Behavioral Modification as a Putative Mediator of Digital Therapeutic Response in Temporomandibular Disorders:...

Temporomandibular disorders (TMDs) are common chronic conditions involving orofacial pain and functional limitations. Digital therapeutics (DTx) have demonstrated efficacy in TMD management; yet, the behavioral and clinical mechanisms underlying treatment response remain poorly characterized, particularly whether behavioral modification or DTx engagement intensity drives therapeutic benefit.

This study aimed to investigate the behavioral mechanisms, responder profiles, and moderators of clinical response to a DTx intervention for TMD through a post hoc analysis integrating self-reported, server-derived, and clinician-rated outcome measures.

We performed a post hoc secondary analysis of a multicenter, double-blind, sham-controlled randomized superiority trial conducted at 2 tertiary care centers in South Korea. The per-protocol cohort comprised 93 participants (DTx: n=44; sham: n=49). Five complementary analyses were applied: responder logistic regression at ≥30%, ≥50%, and ≥70% Visual Analog Scale (VAS) pain-reduction thresholds; subgroup comparison by Oral Behaviors Checklist (OBC) modifier status; causal mediation analysis using the potential outcomes framework with bootstrap CIs; week-4 sensitivity analysis; and moderator analysis testing the treatment×Patient Health Questionnaire-4 (PHQ-4) interaction on VAS change.

DTx assignment was consistently associated with clinically meaningful pain reduction across all 3 responder thresholds (adjusted odds ratios [ORs] 5.39, 95% CI 1.72-16.94 at ≥30%; 3.21, 95% CI 1.14-8.99 at ≥50%; and 3.45, 95% CI 1.12-10.63 at ≥70%; all P<.05). Mediation analysis suggested that approximately 29.1% of the total VAS treatment effect may be transmitted via OBC-defined behavioral modification (natural indirect effect -6.91 mm; 95% CI -13.23 to -0.58; P=.03), with the mediated proportion rising from 19.6% to 30.2% as responder thresholds became more stringent. Participants with OBC modifiers achieved substantially greater pain reduction than nonmodifiers (-45.71 vs -22.61 mm; difference -23.11; 95% CI -36.97 to -9.24; P<.01) despite no significant differences in any objective DTx engagement metric. Treatment ORs were 33%-42% higher at week 4 than at the 6-week end point (week-4 ORs 7.15, 95% CI 2.39-21.32 at ≥30%; 4.48, 95% CI 1.68-11.94 at ≥50%; and 4.91, 95% CI 1.74-13.87 at ≥70%), suggesting that week 4 may be a candidate time point for future adaptive protocols. Baseline psychological distress (PHQ-4 ≥3) appeared to moderate the treatment response (interaction β=-19.63; 95% CI -37.86 to -1.39; P=.04).

Sham-controlled randomized trials in TMD that empirically differentiate behavioral realization from digital engagement volume remain scarce. Behavioral modification, rather than engagement volume, appears to be an important pathway associated with DTx efficacy and may mediate approximately 29% of the pain-reduction effect under exploratory causal assumptions. This advances mechanism-based evaluation of DTx beyond engagement-based surrogates. Week 4 may represent a promising candidate for future adaptive protocols, and baseline psychological distress may warrant investigation for precision patient selection. These preliminary findings should be corroborated by future prospective studies and further mechanistic investigations.