{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:27:56Z","timestamp":1792106876626,"version":"4.4.0"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V108C-12645, V109C-135"],"award-info":[{"award-number":["V108C-12645, V109C-135"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Study Objective: Tinnitus is a common disorder characterized by sound in the ear in the absence of external or internal stimuli. Low-level laser therapy (LLLT) was discovered enhancing tissue repair via increasing the blood microcirculation and cell proliferation in 1960s. In the last two decades, LLLT delivered to the cochlea has frequently been used to reduce the severity of tinnitus. However, whether LLLT effectively attenuates the severity of tinnitus remains controversial. We aimed to evaluate the efficacy of low-level laser therapy on adult patients with complaints of tinnitus. Design: Systematic review and meta-analysis with trial sequential analysis. Interventions: Low-level laser therapy (LLLT). Measurements: Tinnitus Handicap Inventory (THI) score; improvement rates of the visual analog scale (VAS), verbal rating scale (VRS) and numeric rating scale (NRS) scores. Methods: We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library from inception through 17 September 2020. Randomized control trials that involved adult patients with complaints of tinnitus, compared LLLT to a placebo and provided sufficient information for meta-analysis were considered eligible. Main Results: Overall, 11 studies involving 670 patients were included. No significant difference in the overall effect according to the THI score (mean difference (MD), \u22122.85; 95% CI, \u22128.99 to 3.28; p = 0.362; I2 = 0%) and the rating scale score improvement rate (risk ratio (RR), 1.35; 95% CI, 0.81 to 2.27; p = 0.250; I2 = 67%) was demonstrated between patients receiving LLLT and those receiving a placebo. None of the subgroup analyses showed significant differences, regardless of underlying sensorineural hearing loss, the number of irradiation sessions or the wavelength used. Conclusions: Our meta-analysis suggests that the value of LLLT in controlling the severity of tinnitus remains unclear, in part due to the relatively small number of patients and underlying heterogeneity. More large-scale investigations of LLLT for tinnitus related to inner ear disease are required to further elucidate the therapeutic effects.<\/jats:p>","DOI":"10.3390\/brainsci10120931","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T07:49:54Z","timestamp":1606895394000},"page":"931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Efficacy of Low-Level Laser Therapy for Tinnitus: A Systematic Review with Meta-Analysis and Trial Sequential Analysis"],"prefix":"10.3390","volume":"10","author":[{"given":"Chih-Hao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chii-Yuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6958-4425","authenticated-orcid":false,"given":"Chun-Yu","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1995-5854","authenticated-orcid":false,"given":"Yen-Fu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Brain Science, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.5935\/0946-5448.20190010","article-title":"A preliminary study on the efficacy and safety of low level light therapy in the management of cochlear tinnitus: A single blind randomized clinical trial","volume":"23","author":"Choi","year":"2019","journal-title":"Int. Tinnitus J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.anl.2012.05.005","article-title":"A cohort study of patients with tinnitus and sensorineural hearing loss in a Swedish population","volume":"40","author":"Zarenoe","year":"2013","journal-title":"Auris Nasus Larynx"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neuron.2010.12.002","article-title":"Dysregulation of Limbic and Auditory Networks in Tinnitus","volume":"69","author":"Leaver","year":"2011","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0030-6665(02)00170-6","article-title":"Pathophysiology of tinnitus","volume":"36","year":"2003","journal-title":"Otolaryngol. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Haider, H.F., Hoare, D.J., Costa, R.F.P., Potgieter, I., Kikidis, D., Lapira, A., Nikitas, C., Caria, H., Cunha, N.T., and Pa\u00e7o, J.C. (2017). Pathophysiology, Diagnosis and Treatment of Somatosensory Tinnitus: A Scoping Review. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00207"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0014-5793(84)80577-3","article-title":"Increase of proton electrochemical potential and ATP synthesis in rat liver mitochondria irradiated in vitro by helium-neon laser","volume":"175","author":"Passarella","year":"1984","journal-title":"FEBS Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/lsm.1900120512","article-title":"Power density and exposure time of He-Ne laser irradiation are more important than total energy dose in photo-biomodulation of human fibroblasts in vitro","volume":"12","year":"1992","journal-title":"Lasers Surg. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S1011-1344(99)00155-4","article-title":"Effects of 780 nm diode laser irradiation on blood microcirculation: Preliminary findings on time-dependent T1-weighted contrast-enhanced magnetic resonance imaging (MRI)","volume":"54","author":"Schaffer","year":"2000","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s10103-015-1851-1","article-title":"Safety assessment of trans-tympanic photobiomodulation","volume":"31","author":"Moon","year":"2016","journal-title":"Lasers Med. Sci."},{"key":"ref_10","first-page":"CD002049","article-title":"Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis","volume":"4","author":"Brosseau","year":"2005","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e031142","DOI":"10.1136\/bmjopen-2019-031142","article-title":"Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: Systematic review and meta-analysis of randomised placebo-controlled trials","volume":"9","author":"Stausholm","year":"2019","journal-title":"BMJ Open"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1186\/s13075-015-0882-0","article-title":"The effectiveness of low-level laser therapy for nonspecific chronic low back pain: A systematic review and meta-analysis","volume":"17","author":"Huang","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1016\/S0140-6736(09)61522-1","article-title":"Efficacy of low-level laser therapy in the management of neck pain: A systematic review and meta-analysis of randomised placebo or active-treatment controlled trials","volume":"374","author":"Chow","year":"2009","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bjordal, J.M., Lopes-Martins, R.A., Joensen, J., Couppe, C., Ljunggren, A.E., Stergioulas, A., and Johnson, M.I. (2008). A systematic review with procedural assessments and meta-analysis of low level laser therapy in lateral elbow tendinopathy (tennis elbow). BMC Musculoskelet. Disord., 9.","DOI":"10.1186\/1471-2474-9-75"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/1096-9101(2001)28:1<18::AID-LSM1011>3.0.CO;2-C","article-title":"Lightdosimetric quantitative analysis of the human petrous bone: Experimental study for laser irradiation of the cochlea","volume":"28","author":"Tauber","year":"2001","journal-title":"Lasers Surg. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s13534-019-00114-y","article-title":"Applications of photobiomodulation in hearing research: From bench to clinic","volume":"9","author":"Lee","year":"2019","journal-title":"Biomed. Eng. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0004-9514(14)60473-6","article-title":"Factors affecting low level laser therapy","volume":"39","author":"Laakso","year":"1993","journal-title":"Aust. J. Physiother."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and Group, P. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12874-017-0315-7","article-title":"Trial Sequential Analysis in systematic reviews with meta-analysis","volume":"17","author":"Wetterslev","year":"2017","journal-title":"BMC Med. Res. Methodol."},{"key":"ref_21","unstructured":"R Core Team (2020). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_22","unstructured":"(2016). Trial Sequential Analysis Software, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet. Available online: http:\/\/www.ctu.dk\/tsa."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1017\/S0022215107009619","article-title":"Effectiveness of transmeatal low power laser irradiation for chronic tinnitus","volume":"122","author":"Gungor","year":"2008","journal-title":"J. Laryngol. Otol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1097\/00129492-200205000-00011","article-title":"Transmeatal low-power laser irradiation for tinnitus","volume":"23","author":"Nakashima","year":"2002","journal-title":"Otol. Neurotol."},{"key":"ref_25","first-page":"32","article-title":"Effect of low-level laser therapy in the treatment of cochlear tinnitus: A double-blind, placebo-controlled study","volume":"94","author":"Dehkordi","year":"2015","journal-title":"Ear Nose Throat J."},{"key":"ref_26","first-page":"71","article-title":"Low level laser effect in treatment of patients with intractable tinnitus due to sensorineural hearing loss","volume":"5","author":"Mirvakili","year":"2014","journal-title":"J. Lasers Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s00405-013-2491-3","article-title":"The effectiveness of transmeatal low-power laser stimulation in treating tinnitus","volume":"271","author":"Ngao","year":"2014","journal-title":"Eur. Arch. Oto Rhino Laryngol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1159\/000161235","article-title":"Transmeatal low-level laser therapy for chronic tinnitus with cochlear dysfunction","volume":"14","author":"Teggi","year":"2009","journal-title":"Audiol. Neuro Otol."},{"key":"ref_29","first-page":"175","article-title":"Effectiveness of combined counseling and low-level laser stimulation in the treatment of disturbing chronic tinnitus","volume":"14","author":"Cuda","year":"2008","journal-title":"Int. Tinnitus J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rhee, C.K., Lim, E.S., Kim, Y.S., Chung, Y.W., Jung, J.Y., and Chung, P.S. (2006, January 21\u201326). Effect of low level laser (LLL) on cochlear and vestibular inner ear including tinnitus. Proceedings of the SPIE Photonics West conference, San Jose, CA, USA.","DOI":"10.1117\/12.659654"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1046\/j.1365-2273.1999.00277.x","article-title":"The low-power laser in the treatment of tinnitus","volume":"24","author":"Mirz","year":"1999","journal-title":"Clin. Otolaryngol. Allied Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mollasadeghi, A., Mirmohammadi, S.J., Mehrparvar, A.H., Davari, M.H., Shokouh, P., Mostaghaci, M., Baradaranfar, M.H., and Bahaloo, M. (2013). Efficacy of low-level laser therapy in the management of tinnitus due to noise-induced hearing loss: A double-blind randomized clinical trial. Sci. World J., 2013.","DOI":"10.1155\/2013\/596076"},{"key":"ref_33","first-page":"1","article-title":"Variations in the External Auditory Canal of 185 Adult Individuals: A Clinico-Morphological Study","volume":"3","author":"Kumar","year":"2013","journal-title":"Int. J. Sci. Res. Publ."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0378-5955(84)90078-9","article-title":"Hypersensitivity to electrical stimulation of auditory nuclei follows hearing loss in cats","volume":"13","author":"Gerken","year":"1984","journal-title":"Hear. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0378-5955(99)00197-5","article-title":"Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance to tone-evoked activity: A physiological model for tinnitus","volume":"140","author":"Kaltenbach","year":"2000","journal-title":"Hear. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1212\/WNL.50.1.114","article-title":"The functional neuroanatomy of tinnitus: Evidence for limbic system links and neural plasticity","volume":"50","author":"Lockwood","year":"1998","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1288\/00005537-199210000-00012","article-title":"Some forms of tinnitus may involve the extralemniscal auditory pathway","volume":"102","author":"Yokota","year":"1992","journal-title":"Laryngoscope"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1055\/s-0042-1748038","article-title":"Similarities between Severe","volume":"11","author":"Moller","year":"2000","journal-title":"J. Am. Acad. Audiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/nrneurol.2016.12","article-title":"Maladaptive plasticity in tinnitus\u2014Triggers, mechanisms and treatment","volume":"12","author":"Shore","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Marks, K.L., Martel, D.T., Wu, C., Basura, G.J., Roberts, L.E., Schvartz-Leyzac, K.C., and Shore, S.E. (2018). Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans. Sci. Transl. Med., 10.","DOI":"10.1126\/scitranslmed.aal3175"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1007\/s00405-016-4401-y","article-title":"A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus","volume":"274","author":"Zenner","year":"2017","journal-title":"Eur. Arch. Oto Rhino Laryngol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s40463-017-0219-x","article-title":"Current insights in noise-induced hearing loss: A literature review of the underlying mechanism, pathophysiology, asymmetry, and management options","volume":"46","author":"Le","year":"2017","journal-title":"J. Otolaryngol. Head Neck Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s101620020028","article-title":"Dynamics of noise-induced cellular injury and repair in the mouse cochlea","volume":"3","author":"Wang","year":"2002","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1089\/pho.2016.4240","article-title":"Efficacy of Low-Level Laser Therapy in Subjective Tinnitus Patients with Temporomandibular Disorders","volume":"35","author":"Demirkol","year":"2017","journal-title":"Photomed. Laser Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1179\/0886963413Z.0000000004","article-title":"Low-level laser therapy for management of TMJ osteoarthritis","volume":"32","author":"Madani","year":"2014","journal-title":"Cranio\u00ae"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1177\/0003489419842577","article-title":"Association Between Tinnitus and Temporomandibular Disorders: A Systematic Review and Meta-Analysis","volume":"128","author":"Omidvar","year":"2019","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1001\/archotol.134.4.389","article-title":"Temporomandibular Disorder and New Aural Symptoms","volume":"134","author":"Cox","year":"2008","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1097\/00005537-199910000-00022","article-title":"Aural Symptoms and Signs of Temporomandibular Disorder in Association With Treatment Need and Visits to a Physician","volume":"109","author":"Kuttila","year":"1999","journal-title":"Laryngoscope"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Nowaczewska, M., Wici\u0144ski, M., Straburzy\u0144ski, M., and Ka\u017amierczak, W. (2020). The Prevalence of Different Types of Headache in Patients with Subjective Tinnitus and Its Influence on Tinnitus Parameters: A Prospective Clinical Study. Brain Sci., 10.","DOI":"10.3390\/brainsci10110776"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s10194-020-01121-6","article-title":"Increased risk of tinnitus following a trigeminal neuralgia diagnosis: A one-year follow-up study","volume":"21","author":"Cheng","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_51","unstructured":"Cheng, Y.F., Xirasagar, S., Yang, T.H., Wu, C.S., Kuo, N.W., and Lin, H.C. (2020). A population-based case-control study of the association between cervical spondylosis and tinnitus. Int J. Audiol., 1\u20135."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/10\/12\/931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:40:32Z","timestamp":1760179232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/10\/12\/931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["brainsci10120931"],"URL":"https:\/\/doi.org\/10.3390\/brainsci10120931","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}