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The effect of photobiomodulation on tinnitus: a systematic review

Published online by Cambridge University Press:  23 November 2023

Yasmin Nikookam
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
Nawal Zia
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
Andrew Lotfallah
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
Jameel Muzaffar
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK Department of Clinical Neurosciences, Addenbrooke's Health Campus, University of Cambridge, Cambridge, UK
Jennifer Davis-Manders
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
Peter Kullar
Affiliation:
Department of Clinical Neurosciences, Addenbrooke's Health Campus, University of Cambridge, Cambridge, UK
Matthew E Smith
Affiliation:
Department of Clinical Neurosciences, Addenbrooke's Health Campus, University of Cambridge, Cambridge, UK
Gemma Bale
Affiliation:
Department of Physics, University of Cambridge, Cambridge, UK Department of Electrical Engineering, University of Cambridge, Cambridge, UK
Patrick Boyle
Affiliation:
Advanced Bionics, Cambridge, UK
Richard Irving
Affiliation:
Department of Ear, Nose and Throat Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
Dan Jiang
Affiliation:
Hearing Implant Centre, St Thomas’ Hospital, Guy's and St Thomas’ NHS Foundation Trust, London, UK, Centre for Craniofacial and Regenerative Biology, Guy's Hospital Campus, King's College London, London, UK
Manohar Bance*
Affiliation:
Department of Clinical Neurosciences, Addenbrooke's Health Campus, University of Cambridge, Cambridge, UK
*
Corresponding author: Manohar Bance; Email: mlb59@cam.ac.uk
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Abstract

Objective

To establish outcomes following photobiomodulation therapy for tinnitus in humans and animal studies.

Methods

A systematic review and narrative synthesis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The databases searched were: Medline, Embase, Cochrane Central Register of Controlled Trials (‘Central’), ClinicalTrials.gov and Web of Science including the Web of Science Core collection. There were no limits on language or year of publication.

Results

The searches identified 194 abstracts and 61 full texts. Twenty-eight studies met the inclusion criteria, reporting outcomes in 1483 humans (26 studies) and 34 animals (2 studies). Photobiomodulation therapy parameters included 10 different wavelengths, and duration ranged from 9 seconds to 30 minutes per session. Follow up ranged from 7 days to 6 months.

Conclusion

Tinnitus outcomes following photobiomodulation therapy are generally positive and superior to no photobiomodulation therapy; however, evidence of long-term therapeutic benefit is deficient. Photobiomodulation therapy enables concentrated, focused delivery of light therapy to the inner ear through a non-invasive manner, with minimal side effects.

Type
Review Article
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press on behalf of J.L.O. (1984) LIMITED

Introduction

Background and epidemiology

Tinnitus can be defined as the perception of sounds without an external source.Reference Heller1 It can be classified into objective and subjective types. Subjective tinnitus is more common and not audible to the observer, usually arising from neuropsychological problems. Objective tinnitus is defined as tinnitus that is audible to another person as a sound emanating from the ear canal.Reference Han, Lee, Kim, Lim and Shin2 The British Tinnitus Association state that around one in eight people live with persistent tinnitus in the UK.3 Tinnitus impairs daily life activities for 3–5 per cent of individuals, causing complications such as sleep deprivation, anxiety and depression.Reference Bhatt, Lin and Bhattacharyya4 There are a wide range of causes, but given the limited knowledge of its physiology, it remains an obscure symptom with limited treatment success.

It is estimated that 1.05 million primary care consultations take place every year in the UK regarding tinnitus, with the treatment pathway for tinnitus costing the National Health Service £750 million annually.3 Treatment for tinnitus is limited, and largely dependent upon the underlying cause. Currently, there are no curative pharmacological therapies, with such approaches often limited to addressing anxiety and depression associated with tinnitus. Whilst pharmacotherapy is not a mainstay of treatment, several agents have been used, typically without a strong evidence base. Such drugs include sedatives, anticonvulsants, antidepressants, local anaesthetics, antihistamines, antipsychotics and botulinum toxin A.Reference Langguth, Salvi and Elgoyhen5 Such treatment options provide mixed or inconsistent benefits for tinnitus. Non-pharmacological and surgical approaches have been used in selected cases; these modalities have not shown dramatic therapeutic effects.Reference Kapkin, Satar and Yetiser6,Reference Soleymani, Pieton, Pezeshkian, Miller, Gorgulho and Pouratian7

Photobiomodulation therapy

Photobiomodulation therapy could provide an alternative treatment for patients with chronic tinnitus. Photobiomodulation therapy utilises light energy to enhance or modulate the activities of specific organs, in order to improve or change the function of body tissues. It is a non-invasive therapy used in several medical specialties, particularly in dermatology and neurology, to treat skin lesions and neurodegenerative disorders respectively.Reference Dompe, Moncrieff, Matys, Grzech-Leśniak, Kocherova and Bryja8 Photobiomodulation therapy has been shown to reduce pain and trigger the regeneration of nerves and other tissues.

The mechanism of photobiomodulation therapy on neural cell recovery and regeneration is yet to be fully understood. The prevailing theory focuses on mitochondrial cytochrome c oxidase, a key protein in cellular metabolism and repair, and one of three major proteins in the human body responding to near-infrared wavelength.Reference Wong-Riley, Liang, Eells, Chance, Henry and Buchmann9 These proteins absorb near-infrared wavelength energy and then modulate biochemical reactions within cells. Cytochrome c oxidase is a large transmembrane protein complex in the mitochondrial electron transport chain that consists of five protein complexes which together produce adenosine triphosphate (ATP).Reference Huang, Chen, Carroll and Hamblin10 This theory is further supported by research showing that photobiomodulation therapy enhances ATP production.Reference Oron, Ilic, De Taboada and Streeter11 Increased ATP production may lead to enhanced cell metabolism, promoting the damage–repair process.

Transmeatal cochlear low-level laser irradiation, also known as photobiomodulation therapy, has been introduced as an alternative modality for cochlear dysfunction such as chronic cochlear tinnitus. Clinically, lasers have been used since the 1990s to treat tinnitus.Reference Wilden and Dindinger12 However, the therapeutic benefit remains uncertain, with several studies demonstrating no significant improvement in tinnitus symptoms with photobiomodulation therapy.Reference Dejakum, Piegger, Plewka, Gunkel, Thumfart and Kudaibergenova13,Reference Choi, Lee, Chung and Jung14 To the best of the authors’ knowledge, the efficacy of photobiomodulation therapy use in the management of tinnitus has only been systematically reviewed once previously, with the exclusion of non-randomised controlled trials and non-human trials.Reference Talluri, Palaparthi, Michelogiannakis and Khan15 The current study aimed to systematically review all study types assessing the use of photobiomodulation therapy to treat tinnitus to date.

Objectives

This review aimed to assess if the application of photobiomodulation therapy is effective for the treatment of tinnitus, analysing both animal and human study evidence.

Materials and methods

The study protocol was registered in the International Prospective Register of Systematic Reviews (‘PROSPERO’) (registration number: CRD42020212259), and was created according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) guidelines.Reference Page, McKenzie, Bossuyt, Bourton, Hoffman and Murlow16

Population, inclusion, comparator, outcomes

The population, inclusion, comparator, outcomes (‘PICO’) framework was used to facilitate the literature review. In this instance, the populations are humans or animals, and the intervention is photobiomodulation therapy. There is no formal comparator or control. The comparators are expected to vary according to the study type. Comparators may include other methods of tinnitus symptom control; for example, the administration of drugs via systemic or local routes. The primary outcomes are pre- and post-photobiomodulation therapy tinnitus outcomes. These include: tinnitus visual analogue scales (VASs), the Tinnitus Handicap Inventory, loudness matching of tinnitus, the Persian Tinnitus Questionnaire, a vertigo assessment, the Tinnitus Severity Index and a subjective tinnitus analysis. The secondary outcomes are: general well-being, audiological outcomes, complications, adverse events and side effects associated with photobiomodulation therapy.

Study inclusion criteria

All experimental study designs were eligible for inclusion, including case–control, case series, cohort, randomised controlled trials and animal studies (live, explant and in vitro). Opinion pieces were not included in this review. Animal studies of photobiomodulation therapy for tinnitus were required to include at least one quantitative outcome measure. There were no restrictions placed on the follow-up length or the duration of the study. Only studies with the full text available were included. Exclusion criteria included studies with insufficient data and those that did not assess the effect of photobiomodulation therapy on tinnitus outcomes.

Search strategy

The following electronic databases were searched: Medline, Embase, Cochrane Central Register of Controlled Trials (‘Central’), ClinicalTrials.gov, Web of Science, Biosis, Data Citation Index, Derwent Innovations Index, KCI Korean Journal Database, Medline, Russian Citation Index, Scientific Electronic Library Online (‘SciELO’) Citation index and Zoological Records. No limit was placed on language or year of publication. A search was conducted using Medical Subject Headings and the Boolean search technique for ‘tinnitus’ and ‘photobiomodulation’.

The search strategy for the Embase database is presented in Table 1; modified versions of this search strategy were used for other electronic databases (Appendix 1). Manual searches of the reference lists of the included and relevant systematic reviews and a citation search were conducted to identify additional studies missed from the electronic database searches.

Table 1. Search strategy for Embase database

Selection of studies

Searches were performed on 20 December 2020 by one author (YN) and checked by a second author (NZ). Two reviewers (YN and NZ) independently screened titles and abstracts of the studies from the database search for duplicates and inclusion. Full texts were reviewed by two authors (YN and NZ) independently against the inclusion and exclusion criteria. Disagreements at the abstract and full-text screening stages were discussed within the author team (YN and NZ) and, where applicable, with a third reviewer (JM), whereupon consensus was reached in determining eligible studies for inclusion. In the same manner, a secondary search was conducted on 21 November 2022 by two authors (AL and JD-M), to ensure all eligible studies were included at the time of publication, and corroborated by a third author (JM).

Data extraction

A standardised form using Microsoft Excel® software was used for data extraction from the included studies. This was designed and piloted prior to the data extraction phase. Data were extracted by the first reviewer (YN) and then checked by second reviewer (NZ). The data of interest were: study characteristics (study design, location and duration), primary and secondary outcome data, and adverse events. Missing data were sought, where possible, by email contact with study authors. Any discrepancies were identified and resolved through discussion within the author team. This process was followed for the secondary search conducted by two authors (AL and JD-M).

Risk of bias quality assessment

Two review authors (YN and NZ) independently assessed the methodological quality of the included studies. Animal studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (‘SYRCLE’) tool.Reference Hooijmans, Rovers, de Vries, Leenaars, Ritskes-Hoitinga and Langendam17 Human studies were assessed using the Oxford Centre for Evidence Based Medicine grading system, the Cochrane Risk of Bias 2 tool for randomised trials (‘RoB 2’) and the Brazzelli risk of bias tool for non-randomised studies.18Reference Brazzelli, Cruickshank, Tassie, McNamee, Robertson and Elders20 Any disagreements were resolved through discussion between two authors (YN and NZ), and, where necessary, via consultation with the third review author (JM). The above process was repeated for the secondary search, conducted by two authors (AL and JD-M).

Results

A flow sheet detailing study selection according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, based on initial searches, is included in Figure 1. Given the heterogeneity of sampling, reporting, treatment and outcome measures, a meta-analysis was not performed.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) flow diagram.

Description of studies

Twenty-eight studies met the inclusion criteria, with a total of 1517 subjects (1483 humans in 26 studies, and 34 animals in 2 studies).Reference Wilden and Dindinger12Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21Reference Cuda and De Caria44 At least 916 subjects underwent photobiomodulation therapy intervention. One study reported two trial outcomes for both human and animal subjects;Reference Rhee, Lim, Kim, Chung, Jung and Chung21 this review has reported these trial outcomes as two separate studies throughout.

Twenty-six studies assessed the effect of photobiomodulation therapy on humans with tinnitus; these were published between 1995 and 2022.Reference Wilden and Dindinger12Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21Reference Silva, Scheffer, Bastos, Chavantes and Mondelli43 Among these, 18 were randomised controlled trials (including 1 pilot study), 5 were cohort studies, 2 were case series and 1 was a self-controlled clinical study. The type of photobiomodulation therapy used was described in detail in all studies. The wavelength used was classified in all studies: 12 used 650 nm, 4 used 840 nm, 2 used 810 nm, 2 used 904 nm, 1 used 830 nm, 1 used 808 nm, 1 used 808 nm and 630 nm, 1 used 808 nm and 660 nm, 1 used 830 nm and 632.8 nm, and 1 used 635 nm or 830 nm. The duration of photobiomodulation therapy ranged from 7 days to 6 months, and the application time per session ranged from 9 seconds to 30 minutes.

Two studies were conducted on animal models, published in 2006 and 2013, with the former dually reporting on human subjects as a separate study.Reference Rhee, Lim, Kim, Chung, Jung and Chung21,Reference Park, Na, Park, Suh, Rhee and Chung22 Rhee et al. reported a randomised controlled trial. Park et al. used rat models, whilst Rhee et al. used guinea pig models. The type of photobiomodulation therapy was described in detail in both studies. The wavelength used was 830 nm for a duration of 30 minutes per session in both. The follow-up duration was not stated by Rhee et al. and was 24 hours post treatment in the study by Park et al.Reference Rhee, Lim, Kim, Chung, Jung and Chung21,Reference Park, Na, Park, Suh, Rhee and Chung22 Study characteristics for the human and animal studies included in this review are summarised in Table 2.Reference Wilden and Dindinger12Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21Reference Cuda and De Caria44

Table 2. Study characteristics

PBMT = photobiomodulation therapy; RCT = randomised, controlled trial; min = minutes

Quality of studies

Included studies mainly consisted of human randomised controlled trials (18 of 28 studies). All included studies were prospective.

The 26 human studies had a minimum of 10 subjects who underwent photobiomodulation therapy. The studies included were Oxford Centre for Evidence Based Medicine grade I (n = 19), grade II (n = 6) and grade III (n = 1). All animal studies (n = 2) had a minimum of seven animals that underwent photobiomodulation therapy.

The heterogeneity of tinnitus outcome measures, photobiomodulation therapy duration, power and wavelength outcomes, within and between human and animal studies, precluded a meta-analysis. Within the human studies, the limitations were: reporting of adverse events following photobiomodulation therapy, average age of subjects, and values of the pre-photobiomodulation therapy assessment. Quality assessment of the human studies is summarised in Figures 2 and 3. Within the animal studies, there were limitations in: post-treatment observation duration of animals receiving photobiomodulation therapy, tinnitus data prior to photobiomodulation therapy delivery, and housing of animals. Quality assessment of animal studies is summarised in Figure 4.

Figure 2. Cochrane Risk of Bias 2 tool.

Figure 3. Brazzelli risk of bias assessment.

Figure 4. Systematic Review Centre for Laboratory Animal Experimentation (‘SYRCLE’) risk of bias assessment.

Tinnitus outcomes

Tinnitus outcomes in humans are summarised in Table 3. A total of 11 different tinnitus outcome measures were used. There were inconsistencies regarding the use of pre- and post-photobiomodulation therapy across all included studies. All studies, except one,Reference Yildirim, Berkiten, Ugras and Salturk26 reported that pre-photobiomodulation therapy tinnitus assessments were conducted. Tinnitus VASs were recorded in 17 studies, the Tinnitus Handicap Inventory in 12 studies, and audiological outcomes and subjective tinnitus analysis were reported in 7 studies respectively. Other post-photobiomodulation therapy outcome parameters included loudness matching of tinnitus, the Tinnitus Questionnaire, the Persian Tinnitus Questionnaire, general well-being assessment, vertigo assessment, the Tinnitus Severity Index and cervical range of motion (each reported in a single study). Whilst the cause of tinnitus was not always stated, tinnitus severity and type were recorded in all studies. Photobiomodulation therapy administration details were present in all studies, detailing the range of delivery and duration.

Table 3. Primary outcomes in human studies

PBMT = photobiomodulation therapy; min = minutes; OCEBM = Oxford Centre for Evidence Based Medicine; RoB 2 = Cochrane Risk of Bias 2; THI = Tinnitus Handicap Inventory; VAS = visual analogue scale; Nd:YAG = neodymium-doped yttrium aluminium garnet; TEOAE = transient evoked otoacoustic emissions; LLLT = low-level laser therapy; SNHL = sensorineural hearing loss; SD = standard deviation; LMT = loudness matching of tinnitus; DPOAE = distortion product otoacoustic emissions; BD = twice daily; TMS = transcranial magnetic stimulation

Tinnitus outcomes in animals are summarised in Table 4. A total of three different tinnitus outcomes measures were used. There were inconsistencies regarding the use of pre- and post-photobiomodulation therapy across the included studies. Only one study reported the values of the pre-photobiomodulation therapy tinnitus assessment. Gap pre-pulse inhibition of the acoustic startle reflex was recorded in one study before and after photobiomodulation therapy.Reference Park, Na, Park, Suh, Rhee and Chung22 Values of gain in the slow harmonic acceleration rotation test and values of modulation in the off-vertical axis rotation test were measured in one study post-photobiomodulation therapy.Reference Rhee, Lim, Kim, Chung, Jung and Chung21

Table 4. Primary outcomes in animal studies

PBMT = photobiomodulation therapy; min = minutes; GPIAS = gap pre-pulse inhibition of acoustic startle; LLLT = low-level laser therapy; OCEBM = Oxford Centre for Evidence Based Medicine; SYRCLE = Systematic Review Centre for Laboratory Animal Experimentation

Overall, there was a trend towards benefit from photobiomodulation therapy in both the animal and human studies, despite variations in parameters of delivery, wavelength, animal species or power used. Tinnitus outcomes improved in 20 of 26 human studies and 2 of 2 animal studies following photobiomodulation therapy, compared to no photobiomodulation therapy. One human study illustrated uncertain outcomes following photobiomodulation therapy for tinnitus, because of speculation regarding whether the placebo effect influenced the results.Reference Dejakum, Piegger, Plewka, Gunkel, Thumfart and Kudaibergenova13 Another human study demonstrated that the improvement in tinnitus outcomes following photobiomodulation therapy was not statistically significant, but hearing outcomes were statistically improved.Reference Mirz, Zachariae, Andersen, Nielsen, Johansen and Bjerring23 Moreover, five human studies found that photobiomodulation therapy improved tinnitus outcomes in the short term, but did not yield statistically significant results at follow up ranging between two weeks and three months.Reference Choi, Lee, Chung and Jung14,Reference Mirvakili, Mehrparvar, Mostaghaci, Mollasadeghi, Mirvakili and Baradaranfar24Reference Tauber, Schorn, Beyer and Baumgartner27 However, four human studies did report sustained therapeutic benefit at follow up, which was demonstrated to be statistically significant (with follow up ranging between two and four weeks).Reference Okhovat, Berjis, Okhovat, Malekpour and Abtahi28Reference Toson, Khalaf, Seleim and Hassan31 Three further studies reported statistically significant improvement immediately following treatment completion, but provided no follow-up data to demonstrate sustained benefit.Reference Rhee, Lim, Kim, Chung, Jung and Chung21,Reference Elsayed and Alsharif32,Reference Eladl, Elkholi, Eid, Abdelbasset, Ali and Bahey El-Deen33 A further human study showed no objective improvement in transient evoked otoacoustic emissions measurement, but participants stated a subjective improvement in tinnitus.Reference Elsanadiky and Nafie34 Six studies reported no significant improvement in tinnitus with photobiomodulation therapy.Reference Dejakum, Piegger, Plewka, Gunkel, Thumfart and Kudaibergenova13,Reference Mirz, Zachariae, Andersen, Nielsen, Johansen and Bjerring23,Reference Elsanadiky and Nafie34Reference Teggi, Bellini, Piccioni, Palonta and Bussi37 It is uncertain whether there is a relationship between longer duration of photobiomodulation therapy and greater improvement in tinnitus outcomes, given the heterogeneity of photobiomodulation therapy delivery, duration and outcomes assessment.

The wavelength and power used in the human studies were similar to those in the animal studies; however, animal studies comprised a shorter duration of administration and follow up when compared to human studies.Reference Rhee, Lim, Kim, Chung, Jung and Chung21,Reference Park, Na, Park, Suh, Rhee and Chung22 Reports of the assessment method used and the follow-up duration were heterogeneous across all human and animal studies.

Photobiomodulation therapy adverse events

None of the included studies reported on immediate adverse effects following photobiomodulation therapy administration. However, two studies reported side effects of the treatment.Reference Mirz, Zachariae, Andersen, Nielsen, Johansen and Bjerring23,Reference Salahaldin, Abdulhadi, Najjar and Bener38 More common side effects included: itching, red spots, congestion in the deep external auditory canal wall, and mild allergic manifestation.Reference Salahaldin, Abdulhadi, Najjar and Bener38 No other studies reported any visible changes during or after treatment to the tympanic membrane. No human or animal deaths were reported in any of the included studies.

Photobiomodulation therapy technique

Twenty-six studies outlined the photobiomodulation therapy technique and delivery method, and one study did not.Reference Yildirim, Berkiten, Ugras and Salturk26 Five studies, including one animal study,Reference Park, Na, Park, Suh, Rhee and Chung22 outlined the distance from the photobiomodulation therapy target site to the end of the optical fibre tip.Reference Dejakum, Piegger, Plewka, Gunkel, Thumfart and Kudaibergenova13,Reference Choi, Lee, Chung and Jung14,Reference Park, Na, Park, Suh, Rhee and Chung22,Reference Plath and Olivier39,Reference Montazeri, Mahmoudian, Razaghi and Farhadi40 This ranged from 1 mm to 150 mm, with an average distance of 39.5 mm. All studies, except for one,Reference Yildirim, Berkiten, Ugras and Salturk26 outlined where photobiomodulation therapy was anatomically focused onto.

Sixteen studies appropriately summarised all three of the following: wavelength used, duration of photobiomodulation therapy and follow-up period.Reference Dejakum, Piegger, Plewka, Gunkel, Thumfart and Kudaibergenova13,Reference Choi, Lee, Chung and Jung14,Reference Mirz, Zachariae, Andersen, Nielsen, Johansen and Bjerring23Reference Toson, Khalaf, Seleim and Hassan31,Reference Elsanadiky and Nafie34,Reference Nakashima, Ueda, Misawa, Suzuki, Tominaga and Ito36,Reference Teggi, Bellini, Piccioni, Palonta and Bussi37,Reference Thabit, Fouad, Shahat and Youssif41,Reference Shiomi, Takahashi, Honjo, Kojima, Naito and Fujiki42 The wavelength size of 650 nm was the most used (n = 12).

Photobiomodulation therapy outcomes

Photobiomodulation therapy was found to be effective in initially improving tinnitus symptoms, reducing tinnitus loudness, annoyance and duration, and improving subjective analyses in most of the included studies. One study reported a statistically significant improvement in subjective tinnitus (p = 0.001) following photobiomodulation therapy used in combination with an neodymium-doped yttrium aluminium garnet laser when compared to placebo (p = 0.065), and this combined treatment was superior to photobiomodulation therapy in isolation (p = 0.005).Reference Demirkol, Usumez, Demirkol, Sari and Akcaboy29 Another study found that central repetitive transcranial magnetic stimulation and peripheral photobiomodulation therapy in combination was superior to either therapy in isolation, with statistical significance.Reference Thabit, Fouad, Shahat and Youssif41 One study found that photobiomodulation therapy following an injection of 50 mg gingko biloba extract was superior to placebo.Reference Plath and Olivier39 Another study evaluated the effectiveness of a 635 nm laser or a 830 nm laser on tinnitus outcomes, and found that there was no significant difference of laser-induced effects on the degree of tinnitus between the two different wavelengths.Reference Tauber, Schorn, Beyer and Baumgartner27

Two studies used a combined laser technique.Reference Wilden and Dindinger12,Reference Montazeri, Mahmoudian, Razaghi and Farhadi40 One used a 630 nm diode laser and an 808 nm infrared laser to deliver photobiomodulation therapy; these lasers were applied sequentially. The results revealed a subjective short-term improvement of tinnitus.Reference Montazeri, Mahmoudian, Razaghi and Farhadi40 One study used a combined 632.8 nm, 20 mW helium–neon, and an 830 nm, 100 mW infrared diode laser. Their results revealed a statistically significant improvement in symptom relief in the treatment group.Reference Wilden and Dindinger12 A third study used a red wavelength of 660 nm to the tympanic membrane and an infrared wavelength of 808 nm to the mastoid tip bilaterally.Reference Silva, Scheffer, Bastos, Chavantes and Mondelli43 That study showed no significant improvement in audiological assessment findings or in subjective improvement between the intervention and placebo groups.

Ngao et al. assessed the effect of photobiomodulation therapy used in combination with oral betahistine 24 mg taken twice daily, which showed this was not superior to the control (sham photobiomodulation therapy device and 24 mg oral betahistine twice daily).Reference Ngao, Tan, Narayanan and Raman35

Overall, comparisons of the photobiomodulation therapy doses indicate that higher doses have a greater positive effect on tinnitus, though methodological and statistical heterogeneity precluded meta-analysis to quantify this.

Discussion

This systematic review and narrative synthesis aimed to report on photobiomodulation therapy outcomes in the treatment of tinnitus, in both human and animal subjects. Whilst most studies reported initial improvement in tinnitus outcomes following therapy completion, few were able to demonstrate sustained improvement at follow up. Of studies that did report statistically significant sustained improvement, the longest follow-up period was one month post therapy.Reference Demirkol, Usumez, Demirkol, Sari and Akcaboy29

Photobiomodulation therapy versus placebo

Ten human studies reported photobiomodulation therapy to be superior to placebo and control groups at treating tinnitus symptoms.Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21,Reference Mirvakili, Mehrparvar, Mostaghaci, Mollasadeghi, Mirvakili and Baradaranfar24,Reference Mollasadeghi, Mirmohammadi, Mehrparvar, Davari, Shokouh and Mostaghaci25,Reference Demirkol, Usumez, Demirkol, Sari and Akcaboy29Reference Elsayed and Alsharif32,Reference Plath and Olivier39,Reference Cuda and De Caria44 Six of these reported follow-up data, including two randomised controlled trials, which noted statistically significant improvements immediately following treatment but not at the three-month follow up.Reference Mirvakili, Mehrparvar, Mostaghaci, Mollasadeghi, Mirvakili and Baradaranfar24,Reference Mollasadeghi, Mirmohammadi, Mehrparvar, Davari, Shokouh and Mostaghaci25

Similarly, both animal studies reported improved outcomes, demonstrating that photobiomodulation therapy had a therapeutic effect. However, Rhee et al., noted that the initial therapeutic benefit was not maintained at 24 hours’ follow up. This suggests that the therapeutic benefit of photobiomodulation therapy on tinnitus may diminish over time, as has been suggested in three other studies involving two- to three- month follow-up data.Reference Mirvakili, Mehrparvar, Mostaghaci, Mollasadeghi, Mirvakili and Baradaranfar24Reference Yildirim, Berkiten, Ugras and Salturk26

Overall, despite differences in the results obtained from various studies, it appears there may be several factors determining whether photobiomodulation therapy success is demonstrated, including the application of proper technical parameters, correct study design methods and sufficient treatment duration.

Photobiomodulation therapy as a combination therapy

Cuda and De Caria investigated the effect of a combined counselling protocol constituting hypnotherapeutic and muscle relaxation techniques with photobiomodulation therapy.Reference Cuda and De Caria44 They found combined therapy to be more beneficial than counselling only. These findings suggest the scope for the implementation of photobiomodulation therapy as a combination therapy in addition to patients’ usual treatment. This was corroborated by Eladl et al., who investigated the use of photobiomodulation therapy alongside a supervised physical therapy exercise programme compared with photobiomodulation therapy alone, demonstrating a statistically significant improvement in the former group.Reference Eladl, Elkholi, Eid, Abdelbasset, Ali and Bahey El-Deen33 Photobiomodulation therapy combination therapies warrant further evaluation and research to establish therapeutic benefit when compared to photobiomodulation therapy alone.

Photobiomodulation therapy positioning and characteristics

The positioning of photobiomodulation therapy for optimal delivery varies across studies. There were two main methods of irradiation reported within this systematic review. Irradiation can primarily be directed at the mastoid or across the tympanic membrane.Reference Beyer, Baumgartner and Tauber45 Beyer et al. found that irradiation of the mastoid leads to therapeutically insufficient light doses when compared to irradiation through the tympanic membrane.Reference Beyer, Baumgartner and Tauber45 In the animal study performed by Rhee et al., no penetration was measurable through the mastoid bone.Reference Rhee, Lim, Kim, Chung, Jung and Chung21 Therefore, for optimum dosimetry, evaluation of the light transmission factors for chosen irradiation modalities is necessary. The externally applied light dose needs to be calculated according to the tonotopy of the cochlea as well, as different anatomical regions transduce different frequencies; this includes the position of the cochlea with respect to surface radiation portals. Further investigations are necessary in order to determine the optimum light doses for photobiomodulation therapy.

The wavelength of the laser is comparable with the chemical composition of a drug, and the power is comparable to the dosage of a drug. A drug will not be effective if either the chemical composition or dosage is incorrect. Similarly, as in a drug overdose, an excess amount of laser irradiation may lead to destruction rather than promotion.Reference Sommer, Pinheiro, Mester, Franke and Whelan46 Consequently, determining photobiomodulation therapy parameters is important, although there will likely be a large amount of overhead between therapeutic and toxic doses. These parameters must be balanced with the challenges of delivering photobiomodulation therapy safely. It is widely known that there is a typical responsive wavelength for cytochrome c oxidase (approximately 670 nm);Reference Wong-Riley, Liang, Eells, Chance, Henry and Buchmann9 nonetheless, this wavelength is within the visible light range and has a lower tissue penetrance than the near-infrared range.Reference Wong-Riley, Liang, Eells, Chance, Henry and Buchmann9 Cytochrome c oxidase mediates photobiomodulation in the far red and near-infrared range. Therefore, it becomes difficult to deliver a laser of this wavelength to the otic capsule if it must penetrate the tympanic membrane, bone and other tissues.Reference Rhee, He, Jung, Ahn, Chung and Suh47 Wavelengths must be carefully selected according to how the photobiomodulation therapy will be delivered, what it is targeting, and which structures the light must pass through to reach the cochlea.

Additionally, it is important to ascertain whether shorter, concentrated bursts of delivery of photobiomodulation therapy induces a greater significant effect on tinnitus symptoms when compared to a prolonged delivery.

Tinnitus assessment tools

A total of 11 different assessment tools were noted to be used across all studies, resulting in inconsistency in outcome measures. Choosing a suitable assessment tool plays an important role in evaluating therapeutic effects. Tinnitus is a subjective perception; therefore, a patient's estimation of it is highly individual. Subjective evaluation tools are valuable for monitoring therapeutic effects. However, one study reported that tinnitus subjects encountered difficulties in rating their subjective perceptions on VAS, which could introduce error.Reference Montazeri, Mahmoudian, Razaghi and Farhadi40 Consequently, it is important to consider the use of objective assessment measures (e.g. electroencephalograph markers) before and after photobiomodulation therapy in tinnitus subjects. These, however, are not yet considered robust.

Future of photobiomodulation therapy

Overall, the heterogeneity of study design, including tinnitus outcome measures, photobiomodulation therapy duration, power and wavelength, precludes definitive conclusions on photobiomodulation therapy efficacy in the treatment of tinnitus. Most studies to date have been conducted on human models. The majority assessed outcomes over a short length of time, with the longest follow-up period being six months. This relatively short duration precludes comment on the long-term effects that photobiomodulation therapy may have on resolving tinnitus symptoms, or whether further courses are needed to suppress tinnitus returning and maintain individuals’ therapeutic response. Most human studies concluded that the short-term effects of photobiomodulation therapy had a positive effect on tinnitus outcomes. The follow-up period across the studies included is low and therefore long-term outcomes of photobiomodulation therapy could not be evaluated. Enabling a follow-up period of at least a year will allow researchers to assess the longer-term effects and complications of photobiomodulation therapy. Further robust trials with consistency in terms of photobiomodulation therapy parameters, tinnitus assessment tools and follow-up period are essential for the evaluation of photobiomodulation therapy in the management of tinnitus.

Conclusion

Whilst tinnitus outcomes following photobiomodulation therapy appear to be superior to non-photobiomodulation therapy in most studies, inconsistencies in study design and short follow-up duration preclude definitive consensus. With tinnitus affecting 1 in 10 adults, and with limited treatments proven to show benefit, the demand for treatment and solutions for tinnitus symptoms is paramount. It is imperative that solutions are sought that incur minimal risks and damage to patients. The minimal risk profile of photobiomodulation therapy to date highlights its promising use in the field of otolaryngology. It is essential that further research considers the optimal design, duration, position and follow up of photobiomodulation therapy.

Supplementary material

The supplementary material for this article can be found at [https://doi.org/10.1017/S0022215123002165].

Competing interests

None declared

Footnotes

Manohar Bance takes responsibility for the integrity of the content of the paper

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Figure 0

Table 1. Search strategy for Embase database

Figure 1

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) flow diagram.

Figure 2

Table 2. Study characteristics

Figure 3

Figure 2. Cochrane Risk of Bias 2 tool.

Figure 4

Figure 3. Brazzelli risk of bias assessment.

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Figure 4. Systematic Review Centre for Laboratory Animal Experimentation (‘SYRCLE’) risk of bias assessment.

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Table 3. Primary outcomes in human studies

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Table 4. Primary outcomes in animal studies

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