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Pain is the complaint that most often leads to a diagnosis of venous disease, and it has a significant impact on patients’ quality of life. For all those involved with chronic venous disease (CVD), pain is difficult to assess both because of its multidimensional nature and because of the lack of a close relationship between pain as a symptom and severity of venous disease. Current hypotheses on the mechanisms of pain induction in CVD highlight its local inflammatory origin. A variety of inflammatory mediators are released locally in the early stages of CVD, which activate unmyelinated C-fibers in the venous wall, leading to pain. In the last five years, there has been a veritable explosion in the number of indicators suggesting an inflammatory reaction in varicose veins. The precise mechanisms governing the interaction between venous nociceptors and mediators of inflammation, which may account for the variability of pain experienced in venous disease, remain difficult to explain.

The quality of life of chronic venous disease (CVD) patients is greatly affected by pain,^1,2 the complaint that most often leads to diagnosis of venous disease.^3,4 For everyone involved in CVD, pain is difficult to measure. Often pain of venous origin is found in association with other disagreeable sensations that do not belong in the range of nociceptive symptoms, eg, pruritus or a sensation of cramp, heaviness, or tension in the legs.³ The intensity of pain can also fluctuate substantially, from patient to patient or in the same patient with progression of the disease over a period of time.

A causal relationship between CVD and pain of venous origin remains difficult to clarify, both clinically and experimentally. This difficulty could be attributed to the absence of a close link between pain and the severity of CVD. Nevertheless, the future looks promising as the neurophysiological mechanisms of pain of venous origin are now better understood,⁵ and several biochemical and cellular processes involved in varicose vein remodeling have been explained.^6-8

Venous innervation and the physiological properties of venous and perivenous nociceptors

Veins are innervated by sensory nerve fibers whose cell body is situated in the dorsal root ganglia of the spinal cord.⁵ Sensory fibers are located along the venous wall and subdivide into collateral branches. Some cross the tunica adventitia and termi- nate in the venous wall between endothelial cells and smooth muscle cells of the tunica media. Other collateral branches penetrate the connective tissue of the perivenous space where they branch further into unmyelinated free nerve endings in proximity to the microcirculation. These subendothelial and perivascular nerve endings are nociceptors: their sole purpose is the transmission of nociceptive afferent signals generated both in the venous wall and in the perivenous connective tissue, respectively.

Figure 1. Experimental set-up to study pain evoked by stimulation
of an isolated venous segment in man.

Recently, these types of nerve endings have been shown to be present in the wall of human varicose veins.⁹ These nociceptors account for the stimuli that generate pain sensations of venous origin. This type of pain can be induced by a variety of different stimuli. Mechanical stimuli used include traction exerted on a vein, venipuncture, or the presence of a catheter, while nonphysiological chemical stimuli used include the injection of a strongly acidic (pH <4) or alkalinic (pH >11) solution, the injection of hyperosmolar saline or a glucose solution, or the injection of “cold” isotonic saline (<20°C).¹⁰

Animal studies have shown that there are two types of afferent fibers that transmit nociceptive signals of venous origin. Electrophysiological tracings of nerve fibers innervating venous wall have shown that there is a type Aδmyelinated afferent nerve fiber and a type C unmyelinated afferent nerve fiber.11 Aδ fibers, with their higher conduction velocities, are responsible for the acute, sharp sensation of pain that is felt first. They respond to a weaker intensity of stimulus than Cfibers. C-fibers, which are deemed polymodal because they respond to an assortment of stimuli, are responsible for the sensation of longer-lasting, slow, dull pain. Other sources of acute pain of venous origin include superficial venous inflammation or deep vein thrombosis, both of which are often observed in clinical practice. Traditionally, the properties of venous nociceptors have been elucidated experimentally in humans by mechanically, thermally, or chemically stimulating an isolated venous segment and asking the subject to grade the intensity of the sensation induced (Figure 1).¹² This pain model has shown that a variety of nonphysiological endovenous stimuli, such as the application of cold or heat, balloon dilation of the vein, electrical stimulus, and infusion of hyperosmolar saline, produce a painful sensation that starts at a particular threshold and whose quality is the same whatever the method of stimulation used.

Furthermore, the intensity of the sensation of pain increases exponentially with the intensity of the stimulus and completely disappears after injection of a local anesthetic in the isolated venous segment.⁵ Regardless of the source of the pain stimulus, the stimulus-sensation curves (intensity of sensation of pain with increasing intensity of applied stimulus) are all the same. These intriguing results suggest that the different stimuli activate the same venous nociceptors, which means that most nociceptors located in the venous wall are polymodal nociceptors.

These experiments have shown that venous dilation is unlikely to be an important factor in the sensation of venous pain. Mechanical venous balloon dilation has to increase the diameter of a vein by three times its normal value before pain begins to be experienced. If we add to this observation the fact that venous dilation is not normally perceived as painful when induced by pharmacological methods such as the local application of adenosine,¹³ it appears that even major venous dilation is not in itself a significant source of venous pain in normal subjects. Moreover, arteriovenous fistulae created for the purpose of hemodialysis are painless, another strand of support for this conclusion.

Pain experienced and clinical severity of venous disease

Numerous epidemiological studies have shown that the existence, intensity, or both of lower limb symptoms associated with CVD do not correlate with the severity of clinically evaluated venous disease. The quantitative evaluation of CVD is normally based on the CEAP (Clinical-Etiological-Anatomical- Pathophysiological) classification,¹⁴ a system for classifying clinical signs in one of seven classes (C0 to C6) (Table I) according to their severity. In a population study of over 1500 subjects aged 18 to 64 years, the Edinburgh Vein Study, Bradbury et al demonstrated a correlation between the presence of truncular varices and three lower limb symptoms in women: pain, sensation of heaviness or tension, and pruritus.³ Even though the correlations were statistically significant, they were insufficient to determine a causal relationship with the discomfort or pain associated with confirmed venous disease. In fact, 45% of patients who complained of lower limb pain compatible with CVD did not have varicose veins, while about 40% of women presenting with varicose veins in the clinical examination were asymptomatic. Moreover, in men, no significant correlation was found between pain and the existence of truncular varices.

Table I. The CEAP classification.

Regardless of the sex of the patient, no symptoms seemed to vary according to the severity of varicose veins. Several studies of patients with advanced CVD (classes C4 to C6) have shown that there is a relation between the degree of Doppler scanning–identified venous reflux and the severity of venous clinical signs and symptoms. Nonetheless, this does not seem to be the case for early-stage CVD. The search for such a correlation in the Edinburgh Vein Study, which focused primarily on patients presenting with early-stage venous disease, proved disappointing.¹⁵ In the Edinburgh Vein Study, the correlation observed between pathologic superficial venous reflux (duration greater than or equal to 0.5 seconds) and sensation of swelling, heaviness, or tension was low. In addition, this correlation was limited either solely to men (sensation of swelling) or solely to women (sensation of heaviness or tension). Strictly speaking, no significant correlation was observed between superficial venous reflux and pain.

A lack of correlation between the presence of venous symptoms and pain was not only limited to superficial veins; this was also the case for deep veins, too. When venous symptoms were compared with deep venous reflux (popliteal vein), no correlation was found, irrespective of the patient’s sex. Equally, in a study of over 120 patients with mild to moderate CVD,¹⁶ no correlation was seen between pain intensity and clinical severity of venous disease based on the CEAP classification.

Furthermore, Howlader and Smith reported no statistical relation between the pain score or heaviness score of a patient, evaluated on a 10-point visual analogue scale, and the clinical severity of venous disease, in a cohort study of 132 patients.¹⁷ The median pain score was 2.8 in the group of patients with class C2 venous disease, 4.5 in class C3, only 0.5 in class C4 and 0 in patients with class C5 venous disease. No difference was noted in pain scores between patients presenting with superficial venous reflux and those presenting with deep venous reflux. These results fully uphold the findings of a French survey on the frequency of clinical symptoms according to the duration of venous disease.⁴

The French survey illustrated a very significant decrease in the frequency of functional signs of venous disease, in particular pain, over time. So, for example, the frequency of the painful heaviness sensation dropped from 71% in the group with symptoms of less than 5 years’ duration to 50% in the group whose symptoms were of 30 years’ duration or longer. These findings concur with the results of a Swiss epidemiological study that indicate the prevalence of varicose veins increases with age, while pain decreases with age.¹⁸

Inflammatory autoamplification and pain mechanisms in venous disease

Present-day hypotheses on how pain mechanisms act in venous disease focus on a local inflammatory origin, related to venous stasis. The processes that generate pain in venous disease in the short termseemto be identical to those involved in the process of varicose vein remodeling, defined as all of the qualitative and quantitative alterations in the cellular and matrix components of the venous wall, in the longer term.¹⁹

Local hypoxia associated with capillary stasis is probably the origin of these mechanisms. The partial pressure of oxygen has been demonstrated to fall significantly in lower limb veins in venous disease after 30 minutes in a standing position,⁸ and many studies have shown that capillary stasis–induced hypoxia activates endothelial cells.⁷ This type of activation is signaled by the elevation of calcium concentrations in the cytoplasm of endothelial cells,²⁰ which upregulate phospholipase A2 activity.²¹

Activation of phospholipase A₂, in turn, leads to the synthesis and local release of proinflammatory mediators such as platelet-activating factor (PAF), bradykinin, prostaglandins E₂ and D₂, and leukotriene B₄.^22,23 PAF seems to play a key role: it boosts the local release of histamine and serotonin; it caus- es abnormal adherence of neutrophils to the venous endothelium, prior to their infiltration through the venous wall itself; and, finally, it stimulates the synthesis of leukotriene B₄ by activated neutrophils. In the last few years, the amount of evidence for the existence of this type of inflammatory reaction in patients with varicose veins has snowballed,₂₄ and the biochemical changes identified point to endothelial cells and neutrophils as the source of this local inflammation (Figure 2).^8,25-29

Figure 2. Photomicrographs of propidium iodide–positive cells along the upstream (elevated micropressure) and downstream (low micropressure)
segment of an occluded rat venule.

There are a plethora of indicators of inflammation in venous disease: the presence of neutrophils, monocytes, and activated T lymphocytes; the accumulation of macrophages and mast cells; the expression of adhesion molecules on the surface of leukocytes and endothelial cells (eg, LFA-1, VLA-4, ELAM-1, ICAM-1, VCAM-1); and the synthesis of cytokines (eg, IL-1β, IL-6, TNF-α) and prothrombotic factors (eg, von Willebrand factor) are all indicators of inflammation in venous disease.^14,30 Venous nociceptors can be activated by proinflammatory mediators released locally as a result of hypoxia. The intravenous or perivenous application of one such mediator, bradykinin, evoked a sensation of pain in healthy subjects, which unambiguously establishes the role of this neuromediator in venous pain.³¹

Many studies have highlighted the vital role of nitric oxide release by endothelial cells, smooth muscle cells in the wall of the vein, or both³² and the subsequent activation of cyclic guanosine monophosphate synthesis³³ in the production of pain by bradykinin. Local administration of prostaglandin E₂ potentiates this algogenic action of bradykinin.³⁴ Prostaglandin E₂, whose application by itself is painless, appears to sensitize venous nociceptors. This type of autoamplification reaction cascade causes the release of an “inflammatory mixture,” which activates venous and perivenous nociceptors as well as causing the extravasation of plasma leading to transmural and tissue edema. Over time, varicose vein remodeling occurs, and this is characterized by cellular and matrix changes that compromise the structural integrity of the venous wall and its elastic properties.¹⁹

A finding that substantiates this hypothesis comes from a study by Howlader and Smith, which demonstrated that nitric oxide concentrations measured in blood collected in the saphenous vein or in a vein in the dorsal aspect of the foot were significantly higher in patients with the most severe stage of venous disease.³⁵ Likewise, certain studies have reported higher levels of markers of endothelial activation in experimental venous hypertension in the most advanced stages of venous disease.³⁶

Given the importance of these inflammatory processes in pain production as well as in varicose vein remodeling, a correlation between levels of inflammatory markers and the intensity of pain in venous disease might be expected to exist. However, this is not the case, inmuch the same way that the clinical estimation and evaluation of venous pain by venous Doppler scanning proved negative.¹⁷ No significant correlation was found between levels of 12 inflammatory markers (measured in a vein on the dorsal aspect of the foot) and pain intensity score on a visual analogue scale in a population of 132 patients with CVD ranging from class C2 to C5. The relationship between the venous wall inflammatory cascade and pain associated with venous disease seems difficult to demonstrate formally.

Pain and objective markers of venous disease

_ Pain, clinical severity, and inflammatory markers
If the intensity of pain of venous origin does not correlate with the extent of truncular varices observed in clinical examination, the severity of reflux measured with Doppler scanning, or levels of inflammatory markers measured in a lower limb vein, could hypoxia offer a possible explanation? It is entirely possible that many painful hypoxia-related conditions may occur transiently in patients, eg, after standing for a prolonged period, at the end of the day, or during certain periods of the menstrual cycle, if hypoxia is indeed a major factor that triggers pain of venous origin.

If venous and perivenous nociceptor-activating chemical cascades were to occur before significant remodeling of large venous vessels arises, this might explain the frequency of functional signs, such as pain or heaviness in the legs, in patients who do not have varicose veins and the lack of abnormal reflux seen in a Doppler scan, as in the Edinburgh Vein Study. While the same essentially inflammatory biochemical and cellular processes are implicated in pain and varicose vein remodeling, the time frame over which these pathological mechanisms occur is different.

Pain appears to be a short-term consequence of venous hypoxia, while varicose vein remodeling seems to take place at a much later stage of CVD. Because the occurrence of pain does not appear to be closely related to objective parameters of varicose vein remodeling, incompetent venous valves, or inflammation, this suggests the primary site of venous/ perivenous nociceptor activation may not be the large venous vessels. In light of this fact, the hypothesis of local activation of nociceptors in the microcirculation, where contact between nerve endings, the arteriole, the vein, and the capillary is probably much closer than at the macrovascular level, seems highly conceivable.

As a result, several studies looked at microcirculatory parameters of venous disease.^37,38 In addition, several studies using an experimental model of acute venous occlusion in the rat showed that an increase in microvascular pressure triggered an inflammatory reaction characterized by infiltration of neutrophils into the endothelium and adjacent tissues.²⁷

Shear stress on the endothelium produced by blood flow is another essential factor that promotes inflammation of the venous wall.²⁴ Shear stress can influence many intracellular biochemical processes, such as protein G phosphorylation, activation of tyrosine kinases, free radical production, and the synthesis of different nuclear transcription factors, via integrins anchored in the endothelial cell membrane.^39-41 Physiologically normal shear stress produces a potent, local anti-inflammatory effect, while a reduction or an increase in this force below or above a given physiological threshold can lead to overexpression of proinflammatory genes.^24,30

_ Explaining the disappearance of pain in advanced stages of CVD
Alteration of innervation of the venous wall and the perivenous tissue may explain the significant decrease in the frequency and intensity of pain in the most advanced stages of venous disease. This change in nerve fibers may reflect sensory peripheral neuropathy, perhaps related to ischemia secondary to venous microangiopathy, and an increase in endoneural pressure.⁴² The threshold of tactile, vibrational, and thermal sensation in the extremities in patients with CVD is significantly higher than normal, suggesting the loss of sensory axons.^43,44 This sensory threshold elevation was significantly more distinct in class C5 than in class C2 disease.⁴⁴ A reduction in the number of venous and perivenous nociceptors could well account for a lessening of pain in the most advanced stages of venous disease.

_ Interindividual pain variability in venous disease
The range and intricacy of mechanisms involved in the pathogenesis of venous disease pain are a significant source of interindividual variability. Both the reactivity of the cellular components involved (endothelial cells, neutrophils, and venous and perivenous nociceptors) and the ways in which nociceptive stimuli are processed in the brain produce this variability. At a cellular level, for example, experimental studies of human umbilical cord venous endothelial cells have demonstrated that the quantity of different prostaglandins released as a result of hypoxia can differ by a factor of 10 depending on the donor.⁷ By the same token, neutrophil reactivity to other inflammatory signals varies with age and previous sensitization (“priming”).What’smore, the density of venous and perivenous innervation as well as the presence of nociceptors in ion channels, which allows the conversion of a chemical message into a nerve impulse relaying nociceptive information, can also vary considerably from one person to another.

Interindividual variability in the way the brain reacts to pain stimuli will also play a part. The intensity of brain modulation of nociceptive signals resulting from the release of endogenous opioids, whose concentrations vary from subject to subject due in part to genetic factors, is also likely to account for some of the pain sensitivity in a given individual with regard to venous nociceptive stimuli. For instance, the genotype of the catechol-O-methyl-transferase enzyme, which determines the quantity of endogenous opioid released during a pain stimulus, significantly affects pain sensitivity.⁴⁵

However, all these variables are just relative obstacles in the elucidation of pain mechanisms in venous disease. In the absence of a correlation between the state of large venous vessels and the degree of pain reported, perhaps we ought to be examining the interaction between the mediators of inflammation and venous nociceptors in more detail, with a mind to developing a method of testing nociceptive function in venous disease microcirculation. _

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Keywords: pain; chronic venous disease; inflammation; nociceptors; C-fibers