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 Dindinger12–Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21–Reference 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 Dindinger12–Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21–Reference 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 Dindinger12–Reference Choi, Lee, Chung and Jung14,Reference Rhee, Lim, Kim, Chung, Jung and Chung21–Reference 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 Baradaranfar24–Reference 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 Abtahi28–Reference 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 Nafie34–Reference 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 Bjerring23–Reference 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.