Controversal Question – Is lower-limb pain reduction a meaningful treatment outcome?



Is lower-limb pain reduction a meaningful treatment outcome?


1. S. Agarwal, India
2. Y. Akcali, Turkey
3. M. Bokuchava, Georgia
4. D. Branisteanu, Romania
5. E. Ferreira, Portugal
6. F. F. Haddad, Lebanon
7. D. T. T. Huong, Vietman
8. D. Karetová, Czech Republic
9.G. Lessiani, Italy
10. H. Lotfy, Egypt
11. C. Ruangsetakit, Thailand
12. C. E. Virgini-Magalhães, Brazil
13. I. A. Zolotukhin, Russia


1. S. Agarwal, India

Sandeep AGARWAL, MS, FIVS
Vice Chairman and Senior Consultant
Department of Vascular and Endovascular Surgery
Sir Ganga Ram Hospital
New Delhi 110060, INDIA
(e-mail: sagarwal3566@yahoo.com)



The syndrome of chronic venous disease (CVD) is common. In India, about 15% of the population has varicose veins, and 2.5% venous leg ulcers. However, among outpatients in the general practice setting, the frequency is much higher. Leg pain is a major symptom of CVD. In a crosssectional survey of 300 patients with CVD, clinical, etiological, anatomical, pathophysiological (CEAP) classification C0 to C4, 97% complained of lower-limb pain, and their quality of life (QoL) assessed by a visual analogue scale was reduced by one-fourth. The most severe pain and loss of QoL is in patients with leg ulcers (CEAP C5 and C6).

The origin of lower-limb pain in CVD is microvascular inflammation. This pathogenic process is initiated by an idiopathic loss of venous tone or thrombophlebitis involving the veins of the lower limb. The resulting valvular incompetence and venous reflux leads to venous hypertension and venous stasis in the lower limb. Venous stasis acts as a signal for the marginalization of white cells and their adhesion to the vein wall. This triggers white-cell activation and release of inflammatory mediators such as free radicals, thromboxane, and prostaglandins. A sterile inflammation develops in the wall of capillaries making them more permeable and friable. This microcirculatory inflammation gives rise to pain and the other cardinal symptoms of CVD, such as heaviness, cramps, and sensation of swelling in the leg.

The leg pain of CVD is responsive to specific treatment. Measures to improve venous tone, reduce venous hypertension, suppress microvascular inflammation, and increase lymphatic drainage are effective. In experimental studies, micronized purified flavonoid fraction (MPFF) has been shown to significantly increase venous tone, augment lymphatic drainage, suppress inflammatory mediators (free radicals, thromboxane B2, and prostaglandins E2 and F2), and reduce capillary hyperpermeability. When patients with CVD were randomly treated with MPFF 1000 mg or placebo for 3 months, there was a significant improvement in lower-limb pain together with plathesmographic increase in venous tone with MPFF 1000 mg treatment compared with placebo. This has since been demonstrated in several studies. In India, QoL was first assessed in a 6-month study on patients with CVD (CEAP C0 to C4) in 1998. Treatment with MPFF 1000 mg together with leg elevation reduced pain by 76%, and improved QoL by 65%.1

Against this background of high prevalence, and availability of effective treatment, it is worthwhile to treat leg pain due to CVD. ■

Reference
1. Pinjala R. Long-term treatment of chronic venous insufficiency of the leg with micronized purified flavonoid fraction in the primary care setting of India. Phlebology. 2004;19(4):179-184.


2. Y. Akcali, Turkey

Yigit AKCALI, MD
Cardiothoracic and Vascular Surgeon
Department of Cardiac and Vascular Surgery
Erciyes University Medical Faculty
Kayseri, TURKEY
(e-mail: yakcali@erciyes.edu.tr)



Venous disorders in the legs, which may be considered a nearly normal part of the aging process, are perhaps the most common afflictions of the bipedal human. Venous leg pain is the most important differentiation between “venous disorder” and “venous disease.” Therefore, it should be systematically asked whether a patient is suffering from venous leg pain. In the event of a painful leg, other vascular, neurogenic, orthopedic, or rheumatologic disorders should be considered as differential diagnoses.

Leg pain related to chronic venous disease (CVD) can be exacerbated by a standing position in the course of the day, immobility (for example, in a prolonged sitting position), warmth, and menstrual cycle, and can be relieved with resting, leg elevation, and cold exposure. However, patients complaining of severe venous pain should be investigated for venous intermittent claudication (IC) and coexisting peripheral arterial disease (PAD).1 Venous IC is a rare consequence following hemodynamically significant obstruction of the deep venous system, especially after iliofemoral deep venous thrombosis (DVT) without adequate collateralization. Patients often experience severe thigh “bursting” pain or cramps and the sensation of tightness with walking or exercise, sometimes mimicking claudication secondary to PAD. However, in contrast to arterial claudication, 15 to 20 minutes of rest combined with leg elevation often relieve the pain.

Venous pain, which is the main symptom that guides the diagnosis of CVD, has a substantial impact on patients’ quality of life.2 Therefore, the absence of venous pain is considered to be the most important outcome after venous treatment.

Pain is a symptom of chronic venous “disease,” but not of chronic venous “disorder.” Most patients who have visible signs in the leg(s) do not need referral to the hospital. Furthermore, visible signs, pain, or reflux in the affected vein may interact in the pathophysiological process, and consequently, is as important as the appearance of visible signs on the legs and reflux in the affected vein. Hence, in my clinical practice I do not perform surgical or endovenous saphenous ablation unless all of the following indications are present: (i) clinical indication: CVD-related symptoms, mainly pain; (ii) anatomical indication: dilated, tortuous and/or elongated superficial veins ≥6 mm; and (iii) pathophysiological indication: reflux in the affected vein >0.5 seconds. So I consider that pain relief, disappearance of visible signs on the legs, and the absence of reflux in the diseased veins after the treatment of CVD are the most important therapeutic outcomes.

If a patient who has been treated for their diseased veins or skin (clinical, etiological, anatomical, pathophysiological [CEAP] class C4 to C6 ) with satisfactory clinical and duplex ultrasound outcomes continues to complain of leg pain, they should be re-evaluated meticulously for other vascular or nonvascular diseases (obesity, calf muscle venous pump dysfunction, etc). After the diagnosis of coexisting PAD, which increases with advanced age just as in CVD, have been excluded, the deep venous system is reinvestigated for thrombotic or nonthrombotic insufficiency. Sometimes a saphenous vein can function as a collateral pathway in a patient who has deep vein aplasia or hypoplasia with Klippel-Trenaunay syndrome. Then, if saphenous ablation is performed without an adequate clinical and radiological evaluation, venous leg pain can continue and even augment postoperatively. A similar clinical picture is discussed for postthrombotic syndrome, which is primarily diagnosed on clinical grounds. ■

References
1. Akcali Y. Vascular leg ulcers. In: Coban YK, ed. Lower Extremity Wounds. Kerala, India: Transworld Research Network; 2013:59-76.
2. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life Res. 1996;5:539-554.


3. M. Bokuchava, Georgia

Mamuka BOKUCHAVA, MD, PhD
President of Georgian Association of
Angiologists and Vascular Surgeons
Deputy Director of N. Bokhua Heart
and Vascular Center Clinic
Tbilisi, GEORGIA
(e-mail: bmamuka@hotmail.com)



Leg pain is the complaint that occurs in 80% of patients with chronic venous disease (CVD)1-3 and has a significant impact on patient’s quality of life (QoL). This pain is mostly associated with a feeling of heaviness or tiredness in the legs, numbness, burning, or a sensation of swelling.4,5

In my clinical practice, the first thing to do is to gain the anamnesis of a venous patient and to find out whether there is a family history of varicose disease, thromboembolism,or thrombophilia. I systematically ask patients about leg pain and its origin—symptoms, when and under what circumstances the pain appears, and its correlation with patient’s daily activities. In women, it is important to have information about the number of pregnancies, and the use of contraceptives and hormonal therapy.

Venous pain is usually diffuse, with no clear location. Also, it is known that the intensity of pain is not correlated with the severity of venous disease—many patients suffering from venous pain have no objective clinical or paraclinical abnormalities.4,6 The pain must be differentiated from other lower-limb pain of different etiologies: mechanical factors usually related to activities and movements such as walking up the stairs and lifting, “intermittent claudication” (in patients with chronic ischemic peripheral arterial disease), or by the pain associated with joint disease. A complaint of severe venous pain requires further investigation. For me as a specialist, the most important thing is to adapt the treatment to the patient. For this purpose we must start with an analysis of the patient’s clinical status, taking into account his expectations, and of course to have a good knowledge of the indications and outcomes of various treatment options. So, the most important outcome after CVD treatment is not only the disappearance of one clinical sign or symptom, but a disappearance of all— visible signs, pain, reflux in the affected vein, and severity of heavy or tired legs.

In the case of continuous leg pain despite venous pathology having been successfully treated (including ulcer healing), with good clinical and duplex ultrasound results, I suggest further investigations with other specialists, eg, neurology or orthopedics/ traumatology, in order to exclude other pathology.

The treatment strategy used for the management of chronic venous pathology is complex, including medical treatment (such as venoactive drugs to prevent the progression of the disease and to avoid complications), elastic compression therapy, and surgery.

To conclude, leg pain affects 80% of patients with CVD, so it is important to consider this kind of venous pain as a therapeutic target to improve the QoL of these patients.2,4

References
1. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symptoms of varicose veins? Edinburgh Vein Study cross sectional population survey. BMJ. 1999;318:353-356.
2. Eklof B, Rutherford RB, Bergan JJ, et al. American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-1252.
3. Widmer LK, Zemp E. Diagnosis and treatment of varicose veins. Deduction from on a Basel prospective epidemiological study. Helv Chir Acta. 1988;54:531-539.
4. Duque MI, Yosipovitch G, Chan YH, Smith R, Levy P. Itch, pain, and burning sensation are common symptoms in mild to moderate chronic venous insufficiency with an impact on quality of life. J Am Acad Dermatol. 2005;53:504-508.
5. Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous diseases. N Engl J Med. 2006;355:488-498.
6. Bradbury A, Evans CJ, Allan P, Lee AJ, Ruckley CV, Fowkes FG. The relationship between lower limb symptoms and superficial and deep venous reflux on duplex ultrasonography: The Edinburgh Vein Study. J Vasc Surg. 2000;32:921-931.


4. D. Branisteanu, Romania

Daciana BRANISTEANU, MD, PhD
Associate Professor
Department of Dermatology
University of Medicine and
Pharmacy « Gr.T.Popa »
Iasi, ROMANIA
(e-mail: debranisteanu@yahoo.com)



Venous pain was and still is an issue of intense debate among phlebologists because of its clinical and pathophysiological particularities. There were, and probably still are, doctors who believe that leg pain is difficult to attribute to venous disease. On the other hand, venous pain is difficult to describe by patients, the sensation of pain being associated with other multiple symptoms of chronic venous disease (CVD): cramps, pruritus, sensation of swelling, feelings of heaviness, tension in the legs, etc.

Recent studies provide information on the physiological mechanism underlying venous pain and elucidate some cellular and biochemical processes. Still, incomplete and even erroneous concepts of the importance of venous pain persist in the medical community. More precisely, patients find it difficult to describe and even to realize that leg pain is related to venous disease. A detailed, targeted history may lead to the active detection of this complex symptom of venous disease.

However, the insidious onset and chronicity of venous pain means that the importance of venous pain in the diagnosis, course, and effectiveness of therapy for venous disease is often underestimated by both patient and doctor.

Venous pain is poorly quantified in the clinical, etiological, anatomical, pathophysiological (CEAP) classification; there is no concrete scientific assessment of venous pain intensity, only the differentiation between the presence or absence of venous pain. The Venous Clinical Severity Score (VCSS) also doesn’t consider venous pain as a criterion for assessing the severity of venous disease, although the fact that venous pain leads to a change in the quality of life of patients with venous disease is recognized.

Practical clinical experience suggests a great diversity of venous pain expression in patients with venous disease. Thus, some patients with advanced CVD (CEAP class C4 or C5 ) presenting with significant and diverse trophic skin changes and severe duplex ultrasound findings do not have significant venous pain. On the other hand, there are patients who complain of significant leg pain in the absence of consistent clinical or ultrasound changes. These clinical findings suggest that there is no correlation between the presence and intensity of venous pain, and between pain and the severity of pathophysiological, clinical, and ultrasound changes, thus further complicating the correct diagnosis, and short- and long-term management of CVD.

In daily practice, active detection of leg pain is very important in all patients with venous disease. This way, the doctor-patient relationship related to leg pain as a symptom of venous disease can be improved. Assessment of leg pain as “severe” on the Visual Analogue Scale should prompt the physician to refer the patient to more complex ultrasound examinations for an accurate diagnosis.

The most important outcome after venous treatment is halting the progression of CVD to advanced stages, and even regression in less severe stages of disease. Given this goal, reducing venous hypertension in leg circulation and the disappearance of reflux in the affected vein are essential. Depending on the CVD stage, it is desirable that visible signs on the leg disappear or diminish. From a patient’s point of view, I believe that the most important outcome after venous treatment is the disappearance, or at least the relief, of CVD symptoms, especially leg pain, followed by healing of clinical signs visible on the legs.

If leg pain persists despite correct and complex treatment for CVD, controlled clinical signs, and satisfactory duplex ultrasound results, I think it is appropriate to investigate for other etiology (eg, arterial, neurological, articular, muscular, infectious, etc). Large epidemiological studies are needed to determine the true incidence and intensity of venous pain in CVD, such as detecting the factors that cause variations in pain intensity from one patient to another. ■

5. E. Ferreira, Portugal

Emilia FERREIRA,MD
Head of the Angiology
and Vascular Department
Santa Marta Hospital
Rua Conselheiro Lopo Vaz
Lote AB, 7°D, 1800-152, Lisbon
PORTUGAL
(e-mail: emiliaferreira@cirurgiavascular.pt)



Chronic venous disease (CVD) is the most prevalent vascular disorder in developed countries and is associated with significant costs (2% to 3% of the health budget of Western countries). According to the clinical, etiological, anatomical, pathophysiological (CEAP) classification, all classes of CVD can be associated with symptoms, and there is no direct relationship between symptoms and stage of disease.

One of the symptoms of CVD is leg pain. Quality of life (QoL) has been reported to be negatively affected by leg pain among patients with CVD. The prevalence of leg pain in CVD is often underestimated by physicians, since it is difficult to evaluate and could suggest different diagnoses (rheumatic, orthopedic, neuropathic, etc). However, we can describe some features that may suggest CVD:
◆ Symptoms worsen towards the end of the day.
◆ Symptoms are more intense during the hot season.
◆ Symptoms show an activity-related variation throughout the day-night cycle; usually unresponsive to analgesics or nonsteroidal anti-inflammatory drugs.
◆ Venous obstruction or reflux removal, as well as the use of compression stockings and venoactive drugs, leads to improvement.

Until recently, treatment effectiveness did not take into account patient-centered outcomes such as QoL. Currently, modern medicine has greatly shifted its focus to the patient’s perspective of the disease and it has become indispensable when treatment outcomes are assessed. So, on the first contact with the patient, it is essential to clarify the reason for consultation including cosmetic complaints, symptoms (pain, edema, restless legs, pruritus), impact on QoL, fear of disease progression, and patient expectations (this is our most important outcome measure).

A complete clinical history, physical examination, and a continuous wave Doppler evaluation, are then performed. According to the findings, we can have a diagnosis, classify the severity of CVD, and propose a treatment regimen. Duplex ultrasound is generally reserved for patients with C3 or more advanced stages of the CEAP classification. Patient education on healthy lifestyle is fundamental. The following instructions must be convincing and regularly repeated to the patient: (i) walk daily, as often as possible; (ii) elevate legs by 30° during rest periods throughout the day; (iii) elevate the foot of the bed, 10 cm to 15 cm during the night; (iv) take cold showers; (v) regular participation in sports—walking, cycling, swimming, running, etc; and (vi) regular use of compression stockings.

If leg pain is the main complaint, and if its severity has an impact on patient lifestyle, venoactive drugs should also be prescribed.

At this time, according to the CVD classification, sclerotherapy or classic vs endovenous surgery will be discussed. If a patient that has been satisfactorily treated (according to clinical and ultrasound results) continues to complain of leg pain, the physician should investigate further.

Therefore, it is mandatory to confirm if the etiology of the pain is just a symptom of venous disease or whether there are other objective causes for these symptoms. If all other causes, including psychological, have been excluded, venoactive drugs are prescribed. The most important outcome after venous treatment is measured by the satisfaction of the patient. ■

6. F. F. Haddad, Lebanon

Fady F. HADDAD,MD, FACS
Associate Professor of Clinical Surgery
Vascular and Endovascular Surgery
Director, the Ismail Khalil Vascular Laboratory
Coordinator Endovascular Program
American University of Beirut Medical Center
LEBANON
(e-mail: fh16@aub.edu.lb)



“Pain is a feature of venous disease often overlooked and commonly undertreated.”1

Since before ancient times, mankind described, suffered from, and treated varicose veins; clearly not all for cosmetic reasons. The San Diego Population Study reported data on symptoms of venous disease: aching was the most commonly reported venous symptoms with a prevalence of 17.7% (though swelling was slightly more specific).2 Symptoms increased in severity with the increase in functional and visible disease.

It is established that symptoms in varicose veins play a key role in overall assessment, as stressed by class C0s in the clinical, etiological, anatomical, pathophysiological (CEAP) classification; however, pain does not stand out specifically in this grading. The symptom of pain, despite the mixed reporting in relation to the physical signs and severity of disease, does carry serious medical implications. Indeed, recent onset pain, warmth, and erythema in the distal leg can be signs of early lipodermatosclerosis at the level of the perforators and a prelude for future ulceration.3 Not surprisingly, in the most recent NICE guidance, patients are to be referred for vascular specialist care if varicose veins are associated with any “troubleshooting symptoms” such as “pain.”4 In addition, the fact that venous pain may not be correlated with incompetent valves or absence of reflux (CEAP class C0s) supports the findings of microvalvular incompetence at very distal tributaries.5 Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. The ultimate assessment of disease impact and treatment outcomes is quality of life (QoL); looking at the recently revised ChronIc Venous Insufficiency quality of life Questionnaire (CIVIQ)–14 score, one of the three dimensions of this tool is “pain.” Currently, this is one of the most reliable and validated QoL scores in chronic venous disease.6

Importantly, varicose veins are one of the rare etiologies of pain in the legs that are actually visualized by the patient. Hence, any complaint in the presence of varicosities is automatically related to the latter. Having pain assessment and reassessment, initially and at follow-up, is an important outcome tool. If this is unchanged after treatment, it is likely that further investigation is warranted to explore possible etiologies. Regardless, as with any other pathology, outcome assessment should cover the original complaint that brought the patient for consult. This issue was addressed partly with the revised Venous Clinical Severity Score, which is also endorsed by the Society for Vascular Surgery and the American Venous Forum recommendation.7 This does not, unfortunately, include staging of the disease, and CEAP classification would still be in order. Ideally, a single venous assessment and outcome tool should be available that looks at the patient stage, well-being, and QoL, with a fair representation of the pain scale in its component. ■

References
1. Barron GS, Jacob SE, Kirsner RS. Dermatologic complications of chronic venous disease: medical management and beyond. Ann Vasc Surg. 2007;21(5): 6526-6562.
2. Langer RD, Ho E, Denenberg JO, Fronek A, Allison M, Criqui MH. Relationships between symptoms and venous disease: the San Diego Population Study. Arch Intern Med. 2005;165(12):1420-1424.
3. Bergen J. Symptoms of varicose veins. In: Bergen J, ed. The Vein Book. Cambridge, MA: Elsevier Inc; 2007:122.
4. NICE. Varicose veins in the legs. The diagnosis and management of varicose veins. NICE clinical guideline 168. http://www.nice.org.uk/guidance/cg168/resources/ guidance-varicose-veins-in-the-legs-pdf. Issued July, 2013. Accessed August 28, 2014.
5. 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(6 suppl):62S-69S.e1-e3.
6. Launois R, Le Moine JG, Lozano FS, Mansilha A. Construction and international validation of CIVIQ-14, a new questionnaire with a stable factorial structure. Qual life Res. 2012;21:1051-1058.
7. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53(5 suppl):2S-48S.


7. D. T. T. Huong, Vietnam

Dinh Thi Thu HUONG,PhD
National Cardiology Institute
Hanoi Medical University
Hanoi, VIETNAM
(e-mail: thuhuong60@gmail.com)



As a cardiovascular doctor, I have to examine patients who have heart and vascular diseases. While examining these patients, I tend to investigate potential risk factors for these diseases. Clinical practice has shown that many patients suffering unpleasant sensations in their legs (including heaviness, cramps, and tension) at the end of the day show absence of reflux in the superficial or deep veins on duplex ultrasound.

In contrast, patients with varicose veins often do not complain about leg pain. It is clear that there is no correlation between the clinical state and the presence of reflux, or between the intensity of the pain and the severity of venous disease.

In practice, while examining patients, I often concentrate on asking them to describe and rate the intensity and the property of pain, and clarify whether their pain is stimulated by physical activities or not. These questions help to differentiate leg pain due to venous disease from leg pain caused by other stimuli, such as arthropathy, nervous pain, etc.

Careful investigation is essential in examining venous disease. Many patients are still diagnosed as having chronic venous disease by general practitioners, even though they do not have chronic varicose veins, and vice versa. For all patients who complain about leg pain, to orientate medical treatment, intervention, or surgical treatment, I always ensure a duplex ultrasound scan is carried out by vascular ultrasound specialists. I believe the quality of evaluation of treatment results depends on numerous criteria:
◆ For young women with high esthetic requirements, it is important to provide a treatment that improves the esthetics of the legs.
◆ For the vast majority of patients, the absence of leg pain, which thus enables them to enjoy daily life without the feeling of heaviness or cramps at the end of the day, is the best treatment outcome.
◆ For patients with varicose veins treated with radiofrequency or laser, the good treatment outcome is no reperfusion or reflux in the treated veins.

However, in clinical practice there are many patients who, after being treated by a cardiovascular intervention or surgery, still complain of leg pain, despite the absence of clinical signs or duplex ultrasound results of varicose. These patients still need to continue using venotonic drugs, because the mechanism of venous pain is complex. Studies on the mechanism of skin pain have clearly shown that inflammatory mediators may activate nociceptors in the skin. Among the peripheral mediators involved, protons, bradykinin, serotonin, prostaglandins, and leukotrienes appear to be the most potent activators of cutaneous nociceptors. Other substances, such as platelet-activating factor, histamine (pruriginous at low concentration, painful at high concentration), certain interleukins, and neuropeptides also play a major role in the activation of cutaneous nociceptors. These data on cutaneous nociceptors have led to several studies of the neuromediators involved in the activation of venous and perivenous nociceptors in human subjects. Study of the painful feeling induced by bradykinin’s intravenous or perivenous application unambiguously shows that bradykinin is involved in the generation of venous pain. In view of this response to chemical stimulation, venous nociceptors can be considered to be chemoreceptors. ■

8. D. Karetová, Czech Republic

Debora KARETOVÁ,MD, PhD
Second Department of Medicine
Department of Cardiovascular Medicine
First Faculty of Medicine and
General University Hospital
U Nemocnice 3, 128 08 Prague 2
CZECH REPUBLIC
(e-mail: dkare@lf1.cuni.cz)



Chronic venous disease (CVD) is often accompanied by “venous pain,” which is a consequence of the overpressure in microcirculation. Current hypotheses on pain mechanisms in venous disease are focused on a local inflammatory origin related to venous stasis, and on a local activation of nociceptors in the microcirculation, where contact between nerve endings and the capillary is probably much closer than on the macrovascular level. The diminution of pain in the advanced stages of venous disease may be related to peripheral sensory neuropathy induced by venous microangiopathy.

The chief complaint of pain has a significant impact on patients’ quality of life. However, pain is difficult to assess, both because of its multifaceted nature and because of the lack of a precise correlation between pain as a symptom and severity of venous disease. There are at least three other reasons.

First, pain of venous origin is frequently associated with other unpleasant sensations such as heaviness, cramps, tension in the legs, or pruritus. It is also often difficult to describe. Second, the intensity of pain can fluctuate substantially, both from patient to patient or in the same patient with progression of the disease over a period of time. Lastly, although the neurophysiological mechanisms of pain of venous origin are better understood, and some biochemical and cellular processes involved in varicose vein remodeling have been explained by recent studies, the causal relationship between CVD and pain of venous origin remains difficult to understand. The most obvious symptoms of CVD, except for pain, are tiredness or heaviness in the legs, sensation of swelling, fullness or even aching, and later swelling of ankles, especially in the second part of the day after extended periods of standing. Flaking or itching skin on the legs could also mimic neuropathy. The story of CVD could be quite different in various patients. Some patients present with CVD in the most advanced stage, with marked skin changes, but without any pain at all. However, others have very tiny vein changes, but serious pain complaints. Doctors must assess their patients thoroughly to better understand and evaluate their pain. For example, differentiating pain of venous origin from neuropathic pain can be difficult. The two may also coexist and both could be exacerbated in the evening hours.

Many scoring systems for evaluation of the severity of CVD have been developed. Although these systems are used especially in clinical studies (eg, ChronIc Venous Insufficiency quality of life Questionnaire [CIVIQ]), they are too complicated for everyday practice. Instead of these complicated sets of questionnaires, a much more helpful tool is a set of simple questions allowing physicians to conclude whether the patient really suffers from venous hypertension.

Examples of these questions are as follows: Is it more comfortable to have your legs up or down? Do you have more pain in your legs early in the morning or later in the afternoon? Do you have problems while walking?

The evaluation of these answers is much more important for the decision of whether to treat CVD than the extent of the disease determined by physical or ultrasound examination. Once physicians come to the conclusion that the problem could be venous hypertension, then therapeutic testing with a potent venoactive drug, such as micronized purified flavonoid fraction can be done. The relief of pain is the best proof of hitting the target.

In conclusion, there is a huge discrepancy between the severity of pain in venous disease based on clinical findings and the degree of pain reported by patients. This discrepancy complicates the objective evaluation of the result of therapies in venous disease. The evaluation of leg pain requires a proper history and physical examination, as well as neurologic evaluation in some cases. Vascular evaluation should include general screening with noninvasive vascular studies. The localized release of proinflammatory mediators seems to play a decisive role in the activation of venous and perivenous nociceptors and may account for the occurrence of pain at early stages of venous disease. ■

9. G. Lessiani, Italy

Gianfranco LESSIANI,MD
Angiology Unit
Department of Medicine and Geriatrics
Città Sant’Angelo Hospital
ITALY
(e-mail: g.lessiani@libero.it)



Chronic venous disease (CVD) is one of the most widespread conditions afflicting a great part of the world’s population. The exact prevalence of CVD is difficult to determine because there is a wide variation in study population, selection criteria, and disease definition between different studies. Generally, symptoms ascribed to CVD are: heaviness, cramps, aching, itching, feeling of swelling, tingling, etc.

Pain is the most frequent reason for medical evaluation by patients with CVD, and generally is the complaint that leads to the diagnosis of venous disease. Quality of life (QoL) of patients with CVD is greatly affected, especially by pain. However, pain in CVD is very difficult to understand. Indeed, epidemiological studies have established that the presence and intensity of leg symptoms related to CVD, are not correlated with the clinical assessment of severity disease. Bradbury et al showed in the Edinburgh Vein Study that about 40% of asymptomatic patients had varicose veins on clinical examination and 45% of the patients complaining of leg pain compatible with CVD had no varicose veins on examination.1 Moreover, no correlation was observed between the presence of pain and the observation by Doppler ultrasound of superficial or deep venous reflux. Also, many patients complain of pain at an early stage of venous disease, when they also have a normal clinical and Doppler examination. Howlader and Smith reported no statistical relation between the pain score or heaviness score of a patient,2 evaluated with a 10-point visual analogue scale, and the clinical severity of venous disease.

Pain of venous origin is often associated with other disagreeable sensations that are very difficult to describe (tension in the leg, pruritus, feeling of heaviness). Pain in venous disease may vary over time in intensity, within the same patients. Generally in clinical practice, physicians tend to underestimate the intensity of pain in venous disease, especially when it is chronic, poorly defined, poorly located, and when underlying mechanisms are not clearly identified. Moreover, clinical, etiological, anatomical, pathophysiological (CEAP) classification and the Venous Clinical Severity Score (VCSS) underestimate pain. The CEAP classification only differentiates between symptomatic or asymptomatic patients, and VCSS defines venous pain in a generic way. For these reasons, there is a growing interest in patient-reported outcomes (PROs), which are considered to be key outcomes that cover several aspects: preference of care received, outcome of care (health-related QoL, patient satisfaction, subjective symptoms), and allows monitoring of pain and the progression of the disease.3,4 The use of QoL questionnaires in patients suffering from CVD can provide relevant and more complete information, also in relation to psychology, social aspects, and pain.

Interesting neurophysiological mechanisms of pain in CVD, and some biochemical and cellular process involved in pain and vein remodeling have been explained. The strong trigger for these mechanisms is local hypoxia caused by venous stasis. The hypoxia activates endothelial cells resulting in the synthesis and local release of mediators that modulate pain (activation of venous and perivenous nociceptors) and are proinflammatory. Over time, this process also leads to venous remodeling characterized by cellular and matrix alterations resulting in loss of structural integrity of the vein wall and its elastic properties. Activation of venous and perivenous nociceptors plays a relevant role in determining pain, even in the early stage of disease.

In clinical practice, we consider it very important to focus on venous pain during evaluation of the patient, at initial evaluation and on follow-up. For this reason, we systematically perform a QoL questionnaire and visual analogue scale for pain. With a complaint of severe venous pain, we perform a thorough clinical and haemodynamic evaluation, and try to exclude other causes. After venous treatment, we consider relevant outcomes, correction of hemodynamic alterations, and absence of pain, rather than disappearance of visible signs. If the patient continues to complain of leg pain despite satisfactory treatment (clinical and ultrasound results), we re-evaluate for other possible causes, and review pharmacological therapy, taking into account drugs with proven efficacy against venous pain. ■

References
1. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ. 1999;318:353-356.
2. Howlader MH, Smith PD. Symptoms of chronic venous disease and association with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.
3. Fung CH, Hays RD. Prospects and challenges in using patient-reported outcomes in clinical practice. Qual Life Res. 2008;17:1297-1302.
4. Willke RJ, Burke LB, Erickson P. Measuring treatment impact a review of patientreported outcomes and other efficacy endpoints in approved product labels. Control Clin Trials. 2004;25:536-562.


10. H. Lotfy, Egypt

Hassan LOTFY,MBBCh, MRCS
Faculty of Medicine
Alexandria
EGYPT
(e-mail: hassanlotfy@hotmail.com)



Pain!! Is it some sort of punishment from God, is it an evil spirit intruding the body, is it a gift from The Lord to be able to recognize that there is something going wrong, or is it due to chemical mediators and noxious stimuli either from within or from outside the body? All these questions have mystified scientists and philosophers over the ages; each tries to explain pain according to his own point of view.

So, what is pain? Pain—as we all know—is that unpleasant sensory and/or emotional feeling caused by an underlying pathology. Pain can be acute or chronic according to the duration of suffering. It varies in severity from mild discomfort that may affect the patient’s quality of life, to severe pain that significantly affects normal daily activity and disturbs sleep. The lower limb is the most common site to experience tiredness and pain. It is the price paid for the upright position of mankind. Venous pathology, as a cause for pain, is considered the most common factor resulting in muscle fatigue and venous congestion after standing idle for a long time.

It is not surprising that pain is the most common complaint of patients and the most common reason to seek medical advice. Pain is ranked first in vascular complaints. It may precede cosmetic concern. In my opinion, vascular surgeons must focus on the analysis of pain to probe the real cause of pain and to exclude other causes that mimic venous pain.

It is strange to find that different sophisticated scoring systems for venous disease, such as the clinical, etiological, anatomical, pathophysiological (CEAP) classification and the Venous Clinical Severity Score (VCSS), do not address pain as a main component. They just consider whether pain or discomfort is present, regardless of its severity.

It is not uncommon to find patients with remarkable venous problems free from pain or discomfort, meanwhile patients with mild pathology may have pain out of proportion to their problem. It is essential to investigate the depth of the condition to find out the actual cause of pain. The most important issue is to handle the patient’s complaints in view of the presented pathology, considering that the most important outcome is to alleviate pain. It is not worth removing dilated veins or alleviating venous reflux while the patient is still suffering. Answering a patient’s question of “How can I reduce my leg pain?” by an answer such as “You have had your veins ablated and are free from varicosities, so there is nothing else that can be done—you have to live with it,” is very frustrating and disappointing. The patient will certainly wonder why he has had all these tedious and expensive investigations and procedures.

A large number of patients go to work in spite of the presence of pain. This may be attributed to the difference between populations with regards to pain threshold. The financial aspect also plays an important role as many individuals are breadwinners for their families.

In conclusion, pain relief must be considered as a human right for every patient to end his suffering and improve quality of life. Physicians and medical personnel must consider pain alleviation as the main target that must be achieved while simultaneously treating the causative factor. ■

11. C. Ruangsetakit, Thailand

Chanean RUANGSETAKIT,MD, FRCS, MSc
Associate Professor
Vascular Surgery Unit
Department of Surgery
Siriraj Medical School
Mahidol University
Bangkok 10700, THAILAND
(e-mail: chaneansi@gmail.com)



The incidence and prevalence of chronic venous disease (CVD) varies widely depending on the definition of disease and studied geographic area. In Thailand, the incidence and prevalence have not yet been established. CVD is a common problem in our vascular clinic, at Siriraj Hospital, Mahidol University, and the patients who visit our clinic have varied clinical manifestations. Common clinical manifestations are limb swelling, pain, varicose veins, dermatitis, and venous ulcers. Leg pain in venous patients can be due to venous or other causes. Other causes may coexist, such as arthritis, neuropathy, claudication, and spinal stenosis. In these patients, it is important to determine the likelihood that leg pain is related to venous insufficiency, to enable appropriate venous management.

For venous patients suffering from leg pain, a physician needs to study the details of their history and physical examination to identify the cause. Onset, duration, characteristic of pain, aggravating and releasing factors, and associated symptoms— all these details of leg pain usually point to the etiology. In the case of patients where the etiology is not evident from history and examination, investigations need to be done, especially in patients with severe venous pain.

Venous physiological tests are very useful for chronic venous insufficiency. Photoplethysmography can demonstrate the presence or absence of venous insufficiency. Air plethysmography can not only identify venous insufficiency, but also demonstrates severity of venous insufficiency and the outcome of venous treatment. Duplex ultrasonography is necessary to identify the cause of venous insufficiency such as deep vein thrombosis (DVT), the site of reflux, evaluate the deep and perforator systems, and guide intervention. It is necessary to promptly identify the cause of severe venous pain, as it may be due to deep vein occlusion or a complication of primary CVD and can disturb daily activities.

When patients with CVD are diagnosed, they can undergo treatment. At present, venous treatment can be categorized into conventional and endovenous treatment for superficial and deep venous systems. The outcomes after venous treatment depend on the patient’s symptoms and concerns. These include leg swelling, leg pain, visible varicose vein, hyperpigmentation, dermatitis, and leg ulcers. The disappearance or improvement of visible signs on the leg and of leg pain are satisfactory outcomes for the patients. Even though the improvement of the patient’s symptoms and concerns can be demonstrated, some patients still have reflux in the affected vein. Conversely, some patients show absent reflux in the affected vein, but still have the symptoms.

I consider that symptoms, concerns, and venous hemodynamics make patients visit the clinic. In my opinion, the patients’ symptoms and concerns are more important than the absence of reflux in the affected vein. In patients whose clinical and duplex ultrasound results are satisfactory, but who still continue to complain about leg pain, I explain and discuss the possible causes of leg pain, and give recommendations about avoiding or reducing activity that increases venous stasis and pressure. I also advise regular calf muscle exercises. Occasionally, these patients need muscle relaxants, painkillers, and venoactive drugs. In my practice, leg pain may improve or disappear in patients who receive treatment. Lower-limb pain in venous patients can limit their activity and work. Identifying the cause of pain and managing appropriately could bring about good outcomes. However, pathogenesis of pain in venous disease is still not clearly understood. ■

12. C. E. Virgini-Magalhães, Brazil

Carlos E. VIRGINI-MAGALHÃES,MD, PhD
Department of Surgery
Pedro Ernesto University Hospital
State University of Rio de Janeiro,
Rio de Janeiro, BRAZIL
(e-mail: cevirgini@gmail.com)



Despite recent advances in pathophysiology andmechanisms involved in the clinical expression of chronic venous disorders, scientific understanding is still disappointing. Such deficiency becomes even more expressive in daily practice, where we are currently challenged with diverse clinical presentations. Many patients present with a typical history and symptoms, but without any objective signs of chronic venous disorders. On the other hand, some present with varicose veins and venous hypertension stigmata without any clinical complaints.

Leg pain is probably the earliest symptom of chronic venous disorders. Although many patients with venous disease do not complain of leg pain, several epidemiological studies indicate that it is a very common symptom, even in the early stages of the clinical, etiological, anatomical, pathophysiological (CEAP) classification.1-4 It seems intuitive to associate the degree of the inflammatory process associated to chronic venous disorders to the intensity of pain in these patients, since pain is a common symptom associated with inflammation in other medical conditions. However, recent studies failed to show a clear correlation between pain intensity and venous disease severity.

The concept of pain relates to an unpleasant sensory and emotional experience associated with actual or potential damage. Several aspects are involved in the expression and modulation of pain, which attributes great subjectivity and individuality to this sensation. However, this symptom has a direct impact on perceived quality of life among these patients, and this is an important issue that should be considered.5 Lack of specificity means that venous pain is underestimated by many physicians, and the eventual absence of a clear anatomical substrate leads to the neglect of diagnostic investigations or even disregard of the possibility of treating these individuals. Certainly, chronic venous disorders have multifactorial causes that vary from one individual to another, but a significant group of patients slowly evolve a vicious cycle fueled by the inflammatory cascade that gradually promotes remodeling of macro- and microcirculation, worsening the consequences of stasis and venous hypertension.

We believe that venous pain is the first clinical evidence of this inflammatory process. Therefore, the most effective way to approach chronic venous disorders seems to be the early identification and management of this inflammatory cascade. Any patient with typical venous disease complaints associated with a prolonged orthostatic position such as itching, burning or swelling should be investigated for chronic venous disorders. Patients with typical venous pain should have a duplex scan study searching for venous truncal reflux, insufficient tributaries, and perforating veins in the lower limbs.

In addition, leg pain should be considered a therapeutic target for chronic venous disorder treatment and we believe that the disappearance of pain should be a good and interesting parameter to evaluate therapeutic success, as we recurrently see, for example, patients presenting with painful venous ulcers that improve after a session of foam sclerotherapy or saphenous thermal ablation procedure.

It is possible that in a few years we will understand more about the natural history and evolution of chronic venous disorder patients. Meanwhile, it seems reasonable to use clinical parameters such as pain as a therapeutic premise and as a clinical reference of an ongoing inflammatory process that may extend over a long period of time, if not treated. ■

References
1. Carpentier PH, Cornu-Thénard A, Uhl JF, Partsch H, Antignani PL. Appraisal of the information content of the C classes of CEAP clinical classification of chronic venous disorders: a multicenter evaluation of 872 patients. J Vasc Surg. 2003; 37(4):827-833.
2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol. 2012;31(2):105-115.
3. Langer RD, Ho E, Denenberg, JO, Fronek A, Allison M, Criqui MH. Relationships between symptoms and venous disease: the San Diego Population Study. Arch Intern Med. 2005;165(12):1420-1424.
4. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Telangiectasia in the Edinburgh Vein Study: epidemiology and association with trunk varices and symptoms. Eur J Vasc Endovasc Surg. 2008;36(6):719-724.
5. Kaplan RM, Criqui MH, Denenberg JO, Bergan J, Fronek A. Quality of life in patients with chronic venous disease: San Diego population study. J Vasc Surg. 2003;37:1047-1053.


13. I. A. Zolotukhin, Russia

Igor A. ZOLOTUKHIN,MD, PhD
Department of Angiology
and Vascular Surgery
Pirogov’s Russian National Research
Medical University
Moscow, RUSSIA
(e-mail: zoloto70@bk.ru)



This topic has been of interest to me for many years and it is a great idea to raise it in discussion among specialists in venous diseases. In thinking about what is a meaningful outcome in chronic venous disease (CVD), I prefer not to refer to reflux at all, as reflux is not a disease, but only a hemodynamic phenomenon that is quite often not correlated with the presence and severity of symptoms and signs.

So, the dynamic of symptoms and signs is my choice in estimating treatment efficacy. In my point of view, venous pain is absolutely a meaningful outcome. It should be taken into account in any case of CVD, regardless of whether or not the patient has it at the time of consultation, because lack of pain today does not mean lack of pain tomorrow. Wide acceptance of this symptom as a useful tool in clinical practice or even in clinical trials faces many challenges.

The most important is the precise definition and description of venous pain. Every patient with CVD that I see in clinic is asked about symptoms; nearly four out of five are symptomatic. Most patients with venous symptoms say that they have leg pain.

However, when asked in detail, they frequently say that this symptom is not exactly pain. They describe it as a complex sensation consisting of a mix of symptoms such as discomfort, heaviness, tiredness, etc. This is not only my observation, but that of my colleagues too. Maybe the problem is discrepancy in interpretation of the pain in different languages. If it is, the commonly accepted definition of venous pain may need validation in different countries, as by the example of quality of life (QoL) questionnaires.

The next problem is the choice of patients for whom pain would be a valuable outcome. Some, especially young patients with both venous pain and cosmetic complaints, look above all for the disappearance of visible signs. For senior patients, cosmetic results are usually less meaningful and we have to concentrate upon eliminating symptoms rather than signs. Therefore, using the same main clinical outcome in different groups of patients seems to be really controversial.

Rarely, venous pain can be severe. On the one hand, this helps in differential diagnostics—if a patient has severe lower limb pain we should suspect an alternative origin rather than venous. As a result, we have to make further diagnostic steps to exclude other pathology. On the other hand, if the pain is really venous, it rarely exceeds 4 cm to 5 cm on a visual analog scale (VAS) and the next question arises—how can we estimate a positive impact of our treatment with such a tool? Of course, if pain completely disappears after treatment, the result is undeniably positive. But if we only see the regression of pain, what should be considered as a success? Is 2 cm of pain significantly better than 3 cm on the VAS? Other aspects that are not usually taken into account are the frequency of pain and its duration. One patient may have 4 cm of pain on a VAS, but it appears once or twice a week, while another patient may have 2 cm of pain daily. In some patients, 4 cm of pain starts after several hours of orthostasis, while others experience such a pain only at the end of the day. Of course, there are QoL instruments we now use, but they are not venous pain specific. It seems that the development of a complex tool for the measurement and estimation of venous pain would be of great value for both investigators and practitioners. ■