{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:24:27Z","timestamp":1790087067730,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Medically unexplained oral symptoms\/syndromes (MUOS), such as Burning Mouth Syndrome and Persistent Idiopathic Facial Pain, present significant management challenges due to the lack of standardized treatments and high-level evidence. While pharmacotherapy is often employed, real-world data on treatment adherence\u2014a pragmatic proxy for effectiveness and tolerability\u2014remain sparse, especially in Japan. This study aimed to describe the real-world prescribing patterns of antidepressants and dopamine receptor partial agonists (DPAs) for MUOS and retrospectively investigate their association with treatment continuation. Methods: This retrospective observational study analyzed data from patients initiating pharmacotherapy for MUOS at a specialized clinic in Japan (April 2021\u2013March 2023). We used Cox proportional hazards models to evaluate treatment continuation for amitriptyline monotherapy and antidepressant\u2013aripiprazole adjunctive therapy. The primary outcome was the time to discontinuation. Dosage effects were modeled using B-splines to capture nonlinearity. Results: Among 702 MUOS patients who started pharmacotherapy, 493 received amitriptyline as the first prescription, and 108 received aripiprazole as an adjunctive therapy. For amitriptyline monotherapy, a nonlinear relationship was observed between dosage and discontinuation risk, with a relatively lower hazard around 25 mg\/day across age groups. In the antidepressant\u2013aripiprazole adjunctive group, the overall hazard ratio for discontinuation was higher (HR = 4.75, p &lt; 0.0005) compared to non-adjunctive therapy, likely due to indication bias reflecting more treatment-resistant cases. However, within the aripiprazole adjunctive group, a U-shaped relationship was identified between maximum aripiprazole dosage and discontinuation risk, with the lowest hazard (HR \u2248 0.30) observed at approximately 1.7\u20131.8 mg\/day. Mild side effects such as drowsiness, dry mouth, constipation, tremor, insomnia, and weight gain were noted, but no severe adverse events occurred. Conclusions: This real-world data analysis suggests specific dosage ranges (amitriptyline \u2248 25 mg\/day; aripiprazole augmentation \u2248 1.7\u20131.8 mg\/day) are associated with longer treatment continuation in MUOS patients. Treatment continuation reflects a crucial balance between symptom relief and tolerability, essential for managing these chronic conditions. It is critical to emphasize that these findings are descriptive and observational, derived from a specialized setting, and do not constitute prescriptive recommendations. They highlight the importance of individualized dosing. Definitive evidence-based strategies require validation through prospective randomized controlled trials.<\/jats:p>","DOI":"10.3390\/ph18091282","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T15:49:34Z","timestamp":1756309774000},"page":"1282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Real-World Prescribing Patterns and Treatment Continuation of Amitriptyline Monotherapy and Aripiprazole Augmentation for Medically Unexplained Oral Symptoms\/Syndromes in Japan"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9344-8828","authenticated-orcid":false,"given":"Chizuko","family":"Maeda","sequence":"first","affiliation":[{"name":"Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Bunkyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7907-2127","authenticated-orcid":false,"given":"Takayuki","family":"Suga","sequence":"additional","affiliation":[{"name":"Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Bunkyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0690-6271","authenticated-orcid":false,"given":"Takahiko","family":"Nagamine","sequence":"additional","affiliation":[{"name":"Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Bunkyo 113-8510, Japan"},{"name":"Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Hofu 747-0066, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9498-3014","authenticated-orcid":false,"given":"Akira","family":"Toyofuku","sequence":"additional","affiliation":[{"name":"Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Bunkyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Suga, T., and Toyofuku, A. (2025). Working-age patients with medically unexplained oral symptoms who receive public assistance in Japan. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-14427-9"},{"key":"ref_2","first-page":"b151","article-title":"Management of burning mouth syndrome","volume":"77","author":"Klasser","year":"2011","journal-title":"J. Can. Dent. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.1600-0528.2011.00645.x","article-title":"Cost-effectiveness analysis of burning mouth syndrome therapy","volume":"40","author":"Hens","year":"2012","journal-title":"Community Dent. Oral Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41415-024-7057-9","article-title":"Oral dysaesthesia: A special focus on aetiopathogenesis, clinical diagnostics and treatment modalities","volume":"236","author":"Farag","year":"2024","journal-title":"Br. Dent. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"421","DOI":"10.4103\/jiaomr.jiaomr_113_18","article-title":"Oral cenesthopathy\u2014The psychological malady: Report of two cases","volume":"30","author":"Ruparelia","year":"2018","journal-title":"J. Indian Acad. Oral Med. Radiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.15403\/jgld-4245","article-title":"Burning Mouth Syndrome Etiology: A Narrative Review","volume":"31","author":"Russo","year":"2022","journal-title":"J. Gastrointestin. Liver. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dugan, C., Parlatescu, I., Dobre, M., Pirvu, R.E., and Milanesi, E. (2022). Insights on brain functions in burning mouth syndrome. Front. Syst. Neurosci., 16.","DOI":"10.3389\/fnsys.2022.975126"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Orliaguet, M., and Misery, L. (2021). Neuropathic and Psychogenic Components of Burning Mouth Syndrome: A Systematic Review. Biomolecules, 11.","DOI":"10.3390\/biom11081237"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1177\/0333102417694883","article-title":"Burning mouth syndrome","volume":"37","author":"Jaaskelainen","year":"2017","journal-title":"Cephalalgia"},{"key":"ref_10","first-page":"615","article-title":"Burning mouth syndrome","volume":"65","author":"Grushka","year":"2002","journal-title":"Am. Fam. Physician"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.2147\/NDT.S167527","article-title":"Clinical characteristics and course of oral somatic delusions: A retrospective chart review of 606 cases in 5 years","volume":"14","author":"Umezaki","year":"2018","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jpsychores.2014.11.010","article-title":"Psychiatric comorbidities and psychopharmacological outcomes of phantom bite syndrome","volume":"78","author":"Watanabe","year":"2015","journal-title":"J. Psychosom. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Foerster, Z., Kleinmann, B., Schlueter, N., Vach, K., and Wolter, T. (2022). Multimodal pain therapy for persistent idiopathic facial pain\u2014A pilot study. Biopsychosoc. Med., 16.","DOI":"10.1186\/s13030-022-00254-1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/joor.12950","article-title":"Occlusal dysesthesia\u2014A clinical guideline","volume":"47","author":"Imhoff","year":"2020","journal-title":"J. Oral Rehabil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2174\/0118746098279205240812113353","article-title":"Challenges of Diagnosis and Management of Burning Mouth Syndrome: A Literature Review","volume":"18","author":"Almeida","year":"2024","journal-title":"Curr. Aging. Sci."},{"key":"ref_16","unstructured":"World Health Organization (2025). International Classification of Diseases 11th Revision (ICD-11) Browser, WHO. Available online: https:\/\/icd.who.int\/browse\/2025-01\/mms\/en."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2022). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing. [5th ed.]. Text Revision (DSM-5-TR).","DOI":"10.1176\/appi.books.9780890425787"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Watanabe, M., Takao, C., Liu, Z., Nayanar, G., Suga, T., Hong, C., Tu, T.T.H., Yoshikawa, T., Takenoshita, M., and Motomura, H. (2022). The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients with BMS. Front. Pain. Res., 3.","DOI":"10.3389\/fpain.2022.809207"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1097\/WNF.0b013e31827453fa","article-title":"Effectiveness of Duloxetine for the Treatment of Chronic Nonorganic Orofacial Pain","volume":"35","author":"Nagashima","year":"2012","journal-title":"Clin. Neuropharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1177\/03331024211036152","article-title":"A systematic review of treatment for patients with burning mouth syndrome","volume":"42","author":"Tan","year":"2022","journal-title":"Cephalalgia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.2147\/NDT.S235669","article-title":"Therapeutic Dose of Amitriptyline for Older Patients with Burning Mouth Syndrome","volume":"15","author":"Suga","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Clayton, A.H., Baker, R.A., Sheehan, J.J., Cain, Z.J., Forbes, R.A., Marler, S.V., Marcus, R., Berman, R.M., and Thase, M.E. (2014). Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors\/serotonin\u2013norepinephrine reuptake inhibitors: Analysis of patients beginning adjunctive treatment in a 52-week, open-label study. BMC Res. Notes, 7.","DOI":"10.1186\/1756-0500-7-459"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1017\/S1092852900020216","article-title":"Aripiprazole augmentation in major depressive disorder: A double-blind, placebo-controlled study in patients with inadequate response to antidepressants","volume":"14","author":"Berman","year":"2009","journal-title":"CNS Spectr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/JCP.0b013e31816774f9","article-title":"The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Second Multicenter, Randomized, Double-Blind, Placebo-Controlled Study","volume":"28","author":"Marcus","year":"2008","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1517\/eoid.12.4.655.23750","article-title":"Aripiprazole: A partial dopamine D2 receptor agonist antipsychotic","volume":"12","author":"Keck","year":"2003","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e187421062201120","DOI":"10.2174\/18742106-v16-e2201120","article-title":"Pharmacological Approach to Atypical Odontalgia Patients: A Systematic Review of Case Reports","volume":"16","author":"Siregar","year":"2022","journal-title":"Open Dent. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0149-2918(04)90066-5","article-title":"Aripiprazole: A comprehensive review of its pharmacology, clinical efficacy, and tolerability","volume":"26","author":"DeLeon","year":"2004","journal-title":"Clin. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jpsychires.2018.08.017","article-title":"Second generation atypical antipsychotics olanzapine and aripiprazole reduce expression and secretion of inflammatory cytokines in human immune cells","volume":"105","author":"Stapel","year":"2018","journal-title":"J. Psychiatr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102170","DOI":"10.1016\/j.jchemneu.2022.102170","article-title":"Neuroprotective effects of aripiprazole in stress-induced depressive-like behavior: Possible role of CACNA1C","volume":"126","author":"Dashti","year":"2022","journal-title":"J. Chem. Neuroanat."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Armstrong, M., Castellanos, J., and Christie, D. (2024). Chronic pain as an emergent property of a complex system and the potential roles of psychedelic therapies. Front. Pain Res., 5.","DOI":"10.3389\/fpain.2024.1346053"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/jop.13641","article-title":"Burning Mouth Syndrome: Unlocking the Future of Pharmacological Treatment","volume":"54","author":"Adamo","year":"2025","journal-title":"J. Oral Pathol. Med."},{"key":"ref_32","first-page":"Cd008242","article-title":"Amitriptyline for neuropathic pain in adults","volume":"2015","author":"Moore","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1001\/jamainternmed.2014.7663","article-title":"Cumulative use of strong anticholinergics and incident dementia: A prospective cohort study","volume":"175","author":"Gray","year":"2015","journal-title":"JAMA Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s40266-020-00796-5","article-title":"Drug-Related Orthostatic Hypotension: Beyond Anti-Hypertensive Medications","volume":"37","author":"Rivasi","year":"2020","journal-title":"Drugs Aging"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jung, Y.S., Suh, D., Choi, H.S., Park, H.D., Jung, S.Y., and Suh, D.C. (2022). Risk of Fall-Related Injuries Associated with Antidepressant Use in Elderly Patients: A Nationwide Matched Cohort Study. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19042298"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1111\/odi.14966","article-title":"Amitriptyline at low dose for burning mouth syndrome","volume":"30","author":"Nagamine","year":"2024","journal-title":"Oral Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/clpt.2013.2","article-title":"Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants","volume":"93","author":"Hicks","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"(2023). American Geriatrics Society 2023 updated AGS Beers Criteria\u00ae for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc., 71, 2052\u20132081.","DOI":"10.1111\/jgs.18372"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Yoshino, A., Okamoto, Y., Doi, M., Okada, G., Takamura, M., Ichikawa, N., and Yamawaki, S. (2017). Functional Alterations of Postcentral Gyrus Modulated by Angry Facial Expressions during Intraoral Tactile Stimuli in Patients with Burning Mouth Syndrome: A Functional Magnetic Resonance Imaging Study. Front. Psychiatry, 8.","DOI":"10.3389\/fpsyt.2017.00224"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tan, Y., Wu, X., Chen, J., Kong, L., and Qian, Z. (2019). Structural and Functional Connectivity Between the Amygdala and Orbital Frontal Cortex in Burning Mouth Syndrome: An fMRI Study. Front. Psychol., 10.","DOI":"10.3389\/fpsyg.2019.01700"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0304-3959(02)00323-8","article-title":"Striatal dopamine D1 and D2 receptors in burning mouth syndrome","volume":"101","author":"Hagelberg","year":"2003","journal-title":"Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.ejphar.2004.07.024","article-title":"Striatal dopamine D2 receptors in modulation of pain in humans: A review","volume":"500","author":"Hagelberg","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ejphar.2008.09.008","article-title":"Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors","volume":"597","author":"Tadori","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pan, B., Chen, J., Lian, J., Huang, X.F., and Deng, C. (2015). Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3beta Signalling Pathways in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132722"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s40263-015-0278-3","article-title":"Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism","volume":"29","author":"Tomasetti","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1002\/syn.20548","article-title":"Aripiprazole and its human metabolite OPC14857 reduce, through a presynaptic mechanism, glutamate release in rat prefrontal cortex: Possible relevance to neuroprotective interventions in schizophrenia","volume":"62","author":"Yang","year":"2008","journal-title":"Synapse"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15593258221109335","DOI":"10.1177\/15593258221109335","article-title":"A Conserved Mechanism for Hormesis in Molecular Systems","volume":"20","author":"Greenwood","year":"2022","journal-title":"Dose Response"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1192\/bjp.2021.165","article-title":"Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: Preliminary findings based on a systematic review and dose-effect meta-analysis","volume":"221","author":"Furukawa","year":"2022","journal-title":"Br. J. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.jocn.2006.09.002","article-title":"Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score","volume":"14","author":"Yilmaz","year":"2007","journal-title":"J. Clin. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1001\/jamaoto.2020.0526","article-title":"Association Between Burning Mouth Syndrome and the Development of Depression, Anxiety, Dementia, and Parkinson Disease","volume":"146","author":"Kim","year":"2020","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6358624","DOI":"10.1155\/2018\/6358624","article-title":"\u201cBrave Men\u201d and \u201cEmotional Women\u201d: A Theory-Guided Literature Review on Gender Bias in Health Care and Gendered Norms towards Patients with Chronic Pain","volume":"2018","author":"Samulowitz","year":"2018","journal-title":"Pain Res. Manag."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/jnr.23856","article-title":"Sex-based differences in brain alterations across chronic pain conditions","volume":"95","author":"Gupta","year":"2017","journal-title":"J. Neurosci. Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1282\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:55Z","timestamp":1760034835000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,27]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ph18091282"],"URL":"https:\/\/doi.org\/10.3390\/ph18091282","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,27]]}}}