The objectives of this research project were 1) To evaluate the effectiveness of amitriptyline therapy on improving pain and the oral health-related quality of life (OHRQoL) in BMS patients when compared to palliative topical therapies (sodium bicarbonate mouthwash). 2) To determine the association between therapy of amitriptyline and heart rate variability (HRV) parameters. 3) To assess the association between pain outcomes and fluctuations in HRV parameters. This project was composed of a retrospective and a prospective study, and subjects were primary BMS patients recruited at the Oral Medicine Clinic, Faculty of Dentistry, Chulalongkorn University. In the retrospective study, 20 female participants were phone interviewed with 3 validated questionnaires and specific data was retrieved from the subject's clinical charts. Four females already taking amitriptyline or sodium bicarbonate mouthwash were then recruited into a pilot prospective study to evaluate changes on pain, OHRQoL and HRV between baseline, 3-month and 6-month follow-up visits. No significant differences on patient global impression of change (PGI-C) and OHRQoL between different age groups, working status, treatment options or psychological profile were found in the retrospective study (p<0.05). Regarding the prospective study, pain intensity in the sodium bicarbonate group was decreased from baseline to 3 months, while in amitriptyline group it increased and PGI-C was not changed. OHRQoL in sodium bicarbonate group and amitriptyline group were comparable at baseline and 6 months. HRV parameters in the amitriptyline group was higher than subjects in sodium bicarbonate group. These findings emphasize the value of PGI-C and OHRQoL assessments when it comes to adjust strategies during pain management in each individual with primary BMS. However, this is a pilot prospective study and must be interpreted with caution because of the limited sample size. Future investigations should be performed to confirm our findings with a randomized controlled clinical trial and also to determine the number of primary BMS patients that need to be treated (NNT) to have a clinical impact.