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Dr. Chao H. Huang explains his skepticism regarding a recent study that linked chronic pain to significantly higher lung cancer incidence and mortality rates.

Chronic pain is associated with increased lung cancer mortality as well as a greater incidence of the disease, according to preprinted findings from The Lancet recently published via SSRN.

Chronic pain’s role in cancer development and outcomes remains underexplored. “Previous research on chronic pain and cancer has primarily concentrated on managing cancer-induced pain. It has been shown that chronic stress caused by cancer can increase the risk of tumor metastasis and reduce overall survival rates,” wrote Jing Xu, Harbin Medical University, and colleagues. To assess whether chronic pain influences lung cancer incidence and mortality, the investigators conducted a large prospective cohort study, supplemented by Mendelian randomization.

Analyzing the Data

The team analyzed data from 467,169 UK Biobank participants who, from 2006 to 2010, were aged 37 to 73. Excluding individuals with incomplete baseline pain or analgesic-use data or preexisting lung cancer, researchers collected baseline self-reports of pain at various anatomical sites—face, head, neck, shoulders, abdomen, stomach, hips, knees—and “general pain.” The researchers tracked lung cancer incidence via ICD-10 codes over a median follow-up of 11.7 years. To prove causality, they applied summary-based Mendelian randomization and co-localization methods to identify chronic pain-related DNA methylation changes that could potentially impact lung cancer risk.

Higher Risk & Mortality

Among 4,144 incident lung cancer cases (2,881 deaths), widespread chronic pain was associated with a 57% higher risk for developing lung cancer and a 49% higher risk for mortality compared with chronic pain-free individuals, Xu and colleagues reported. Genetic markers for widespread chronic pain correlated with increased lung cancer risk (OR 1.75, 95% CI 1.32–2.31).

Stratified by chronic pain severity and number of sites, mild pain (one–two sites) carried modest risk elevation (HR 1.132; 95% CI 1.057–1.211), moderate-to-severe multisite pain (three–seven sites) greater risk (HR 1.324; 95% CI 1.198–1.464), and widespread pain the highest risk (HR 1.573; 95% CI 1.306–1.896).

Xu and colleagues also identified DNA methylation changes in two genes—FKBPL and RPS6KA2—that reportedly contributed to a susceptibility to lung cancer among patients with chronic pain.

Expert Interpretation

Dr. Chao Huang, MD, an oncologist and hematologist focusing on lung cancer at The University of Kansas Cancer Center, who was not involved in the study, contends that pain often reflects underlying malignancy rather than driving tumorigenesis. “The pain is a manifestation of the disease, and it also could be associated with more advanced lung cancer disease,” he explains, noting pulmonary hypertrophic osteoarthropathy as a cancer-related arthritis. “I am skeptical that pain is the cause of lung cancer. It is more likely that it is a manifestation of cancer; therefore, it is associated with lung cancer, and the investigators looked in a population that is likely to have lung cancer.”

Dr. Huang further criticized the absence of a control cohort experiencing pain from non-cancer causes—such as post-fracture or sciatica—to determine whether pain independently predicts lung cancer. “If these patients who also have chronic pain due to specific reasons also had a higher incidence of lung cancer, then this would identify pain as a risk factor,” he said. He cautioned that the paper “states that chronic pain is associated with lung cancer and gives the impression that it is the cause of lung cancer, which is not accurate. The study researched a population that is likely to have some form of illness, as patients with chronic cough are likely also to have a high association with lung cancer.”

‘Provocative’ Genetic Associations

Although the findings of methylation on certain key genes were interesting, Huang said, they also raised questions.

“Both genes FKBPL and RPS6KA2 found to be methylated are genes that control cell cycle and proliferation. Therefore, these are genes involved in cell division and if they are affected, they are likely involved in the pathogenesis of cancer which is expected,” says Dr. Huang. “It did not find any correlation with genes related to pain receptors or alterations in the pain pathway. Therefore, it is a provocative finding that needs further investigation to determine if they are isolated markers of lung cancer genesis and associated with pain or independent of pain symptoms.”

Clinical Implications

Regardless, Dr. Huang said the findings should raise awareness in both clinicians and patients that chronic pain can indicate serious illness.

“Patients who are at risk of lung cancer, like smokers, should report pain symptoms to their physicians and should also have lung cancer screening based on the recommendations and have tests done to determine if the pain could be an indication of more serious disease,” says Dr. Huang. “Patients with chronic pain should be investigated for a more serious illness like cancer … If a patient without a diagnosis of cancer has chronic pain, the clinician should at minimum complete all the necessary cancer screening tests, not just for lung cancer but also for breast, prostate, and colorectal cancers before attributing it to just common osteoarthritis.”