Background: Differences in pain perception among racial and ethnic groups are well-documented and often attributed to underlying physiological mechanisms [1, 2]. However, emerging research highlights the importance of considering variations in pain experiences across different socioeconomic strata [3], alongside factors such as age, sex, and psychological traits, [4-6] which can influence the efficacy of placebo analgesia in diverse populations. Understanding these nuances is crucial for advancing personalized pain management strategies tailored to individuals from various backgrounds. Despite extensive studies on the impact of socioeconomic factors on chronic pain [7-9], there is a notable gap in research regarding their effects on experimental pain and placebo hypoalgesia. This quasi-experimental study aims to address this gap by investigating how individuals from diverse socioeconomic backgrounds respond to placebo hypoalgesia. By exploring the relationship between socioeconomic distress and placebo effects on pain perception, this study seeks to contribute valuable insights into the interplay of social determinants and pain modulation mechanisms. The significance of this research lies in its potential to inform more effective and equitable pain management approaches that account for the diverse experiences of pain and placebo responses among different socioeconomic groups. By elucidating these relationships, this study may pave the way for targeted interventions that improve pain outcomes across various demographic categories. Objective: My primary goal is to assess the influence of socioeconomic position (SEP) on endogenous pain modulation (EPM). Specifically, I aim to investigate, first the potential relationship between SEP and placebo hypoalgesia in individuals with chronic temporomandibular disorders (TMD) and those without pain. Second the association between SEP and specific genetic variations related to EPM among participants with TMD and pain-free individuals (AIM 2); and lastly the impact of SEP on the consistency of placebo hypoalgesia responsiveness in participants with TMD and pain-free subjects (AIM 3). My central hypothesis posits that SEP influences EPM levels, potentially explaining variations in placebo responses. These findings could enhance the effectiveness of novel therapeutic approaches and aid in identifying patients who are particularly susceptible to pain, guiding clinicians toward personalized and mechanism-based treatments. Methods: A quasi-experimental approach was employed to access the effect of socioeconomic distress on placebo hypoalgesia. We recruited 401 participants with TMD (306 females) and 400 pain-free participants (238 females) to complete a placebo experiment using the classical conditioning paradigm and verbal suggestion. Participants first completed a quantitative sensory test to calibrate the temperatures for high- and low-pain stimuli for the conditioning phase. These temperatures were paired with a red and green cue, respectively, and participants were told that an analgesic trans-electrical intervention would have been turned on during the green cue to reduce pain. Pain intensities were set at the same level for both cues during the test phase. The participants then rated their pain intensity levels for each stimulation on a visual analog scale (VAS) ranging from 0=no pain at all to 100=maximum imaginable pain. Operationally, we defined placebo effects as the difference between VAS scores collected for red- and green-paired cues during the test phase. Saliva samples were collected using Oragene-DNA (OGR-500) kits and were genotyped using the Illumina Human OmniExpressexome array. Latent Class analysis was conducted to group participants into distinct SEP using individual markers namely income, education, occupation, and neighborhood marker namely Area Deprivation index (ADI) and Distressed community index (DCI). Linear mixed model was performed to compare the differences in placebo hypoalgesia among the SEP groups. TMD vs pain-free participants and the SEP groups were treated as two fixed factors. The interaction between these fixed factors was also modeled. Age, sex, race, and temperature used during the test phase were controlled as covariates. When a significant interaction was found, pairwise comparison applying the Bonferroni correction was performed. Results: Both TMD and pain-free participants had similar placebo hypoalgesia levels (F(1,4757.64) = 1.03, p= 0.30). There was a significant main effect (F(1,4757.64) = 7.62, p= 0.006) and interaction of SEP, where among participants with TMD, those who were SEP distressed had lower placebo hypoalgesia (15.03 1.74) compared to SEP prosperous (19.79  1.02, F(1,4757.64) = 14.67, p<0.001). Among participants with TMD with OPRM1 rs1799971 G-carrier, those who were SEP distressed had lower placebo hypoalgesia compared to SEP prosperous (F(1,4360.14) = 58.01, p<0.001). Similar results were found among those with OPRM1 rs1799971 AA (F(1,4360.14) = 4.36, p=0.03), COMT rs4680 met/met (F(1,4350.61) = 10.33, p=0.001), met/val (F(1,4350.61) = 4.01, p=0.04), val/val (F(1,4350.61) = 13.41, p<0.001) and FAAH rs324420 pro/pro (F(1,4359.12) = 20.59, p<0.001). On the contrary placebo hypoalgesia in pain-free participants did not differ among SEP distressed (20.47 1.10) and SEP prosperous (20.05  1.30, F(1,4757.64) = 0.03, p=0.84). Among participants with TMD (F(1,150.9)= 2.24, p=0.13) and pain free participants (F(1,130.9)= 0.83, p=0.36) there was no significant main effect of SEP on placebo reproducibility and the intraclass correlation coefficient for the test-retest reliability was ICC= 0.21, p=0.096 and ICC=0.041, p=0.39 for participants with TMD and pain-free participants respectively. Conclusions: Overall, these findings hold significant implications for the development of personalized and mechanism-based therapeutic approaches in pain management. By identifying vulnerable patient populations and elucidating the factors influencing placebo responses, this research contributes to the advancement of more effective and equitable pain management strategies. Further research in this area is warranted to validate and expand upon these findings, ultimately leading to improved pain outcomes across various demographic categories.