Infrared Therapy

Number: 0604

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses infrared therapy.

  1. Medical Necessity

    Aetna considers infrared coagulation medically necessary for the following:

    1. Anal dysplasia;
    2. For members with grade I or grade II internal hemorrhoids that are painful or persistently bleeding. (See Appendix for grading of internal hemorrhoids).

      Note: Infrared light treatment is considered medically necessary as a heat modality in physical therapy.
  2. Experimental and Investigational

    The following interventions are considered experimental and investigational because the effectiveness of these approaches has not been established:

    1. Low-level infrared light (infrared therapy, Anodyne Therapy System) for the treatment of the following indications because of insufficient evidence regarding the effectiveness of infrared therapy for these indications (not an all-inclusive list):
      1. Acne;
      2. Back (lumbar and thoracic) pain;
      3. Bell's palsy;
      4. Bone regeneration;
      5. Brain disorders (including dementia);
      6. Calcaneal tendon injury;
      7. Cancer;
      8. Cardiovascular diseases;
      9. Central nervous system injuries;
      10. Chronic kidney diseases;
      11. Chronic non-healing wounds (including pressure ulcers);
      12. Diabetes mellitus (including diabetic macular edema and diabetic peripheral neuropathy);
      13. Disorders of consciousness;
      14. Ischemic stroke;
      15. Lymphedema;
      16. Migraines;
      17. Neck pain;
      18. Non-diabetic peripheral neuropathy;
      19. Onychomycosis;
      20. Osteoarthritis;
      21. Parkinson's disease;
      22. Retinal degeneration;
      23. Seasonal affective disorder (for prevention);
      24. Spinocerebellar ataxia;
      25. Stroke;
      26. Temporomandibular disorder;
      27. Tendinopathy;
      28. Traumatic brain injury;
      29. Xerostomia.
    2. The infrared glove (e.g. the Prolotex Therapy Glove) for the treatment of Raynaud's syndrome and all other indications;
    3. Photo-biomodulation using infrared light-emitting diode for the treatment of asthma. 
  3. Related Policies


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

46930 Destruction of internal hemorrhoid(s), by thermal energy (eg, infrared coagulation, cautery, radiofrequency)

CPT codes not covered for indications listed in the CPB:

Low level infrared light (infrared therapy, Anodyne Therapy system) or photo-biomodulation using infrared light-emitting diode- no specific code
97026 Application of a modality to one or more areas; infrared

HCPCS codes not covered for indications listed in the CPB:

A4639 Replacement pad for infrared heating pad system, each
E0221 Infrared heating pad system

ICD-10 codes covered if selection criteria are met:

K62.82 Dysplasia of anus
K64.0 - K64.1 First degree and second degree hemorrhoids

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

B35.1 Tinea unguium [onychomycosis]
C00.0 - D09.9 Malignant neoplasms and carcinoma in situ
E08.00 - E13.9 Diabetes mellitus
F01.50 – F01.C4 Vascular dementia
F02.80 – F02.81 Dementia in other diseases classified elsewhere
F03.90 – F03.91 Unspecified dementia
F33.0 - F33.9 Major depressive disorder, recurrent [not covered for prevention of seasonal affective disorder]
G11.1 Early-onset cerebellar ataxia
G20 - G21.9 Parkinson's disease
G43.001 - G43.901 Migraines
G51.0 Bell's palsy
G60.0 - G62.9 Non-diabetic peripheral neuropathy
G91.0 – G91.9 Hydrocephalus
G92 Toxic encephalopathy
G93.1 – G93.9 Other disorders of brain
H35.30 - H35.466 Degeneration of macula and posterior pole and peripheral retinal
I00 - I52 Acute rheumatic fever, chronic rheumatic heart diseases, hypertensive disease, ischemic heart disease, pulmonary heart disease and disease of pulmonary circulation and other forms of heart diseases [cardiovascular diseases]
I63.00 - I63.9 Cerebral infarction
I73.00 - I73.01 Raynaud's syndrome
I89.0 Lymphedema, not elsewhere classified
I97.2 Postmastectomy lymphedema syndrome
J45.20 - J45.22 Mild intermittent asthma
J45.30 - J45.32 Mild persistent asthma
J45.40 - J45.42 Moderate persistent asthma
J45.50 - J45.52 Severe persistent asthma
J45.901 - J45.909 Unspecified asthma
J45.990 - J45.998 Other asthma
L70.0 - L70.9 Acne
L89.000 - L89.95 Pressure ulcer
M15.0 - M19.93 Osteoarthritis
M26.601 - M26.609 Temporomandibular joint disorders
M54.2 Cervicalgia
M54.50 - M54.59 Low back pain
M54.6 Pain in thoracic spine
M54.9 Dorsalgia, unspecified
M67.00 - M67.99 Other disorder of synovium and tendon
M80.00 - M81.8 Osteoporosis
M85.80 - M85.9 Other specified disorders of bone density and structure [osteopenia]
N18.1 - N18.9 Chronic kidney disease (CKD)
Q82.0 Hereditary lymphedema
R40.0 - R40.4 Somnolence, stupor and coma [disorders of consciousness]
R68.2 Dry mouth, unspecified
S02.0xx+ - S02.19x+, S02.91x+ (must be billed with intracranial injury codes) Fracture of vault and base of skull
S06.0X0A - S06.A1XS, S06.0XAA - S06.9XAS (must be billed with fracture of skull codes) Intracranial injury
S12.000+ - S12.9xx+, S22.000+ - S22.089+, S32.000+ - S32.2xx+ (must be billed with spinal cord injury codes) Fracture of vertebral column
S14.0xx+ - S14.9, S24.0xx+ - S24.9, S34.01x+ - S34.9xx+ (must be billed with fracture of vertebral column codes) Spinal cord injury
T81.30X+ - T81.33X+ Disruption of wound, not elsewhere classified
T81.89X+ Other complications of procedures, not elsewhere classified [non-healing surgical wound]
Numerous options Open Wounds [chronic non-healing wounds] [Codes not listed due to expanded specificity]


Low-Level Infrared Therapy

Low-level infrared therapy, or monochromatic infrared energy (MIRE) therapy, is a type of low-energy laser that uses light in the infrared spectrum. MIRE therapy involves the use of devices that deliver single wavelength nonvisible light energy from the red end of the light spectrum via flexible pads that are applied to the skin. Each pad contains 60 infrared-emitting diodes. MIRE therapy is thought to stimulate the release of nitric oxide from the hemoglobin of the blood, which dilates the blood vessels, thereby reducing swelling and increasing circulation. MIRE has been proposed for treatment of conditions such as peripheral neuropathy, pain management and wound healing. An example of an MIRE device includes, but may not be limited to, the Anodyne Therapy System.

The Anodyne Therapy System is a type of low-level infrared therapy, developed by Integrated Systems Physiology Inc. (Aurora, CO), that has been promoted for augmenting wound healing, for reversing the symptoms of peripheral neuropathy in people with diabetes, and for treating lymphedema.  The manufacturer states that the Anodyne Therapy System increases circulation and reduces pain by increasing the release of nitric oxide.

Several meta-analyses have examined the evidence supporting the use of low-level (cold) lasers, including low-level infrared lasers, for treatment of chronic non-healing wounds.  These meta-analyses are unanimous in concluding that there is insufficient evidence to support low-level laser in the treatment of chronic venous ulcers or other chronic non-healing wounds.

There is no evidence that infrared light therapy is any more effective than other heat modalities in the symptomatic relief of musculoskeletal pain.  Glasgow (2001) reported on the results of a randomized controlled clinical trial of low-level infrared therapy in 24 subjects with experimentally induced muscle soreness, and found no significant differences between treatment and placebo groups.

There are no published studies of the effectiveness of low-level infrared therapy for treatment of diabetic peripheral neuropathy.  The case series presented by the manufacturer of the Anodyne System on its web site have not been published in a peer-reviewed medical journal.

Finally, there is no evidence in the published peer-reviewed medical literature on the effectiveness of infrared therapy for the treatment of lymphedema.  The Canadian Coordinating Office of Health Technology Assessment (2002) found that "[t]here is little high quality controlled clinical trial evidence for these therapies." 

In a randomized, placebo-controlled study, Leonard et al (2004) examined whether treatments with the Anodyne Therapy System (ATS) would decrease pain and/or improve sensation diminished due to diabetic peripheral neuropathy (DPN).  Tests involved the use of the 5.07 and 6.65 Semmes Weinstein monofilament (SWM) and a modified Michigan Neuropathy Screening Instrument (MNSI).  Twenty-seven patients, 9 of whom were insensitive to the 6.65 SWM and 18 who were sensitive to this filament but insensitive to the 5.07 SWM, were studied.  Each lower extremity was treated for 2 weeks with sham or active ATS, and then both received active treatments for an additional 2 weeks.  The group of 18 patients who could sense the 6.65 SWM but were insensitive to the 5.07 SWM at baseline obtained a significant decrease in the number of sites insensate after both 6 and 12 active treatments (p < 0.02 and 0.001).  Sham treatments did not improve sensitivity to the SWM, but subsequent active treatments did (p < 0.002).  The MNSI measures of neuropathic symptoms decreased significantly (from 4.7 to 3.1; p < 0.001).  Pain reported on the 10-point visual analog scale (VAS) decreased progressively from 4.2 at entry to 3.2 after 6 treatments and to 2.3 after 12 treatments (both p < 0.03).  At entry, 90 % of subjects reported substantial balance impairment; after treatment, this decreased to 17 %.  However, among the group of 9 patients with greater sensory impairment measured by insensitivity to the 6.65 SWM at baseline, improvements in sensation, neuropathic symptoms, and pain reduction were not significant.  The authors concluded that ATS treatments improved sensation in the feet of subjects with DPN, improved balance, and reduced pain.

There are a few drawbacks in this study.  They include the small size of the study, and that it involved a single investigator group, arguing for the need to replicate this study.  There is also no information about whether the improvements were durable.  Furthermore, although the results are encouraging, more discreet quantitative sensory tests would be helpful in determining the exact degree of sensory improvement experienced after the administration of ATS treatments.

Bhardwaj et al (2005) stated that an evolving understanding of laser-tissue interactions involving Propionibacterium acnes-produced porphyrins, and the development of infrared non-ablative lasers to target sebaceous glands, has lead to the development of an escalating number of laser, light and radiofrequency devices for acne.  Used as monotherapy or in combination, these devices are showing promise as a method to clear acne in a convenient, non-invasive manner, though there remains a clear need for long-term data and randomized, blinded studies.

Chow and Barnsley (2005) examined the effectiveness of low-level laser therapy (LLLT) in the treatment of neck pain through systematically reviewing the literature.  A search of computerized bibliographic databases covering medicine, physiotherapy, allied health, complementary medicine, and biological sciences was undertaken from date of inception until February 2004 for randomized controlled trials (RCTs) of LLLT for neck pain.  A comprehensive list of search terms was applied and explicit inclusion criteria were developed a priori.  A total of 20 studies were identified, 5 of which met the inclusion criteria.  Significant positive effects were reported in 4 of 5 trials in which infrared wavelengths (lambda = 780, 810 to 830, 904, 1,064 nm) were used.  Heterogeneity in outcome measures, results reporting, doses, and laser parameters precluded formal meta-analysis.  Effect sizes could be calculated for only 2 of the studies.  The authors concluded that this review provides limited evidence from 1 RCT for the use of infrared laser for the treatment of acute neck pain (n = 71) and chronic neck pain from 4 RCTs (n = 202).  They noted that larger studies are needed to confirm the positive findings, and determine the most effective laser parameters, sites and modes of application.

In a randomized controlled cross-over study, Stange-Rezende et al (2006) examined the effect of infrared radiation of a tiled stove on patients with hand osteoarthritis (OA).  A total of 45 patients with hand OA were randomly assigned to two groups:
  1. group A -- [first 3 hours spent 3 times a week during 3 weeks in a heated tiled stove room ('Stove Period') and after 2 weeks without treatment this group was observed for another 3 weeks ('control period')]; and
  2. group B (first assigned to the control period and the stove period following the treatment-free period). 

Assessments included the VAS for general pain, pain in the hands, and global hand function, grip strength, the Moberg Picking-up Test (MPUT), the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), and the Medical Outcomes Study (MOS) 36-item Short-Form Health Status Survey (SF-36).  A total of 14 (31 %) patients improved on the VAS for general pain at the end of the tiled stove period as compared to 10 patients (22 %) during the control period (p = 0.314, chi2-test).  The AUSCAN pain domain showed a significant improvement after the tiled stove period (p = 0.034).  Others pain parameters analyzed (VAS for pain in hands and SF-36 bodily pain) showed moderate but not significant improvement (p = 0.682 and p = 0.237, respectively) compared to the control period.  The authors concluded that this study did not prove positive effects of the tiled stove exposure, although the numerical improvement in all pain measures suggests some possible positive effects on this symptom of hand OA.

Lampl and colleagues (2007) assessed the safety and effectiveness of the NeuroThera Laser System to improve the 90-day outcomes in ischemic stroke patients treated within 24 hours from stroke onset.  The NeuroThera Laser System therapeutic approach involves use of infrared laser technology and has shown beneficial effects in animal models of ischemic stroke.  A total of 120 ischemic stroke patients were randomized in a 2:1 ratio (n = 79 patients in the active treatment group and n = 41 in the placebo control group).  Only patients with baseline stroke severity measured by National Institutes of Health Stroke Scale (NIHSS) scores of 7 to 22 were included.  Patients who received tissue plasminogen activator were excluded.  Outcome measures were the patients' scores on the NIHSS, modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale at 90 days after treatment.  The primary outcome measure was successful treatment, documented by NIHSS.  This was defined as a complete recovery at day 90 (NIHSS 0 to 1), or a decrease in NIHSS score of at least 9 points (day 90 versus baseline), and was tested as a binary measure (bNIH).  Secondary outcome measures included mRS, Barthel Index, and Glasgow Outcome Scale.  Primary statistical analyses were performed with the Cochran-Mantel-Haenszel rank test, stratified by baseline NIHSS score or by time to treatment for the bNIH and mRS.  Logistic regression analyses were conducted to confirm the results. Mean time to treatment was greater than 16 hours (median time to treatment 18 hours for active and 17 hours for control).  Time to treatment ranged from 2 to 24 hours.  More patients (70 %) in the active treatment group had successful outcomes than did controls (51 %), as measured prospectively on the bNIH (p = 0.035 stratified by severity and time to treatment; p = 0.048 stratified only by severity).  Similarly, more patients (59 %) had successful outcomes than did controls (44 %) as measured at 90 days as a binary mRS score of 0 to 2 (p = 0.034 stratified by severity and time to treatment; p = 0.043 stratified only by severity).  Also, more patients in the active treatment group had successful outcomes than controls as measured by the change in mean NIHSS score from baseline to 90 days (p = 0.021 stratified by time to treatment) and the full mRS ("shift in Rankin") score (p = 0.020 stratified by severity and time to treatment; p = 0.026 stratified only by severity).  The prevalence odds ratio for bNIH was 1.40 (95 % confidence interval [CI]: 1.01 to 1.93) and for binary mRS was 1.38 (95 % CI: 1.03 to 1.83), controlling for baseline severity.  Similar results held for the Barthel Index and Glasgow Outcome Scale.  Mortality rates and serious adverse events (SAEs) did not differ significantly (8.9 % and 25.3 % for active 9.8 % and 36.6 % for control, respectively, for mortality and SAEs).  The authors concluded that the NEST-1 study indicated that infrared laser therapy has shown initial safety and effectiveness for the treatment of ischemic stroke in humans when initiated within 24 hours of stroke onset.  They stated that a larger confirmatory trial to demonstrate safety and effectiveness is warranted.

A decision memorandum from the Centers for Medicare and Medicaid Services (2006) has concluded that “there is sufficient evidence to conclude that the use of infrared devices is not reasonable and necessary for treatment of Medicare beneficiaries for diabetic and non-diabetic peripheral sensory neuropathy, wounds and ulcers, and similar related conditions, including symptoms such as pain arising from these conditions”.

In a double-blind, sham-controlled, randomized study, Lavery et al (2008) examined the effectiveness of Anodyne monochromatic infrared energy (MIRE) in-home treatments over a 90-day period to improve peripheral sensation and self-reported quality of life (QOL) in individuals with diabetes.  A total of 69 individuals with diabetes and a vibration perception threshold (VPT) between 20 and 45 V were randomly assigned to 2 treatment groups:
  1. active or
  2. sham treatment. 

Sixty patients (120 limbs) completed the study.  Anodyne units were used at home every day for 40 minutes for 90 days.  Nerve conduction velocities, VPT, Semmes-Weinstein monofilaments (SWM) (4-, 10-, 26-, and 60-g monofilaments), the Michigan Neuropathy Screening Instrument (MNSI), a 10-cm visual analog pain scale, and a neuropathy-specific QOL instrument were measured.  A nested repeated-measures multiple ANOVA design was employed.  Two sites (great toe and 5th metatarsal) were tested on both the left and right feet of each patient, so two feet were nested within each patient and two sites were nested within each foot.  To analyze the ordinal SWM scores, a non-parametric factorial analysis for longitudinal data was used.  There were no significant differences in measures for QOL, MNSI, VPT, SWM, or nerve conduction velocities in active or sham treatment groups (p > 0.05).  The authors concluded that Anodyne MIRE therapy was no more effective than sham therapy in the treatment of sensory neuropathy in individuals with diabetes.

In a controlled, double-blind, randomized clinical study, Franzen-Korzendorfer et al (2008) examined the effect of monochromatic infrared energy on transcutaneous oxygen measurements and protective sensation in patients with diabetes and a loss of protective sensation.  A total of 18 adults (12 men, 6 women; mean age of 65 +/-13 years, range of 39 to 86 years) with diabetes and loss of protective sensation were recruited using convenience sampling methods.  All patients served as their own control.  Pre- and post-treatment tests assessed sensation, pain, and transcutaneous oxygen measurements on 2 sites/foot.  Subjects underwent a series of 30-min monochromatic infrared energy treatments (1 foot active treatment, 1 foot sham).  Monochromatic infrared energy was delivered at the manufacturer pre-set level of energy of 1.5 J/cm(2)/min at a wavelength of 890 nm; sham units delivered no energy.  Scores were analyzed using paired t-tests and Pearson's correlation coefficient. No significant differences were observed between active and sham treatments for transcutaneous oxygen values, pain, or sensation.  Both active and sham monochromatic infrared energy-treated feet had significantly improved sensation when compared to pretest baseline scores (p < 0.05).  No statistical relationship was found between transcutaneous oxygen and sensation.  The authors concluded that these findings did not demonstrate any effects of monochromatic infrared energy treatment on transcutaneous oxygen measurements, pain, or sensation in adults with diabetes and loss of protective sensation.

Ko and Berbrayer (2002) determined the effectiveness of ceramic impregnated gloves in the treatment of Raynaud's syndrome.  A total of 93 patients met the "Pal" criteria for Raynaud's syndrome.  Treatment period of 3 months with use of ceramic-impregnated gloves was adopted.  Primary end points included pain VAS ratings and diary; disabilities of the arm, shoulder, hand (DASH) questionnaire; Jamar grip strength; and Purdue board test of hand dexterity.  Secondary end points were infrared skin temperature measurements; 7-point Likert scale rating of treatment.  In 60 participants with complete data, improvements were noted in the VAS rating (p = 0.001), DASH score (p = 0.001), Jamar grip strength (p = 0.002), infrared skin fingertip temperature (p = 0.003), Purdue hand dexterity test (p = 0.0001) and the Likert scale (p = 0.001) with ceramic gloves over the placebo cotton gloves.  The authors concluded that the ceramic-impregnated "thermoflow" gloves have a clinically important effect in Raynaud's syndrome.  The findings of this study need to be validated by well-designed studies with larger number of patients and longer follow-ups.

Fitzgerald et al (2013) stated that abstract Irradiation in the red/near-infrared spectrum (R/NIR, 630 to 1,000 nm) has been used to treat a wide range of clinical conditions, including disorders of the central nervous system (CNS), with several clinical trials currently underway for stroke and macular degeneration.  However, R/NIR irradiation therapy (R/NIR-IT) has not been widely adopted in clinical practice for CNS injury or disease for a number of reasons, which include;
  1. the mechanism(s) of action and implications of penetration have not been thoroughly addressed,
  2. the large range of treatment intensities, wavelengths and devices that have been assessed make comparisons difficult, and
  3. a consensus paradigm for treatment has not yet emerged.

Furthermore, the lack of consistent positive outcomes in RCTs, perhaps due to sub-optimal treatment regimens, has contributed to skepticism.  These researchers provided a balanced summary of outcomes described in the literature regarding treatment modalities and efficacy of R/NIR-IT for injury and disease in the CNS.  They have addressed the important issues of specification of treatment parameters, penetration of R/NIR irradiation to CNS tissues and mechanism(s), and provided the necessary detail to demonstrate the potential of R/NIR-IT for the treatment of retinal degeneration, damage to white matter tracts of the CNS, stroke and Parkinson's disease.

Vujosevic et al (2013) reviewed the most important metabolic effects and clinical safety data of sub-threshold micropulse diode laser (D-MPL) in diabetic macular edema (DME).  The MPL treatment does not damage the retina and is selectively absorbed by the retinal pigment epithelium (RPE).  Micropulse diode laser stimulates secretion of different protective cytokines by the RPE.  No visible laser spots on the retina were noted on any fundus image modality in different studies, and there were no changes of the outer retina integrity.  Mean central retinal sensitivity (RS) increased in D-MPL group compared to standard Early Treatment Diabetic Retinopathy Study (ETDRS) photocoagulation group.  The authors concluded that MPL is a new, promising treatment option in DME, with both infrared and yellow wavelengths using the less aggressive duty cycle (5 %) and fixed power parameters.

The Work Loss Data Institute’s guideline on “Low back -- lumbar & thoracic (acute & chronic)” (2013) noted that infrared therapy is one of the interventions/procedures that were considered, but not recommended.

The evidence-based guidelines for the chiropractic treatment of adults with neck pain (Bryans et al, 2014) stated that “Based on inconsistent findings from 3 low-risk-of-bias studies, there is insufficient evidence that supports a recommendation for the use of infrared laser (830 nm) in the treatment of chronic neck pain”.

Choi et al (2016) noted that maintenance of a well-functioning vascular access and minimal needling pain are important goals for achieving adequate dialysis and improving the quality of life in hemodialysis (HD) patients. Far-infrared therapy may improve endothelial function and increase access blood flow (Qa) and patency in HD patients.  These researchers evaluated effects of FIR therapy on Qa and patency, and needling pain in HD patients.  This prospective clinical trial enrolled 25 outpatients who maintained HD with arterio-venous fistula.  The other 25 patients were matched as control with age, sex, and diabetes; FIR therapy was administered for 40 minutes during HD 3 times/week and continued for 12 months.  The Qa was measured by the ultrasound dilution method, whereas pain was measured by a numeric rating scale at baseline, then once per month.  One patient was transferred to another facility, and 7 patients stopped FIR therapy because of an increased body temperature and discomfort.  Far-infrared therapy improved the needling pain score from 4 to 2 after 1 year; FIR therapy increased the Qa by 3 months and maintained this change until 1 year, whereas control patients showed the decrease in Qa.  The 1-year unassisted patency with FIR therapy was not significantly different from control.  The authors concluded that FIR therapy improved needling pain.  Moreover, they stated that although FIR therapy improved Qa, the unassisted patency was not different compared with the control.  They stated that a larger and multi-center study is needed to evaluate the effect of FIR therapy.

Infrared Coagulation for the Treatment of Hemorrhoids

Infrared coagulation is one of the several non-surgical outpatient therapies in treating hemorrhoids.  Linares et al (2001) examined the effectiveness of rubber band ligation (RBL) and infrared photocoagulation (IRC) in treating internal hemorrhoids in 358 patients with a total of 817 hemorrhoid.  There was a follow-up period of 36 months.  Two hundred ninety five of 358 patients were treated with RBL (82.4 %), this treatment being effective in 98 % of the patients after 180 days and very good after 36 months.  There were 6/295 relapses at 36 months (2 %).  All minor and major complications were observed within the first 15 days of treatment: rectal tenesmus in 96/295 patients (32.5 %), mild anal pain in 115/295 (38.9 %), self-limited and mild bleeding after the detachment of the bands in 30/295 (10 %), and febricula in one patient.  Sixty-three of 358 patients were treated with IRC (17.6 %).  In this group, relapses were observed in 6/63 patients (9.5 %) at 36 months, all of them with grade III hemorrhoids that required additional treatment with RBL.  All the complications (inherent to the technique) were observed within the first days: mild anal pain in 40/63 patients (63.4 %) and mild bleeding in 1/63 (1.6 %).  The treatment with RBL or IRC depended on the number of hemorrhoids and the hemorrhoidal grade.  No significant differences were found regarding the effectiveness between RBL and IRC for the treatment of grade I-II hemorrhoids, while RBL was more effective for grade III and IV hemorrhoids (p < 0.05).  The authors concluded that RBL and IRC should be considered as a good treatment for all grades of hemorrhoids, due to its effectiveness, its cost-benefit and its small short-term and long-term morbidity.

In a randomized study, Gupta (2003) compared infrared coagulation and rubber band ligation in treating patients with early stages of hemorrhoids.  One hundred patients with second degree bleeding piles were randomized prospectively to either rubber band ligation (n = 54) or infrared coagulation (n = 46).  Parameters measured included post-operative discomfort and pain, time to return to work, relief in incidence of bleeding, and recurrence rate.  Post-operative pain during the first week was more intense in the band ligation group (2 to 5 versus 0 to 3 on a VAS).  Post-defecation pain was more intense with band ligation and so was rectal tenesmus (p = 0.0059).  The patients in the infrared coagulation group resumed their duties earlier (2 versus 4 days, p = 0.03), but also had a higher recurrence or failure rate (p = 0.03).  The authors concluded that band ligation, although more effective in controlling symptoms and obliterating hemorrhoids, is associated with more pain and discomfort to the patient.  As infrared coagulation can be conveniently repeated in case of recurrence, it could be considered to be a suitable alternative office procedure for the treatment of early stage hemorrhoids.

The American Gastroenterological Association’s technical review on the diagnosis and treatment of hemorrhoids (Madoff and Fleshman, 2004) stated that 1st degree and 2nd degree hemorrhoids (i.e., Grade I and Grade II hemorrhoids) can be treated with non-operative therapies such as infrared photocoagulation.  Surgery is generally reserved for individuals who have large 3rd degree or 4th degree hemorrhoids, acutely incarcerated and thrombosed hemorrhoids, hemorrhoids with an extensive and symptomatic external component, or individuals who have undergone less aggressive therapy with poor results.


Nenoff et al (2014) noted that since 2010 the Food and Drug Administration (FDA) has approved laser systems as capable of producing a "temporary increase in clear nails" in patients with onychomycosis.  Fungal eradication is probably mediated by heat in infrared laser systems; their efficacy has been confirmed thermographically, histologically and in electron microscopy.  Another approach to decontaminate the nail organ is to disrupt fungi and spores by q-switched pulse applications.  Recently specific combinations of wavelengths have been tested for their ability to disrupt the mitochondrial transmembrane potential at physiological temperatures by generating ATP and ROS.  While clinically extremely high clearance rates of approximately 87.5 to 95.8 % have been reported, in-vitro investigations have failed to confirm the clearance.  The variety of systems and advised parameters hampers a systematic evaluation.  Recommendations for safe and practical treatment protocols, informed consent items, and combination with conventional treatment options are all areas of active work.  The authors concluded that currently there is a lack of data concerning the long-term efficacy of laser therapy of onychomycosis; certified treatment protocols are needed.

An UpToDate review on “Onychomycosis” (Goldstein, 2015) states that “Laser/light therapy -- Although neodymium-doped:yttrium aluminum garnet (Nd:YAG) and diode lasers have emerged as treatment options for onychomycosis, data on the efficacy of these interventions are limited and the mechanisms of action and optimal regimens for these treatments remain unclear.  Until more robust data supporting the efficacy of laser therapy for onychomycosis are available, we cannot recommend the routine use of this modality.  Support for the efficacy of such laser devices is primarily limited to uncontrolled studies that document clinical improvement in varying proportions of patients.  One small randomized trial found improvement in onychomycosis following the use of a dual wavelength near-infrared diode laser.  In contrast, a randomized trial in which 27 patients with onychomycosis involving 125 nails were randomly assigned to two treatments with a 1,064 nm Nd:YAG laser (17 patients) or no treatment (10 patients) did not find a statistically difference in the proportion of patients with mycological clearance of all affected nails after three months.  In addition, a non-significant trend towards greater proximal nail clearance in the active treatment group detected at the 3-month time point dissipated by 12 months.  Of note, responses could not be assessed in 5 of the 17 patients in the laser treatment group because of a failure to return for follow-up.  Further study with randomized trials that compare laser devices to placebo and other onychomycosis treatments as well as long-term follow-up studies will be useful for clarifying the efficacy, mechanisms, optimal regimens, and indications for laser therapy”.

Pressure Ulcers

The National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance’s clinical practice guideline on “Treatment of pressure ulcers” (2014) stated that “Due to current insufficiency of evidence to support or refute the use of infrared therapy in the treatment of pressure ulcers, infrared therapy is not recommended for routine use at this time”.

Other Indications

Shui and colleagues (2015) noted that physical therapy (physiotherapy), a complementary and alternative medicine therapy, has been widely applied in diagnosing and treating various diseases and defects.  Increasing evidence suggests that convenient and non-invasive far-infrared (FIR) rays, a vital type of physiotherapy, improve the health of patients with cardiovascular disease, diabetes mellitus, and chronic kidney disease.  Nevertheless, the molecular mechanisms by which FIR functions remain elusive.  These researchers reviewed and summarized the results of previous investigations and elaborated on the molecular mechanisms of FIR therapy in various types of disease.  The authors concluded that FIR therapy may be closely related to the increased expression of endothelial nitric oxide synthase as well as nitric oxide production and may modulate the profiles of some circulating miRNAs; thus, it may be a beneficial complement to treatments for some chronic diseases that yields no adverse effects.

Disorders of Consciousness

Werner et al (2016) stated that in order to promote alertness and awareness in patients with severe disorders of consciousness (DOC) frontal near infrared laser stimulation (N-LT) or transcranial focused shock wave therapy (F-SWT) might be an option. The study compared both techniques in severe chronic DOC patients.  A total of 16 DOC patients were allocated to 2 groups (A and B).  A 3-week baseline either followed a frontal N-LT (0,1 mJ/mm2, 10 mins per session), 5 times a week over 4 weeks (group A), or a F-SWT (0,1 mJ/mm2, 4,000 stimuli per session) 3 times a week over 4 weeks (group B).  The primary variable was the revised Coma Recovery Scale (r-CRS, 0-23), blindly assessed.  Both groups improved in the r-CRS over time, but revealed no differences between groups.  One patient of group B had a focal seizure in the 3rd therapy week; 1 patient with akinetic mutism improved most and 3 patients with global hypoxia did not improve at all.  The authors concluded that both options might be an option to increase alertness and awareness of chronic DOC patients.  An akinetic mutism appeared to be a positive and severe cerebral hypoxia a negative predictor; epileptic seizures are a potential unwanted side effect.  The author stated that more clinical studies are needed.

Seasonal Affective Disorder

In a Cochrane review, Nussbaumer et al (2015) evaluated the safety and effectiveness of light therapy (in comparison with no treatment, other types of light therapy, 2nd-generation antidepressants, melatonin, agomelatine, psychological therapies, lifestyle interventions and negative ion generators) in preventing seasonal affective disorder (SAD) and improving patient-centered outcomes among adults with a history of SAD. A search of the Specialised Register of the Cochrane Depression, Anxiety and Neuorosis Review Group (CCDANCTR) included all years to August 11, 2015.  The CCDANCTR contained reports of relevant RCTs derived from Embase (1974 to date), Medline (1950 to date), PsycINFO (1967 to date) and the Cochrane Central Register of Controlled Trails (CENTRAL).  Furthermore, these investigators searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, the Cochrane Library and the Allied and Complementary Medicine Database (AMED) (to May 26, 2014).  These researchers also conducted a grey literature search and hand-searched the reference lists of all included studies and pertinent review articles.  For effectiveness, the authors included RCTs on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study.  For adverse events, the authors also intended to include non-randomized studies.  They intended to include studies that compared any type of light therapy (e.g., bright white light, administered by visors or light boxes, infrared light, dawn stimulation) versus no treatment/placebo, 2nd-generation antidepressants (SGAs), psychological therapies, melatonin, agomelatine, lifestyle changes, negative ion generators or another of the afore-mentioned light therapies.  The authors also planned to include studies that looked at light therapy in combination with any comparator intervention and compared this with the same comparator intervention as monotherapy.  Two review authors screened abstracts and full-text publications against the inclusion criteria.  Two review authors independently abstracted data and assessed risk of bias of included studies.  These investigators identified 2,986 citations after de-duplication of search results.  They excluded 2,895 records during title and abstract review.  They assessed 91 full-text papers for inclusion in the review, but only 1 study providing data from 46 people met the eligibility criteria.  The included RCT had methodological limitations.  These researchers rated it as having high risk of performance and detection bias because of lack of blinding, and as having high risk of attrition bias because study authors did not report reasons for drop-outs and did not integrate data from drop-outs into the analysis.  The included RCT compared preventive use of bright white light (2,500 lux via visors), infrared light (0.18 lux via visors) and no light treatment.  Overall, both forms of preventive light therapy reduced the incidence of SAD numerically compared with no light therapy.  In all, 43 % (6/14) of participants in the bright light group developed SAD, as well as 33 % (5/15) in the infrared light group and 67 % (6/9) in the non-treatment group.  Bright light therapy reduced the risk of SAD incidence by 36 %; however, the 95 % CI was very broad and included both possible effect sizes in favor of bright light therapy and those in favor of no light therapy (risk ratio (RR) 0.64, 95 % CI: 0.30 to 1.38).  Infrared light reduced the risk of SAD by 50 % compared with no light therapy, but in this case also the CI was too broad to allow precise estimations of effect size (RR 0.50, 95 % CI 0.21 to 1.17).  Comparison of both forms of preventive light therapy versus each other yielded similar rates of incidence of depressive episodes in both groups (RR 1.29, 95 % CI: 0.50 to 3.28).  The quality of evidence for all outcomes was very low.  Reasons for down-grading evidence quality included high risk of bias of the included study, imprecision and other limitations, such as self-rating of outcomes, lack of checking of compliance throughout the study duration and insufficient reporting of participant characteristics.  Investigators provided no information on adverse events.  These researchers could find no studies that compared light therapy versus other interventions of interest such as SGA, psychological therapies, melatonin or agomelatine.  The authors concluded that evidence on light therapy as preventive treatment for patients with a history of SAD is limited.  Methodological limitations and the small sample size of the only available study have precluded review author conclusions on effects of light therapy for SAD. 

Nussbaumer-Streit and colleagues (2019) noted that SAD is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring.  The prevalence of SAD ranges from 1.5 % to 9 %, depending on latitude.  The predictable seasonal aspect of SAD provides a promising opportunity for prevention.  This review -- 1 of 4 reviews on efficacy and safety of interventions to prevent SAD -- focused on light therapy as a preventive intervention.  Light therapy is a non-pharmacological therapy that exposes people to artificial light; mode of delivery and form of light vary.  These investigators examined the safety and efficacy of light therapy (in comparison with no treatment, other types of light therapy, 2nd-generation anti-depressants, melatonin, agomelatine, psychological therapies, lifestyle interventions and negative ion generators) in preventing SAD and improving patient-centered outcomes among adults with a history of SAD.  They searched Ovid Medline (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to June 19, 2018.  An earlier search of these data-bases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to August 11, 2015).  Furthermore, these investigators searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to June 19, 2018).  They also conducted a grey literature search and hand-searched the reference lists of included studies and pertinent review articles.  For efficacy, these investigators included RCTs on adults with a history of winter-type SAD who were symptoms-free at the beginning of the study.  For AEs, these researchers also intended to include non-randomized studies.  These researchers intended to include studies that compared any type of light therapy (e.g., bright white light, administered by visors or light boxes, IR light, dawn stimulation) versus no treatment/placebo, 2nd-generation anti-depressants, psychological therapies, melatonin, agomelatine, lifestyle changes, negative ion generators or another of the afore-mentioned light therapies.  They also planned to include studies that examined light therapy in combination with any comparator intervention.  Two review authors screened abstracts and full-text publications, independently abstracted data and assessed risk of bias of included studies.  They identified 3,745 citations after de-duplication of search results, excluded 3,619 records during title and abstract review.  These investigators evaluated 126 full-text papers for inclusion in the review, but only 1 study providing data from 46 people met the eligibility criteria.  The included RCT had methodological limitations.  These investigators rated it as having high risk of performance and detection bias because of lack of blinding, and as having high risk of attrition bias because study authors did not report reasons for drop-outs and did not integrate data from drop-outs into the analysis.  The included RCT compared preventive use of bright white light (2,500 lux via visors), IR light (0.18 lux via visors) and no light treatment.  Overall, white light and IR light therapy reduced the incidence of SAD numerically compared with no light therapy.  In all, 43 % (6/14) of subjects in the bright light group developed SAD, as well as 33 % (5/15) in the IR light group and 67 % (6/9) in the non-treatment group.  Bright light therapy reduced the risk of SAD incidence by 36 %; however, the 95 % CI was very broad and included both possible effect sizes in favor of bright light therapy and those in favor of no light therapy (RR 0.64, 95 % CI: 0.30 to 1.38; 23 subjects, very low-quality evidence).  Infrared light reduced the risk of SAD by 50 % compared with no light therapy, but the CI was also too broad to allow precise estimations of effect size (RR 0.50, 95 % CI: 0.21 to 1.17; 24 subjects, very low-quality evidence).  Comparison of both forms of preventive light therapy versus each other yielded similar rates of incidence of depressive episodes in both groups (RR 1.29, 95 % CI: 0.50 to 3.28; 29 subjects, very low-quality evidence).  Reasons for down-grading evidence quality included high risk of bias of the included study, imprecision and other limitations, such as self-rating of outcomes, lack of checking of compliance throughout the study duration and insufficient reporting of subject characteristics.  Investigators provided no information on AEs.  They found no studies that compared light therapy versus other interventions of interest such as 2nd-generation anti-depressants, psychological therapies, melatonin or agomelatine.  The authors concluded that evidence on light therapy as preventive treatment for individuals with a history of SAD was limited.  Methodological limitations and the small sample size of the only available study have precluded review author conclusions on effects of light therapy for SAD.  These researchers stated that given that comparative evidence for light therapy versus other preventive options was limited, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences.


Tsai and Hamblin (2017) noted that IR radiation is electromagnetic radiation with wavelengths between 760 and 100,000 nm while LLLT or photobiomodulation (PBM) therapy generally employs light at red and near-IR wavelengths (100 to 600 nm) to modulate biological activity.  Many factors, conditions, and parameters influence the therapeutic effects of IR, including fluence, irradiance, treatment timing and repetition, pulsing, and wavelength.  Increasing evidence suggested that IR can carry out photo-stimulation and PBM effects particularly benefiting neural stimulation, wound healing, and cancer treatment.  Nerve cells respond particularly well to IR, which has been proposed for a range of neuro-stimulation and neuro-modulation applications, and recent progress in neural stimulation and regeneration were discussed in this review.

Hou and co-workers (2017) stated that theranostics based on nanoparticles have developed rapidly in the past decade and have been widely used in the diagnosis and treatment of liver cancer, breast cancer, and other tumors.  However, for skin cancers, there are limited studies.  These researchers successfully synthesized a theranostic nanoparticle by grating IR820 onto the surface of chitosan-coated magnetic iron oxide, IR820-CS-Fe3O4, showing an excellent magnetic resonance imaging (MRI) capability and cytotoxic effects against melanoma under irradiation with a near-infrared (NIR) laser (808 nm) in-vitro.  Furthermore, good stability for up to 8 days and negligible cytotoxicity were observed; these characteristics are important for biomedical applications of nanoparticles.  The authors concluded that they provided a novel and potential theranostic platform for melanoma treatment and detection.

Zhang and colleagues (2017) noted that although triple-negative breast cancer (TNBC) is a small percentage of all breast cancers, to date, TNBC is one of the most challenging types of breast cancer for basic and clinic research because TNBC patients display a high risk of relapse, shorter overall survival (OS) and limited therapeutic options after completion of conventional chemotherapy compared with patients with other BC subtypes.  The epidermal growth factor receptor (EGFR) is a promising target for TNBC treatment.  Although NIR photo-thermal therapy (NIR-PTT) using anti-EGFR antibody-conjugated gold nanorods (anti-EGFR-GNs), has attracted considerable interest for non-invasive and targeted TNBC treatment through an activation of apoptotic pathway, it is unclear whether anti-EGFR-GNs-combined NIR-PTT modulates the induction of autophagy contributing to cell death.  These researchers examined the autophagic cell death in cultured TNBC cells and mouse xenograft tumors during anti-EGFR-GNs-combined NIR-PTT.  They found that the cytotoxicity induced by anti-EGFR-GNs-combined NIR-PTT was rescued by treatment with autophagy inhibitor, 3-methyladenine (3-MA).  Anti-EGFR-GNs-combined NIR-PTT induced remarkable levels of autophagy activity as evidenced by a large number of autophagic vesicles and a significant increase in autophagy-specific proteins; microtubule-associated protein light chain 3 (LC3), p62, beclin-1, and autophagy-related gene5 (Atg5), accompanying the inhibition of AKT-mTOR signaling pathway responsible for inducing autophagy.  Moreover, in mouse xenograft tumors, anti-EGFR-GNs-combined NIR-PTT also increased LC3 and beclin-1 levels.  The authors concluded that these findings, for the first time, demonstrated that anti-EGFR-GNs-combined NIR-PTT remarkably induced autophagy leading to EGFR-targeted cancer cell death.

Xu and associates (2017) stated that while immunotherapy has become a highly promising paradigm for cancer treatment (e.g., colorectal cancer) in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger anti-tumor immune responses.  However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors.  Up-conversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist.  The obtained multi-tasking UCNP-Ce6-R837 nanoparticles under NIR irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong anti-tumor immune responses.  More significantly, PDT with UCNP-Ce6-R837 in combination with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only showed excellent effectiveness in eliminating tumors exposed to the NIR laser, but also resulted in strong anti-tumor immunities to inhibit the growth of distant tumors left behind after PDT treatment.  Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell re-challenge.  The authors concluded that these findings presented an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence via the immune memory effect.


Song et al (2015) examined the clinical value of the combination of ultrasound-and-hyponome-guided type A botulinum toxin injection and infrared polarized light on treating chronic migraine.  A total of 91 patients with chronic migraine were randomly divided into 4 groups:
  1. in the control group (group A, 22 cases in total), nimodipine was used in the treatment of chronic migraine for 2 months;
  2. in the infrared polarized light therapy group (group B, 22 cases in total), infrared polarized light was adopted in the treatment of chronic migraine for 50 to 60 days;
  3. in the botulinum toxin treatment group (group C, 24 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin was injected into frontal, temporal, and occipital muscles in treating chronic migraine; and
  4. in the joint treatment group (group D, 23 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin injection in group C and infrared polarized light in group B were both used here in the treatment of chronic migraine. 

Infrared polarized light therapy lasted 50 to 60 days and the time of study lasted 6 months.  The survey would include the conditions of patients with chronic migraine 3 months before treatment and at 1, 3 and 6 months after treatment.  Patients were asked to fill the MIDAS (migraine disability assessment questionnaire) and were graded on the evaluation scale of quality of life (QOL), so that the researchers would be able to compare attack frequency, duration of attack, attack severity, the use of painkillers and their recovery from chronic migraine, and then observe their adverse reactions.  A total of 11 cases dropped out during the treatment, 3 cases in A group, 2 cases in group B, 4 cases in group C and 2 cases in group D.  At 1, 3 and 6 months after treatment, the MIDAS scores in group A, B, C and D were significantly lower than before the treatment.  Hence, the differences were statistically significant (p < 0.01).  The scores in QOL rating scale were significantly higher than pre-treatment scores, so the difference was statistically significant (p < 0.01).  The MIDAS scores and QOL rating scale scores in group D were compared with those in group A, B, and C respectively, and the differences were statistically significant (p < 0.05); 2 patients were recorded with dizziness, and the dizziness disappeared after 2 weeks with no treatments at all.  Forehead lines and crow's feet of 21 patients shallowed or disappeared in varying degrees after the injection.  The authors concluded that the combination of ultrasound-and-hyponome-guided type A botulinum toxin injection and infrared polarized light on treating chronic migraine demonstrated a significant clinical effect.  Moreover, they stated that further studies in large samples and multi-centers are needed in the clinical application.  This was a small study (n = 23 in the joint treatment group with 2 dropouts) and its findings were confounded by the combined use of Botox and infrared therapy.

Furthermore, UpToDate reviews on “Chronic migraine” (Garza and Schwedt, 2018), “Acute treatment of migraine in adults” (Bajwa and Smith, 2018a), and “Preventive treatment of migraine in adults” (Bajwa and Smith, 2018b) do not mention infrared as a therapeutic option.

Non-Diabetic Peripheral Neuropathy

Miriutova et al (2002) reported the findings of 73 patients with compression-ischemic myeloradiculopathy received treatment including infrared laser radiation on the paravertebral fields, motor points of the affected nerves and biologically active points Y63, Y67, YB34, YB42, YB43, E34, E42 (1.0 to 5.0 mW/cm2; 5- and 5,000-Hz), electrostimulation of motor nerve points and innervated by them muscles by double square impulses with a fixed gap 5 ms.  The authors concluded that impulse infrared laser therapy relieved pain syndrome, stimulated repair processes in the affected nerve structures.  Further modified electric stimulation activated a regenerative growth of the nerve fibers, re-innervation of the limb muscles.  This was an uncontrolled study.

Foto et al (2007) compared the accuracy, reliability, and essential features of 9 commercially available hand-held infrared thermometers used to manage the neuropathic foot.  The thermometers were compared using 2 temperature-control sources simulating physiologic conditions found in a foot-care clinic.  With each control source independently set, temperature difference ranges of 0 degrees, 2 degrees, 4 degrees, and 6 degrees C were randomly sampled and analyzed for each thermometer by 2 testers.  The order of testing was randomly assigned for testers and instruments.  There were differences in mean temperature change among thermometers (p < 0.001) and between testers (p = 0.0247).  Differences in mean temperature change among instruments (less than 0.5 degrees C), although small, could affect interpretation of skin temperature if temperature comparisons were made using 2 different instruments.  The difference in temperature change between testers (0.06 degrees C) was not large enough to affect decisions in clinical practice.  Instrument response time, distance-to-spot ratio, sensor diameter, display resolution, emissivity, and cost were compared.  The authors concluded that the low-cost, general-use infrared thermometers used in this study showed good accuracy, reliability, and performance and were appropriate for use in a foot-care clinic.  This study did not provide any data to support the effectiveness of these devices in treating peripheral neuropathy.

Schencking et al (2008) reported on the case of a 67-year old female patient who suffered from a persisting and acutely exacerbated radiculopathy (L5/S1 right) due to metastases of breast cancer (pT1bL0N1R1G2M1/osseous; ER 95 %, PR 95 %, Her2-new-score 3+) in the lumbar spine.  Traditional treatments had failed to yield sufficient therapeutic effects.  These investigators performed 6 sessions of water-filtered infrared-A whole-body hyperthermia using a commercial system (Iratherm 1000; Von Ardenne Institute for Applied Medical Research, Dresden, Germany).  The wave-length was 600 to 1,300 nm, the aimed body core temperature was 38.5 degrees C.  The intensity of pain was assessed by visual analog scale (VAS).  Pain intensity (VAS) decreased from 9 (initial) to 3 points after the first 3 treatment sessions.  The patient was completely free of pain after 6 sessions.  No side-effects were observed.  At follow-up after 3 and 24 weeks the patient was still pain-free.  The authors concluded that infrared-A whole-body hyperthermia might be an effective therapeutic procedure with rare side-effects for tumor-induced neuropathic pain.  However, its use should be investigated further in controlled clinical trials.

Spinocerebellar Ataxia

Liu and colleagues (2019) noted that spinocerebellar ataxia type 3 (SCA3) is a poly-glutamine neurodegenerative disease resulting from the mis-folding and accumulation of a pathogenic protein, causing cerebellar dysfunction, and this disease currently has no effective treatments.  Far-infrared radiation (FIR) has been found to protect the viability of SCA3 cells by preventing mutant ataxin-3 protein aggregation and promoting autophagy.  However, this possible treatment still lacks in-vivo evidence.  These researchers examined the effect of FIR therapy on SCA3 in-vivo by using a mouse model over 28 weeks.  Control mice carried a healthy wild-type ATXN3 allele that had a poly-glutamine tract with 15 CAG repeats (15Q), whereas SCA3 transgenic mice possessed an allele with a pathological poly-glutamine tract with expanded 84 CAG (84Q) repeats.  The results showed that the 84Q SCA3 mice displayed impaired motor coordination, balance abilities, and gait performance, along with the associated loss of Purkinje cells in the cerebellum, compared with the normal 15Q controls; nevertheless, FIR treatment was sufficient to prevent those defects. FIR significantly improved performance in terms of maximal contact area, stride length, and base support in the fore-paws, hind-paws, or both.  Moreover, FIR treatment supported the survival of Purkinje cells in the cerebellum and promoted the autophagy, as reflected by the induction of autophagic markers, LC3II and Beclin-1, concomitant with the reduction of p62 and ataxin-3 accumulation in cerebellar Purkinje cells, which might partially contribute to the rescue mechanism.  The authors concluded that these findings revealed that FIR conferred therapeutic effects in an SCA3 transgenic animal model and therefore has considerable potential for future clinical use.

Traumatic Brain Injury

Yao and colleagues (2018) stated that traumatic brain injury (TBI) has become a major health and socioeconomic problem affecting young people and military personnel.  Numerous TBI patients experienced the sequela of brain injury called cognitive impairment, which reduced functions in attention, working memory, motivation, and execution.  In recent years, transcranial near-infrared laser therapy (tNiRLT) as a possible therapy gradually applied in treating cognitive impairment post-TBI.  In the present review, the biological mechanisms of transcranial tNiRLT for TBI are synthesized mainly based on the photonic impact to chronic mild TBI.  Various exciting molecular events possibly occur during the procedure, such as stimulation of ATP production, regional cerebral blood flow (CBF), acupoint, neurogenesis and synaptogenesis, reduction of anti-inflammatory also existed.  Some animal experiments and clinical studies of tNiRLT for TBI were outlined.  Several labs have displayed that tNiRLT is effective not only improving neurological functions but also increasing memory and learning capacity in rodent animals’ model of TBI.  In a 2-patient case report and a 11-case series, cognitive functions were ameliorated.  Efficacy on cognitive and emotional effects was also observed in a double-blind, controlled clinical study.  The authors concluded that several randomized, parallel, double-blinded, sham-controlled trials are underway, aiming to evaluating the efficacy of tLED on cognitive functions and neuropsychiatric status in participants with TBI.  Thus, tNiRLT is a promising method applied to cognitive impairment following TBI.

In a case-series study, Hipskind and colleagues (2019) examined the outcome of applying red/near-infrared light therapy using light-emitting diodes (LEDs) pulsed with 3 different frequencies trans-cranially to treat TBI in military veterans.  A total of 12 symptomatic subjects diagnosed with chronic TBI of greater than 18 months post-trauma received pulsed trans-cranial PBM therapy (tPBMT) using 2 neoprene therapy pads containing 220 infrared and 180 red LEDs, generating a power output of 3.3 W and an average power density of 6.4 mW/cm2 for 20 mins, thrice-weekly over 6 weeks.  Outcome measures included standardized neuropsychological test scores and qualitative and quantitative single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF).  Pulsed tPBMT significantly improved neuropsychological scores in 6 of 15 subscales (40.0 %; p < 0.05; 2-tailed).  SPECT analysis showed increase in rCBF in 8 of 12 (66.7 %) study subjects.  Quantitative SPECT analysis revealed a significant increase in rCBF in this subgroup of study subjects and a significant difference between pre-treatment and post-treatment gamma ray counts/cc [t = 3.77, df = 7, p = 0.007, 95 % CI: 95,543.21 to 21,931.82].  The authors noted that this was the first study to report quantitative SPECT analysis of rCBF in regions of interest following pulsed tPBMT with LEDs in TBI.  They concluded that pulsed tPBMT using LEDs showed promise in improving cognitive function and rCBF several years after TBI; moreover, larger, controlled studies are needed.

The authors concluded that the limitations of this study included the use of a small, voluntary sample (n = 12) with no control or sham treatment groups for comparison.  This was a case series design in which all subjects received the same treatment and blinding of subjects and clinicians administering the treatment was not performed.  Unconscious experimenter bias and placebo effects must be controlled in future studies.  Alternate forms of neuropsychological assessments were not used due to budget, personnel, and time constraints, introducing potential practice effects.  A third limitation was the possibility that regression to the mean could partially explain the results of the quantitative SPECT analyses due to the selection criteria cut-off of z less than or equal to 1.00.  Theoretically, removal of selection criteria would alleviate this issue; however, it is one of the best practice identifiers for the decreased rCBF associated with TBI.  Another possible limitation was the reproducibility of SPECT, although research showed SPECT reproducibility to be between ± 1.3 % and 5 %.

Bone Regeneration

Tani and colleagues (2018) noted that PBM has been used for bone regenerative purposes in different fields of medicine and dentistry, but contradictory results demand a skeptical look for its potential benefits.  In an in-vitro study, these researchers compared PBM potentiality by red (635 ± 5 nm) or near-infrared (NIR, 808 ± 10 nm) diode lasers and violet-blue (405 ± 5 nm) light-emitting diode operating in a continuous wave with a 0.4 J/cm² energy density, on human osteoblast and mesenchymal stromal cell (hMSC) viability, proliferation, adhesion and osteogenic differentiation.  PBM treatments did not alter viability (PI/Syto16 and MTS assays).  Confocal immunofluorescence and RT-PCR analyses indicated that red PBM on both cell types increased vinculin-rich clusters, osteogenic markers expression (Runx-2, alkaline phosphatase, osteopontin) and mineralized bone-like nodule structure deposition; and on hMSCs induced stress fiber formation and up-regulated the expression of proliferation marker Ki67.  Interestingly, osteoblast responses to red light were mediated by Akt signaling activation, which appeared to positively modulate reactive oxygen species levels.  Violet-blue light-irradiated cells behaved essentially as untreated ones and NIR irradiated ones displayed modifications of cytoskeleton assembly, Runx-2 expression and mineralization pattern.  The authors concluded that although within the limitations of an in-vitro experimentation, this study may suggest PBM with 635 nm laser as potential effective option for promoting/improving bone regeneration.

Temporomandibular Disorder

Sousa and colleagues (2019) temporomandibular disorder (TMD) is considered the main cause of orofacial pain of non-dental origin, and a public health problem.  The symptomatology is muscular and/or articular pain, restriction of the mandibular range of motion (ROM), and changes in the mandibular movement pattern.  Due to its complexity there are already treatments using various forms of therapy.  Photo-biomodulation using light sources, such as low-level laser or light emitting diodes (LED), with different wavelengths, in a single or combined form, allows one more therapeutic resource to be explored.  The objective of this study is to evaluate the effects of PBM with the simultaneous use of red and infrared LEDs, on pain, range of mandibular movements, and on the electrical activity of masticatory muscles in individuals with TMD.  A randomized, controlled, double-blind clinical trial is proposed, which will involve 33 individuals (n  = 11 per group) of both sexes, aged 18 to 45 years in 3 groups: LED group; placebo group; and control group, submitted to 6 non-consecutive sessions of PBM totaling 2 weeks of treatment.  The Research Diagnostic Criteria for Temporomandibular Disorders-RDC/TMD will be used to assess and determine subjects’ TMD; pain will be assessed using the VAS, the mandibular ROM will be determined with the aid of a digital caliper, and the electrical activity of the masticatory muscles will be verified by electromyography (EMG).  A mixed plate of 18 red LEDs-660 nm and 18 infrared LEDs-850 nm with power of 3.5 mW per LED, 4.45 mW/cm, radiant exposure of 5.35 J/cm, will be used for PBM.  The irradiated area will be 14.13 cm, and energy of 75.6 J, in the TMJ region and in the bilateral masseter and temporal muscles.  Subjects from all groups will be re-assessed after the first therapeutic intervention, and at the end of treatment.  The authors expect the use of PBM with LEDs, infra and red, to reduce pain, improve temporomandibular joint function in patients with TMD, and thus improve the general conditions of the patient.


Tripodi et al (2022) noted that tendinopathy is a common clinical condition that can significantly affect a person's physical function and QOL.  Despite exercise therapy being the mainstay of tendinopathy management, there are many potential adjunct therapies that remain under-investigated, one of which is PBM, which employs varied wavelengths of light to create a biological effect.  While PBM is used frequently in the management of tendinopathy, high quality evidence supporting its use is lacking.  These researchers carried out a systematic search of the PubMed, CINAHL, SCOPUS, Cochrane Database, Web of Science and SPORTSDICUS databases for eligible articles in August 2020; RCTs that employed red or near-IR PBM to treat tendinopathy disorders that made comparisons with a sham or “other” intervention were included.  Pain and function data were extracted from the included studies.  The data were synthesized using a random effects model.  The meta-analysis was performed using the mean difference (MD) and standardized mean difference (SMD) statistics.  A total of 17 trials were included (n = 835).  When compared solely to other interventions, PBM resulted in similar decreases in pain (MD -0.09; 95 % CI: - 0.79 to 0.61) and a smaller improvement in function (SMD -0.52; 95 % CI: - 0.81 to - 0.23).  When PBM plus exercise was compared to sham treatment plus exercise, PBM demonstrated greater decreases in pain (MD 1.06; 95 % CI: 0.57 to 1.55) and improved function (MD 5.65; 95 % CI: 0.25 to 11.04).  When PBM plus exercise was compared to other interventions plus exercise, no differences were noted in pain levels (MD 0.31; 95 % CI: - 0.07 to 0.70).  Most studies were judged as low risk of bias.  The outcome measures were classified as very-low-to-moderate evidence quality according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool.  The authors concluded that there is very-low-to-moderate quality evidence demonstrating that PBM has utility as a stand-alone and/or adjunctive therapy for tendinopathy disorders.  Moreover, these researchers stated that more robust RCTs that adhere to the Consolidated Standard of Reporting Trials (CONSORT) guidelines need to be performed to further examine its effectiveness.

The authors stated that this review had several drawbacks.  First, according to the GRADE classification system, all outcome measure assessed were classified as very-low, low, or moderate quality of evidence.  This was largely due to many of studies been classified as inconsistent (I2 greater than 50 %) and imprecise (less than 400 subjects per outcome measure) and judged to be at high-risk of bias (greater than 25 % trials are classified as high-risk).  Although the imprecision could be addressed with the inclusion of more studies, the fact that these researchers were unable to evaluate for publication bias, as no outcomes had more the 10 included trials, was something that will have to be addressed in future trials and reviews.  Furthermore, 31.9 % of the risk of bias variables assessed were judged to be of unknown or high-risk of bias, which should be taken into account when interpreting the findings of this review.  It is well-documented throughout the literature that the inconsistent nature of PBM experiments, both clinical and in-vitro, are a significant hurdle in establishing both a concrete physiological mechanism, and a widely used and accepted set of clinical implementation guidelines.  Examining the studies included in this review, these investigators observed many differing forms of PBM application, including total number of treatments, treatment sites, and irradiation per site.  This was understandable given they were treating different areas of tendon pathology, however, there were some studies that did not report all the required treatment variables, making exact replication challenging, in the process affecting the quality of evidence.  The World Association for Laser Therapy (WALT) recommendations are a set of therapeutic recommendations for clinical and scientific application of red and NIR spectrum PBM.  Only 4 of the trials in this review referenced the WALT recommendations in their study, further underlining the need for higher levels of inter-study consistency.  Heavy strength and plyometric training, in addition to training load management, appeared to be the most effective exercise modalities to employ during tendinopathy management.  This review demonstrated very-low quality evidence that PBM could be used as an adjunct therapy to enhance the effects of exercise rehabilitation.  That said, a limitation of this analysis was that all the exercise modalities from each study were pooled in each outcome measure, hence different exercise prescriptions may have affected the results.  Future research in this area should more stringently control the exercise prescription groups in line with tendinopathy best practice.  Interestingly, this review also found that when compared to other interventions, PBM was equally as effective at decreasing pain, however, this was again limited by the pooling of all other interventions.  Many of the other interventions that used a pharmacological anti-inflammatory agent, such as phonophoresis, iontophoresis and corticosteroids (CS) injection, could cause unwanted patient side effects.  In fact, it is now recommended that practitioners move away from these methods, CS injections in particular, due to the long-term harmful tissue effects they can have.  In light of this, PBM may represent a non-invasive, cost-effective and safe alternative to the more traditional injection and anti-inflammatory based therapies used in tendinopathy management.  However, more robust trials are needed to elucidate this effect.

Infrared Coagulation for the Treatment of Anal Dysplasia

Goldstone and co-workers (2011) stated that they had previously reported on infra-red coagulation (IRC) of anal high-grade intraepithelial squamous lesions (HSILs) in human immunodeficiency virus (HIV)-positive and HIV-negative men who have sex with men (MSM) with a median follow-up of 1.5 years.  In a retrospective, cohort study, these researchers determined HSILs recurrence rates after long-term follow-up for IRC, and whether patients progressed to invasive cancer.  This study was carried out in an office-based practice setting.  The patients evaluated were MSM who underwent at least 1 IRC anal HSILs ablation between 1999 and 2005 with at least 1-year additional follow-up.  The primary outcomes measured were HSILs recurrence and progression to anal squamous-cell carcinoma (SCC).  A total of 96 MSM were included (44 HIV-positive) with a median follow-up of 48 and 69 months in HIV-negative and HIV-positive MSM; 35 % of HIV-positive and 31 % of HIV-negative subjects from the original cohort were lost to follow-up.  In HIV-negative MSM, 32 (62 %) had a recurrence in a mean of 14 months.  Recurrence rates after the 2nd and 3rd treatments were 48 % and 57 %.  In HIV-positive MSM, 40 (91 %) had a recurrence in a mean of 17 months.  Recurrence rates after the 2nd, 3rd, and 4th IRC were 63 %, 85 %, and 47 %.  After the 1st ablation, HIV-positive MSM were 1.9 times more likely to have a recurrence than HIV-negative MSM (p = 0.009).  One year after the 1st ablation, 61 % of HIV-positive MSM had recurrent HSILs in comparison with 38 % of HIV-negative MSM.  One year after the 2nd ablation, 49 % of HIV-positive MSM had recurrent HSILs in comparison with 28 % of HIV-negative MSM.  In HIV-negative and HIV-positive MSM, the probability of curing an individual lesion after 1st ablation was 80 % and 67 %.  Most recurrence was due to the development of metachronous lesions occurring in 82 % and 52 % of HIV-positive and HIV-negative subjects after their 1st IRC treatment.  The mean number of recurrent lesions for both HIV-positive and HIV-negative MSM was never greater than 2.  No MSM developed SCC, and there were no SAEs.  At last visit, 82 % of HIV-positive MSM and 90 % of HIV-negative MSM were HSIL-free.  The authors concluded that IRC ablation was an effective treatment for HSILs, and no patients progressed to cancer; HIV-positive patients were significantly more likely to have a recurrence, and recurrence occurred more rapidly in these patients.  These researchers stated that the main drawbacks of this study were its retrospective design, and that it was an observational study with significant loss to follow-up (35 % of HIV-positive and 31 % of HIV-negative subjects from the original cohort).

Alam and associates (2016) noted that there is ambiguity regarding the optimal management of anal intraepithelial neoplasia (AIN) III.  In a systematic review, these investigators compared international/national society guidelines currently available in the literature on the management, treatment and surveillance of AIN III.  In addition, they examined the quality of the studies used to compile the guidelines and clarified the terminology used in histological assessment.  These researchers carried out an electronic search of PubMed and Embase using the search terms “anal intraepithelial neoplasia”, “AIN”, “anal cancer”, “guidelines”, “surveillance” and “management”.  Literature reviews and guidelines or practice guidelines in peer-reviewed journals from January 1, 2000 to December 31, 2014 assessing the treatment, surveillance or management of patients with AIN related to human papilloma virus (HPV) were included.  The guidelines identified by the search were assessed for the quality of evidence behind them using the Oxford Centre for Evidence-based Medicine 2011 Levels of Evidence.  The database search identified 5,159 articles and 2 further guidelines were sourced from official body guidelines.  After inclusion criteria were applied, 28 full-text papers were reviewed; 25 of these were excluded, leaving 3 guidelines for inclusion in the systematic review: those published by the Association of Coloproctology of Great Britain and Ireland, the American Society of Colon and Rectal Surgeons and the Italian Society of Colorectal Surgery.  No guidelines were identified on the management of AIN III from human papilloma virus associations and societies.  All 3 guidelines agreed that a high index of clinical suspicion was essential for diagnosing AIN with a disease-specific history, physical examination, digital rectal examination (DRE) and anal cytology.  There was interchange of terminology from high-grade AIN (HGAIN) (which incorporated AIN II/III) and AIN III in the literature leading to confusion in therapy use.  Treatment varied from immunomodulation and PDT to targeted destruction of areas of HGAIN/AIN II/III using IRC, electrocautery, cryotherapy or surgical excision but with little consensus between the guidelines.  Recommendations on surveillance strategies were similarly discordant, ranging from 6-monthly physical examination to annual anoscopy ± biopsy.  Over 50 % of the recommendations were based on Level III or Level IV evidence and many were compiled using studies that were more than 10-year old.  The authors concluded that despite concordance regarding diagnosis, there was significant variation in the guidelines over recommendations on the treatment and surveillance of patients with HGAIN/AIN II/III.  All 3 sets of guidelines were based on low-level, outdated evidence originating from the 1980s and 1990s.

Goldstone and colleagues (2019) noted that anal HSILs ablation may reduce the incidence of invasive cancer; however, few data exist on treatment efficacy and natural regression without treatment.  In a randomized, multi-center, open-label study, these researchers examined the effects of IRC on anal HSILs (index HSILs) in HIV-infected adults aged greater than or equal to 27 years with 1 to 3 biopsy-proven anal HSILs without prior history of HSIL.  Subjects were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]).  Subjects were followed every 3 months with high-resolution anoscopy.  Treatment subjects underwent anal biopsies of suspected new or recurrent HSILs.  The AM subjects underwent biopsies only at month 12.  The primary end-point was complete clearance of index HSIL at month 12.  These investigators randomized 120 subjects.  Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62 % versus 30 %; risk difference, 32 %; 95 % CI: 13 % to 48 %; p < 0.001).  Complete or partial clearance (clearance of greater than or equal to 1 index HSIL) occurred more commonly in the treatment group (82 % versus 47 %; risk difference, 35 %; 95 % CI: 16 % to 50 %; p < 0.001).  Having a single index lesion, compared with having 2 to 3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95 % CI: 1.22 to 3.10).  The most common AEs related to treatment were mild or moderate anal pain and bleeding.  No SAEs were deemed related to treatment or study participation.  The authors concluded that IRC ablation of anal HSILs resulted in more clearance of HSILs than observation alone.

The authors stated that this study had several drawbacks.  As previously mentioned, more subjects with 2 or 3 index lesions were randomized to AM, which could affect results.  It was possible that the absolute difference in HSILs was over-estimated, given that at baseline the AM group had more HSILs than the treatment group, but in the multi-variable model the RR of HSIL clearance was still significant.  These investigators enrolled subjects with small lesions, which could over-estimate response, because small lesions may be more likely than large lesions to resolve with treatment or regress without treatment.  These researchers were all fairly experienced in treating HSILs and subjects were mostly white, HIV-infected men with limited disease, receiving anti-retroviral therapy  with satisfactory viral suppression and immune reconstitution, making results less generalizable to other providers and populations.  The overall strength of this study rested on the fact that it was the first prospective, multi-site, randomized study powered to determine whether or not HSIL ablation was superior to AM alone in clearing HSILs in HIV-infected individuals.

Corral and associates (2019) stated that anal intraepithelial neoplasia (AIN) (or low/high grade squamous intraepithelial neoplasia (L/HSIL)) is the precursor of early invasive anal cancer.  Different therapeutic options for local ablation of localized lesions have been reported.  In a systematic review, these investigators analyzed the safety and efficacy of IRC for the treatment of anal dysplasia.  They carried out a search of the literature in 2019 using PubMed and Cochrane to identify all eligible trials published reporting data on the treatment of anal dysplasia with IRC.  The percentage of SCC of the anus that developed in the follow-up and results on major complications after treatment were the primary outcomes.  A total of 24 articles were identified from which 6 were selected with a total of 360 patients included, with a median age of 41.8 years; 3 studies were prospective and 3 retrospective, only 1 was a randomized trial.  All articles included males, 4 articles included HIV-positive women and only 1 article included non-HIV infected males.  No patient developed major complications after IRC therapy.  Pain was the most common symptom found after the procedure in the different series and mild bleeding that did not require transfusion was the most common complication occurring in 4 to 78 % of patients.  Median follow-up was between 4.7 and 69 months.  No patient developed SCC after IRC.  Recurrent HSIL varied from 10 to 38 %; 2 studies reported results from follow-up of untreated patients showing that between 72 and 93 % of them had persistent HSIL at last follow-up and 4.8 % developed SCC.  The authors concluded that IRC was a safe and effective method for ablation of high-grade anal dysplasia that could help prevent anal cancer; continued surveillance is recommended due to the risk of recurrence.

Furthermore, an UpToDate review on “Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment” (Palefsky and Cranston, 2020) states that “Infrared coagulation, hyfrecation, argon plasma coagulation, and radiofrequency ablation -- For lesions that are too large for TCA, office-based infrared coagulation (IRC) can be used.  This device is approved by the US Food and Drug Administration (FDA) for the treatment of hemorrhoids and anal warts.  Treatment consists of the direct application of a 1.5-second pulse of irradiation in the infrared range to the dysplastic anal epithelium, which results in tissue destruction to a depth of approximately 1.5 mm.  The coagulated tissue can then be debrided using Tischler biopsy forceps.  Possible procedure-related complications include immediate and delayed bleeding and infection.  IRC is not yet FDA approved for treatment of anal SIL.  Multiple studies have demonstrated the safety and efficacy of IRC in both HIV-infected and HIV-uninfected individuals.  For example, in an open-label randomized trial of 120 HIV-infected adults with anal HSIL, complete-index HSIL clearance was more frequent in the treatment group than in the monitoring group (62 versus 30 %, risk difference 32 %, 95 % CI 13 to 48 %).  As another example, in a retrospective study of 96 men, treatment with IRC was followed by recurrence in a mean of 14 months in 62 % of those who were HIV uninfected and in 91 % of those who were HIV infected.  Although multiple retreatments were required in the majority of cases, none of the men progressed to squamous cell carcinoma.  There were no serious adverse events”.

Brain Disorders (Including Dementia)

Salehpour and colleagues (2021) noted that PBM entails the use of red and/or near-infrared light from lasers or LEDs to improve a wide range of medical disorders.  Trans-cranial PBM, sometimes accompanied by intra-nasal PBM, has been tested to improve many brain disorders, including dementia. These researchers carried out a systematic review according to the Preferred Reporting Items for Meta-Analysis (PRISMA) guidelines of pre-clinical and clinical studies reporting the use of PBM, which were considered relevant to dementia.  Literature was searched between 1967 and 2020 using a range of keywords relevant to PBM and dementia.  The light source and wavelength(s), output power, irradiance, irradiation time, fluence or total energy (dose), operation mode (continuous or pulsed) irradiation, approach and site, number of treatment sessions, as well as study outcome(s) were extracted.  Out of 10,473 initial articles, 36 studies met the inclusion criteria; 9 articles reported in-vitro studies, 17 articles reported studies in animal models of dementia, and 10 studies were performed in dementia patients.  All of the included studies reported positive results.  The clinical studies were limited by the small number of patients, lack of placebo controls in some instances, and only a few used objective neuroimaging methods.  The authors concluded that these preliminary findings of clinical benefit, the lack of any adverse effects, and the remarkable ease of use, suggested that larger clinical trials should be conducted as soon as possible.

Calcaneal Tendon Injury

In a systematic review, Silva and colleagues (2020) analyzed the light parameters and the effects of photobiomodulation therapy (PBMT) via LLLT and/or LED on tendon repair of rats submitted to calcaneal injury.  This study was carried out in accordance with the guidelines of the PRISMA, and PubMed and Medline databases were searched for eligible studies published in English.  The search terms were as follows: "Achilles tendon" or "calcaneal tendon" or "tendon injuries" or "soft tissue injuries" and "tendinopathy" or "tendinitis" and "low-level light therapy" or "low-level laser therapy" or "low intensity power therapy" or "light-emitting diode" or photobiomodulation".  The SYRCLE (SYstematic Review Center for Laboratory animal Experimentation) risks of bias was used to evaluate the risk of bias for selected studies.  A total of 225 studies were found based on the descriptors used, and only 33 studies were eligible.  Light parameters identified per point of irradiation were approximately 60 mW (continuous mode at infrared spectra), 2 W cm-2 , 2 J and 45 J cm-2.  Light parameters at red spectra, continuous versus pulsed mode, and PBMT combined or compared with other therapies such as ultrasound (US), and studies using unhealthy rats (ovariectomized and/or diabetic models) were also identified and grouped according to these similarities.  The main effects found were decreased inflammatory markers and signs of inflammatory process.  The authors concluded that PBMT (laser/LED) has positive effects in reducing the inflammatory and time for tissue repair in animal models of tendon injury and/or tendinitis using parameters identified.


In a systematic review and meta-analysis, Galiano-Castillo and colleagues (2021) examined the effectiveness of PBMT in the treatment of patients with xerostomia and/or hypo-salivation due to the most prevalent clinical diagnoses.  These investigators searched PubMed, Scopus, Web of Science, CINAHL and Cochrane Library for RCTs or clinical controlled trials (CCTs) published until October 31, 2019.  Risk of bias assessment and meta-analysis were carried out using the Cochrane tools.  A total of 274 records were retrieved, and 11 met the inclusion criteria.  Interventions whose parameters ranged between wavelengths of 790 to 830 nm (infrared), 30 to 120 mW of power and an energy density below 30 J/cm-2 were associated with improvements in xerostomia/hypo-salivation.  As for the evaluation of methodological quality, 10 of the 11 articles included had a high risk of overall bias.  Only 3 articles provided sufficient information to perform a meta-analysis for QOL, compared with placebo in patients with burning mouth syndrome, showing a standardized mean difference between groups from baseline of -0.90 (-1.48; -0.32).  The authors concluded that the findings of this review and meta-analysis suggested that PBMT was an effective, non-invasive and safe approach in patients with xerostomia; however, despite the potential, it is not possible to reach a reliable consensus on the parameters to be used, and future studies should be carried out by standardizing intervention protocols.

Photo-Biomodulation Using Infrared Light-Emitting Diode for the Treatment of Asthma

Brochetti et al (2022) stated that corticosteroid-resistant asthma (CRA) is a severe form of disease and clinically important, since patients do not respond to mainstay corticosteroid therapies; therefore, new therapies are needed.  However, a big limiting factor in the understanding of CRA is the existence of different immunological and inflammatory phenotypes, making it difficult to reproduce experimentally; PBM emerges as an alternative therapy based on earlier studies.  These researchers examined the effect of PBM using infrared light-emitting diode (ILED) on the development of CRA.  In this study, groups of rats were sensitized and challenged with ovalbumin (OVA) plus Freund's adjuvant for the induction of CRA; and treated or not with ILED directly in the respiratory tract on the skin (wavelength 810 nm; power 100 mW; density energy 5 J/cm; total energy 15 J; time 150 s).  This experimental model was capable to induce neutrophilic asthma.  Besides that, the corticosteroid treatment did not reverse the lung cell migration as well as the levels of leukotriene B4, and interleukins (ILs) 17 and 6.  The treatment with ILED reduced the lung cell migration; myeloperoxidase activity; mast cell degranulation; and the levels of leukotriene B4, thromboxane B2, prostaglandin E2, tumoral necrosis factor (TNF)-alpha, and IL-17 and IL-6; and ILED increased the level of IL-10.  The authors concluded that the findings of this study showed promising effects of ILED when irradiated directly in the respiratory tract as adjuvant treatment of CRA.

Alonso et al (2022) noted that asthma is characterized by recurrent and reversible episodes of wheezing, dyspnea, chest stiffness, and cough.  Its treatment includes several drugs, high cost, and considerable side effects; PBM emerges as an alternative treatment, showing good results, and it can be applied locally or systemically.  These investigators examined the effect of transcutaneous systemic PBM (TSPBM) by red diode light.  Adult rats were sensitized and challenged with OVA plus alum for induction of asthma and irradiated or not with TSPBM in the caudal vein (wavelength 660 ± 10 nm; total radiant emission 15 J; area 2.8 cm2; energy density 5.35 J/cm2; irradiance 33.3 mW/cm2; exposure time 150 s).  These investigations prioritized the cell migration into the alveolar space and lung, tracheal responsiveness, release and gene expression of cytokines, mast cell degranulation, and anaphylactic antibodies.  Results showed that TSPBM reduced the cell migration and mast cell degranulation without altering the tracheal responsiveness and OVA antibody titers.  Indeed, TSPBM increased the levels of IL-10 in the BAL fluid without altering the gene expression of cytokines in the lung tissue.  The authors concluded that the findings of this study showed that transcutaneous systemic irradiation reduced lung inflammation by altering mast cells degranulation and IL-10 level.  These researchers stated that considering that this study is a pioneer in the use of light by the systemic route for the treatment of asthma, these findings are interesting and encourage future investigations, mainly in relation to the mechanisms involved and in dosimetry.


Infrared coagulation usually requires 2 sessions to eradicate the hemorrhoids.

Internal hemorrhoids are classified by the following grades:

  • Grade I: Bleeding without prolapse
  • Grade II: Prolapse with spontaneous reduction
  • Grade III: Prolapse with manual reduction
  • Grade IV: Incarcerated, irreducible prolapse.


The above policy is based on the following references:

  1. Accarpio G, Ballari F, Puglisi R, e al. Outpatient treatment of hemorrhoids with a combined technique: Results in 7850 cases. Tech Coloproctol. 2002;6(3):195-196.
  2. Alam NN, White DA, Narang SK, et al. Systematic review of guidelines for the assessment and management of high-grade anal intraepithelial neoplasia (AIN II/III). Colorectal Dis. 2016;18(2):135-146.
  3. Alonso PT, Schapochnik A, Klein S, et al. Transcutaneous systemic photobiomodulation reduced lung inflammation in experimental model of asthma by altering the mast cell degranulation and interleukin 10 level. Lasers Med Sci. 2022;37(2):1101-1109.
  4. Anodyne Therapy, LLC. Anodyne testimonials. Tampa, FL:; 1998. Available at: Accessed January 15, 2002.
  5. Anodyne Therapy, LLC. Anodyne Therapy. Tampa, FL: Anodyne; 2004. Available at: Accessed September 15, 2004.
  6. Bajwa ZH, Smith JH. Acute treatment of migraine in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2018a.
  7. Bajwa ZH, Smith JH. Preventive treatment of migraine in adults. UpToDate [online serial], Waltham, MA: UpToDate; reviewed April 2018b.
  8. Beckerman H, de Ble R, Bouter L, et al. The efficacy of laser therapy for musculoskeletal and skin disorders: A criteria-based meta-analysis of randomized clinical trials. Physical Ther. 1992;72:483-491.
  9. Bhardwaj SS, Rohrer TE, Arndt K.Lasers and light therapy for acne vulgaris. Semin Cutan Med Surg. 2005;24(2):107-112.
  10. Brochetti RA, Klein S, Alonso PT, et al. Beneficial effects of infrared light-emitting diode in corticosteroid-resistant asthma. Lasers Med Sci. 2022;37(3):1963-1971.
  11. Bryans R, Decina P, Descarreaux M, et al. Evidence-based guidelines for the chiropractic treatment of adults with neck pain. J Manipulative Physiol Ther. 2014;37(1):42-63.
  12. Canadian Coordinating Office of Health Technology Assessment (CCOHTA). Photonic stimulation for the treatment of chronic pain. Pre-assessment No. 11. Ottawa, ON; CCOHTA; November 2002.
  13. Centers for Medicare and Medicaid Services (CMS). Decision memo for infrared therapy devices (CAG-00291N). Medicare Coverage Database. Baltimore, MD: CMS; October 24, 2006.
  14. Choi SJ, Cho EH, Jo HM, et al. Clinical utility of far-infrared therapy for improvement of vascular access blood flow and pain control in hemodialysis patients. Kidney Res Clin Pract. 2016;35(1):35-41.
  15. Chow RT, Barnsley L. Systematic review of the literature of low-level laser therapy (LLLT) in the management of neck pain. Lasers Surg Med. 2005;37(1):46-52.
  16. Corral J, Pares D, García-Cuyas F, et al. Clinical results of infrared coagulation as a treatment of high-grade anal dysplasia: A systematic review. Tech Coloproctol. 2019;23(8):707-712.
  17. Cullum N, Nelson EA, Flemming K, et al. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. Health Technol Assess. 2000;4(21):1-237.
  18. Fitzgerald M, Hodgetts S, Van Den Heuvel C. Red/near-infrared irradiation therapy for treatment of central nervous system injuries and disorders. Rev Neurosci. 2013;24(2):205-226.
  19. Flemming K, Cullum N. Laser therapy for venous leg ulcers. Cochrane Database Syst Rev. 1999;(1):CD001182. 
  20. Flemming KA, Cullum NA, Nelson EA. A systematic review of laser therapy for venous leg ulcers. J Wound Care. 1999;8(3):111-114.
  21. Foto JG, Brasseaux D, Birke JA. Essential features of a handheld infrared thermometer used to guide the treatment of neuropathic feet. J Am Podiatr Med Assoc. 2007;97(5):360-365.
  22. Franzen-Korzendorfer H, Blackinton M, Rone-Adams S, McCulloch J. The effect of monochromatic infrared energy on transcutaneous oxygen measurements and protective sensation: Results of a controlled, double-blind, randomized clinical study. Ostomy Wound Manage. 2008;54(6):16-31.
  23. Galeano M. Lymphedema case study. Tampa, FL: MedAssist Group; 2001. Available at: Accessed January 15, 2002.
  24. Galiano-Castillo N, Liu L, Lozano-Lozano M, et al. Acute and cumulative benefits of photobiomodulation for xerostomia: A systematic review and meta-analysis. Oral Dis. 2021;27(5):1115-1126.
  25. Garza I, Schwedt TJ. Chronic migraine. UpToDate [online serial], Waltham, MA: UpToDate; reviewed April 2018.
  26. Glasgow PD, Hill ID, McKevitt AM, et al. Low intensity monochromatic infrared therapy: A preliminary study of the effects of a novel treatment unit upon experimental muscle soreness. Lasers Surg Med. 2001;28(1):33-39.
  27. Gogia PP, Hurt BS, Zirn TT. Wound management with whirlpool and infrared cold laser treatment. A clinical report. Phys Ther. 1988;68(8):1239-1242.
  28. Goldstein AO. Onychomycosis. UpToDate [online serial], Waltham, MA: UpToDate; reviewed April 2015.
  29. Goldstone RN, Goldstone AB, Russ J, Goldstone SE. Long-term follow-up of infrared coagulator ablation of anal high-grade dysplasia in men who have sex with men. Dis Colon Rectum. 2011;54(10):1284-1292.
  30. Goldstone SE, Lensing SY, Stier EA, et al. A randomized clinical trial of infrared coagulation ablation versus active monitoring of intra-anal high-grade dysplasia in adults with human immunodeficiency virus infection: An AIDS malignancy consortium trial. Clin Infect Dis. 2019;68(7):1204-1212.
  31. Gupta AK, Filonenko N, Salansky N, et al. The use of low energy photon therapy (LEPT) in venous leg ulcers: A double-blind, placebo-controlled study. Dermatol Surg. 1998;24(12):1383-1386.
  32. Gupta PJ. Infrared coagulation versus rubber band ligation in early stage hemorrhoids. Braz J Med Biol Res. 2003;36(10):1433-1439.
  33. Hamilton FL, Car J, Lyons C, et al. Laser and other light therapies for the treatment of acne vulgaris: Systematic review. Br J Dermatol. 2009;160(6):1273-1285.
  34. Hipskind SG, Grover FL Jr, Fort TR, et al. Pulsed transcranial red/near-infrared light therapy using light-emitting diodes improves cerebral blood flow and cognitive function in veterans with chronic traumatic brain injury: A case series. Photobiomodul Photomed Laser Surg. 2019;37(2):77-84.
  35. Hong C-T, Hu C-J, Lin H-Y, Wu D. Effects of concomitant use of hydrogen water and photobiomodulation on Parkinson disease: A pilot study. Medicine (Baltimore). 2021;100(4):e24191.
  36. Horwitz LR, Burke TJ, Carnegie D. Augmentation of wound healing using monochromatic infrared energy. Exploration of a new technology for wound management. Adv Wound Care. 1999;12(1):35-40.
  37. Hou X, Zhou H, Wang L, et al.  Multifunctional near-infrared dye-magnetic nanoparticles for bioimaging and cancer therapy. Cancer Lett. 2017;390:168-175.
  38. Jin JZ, Bhat S, Lee K-T, et al. Interventional treatments for prolapsing haemorrhoids: Network meta-analysis. BJS Open. 2021;5(5):zrab091.
  39. Ko GD, Berbrayer D. Effect of ceramic-impregnated "thermoflow" gloves on patients with Raynaud's syndrome: Randomized, placebo-controlled study. Altern Med Rev. 2002;7(4):328-335.
  40. Kocham AB, Carnegie D, Burke TJ. Symptomatic reversal of peripheral neuropathy in diabetic patients. Aurora, CO: Integrated Systems Physiology, Inc.; 2001. Available at: Accessed January 15, 2002.
  41. Lagan KM, Clements BA, McDonough S, et al. Low intensity laser therapy (830nm) in the management of minor postsurgical wounds: A controlled clinical study. Lasers Surg Med. 2001;28(1):27-32.
  42. Lampl Y, Zivin JA, Fisher M, et al. Infrared laser therapy for ischemic stroke: A new treatment strategy: Results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke. 2007;38(6):1843-1849.
  43. Lapchak PA, Araujo DM. Advances in ischemic stroke treatment: Neuroprotective and combination therapies. Expert Opin Emerg Drugs. 2007;12(1):97-112. 
  44. Lavery LA, Murdoch DP, Williams J, Lavery DC. Does anodyne light therapy improve peripheral neuropathy in diabetes? A double-blind, sham-controlled, randomized trial to evaluate monochromatic infrared photoenergy. Diabetes Care. 2008;31(2):316-321.
  45. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy: A double-blind, randomized, placebo-controlled study with monochromatic near-infrared treatment. Diabetes Care. 2004;27(1):168-172.
  46. Linares Santiago E, Gomez Parra M, et al. Effectiveness of hemorrhoidal treatment by rubber band ligation and infrared photocoagulation. Rev Esp Enferm Dig. 2001;93(4):238-247.
  47. Liu SW, Chang JC, Chuang SF, et al. Far-infrared radiation improves motor dysfunction and neuropathology in spinocerebellar ataxia type 3 mice. Cerebellum. 2019;18(1):22-32.
  48. Lucas C, Stanborough RW, Freeman CL, De Haan RJ. Efficacy of low-level laser therapy on wound healing in human subjects: A systematic review. Lasers Med Science. 2000;15(2):84-93.
  49. MacKay D. Hemorrhoids and varicose veins: A review of treatment options. Altern Med Rev. 2001;6(2):126-140.
  50. Madoff RD, Fleshman JW; Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology. 2004;126(5):1463-1473.
  51. Marques CF, Nahas SC, Nahas CS, et al. Early results of the treatment of internal hemorrhoid disease by infrared coagulation and elastic banding: A prospective randomized cross-over trial. Tech Coloproctol. 2006;10(4):312-317.
  52. Miriutova NF, Abdulkina NG, Luksha LV, Levitskiĭ EF. Laser therapy and electric stimulation in rehabilitation treatment of peripheral neuropathy. Vopr Kurortol Fizioter Lech Fiz Kult. 2002;(4):25-27.
  53. Mishalov VH, Dibrova IuA, Tsema IeV, Dibrova VA. Quality of life in patients with chronic internal hemorrhoids treated with infrared photocoagulation. Klin Khir. 2009;(3):24-27.
  54. Mundy L, Merlin T, Parrella A, et al. Anodyne therapy system: Treatment of peripheral neuropathy in diabetic patients. Horizon Scanning Prioritising Summary - Volume 5. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2004.
  55. Nagaya T, Okuyama S, Ogata F, et al. Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody. Oncotarget. 2018;9(27):19026-19038.
  56. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance. Treatment of pressure ulcers. In: Prevention and treatment of pressure ulcers: Clinical practice guideline. Washington (DC): National Pressure Ulcer Advisory Panel; 2014. p. 126-208.
  57. Nenoff P, Grunewald S, Paasch U. Laser therapy of onychomycosis. J Dtsch Dermatol Ges. 2014;12(1):33-38.
  58. Nussbaumer B, Kaminski-Hartenthaler A, Forneris CA, et al. Light therapy for preventing seasonal affective disorder. Cochrane Database Syst Rev. 2015;11:CD011269.
  59. Nussbaumer-Streit B, Forneris CA, Morgan LC, et al. Light therapy for preventing seasonal affective disorder. Cochrane Database Syst Rev. 2019;3(3):CD011269.
  60. Palefsky JM, Cranston RD. Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2020.
  61. Poen AC, Felt-Bersma RJ, Cuesta MA, et al. A randomized controlled trial of rubber band ligation versus infra-red coagulation in the treatment of internal haemorrhoids. Eur J Gastroenterol Hepatol. 2000;12(5):535-539.
  62. Quirk BJ, Desmet KD, Henry M, et al. Therapeutic effect of near infrared (NIR) light on Parkinson's disease models. Front Biosci (Elite Ed). 2012;4:818-823.
  63. Reese GE, von Roon AC, Tekkis PP. Haemorrhoids. Clin Evid (Online). 2009. pii: 0415.
  64. Ricci MP, Matos D, Saad SS. Rubber band ligation and infrared photocoagulation for the outpatient treatment of hemorrhoidal disease. Acta Cir Bras. 2008;23(1):102-106.
  65. Ronthal M. Bell's palsy: Prognosis and treatment in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2012.
  66. Salehpour F, Hamblin MR. Photobiomodulation for Parkinson's disease in animal models: A systematic review. Biomolecules. 2020;10(4):610.
  67. Salehpour F, Khademi M, Hamblin MR. Photobiomodulation therapy for dementia: A systematic review of pre-clinical and clinical studies. J Alzheimers Dis. 2021;83(4):1431-1452.
  68. Santana-Blank LA, Rodriguez-Santana E, Santana-Rodriguez KE. Photo-infrared pulsed bio-modulation (PIPBM): A novel mechanism for the enhancement of physiologically reparative responses. Photomed Laser Surg. 2005;23(4):416-424.
  69. Schencking M, Frese T, Sandholzer H. Treatment of a radiculopathia by whole-body hyperthermia. Forsch Komplementmed. 2008;15(5):273-276.
  70. Schneider WL, Hailey D. Low level laser therapy for wound healing. HTA-19. Edmonton, AB: Alberta Heritage Foundation for Medical Research (AHFMR); 1999.
  71. Shui S, Wang X, Chiang JY, Zheng L. Far-infrared therapy for cardiovascular, autoimmune, and other chronic health problems: A systematic review. Exp Biol Med (Maywood). 2015;240(10):1257-1265.
  72. Silva RSDL, Pessoa DR, Mariano RD, et al. Systematic review of photobiomodulation therapy (PBMT) on the experimental calcaneal tendon injury in rats. Photochem Photobiol. 2020;96(5):981-997.
  73. Simon A. Low level laser therapy for wound healing: An update. IP-22 Information Paper. Edmonton, AB: Alberta Heritage Foundation for Medical Research (AHFMR); 2004.
  74. Song JH, Zhang GB, Ding XD, et al. Efficacy of type a botulinum toxin injections and infrared polarized light on treating chronic migraine. Eur Rev Med Pharmacol Sci. 2015;19(11):1976-1982.
  75. Sousa DFM, Gonçalves MLL, Politti F, et al. Photobiomodulation with simultaneous use of red and infrared light emitting diodes in the treatment of temporomandibular disorder: Study protocol for a randomized, controlled and double-blind clinical trial. Medicine (Baltimore). 2019;98(6):e14391. 
  76. Stange-Rezende L, Stamm TA, Schiffert T, et al. Clinical study on the effect of infrared radiation of a tiled stove on patients with hand osteoarthritis. Scand J Rheumatol. 2006;35(6):476-480.
  77. Tani A, Chellini F, Giannelli M, et al. Red (635 nm), near-infrared (808 nm) and violet-blue (405 nm) photobiomodulation potentiality on human osteoblasts and mesenchymal stromal cells: A morphological and molecular in vitro study. Int J Mol Sci. 2018;19(7).
  78. Thomasson TL. Effects of skin-contact monochromatic infrared irradiation on tendonitis, capsulitis, and myofascial pain. J Neurol Orthop Med Surg. 1996;16:242-245.
  79. Tripodi N, Feehan J, Husaric M, et al. The effect of low-level red and near-infrared photobiomodulation on pain and function in tendinopathy: A systematic review and meta-analysis of randomized control trials. BMC Sports Sci Med Rehabil. 2021;13(1):91.
  80. Tsai SR, Hamblin MR. Biological effects and medical applications of infrared radiation. J Photochem Photobiol B. 2017;170:197-207.
  81. Vujosevic S, Martini F, Convento E, et al. Subthreshold laser therapy for diabetic macular edema: Metabolic and safety issues. Curr Med Chem. 2013;20(26):3267-3271.
  82. Werner C, Byhahn M, Hesse S. Non-invasive brain stimulation to promote alertness and awareness in chronic patients with disorders of consciousness: Low-level, near-infrared laser stimulation vs. focused shock wave therapy. Restor Neurol Neurosci. 2016;34(4):561-569.
  83. Work Loss Data Institute. Low back -- lumbar & thoracic (acute & chronic). Encinitas, CA: Work Loss Data Institute; December 4, 2013.
  84. Xu J, Xu L, Wang C, et al. Near-infrared-triggered photodynamic therapy with multitasking upconversion nanoparticles in combination with checkpoint blockade for immunotherapy of colorectal cancer. ACS Nano. 2017;11(5):4463-4474.
  85. Yao X, Liu C, Feng D, et al. Transcranial near-infrared laser therapy in improving cognitive recovery of function following traumatic brain injury. Curr Neuropharmacol. 2018;16(9):1320-1326.
  86. Zhang M, Kim HS, Jin T, Moon WK. Near-infrared photothermal therapy using EGFR-targeted gold nanoparticles increases autophagic cell death in breast cancer. J Photochem Photobiol B. 2017;170:58-64.