patients with

rheumatoid arthritis were included in this study. The

experimental group was submitted to the application of laser

therapy, whereas the control group received a placebo laser.

Aluminum gallium arsenide laser was used, at a wavelength of

785 nm, dose of 3 J/cm(2) and mean power of 70 mW. The

groups were homogenous at the beginning of the study with

regard to the main variables (p > 0.05). There were no

statistically significant differences between groups in most of

the measurements taken at the end of the intervention

including the primary variables; the following variables were

the exceptions: favoring the experimental group --

inflammation of the inter-phalangeal joint of the right thumb (p

= 0.012) and perimetry of the inter-phalangeal joint of the left

thumb (p = 0.013); and favoring the control group -- flexion of

the proximal inter-phalangeal joint of the right fifth finger (p =

0.021), perimetry of the third proximal inter-phalangeal joint of

the right hand (p = 0.044), grip strength in the left hand (p =

0.010), and the work domain of the Disabilities of the Arm,

Shoulder and Hand (DASH) questionnaire (p = 0.010). The




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authors concluded that low-level aluminum gallium arsenide

laser therapy is not effective at the wavelength, dosage, and

power studied for the treatment of hands among patients with

rheumatoid arthritis.

The Blue Cross and Blue Shield Association Technology

Evaluation Center (2010) concluded that LLLT for either carpal

tunnel syndrome or for chronic neck pain does not meet the

Blue Cross and Blue Shield Association Technology

Evaluation Center (TEC) criteria. Furthermore, the Work Loss

Data Institute's clinical practice guideline on "Carpal tunnel

syndrome" (2011) does not recommend LLLT as a therapeutic

option.

Kadhim-Saleh et al (2013) e xamined the effectiveness of LLLT

in reducing acute and chronic neck pain as measured by the

VAS. A systematic search of 9 electronic databases was

conducted to identify original articles. For study selection, 2

reviewers independently assessed titles, abstracts, and full

text for eligibility. Methodological quality was assessed using

the Detsky scale. Data were analyzed using random-effects

model in the presence of heterogeneity and fixed-effect model

in its absence. Heterogeneity was assessed using Cochran's

Q statistic and quantifying I (2). Risk ratios (RR) with 95 %

confidence intervals (CI) were reported. Eight RCTs involving

443 patients met the strict inclusion criteria. Inter-rater

reliability for study selection was 92.8 % (95 % CI: 80.9 to 100

%) and for methodological quality assessment was 83.9 % (95

% CI: 19.4 to 96.8 %). Five trials included patients with

cervical myofascial pain syndrome (CMPS), and 3 trials

included different patient populations. A meta-analysis of 5

CMPS trials revealed a mean improvement of VAS score of

10.54 with LLLT (95 % CI: 0.37 to 20.71; heterogeneity I(2) =

65 %, p = 0.02). The authors concluded that this systematic

review provided inconclusive evidence because of significant

between-study heterogeneity and potential risk of bias. They




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stated that the benefit seen in the use of LLLT, although

statistically significant, does not constitute the threshold of

minimally important clinical difference.

van Middelkoop et al (2011) determined the effectiveness of

physical and rehabilitation interventions (i.e. exercise therapy,

back school, transcutaneous electrical nerve stimulation

(TENS), LLLT, education, massage, behavioral treatment,

traction, multi-disciplinary treatment, lumbar supports, and

heat/cold therapy) for chronic low back pain (LBP). The

primary search was conducted in MEDLINE, EMBASE,

CINAHL, CENTRAL, and PEDro up to 22 December 2008.

Existing Cochrane reviews for the individual interventions were

screened for studies fulfilling the inclusion criteria. The search

strategy outlined by the Cochrane Back Review Groups

(CBRG) was followed. The following were included for

selection criteria: (i) RCTs, (ii) adult (greater than or equal to

18 years) population with chronic (greater than or equal to

12 weeks) non-specific LBP, and (iii) evaluation of at least

one of the main clinically relevant outcome measures (pain,

functional status, perceived recovery, or return to work).

Two reviewers independently selected studies and extracted

data on study characteristics, risk of bias, and outcomes at

short, intermediate, and long-term follow-up. The GRADE

approach was used to determine the quality of evidence. In

total, 83 RCTs met the inclusion criteria: exercise therapy (n =

37), back school (n = 5), TENS (n = 6), LLLT (n = 3),

behavioral treatment (n = 21), patient education (n = 1),

traction (n = 1), and multi-disciplinary treatment (n = 6).

Compared to usual care, exercise therapy improved post-

treatment pain intensity and disability, and long-term function.

Behavioral treatment was found to be effective in reducing

pain intensity at short-term follow-up compared to no

treatment/waiting list controls. Finally, multi-disciplinary

treatment was found to reduce pain intensity and disability at

short-term follow-up compared to no treatment/waiting list

controls. Overall, the level of evidence was low. Evidence




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from RCTs demonstrated that there is low quality evidence for

the effectiveness of exercise therapy compared to usual care,

there is low evidence for the effectiveness of behavioral

therapy compared to no treatment and there is moderate

evidence for the effectiveness of a multi-disciplinary treatment

compared to no treatment and other active treatments at

reducing pain at short-term in the treatment of chronic LBP.

Based on the heterogeneity of the populations, interventions,

and comparison groups, the authors concluded that there are

insufficient data to draw firm conclusion on the clinical effect of

back schools, LLLT, patient education, massage, traction,

superficial heat/cold, and lumbar supports for chronic LBP.

Lake and Wofford (2011) examined the effectiveness of

therapeutic modalities for the treatment of patients with

patella-femoral pain syndrome (PFPS). Medline was searched

using the following databases: PubMed, CINAHL, Web of

Science Citation Index, Science Direct, ProQuest Nursing &

Allied Health, and Your Journals@OVID. Selected studies

were RCTs that used a therapeutic modality to treat patients

with PFPS. The review included articles with all outcome

measures relevant for the PFPS patient: knee extension and

flexion strength (isokinetic and isometric), patella-femoral pain

assessment during activities of daily life, functional tests (e.g.,

squats), Kujala patella-femoral score, and electromyographic

recording from knee flexors and extensors and quadriceps

femoris cross-sectional areas. Authors conducted

independent quality appraisals of studies using the PEDro

Scale and a system designed for analysis of studies on

interventions for patella-femoral pain. A total of 12 studies met

criteria: 1 on the effects of cold and ultrasound together, ice

alone, iontophoresis, and phonophoresis; 3, neuromuscular

electrical stimulation; 4, electromyographic biofeedback; 3,

electrical stimulation for control of pain; and 1, laser. Most

studies were of low to moderate quality. Some reported that

therapeutic modalities, when combined with other treatments,

may be of some benefit for pain management or other

symptoms. There was no consistent evidence of any




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beneficial effect when a therapeutic modality was used alone.

Studies did not consistently provide added benefit to

conventional physical therapy in the treatment of PFPS. The

authors concluded that none of the therapeutic modalities

reviewed has sound scientific justification for the treatment of

PFPS when used alone.

The American College of Occupational and Environmental

Medicine’s clinical guideline on “Elbow disorders” (ACOEM,

2012) listed low-level laser therapy as one of the

interventions/procedures that were considered, but are not

currently recommended.

In a meta-analysis, Sgolastra et al (2013) evaluated the

effectiveness of lasers in reducing dentin hypersensitivity (DH)

as compared with placebo or no treatment. Seven electronic

databases and a manual search resulted in 2,538 unique

publications. After selection, 13 studies were included in the

meta-analysis. A CONSORT-based quality assessment

revealed that 3 and 10 studies were at low- and high-risk of

bias, respectively. A random-effects model with the generic

inverse variance standardized mean difference (SMD) was

used because of expected heterogeneity. Meta-analyses of

the baseline-end of follow-up changes in pain revealed no

differences for Er,Cr:YSSG versus placebo (SMD = 2.49; 95 %

CI: -0.25 to 5.22; p = 0.07) but did reveal differences in favor of

lasers for Er:YAG versus placebo (SMD, 2.65; 95 % CI: 1.25 to

4.05; p = 0.0002), Nd:YAG versus placebo (SMD, 3.59; 95 %

CI: 0.49 to 6.69; p = 0.02), and GaAlAs versus placebo (SMD,

3.40; 95 % CI: 1.93 to 4.87; p < 0.00001). High and significant

heterogeneity was found for all comparisons. The authors

concluded that Er:YAG, Nd:YAG, and GaAlAs lasers appear to

be effective in reducing DH. However, given the high

heterogeneity of the included studies, future RCTs are needed

to confirm these results.




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In a Cochrane review, Peters et al (2013) reviewed the

effectiveness of rehabilitation following carpal tunnel syndrome

(CTS) surgery compared with no treatment, placebo, or

another intervention. On April 3, 2012, these investigators

searched the Cochrane Neuromuscular Disease Group

Specialized Register (April 3, 2012), CENTRAL (2012, Issue

3), MEDLINE (January 1966 to March 2012), EMBASE

(January 1980 to March 2012), CINAHL Plus (January 1937 to

March 2012), AMED (January 1985 to April 2012), LILACS

(January 1982 to March 2012), PsycINFO (January 1806 to

March 2012), PEDRO (January 29, 2013) and clinical trials

registers (January 29, 2013). Randomized or quasi-

randomized clinical trials that compared any post-operative

rehabilitation intervention with no intervention, placebo or

another post-operative rehabilitation intervention in individuals

who had undergone CTS surgery were selected for analysis.

Two reviewers independently selected trials for inclusion,

extracted data and assessed the risk of bias according to

standard Cochrane methodology. These researchers included

20 trials with a total of 1,445 participants. They studied

different rehabilitation treatments including immobilization

using a wrist orthosis, dressings, exercise, controlled cold

therapy, ice therapy, multi-modal hand rehabilitation, laser

therapy, electrical modalities, scar desensitization, and arnica.

Three trials compared a rehabilitation treatment to a placebo

comparison; 3 trials compared rehabilitation to a no treatment

control; 3 trials compared rehabilitation to standard care; and

14 trials compared various rehabilitation treatments to one

another. Overall, the included studies were very low in quality.

Eleven trials explicitly reported random sequence generation

and, of these, 3 adequately concealed the allocation

sequence. Four trials achieved blinding of both participants

and outcome assessors. Five studies were at high-risk of bias

from incompleteness of outcome data at one or more time

intervals. Eight trials had a high-risk of selective reporting

bias. The trials were heterogeneous in terms of the treatments

provided, the duration of interventions, the nature and timing of

outcomes measured and setting. Therefore, these




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researchers were not able to pool results across trials. Four

trials reported the authors’ primary outcome, change in self-

reported functional ability at 3 months or longer. Of these, 3

trials provided sufficient outcome data for inclusion in this

review. One small high quality trial studied a desensitization

program compared to standard treatment and revealed no

statistically significant functional benefit based on the Boston

Carpal Tunnel Questionnaire (BCTQ) (MD -0.03; 95 % CI:

-0.39 to 0.33). One moderate quality trial assessed

participants 6 months post-surgery using the Disabilities of the

Arm, Shoulder and Hand (DASH) questionnaire and found no

significant difference between a no formal therapy group and a

2-week course of multi-modal therapy commenced at 5 to 7

days post-surgery (MD 1.00; 95 % CI: -4.44 to 6.44). One very

low quality quasi-randomized trial found no statistically

significant difference in function on the BCTQ at 3 months

post-surgery with early immobilization (plaster wrist orthosis

worn until suture removal) compared with a splint and late

mobilization (MD 0.39; 95 % CI: -0.45 to 1.23). The

differences between the treatments for the secondary outcome

measures (change in self-reported functional ability measured

at less than 3 months; change in CTS symptoms; change in

CTS-related impairment measures; presence of iatrogenic

symptoms from surgery; return to work or occupation; and

change in neurophysiological parameters) were generally

small and not statistically significant. Few studies reported

adverse events. The authors concluded that there is limited

and, in general, low-quality evidence for the benefit of the

reviewed interventions. People who have had CTS surgery

should be informed about the limited evidence of the

effectiveness of post-operative rehabilitation interventions.

Until the results of more high-quality trials that evaluate the

safety and effectiveness of various rehabilitation treatments

have been reported, the decision to provide rehabilitation

following CTS surgery should be based on the clinician's

expertise, the patient's preferences and the context of the

rehabilitation environment. It is important for researchers to

identify patients who respond to a certain treatment and those




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who do not, and to undertake high-quality studies that evaluate

the severity of iatrogenic symptoms from the surgery, measure

function and return-to-work rates, and control for confounding

variables.

He and co-workers (2013) examined the effectiveness of LLLT

in the management of orthodontic pain. This systematic

review and meta-analysis was carried out in accordance with

Cochrane Handbook and the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA) statement.

An extensive literature search for RCTs, quasi-RCTs, and

controlled clinical trials (CCTs) was performed through

CENTRAL, PubMed, Embase, Medline, CNKI, and CBM up to

October 2011. Risk of bias assessment was performed via

referring to the Cochrane tool for risk of bias assessment.

Meta-analysis was implemented using Review Manager 5.1.

As a result, 4 RCTs, 2 quasi-RCTs, and 2 CCTs were

selected from 152 relevant studies, including 641 patients from

6 countries. The meta-analysis demonstrated that 24 % risk of

incidence of pain was reduced by LLLT (RR = 0.76, 95 % CI:

0.63 to 0.92, p = 0.006). In addition, compared to the control

group, LLLT brought forward "the most painful day" (MD =

-0.42, 95 % CI: -0.74 to -0.10, p = 0.009). Furthermore, the

LLLT group also implied a trend of earlier end of pain

compared with the control group (MD = -1.37, 95 % CI: -3.37 to

0.64, p = 0.18) and the pseudo-laser group (MD = -1.04, 95 %

CI: -4.22 to 2.15, p = 0.52). However, the authors concluded

that because of the methodological shortcomings and risk of

bias of included trials, LLLT was proved with limited evidence

in delaying pain onset and reducing pain intensity. Moreover,

they stated that in the future, larger and better-designed RCTs

are needed to provide clearer recommendations.

Thornton et al (2013) stated that shoulder pain is a common

musculo-skeletal condition that affects up to 25 % of the

general population. Shoulder pain can be caused by any

number of underlying conditions including subacromial

impingement syndrome, rotator-cuff tendinitis, and biceps




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tendinitis. Regardless of the specific pathology, pain is

generally the number 1 symptom associated with shoulder

injuries and can severely affect daily activities and quality of

life of patients with these conditions. Two of the primary goals

in the treatment of these conditions are reducing pain and

increasing shoulder ROM. Conservative treatment has

traditionally included a therapeutic exercise program targeted

at increasing ROM, strengthening the muscles around the

joint, proprioceptive training, or some combination of those

activities. In addition, these exercise programs have been

supplemented with other interventions including non-steroidal

anti-inflammatory drugs, corticosteroid injections, manual

therapy, activity modification, and a wide array of therapeutic

modalities (e.g., cryotherapy, EMS, ultrasound). Recently,

LLLT has been used as an additional modality in the

conservative management of patients with shoulder pain.

However, the authors noted that true effectiveness of LLLT in

decreasing pain and increasing function in patients with

shoulder pain is unclear.

Amid et al (2014) reviewed the data published in the field of

the effects of LLLT on proliferation and differentiation of the

cells contributing in bone regeneration. These researchers

performed an electronic search in PubMed from 2001 to April

2014. English language published papers on LLLT were found

using the selected keyword. The full texts of potentially

suitable articles were obtained for final assessment according

to the exclusion and inclusion criteria. A total of 240 articles

were found from 2001 to April 2014. Following the initial

screening of titles and abstracts as well as the final screening

of full texts, 22 articles completely fulfilled the inclusion criteria

of this study. Wavelength used in LLLT irradiation varied

between 600 to 1,000 nm with an energy density of 0.04 to

60J/cm(2). Although almost all studies agreed on getting

positive effects from LLLT, some had opposing results. The

authors concluded that low level laser with low-energy density

range appears to exert a bio-stimulatory effect on bone tissue,

enhance osteoblastic proliferation as well as differentiation on




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cell lines used in in-vitro studies. They stated that despite the

fact that many researches have been recently done on the

effects of LLLT on different cell lines, without knowing the

precise mechanism and effects, they were not able to offer a

clinical treatment protocol.

Doeuk et al (2015) noted that LLLT is currently being used for

various disorders, but with no convincing scientific evidence.

Most recently these investigators have noticed an increase in

published RCTs that have focused on its applications in wound

healing, scarring, disorders of the temporomandibular joint

(TMJ), oral mucositis, and dental pain. These researchers

evaluated the scientific evidence about its effectiveness in

maxillofacial surgery. They reviewed PubMed from January

2003 to January 2013 using the key phrase "low level laser

treatment". The inclusion criterion was intervention studies in

humans of more than 10 patients. The authors excluded

animal studies and papers in languages other than English,

French, and German. These researchers found 45 papers

that they screened independently. The resulting full texts were

scrutinized by 2 authors who awarded a maximum of 5 points

using the Jadad scale for assessing the quality of RCT, and

extracted the data according to sample size, variables of LLLT,

the authors' conclusions, and the significance of the result.

The authors concluded that LLLT seems to be effective for the

treatment of oral mucositis after treatment for head and neck

cancer. However, it cannot yet be considered a valid

treatment for disorders of the TMJ; and it seems to improve

gingival healing, and myofascial and dental pain.

Huang et al (2015) examined the effectiveness of LLLT of

knee osteoarthritis (KOA) by a systematic literature search

with meta-analyses on selected studies. MEDLINE, EMBASE,

ISI Web of Science and Cochrane Library were systematically

searched from January 2000 to November 2014. Included

studies were RCTs written in English that compared LLLT (at

least 8treatment sessions) with sham laser in KOA patients.

The efficacy effective size was estimated by the SMD.




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Standard fixed or random-effects meta-analysis was used,

and inconsistency was evaluated by the I-squared index (I(2)).

Of 612 studies, 9 RCTs (7 double-blind, 2 single-blind, totaling

518 patients) met the criteria for inclusion. Based on 7

studies, the SMD in VAS pain score right after therapy (RAT)

(within 2 weeks after the therapy) was not significantly different

between LLLT and control (SMD = -0.28 [95 % CI: -0.66 to

0.10], I(2) = 66 %). No significant difference was identified in

studies conforming to the World Association of Laser Therapy

(WALT) recommendations (4 studies) or on the basis of OA

severity. There was no significant difference in the delayed

response (12 weeks after end of therapy) between LLLT and

control in VAS pain (5 studies). Similarly, there was no

evidence of LLLT effectiveness based on Western Ontario and

McMaster Universities Arthritis Index (WOMAC) pain, stiffness

or function outcomes (5 and 3 studies had outcome data right

after and 12 weeks after therapy respectively). The authors

concluded that the findings of this study indicated that the best

available current evidence does not support the effectiveness

of LLLT as a therapy for patients with KOA.

Aphthous Stomatitis / Ulcers

Pavlic et al (2015) stated that recurrent aphthous stomatitis

(RAS) is defined as multi-factor immunologic inflammatory

lesions in the oral cavity, characterized by painful, recurrent

single/multiple, shallow, round or ovoid ulcerations of mucosal

tissues. To-date, a considerable number of RAS treatment

protocols have been suggested, but since the etiology of RAS

is idiopathic, these therapeutic options have symptomatic

rather than curative or preventive effect. Recently, it has been

suggested that laser therapy could be successfully used as an

efficient treatment approach in therapy of RAS. These

investigators estimated the effects of laser therapy in treatment

of RAS analyzing results of clinical studies published in peer-

reviewed journals. The studies published until December 31,

2013 were obtained from the Medline/PubMed, Science Direct

and Cochrane Library of the Cochrane Collaboration




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(CENTRAL) online databases, using following search terms

and key words: "laser" and "recurrent aphthous stomatitis",

"laser" and "aphthous", and "laser" and "aphthae". A total of 4

original research articles met the all required

inclusion/exclusion criteria, and were used for this review. The

main outcome measures assessed were: a reduction of pain

associated with RAS and a reduction in episode duration

(faster RAS healing). The assessed literature demonstrated

the benefits of laser therapy mainly due to immediate

analgesia and ability to speed up a RAS healing process. The

authors concluded that although the assessed literature

suggested beneficial outcomes of laser therapy in treatment of

RAS, these results should be interpreted with caution. They

stated that the issues related to the study designs and different

sets of laser irradiation parameters of a limited number of

available studies with the same treatment outcomes prevented

them from making definite conclusions.

Vale et al (2015) noted that recurrent aphthous ulcers (RAUs)

are the most common lesion found in the oral cavity. There is

no definitive cure for RAUs and current treatments are aimed

at minimizing symptoms. Since LLLT modulates inflammatory

responses, and promotes pain reduction and cellular bio-

stimulation, LLLT can be suggested as an alternative

treatment for RAUs. The literature concerning the potential of

LLLT in the treatment of RAUs was evaluated. A systematic

literature review identified 22 publications, of which only 2

studies were adopted. The eligibility criteria consisted of

RCTs. Both RCTs achieved significant results concerning

LLLT and pain-level reductions and reduced healing times.

Despite the variance in irradiation conditions applied in both

studies, very similar wavelengths were adopted. There is

accordingly strong evidence that wavelength plays an

important role in RAU treatment. Taking into account the

different parameters applied by selected RCTs, it is not

possible to suggest that a specific protocol should be used.

However, in light of the significant results found in both

studies, LLLT can be suggested as an alternative for RAU




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treatment. The authors concluded that additional RCTs should

be performed in order to reach a clinical protocol and better

understand the application of LLLT in RAU treatment.

In a systematic review, Ahmed and colleagues (2020)

compared LLLT with topical medications for the treatment of

aphthous ulcers. These investigators carried out a search of

articles in 6 databases. Treatment and comparative groups

comprised of patients subjected to laser therapy and topical

medications, respectively. Two different treatment outcomes

were considered; pain and size of the lesion. Risk of bias was

examined using the Revised Cochrane risk-of-bias tool for

randomized trials. From 109 articles, 5 RCTs fulfilled the

selection criteria. The overall sample comprised of 98 men

and 232 women, with a mean age of 32.4 years. The laser

therapies in each included study had different active media

and varying wavelengths. Topical medication used in the

comparative group were triamcinolone acetonide, amlexanox,

granofurin, and solcoseryl. Findings showed that patients who

reported lower pain and decreased aphthous ulcer lesions

were more in the laser therapy group than in the topical

medication group. The authors concluded that LLLT was

better in treating aphthous ulcer lesions in comparison to

topical medications; and all laser wavelengths in the included

reports were found to be effective. However, the results

should be interpreted with caution, because none of the

included studies demonstrated a low-risk of bias in all the

assessed domains.

The authors stated that the risk of bias assessment judgment

inferred that most of the studies did not describe how the

randomization process was performed. Furthermore, 4 out of

5 studies did not have a blinded investigator to evaluate the

outcome. Cochrane guidelines state that each step in the

methodology should be clearly explained to achieve a low-risk

score in the 5 domains of assessment; thus, further evidence

using robust methodologies is needed to validate the

effectiveness of laser therapy over other treatment




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approaches. In addition, RCTs should consider reporting the

potential side-effects that are experienced by the patients

while undergoing laser therapies and/or treatment by

medication. Finally, it is highly recommended that a general

clinical protocol be derived for the use of laser therapy in

treating aphthous ulcer lesions.

Bone Regeneration / Bone Healing

Atasoy and colleagues (2017) evaluated the effectiveness of

low-level 940 nm laser therapy with energy intensities of 5, 10

and 20 J/cm2 on bone healing in an animal model. A total of

48 female adult Wistar rats underwent surgery to create bone

defects in the right tibias. Low-level laser therapy was applied

immediately after surgery and on post-operative days 2, 4, 6,

8, 10 and 12 in 3 study groups with energy intensities of 5

J/cm2, 10 J/cm2 and 20 J/cm2 using a 940 nm Gallium-

Aluminum-Arsenide (Ga-Al-As) laser, while 1 control group

underwent only the tibia defect surgery. All animals were

sacrificed 4 or 8 weeks post-surgery. Fibroblasts, osteoblasts,

osteocytes, osteoclasts and newly formed vessels were

evaluated by a histological examination. No significant change

was observed in the number of osteocytes, osteoblasts,

osteoclasts and newly formed vessels at either time period

across all laser groups. Although LLLT with the 10 J/cm2

energy density increased fibroblast activity at the 4th week in

comparison with the 5 and 20 J/cm2 groups, no significant

change was observed between the laser groups and the

control group. The authors concluded that these findings

showed that low-level 940 nm laser with different energy

intensities may not have marked effects on the bone healing

process in both phases of bone formation.

In a systematic review, Skondra and colleagues (2018)

evaluated the evidence on the effects of LLLT on bone healing

following rapid maxillary expansion (RME). Electronic search

was performed in Medline, Scopus, and Embase databases

using appropriate Medical Subject Heading terms, with no time




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restriction. ClinicalTrials.gov ( www.clinicaltrials.gov ) was also

searched using the terms "low level laser therapy" and

"maxillary expansion". Original research articles on human

clinical trials that involved both RME and LLLT were included.

Animal studies were also assessed on an exploratory basis.

The search strategy resulted in 12 publications (4 RCTs, 8

animal studies). In human studies, bone density was

assessed radiographically (either 2-Dl or 3-D imaging).

Regardless of the discrepancies in the intervention protocols,

the total of the trials revealed that LLLT had stimulatory effects

on bone regeneration following RME. The studies in animal

models measured the formation and maturation of new bone

qualitatively or quantitatively. The authors concluded that

despite the limited evidence, LLLT appeared to be a promising

intervention for stimulating immediate bone regeneration and

healing following mid-palatal suture expansion. Moreover,

these researchers stated that long-term, RCTs are needed to

formulate safe results and establish a reliable clinical protocol,

rendering the method clinically applicable.

Carpal Tunnel Syndrome

Li and colleagues (2016) evaluated the effectiveness of LLLT

in the treatment of mild-to-moderate CTS using a Cochrane

systematic review. The authors concluded that the findings of

this study revealed that LLLT improved hand grip, VAS, and

SNAP after 3 months of follow-up for mild-to-moderate CTS.

However, they stated that more high-quality studies using the

same laser intervention protocol are needed to confirm the

effects of LLLT in the treatment of CTS.

Bekhet and associates (2017) performed a meta-analysis to

investigate the efficacy of LLLT in the management of mild-to-

moderate CTS. These investigators searched PubMed, Web

of Knowledge, Scopus, Cochrane Central, and Virtual Health

Library for RCTs that compared the effects of LLLT with or

without splinting versus placebo on functional and

electromyographic (EMG) outcomes in CTS. All outcomes



http://www.clinicaltrials.gov

http://ClinicalTrials.gov


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were pooled as mean differences (MD) under the inverse

variance or random effects model, using the statistical add-in

(MetaXL, version 5.0). A total of 8 RCTs (473 patients/631

wrists) were eligible for the final analysis. The overall effect

estimates did not favor LLLT therapy group over placebo in all

primary outcomes: VAS (MD -1.11, 95 % CI: -2.58 to 0.35),

symptom severity scale score (MD -1.41, 95 % CI: -5.12 to

2.29), and functional status scale score (MD -1.33, 95 % CI:

-3.27 to 0.61). However, LLLT was superior to placebo in

terms of grip strength (MD 2.19, 95 % CI: 1.63 to 2.76) and

inferior to placebo in terms of sensory nerve action potential

(MD -2.74, 95 % CI: -3.66 to -1.82]). The authors concluded

that laser therapy was superior to placebo in terms of

improving the grip strength; however, no significant difference

was found between both groups in terms of functional status

improvement, pain reduction, or motor electro-diagnostic

evaluations. They stated that further high-quality trials with

longer follow-up periods are needed to establish the efficacy of

LLLT for CTS treatment.

Temporomandibular Joint Disorders

Shukla and Muthusekhar (2016) evaluated the effectiveness of

LLLT in patients with temporomandibular disorders (TMDs).

Medline search was done from 1997 to 2011 using search

terms appropriate to establishing a relation between LLLT and

TMD. Only RCTs were included in this study. Outcome

variables related to pain, muscle tenderness, mandibular

movements, and EMG activity were considered. Of the 242

articles examined, 13 were finally included in the critical

analysis conducted as a part of the present systematic review;

7 articles showed significant improvement in the study group,

whereas 5 showed no significant improvement between the

study and control groups. The primary outcome of most of the

studies was pain. Other variables considered were muscle

tenderness, mandibular movements; EMG activity was

considered. The authors concluded that LLLT appeared to be

effective in reduction of pain in TMDs. The hypothesis that




5/26/2021

LLLT acts through a dose-specific anti-inflammatory effect in

the irradiated joint capsule is a possible explanation of the

positive results. However, due to the limitations of this review,

findings must be interpreted with caution. Moreover, they

stated that there is a need for more well-conducted RCTs

examining LLLT as interventions for TMDs. These studies

need to be clear in the reporting of allocation, blinding,

sequence generation, withdrawals, intention-to-treat analysis,

and any other potential source of bias in the study. In addition,

there should be use of well-validated standardized outcomes

so that the RCTs could be compared with other similar trials.

The sample size of the RCTs should also be calculated

beforehand so that the study has adequate statistical power.

Magri and colleagues (2017) noted that women with TMD

frequently report pain areas in body regions. This process is

associated with central sensitization phenomena, present in

chronic pain; LLLT has been reported as a therapeutic option

for the painful TMD treatment. These investigators analyzed

the effect of LLLT on pain intensity (VAS), pain sensitivity in

orofacial and corporal points (pressure pain threshold, PPT),

and on Short Form-McGill Pain Questionnaire (SF-MPQ)

indexes of women with myofascial pain (subtype of muscle

TMD). A total of 91 women (18 to 60 years) were included in

the study, among which 61 were diagnosed with myofascial

pain (Research Diagnostic Criteria for Temporomandibular

Disorder-Ia and Ib) and were divided into laser (n = 31) and

placebo group (n = 30), and 30 were controls; LLLT was

applied at pre-established points, twice-weekly, 8 sessions

(780 nm; masseter and anterior temporal = 5 J/cm2, 20 mW,

10 s; TMJ area = 7.5 J/cm2, 30 mW, 10 s). Pain intensity, pain

sensitivity, and the SF-MPQ indexes were measured at the

baseline, during laser sessions, and 30 days after treatment.

For intra-group comparisons, the Friedman test was

performed, and for inter-group, the Mann-Whitney test.

Increased pain sensitivity was found in women with

myofascial pain when compared to controls (p < 0.05). There

was a reduction in pain intensity for both groups after LLLT.




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However, LLLT did not change the PPT for any group (p >

0.05). Active laser and placebo reduced the indexes of

sensory, total pain, and VAS, maintaining the results after 30

days; there was a reduction in the affective pain rating index

for both groups, with no maintenance after 30 days for

placebo, and the present pain intensity decreased in the laser

group and did not change in the placebo after LLLT. The

authors concluded that LLLT active or placebo were effective

in reducing the overall subjective perception of myofascial pain

(VAS and SF-MPQ indexes); however, they had no

effectiveness in reducing the pain sensitivity in orofacial and

corporal points (PPT increase).

Neuropathic Orofacial Pain (e.g., Burning Mouth Syndrome, Occipital Neuralgia, and Trigeminal Neuralgia)

Arbabi-Kalati and colleagues (2015) evaluated the

effectiveness of LLLT in improving the symptoms of burning

mouth syndrome (BMS). A total of20 patients with BMS were

enrolled in this study; they were divided in 2 groups randomly.

In the laser group, in each patient, 10 areas on the oral

mucosa were selected and underwent LLL irradiation at a

wavelength of 630 nm, and a power of 30 mW for 10 seconds

twice-weekly for 4 weeks. I n the placebo group, silent/off laser

therapy was carried out during the same period in the same

areas. Burning sensation and quality of life were evaluated.

Burning sensation severity and quality of life in the 2 groups

after intervention were different significant (p = 0.004, p = 0.01,

respectively). Patients in laser group had better results. The

authors concluded that LLLT might decrease the intensity of

BMS. However, the present study had some limitations,

including the small sample size and long duration of the

application of LLL, which decreases the cooperation of

patients. These researchers stated that further research is

needed to validate our findings.




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Al-Maweri and colleagues (2017) stated that BMS is a chronic

pain condition with indefinite cure, predominantly affecting

post-menopausal women. These researchers reviewed the

effectiveness of LLLT in the treatment of BMS. PubMed,

Embase and Scopus were searched from date of inception till

and including October 2016 using various combinations of the

following keywords: burning mouth syndrome, BMS,

stomatodynia, laser therapy, laser treatment and

phototherapy. The inclusion criteria were: prospective,

retrospective and case series studies. Letter to editors,

reviews, experimental studies, studies that were not published

in English, theses, monographs, and abstracts presented in

scientific events were excluded. Due to heterogeneity of data

no statistical analyses were performed. A total of 10 clinical

studies fulfilled the eligibility criteria, 5 of which were

randomized clinical trials. In these studies, the laser

wavelengths, power output and duration of irradiation ranged

between 630 to 980 nm, 20 to 300 mW, 10 seconds to

15minutes, respectively. Most of studies reported laser to be

an effective therapy strategy for management of BMS. The

authors concluded that the majority of the studies showed that

laser therapy seemed to be effective in reducing pain in BMS

patients. However, they stated that due to the varied

methodologies and substantial variations in laser parameters

among these studies, more clinical trials are needed to

determine the effectiveness of laser for treating BMS.

In a systematic review, de Pedro and colleagues (2020)

examined the efficacy of LLLT for the management of

neuropathic orofacial pain. This systematic review was

conducted according to PRISMA guidelines. A comprehensive

search of the literature was conducted in the PubMed/Medline,

Scopus, and Cochrane Library databases up to March 8,

2018, using terms such as low-level laser therapy, neuropathic

pain, orofacial pain, neuralgia, neuropathy, and all the entities

described in section 13 of the International Classification of

Headache Disorders, 3rd edition. The primary outcome was

measurement of pain intensity. A total of 997 studies were




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obtained with the initial search; 13 (8 RCTs, 2 prospective

studies, and 3 case series) met the inclusion criteria and were

analyzed for data extraction; 3 provided data for the treatment

of trigeminal neuralgia (TN), 1 for occipital neuralgia, and 10

for BMS. All studies showed a reduction in pain intensity

(most of them significant). The different studies analyzed

LLLT alone and compared to placebo, to another treatment, or

to different LLLT application protocols. The authors concluded

that LLLT appeared to be effective as a therapeutic option for

different neuropathic orofacial pain entities such as TN,

occipital neuralgia, and BMS as a single or combined

treatment. Moreover, these researchers stated that more

quality studies assessing all outcome measures of chronic

pain are needed in the medium- and long-terms. Furthermore,

due to the lack of standardization of the application technique,

more well-designed studies are needed to confirm the results

of this systematic review.

Cardio-Protection Following Myocardial Infarction / Heart Failure

Carlos and colleagues (2016) systematically reviewed the role

of LLLT in cardiac remodeling after myocardial infarction (MI).

Literatures were systematically searched in several electronic

databases. These researchers included only studies with a

well-standardized coronary occlusion model in-vivo LLLT

application. After screening, a total of 14 studies were eligible

for review. The study heterogeneity was described in terms of

rationality, gender, irradiation parameters, treatment numbers

and moment of LLLT application; 3 studies showed a null role

of LLLT on infarct size, and only 1 study found positive LLLT

effects on the cardiac performance. The cardio-protective role

of LLLT was mediated by anti-inflammatory, pro-angiogenic

and anti-oxidant actions. The authors concluded that the

reduction in infarct size was a major finding. The stated that

LLLT cardio-protection may be mediated by several molecular




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and cellular mechanisms; although these results are exciting,

there are many limitations that must be resolved before LLLT

clinical trials.

Manchini and associates (2017) noted that LLLT has been

targeted as a promising approach that can mitigate post-

infarction cardiac remodeling. There is some interesting

evidence showing that the beneficial role of the LLLT could

persist long-term even after the end of the application, but it

remains to be systematically evaluated. These researchers

tested the hypothesis that LLLT beneficial effects in the early

post-infarction cardiac remodeling could remain in overt heart

failure (HF) even with the disruption of irradiations. Female

Wistar rats were subjected to the coronary occlusion to induce

MI or sham operation. A single LLLT application was carried

out after 60 seconds and 3 days post-coronary occlusion,

respectively. Echocardiography was performed 3 days and at

the end of the experiment (5 weeks) to evaluate cardiac

function. After the last echocardiographic examination, LV

hemodynamic evaluation was performed at baseline and on

sudden afterload increases. Compared with the sham group,

infarcted rats showed increased systolic and diastolic internal

diameter as well as a depressed shortening fraction of LV.

The only benefit of the LLLT was a higher shortening fraction

after 3 days of infarction. However, treated-LLLT rats showed

a lower shortening fraction in the 5th week of study when

compared with sham and non-irradiated rats. A worsening of

cardiac function was confirmed in the hemodynamic analysis

as evidenced by the higher left ventricular end-diastolic

pressure and lower +dP/dt and -dP/dt with 5 weeks of study.

Cardiac functional reserve was also impaired by infarction as

evidenced by an attenuated response of stroke work index and

cardiac output to a sudden afterload stress, without LLLT

repercussions. No significant differences were found in the

myocardial expression of Akt1/VEGF pathway. The authors

concluded that these findings showed that LLLT improved LV

systolic function in the early post-infarction cardiac remodeling;

however, this beneficial effect may be dependent on the




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maintenance of phototherapy. They stated that long-term

studies with LLLT application are needed to establish whether

these effects ultimately translate into improved cardiac

remodeling.

Hair Loss

Zarei and colleagues (2016) noted that despite the current

treatment options for different types of alopecia, there is a

need for more effective management options. Recently, LLLT

was evaluated for stimulating hair growth. These investigators

reviewed the current evidence on the LLLT effects with an

evidence-based approach, focusing more on RCTs by critically

evaluating them. In order to examine if in individuals

presenting with hair loss (male pattern hair loss (MPHL),

female pattern hair loss (FPHL), alopecia areata (AA), and

chemotherapy-induced alopecia (CIA)) LLLT is effective for

hair re-growth, several databases including PubMed, Google

Scholar, Medline, Embase, and Cochrane Database were

searched using the following keywords: alopecia, hair loss,

Hair growth, low level laser therapy, low level light therapy, low

energy laser irradiation, and photobiomodulation (PBM). From

the searches, 21 relevant studies were summarized in this

review including 2 in-vitro, 7 animal, and 12 clinical studies.

Among clinical studies, only 5 were RCTs, which evaluated

LLLT effect on male and female pattern hair loss. The RCTs

were critically appraised using the created checklist according

to the Critical Appraisal for Therapy Articles Worksheet

created by the Center of Evidence-Based Medicine, Oxford.

The results demonstrated that all the performed RCTs have

moderate to high quality of evidence. However, only 1 out of 5

studies performed intention-to-treat analysis, and only another

study reported the method of randomization and subsequent

concealment of allocation clearly; all other studies did not

include this very important information in their reports. None of

these studies reported the treatment effect of factors such as

number needed to treat. Based on this review on all the

available evidence about effect of LLLT in alopecia, these




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researchers found that the FDA-cleared LLLT devices are both

safe and effective in patients with MPHL and FPHL who did

not respond or were not tolerant to standard treatments. The

authors concluded that future RCTs of LLLT are strongly

encouraged to be conducted and reported according to the

Consolidated Standards of Reporting Trials (CONSORT)

statement to facilitate analysis and comparison.

In a Cochrane review, van Zuuren and associates (2016)

evaluated the safety and effectiveness of the available options

for the treatment of female pattern hair loss in women. These

investigators updated their searches of the following

databases to July 2015: the Cochrane Skin Group Specialized

Register, CENTRAL in the Cochrane Library (2015, Issue 6),

Medline(from 1946), Embase (from 1974), PsycINFO (from

1872), AMED (from 1985), LILACS (from 1982), PubMed (from

1947), and Web of Science (from 1945). They also searched

5 trial registries and checked the reference lists of included

and excluded studies. They included RCTs that assessed the

effectiveness of interventions for FPHL in women; 2 review

authors independently assessed trial quality, extracted data

and carried out analyses. The authors concluded that

although there was a predominance of included studies at

unclear to high risk of bias, there was evidence to support the

safety and effectiveness of topical minoxidil in the treatment of

FPHL (mainly moderate-to-low quality evidence).

Furthermore, there was no difference in effect between the

minoxidil 2 % and 5 % with the quality of evidence rated

moderate-to-low for most outcomes. Finasteride was no more

effective than placebo (low quality evidence). They stated that

there were inconsistent results in the studies that evaluated

laser devices (moderate-to-low quality evidence), but there

was an improvement in total hair count measured from

baseline. These investigators stated that further RCTs of other

widely-used treatments, such as spironolactone, finasteride

(different dosages), dutasteride, cyproterone acetate, and laser-

based therapy are needed.




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Gupta and Foley (2017) consolidated evidence and

established which data are still required for the widespread

acceptance of LLLT for hair loss therapy. A thorough search

of the PubMed database was conducted to obtain studies

investigating LLLT for andro-genetic alopecia (AGA) in men

and women. A total of 9 trials were identified for comb and

helmet/cap devices, 5 of which were RCTs. Data comparison

across LLLT trials and with traditional hair loss therapy

(minoxidil, finasteride) was not straight forward because there

was a lack of visual evidence, sample sizes were low, and

there were large variations in study duration and effectiveness

measurements. The authors concluded that there are a

number of unanswered questions about the optimum

treatment regimen, including maintenance treatment and the

long-term consequences of LLLT use. They stated that

moving forward, protocols should be standardized across

trials; and it is recommended that future trials include visual

evidence and trial duration be expanded to 12 months.

Afifi and co-workers (2017) reviewed the existing research

studies to examine if LLLT is an effective therapy for AGA

based on objective measurements and patient satisfaction.

These researchers performed a systematic literature review to

identify articles on Medline, Google Scholar, and Embase that

were published between January 1960 and November 2015.

All search hits were screened by 2 reviewers and examined for

relevant abstracts and titles. Articles were divided based on

study design and assessed for risk of bias. A total of 11

studies were evaluated, which investigated a total of 680

patients, consisting of 444 males and 236 females; 9 out of 11

studies assessing hair count/hair density found statistically

significant improvements in both males and females following

LLLT treatment. Additionally, hair thickness and tensile

strength significantly improved in 2 out of 4 studies. Patient

satisfaction was investigated in 5 studies, and was overall

positive, though not as profound as the objective outcomes.

The authors concluded that the majority of studies covered in

this review found an overall improvement in hair re-growth,




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thickness, and patient satisfaction following LLLT therapy.

They stated that although caution is needed when interpreting

these findings, LLLT therapy appeared to be a promising

monotherapy for AGA and may serve as an effective

alternative for individuals unwilling to use medical therapy or

undergo surgical options.

Darwin and colleagues (2018) examined the clinical trials to

determine whether the body of evidence supports the use of

low-level laser therapy (LLLT) to treat androgenic alopecia

(AGA). A literature search was conducted through PubMed,

Embase, and Clinicaltrials.gov for clinical trials using LLLT to

treat AGA. Thirteen clinical trials were assessed. Review

articles were not included. Ten of 11 trials demonstrated

significant improvement of androgenic alopecia in comparison

to baseline or controls when treated with LLLT. In the

remaining study, improvement in hair counts and hair diameter

was recorded, but did not reach statistical significance. Two

trials did not include statistical analysis, but showed marked

improvement by hair count or by photographic evidence. Two

trials showed efficacy for LLLT in combination with topical

minoxidil. One trial showed efficacy when accompanying

finasteride treatment. LLLT appears to be a safe, alternative

treatment for patients with androgenic alopecia. Clinical trials

have indicated efficacy for androgenic alopecia in both men

and women. It may be used independently or as an adjuvant

of minoxidil or finasteride. More research needs to be

undertaken to determine the optimal power and wavelength to

use in LLLT as well as LLLT's mechanism of action.

Delaney and Zhang (2018) stated that alopecia is a common

disorder affecting over 50 % of the world's population. Within

this condition, androgenic alopecia (AA) is the most common

type, affecting 50 % of men over 40 years of age and 75 % of

women over 65. Anecdotal paradoxical hypertrichosis noted

during laser epilation has generated interest in the possibility

of using laser to stimulate hair growth. These investigators

evaluated the application of LLLT for the treatment of AA in



http://Clinicaltrials.gov


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adults. They carried out a systematic review on studies

identified on Medline, Embase, Cochrane database, and

clinicaltrials.org. Double-blinded RCTs were selected and

analyzed quantitatively (meta-analysis) and qualitatively

(quality of evidence, risk of bias). The authors concluded that

LLLT appeared to be a promising non-invasive treatment for

AA in adults that is safe for self-administration in the home-

setting. These researchers stated that although shown to

effectively stimulate hair growth when compared to sham

devices, these results must be interpreted with caution. They

stated that further studies with larger samples, longer follow-

up, and independent funding sources are needed to determine

the clinical effectiveness of this novel therapy.

Liu and colleagues (2019) examined the effectiveness of LLLT

in the treatment of adult AA (AAA). A systematic search of

studies on LLLT for AAA was conducted mainly in PubMed,

Embase, and Cochrane Systematic Reviews. The SMD in the

changes of hair density treated by LLLT versus sham devices

was analyzed. The meta-analysis included 8 studies

comprising a total of 11 double-blinded RCTs. The

quantitative analysis showed a significant increase in hair

density for those treated by LLLT versus sham group (SMD

1.316, 95 % CI: 0.993 to 1.639) . The subgroup analysis

demonstrated that LLLT increased hair growth in both

genders, in both comb- and helmet-type devices, and in short-

and long-term treatment course. The subgroup analysis also

showed a more significant increase of hair growth for the LLLT

versus sham in the low-frequency treatment group (SMD

1.555, 95 % CI: 1.132 to 1.978) than in the high-frequency

group (SMD 0.949, 95 % CI: 0.644 to 1.253). The review was

limited by the heterogeneity of included trials; LLLT

significantly increased hair density in AAA. The authors

concluded that the findings of this meta-analysis suggested

that low treatment frequency by LLLT had a better hair growth

effect than high treatment frequency. They stated that LLLT

represents a potentially effective treatment for AAA in both

male and female.



http://Clinicaltrials.org


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Marchitto and colleagues (2019) noted that alopecia areata

(AA) is a common form of patchy, non-scarring hair loss.

Although intralesional steroid injections are currently the

mainstay therapy for AA, other non-steroid-based therapies,

including platelet-rich plasma (PRP), ultra-violet radiation

(UVR), and laser-based modalities, are emerging as

management options. These researchers systematically

reviewed non-steroid-based therapies for the treatment of AA.

They carried out a systematic review of the literature searching

PubMed/Medline databases identifying studies examining

PRP, UVR, and laser-based modalities for the treatment of

AA. Literature search yielded 644 articles entailing PRP, UVR,

and laser treatment modalities for AA. Of the 644 articles, 46

met inclusion criteria. Although numerous reports

demonstrated strong potential for PRP, UVR, and laser

modalities in treating AA, high-quality evidence supporting

their efficacy is still lacking. The authors concluded that there

is an abundance of evidence for non-steroid-based therapies

in the treatment of AA. Moreover, these researchers stated

that RCTs comparing these therapeutic options head-to-head

should be conducted to better understand the true

effectiveness of these therapies.

Head and Neck Cancer

Zecha and colleagues (2016) noted that recent advances in

PBM technology, together with a better understanding of

mechanisms involved, may expand the applications for PBM in

the management of other complications associated with head

and neck cancer (HNC) treatment. This article (part 1)

described PBM mechanisms of action, dosimetry, and safety

aspects and, in doing so, provided a basis for a companion

paper (part 2), which described the potential breadth of

potential applications of PBM in the management of side-

effects of (chemo)radiation therapy in patients being treated

for HNC and proposed PBM parameters. These investigators

reviewed PBM mechanisms of action and dosimetric

considerations. Virtually, all conditions modulated by PBM




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(e.g., ulceration, inflammation, lymphedema, pain, fibrosis,

neurological and muscular injury) are thought to be involved in

the pathogenesis of (chemo)radiation therapy-induced

complications in patients treated for HNC. The impact of PBM

on tumor behavior and tumor response to treatment has been

insufficiently studied. In-vitro studies assessing the effect of

PBM on tumor cells report conflicting results, perhaps

attributable to inconsistencies of PBM power and dose.

However, the biological bases for the broad clinical activities

ascribed to PBM have also been noted to be similar to those

activities and pathways associated with negative tumor

behaviors and impeded response to treatment. While there

are no anecdotal descriptions of poor tumor outcomes in

patients treated with PBM, confirming its neutrality with respect

to cancer responsiveness is a critical priority. The authors

concluded that based on its therapeutic effects, PBM may

have utility in a broad range of oral, oropharyngeal, facial, and

neck complications of HNC treatment. They stated that

although evidence suggested that PBM using LLLT is safe in

HNC patients, more research is imperative and vigilance

remains warranted to detect any potential adverse effects of

PBM on cancer treatment outcomes and survival.

Furthermore, National Comprehensive Cancer Network’s

clinical practice guideline on “Head and neck cancers

“ (Version 1.2017) does not mention LLLT as a management

option.

Neuropathic Pain

de Andrade and colleagues (2016) reviewed the literature on

the use of LLLT in neuropathic pain with the goal of

establishing a "therapeutic window" for the effective use of this

treatment. These researchers analyzed 14 articles, 10 in

experimental animals and 4 in humans. The results were

presented in 3 tables, the first being for comparison of the

studies' application parameters, the second showing the

average and median parameters experimental studies and




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third showing the clinical studies embodiment. The

experimental studies revealed better results for LLLT and

infrared laser powers above 70 mW. Clinical studies were

inconclusive as to the application parameters, due to the

discrepancy; however all demonstrated the effectiveness of

LLLT. According to the data presented, the authors concluded

that LLLT had positive effects on the control of analgesia for

neuropathic pain, but further studies with high scientific rigor

are needed in order to define treatment protocols that optimize

the action LLLT in neuropathic pain.

Oral Mucositis

Bayer and colleagues (2017) stated that oral mucositis (OM)

induces severe pain and limits fundamental life behaviors such

as eating, drinking, and talking for patients receiving

chemotherapy or radiotherapy. In addition, through

opportunistic microorganisms, OM frequently leads to systemic

infection, which then leads to prolonged hospitalization.

Severe lesions often adversely affect curative effects in

cancer cases. Thus, the control of OM is important for oral

health quality of life and prognosis. Low-level laser therapy

and ozone may be useful to accelerate wound healing. In this

study, 24 Sprague-Dawley rats were divided into 3 groups: (i)

control, (ii) ozone, and (iii) laser groups. All groups received

5-fluorouracil intra-peritoneally and trauma to the mouth pouch

with a needle. After the formation of OM in the mouth, the

control group had no treatment; the ozone group was

administered ozone, and the laser group, LLLT. Then, all

groups were sacrificed and basic fibroblast growth factor

(bFGF), transforming growth factor (TGF-β), and platelet-

derived growth factor (PDGF) were evaluated in all groups;

LLLT was found to be statistically significantly more effective

than ozone on FGF and PDGF. However, in respect of

TGF-β, no statistically significant difference was observed

between the groups. The authors concluded that within the

limitations of this study, LLLT was more effective than ozone;

however, further studies on this subject are needed.




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de Lima et al (2020) reported on a systematic review and

meta-analysis to determine the effectiveness of low-level laser

therapy in preventing oral mucositis in patients undergoing

chemoradiotherapy for head and neck cancer. The following

databases were searched through September 2018, with last

search performed on May 2019, for clinical trials: MEDLINE via

PubMed, Cochrane Central, Scopus, Lilacs, ISI Web of

Science and SIGLE via Open Grey. From 14,525 records, 4

studies were included in the review and 3 studies were

included in meta-analysis. Data from 500 patients (mean age

of 53.595 and 54.14 for intervention and control groups,

respectively) were analyzed. Meta-analysis showed that laser

therapy prevents oral mucositis incidence in 28% and 23% of

cases during the third and fourth follow-up week, respectively,

in comparison to a placebo-treated control group. There was

no statistically significant difference the prevention of pain;

dysphagia and quality of life were not analyzed due to missing

data. The authors concluded that laser therapy was effective in

preventing oral mucositis from the 15th to the 45th days of

chemoradiotherapy. However, new primary studies with low

risk of bias are needed so a higher scientific evidence can be

obtained.

Peralta-Mamani and colleagues (2019) noted that dosimetry

for LLLT depends on several parameters, such as target tissue

type, lesion type and laser equipment used. These

researchers determined the most used LLLT dosimetry for the

treatment and prevention of OM resulting from radiation

therapy (RT) in head and neck cancer patients (HNCP). This

research was conducted according to the PRISMA guidelines

using the PICO framework. After extensively searching

PubMed, Web of Science, Embase, Scopus, BVS and

Cochrane Library databases, these investigators found 130

records and selected 7 studies, involving 363 HNCP with an

average age of 60.6 years who received RT. Briefly, sites

affected by tumors were the following: oral cavity (n = 170),

oropharynx (n = 91), throat (n = 42), larynx (n = 32),




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nasopharynx (n = 11), hypopharynx (n = 9), and in 8 cases,

sites were not reported. These studies used several

classifications for OM (RTOG/EORTC, WHO, NCI-CTC) and

pain (numeric rating scale [NRS], VAS and modified VAS).

These various researchers performed the LLLT punctual

application of different forms using several protocols making

analysis difficult. However, LLLT was effective regardless of

the parameters used (632.8 nm to 685 nm, 1.8 J/cm2 to 3.0

J/cm2, 10 mW to 60 Mw, 0.8 J to 3.0 J). The meta-analysis

showed a better results with preventive LLLT 660 nm, 3.8

J/cm2, 15 mW; 0.15 J compared to preventive LLLT 660 nm,

1.3 J/cm2, 5 mW; 0.05 J (OMS: p = 0.03; NCI-CTC: p = 0.027).

The authors concluded that there is, as of yet, no evidence of

better laser dosimetry being more effective; RCTs to determine

which doses of LLLT are most appropriate for treating and

preventing OM due to RT are lacking and should be further

investigated.

Pressure Ulcers

Machado and colleagues (2017) evaluated the effects of LLT

in pressure ulcers (PU) in humans through a systematic review

of randomized studies. The search includes the databases

Medline, PEDro, Cochrane CENTRAL, and Lilacs, as well a

manual search until May, 2016. This included randomized

clinical trials of LLT compared with other interventions,

different types of LLT, LLT placebo, or control in the treatment

of PU. The outcomes evaluated were the ulcer area, healing

rate, and overall healing rate. The risk of bias was evaluated

using the tool of the Cochrane Collaboration, and the results

were analyzed descriptively. From the 386 articles identified,

only 4 studies were included, with 2 LLT used with single

wavelength (1: 904 nm versus control and 2: 940 nm versus

808 nm versus 658 nm versus placebo) and 2 LLT used to

probe cluster. One study compared to different single

wavelengths showed a significant 71 % reduction of the PU

and an improved healing rate in which 47 % of PU healed

completely after 1 month of therapy with the use of LLT with a




5/26/2021

wavelength of 658 nm compared with other lengths. The other

analyzed wavelengths were not significant in the assessed

outcomes. Significant results were observed in the use of LLT

with a 658 nm wavelength, and no evidence was found for use

of wavelengths above that for the treatment of PU. The

authors also found no evidence in the laser used to probe the

cluster.

Furthermore, an UpToDate review on “Overview of treatment

of chronic wounds” (Evans and Kim, 2017) does not mention

LLLT as a therapeutic option.

Traumatic Brain Injury

Thunshelle and Hamblin (2016) LLLT or PBM is a possible

treatment for brain injury, including traumatic brain injury

(TBI). These investigators reviewed the fundamental

mechanisms at the cellular and molecular level and the effects

on the brain were discussed. There are several contributing

processes that have been proposed to lead to the beneficial

effects of PBM in treating TBI such as stimulation of

neurogenesis, a decrease in inflammation, and

neuroprotection. Both animal and clinical trials for ischemic

stroke were outlined. A number of articles have shown how

transcranial LLLT (tLLLT) is effective at increasing memory,

learning, and the overall neurological performance in rodent

models with TBI. The authors’ laboratory has conducted 3

different studies on the effects of tLLLT on mice with TBI. The

1st studied pulsed against continuous laser irradiation, finding

that 10 Hz pulsed was the best. The 2nd compared 4 different

wavelengths, discovering only 660 and 810 nm to have any

effectiveness, whereas 732 and 980 nm did not. The 3rd

looked at varying regimens of daily laser treatments (1, 3, and

14 days) and found that 14 laser applications was excessive.

The authors also reviewed several studies of the effects of

tLLLT on neuroprogenitor cells, brain-derived neurotrophic




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factor and synaptogenesis, immediate early response

knockout mice, and tLLLT in combination therapy with

metabolic inhibitors.

Furthermore, an UpToDate review on “Management of acute

severe traumatic brain injury” (Hemphill and Phan, 2017) does

not mention LLLT as a therapeutic option.

Breast Cancer-Related Lymphedema

In a systematic review, Baxter and associates (2017)

evaluated the effectiveness of LLLT (also known as

photobiomodulation (PBM)) in the management of breast

cancer related lymphedema (BCRL). Clinical trials were

searched in PubMed, AMED, Web of Science, and China

National Knowledge Infrastructure up to November 2016; 2

reviewers independently assessed the methodological quality

and adequacy of LLLT in these clinical trials. Primary outcome

measures were limb circumference/volume, and secondary

outcomes included pain intensity and ROM. Because data

were clinically heterogeneous, best evidence synthesis was

performed. A total of 11 clinical trials were identified, of which

7 RCTs were chosen for analysis. Overall, the methodological

quality of included RCTs was high, whereas the reporting of

treatment parameters was poor. Results indicated that there

was strong evidence (3 high quality trials) showing LLLT was

more effective than sham treatment for limb

circumference/volume reduction at a short-term follow-up.

There was moderate evidence (1 high quality trial) indicating

that LLLT was more effective than sham laser for short-term

pain relief, and limited evidence (1 low quality trial) that LLLT

was more effective than no treatment for decreasing limb

swelling at short-term follow-up. The authors concluded that

based upon the current systematic review, LLLT may be

considered an effective treatment approach for women with

BCRL. However, they stated that due to the limited numbers




5/26/2021

of published trials available, there is a clear need for well-

designed high-quality trials in this area. The optimal treatment

parameters for clinical application have yet to be elucidated.

Obesity

Silva and colleagues (2018) noted that obesity represents a

continuously growing global epidemic and is associated with

the development of type 2 diabetes mellitus (T2DM). The

etiology of T2DM is related to the resistance of insulin-

sensitive tissues to its action leading to impaired blood glucose

regulation. Photobiomodulation therapy might be a non-

pharmacological, non-invasive strategy to improve insulin

resistance. It has been reported that PBM therapy in

combination with physical exercise reduces insulin resistance.

These researchers examined the effects of PBM therapy on

insulin resistance in obese mice. Male Swiss albino mice

received low-fat control diet (n = 16, LFC) or high-fat diet (n =

18, HFD) for 12 weeks. From 9th to 12th week, the mice

received PBM therapy (laser) or sham (light-off) treatment and

were allocated into 4 groups: LFC sham (n = 8), LFC PBM (n =

8), HFD sham (n = 9), and HFD PBM (n = 9). The PBM

therapy was applied in 5 locations: to the left and right

quadriceps muscle, upper limbs and center of the abdomen,

during 40 s at each point, once-daily, 5 days a week, for 4

weeks (780 nm, 250 mW/cm2, 10 J/cm2, 0.4 J per site; 2 J

total dose per day). Insulin signaling pathway was evaluated

in the epididymal adipose tissue. PBM therapy improved

glucose tolerance and phosphorylation of Akt (Ser473) and

reversed the HFD-induced reduction of GLUT4 content and

phosphorylation of AS160 (Ser588). Also, PBM therapy

reversed the increased area of epididymal and mesenteric

adipocytes. The authors concluded that these findings

showed that chronic PBM therapy improved parameters

related to obesity and insulin resistance in HFD-induced

obesity in mice.



Oral Lichen Planus


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Al-Maweri and co-workers (2017) stated that oral lichen planus

(OLP) is a chronic inflammatory disease of unknown etiology

and indefinite cure. In a systematic review, thee investigators

assessed the efficacy LLLT in the treatment of symptomatic

OLP. Electronic databases (PubMed, Scopus, and Web of

Science) were searched from date of inception till and

including December 2016, using various combinations of the

following keywords: oral lichen planus, laser therapy, low-level

laser therapy, and phototherapy. Owing to heterogeneity of

data, no statistical analyses were conducted. Initially, 227

publications were identified. After selection, only 6 studies

were included in this systematic review. In these studies, the

laser wavelengths, power output, and duration of irradiation

ranged between 630 to 980 nm, 20 to 300 mW, and 10 s to 15

min, respectively. All of the included studies found laser to be

effective in management of OLP, without any reported adverse

effects. The authors concluded that the results of the included

studies confirmed that LLLT was effective in management of

symptomatic OLP and could be used as an alternative to

corticosteroids. However, they stated that due to variety of

methods and substantial variations in laser parameters among

these studies, more RCTs with large sample sizes are needed.

In a systematic review, Akram and colleagues (2018)

evaluated the efficacy of LLLT, in comparison with

corticosteroid therapy, in the treatment of OLP. This

systematic review aimed to address the following focused

question: "Does LLLT yield better clinical outcomes than

corticosteroid therapy in the treatment of OLP"? Indexed

databases were searched up to and including April 2017.

Clinical trials in humans diagnosed clinically and/or

histologically with OLP allocated to test (LLLT) versus control

(steroid therapy) groups were included. A total of 5 clinical

studies were included. The risk of bias was considered high in

4 studies and moderate in 1 study. Laser wavelengths, power,

spot size, and duration of laser exposure ranged between 630




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and 970 nm, 10 to 3,000 mW, 0.2 to 1.0 cm2 , and 6 to 480

seconds, respectively. The follow-up period ranged from 4 to

48 weeks. All included studies reporting clinical scores

showed that LLLT was effective in the treatment of OLP in

adult patients at follow-up; 3 studies showed significantly

higher improvements with topical use of corticosteroids

compared to LLLT, while 1 study showed significant

improvement with LLLT; 1 study showed comparable

outcomes between LLLT and corticosteroid application. The

authors concluded that it remained debatable whether LLLT is

more effective as compared to corticosteroids in the treatment

of OLP, given that the scientific evidence was weak.

Moreover, they stated that these findings were preliminary

and further RCTs are recommended.

Pemphigus Vulgaris

Yousef and associates (2017) stated that pemphigus vulgaris

is a chronic blistering skin disease. Management of

recalcitrant pemphigus ulcers is a great problem; LLLT is

known to supply direct bio-stimulative light energy to body

cells. In a pilot study, these investigators evaluated the

efficacy of low power laser in the healing of pemphigus

lesions. A total of 10 patients with pemphigus vulgaris were

enrolled in the trial. The LED-LLLT system used was the Thor

LED clusters (109, 69 or 19 diode) with 660-nm wavelength in

continuous wave (CW) and 30 mW energy. Both sides of the

patients' lesion were photographed prior to the study and in

each laser therapy session. The pattern of changes in

qualitative wound score (QWS) patterns differed significantly

over time between the 2 therapies (treatment × time

interactions, p < 0.0001). When compared to the routine

therapy, the laser therapy showed more decrease in mean

QWS in all sessions in comparison with baseline. The authors

concluded that application of LLLT simultaneously with

conventional therapy could result in sensational healing of

ulcers especially in patients who did not respond to

conventional treatment or suffering from recalcitrant lesions.




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Moreover, they stated that since this was a pilot study with a

small sample size (n = 10), it is suggested that further

research be performed. In order to determine the real efficacy

of LLLT (the optimal set of laser irradiation parameters and

well-defined duration and frequency of intervals), further

carefully designed long-term clinical trials with a larger sample

size (possibly international) are needed as well as prolonged

follow-up period.

Diabetic Foot Ulcers

Beckmann et al (2014) stated that diabetic foot ulcers (DFUs)

are one of the most common complications of diabetes

mellitus are defined as non-healing or long-lasting chronic skin

ulcers in diabetic patients. Multi-disciplinary care for the

diabetic foot is common, but treatment results are often

unsatisfactory. Low level laser therapy on wound areas as

well as on acupuncture points, as a non-invasive, pain-free

method with minor side effects, has been considered as a

possible treatment option for the diabetic foot syndrome. A

systematic literature review identified 1,764 articles on this

topic. These researchers adopted 22 eligible references; 8 of

them were cell studies, 6 were animal studies, and 8 were

clinical trials. Cell studies and animal studies gave evidence

of cellular migration, viability, and proliferation of fibroblast

cells, quicker re-epithelization and reformed connective tissue,

enhancement of microcirculation, and anti-inflammatory effects

by inhibition of prostaglandins, interleukin, and cytokine as well

as direct anti-bacterial effects by induction of reactive oxygen

species (ROS). The transferal of these data into clinical

medicine is under debate. The majority of clinical studies

showed a potential benefit of LLLT in wound healing of

diabetic ulcers. But there are a lot of aspects in these studies

limiting final evidence about the actual output of this kind of

treatment method. The authors concluded that all studies

gave enough evidence to continue research on laser therapy

for diabetic ulcers, but clinical trials using human models do

not provide sufficient evidence to establish the usefulness of




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LLLT as an effective tool in wound care regimes at present.

They stated that further well-designed studies are needed to

determine the true value of LLLT in routine wound care.

In a systematic review and meta-analysis, Li and colleagues

(2018) examined if LLLT is effective at healing DFU and

provided evidence-based recommendations and clinical

guidelines for the future clinical treatment of DFUs. Medline,

Embase, Scopus, Cochrane Library, and Web of Science

databases were searched for studies published up to June 30,

2017, without language or data restrictions; RCTs that

examined the use of LLLT for DFU treatment were included.

Standard methods of meta-analysis were performed to

evaluate outcomes of LLLT on the healing of DFU. A total of 7

RCTs involving 194 participants were eligible for this

systematic review and meta-analysis. The results of meta-

analysis showed that LLLT has emerged as a potential non-

invasive treatment for DFUs, as LLLT was found to effectively

reduce the ulcer area [weighted MD (WMD) 34.18, 95 % CI:

19.38 to 48.99, p < 0.00001], improve the complete healing

rate [odds ratio (OR) 6.72, 95 % CI: 1.99 to 22.64, p = 0.002].

Qualitative analysis of the included RCTs found that LLLT

also played a role in the treatment of DFUs through promoting

rapid granulation formation and shortening ulcer closure time,

as well as alleviating foot ulcer pain. None of the treatment-

related adverse event (AE) was reported. The authors

concluded that LLLT was recognized as a potential method in

the comprehensive treatment of DFUs. These researchers

stated that further well designed and high-quality studies are

needed to confirm the role of LLLT in the management of

DFUs.

Dos Santos and colleagues (2020) noted that DFUs are

considered one of the most aggressive and expensive

complications of diabetes; and LLLT has been highlighted as a

potential modality of treatment to accelerate the healing of

ulcers. In a systematic review and meta-analysis, these

researchers examined the efficacy of LLLT in the treatment of




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DFU and identified the LLLT application parameters

recommended for the treatment of DFU over the past 10

years. They carried out a systematic search in PubMed, BVS,

PEDro, Scopus, Web of Science, and CINAHL up to March 31,

2019. Following the PRISMA guidelines, RCTs that examined

the effect of LLLT on the treatment of DFU were included. A

total of 13 RCTs with a total of 361 subjects were included in

this review; 3 RCTs reported a reduction in the percentage

size of the ulcers and were included in the meta-analysis. The

meta-analysis of the percentage size difference showed a

significant reduction in ulcer size in the LLLT group compared

with controls (22.96 [95 % CI: 18.22 to 27.69; z = 9.51, p <

0.0001]). Treatment with 632.8 to 685 nm, 50 mW/cm2, 3 to 6

J/cm2, and irradiation for 30 to 80 seconds, 3 times weekly for

a month was of benefit to patients with DFU. The authors

concluded that LLLT was safe and effective for the treatment

of DFU. Moreover, these researchers stated that well-

designed, high-quality studies are needed to allow its ideal

parameterization for clinical practice.

Herpes Labialis

de Paula Eduardo et al (2014) noted that recurrent herpes

labialis (RHL) is a worldwide life-long oral health problem that

remains unsolved. It affects approximately 1/3 of the world

population and causes frequent pain and discomfort episodes,

as well as social restriction due to its compromise of esthetic

features. In addition, the available anti-viral drugs have not

been successful in completely eliminating the virus and its

recurrence. Currently, different kinds of laser treatment and

different protocols have been proposed for the management of

recurrent herpes labialis. These investigators reviewed the

literature regarding the effects of laser irradiation on recurrent

herpes labialis and identified the indications and most

successful clinical protocols. The literature was searched with

the aim of identifying the effects on healing time, pain relief,

duration of viral shedding, viral inactivation, and interval of

recurrence. According to the literature, none of the laser




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treatment modalities is able to completely eliminate the virus

and its recurrence. However, laser phototherapy appears to

strongly decrease pain and the interval of recurrences without

causing any side effects. Photodynamic therapy can be

helpful in reducing viral titer in the vesicle phase, and high-

power lasers may be useful to drain vesicles. The main

advantages of the laser treatment appear to be the absence of

side effects and drug interactions, which are especially helpful

for older and immune-compromised patients. The authors

concluded that although these results indicated a potential

beneficial use for lasers in the management of recurrent

herpes labialis, they are based on limited published clinical

trials and case reports. They stated that the literature still

lacks double-blind, controlled clinical trials verifying these

effects and such trials should be the focus of future research.

Al-Maweri and associates (2018) stated that RHL is a highly

prevalent viral infection that affects the orofacial region.

Current therapeutic options have limited efficacy in reducing

healing time and recurrence rate of the disease. Recently,

LLLT has been proposed as a potential treatment alternative

for the management of RHL with no side effects. These

investigators examined the effectiveness of laser therapy in

the management and prevention of RHL. A comprehensive

search of Medline/PubMed, Scopus, and Web of Science was

carried out to identify published clinical trials comparing laser

intervention to active and/or non-active controls for the

treatment of RHL. Due to marked heterogeneity of available

data, studies were assessed qualitatively, and no statistical

analysis was performed. Of the retrieved 227 articles, 6

clinical trials met the eligibility criteria. The wavelengths, the

power output, and energy density ranged between 632.5 to

870 nm, 5 to 80 W, and 2.04 to 48 J/cm2, respectively. All

included studies found laser to be effective in the management

and prevention of RHL, without any side effects. The authors

concluded that the findings of this review suggested that laser

is potentially a safe and effective treatment alternative for the

management of RHL. However, these researchers stated that




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due to high variability in study designs and inconsistency in

laser parameters among the included studies, more well-

designed RCTs with standardized laser parameters are

needed.

Low Back Pain and Neck Pain

In a clinical practice guideline on “Management of neck pain

and associated disorders” from the Ontario Protocol for Traffic

Injury Management (OPTIMa) Collaboration, Cote et al (2016)

concluded that “For neck pain and associated disorders (NAD)

grade III of less than or equal to 3 months duration, clinicians

may consider supervised strengthening exercises in addition

to structured patient education. In view of evidence of no

effectiveness, clinicians should not offer structured patient

education alone, cervical collar, low-level laser therapy, or

traction”.

In a clinical practice guideline for “Physical therapy

assessment and treatment in patients with nonspecific neck

pain” (Bier et al, 2018) stated that “The physical therapist is

advised not to use dry needling, low-level laser,

electrotherapy, ultrasound, traction, and/or a cervical collar”.

The Agency for Healthcare Research and Quality (AHRQ)’s

systematic review on “Noninvasive nonpharmacological

treatment for chronic pain” (Skelly et al, 2018) stated that for

chronic neck pain, low-level laser therapy was associated with

a moderate improvement in short-term function (2 trials,

pooled difference -14.98 , 95 % CI: -23.88 to -6.07, I2 = 39 %,

0 to 100 scale) and pain (3 trials [n = 26, 45, and 30 for laser

treatment; and the quality of the study was fair, good, and fair,

respectively], pooled difference -1.81 on a 0-10 scale, 95 %

CI: -3.35 to -0.27, I2 = 75 %) compared with sham (Strength of

evidence (SOE): Moderate for function and pain). However,

there is no evidence to support its effectiveness for

improvement of intermediate-term and long-term function and

pain. For LBP, SOE on the use of cold laser therapy for the




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treatment of LBP was low (short-term improvement in function

and pain). No clear improvement in function was observed at

intermediate-term for low-level laser therapy (SOE: Low); and

there is no evidence to support its effectiveness for

improvement of long-term function and pain.

Breast Implant Capsular Contracture

Azimi and colleagues (2018) stated that breast reconstruction

with implants can be complicated by symptomatic capsular

contracture, especially after radiotherapy. A phase-I, non-

randomized clinical trial reported improvement in capsular

contracture and avoidance of revision surgery with LLLT. In a

phase-II, double-blind, RCT, these investigators examined the

efficacy of LLLT for treating capsular contracture in women

with breast reconstruction following mastectomy for breast

cancer. Participants had completed their definitive implant-

based reconstruction a minimum of 6 months previously and

were randomized to weekly treatments over 6 weeks with

either an active or inactive LLL hand-piece (Riancorp LTU-

904). Pain, tightness, arm movement, and appearance were

assessed by patient questionnaires. Breast symmetry, shape,

naturalness, softness, and grade of contracture were

assessed by clinician reports. Participants were assessed at 1

and 6 months after completion of the treatments. A total of 42

patients (intervention arm, n = 20; placebo, n = 22) were

assessed in the trial; 32 had post-mastectomy radiotherapy.

There was no significant difference in the change in any

patient-reported outcomes or clinician-reported outcomes of

breast symmetry, shape, or naturalness for the 2 groups.

There was a significantly greater improvement in clinician-

reported breast softness (p < 0.05) and degree of contracture

(p < 0.05) in the placebo group at both 1- and 6-month follow-

up. The authors concluded that LLLT was not an effective

therapy for breast implant capsular contracture in

reconstruction patients. Level of evidence = I.



Hypothyroidism Induced by Autoimmune Thyroiditis


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In a RCT, Hofling and colleagues (2018) examined the efficacy

of LLLT for hypothyroidism induced by chronic autoimmune

thyroiditis (CAT). These researchers evaluated the safety and

actions of LLLT 6 years after completion of the RCT. A total of

43 participants were invited to participate in this study 6 years

after completion of the RCT; 25 were subjected to LLLT (group

L), and 18 were subjected to placebo (group P). Primary

outcome measure was frequency of thyroid nodules, which

were subjected to fine-needle aspiration biopsy. Secondary

outcome measures included dose of levothyroxine needed to

treat hypothyroidism, thyroid peroxidase antibodies (anti-TPO),

and anti-thyroglobulin antibodies (anti-Tg). In group L, a

nodule was observed in 3 patients, who all had a Bethesda II

classification. In group P, a nodule was also observed in 3

patients, with 2 classified as Bethesda II and 1 as Bethesda III.

The levothyroxine dose needed by group L was significantly

lower than that required by group P (p = 0.002). The anti-TPO

and anti-Tg levels did not differ between the 2 groups. The

authors concluded that the findings of this study suggested

that LLLT was safe for the treatment of patients with CAT-

induced hypothyroidism under the specified conditions, and

thus, subsequent applications may be considered for the

purpose of maintaining or improving the obtained results.

These researchers stated that future research will be

important to corroborate these findings.

The authors stated that this study had several drawbacks. The

vascularization was evaluated by means of a subjective

method, with classification of the vascularization into 4

different patterns. Although the evaluation of thyroid

vascularization pattern TVP was performed by a single

experienced examiner, there may be intra-observer variations

in interpretation in the case of borderline patterns. However, 2

separate analyses by 2 independent investigators could also

be employed to improve this evaluation. The use of different

anti-TPO and anti-Tg measurement kits during the RCT and




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the present study made comparative analysis impossible at

those moments. The safety analysis was based on a small

sample of patients. Thus, further research is needed to

confirm these results.

Inferior Alveolar Nerve and Lingual Nerve Injuries

Miloro and Criddle (2018) noted that iatrogenic damage to the

inferior alveolar nerve (IAN) and lingual nerve (LN) may occur

during routine oral and maxilla-facial surgeries. In a

prospective, double-blind RCT, these investigators examined if

the proportion of nerve-injured patients with post-operative

neurosensory improvement over a 3-month period differed

significantly between a LLLT group and a control group. The

study sample consisted of 35 patients with iatrogenic nerve

injury due to 3rd molar odontectomy, dental implant

placement, or local anesthetic injection. The investigators

used a randomized, double-blind laser delivery system to

administer either placebo or LLLT to patients who met the

inclusion criteria. The outcome variable of neurosensory

improvement was defined as a minimum 1-unit increase from

baseline in VAS rating and was based on standard objective

clinical neurosensory testing. Study variables included the

affected nerve (IAN or LN) and time from injury to treatment (3

to 12 months or greater than 12 months). Uni-variate

statistical analysis (χ2 test) was performed to determine

significance between the 2 groups. Neurosensory

improvement was observed in 46.7 % of the LLLT patients,

who showed at least a 1-unit improvement at 3 months,

compared with 38.5 % improvement for controls (p = 0.66),

regardless of the specific nerve involved (IAN or LN). In

addition, no observed difference was noted between the study

groups based on time from injury to treatment. The authors

concluded that this study failed to provide sufficient evidence

to conclude that a difference in neurosensory improvement

exists between the LLLT and placebo groups with IAN or LN

injuries. However, this study was unique in the prospective

double-blind study design and comprehensive neurosensory




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testing protocols. These researchers stated that there is a

continued need for further clinical studies on LLLT in oral and

maxillofacial surgery nerve injuries.

Peri-Implant Mucositis

In a systematic review, Albaker and colleagues (2018)

examined the effect of photodynamic therapy (PDT) or laser

therapy (LT) in the management of peri-implant mucositis

(p-iM). The electronic databases were searched until October

2017. Outcome measures were bleeding on probing (BOP),

plaque index (PI), or probing depth (PD). The addressed

PICO (population-intervention-comparator-outcome) question

was: "Is PDT and LT effective in the management of p-iM?" A

total of 5 studies included in the qualitative analysis, 2 of which

had a low-risk of bias; 3 studies used PDT while 2 studies

used LT. All studies reported a significant improvement in

clinical peri-implant inflammatory parameters in p-iM. For

PDT, 1 study demonstrated a significant reduction for PDT

group as compared to manual debridement (MD), while 1

study indicated comparable outcomes when tested with

probiotics at follow-up. One study used PDT alone and

indicated significant improvements in peri-implant parameters

at follow-up. However, in the studies using LT, one study

demonstrated a significant improvement in peri-implant

parameters as compared to scaling and root planing alone,

while other study indicated comparable outcomes when

compared with manual debridement / chlorhexidine group at

follow-up. The authors concluded that this systematic review

demonstrated inconclusive findings to show the effect of PDT

or LT in the management of p-iM due to methodological

heterogeneity such as non-standard control groups, laser

parameters and short follow-up period. These researchers

stated that the findings of this review should be considered

preliminary and further, more robust, well-designed studies

with long-term follow-up and standardized comparators with

laser parameters are needed.



Peri-Odontitis


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In a systematic review, Mokeem (2018) examined the efficacy

of LLLT as an adjunct to scaling and root planing (SRP) versus

SRP alone in the treatment of aggressive periodontitis (AgP).

The addressed PICO (Population, Interventions, Comparisons

and Outcomes) question was: Is LLLT as an adjunct to SRP

effective in the treatment of AgP? Electronic databases,

including Medline via PubMed, Cochrane Central Register of

Controlled Trials and Cochrane Oral Health Group Trials, and

Embase, were searched until March 2018. A total of 4 clinical

studies were included; 3 studies showed significant

improvement in periodontal outcomes among LLLT group

compared to SRP alone, whereas only 1 study showed

comparable periodontal outcomes between the adjunctive

LLLT and SRP groups at follow-up. The overall MD for clinical

attachment level gain (WMD = -1.69, 95 % CI: -3.46 to 0.07, p

< 0.061) was non-significant. However, significant difference

for probing depth reduction (WMD = -0.95, 95 % CI: -1.66 to

0.23, p = 0.009) was noticed between groups at follow-up.

Whether LLLT as an adjunct to SRP is more effective than

SRP alone in the treatment of AgP remains debatable. The

authors concluded that further RCTs with long follow-up

periods and standard laser parameters are needed to reach a

strong conclusion.

Skin Burn

Brassolatti and colleagues (2018) noted that burn is defined as

a traumatic injury of thermal origin, which affects the organic

tissue; and LLLT has gained great prominence as a treatment

in this type of injury; however, the application parameters are

still controversial in the literature. These investigators

reviewed the literature studies that use LLLT as a treatment in

burns conducted in an experimental model, discussed the

main parameters used, and high-lighted the benefits found in

order to choose an appropriate therapeutic window to be

applied in this type of injury. The selection of the studies




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related to the theme was performed in the main databases

(PubMed, Cochrane Library, LILACS, Web of Science, and

Scopus in the period from 2001 to 2017). Subsequently, the

articles were then chosen that fell within the inclusion criteria

previously established. A total of 22 studies were evaluated,

and the main parameters were presented. The analyzed

studies presented both LLLT use in continuous and pulsed

mode. Differences between the parameters used (power,

fluence, and total energy) were observed. In addition, the

protocols were distinct as to the type of injury and the number

of treatment sessions. Among the results obtained by the

authors were the improvements in the local micro-circulation

and cellular proliferation; however, a study reported no effects

with LLLT as a treatment. The authors concluded that LLLT

was effective in accelerating the healing process; however,

there is immense difficulty in establishing the most adequate

protocol, due to the great discrepancy found in the applied

dosimetry values.

Tendon Repair

Lucke and colleagues (2019) noted that the cellular therapy

using adipose-derived mesenchymal stem cells (ASCs) aims

to improve tendon healing, considering that repaired tendons

often result in a less resistant tissue. These researchers

examined the effects of the ASCs combined with a LLLT for

the healing processes. Rats calcaneal tendons were divided

into 5 groups: normal (NT), transected (T), transected and

ASCs (SC) or LLLT (L), or with ASCs and LLLT (SCL). All

treated groups presented higher expression of Dcn and

greater organization of collagen fibers. In comparison with T,

LLLT also up-regulated Gdf5 gene expression, ASCs up-

regulated the expression of Tnmd, and the association of LLLT

and ASCs down-regulated the expression of Scx. No

differences were observed for the expression of Il1b, Timp2,

Tgfb1, Lox, Mmp2, Mmp8 and Mmp9, neither in the

quantification of hydroxyproline, TNF-α, PCNA and in the

protein level of Tnmd. A higher amount of IL-10 was detected




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in SC, L and SCL compared to T, and higher amount of

collagen I and III was observed in SC compared to SCL. The

authors concluded that transplanted ASCs migrated to the

transected region, and all treatments altered the re-modelling

genes expression. The LLLT was the most effective in the

collagen reorganization, followed by its combination with

ASCs. These researchers stated that further investigations

are needed to elucidate the molecular mechanisms involved in

the LLLT and ASCs combination during initial phases of

tendon repair.

Brain Photobiomodulation Therapy / Transcranial LLLT

Hennessy and colleagues (2017) noted that transcranial PBM

also known as tLLLT relies on the use of red/near-infrared

(NIR) light to stimulate, preserve and regenerate cells and

tissues. The mechanism of action entails photon absorption in

the mitochondria (cytochrome c oxidase), and ion channels in

cells leading to activation of signaling pathways, up-regulation

of transcription factors, and increased expression of protective

genes. These researchers have studied PBM for treating TBI

in mice using a NIR laser spot delivered to the head. Mice had

improved memory and learning, increased neuro-progenitor

cells in the dentate gyrus and sub-ventricular zone, increased

brain-derived neurotrophic factor (BDNF) and more

synaptogenesis in the cortex. These highly beneficial effects

on the brain suggested that the applications of tLLLT are much

broader than at first conceived. Other groups have studied

Alzheimer's disease (AD), depression, Parkinson's disease

(PD), stroke (animal models and clinical trials), as well as

cognitive enhancement in healthy subjects. The authors

concluded that due to the extremely positive results obtained

in studies in animal models, and the small clinical trials that

have been conducted thus far, broader clinical testing of PBM

and its applications for neurological conditions is certainly

needed, as much as it is necessary if PBM is to ever become a

widely accessible treatment




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Salehpour and co-workers (2018) stated that brain PBM

therapy enhances the metabolic capacity of neurons and

stimulates anti-inflammatory, anti-apoptotic, and antioxidant

responses, as well as neurogenesis and synaptogenesis. Its

therapeutic role in disorders such as dementia and PD, as well

as to treat brain trauma, depression, and stroke has gained

increasing interest. In the transcranial PBM approach,

delivering a sufficient dose to achieve optimal stimulation is

challenging due to exponential attenuation of light penetration

in tissue. Alternative approaches such as intracranial and

intranasal light delivery methods have been suggested to

overcome this limitation.

Fibromyalgia

de Carvalho Pde et al (2012) noted that LLLT has been widely

used as adjuvant strategy for treatment of musculo-skeletal

disorders. The light-tissue interaction (photo-biostimulation)

promotes analgesic and anti-inflammatory effects and

improves tissue healing, which could justify the

recommendation of this therapy for patients with fibromyalgia,

leading to an improvement in pain and possibly minimizing

social impact related to this disease. These researchers

proposed to evaluate the effect of LLLT on tender points in

patients with fibromyalgia, correlating this outcome with quality

of life and sleep. A total of 120 patients with fibromyalgia will

be treated at the Integrated Health Center and the Sleep

Laboratory of the Post Graduate Program in Rehabilitation

Sciences of the Nove de Julho University located in the city of

Sao Paulo, Brazil. After fulfilling the eligibility criteria, a clinical

evaluation and assessments of pain and sleep quality will be

carried out and self-administered quality of life questionnaires

will be applied. The 120 volunteers will be randomly allocated

to an intervention group (LLLT, n = 60) or control group

(CLLLT, n = 60). Patients from both groups will be treated 3

times per week for 4 weeks, totaling 12 sessions. However,

only the LLLT group will receive an energy dose of 6 J per

tender point. A standardized 50-min exercise program will be




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performed after the laser application. The patients will be

evaluated regarding the primary outcome (pain) using the

following instruments: VAS, McGill Pain Questionnaire and

pressure algometry. The secondary outcome (quality of life

and sleep) will be assessed with the following instruments:

Medical Outcomes Study 36-item Short-Form Health Survey,

Fibromyalgia Impact Questionnaire, Berlin Questionnaire,

Epworth Sleepiness Scale and polysomnography. ANOVA

test with repeated measurements for the time factor will be

performed to test between-groups differences (followed by the

Tukey-Kramer post hoc test), and a paired t-test will be

performed to test within-group differences. The level of

significance for the statistical analysis will be set at 5 % (p ≤

0.05).

Winkelmann et al (2012) stated that the scheduled update to

the German S3 guidelines on fibromyalgia syndrome by the

Association of the Scientific Medical Societies was planned

starting in March 2011. The development of the guidelines

was coordinated by the German Interdisciplinary Association

for Pain Therapy, 9 scientific medical societies, as well as 2

patient self-help organizations. Eight working groups with a

total of 50 members were evenly balanced in terms of gender,

medical field, potential conflicts of interest and hierarchical

position in the medical and scientific fields. Literature

searches were performed using the Medline, PsycInfo, Scopus

and Cochrane Library databases (until December 2010). The

grading of the strength of the evidence followed the scheme of

the Oxford Center for Evidence-Based Medicine. The

formulation and grading of recommendations was

accomplished using a multi-step, formal consensus process.

The guidelines were reviewed by the boards of the

participating scientific medical societies. The authors

concluded that low-to-moderate intensity aerobic exercise and

strength training are strongly recommended; chiropractic, laser

therapy, magnetic field therapy, massage, and transcranial

current stimulation are not recommended.




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In a systematic review and meta-analysis, Yeh and colleagues

(2019) examined the efficacy of LLLT on patients with

fibromyalgia. These researchers carried out a systematic

review and meta-analysis of RCTs evaluating the effect of

LLLT on patients with fibromyalgia. PubMed, Embase, and

the Cochrane Library were searched for articles published

before August 2018; RCTs meeting the selection criteria were

included. The methodological quality of the RCTs was

evaluated according to the Cochrane risk-for-bias method.

Review Manager version 5.3 was used to perform the meta-

analysis. The primary outcomes were the total scores on the

Fibromyalgia Impact Questionnaire (FIQ), pain severity, and

number of tender points. The secondary outcomes were

changes in fatigue, stiffness, anxiety, and depression; SMD,

95 % CI, and p values were calculated for outcome analysis.

These investigators identified 9 RCTs that included 325

fibromyalgia patients undergoing LLLT or placebo laser

treatment with or without an exercise program. The meta-

analysis showed that patients receiving LLLT demonstrated

significantly greater improvement in their FIQ scores (SMD:

1.16; 95 % CI: 0.64 to 1.69), pain severity (SMD: 1.18; 95 %

CI: 0.82 to 1.54), number of tender points (SMD: 1.01; 95 %

CI: 0.49 to 1.52), fatigue (SMD: 1.4; 95 % CI: 0.96 to 1.84),

stiffness (SMD: 0.92; 95 % CI: 0.36 to 1.48), depression (SMD:

1.46; 95 % CI: 0.93 to 2.00), and anxiety (SMD: 1.46; 95 % CI:

0.45 to 2.47) than those receiving placebo laser. Furthermore,

when compared with the standardized exercise program

alone, LLLT plus the standardized exercise program provided

no extra advantage in the relief of symptoms. On the other

hand, the results of the only RCT using combined LLLT/LED

phototherapy showed significant improvement in most

outcomes except for depression when compared to placebo.

When compared with pure exercise therapy, combined

LLLT/LED phototherapy plus exercise therapy had additional

benefits in reducing the severity of pain, number of tender

points, and fatigue. The authors concluded that the findings of

this systematic review and meta-analysis indicated that LLLT




5/26/2021

is an emerging, non-invasive, well-tolerated treatment for

fibromyalgia to relieve discomfort, particularly in patients who

do not exercise regularly.

The authors stated that this study had several drawbacks;

mostly because of the low-to-middle methodological quality of

the selected studies. First, most studies did not report the

allocation process clearly and only blinded the patients; neither

phototherapy programmer nor outcome assessor were

blinded. Considering that nearly all outcomes were subjective

parameters, the above shortcomings may introduce allocation

bias, performance bias, and detection bias. Second, one

study used per-protocol analysis because of a 20 % loss to

follow-up without reporting the reasons for, or the distribution

of, the loss to follow-up; this may have introduced attrition bias.

Third, although LLLT was used in all trials, the differences in

laser types, energy sources, and exposure times used in the

studies may have resulted in some heterogeneity. Fourth,

although patients with fibromyalgia did not take associated

medications in most RCTs, patients in 1 trial maintained their

usual pharmacological therapies, another trial included some

patients continuing their regular medications, and the other 3

RCTs did not mention whether subjects were under concurrent

medication; thus, these investigators could not clarify the

separate roles of medication or phototherapy in fibromyalgia.

Finally, long-term follow-up up to 6 months was only

conducted in 1 RCT.

Tinnitus

In a systematic review and meta-analysis, Chen and

associates (2020) examined the effectiveness of LLLT on adult

patients with complaints of tinnitus. These investigators

searched PubMed, Embase, Scopus, Web of Science, and the

Cochrane Library from inception through September 17, 2020;

RCTs that involved adult patients with complaints of tinnitus,

compared LLLT to a placebo and provided sufficient

information for meta-analysis were considered eligible.




5/26/2021

Outcome measures included THI score; improvement rates of

the VAS, verbal rating scale (VRS) and NRS scores. A total of

11 studies involving 670 patients were included. No significant

difference in the overall effect according to the THI score (MD,

-2.85; 95 % CI: -8.99 to 3.28; p = 0.362; I2 = 0 %) and the

rating scale score improvement rate (RR, 1.35; 95 % CI, 0.81

to 2.27; p = 0.250; I2 = 67 %) was demonstrated between

patients receiving LLLT and those receiving a placebo. None

of the subgroup analyses showed significant differences,

regardless of underlying sensori-neural hearing loss (SNHL),

the number of irradiation sessions or the wavelength used.

The authors concluded that the findings of this meta-analysis

suggested that the value of LLLT in controlling the severity of

tinnitus remains unclear, in part due to the relatively small

number of patients and underlying heterogeneity. These

researchers stated that more large-scale studies of LLLT for

tinnitus related to inner ear disease are needed to further

elucidate the therapeutic effects.

In a systematic review, Ferreira and colleagues (2021)

examined the effects of LLLT on the severity of tinnitus when

compared to no therapy or other modalities of therapies.

These investigators carried out a search in each of the

following databases: Embase, LILACS, PubMed, Science

Direct, Scopus, Web of Science, Google Scholar, and

ProQuest. The inclusion criteria consisted of studies in adults

over 16 years of age, randomized clinical trials in which

subjects presented chronic (greater than or equal to 6 months)

and subjective tinnitus (unilateral or bilateral) as well as with or

without bilateral SNHL, and studies that used only LLLT for

treatment of tinnitus compared to no-therapy group or other

modalities of therapy. No language or time restrictions were

stipulated. The references were managed by Endnote Web

and Rayyan QCRI. After the screening process, a total of 7

studies remained that attained the eligibility criteria.

Regarding the risk of bias, only 1 study was categorized as

low-risk of bias; the remaining 6 studies were classified as

moderate-risk of bias. The 7 included studies mainly




5/26/2021

examined the LLLT effects on tinnitus by VAS, THI, pitch and

loudness matching, minimum masking level, and pure-tone

audiometry. All 7 selected studies found different degrees of

significant results regarding tinnitus severity; however, there

was no consensus among the results. The authors concluded

that although LLLT showed positive effects in the tinnitus

severity in some studies, it is not possible yet to make any

recommendation over its uses for the treatment of tinnitus

severity.

Achilles Tendinopathy

In a systematic review and meta-analysis, Martimbianco and

colleagues (2020) examined the benefits and harms of LLLT

for the treatment of Achilles tendinopathy. Search strategies

were conducted (from inception to February 2020) in

Cochrane Central Register of Controlled Trials (CENTRAL),

Medline, Embase, Cumulative Index to Nursing and Allied

Health Literature (CINAHL), Literatura Latino Americana em

Ciências da Saúde e do Caribe (LILACS), Physiotherapy

Evidence Database (PEDro), SPORTDiscus,

ClinicalTrials.gov, World Health Organization (WHO)-ICTRP

and OpenGrey databases, to retrieve all RCTs that compared

laser therapy with inactive/active interventions. This study was

reported following the PRISMA statement. The risk of bias

was evaluated using the Cochrane Risk of bias table. Meta-

analyses were carried out on dependence of homogeneity,

otherwise results were reported narratively. The certainty of

evidence was assessed using the Grading of

Recommendations Assessment, Development and Evaluation

(GRADE) approach. A total of 4 trials (119 subjects) were

analyzed. Laser therapy associated to eccentric exercises

when compared to eccentric exercises and sham had very low

to low certainty of evidence in pain and function assessment.

Despite 1 trial favored laser therapy at 2 months (MD -2.55, 95

% CI: -3.87 to -1.23), the CIs did not include important

differences between groups at 3 and 13 months. The function

assessment showed an improvement favoring the placebo



http://ClinicalTrials.gov


5/26/2021

group at 1 month (MD 9.19, 95 % CI: -16.16 to -2.23) and non-

significant difference between groups at 3 and 13 months.

Adverse events (AEs) were poorly reported but restricted to

minor events related to the exercises. The authors concluded

that the certainty of evidence was low to very low, and the

results were insufficient to support the routine use laser

therapy for Achilles tendinopathy.

Burning Mouth Syndrome

Matos and colleagues (2021) noted that primary burning

mouth syndrome (BMS) is a chronic clinical condition of

idiopathic mainly characterized by pain and a burning

sensation in the oral cavity. The application of laser at low

intensity therapy is a therapeutic option. In a systematic

review, these investigators examined the effectiveness of laser

therapy in treating symptoms of BMS. The study was

conducted according to the PRISMA and Cochrane

guidelines. A total of 7 databases were used as primary

sources of research. Only randomized controlled trials (RCTs)

were included. The effectiveness of the therapy was

estimated comparing the values of the visual and numerical

scales of pain before and after laser treatment, via qualitative

analysis. The search yielded 348 records and only 8 met the

eligibility criteria and were included. All studies examined pain

and / or a burning sensation considering a time interval of 2 to

10 weeks. The total sample consisted of 314 patients

submitted to treatment: 123 from the control group, who

participated with laser off or with the tip blocked, and 191 from

the intervention group, treated with LLLT. The female gender

stood out and the average age of the subjects was 60.89

years. The main symptoms reported were pain and a burning

sensation in the oral mucosa and tongue. The parameters

adopted by these researchers for laser treatment were diverse

and the variables were not fully described in the published

studies; VAS and numerical scales were used to evaluate

symptoms; and only 3 studies showed statistical significance.

The authors concluded that it is suggested that laser therapy




5/26/2021

may be an effective alternative in the treatment of BMS.

Moreover, these researchers stated that new randomized

clinical trials should consider well-established protocols to

better understand the effectiveness of laser therapy without

confounding the effects.

Keratosis Pilaris

Kechichian and colleagues (2020) noted that keratosis pilaris

(KP) is a common hereditary keratinization disorder. Keratosis

pilaris rubra and KP atrophicans faciei are less frequent

variants of the disease. Topical treatments often yield

ineffective and temporary results. These researchers

examined available studies that used light and laser devices

for the treatment of KP and its variants. On January 15, 2017,

an online search of the Medline, Embase, and Cochrane

databases was carried out using the following combination of

keywords: "keratosis pilaris" and "treatment". A total of 17

studies related to light and laser treatments were retained for

analysis. The total number of treated patients was 175; of

which, 22 patients had KP atrophicans faciei, 17 patients had

KP rubra, and 136 patients had KP. The authors concluded

that light and laser devices have been emerging as promising

therapeutic options for a disfiguring disease that still lacks,

until today, an effective long-term treatment.

Furthermore, an UpToDate review on “Keratosis

pilaris” (Landis, 2021) states that “Third-line therapies include

systemic retinoids, laser therapy, or other ablative procedures.

Combination treatments with lasers (e.g., pulsed-dye laser,

long-pulsed 755-nm alexandrite laser, 810-nm long-pulsed

diode laser, long-pulsed 1064-nm Nd:YAG laser) and

microdermabrasion have been tried in a few patients with

temporary reduction of perifollicular erythema and skin

roughness”. Moreover, laser is not listed in the “Summary and

Recommendations” section of the review.



Melasma


5/26/2021

Masub and colleagues (2020) stated that melasma is a

common acquired disorder of hyper-pigmentation, classically

manifesting as symmetric brown patches on the face.

Although the exact pathogenesis is still unclear, vascular

abnormalities have been implicated in melasma. In a

systematic review, these researchers examined the laboratory

and clinical evidence regarding the safety and effectiveness of

anti-vascular agents for the treatment of melasma. They

carried out a systematic search of PubMed, Embase, and

Cochrane on May 13, 2020, using the PRISMA guidelines.

Original research articles examining the role of vascularity

and/or evaluating the use of anti-vascular therapeutics in

melasma were included. Clinical recommendations were

based on the American College of Physicians (ACP)

guidelines. A total of 34 original research articles were

identified: 4 laboratory studies, 15 diagnostic studies, and 15

therapeutic studies. The authors concluded that there is

promising evidence supporting the use of tranexamic acid and

laser/light therapies to treat the vascular component of

melasma, and more rigorous clinical trials are needed to

validate their efficacy. Clinicians may consider treatment with

1 or more anti-vascular therapeutics in patients with melasma.

Moreover, these researchers stated that further research is

needed to characterize the role of cutaneous vascularization in

melasma and may provide insights for novel therapies.

Oral Ulcers in Chronic Graft-Versus-Host Disease

In a retrospective study, Finfter and colleagues (2020)

examined the pain-relieving effect of photobiomodulation (low-

level laser) therapy (PBMt) in patients with oral ulcers of

chronic graft-versus-host disease (cGVHD) refractory to 1st-

line therapy with topical corticosteroids. This study included all

patients who underwent PBMt for pain relief of refractory oral

cGVHD lesions. PBMt was applied using an intra-oral

approach to all sites with mucosal lesions, using a 940-nm




5/26/2021

InGaAsP diode laser device, with the following parameters:

pulsed modulation (duty cycle of 50 %), power 0.7 W,

illuminated spot size 7.1 cm2, irradiance 98.6 mW/cm2, and

irradiation time 90 s per point. Pain was self-assessed using a

0 to 10 scale immediately before and after PBMt. Data from

11 patients with a total of 56 PBMt sessions were analyzed. In

48 (85.7 %) sessions, the patients reported less pain

immediately after treatment, with a reduction of greater than or

equal to 50 % of the initial pain level in 43 (76.8 %) sessions.

Mean pre- and post-treatment pain levels were 5.20 ± 2.7 and

1.38 ± 2.1, respectively (p < 0.001), i.e., a post-treatment

reduction of 73.4 % of the initial pain level. The benefits of the

treatment remained for a mean of 6.50 ± 5.4 days (range of 2

to 14 days). No adverse effects were reported. The authors

concluded that PBMt appeared to be a promising treatment

modality for refractory oral cGVHD lesions as a rapid pain

reliever with relatively long-lasting effects. Moreover, these

researchers stated that prospective, larger-scale, randomized

placebo-controlled trials are needed to validate these

preliminary findings.

The authors stated that the drawbacks of this study included

the absence of a placebo control group and the small number

of patients (n = 11); however, in this study, each patient was

compared with him/herself immediately before PBMt, and pain

relief was reported by all patients after the vast majority of

sessions. Despite the small number of patients, the total

number of treatment sessions was sufficient. Thus, these

findings supported previous studies, and together, they

highlighted the potential of PBMt in the treatment of oral

cGVHD lesions.

High Powered Lasers

High power laser therapy devices, also referred to as high

does laser therapy (HDLT), (class IV therapeutic lasers) are

purported to stimulate accelerated healing energy from

superficial to deep levels (six to nine inches) over a larger




5/26/2021

surface treatment area. Its proposed use includes conditions

such as arthritis, carpal tunnel syndrome, epicondylitis,

sprains/strains, trigger points and various other

musculoskeletal disorders. These devices are not to be

confused with class IV surgical lasers. Examples of high power

laser therapy devices that have received US Food and Drug

Administration (FDA) approval are the AVI HP-7.5, AVI HPLL-

12 and Diowave Laser System.

High-power lasers (class IV therapeutic lasers; not to be

confused with class IV surgical lasers) have power output of

up to 7,500 mW; and supposedly offer more power,

deeper penetration (can penetrate up to 10 cm2 instead of 0.5

to 2.0 cm2 for class III lasers) and a larger surface treatment

area (cover up to 77 cm2 instead of 0.3 to 5.0 cm2 for class III

lasers). Despite little scientific support, high-power

lasers have been employed for various indications including

musculoskeletal disorders (e.g., carpal tunnel syndrome and

lateral epicondylitis), pain relief, and wound healing.

Plaghki and Mouraux (2005) noted that laser heat stimulators

selectively activate Adelta and C-nociceptors in the superficial

layers of the skin. Their high-power output produces steep

heating ramps, which improve synchronization of afferent

volleys and thus allow the recording of time-locked events

(e.g., laser-evoked brain potentials). Study of the electrical

brain activity evoked by Adelta- and C-nociceptor afferent

volleys revealed the existence of an extensive, sequentially

activated, cortical network. These electro-physiological

responses are modulated by stimulus-driven and, even more

extensively, top-down processes. The specificity and validity

of these components for pain research are currently under

intense scrutiny.

In a systematic review on treatment of pressure ulcers, Reddy

and colleagues (2008) concluded that there is little evidence to

support routine nutritional supplementation or adjunctive

therapies including laser therapy compared with standard

care.




5/26/2021

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

CPT codes covered if selection criteria are met:

0552T Low-level laser therapy, dynamic photonic and

dynamic thermokinetic energies, provided by a

physician or other qualified health care

professional

CPT codes not covered for indications listed in the CPB:

High-power laser therapy (class IV therapeutic laser) - no specific code:

Other CPT codes related to the CPB:

20560 Needle insertion(s) without injection(s); 1 or 2

muscle(s)

20561 3 or more muscles

HCPCS codes not covered for indications listed in the CPB:

S8948 Application of a modality (requiring constant

provider attendance) to one or more areas; low-

level laser; each 15 minutes

ICD-10 codes covered if selection criteria are met:

C00.0 –

C17.9,

C22.0 –

C96.9

Malignant neoplasm [except Malignant

neoplasm of colon, rectum, rectosigmoid

junction, anus and anal canal]

K12.30 -

K12.39

Oral mucositis (ulcerative)

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

B00.9 Herpesviral infection, unspecified




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C18.0 -

C21.8

Malignant neoplasm of colon, rectum,

rectosigmoid junction, anus and anal canal

D89.811 Chronic graft-versus-host disease

D89.812 Acute on chronic graft-versus-host disease

E06.3 Autoimmune thyroiditis

E66.01 -

E66.9

Overweight and obesity

E75.00 -

E75.6

Disorders of sphingolipid metabolism and other

lipid storage disorders

F01.50 -

F01.51

Vascular dementia with or without behavioral

disturbance

F02.80 -

F02.81

Dementia in other diseases classified

elsewhere with or without behavioral

disturbance

F03.90 -

F03.91

Unspecified dementia with or without behavioral

disturbance

F32.0 -

F33.9

Major depressive disorder, single episode or

recurrent

G10 -

G37.9

G90.01 -

G94

Degenerative diseases of the central nervous

system

G50.0 Trigeminal neuralgia

G56.00 -

G56.03

Carpal tunnel syndrome [rehabilitation following

carpel tunnel release]

H93.11 -

H93.19

Tinnitus



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H93.A1 -

H93.A9

Pulsatile tinnitus

I21.01 -

I23.8

Myocardial infarction [cardio-protection

following]

I50.1 -

I50.9

Heart failure

I60.00 -

I68.8

Cerebrovascular disease [stroke]

I89.0 -

I89.9

Other noninfective disorders of lymphatic

vessels and lymph nodes

I97.2 Postmastectomy lymphedema syndrome

K04.4,

K04.5,

K05.20 -

K05.229,

K05.30 -

K05.329

Periodontitis

K08.0 -

K08.0

Other disorders of teeth and supporting

structures [orthodontic pain] [dentin

hypersensitivity]

K12.0 Recurrent oral aphthae

K14.6 Glossodynia [burning mouth syndrome]

L10.0 Pemphigus vulgaris

L43.0 -

L43.9

Lichen planus [oral]

L63.0 -

L63.9

Alopecia areata

L64.0 -

L64.9

Androgenic alopecia



5/26/2021https://aetnet.aetna.com/mpa/cpb/300_399/0363.html


L65.0 -

L65.9

Other nonscarring hair loss

L81.1 Chloasma [Melasma]

L85.8 Other specified epidermal thickening [Keratosis

pilaris]

L89 -

L89.95

Pressure ulcer

M00.00 -

M99.9

Diseases of the musculoskeletal system and

connective tissue

N64.4 Mastodynia

Q35.1 -

Q37.9

Cleft lip and cleft palate [bone healing following

rapid maxillary expansion]

S04.30XA

-

S04.32XS

Injury of trigeminal nerve [inferior alveolar nerve

and lingual nerve injuries]

S06.0x0+

-

S06.9x9+

Intracranial injury



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S39.001A

-

S39.093S,

S46.001A

-

S46.999S,

S56.001A

-

S56.999S,

S66.001A

-

S66.999S,

S76.001A

-

S76.999S,

S86.001A

-

S86.999S,

S96.001S

-

S96.999S

Injury of muscle, fascia and tendon




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T20.00A

T20.39S,

T21.00A

T21.39S,

T22.00A

T22.399S,

T23.00A

T23.399S,

T24.00A

T24.399S,

T25.00A

T25.399S,

T26.00A

T26.399S,

T31.00A

T31.99S

Burns [skin]

T81.89x+ Other complications of procedures, not

elsewhere classified [Non-healing surgical

wound]

T85.44A -

T85.44S

Capsular contracture of breast implant

Z98.890 Other specified postprocedural states [wound

healing following hammertoe surgery]

Numerous

options

Open wound [Codes not listed due to expanded

specificity]

The above policy is based on the following references:

1. Abdulwadud O. Does laser therapy improve healing

and function in patients with tendinitis compared to

no treatment? Evidence Centre Evidence Report.




5/26/2021

Clayton, VIC: Centre for Clinical Effectiveness (CCE);

2001.

2. Afifi L, Maranda EL, Zarei M, et al. Low-level laser

therapy as a treatment for androgenetic alopecia.

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3. Ahmed MK, Jafer M, Nayeem M, et al. Low-level laser

therapy and topical medications for treating aphthous

ulcers: A systematic review. J Multidiscip Healthc.

2020;13:1595-1605.

4. Akram Z, Abduljabbar T, Vohra F, Javed F. Efficacy of

low-level laser therapy compared to steroid therapy in

the treatment of oral lichen planus: A systematic

review. J Oral Pathol Med. 2018 Jan;47(1):11-17.

5. Albaker AM, ArRejaie AS, Alrabiah M, Abduljabbar T.

Effect of photodynamic and laser therapy in the

treatment of peri-implant mucositis: A systematic

review. Photodiagnosis Photodyn Ther. 2018;21:147-

152.

6. Alberta Heritage Foundation for Medical Research

(AHFMR), Institute of Health Economics. The use of low

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Results of a survey of physical therapists involved in

rehabilitation, long term care and home care.

Edmonton, AB: AHFMR; 2001.

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mouth syndrome: A systematic review. Photodiagnosis

Photodyn Ther. 2017;17:188-193.

8. Al-Maweri SA, Kalakonda B, AlAizari NA, et al. Efficacy

of low-level laser therapy in management of recurrent

herpes labialis: A systematic review. Lasers Med Sci.

2018;33(7):1423-1430.

9. Al-Maweri SA, Kalakonda B, Al-Soneidar WA, et al.

Efficacy of low-level laser therapy in management of

symptomatic oral lichen planus: A systematic review.

Lasers Med Sci. 2017;32(6):1429-1437.




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10. Altan L, Bingol U, Aykac M, Yurtkuran M. Investigation

of the effect of GaAs laser therapy on cervical

myofascial pain syndrome. Rheumatol Int. 2005;25

(1):23-27.

11. American College of Occupational and Environmental

Medicine. Elbow disorders. In: Hegmann KT, eds.

Occupational medicine practice guidelines. Evaluation

and management of common health problems and

functional recovery in workers. 3rd ed. Elk Grove

Village (IL): ACOEM; 2012.

12. Amid R, Kadkhodazadeh M, Ahsaie MG, Hakakzadeh A.

Effect of low level laser therapy on proliferation and

differentiation of the cells contributing in bone

regeneration. J Lasers Med Sci. 2014;5(4):163-170.

13. Arbabi-Kalati F, Bakhshani NM, Rasti M. Evaluation of

the efficacy of low-level laser in improving the

symptoms of burning mouth syndrome. J Clin Exp

Dent. 2015;7(4):e524-e527.

14. Atasoy KT, Korkmaz YT, Odaci E, Hanci H. The efficacy

of low-level 940 nm laser therapy with different energy

intensities on bone healing. Braz Oral Res. 2017;31:e7.

15. Ay S, Doğan SK, Evcik D. Is low-level laser therapy

effective in acute or chronic low back pain? Clin

Rheumatol. 2010;29(8):905-910.

16. Azimi F, Flitcroft K, Mathieu E, et al. Low-level laser

treatment is ineffective for capsular contracture:

Results of the LaTCon randomized controlled trial.

Plast Reconstr Surg. 2018;142(5):621e-631e.

17. Basford JR. Low-energy laser therapy: Controversies

and new research findings. Lasers Surg Med. 1989;9

(1):1-5.

18. Basford JR. Physical agents. In: Rehabilitation

Medicine: Principles and Practice. 2nd ed. JA De Lisa,

ed. Philadelphia, PA: J.B. Lippincott Co.; 1993: 404-424.

19. Baxter GD, Liu L, Petrich S, et al. Low level laser

therapy (Photobiomodulation therapy) for breast




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cancer-related lymphedema: A systematic review. BMC

Cancer. 2017;17(1):833.

20. Bayer S, Kazancioglu HO, Acar AH, et al. Comparison of

laser and ozone treatments on oral mucositis in an

experimental model. Lasers Med Sci. 2017;32(3):673-

677.

21. BC Cancer Agency. Lymphedema. Patient/Public

Information. Vancouver, BC: BC Cancer Agency;

revised November 2007.

22. Beckmann KH, Meyer-Hamme G, Schroder S. Low level

laser therapy for the treatment of diabetic foot ulcers:

A critical survey. Evid Based Complement Alternat

Med. 2014;2014:626127.

23. Bekhet AH, Ragab B, Abushouk AI, et al. Efficacy of low-

level laser therapy in carpal tunnel syndrome

management: A systematic review and meta-analysis.

Lasers Med Sci. 2017;32(6):1439-1448.

24. Bier JD, Scholten-Peeters WGM, Staal JB, et al. Clinical

practice guideline for physical therapy assessment and

treatment in patients with nonspecific neck pain. Phys

Ther. 2018;98(3):162-171.

25. Binder A. Neck pain. In: Clinical Evidence, Issue 7.

Tavistock Square, UK; BMJ Publishing Group; June

2002.

26. Bingol U, Altan L, Yurtkuran M. Low-power laser

treatment for shoulder pain. Photomed Laser Surg.

2005;23(5):459-464.

27. Blue Cross and Blue Shield Association (BCBSA),

Technology Evaluation Center (TEC). Low-level laser

therapy for carpal tunnel syndrome and chronic neck

pain. TEC Assessment Program. Chicago, IL: BCBSA;

November 2010;25(4).

28. Brassolatti P, de Andrade ALM, Bossini PS, et al.

Evaluation of the low-level laser therapy application

parameters for skin burn treatment in experimental

model: A systematic review. Lasers Med Sci. 2018;33

(5):1159-1169.




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29. Brosseau L, Robinson V, Wells G, et al. Low level laser

therapy (Classes I, II and III) for treating rheumatoid

arthritis. Cochrane Database Syst Rev. 2005;

(4):CD002049.

30. Brosseau L, Robinson V, Wells G, et al. Low level laser

therapy (Classes III) for treating osteoarthritis.

Cochrane Database Syst Rev. 2007;(1):CD002046.

31. Bulow PM, Jensen H, Denneskiold-Samsoe B. Low-

power Ga-Al-As laser treatment of painful

osteoarthritis of the knee: A double-blind placebo-

controlled study. Scand J Rehab Med. 1994;26(3):155-

159.

32. California Technology Assessment Forum (CTAF). Low-

energy laser therapy for the treatment of carpal tunnel

syndrome. Technology Assessment. San Francisco, CA:

CTAF; February 15, 2006.

33. Carati CJ, Anderson SN, Gannon BJ, Piller NB.

Treatment of postmastectomy lymphedema with low-

level laser therapy: A double blind, placebo-controlled

trial. Cancer. 2003; 98(6):1114-1122.

34. Carlos FP, Gradinetti V, Manchini M, et al. Role of low-

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Amendment to Aetna Clinical Policy Bulletin Number: 0363 Cold Laser and High‐Power Laser Therapies

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revised 05/21/2021

0363 Cold Laser and High-Power Laser Therapies (2)

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