The Significance of Pain in Chronic Venous Disease and its Medical Treatment

Author(s): Djordje Radak, Igor Atanasijević, Mihailo Nešković*, Esma Isenovic .

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 3 , 2019

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Graphical Abstract:


Abstract:

Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression.

General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease.

Keywords: Chronic venous disease, pain, venoactive drugs, hypertension, spinal cord, treatment.

[1]
Evans CJ, Fowkes FGR, Ruckley CV, et al. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh vein study. J Epidemiol Community Health 1999; 53: 149-53.
[2]
Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001; 52: 5-15.
[3]
Lee AJ, Evans CJ, Allan PL, et al. Lifestyle factors and the risk of varicose veins: Edinburgh vein study. J Clin Epidemiol 2003; 56: 171-9.
[4]
Vlajinac HD, Radak DJ, Marinkovic JM, Maksimovic MZ. Risk factors for chronic venous disease. Phlebology 2012; 27: 416-22.
[5]
Bergan JJ, Schmid-Schonbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med 2006; 355: 488-98.
[6]
Porter JM, Moneta GL. Reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635-45.
[7]
Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248-52.
[8]
Radak DJ, Tanaskovic SZ, Vlajinac HD, et al. Relationship between pain and CEAP C categories of chronic venous disease. Angiology 2016; 67: 670-5.
[9]
Andreozzi GM, Cordova RM, Scomparin A, et al. Quality of life in chronic venous insufficiency. An Italian pilot study of the triveneto region. Int Angiol 2005; 24: 272-7.
[10]
Radak DJ, Vlajinac HD, Marinković JM, et al. Quality of life in chronic venous disease patients measured by short chronic venous disease quality of life questionnaire (CIVIQ-14) in Serbia. J Vasc Surg 2013; 58: 1006-13.
[11]
Ortega-Santana F, Liminana JM, Ruano F, et al. The influence of the CIVIQ dimensions on quality of life of patients with primary superficial venous incompetence. Eur J Vasc Endovasc Surg 2014; 28: 425-8.
[12]
Danziger N. Pain in chronic venous disease: perspectives for research. Medicographia 2011; 33: 325-31.
[13]
Vital A, Carles D, Conde Da Silva Fraga E, et al. Unmyelinated C fibers and inflammatory cells are present in the wall of human varicose veins. A clinico-pathological study. Phlebolymphology 2010; 17: 27.
[14]
Arndt JO, Klement W. Pain evoked by polymodal stimulation of hand veins in humans. J Physiol 1991; 440: 467.
[15]
Klement W, Arndt JO. Adenosine does not evoke pain from venous and paravascular nociceptors in the human. Cardiovasc Res 1992; 26: 186-9.
[16]
Tisato V, Zamboni P, Menegatti E. Endothelial PDGF-BB produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. Cytokine 2013; 63: 92-6.
[17]
Michiels C, Arnould T, Knott I, et al. Stimulation of prostaglandin synthesis by human endothelial cells exposed to hypoxia. Am J Physiol 1993; 264: 866-74.
[18]
Michiels C, Renard P, Bouaziz N, et al. Identification of the phospholipase A(2) isoforms that contribute to arachidonic acid release in hypoxic endothelial cells: limits of phospholipase A(2) inhibitors. Biochem Pharmacol 2002; 63: 321-32.
[19]
Saharay M, Shields DA, Porter JB, et al. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg 1997; 26: 265-73.
[20]
Tisato V, Zauli G, Gianesini S, et al. Modulation of circulating cytokine-chemokine profile in patients affected by chronic venous insufficiency undergoing surgical hemodynamic correction. J Immunol Res 2014; 2014: 473765.
[21]
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: 1248-52.
[22]
Rabe E, Pannier F. Clinical, aetiological, anatomical and pathological classification (CEAP): gold standard and limits. Phlobology 2012; 27: 114-8.
[23]
Radak DJ, Tanaskovic SZ, Vlajinac HD, et al. Relationship between pain and CEAP C categories of relationship between pain and CEAP C categories of chronic venous disease. Angiology 2016; 67: 670-5.
[24]
Amsler F, Blättler W. Compression therapy for occupational leg symptoms and chronic venous disorders–a meta-analysis of randomised controlled trials. Eur J Vasc Endovasc Surg 2008; 35: 366-72.
[25]
Blättler W, Thomae H-J, Amsler F. Venous leg symptoms in healthy subjects assessed during prolonged standing. J Vasc Surg Venous Lymphat Disord 2016; 4: 455-62.
[26]
Van der Velden S, Shadid N, Nelemans P, Sommer A. How specific are venous symptoms for diagnosis of chronic venous disease? Phlebology 2014; 29: 580-6.
[27]
Virgini-Magalhaes CE, Porto CL, Fernandes FF, Dorigo DM, Bottino DA, Bouskela E. Use of microcirculatory parameters to evaluate chronic venous insufficiency. J Vasc Surg 2006; 43: 1037-44.
[28]
Jünger M, Steins A, Hahn M, Häfner H. Microcirculatory dysfunction in chronic venous insufficiency. Microcirculation 2000; 7(1): 3-12.
[29]
Radak DJ, Sotirovic VA. Risk factors for symptomatic chronic venous disorders: results from the international vein consult program. Medicographia 2015; 35(3): 85-91.
[30]
Gschwandtner ME, Ehringer H. Microcirculation in chronic venous insufficiency. Vasc Med 2001; 6(3): 169-79.
[31]
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: 353-6.
[32]
Kahn SR, M’lan CE, Lamping DL, et al. Relationship between clinical classification of chronic venous disease and patient-reported quality of life: results from an international cohort study. J Vasc Surg 2004; 39: 823-8.
[33]
Chiesa R, Marone EM, Limoni C, et al. Chronic venous disorders: correlation between visible signs, symptoms, and presence of functional disease. J Vasc Surg 2007; 46: 322-30.
[34]
Langer RD, Ho E, Denenberg JO, et al. Relationships between symptoms and venous disease. The San Diego population study. Arch Intern Med 2005; 165: 1420-4.
[35]
Conway AM, Nordon IM, Hinchliffe RJ, et al. Patient-reported symptoms are independent of disease severity in patients with primary varicose veins. Vascular 2011; 19: 262-8.
[36]
Duque MI, Yosipovitch G, Chan YH, et al. 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: 504-8.
[37]
Ziegler S. Chronic venous disease is highly prevalent in hospital employees. Phlebolymphology 2006; 13: 150.
[38]
Howlader MH, Smith PG. Symptoms of chronic venous disease and association with systemic inflammatory markers. J Vasc Surg 2003; 38: 950-4.
[39]
Reinhardt F, Wetzel T, Vetten S, et al. Peripheral neuropathy in chronic venous insufficiency. Muscle Nerve 2000; 23: 883-7.
[40]
Yim E, Vivas A, Maderal A, et al. Neuropathy and ankle mobility abnormalities in patients with chronic venous disease. JAMA Dermatol 2014; 150: 385-9.
[41]
Padberg FT, Maniker AH, Carmel G, et al. Sensory impairment: a feature of chronic venous insufficiency. J Vasc Surg 1999; 30: 836-42.
[42]
Michiels C, Bouaziz N, Remacle J. Role of the endothelium and blood stasis in the development of varicose veins. Int Angiol 2002; 21: 18-25.
[43]
Vlajinac HD, Marinkovic JM, Maksimovic MZ, et al. Body mass index and primary chronic venous disease-a cross-sectional study. Eur J Vasc Endovasc Surg 2013; 45: 293-8.
[44]
Robertson LA, Evans CJ, Lee AJ, et al. Incidence and risk factors for venous reflux in the general population: Edinburgh vein study. Eur J Vasc Endovasc Surg 2014; 48: 208-14.
[45]
Göstl K, Obermayer A, Hirschl M. Pathogenesis of chronic venous insufficiency by obesity. Phlebologie 2009; 38: 108-13.
[46]
van Rij AM, De Alwis CS, Jiang P, et al. Obesity and impaired venous function. Eur J Vasc Endovasc Surg 2008; 35: 739-44.
[47]
Maurins U, Hoffman BH, Losch C, et al. Distribution and prevalence of reflux in the superficial and deep venous system in the general population - results from the Bonn vein study, Germany. J Vasc Surg 2008; 48: 680-7.
[48]
Davies HO, Popplewell M, Singhai R, et al. Obesity and lower limb venous disease - The epidemic of phlebesity. Phlebology 2017; 32: 227-33.
[49]
Matic P, Jolic S, Tanaskovic S, et al. Chronic venous disease and comorbidities. Angiology 2015; 66: 539-44.
[50]
Vlajinac H, Marinkovic J, Maksimovic M. Factors related to venous ulceration: a cross-sectional study. Angiology 2014; 65: 824-30.
[51]
Rabe E, Pannier F, Ko A, et al. Incidence of varicose veins, chronic venous insufficiency, and progression of the disease in the Bonn vein study II. J Vasc Surg 2010; 51: 791.
[52]
Onida S, Davies AH, Franklin I. Varicose veins who should be referred? Phlebology 2015; 30: 4-8.
[53]
National Institute for Health and Care Excellence (NICE). Varicose veins: diagnoses and management [Internet]; 2013 July [cited 2017 Nov]. Available from: https://www.nice.org.uk/guidance/cg168
[54]
Venous Forum of the Royal Society of Medicine, et al. Recommendations for the referral and treatment of patients with lower limb chronic venous insufficiency (including varicose veins). Phlebology 2011; 26: 91-3.
[55]
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: 2-48.
[56]
Marston WA. PPG, APG, duplex: which noninvasive tests are most appropriate for the management of patients with chronic venous insufficiency? Semin Vasc Surg 2002; 15: 13-20.
[57]
Christopoulos D, Nicolaides AN, Szendro G. Venous reflux: quantification and correlation with the clinical severity of chronic venous disease. Br J Surg 1988; 75: 352-6.
[58]
Criado E, Farber MA, Marston WA, et al. The role of air plethysmography in the diagnosis of chronic venous insufficiency. J Vasc Surg 1998; 27: 660-70.
[59]
Adams EF. Hippocrates. The genuine works of Hippocrates. In: Adams EF, Ed. Wm Wood & Co. New York 1886; Vol. 2.
[60]
Anning ST. Historical aspects. In: Dodd H, Cockett FB, Eds. The pathology and surgery of veins of the lower limb. Edinburgh: Livingstone 1956; pp. 6-28.
[61]
Gjores JE, Thulesius O. Compression treatment in venous insufficiency evaluated with foot volumetry. Vasa 1977; 6: 364-8.
[62]
Partsch H. Improvement of venous pumping function in chronic venous insufficiency by compression depending on pressure and material. Vasa 1984; 13: 58.
[63]
Anderson JH, Geraghty JG, Wilson YT, et al. Paroven and graduated compression hosiery for superficial venous insufficiency. Phlebology 1990; 5: 271-6.
[64]
Jungbeck C, Thulin I, Darenheim C, et al. Graduated compression treatment in patients with chronic venous insufficiency: A study comparing low and medium grade compression stockings. Phlebology 1997; 12: 142-5.
[65]
Motykie GD, Carpini JA, Arcelus JI, et al. Evaluation of therapeutic compression stockings in the treatment of chronic venous insufficiency. Dermatol Surg 1999; 25: 116-20.
[66]
Lim CS, Davies AH. Graduated compression stockings. CMAJ 2014; 186: 391-8.
[67]
Shingler S, Robertson L, Boghossian S, et al. Compression stockings for the initial treatment of varicose veins in patients without venous ulceration. Cochrane Database Syst Rev 2014; 12: CD008819.
[68]
Callum MF, Ruckley CV, Dale JJ, et al. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. BMJ 1987; 295: 1352.
[69]
Raju S, Hollis K, Neglen P. Use of compression stockings in chronic venous disease. Ann Vasc Surg 2007; 21: 790-5.
[70]
Jull AB, Mitchell N, Arroll J, et al. Factors influencing concordance with compression stockings after venous leg ulcer healing. J Wound Care 2004; 13: 90-2.
[71]
Blattler W, Zimmet SE. Compression therapy in venous disease. Phlebology 2008; 23: 203-5.
[72]
Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions. Eur J Vasc Endovasc Surg 2011; 41: 117-25.
[73]
Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo-alpha-pyrone. N Engl J Med 1993; 329: 1158-63.
[74]
Nicolaides AN1, Allegra C, Bergan J, et al. Management of chronic venous disorders of the lower limbs - guidelines according to scientific evidence. Int Angiol 2014; 33: 87-208.
[75]
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American college of chest physicians task force. Chest 2006; 129: 174-81.
[76]
Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-6.
[77]
Korthuis R, Gutte DC. Post-ischemic leukocyte/endothelial cell interactions and microvascular barrier dysfunction in skeletal muscle: Cellular mechanisms and effect of Daflon 500 mg. Int J Microcirc 1997; 17: 11-7.
[78]
Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assessment and quality of life improvement with micronized flavonoids. Angiology 2002; 53: 245-56.
[79]
Danielsson G, Jungbeck C, Peterson K, et al. A randomised controlled trial of micronised purified flavonoid fraction vs placebo in patients with chronic venous disease. Eur J Vasc Endovasc Surg 2002; 23: 73-6.
[80]
Martinez-Zapata MJ, Vernooij RW, Uriona Tuma SM, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev 2016; 4: CD003229.
[81]
Bush R, Comerota A. Meissner et al. Recommendations for the medical management of chronic venous disease: The role of micronized purified flavanoid fraction (MPFF). Phlebology 2017; 32: 3-19.
[82]
Pokrovsky AV, Saveljev VS, Kirienko AI, et al. Surgical correction of varicose vein disease under micronized diosmin protection (results of the Russian multicenter controlled trial DEFANS). Angiol Sosud Khir 2007; 13: 47-55.
[83]
Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol 2009; 7: 303-8.
[84]
Petruzzellis V, Troccoli T, Candiani C, et al. Oxerutins (Venoruton): efficacy in chronic venous insufficiency--a double-blind, randomized, controlled study. Angiology 2002; 53: 257-63.
[85]
Cesarone MR, Belcaro G, Pellegrini L, et al. Venoruton®vs. Daflon®: evaluation of effects on quality of life in chronic venous insufficiency. Angiology 2006; 57: 131-8.
[86]
Aziz Z, Tang WL, Chong NG, et al. A systematic review of the efficacy and tolerability of hydroxyethylrutosides for improvement of the signs and symptoms of chronic venous insufficiency. J Clin Pharm Ther 2015; 40: 177-85.
[87]
Yildiz CE, Conkbayir C, Huseynov E, et al. The efficiency of O-(beta-hydroxyethyl)-rutosides in reducing the incidence of superficial venous insufficiency in patients with calf muscle pump dysfunction. Phlebology 2017; 32: 179-84.
[88]
Guillaume M, Padioleau F. Veinotonic effect, vascular protection, antiinflammatory and free radical scavenging properties of horse chestnut extract. Arzneimittelforschung 1994; 44: 25-35.
[89]
Dudek-Makuch M, Studzińska-Sroka E. Horse chestnut–efficacy and safety in chronic venous insufficiency: an overview. Revista Brasileira de Farmacognosia 2015; 25: 533-41.
[90]
Tejerina T, Ruiz E. Calcium dobesilate: pharmacology and future approaches. Gen Pharmacol 1998; 31: 357-60.
[91]
Rabe E, Jaeger KA, Bulitta M, Pannier F. Calcium dobesilate in patients suffering from chronic venous insufficiency: a double-blind, placebo-controlled, clinical trial. Phlebology 2011; 26: 162-8.
[92]
Eberhardt RT, Raffetto JD. Chronic venous insufficieny. Circulation 2014; 130: 333-46.
[93]
Christenson JT, Gueddi S, Gemayel G, et al. Prospective randomized trial comparing endovenous laser ablation and surgery for treatment of primary great saphenous varicose veins with a 2-year follow-up. J Vasc Surg 2010; 52: 1234-41.
[94]
Lurie F, Creton D, Eklof B, et al. Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stipping (EVOLVeS): two-year follow up. Eur J Vasc Endovasc Surg 2005; 29: 67-73.
[95]
Helmy ElKaffas K, ElKashef O, ElBaz W. Great saphenous vein radiofrequency ablation versus standard stipping in the management of primary varicose veins-a randomized clinical trial. Angiology 2011; 62: 49-54.


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VOLUME: 17
ISSUE: 3
Year: 2019
Page: [291 - 297]
Pages: 7
DOI: 10.2174/1570161116666180209111826
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