Chronic pain is a pervasive, complex, and often debilitating condition that is increasing in prevalence worldwide, resulting in significant economic and social consequences (1). While it is frequently a sequela of injury or disease, it is also recognized as a distinct condition in its own right, not simply a symptom of other diseases (2). Chronic pain is characterized as a persistent discomfort that surpasses the typical duration of tissue healing. According to the International Association for the Study of Pain, this period is generally considered to exceed 3 months, particularly in the absence of other contributing factors (3). Numerous risk factors are implicated in the onset of chronic pain, encompassing a broad spectrum of domains such as sociodemographic characteristics, psychological conditions, clinical manifestations, and biological attributes (4–12). A thorough understanding of these risk factors can help guide specific prevention and management strategies.

Cadmium is a well-known hazardous pollutant that is widely distributed in the environment (13). Exposure to cadmium in the environment poses a range of public health issues. In the general population, cadmium is commonly absorbed through inhalation of cigarette smoke particles or ingestion of contaminated food, such as shellfish, offal, and vegetables (14). According to previous research, cadmium can be harmful to both the musculoskeletal and neurological systems (15–18), potentially leading to chronic pain (19). Cadmium poisoning is known to cause femoral and lumbar pain initially, followed by the spread of pain to other parts of the body (14). Itai-itai disease represents an extreme manifestation of chronic cadmium toxicity (20) with back pain as a distinguishing symptom (21).

As far as we understand, no existing studies have delved into the association between chronic pain and exposure to cadmium. Consequently, we aim to utilize data from the National Health and Nutrition Examination Survey (NHANES) to conduct an in-depth investigation into the relationship between blood cadmium levels and the incidence of chronic pain among adults in the United States. Our research hypothesis posits that individuals with higher blood cadmium levels are more susceptible to chronic pain.

The objective of this investigation was to elucidate the relationship between blood cadmium levels and chronic pain within the adult population of the United States, utilizing the nationally representative NHANES database. Our findings revealed a positive correlation between elevated blood cadmium levels and the prevalence of chronic pain. This association remained consistent across various subgroups and sensitivity analyses, thereby underscoring the robustness of the relationship between blood cadmium concentrations and chronic pain.

Previous studies on blood cadmium did not focus on chronic pain as a disease in its own right, but rather as a comorbidity of other diseases. However, chronic pain should be considered a healthcare issue and recognized as a disease in its own right (26). Cadmium can cause various diseases accompanied by chronic pain, such as Itai-itai disease, which results from long-term exposure to cadmium-contaminated rice fields. Patients experience a gradual extension of back and hip pain to the rest of the body, which persists for several years (17). Chronic pain is also accompanied by long-term back pain, and cadmium has been significantly associated with arthritis and rheumatoid arthritis in NHANES data (27). However, large cohort studies are still required to supplement the evidence of the relationship between blood cadmium and chronic pain.

While the mechanism underlying the relationship between blood cadmium and chronic pain is not fully understood, it can be explained by cadmium's toxic effects on the skeletal and nervous systems. Cadmium exerts an inhibitory effect on bone formation and stimulates bone resorption, influencing the functional activity of osteoblasts and osteoclasts. It also substitutes calcium in hydroxyapatite crystals, which leads to disorders in calcium metabolism, bone osteoporosis, osteomalacia, and demineralization. Consequently, this results in chronic pain localized in the limbs, pelvis, and spine (28–31). Cadmium has been observed to instigate oxidative stress, augmenting H₂O₂ levels within bone structures, while concurrently diminishing the concentrations of glutathione peroxidase and catalase (32). Furthermore, it stimulates the generation of inflammatory mediators, known as cytokines, within the immune system, leading to significant pain (33). Moreover, cadmium serves as a potent neurotoxic agent, inflicting adverse effects on the peripheral nervous system (34), which leads to oxidative stress (35, 36) and neurogenic damage resulting in neuronal cell death (37). Nerve damage is a major cause of neuropathic pain (19).

Reducing cadmium exposure may help reduce the risk of chronic pain, but it is not easy to achieve. Occupational and environmental exposure to cadmium primarily originates from industrial activities such as battery production, metallurgy, plastic manufacturing, pigments, mining, chemical stabilizers, and metal coatings, as well as contaminated farmland and food (38). Tobacco smoke contains cadmium, which further increases human exposure to cadmium (39). Moreover, cadmium is characterized by an extended biological half-life and a sluggish elimination rate within the human organism, leading to its persistent accumulation (40). Reducing smoking and exposure to secondhand smoke are individual choices that can help reduce cadmium exposure. Identifying food contamination levels and suspected areas and considering public education and awareness programs for cadmium poisoning prevention are also recommended (14).

However, this study has several limitations. Firstly, the pain data in the NHANES database is self-reported through questionnaire surveys, which may be subject to recall bias. However, trained interviewers were used to collect the data, and these methods have been validated and consistent over many years of data collection (41). Secondly, the NHANES database only collected pain data from 1999 to 2004, and there were no more detailed pain data, such as measurements of pain intensity and functional interference. This hinders our ability to examine the intricate details of pain in correlation with blood cadmium levels. Furthermore, the NHANES dataset is collected from the U.S. population, which may lead to regional bias. Finally, retrospective studies have inherent limitations such as missing data for some variables. Nevertheless, multiple imputations were performed and the results were stable. Multivariate logistic regression and subgroup analysis were conducted to reduce residual confounding effects from unknown factors.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the NCHS Research Ethics Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

HW: Conceptualization, Methodology, Supervision, Writing – review & editing. PM: Data curation, Formal analysis, Investigation, Writing – original draft. HD: Data curation, Formal analysis, Investigation, Writing – original draft. SC: Data curation, Investigation, Writing – original draft. XG: Data curation, Investigation, Writing – original draft. XC: Data curation, Investigation, Writing – original draft. YL: Data curation, Investigation, Writing – original draft. GF: Conceptualization, Supervision, Writing – review & editing.