Etiopathogenesis of Hemorrhoids

Hemorrhoids are normal anal cushions of submucosal vascular tissue surrounding the anastomoses between the superior rectal artery and the superior, middle, and inferior rectal veins.⁵ Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg.2016;29(1):22-29.     ⁹ Von Roon AC, Reese GE, Tekkis PP. Haemorrhoids: haemorrhoidal artery ligation. BMJ Clin Evid. 2009;2009:0415.    There are three main anal cushions, located in the left lateral, the right posterolateral, and the right anterolateral aspect of the anal canal.²Yeo D, Tan K-Y. Hemorrhoidectomy - making sense of the surgical options. World J Gastroenterol. 2014;20(45):16976-16983.    ¹⁰ Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24(1):5-13.   ¹¹ Schubert MC, Sridhar S, Schade RR, et al. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209.    These vascular cushions are clusters of elastic connective tissues and smooth muscles. Hemorrhoidal tissue is important in protecting the anal sphincter during defecation, and the expansion of the vascular cushions plays a role in anal occlusion. Besides, the vascular cushions also contribute to anal continence because these provide 15-20% of the resting anal pressure required to maintain continence.¹⁰ Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24(1):5-13.     ¹¹ Schubert MC, Sridhar S, Schade RR, et al. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209.     ¹²Guay DR. Contemporary management of uncomplicated urinary tract infections. Drugs. 2008;68(9):1169-205.Abramowitz L, Weyandt GH, Havlickova B, et al. The diagnosis and management of haemorrhoidal disease from a global perspective. Aliment Pharmacol Ther. 2010;31 Suppl 1:1-58.

Hemorrhoids become a disease when pathologic and dilated changes occur in the vascular cushions and cause the development of symptomatic hemorrhoids.¹¹ Schubert MC, Sridhar S, Schade RR, et al. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209.   ¹²Guay DR. Contemporary management of uncomplicated urinary tract infections. Drugs. 2008;68(9):1169-205.Abramowitz L, Weyandt GH, Havlickova B, et al. The diagnosis and management of haemorrhoidal disease from a global perspective. Aliment Pharmacol Ther. 2010;31 Suppl 1:1-58.  ¹³Haemorrhoids. Available at: http://bestpractice.bmj.com/best-practice/monograph/181/basics/pathophysiology.html. Accessed on 25/10/2017.   The term 'hemorrhoid’ is usually referred to the pathological condition of symptomatic hemorrhoid, which is associated with symptoms such as bleeding, prolapse, pain, pruritus, mucus discharge, and thrombosis.⁵ Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg.2016;29(1):22-29.    ⁹ Von Roon AC,Reese GE, Tekkis PP. Haemorrhoids: haemorrhoidal artery ligation. BMJ Clin Evid. 2009;2009:0415.

The pathophysiology of hemorrhoid development is multifaceted and includes several theories, such as sliding anal canal lining, hyperperfusion of hemorrhoid plexus, vascular abnormality, tissue inflammation and internal rectal prolapse. Among them, the theory of sliding anal canal lining is the most-widely accepted theory. According to this theory, hemorrhoids develop when the supporting tissues of the anal cushions deteriorate or degenerate. This is supported by microscopic findings of muscle fibers being replaced by collagen fibers.²Yeo D, Tan K-Y. Hemorrhoidectomy - making sense of the surgical options. World J Gastroenterol. 2014;20(45):16976-16983.   ³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol.2015;21(31):9245-9252.   ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ¹⁴Cirocco WC. Why Are Hemorrhoids Symptomatic? The Pathophysiology and Etiology of Hemorrhoids. Seminars in Colon and Rectal Surgery. 2007; 18(3): 152-159   Various pathological changes are observed in the anal cushions of patients with hemorrhoids, which include abnormal venous dilatation, vascular thrombosis, degenerative process in the collagen fibers and fibroelastic tissues, distortion and rupture of the anal subepithelial muscle (Box 1). Therefore, hemorrhoids are the pathological term used to describe the abnormal downward displacement of the anal cushions resulting in venous dilatation.⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.

Risk Factors for Hemorrhoids

Several risk factors have been associated with hemorrhoid development including aging, obesity, depressive mood and pregnancy. Besides, factors that increase intra-abdominal pressure, such as prolonged straining and constipation, are considered to contribute to the development of hemorrhoids due to compromised venous drainage of hemorrhoid plexus. Constipation and prolonged straining are thought to increase the shearing force on the anal cushions, further predisposing to the formation of hemorrhoids. Moreover, prolonged straining may lead to the development of symptoms such as bleeding and prolapse in patients with a history of hemorrhoidal disease.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol.2015;21(31):9245-9252.   ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.   ¹⁵Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139. Mounsey AL, Halladay J, Sadiq TS. Hemorrhoids. Am Fam Physician.2011;84(2):204-210.    ¹⁶ Loder PB, Kamm MA, Nicholls RJ, et al. Haemorrhoids: pathology, pathophysiology and aetiology. Br J Surg. 1994;81(7):946-54.

In addition, pregnancy predisposes women to congestion of the anal cushion and symptomatic hemorrhoids; however, they usually resolve soon after birth. Certain dietary factors and lifestyle, including low fiber diet, spicy foods and alcohol intake have also been associated with the development of hemorrhoids and may exacerbate acute hemorrhoid symptoms.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.  ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ¹⁷ Peery AF, Sandler RS, Galanko JA, et al. Risk Factors for Hemorrhoids on Screening Colonoscopy. Green J, ed. PLoS ONE. 2015;10(9):e0139100.

Classification and Grading

Hemorrhoids are usually classified on the basis of their position relative to the dentate line (the junction between columnar and squamous epithelium) and degree of prolapse. A hemorrhoid classification system helps select from the different treatments, and also to compare them.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.      ⁵ Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg.2016;29(1):22- 29.   ¹⁸Hardy A, Chan CL, Cohen CR. The surgical management of haemorrhoids–a review. Dig Surg. 2005;22(1-2):26-33.   On the basis of position, hemorrhoids are classified as internal, external and mixed hemorrhoids. Internal hemorrhoids originate above the dentate line and are covered by anal mucosa, whereas external hemorrhoids originate below the dentate line and are covered with squamous epithelium. Mixed or interno-external hemorrhoids appear both above and below the dentate line.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.      ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ¹⁵Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139. Mounsey AL, Halladay J, Sadiq TS. Hemorrhoids. Am Fam Physician.2011;84(2):204-210.

Internal hemorrhoids are supported by connective tissue within the anal canal. Weakening of this supporting tissue causes the hemorrhoids to prolapse; they distend downward and are pushed outside the anus. Bleeding may or may not be present, and thrombosis is rarely observed. Based on their appearance and degree of prolapse, internal hemorrhoids are further graded, according to the Goligher classification, as first-degree hemorrhoids
(grade I), second-degree hemorrhoids (grade II), third-degree hemorrhoids(grade III), and fourth-degree hemorrhoids (grade IV); Table 1.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.      ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ¹⁸Hardy A, Chan CL, Cohen CR. The surgical management of haemorrhoids–a review. Dig Surg. 2005;22(1-2):26-33.  In contrast, external hemorrhoids are susceptible to thrombosis, and may be classified as acute (hemorrhoidal thrombosis) or chronic (anal skin tags).⁴ Cerato MM, Cerato NL, Passos P, et al. Surgical treatment of hemorrhoids: A critical appraisal of the current options. Arq Bras Cir Dig. 2014;27(1):66-70.    ¹²Guay DR. Contemporary management of uncomplicated urinary tract infections.Drugs. 2008;68(9):1169-205.Abramowitz L, Weyandt GH, Havlickova B, et al. The diagnosis and management of haemorrhoidal disease from a global perspective. Aliment Pharmacol Ther. 2010;31 Suppl 1:1-58.  

Clinical Presentation of Hemorrhoids

The most common manifestation of hemorrhoids is painless rectal bleeding with or without defecation, a swelling, mild discomfort or irritation. The blood, which is characteristically bright red due to direct arteriovenous involvement, can be found on the toilet paper, or dripping into the toilet bowl. Other symptoms may include
sensation of tissue prolapsed, soilage or mucous discharge, pruritus ani, and hygiene problems. Patients with large hemorrhoids also report a feeling of incomplete evacuation or rectal fullness. External hemorrhoids are associated with pain and bleeding when thrombosis or ulceration occurs. On the other hand, internal hemorrhoids, otherwise painless, become symptomatic when they prolapse, thrombose, bleed or get strangulated(Table 2).³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.      ⁵ Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg.2016;29(1):22- 29.   ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.    ¹⁰ Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24(1):5-13.

Management of Hemorrhoids

The management of hemorrhoids usually entails a multifaceted approach, and is reserved for symptomatic hemorrhoids only. The methods involve both pharmacological as well as non-pharmacological (lifestyle interventions) interventions, and in some cases surgery as well.¹⁹ Altomare DF, Giuratrabocchetta S. Conservative and surgical treatment of haemorrhoids. Nat Rev Gastroenterol Hepatol. 2013; 10(9):513-21.   ²⁰ Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327(7419):847-851.   Herein, it should be noted that selection of any therapy must be individualized, and guided by the degree and severity of symptoms, patient’s age, and comorbidities.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.   ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.   ¹⁰ Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24(1):5-13.   ²⁰ Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327(7419):847-851.  One general principle is that the least-invasive approaches should be considered first given the physiologic importance of the hemorrhoid cushions. In all cases, the main aim of treatment is to provide symptomatic relief without any adverse events.⁵ Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg.2016;29(1):22-29.   ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.   ¹⁰ Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24(1):5-13.

An increase in dietary fiber and oral fluids in the diet may help eliminate straining during defecation, thus reducing the damage caused by the shearing action of passing hard stool on the anal mucosa. In addition to increasing dietary fiber and oral fluids, other lifestyle modifications may play a role in the treatment or prevention of hemorrhoids. These changes include reducing fat consumption, having regular exercise, improving anal hygiene, avoiding straining and reading on the toilet, and avoiding medication that causes constipation or diarrhea.⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.    ²¹ Alonso-Coello P, Mills E, Heels-Ansdell D, et al. Fiber for the treatment of hemorrhoids complications: a systematic review and meta-analysis. Am J Gastroenterol. 2006; 101(1):181-8.

For pharmacological therapy, several treatment options, including both topical and oral medications are available. Nonetheless, there is a dearth of data to support the efficacy of topical formulations for symptomatic hemorrhoids. In this context, oral preparations, such as bioflavonoids, may seem a rational approach, and could in fact be considered the first-line agents for hemorrhoids treatment.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.   ²²Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter.2000;151(5):341-4.   Bioflavonoids have been found to exert positive effects in hemorrhoids patients through several possible mechanisms - by increasing venous tone, reducing venous capacity, decreasing capillary permeability, facilitating lymphatic drainage and by exerting an anti-inflammatory effect.³ Lohsiriwat V. Treatment of hemorrhoids: A coloproctologist’s view. World J Gastroenterol. 2015;21(31):9245-9252.      ⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ²⁰ Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327(7419):847-851.   Arguably, the oral bioflavonoid diosmin has emerged as a highly potent agent in treatment of hemorrhoids since it possibly affects all pathophysiological aspects of hemorrhoids.23,24

Role of Diosmin in Hemorrhoids: Well-suited to the Conservative Approach

First introduced as a therapeutic agent in 1969, diosmin is a naturally occurring flavonoid glycoside, and is considered to be a vascular-protecting agent with multimodal action; justifying its role in treatment of hemorrhoids and chronic venous insufficiency.²¹ Alonso-Coello P, Mills E, Heels-Ansdell D, et al. Fiber for the treatment of hemorrhoids complications: a systematic review and meta-analysis. Am J Gastroenterol. 2006; 101(1):181-8.   Diosmin has been widely used for more than 30 years worldwide as a phlebotonic and vascular protecting agent with good efficacy and safety profile. Moreover, being a flavonoid, diosmin also exhibits anti-inflammatory, free-radical scavenging, and anti-mutagenic properties.²⁵ Diosmin monograph. Alternative Medicine Review. 2004;9(3):308-311.    Of note, diosmin exhibits excellent tolerability profile, which makes the drug very easy to handle by the general practitioner, and also useful to the proctologist in the preparation of the patient to further treatments.²²Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter. 2000;151(5):341-4.   Besides, diosmin may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible.²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.

The pharmacokinetic data has reported that the drug attains maximum plasma concentration after about one hour of administration, and demonstrates a half life of 26 to 43 hours.²⁷Milano G, Leone S, Fucile C, et al. Uncommon serum creatine phosphokinase and lactic dehydrogenase increase during Diosmin therapy: two case reports.J Med Case Rep. 2014;8:194.   ²⁸Cova D, De Angelis L, Giavarini F, et al. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1992;30(1):29-33.  Diosmin effectively targets the pathophysiology of hemorrhoids, and hence can reduce the associated disease symptoms including pain, edema, and heaviness. Also, it could affect the recurrence as well, and therefore appears to be well-suited to the conservative approach in hemorrhoids.²³Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol. 2009;7(3):303-8.

Mechanism of Action of Diosmin

Diosmin exhibits a multifaceted mechanism of action, which includes improvement of venous tone, increased lymphatic drainage, protection of capillary bed microcirculation, inhibition of inflammatory reactions, and reduced capillary permeability. Diosmin exerts its phlebotonic effect by prolonging the vasoconstrictor effect of norepinephrine on vein wall, enhances venous tone, and thus reduces distensibility and stasis. Moreover, it helps to restore the capillaries function by inhibiting the release of inflammatory mediators, decreasing intracapillary pressure and capillary permeability. It also potentiates the action of vitamin C, thus increasing the capillary resistance. The protective effect of diosmin against formation of perivascular edema and its therapeutic application in venous stasis could be attributable to its inhibitory action on inflammatory process or ischemia-induced hyperpermeability, and to its stimulatory effect on the pulsatile activity of lymphatic vessels. Additionally, diosmin ameliorates the lymphatic drainage by enhancing the intensity and frequency of lymphatic contractions, and this process helps in clearance of accumulated fluids, and hence reducing the edema. Besides, diosmin causes a marked decrease in plasma levels of endothelial adhesion molecules and reduces neutrophil activation, thus providing protection against microcirculatory damage. Overall, these multifaceted actions of diosmin possibly converge to provide maximal benefit to individuals with hemorrhoids (Figure 1). There is considerable evidence on the efficacy of diosmin, and several investigators have demonstrated the superior results obtained with micronized form of the molecule.²⁵ Diosmin monograph. Alternative Medicine Review. 2004;9(3):308-311.    ²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.   ²⁹ Araujo D, Viana F, Osswald W. Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein. Pharmacol Res. 1991;24(3):253-6.    ³⁰Jean T,Bodinier MC. Mediators involved in inflammation: effects of Daflon 500 mg on their release. Angiology. 1994;45(6 Pt 2):554-9.   ³¹ Labrid C. Pharmacologic properties of Daflon 500 mg. Angiology. 1994;45(6 Pt 2):524-30.    ³²Cyrino FZ, Bottino DA, Lerond L, et al. Micronization enhances the protective effect of purified flavonoid fraction against postischaemic microvascular injury in the hamster cheek pouch. Clin Exp Pharmacol Physiol. 2004;31(3):159-62   ³³Raffetto JD, Khalil RA. Ca2+-Dependent Contraction by the Saponoside Escin in Rat Vena Cava. Implications in Venotonic Treatment of Varicose Veins. J Vasc Surg. 2011;54(2):489-496.    ³⁴ Srinivasan S, Pari L. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chem Biol Interact. 2012;195(1):43-51.    ³⁵ Noorafshan A, Karbalay-Doust S, Karimi F. Diosmin reduces calcium oxalate deposition and tissue degeneration in nephrolithiasis in rats: a stereological study. Korean J Urol. 2013;54(4):252-7.

Use of 100% Pure Micronized Diosmin for Hemorrhoids Versus Other Agents

The 100% pure form of diosmin would have better absorption and bioavailability, since there will be no flavonoid impurities to competitively decrease the tissue absorption and distribution of this monosubstance. Several evidences support the superior clinical efficacy of micronized diosmin in the management of hemorrhoids. In one such clinical study, investigators showed high effectiveness of the diosmin therapy in patients with hemorrhoids. ²²Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter. 2000;151(5):341-4.   ³⁵ Noorafshan A, Karbalay-Doust S, Karimi F. Diosmin reduces calcium oxalate deposition and tissue degeneration in nephrolithiasis in rats: a stereological study. Korean J Urol. 2013;54(4):252-7.   ³⁶. Diosmin Complex. Available at: http://www.fda.gov/ohrms/dockets/ dockets/95s0316/rpt0083_01.pdf. Accessed on:17.11.2017.

Micronized purified flavonoid fraction (MPFF) is a variant of the diosmin preparation that contains various impurities, such as hesperidin, linarin, and isorhoifolin, which can interfere with clinical efficacy of the preparation. ²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.   ³⁵ Noorafshan A, Karbalay-Doust S, Karimi F. Diosmin reduces calcium oxalate deposition and tissue degeneration in nephrolithiasis in rats: a stereological study. Korean J Urol. 2013;54(4):252-7.   Moreover, the composition of MPFF has been inconsistent over years, with variations in the product label for MPFF in domestic and international marke(90% diosmin and 10% hesperidin). This variation, attributable to the additional 10% fraction, might cause differences in clinical efficacy and tolerability of different diosmin formulations in patients. In a study, the percentage of patients with no bleeding after five days of treatment with MPFF was approximately 60% only.³⁹Dimitroulopoulos D, Tsamakidis K, Xinopoulos D, et al. Prospective, randomized, controlled, observer-blinded trial of combined infrared photocoagulation and micronized purified flavonoid fraction versus each alone for the treatment of hemorrhoidal disease. Clin Ther. 2005;27(6):746-54.

Another conservative approach that is often employed in hemorrhoids treatment is the use of herbal and ayurvedic preparations. However, these preparations have also shown variable efficacy in different individuals. Euphorbia prostrata(indigenously known as Dughdhika) is an ayurvedic preparation that has limited clinical efficacy in hemorrhoids patients with treatment failure of 13%.⁴⁰Gupta PJ. The efficacyof Euphorbia prostrata in early grades of symptomatic hemorrhoids – a pilot study. European Review for Medical and Pharmacological Sciences 2011;15:199-203.    Moreover, while its exact mode of action in hemorrhoids is not clear, its efficacy in advanced stages of hemorrhoids and in elderly patients is also not well-established. The preparation contains several constituents other than flavonoids, such as phenolic acid and tannins, which could impact the effectiveness of the preparation. Another instance evaluating use of an ayurvedic preparation found that improvement occurred in only 76% of patients even after combined use of both tablet and ointment forms of the same ayurvedic composition.⁴¹Gupta VK. Haemorrhoids and Conservative Treatment with Pilex. Haryana Medical Journal. 1981;2(3):103.

Another venoactive drug calcium dobesilate has also been considered for use in hemorrhoids; however, the drug has limitation in that it does not have comprehensive action on all stages of the venous disorders. A randomized controlled trial showed that calcium dobesilate was not superior to placebo.⁴² Martínez-Zapata MJ, Moreno RM, Gich I, et al; Chronic Venous Insufficiency Study Group. A randomized, doubleblind multicentre clinical trial comparing the efficacy of calcium dobesilate with placebo in the treatment of chronic venous disease. Eur J Vasc Endovasc Surg.2008;35(3):358-65.    Furthermore, since it is a category C drug, it cannot be used in women with pregnancy and lactation. Due to reports of agranulocytosis, it has been found to be associated with negative concerns relating to benefit-risk balance. ³⁸ Rybak Z. Management of lower-limb venous symptoms: what the guidelines tell us. Medicographia. 2015;37:50-55.

Overall, the above discussion clearly shows that diosmin is an ideal treatment for hemorrhoids when in its 100% pure form as a monosubstance. A study ²²Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter. 2000;151(5):341-4.   substantiated the same wherein the role of purified diosmin was evaluated in a group of 66 patients suffering from primitive hemorrhoids of grade 1-4. The results demonstrated the efficacy of purified diosmin in reducing both pain and bleeding; reduction rates of 79% and 67%, respectively, were achieved in the first week of treatment, and 98% and 86%, respectively, in the second week of treatment. In addition, the drug exhibited excellent tolerability (Figure 2).

Similarly, in a placebo-controlled trial,²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.   authors reported efficacy of micronized diosmin in significantly improving the duration and/ or intensity of individual symptoms of grade 1 or 2 acute internal hemorrhoids. Treatment not only reduced the frequency, duration and/or severity of acute hemorrhoidal symptoms, but improved the overall signs and symptoms of chronic (recurrent) hemorrhoids in comparison to placebo. In all, the efficacy of diosmin is well established in attenuating and treating the symptoms of hemorrhoids. Furthermore, use drug of diosmin in patients referred for surgical therapy may help in reducing the edema and demarcating the area for incision, thereby making surgery convenient with superior outcomes.

Benefits of Micronization

Another approach that is used to enhance the efficacy of diosmin is the modification of the drug-delivery form, particularly through the process of micronization during the drug's preparation. Micronization is a significant process used during drug's preparation to enhance their absorption, and thus efficacy. It is considered that micronization of diosmin to small particle size of 0.3 microns would facilitate better gastrointestinal absorption of the drug. This in turn would confer improved bioavailability, and the consequent effect would be available in form of enhanced clinical effect.²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.   ⁴³ Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol.1998;20(3):211-5.    Besides, by increasing the absorbed fraction, micronization helps decrease inter-patient pharmacokinetic variability and the influence of exogenous factors, such as diet and dosing regimen.⁴⁴Garner RC, Garner JV, Gregory S, et al. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002;91(1):32-40.

A randomized, double-blind, multicenter trial ⁴⁵ Amato C. Advantage of a micronized flavonoidic fraction (Daflon 500 mg) in comparison with a nonmicronized diosmin. Angiology. 1994;45 (6 Pt 2):531-6.s    involving 90 patients with venous disease of lower limbs assessed the pharmacodynamic and clinical activities of micronized and non-micronized forms of diosmin, and demonstrated statistically significant changes in both groups of patients compared to the baseline values. However, there were remarkably greater improvements in all clinical symptoms and plethysmographic parameters with the micronized in comparison to the non-micronized diosmin. The variable effect was evident in the rates of satisfaction among patients as well; satisfaction rate among patients in micronized diosmin-treated group was 95% while in non-micronized diosmin group it was 80% (Figure 3). Available data also suggest that micronized diosmin is well-tolerated, acceptable, and effective in the treatment of hemorrhoids of pregnancy; the treatment is well-accepted, and does not affect pregnancy, fetal development, birth weight, infant growth and feeding.⁴⁶ Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. Int J Gynaecol Obstet. 1997;57(2):145-51.   Thus, micronized form of diosmin offers a myriad of potential therapeutic advantages, and also accounts for higher satisfaction rates among the patients. Altogether, the efficacy of diosmin is well established in treating and ameliorating the symptoms of hemorrhoids. Furthermore, the micronized form of diosmin offers potential therapeutic advantages and would be favorable to use in patients with hemorrhoids.²⁶ Lyseng-Williamson KA, Perry CM.Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.

Conclusion

Hemorrhoid disease is a common but complex multifaceted disorder, which affects millions of people globally and represents a major medical and socioeconomic challenge. The condition has multifactorial etiology, and occurs as a consequence of related arteriovenous and connective tissue abnormalities - abnormal dilation of veins of internal hemorrhoidal venous plexus, abnormal distention of arteriovenous anastomosis, and prolapse of cushions and surrounding connective tissue. Specific treatment choice should be based on individual patient, the degree and severity of their symptoms as well as considering their other medical problems. Nevertheless, conservative approach is often used first in most cases of hemorrhoids. Of note, use of the flavonoid diosmin has been found to be beneficial across all grades of hemorrhoids. Particularly, the 100% pure micronized form of diosmin could be a first choice of therapy since it is free from other impurities and target possibly all pathophysiological aspects of hemorrhoids. The drug improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting microcirculation from inflammatory processes. Diosmin is isolated/extracted from the flavonoid hesperidin. Diosmin containing products are available which may be in combination with hesperidin impurity (diosmin + hesperidin and MPFF). Impurities may lead to decreased clinical effects and increased side effects. As per Pharmacopeia, only diosmin is considered as main therapeutic drug/agent. Hesperidin is considered as impurity, whose amount should not exceed beyond 4% and overall impurity of not more than 8.5%. The 100% purified micronized diosmin preparation thus offers therapeutic advantage through better absorption and bioavailability. Several evidences are available on the efficacy and tolerability of diosmin in patients with hemorrhoids. In all, pharmacological management including 100% pure micronized diosmin appears to be the mainstay of conservative treatment strategy for patients with symptomatic hemorrhoids.

References

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