Pathophysiological underpinnings of lower-limb pain of venous origin

Stony Brook University Medical
Center, Stony Brook
New York, USA

Pathophysiological underpinnings of lower-limb pain of venous origin

by N. Labropoulos, USA

Patients with chronic venous disease (CVD) present with a variety of signs and symptoms. Pain, and similar symptoms such as the feeling of bursting, tiredness, and a burning sensation, is very common in these patients. Many epidemiological and clinical studies have demonstrated that there is a high prevalence of such symptoms and that these symptoms are found in all clinical stages of CVD. The feeling of the symptoms is evident in multiple studies showing that different types of treatment such as medications, compression, and surgical procedures can improve or alleviate pain. The range of pain sensation varies from mild to severe and can be present at rest or during physical activity. The association of pain intensity with the clinical severity of CVD may be weak, as many factors determine the development of pain sensation. The mechanisms of venous pain are not well understood. However, inflammatory mediators seem to have an important role in the activation of the nerve endings. Many inflammatory cells and molecules have been found in the venous wall and perivenous space, both in experimental animal studies and in humans. As inflammation is found in early stages of venous disease this could explain why patients in classes C0 and C1 (clinical, etiological, anatomical, pathophysiological [CEAP] classification) report pain. The diffuse character of venous pain makes it difficult for the patient to define and, therefore, to describe. This is a significant challenge for the practitioners who deal with venous disease. More studies are needed in order to elucidate the strength of the association of pain in CVD and unravel its pathways.

Medicographia. 2015;37:32-36 (see French abstract on page 36)

Chronic venous disease (CVD), as shown by many epidemiological studies, has a high prevalence with a significant socioeconomic impact.1-3 This is due to the signs and symptoms of CVD that affect a great number of patients.3,4 These vary from cosmetic issues and minor complaints, to venous ulceration and pain.3,5 Signs and symptoms develop from venous hypertension at a local or more diffuse area in the lower limb. Increased venous pressure occurs from reflux and obstruction, or a combination of the two. The major contributing factors of CVD and its severity are depicted in Figure 1. Together with reflux and obstruction, the efficiency of the foot and calf muscle pump, the cellular biology and soft tissue responses, risk factors, and genetic predisposition, are all important factors in the development of signs and symptoms of CVD.6-8 The development and progression of CVD is influenced by many factors, to which it is difficult to assign a specific weight as these factors have never been studied properly in a longitudinal manner.9

Figure 1
Figure 1. Factors and pathological features that are responsible for the development
of chronic venous disease.

Therefore, when discussing the signs and symptoms of CVD, and pain in particular, clear associations and evidence-based studies are lacking. Pain is a very common symptom in patients with CVD, but it is poorly understood. It ranges from mild aching usually found in patients with early stages of CVD, to a significant level of pain in patients with venous claudication.10-12 This paper focuses on the pathophysiological underpinnings of pain of venous origin in order to elucidate what is known and define the questions that we still need to answer.

Definition of pain and its relation to chronic venous disease

Pain has been defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” They also wrote that “Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life.”13 The sensation of pain appears early in life in order to serve as a signaling system for tissue damage.13 In patients with CVD, pain is a very common symptom with different degrees of intensity. As the perception of pain is subjective and the thresholds vary significantly among individuals, the clinical presentation and extent of underlying venous disease do not correlate well with the level of pain.

In a recent consensus document from the Union Internationale de Phlébologie (UIP; International Union of Phlebology) the venous symptoms in patients with clinical, etiological, anatomical, pathophysiological (CEAP) classification C0 and C1 disease were discussed.11 The data presented in the consensus were on the following: heaviness, tightness, feeling of swelling, pain after standing, pain during walking, cramps, itching, and restless legs. The prevalence of the symptoms (each examined alone) ranged from 9.5% to 25%, with women being affected more often. Risk factors for developing these symptoms were female sex, higher age, obesity, and a sitting or standing profession. It was stated that symptoms of patients with CVD are not very specific and thus it is essential to differentiate them from other causes. The association of symptoms in the early stages of CVD has been a controversial topic. In our clinics, we have evidence from many patients that pain is present in a good number of patients at the early stages of CVD, after having excluded other causes for pain. However, the degree of this association is not known, since we did not study it in an objective manner. Multiple studies, both epidemiologic and clinical, have indicated that such an association exists and therefore cannot be ignored.14-17

In patients in CEAP class C2, pain is reported more often. Typically, such pain is located along the varicose veins and is more often perceived below the knee. In patients who have pelvic congestion syndrome and present with C2 disease, the pain may sometimes be localized only to the area of varicosities in the groin and perineum. Pain in the pelvis alone may also be found in patients with pelvic congestion syndrome that is associated with the reflux in varicosities after all other causes have been excluded.18,19 Multiple studies have reported relief of pain after treatment with medication, elastic compression stockings, or invasive procedures. The greatest relief has been achieved with the latter, which also has the support of many prospective randomized trials.20-23

In patients with C3 to C6 disease, pain is often seen and can be independent of the presence of varicose veins, as deep vein obstruction and postthrombotic luminal damage are more common in these patients.24 Obviously, many of these patients have varicose veins as well and the pain is most likely a result of both pathologies. When both reflux and obstruction are present, the chance of developing signs and symptoms of CVD is higher.24-26 Pain intensity is usually higher in this group of patients. In fact, venous claudication is exclusively seen in patients with proximal venous obstruction, particularly when the iliofemoral veins are involved.12,27,28 Also, the distribution of pain is more extensive and can be found in both the calf and the thigh.

Representative images of patients with CVD and pain, with the location and daily presentation, are seen in the examples of Figure 2 (page 34). It needs to be emphasized that although the majority of CVD patients present with symptoms, a large number of them are asymptomatic. This is also true for patients who present with ulcers. The reasons for which patients develop symptoms, and more importantly pain, are largely unknown. It is interesting to see that two different patients with a similar history, duration, and extent of CVD, and the same age and sex, can present very differently. One could have itching along the varicose veins and the other, leg heaviness and pain. This is a frequent scenario that leads us to question why this occurs and what triggers symptoms to be present. Precise history and clinical examination are important before assigning certain signs and symptoms to patients with CVD. It is not uncommon to see patients presenting with joint or sciatic pain that is unrelated to CVD.

Figure 2
Figure 2. Examples of patients
with chronic venous disease
and different types of symptoms.

(A) Male patient with varicose veins in
the medial and posterior calf. He had
itching only, at the mid-calf at the area
of the bulging varicosities. (B) Female
patient who presented with varicose
veins in the anterior and medial thigh.
She had mild pain along the lower part
of the varicosities of the leg, with an
itching and burning sensation. (C) Male
patient with extensive skin damage. He
had previous thrombosis with partial
recanalization in the deep veins. Axial
reflux was found in the deep superficial
veins and two pathological perforator
veins were found in the calf.

Clinical relevance of pain in patients with chronic venous disease

One of the most common complaints of patients with CVD is pain. Patients describe different types of pain and in different locations, with variable extent and intensity in the lower extremities. The importance of pain in patients with CVD, despite the lack of understanding of its origin, is well perceived, as all instruments of evaluation such as scales, clinical severity scores, and quality of life questionnaires have included pain assessment. In most published reports, pain has been the most significant factor affecting the health-related instruments mentioned above. Studies in multiple countries have demonstrated that CVD has a major socioeconomic impact, affecting millions of patients worldwide. One of the most frequent symptoms involved in these studies is pain. Despite the subjectivity in reporting and describing pain, it is still the dominant symptom that affects most patients’ quality of life. This is clearly evident from all the clinical trials where treatment has reduced or abolished pain and has significantly improved most measurements, as recorded by the different instruments of pre- and posttreatment assessment.20-23,29,30

Pain and inflammation

Venous pain is closely linked to inflammation. Multiple studies have shown that CVD is an inflammatory disease. The inflammation is evident in the vein wall and the perivenous space.31,32 Infiltration of monocytes/macrophages in the proximal vein wall, wall base of valve leaflet, and in the valve sinus has been demonstrated, while macrophage-monocytes and mast cells were found widely distributed throughout the vein wall.33,34 Endothelial cell activation, with expression of several molecules and inflammatory infiltrates, has been found in several papers.35-37 These inflammatory changes are more pronounced in patients with skin damage, ie, CEAP classes C4 to C6. It has been shown that inflammation parallels the severity of CVD.7,38 Significant changes are observed in small venous networks and capillaries, which are more apparent in patients with skin damage.39 The venous flow in areas of inflammation becomes more pulsatile.

When inflammation is more intense, the cutaneous and perforating arteries have a high flow with increased diastolic velocity and loss of the reverse flow component.7 There are also more lymph nodes, which are enlarged, seen in the groin.7 The skin blood flux is increased and the ability to increase the local flow to thermal stimuli is reduced.38 A schematic diagram of the role of inflammation on the development of CVD is shown in Figure 3.31

Venous pain is linked to the activation of nerve endings that are found on the venous wall and are called nociceptors.40 Perivascular nerves terminating on the adventitia layer of the veins in animal preparations have been mapped. Although, nerve fibers have been illustrated in a few papers in the lower extremity of patients with CVD, the nerve pathways, precise architecture, and function have not been reported. Therefore, the description and associations for venous pain are based on hypothesis and indirect relations. The current hypothesis on the mechanisms of venous pain emphasizes an inflammatory reaction and an interaction on venous nociceptors.40 The association of pain with other unpleasant sensations that are related to nociception such as tightness, feeling of swelling, heaviness, and cramps is very common in patients with CVD, regardless of the clinical class. This may explain why it is difficult to assess how symptoms are related to CVD. Currently, the hypothesis on the mechanism of development of pain and unpleasant perception of the other symptoms discussed may be described as follows. Venous stasis, genetic predisposition, and environmental factors lead to altered shear stress and wall behavior, which results in the activation of endothelial cells and leucocytes. This in turn promotes secretion of algogenic and proinflammatory mediators that induce local inflammation, which stimulates the nerve endings and leads to a pain sensation.

Figure 3
Figure 3. The vicious circle of venous hypertension
and venous inflammation, emphasizing
the importance of inflammation.

Adapted from reference 31: Bergan JJ et al. N Engl
J Med. 2006;355:488-498. © 2006, Massachusetts
Medical Society.

The degree of stimulation may depend on the status of the nerve endings (healthy, damaged, nonfunctional) and on transient stimuli, for example, at the end of the day, menstrual cycle, prolonged standing or sitting. The condition of the nerve endings and degree of stimulation may explain why there can be a disparity among pain intensity and severity of CVD. In patients with C4b to C6 disease, where heavy infiltration of fibrous tissue in the perivenous space and in the vein wall is found, nerve endings may become less functional and therefore the pain intensity could be less comparable to those with earlier stages of CVD. In contrast, some patients with advanced CVD have more pain than usual and can be sensitive to touch, without having an infection. This could be explained by partial nerve damage that may lead to a reduction of the threshold of pain.

Clinical implications

Venous pain may resemble visceral pain. When compared with pain in the cutaneous space, the nociceptive messages that are developed at a visceral level are less localized, may have the same pain intensity, can be perceived as more unpleasant, and may have a more significant emotional impact. The diffuse character of venous pain, with the feeling of aching, tiredness, tightness, discomfort, bursting, heaviness, and burning sensation, which is difficult for the patient to define and thus challenging for the physician to deal with, has a significant impact on patients’ quality of life. There is a need to enhance our knowledge of these associations, and better define venous pain and related symptoms. We need to improve the instruments of evaluation, and further understand the ultrastructural and functional changes observed at the microcirculation. Moreover, a more detailed workup is needed to define the nerve pathways and their function in the lower-limb veins.


It is evident from many epidemiological and clinical studies that venous pain is found in all stages of CVD. The intensity of pain may not correlate with CVD severity, as many factors play a role in the development and sensation of pain. The underlying mechanisms of pain are not well understood. However, inflammatory mediators seem to have an important role. As inflammation starts early in venous disease, this could explain why patients in CEAP classes C0 and C1 may have pain. Experimental studies, together with functional and clinical studies, are needed to further elucidate pain development and its association with CVD. This will help us to better manage patients with CVD and improve their quality of life.

1. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonn Vein Study by the German Society of Phlebology. Epidemiological study to investigate the prevalence and severity of chronic venous disorders in the urban and rural residential populations. Phlebologie. 2003;32:1-14.
2. Carpentier PH, Maricq HR, Biro C, Poncot-Makinen CO, Franco A. Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. J Vasc Surg. 2004;40(4):650-659.
3. Management of chronic venous disorders of the lower limbs – guidelines according to scientific evidence. Int Angiol. 2014;33(2):87-208.
4. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg. 2002;36(3):520-525.
5. Labropoulos N, Delis K, Nicolaides AN, Leon M, Ramaswami G. The role of the distribution and anatomic extent of reflux in the development of signs and symptoms in chronic venous insufficiency. J Vasc Surg. 1996;23:504-510.
6. Raffetto JD. Dermal pathology, cellular biology, and inflammation in chronic venous disease. Thromb Res. 2009;123(suppl 4):S66-S71.
7. Labropoulos N, Leder DM, Kang SS, Mansour MA, Baker WH. Inflammation parallels severity of chronic venous insufficiency. Phlebology. 2003;18:78-82.
8. Labropoulos N, Giannoukas AD, Nicolaides AN, Veller M, Leon M, Volteas N. The role of venous reflux and calf muscle pump function in nonthrombotic chronic venous insufficiency. Correlation with severity of signs and symptoms. Arch Surg. 1996;131:403-406.
9. Labropoulos N, Leon L, Kwon S, et al. Study of the venous reflux progression. J Vasc Surg. 2005;41:291-295.
10. Amsler F, Rabe E, Blättler W. Leg symptoms of somatic, psychic, and unexplained origin in the population-based Bonn vein study. Eur J Vasc Endovasc Surg. 2013;46:255-262.
11. Benigni JP, Bihari I, Rabe E, et al; UIP – Union Internationale de Phlébologie. Venous symptoms in C0 and C1 patients: UIP consensus document. Int Angiol. 2013;32(3):261-265.
12. Labropoulos N, Volteas N, Leon M, et al. The role of venous outflow obstruction in patients with chronic venous dysfunction. Arch Surg. 1997;132(1):46-51.
13. Anand KJ, Craig KD. New perspectives on the definition of pain. Pain. 1996; 67:3-6.
14. Krôger K, Ose C, Rudofsky G, Roesener J, Hirche H. Symptoms in individuals with small cutaneous veins. Vasc Med. 2002;7:13-17.
15. Langer RD, Ho E, Denenberg J, Fronek A, Allison M, Criqui M. Relationships between symptoms and venous disease. The San Diego Population Study. Arch Intern Med. 2005;165:1420-1424.
16. Jantet G; RELIEF Study Group. Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids. Angiology. 2002;53:245-256.
17. Arnould B, Regnault A, Perrin M. Change in quality of life in patients with chronic venous disease: results of a 6-month study using DAFLON 500 mg. Phlebology. 2004;19:146-147.
18. Asciutto G, Asciutto KC, Mumme A, Geier B. Pelvic venous incompetence: reflux patterns and treatment results. Eur J Vasc Endovasc Surg. 2009;38: 381-386.
19. Monedero JL, Ezpeleta SZ, Perrin M. Pelvic congestion syndrome can be treated operatively with good long-term results. Phlebology. 2012;27(suppl 1):65-73.
20. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004;363:1854-1859.
21. Sell H, Vikatmaa P, Albäck A, et al. Compression therapy versus surgery in the treatment of patients with varicose veins: A RCT. Eur J Vasc Endovasc Surg. 2014;47:670-677.
22. Shingler S, Robertson L, Boghossian S, Stewart M. Compression stockings for the initial treatment of varicose veins in patients without venous ulceration. Cochrane Database Syst Rev. 2013;12:CD008819.
23. Rasmussen L, Lawaetz M, Bjoern L, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years. J Vasc Surg. 2013;58: 421-426.
24. Labropoulos N, Patel PJ, Tiongson JE, Pryor L, Leon LR Jr, Tassiopoulos AK. Patterns of venous reflux and obstruction in patients with skin damage due to chronic venous disease. Vasc Endovascular Surg. 2007;41:33-40.
25. Johnson BF, Manzo RA, Bergelin RO, Strandness DE Jr. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a oneto six-year follow-up. J Vasc Surg. 1995;21:307-312.
26. Nicolaides A, Clark H, Labropoulos N, Geroulakos G, Lugli M, Maleti O. Quantitation of reflux and outflow obstruction in patients with CVD and correlation with clinical severity. Int Angiol. 2014;33(3):275-281.
27. Labropoulos N, Waggoner T, Sammis W, Samali S, Pappas PJ. The effect of venous thrombus location and extent on the development of post-thrombotic signs and symptoms. J Vasc Surg. 2008;48:407-412.
28. Comerota AJ. Thrombolysis for deep venous thrombosis. J Vasc Surg. 2012; 55:607-611.
29. Allaert FA. Meta-analysis of the impact of the principal venoactive drugs agents on malleolar venous edema. Int Angiol. 2012;31:310-315.
30. Gohel MS, Davies AH. Pharmacological treatment in patients with C4, C5 and C6 venous disease. Phlebology. 2010;25(suppl 1):35-41.
31. Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med. 2006;355(5):488-498.
32. Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology. 2008;23:85-98
33. Ono T, Bergan JJ, Schmid-Schönbein GW, Takase S. Monocyte infiltration into venous valves. J Vasc Surg. 1998;27:158-166.
34. Sayer GL, Smith PD. Immunocytochemical characterisation of the inflammatory cell infiltrate of varicose veins. Eur J Vasc Endovasc Surg. 2004;28:479-483.
35. Takase S, Bergan JJ, Schmid-Schönbein G. Expression of adhesion molecules and cytokines on saphenous veins in chronic venous insufficiency. Ann Vasc Surg. 2000;14:427-435.
36. Aunapuu M, Arend A. Histopathological changes and expression of adhesion molecules and laminin in varicose veins. Vasa. 2005;34:170-175.
37. Somers P, Knaapen M. The histopathology of varicose vein disease. Angiology. 2006;57:546-555.
38. Labropoulos N, Wierks C, Golts E, et al. Microcirculatory changes parallel the clinical deterioration of chronic venous insufficiency. Phlebology. 2004;19:81- 86.
39. Vincent JR, Jones GT, Hill GB, van Rij AM. Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg. 2011;54:62S-69S.
40. Danzinger N. Pathophysiology of pain in venous disease. Phlebolymphology. 2008;15:107-114.

Keywords: CEAP classification; chronic venous disease; venous pain; venous symptom