Venous blood flow is the blood flow returning to the heart from the periphery, and venous insufficiency results from blood flow disturbances. When problems arise with the return of venous blood flow, blood stagnation may occur in the periphery, and stagnant blood eventually develops into visible varicosities. Pain associated with venous blood flow can manifest in various ways. Aching and cramping are the most common symptoms of venous pain. Further, feeling of weight, paresthesia, and hypo-esthesia can occur. These symptoms are caused by venous hypertension and other hemodynamic mechanisms. Edema can occur because of microcirculation issues. Pain caused by venous insufficiency is the main reason for decreased quality of life in these patients (1). However, the exact cause of venous pain, which manifests in various aspects, remains unclear. These symptoms are not limited to cardio-vascular diseases. Therefore, understanding venous pain is difficult.

Although various studies have investigated the mecha-nism of pain in patients with venous insufficiency, no precise mechanism has been identified. An experiment was conducted to measure venous pain using the veins in the participants’ hands based on a human venous pain model for identifying venous pain, and various stimuli were applied to evaluate pain. The stimuli used include balloon dilatation of the veins, cold, heat, electrical stimulation, and hypertonic saline injections, which caused similar pain levels that disappeared completely (2). To simulate venous insufficiency, stimulation was performed through mecha-nical balloon dilatation and vasodilation, similar to the vasodilation experienced in venous insufficiency. In this case, pain began to be felt when the dilation reached thrice the diameter of the normal vein. However, simple vaso-dilation does not appear to be the primary cause of pain. An example that supports this is that patients do not complain of vascular pain in vasodilation due to growth of an arteriovenous fistula or vigorous activity (2).

Several studies have investigated the correlation between chronic venous insufficiency and lower-extremity symp-toms, including venous pain, but no definitive conclusions have been drawn. Some studies have reported a positive correlation between lower-extremity symptoms and venous reflux (3-5). An international cohort study involving a population sample from the VEINES study conducted from 1994 to 1997 reported that venous pain was associated with patient-reported quality of life even after adjusting for confounding variables in the C class of the Clinical- Etiology-Anatomy-Pathophysiology (CEAP) clinical classi-fication as evaluated by physicians (4). Additionally, an article published in 2016 reported that the incidence of leg pain increased significantly as the C class increased, and severe pain gradually increased as patients advanced to class C6. This association remained significant even after adjusting for the age, body mass index, and family history of patients with chronic venous disease (5).

However, other studies have reported no significant association between the clinical stage of venous disease and patient symptoms. Mohammad et al. reported no association between clinical stages of venous disease and patient symptoms and confirmed that pain and feelings of heaviness were much more severe in classes C2 and C3 than in classes C4 and C5 (6). Importantly, the C class in the CEAP classification is not divided according to the clinical severity of venous disease; therefore, evaluating the associ-ation according to the C class may lead to errors of bias. This is because class C2 typically includes patients with all types of varicose veins while class C3 includes patients with all types of edema (2).

The most widely accepted hypothesis of venous pain is the inflammation theory, which is based on venous blood flow congestion. The biomolecular transduction pathway observed in venous insufficiency shows that venous blood stagnation results from venous valve damage, which leads to relaxation of the venous wall, eventually resulting in venous hypertension. These processes can stretch and compress the venous wall, resulting in mechanomolecular alterations that ultimately cause hypoxia. This causes the stagnation of venous blood flow, resulting in the repetition of a vicious cycle. This process subsequently activates the release of inflammatory mediators and growth factors by endothelial cells. The resultant sensitization and activation of nociceptors by inflammatory mediators that cause characteristic pain in patients with chronic venous insufficiency is known as the inflammation theory (2,7). However, contrary to the claims of the inflammation theory, studies on the correlation between the severity of a patient’s symptoms and inflammatory markers have shown no correlation (6). Inflammatory marker levels increase in cases of severe venous insufficiency, causing skin changes. Inflammatory markers increase in cases of severe venous insufficiency to the extent of causing cutaneous changes. However, no significant association has been shown in other cases, and this does not clearly support the basis of the inflammation theory. The second hypothesis is the patho-mechanism of neuronal damage in patients with chronic venous insufficiency (8). This hypothesis is based on the fact that the pain pattern described in patients with chronic venous insufficiency is similar to that in patients with peripheral neuropathy. A study involving patients with chronic venous insufficiency without the risk of neuropathy showed reduced functions of Ab, Ad, and C nerve fibers. Thus, this hypothesis argues that chronic venous insuf-ficiency, similar to peripheral arterial disease, induces microangiopathy, which can cause extended damage to peripheral tissues; this also explains varicose ulcers (8). Further research is required to elucidate the mechanisms underlying these additional associations between peripheral nerves and venous insufficiency.

The symptoms of venous insufficiency that patients complain of are subjective and diverse. However, these symptoms are serious and compromise the patients’ quality of life. Therefore, the perception that venous insufficiency is just a cosmetic problem should be changed, as it is a disease that should be treated. The exact mechanisms underlying the six symptoms of venous insufficiency have not been elucidated. However, further research on this topic is required.