Chronic pain and major depressive disorder (MDD) impose significant burdens on individuals and healthcare systems, both independently and in combination. Chronic pain affects approximately 21 % of adults globally, leading to reduced quality of life, lost productivity, and increased mortality risk. (Rikard, 2023) MDD, a leading cause of disability, affects 5 % of the global population, with annual economic costs exceeding $1 trillion. (Liu et al., 2024) When co-occurring, these conditions exacerbate disability, with studies estimating that 39.3 % of chronic pain patients experience clinical depression and 40.2 % report anxiety. (Aaron et al., 2025) Similarly, another research found that 55.6 % of the US adults living with depressive or anxiety symptoms also experience chronic pain, comparing with a 17.1 % prevalence among their peers without depressive or anxiety symptoms. (Jennifer et al., 2024) The combined burden is staggering, doubling healthcare utilization and tripling work absenteeism compared to either condition alone. (Fitzcharles et al., 2021) This comorbidity contributes to opioid misuse, increases suicide risk, and strains public health resources, particularly in primary care where both conditions are often first identified. (Smith et al., 2023).

Previous longitudinal studies have highlighted the persistent interplay between pain and depressive symptoms. For instance, a study combining cohorts from the UK and USA found a bidirectional association between pain and depressive symptoms over 12 years, (Werneck and Stubbs, 2024) with pain predicting depressive symptoms two years later and vice versa. Moreover, a 12-month study indicated a bidirectional relationship between depression and pain in individuals with chronic pain, including waves every three years, (Kroenke et al., 2011) indicating that shorter-term changes in pain may also be associated with depressive symptoms and vice versa. However, these studies lacked detailed analyses of medication use patterns surrounding the onset of MDD.

The bidirectional relationship between pain and MDD is mediated by shared neurobiological pathways, including dysregulation of serotonin, norepinephrine, and inflammatory cytokines. (Jiang et al., 2025; Zheng et al., 2022) Chronic pain may precipitate MDD by acting as a chronic stressor, while MDD heightens pain sensitivity, creating a vicious cycle.(Tanguay-Sabourin et al., 2023) Pain medications, such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and gabapentinoids, are commonly prescribed for chronic pain, yet their use patterns around MDD onset remain poorly understood. Untreated pain can undermine antidepressant efficacy, and over-reliance on analgesics, particularly opioids, risks dependency, exacerbating public health challenges. (Boersma et al., 2019).

Population-based studies, using registries, tracking longitudinal pain medication use are scarce, despite the urgent need to understand how pain management intersects with MDD diagnosis. Taiwan's National Health Insurance Research Database (NHIRD), covering 99 % of the population, provides a robust platform to address this gap (Lin et al., 2018). Prior NHIRD analyses have validated MDD diagnoses and highlighted comorbid burdens, but none have examined pain medication trajectories relative to MDD onset (Wu et al., 2020). By leveraging Taiwan's comprehensive National Health Insurance Research Database, our study uniquely captures the temporal dynamics of pain medication prescriptions and diagnoses in relation to MDD onset on a monthly basis, providing critical insights for integrated care strategies.

The primary objective of this study is to examine the temporal patterns of pain-related diagnoses and analgesic prescriptions in the 12 months before and after the diagnosis of MDD, to determine whether escalating pain and medication use serve as prodromal indicators of MDD and whether psychiatric interventions post-diagnosis contribute to reduced reliance on pain medications. These patterns, if confirmed, could inform early screening and integrated care models in primary care settings, potentially mitigating the compounded burden of pain-depression comorbidity and guiding global health policy. We hypothesize that pain medication use and pain diagnoses will escalate before MDD diagnosis, peak at the index month, and decline post-diagnosis due to psychiatric treatment or shifts in clinical focus.