Management of Hemorrhoidal Disease: New Generation of Oral and Topical Treatments

Home , Calcium dobesilate

European Review for Medical and Pharmacological Sciences 2020; 24: 9645-9649 Management of hemorrhoidal disease: new generation of oral and topical treatments

C. RATTO1, R. OREFICE1, D. TISO2, G.B. MARTINISI3, R. PIETROLETTI3

1Proctology Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy 2Servizio di Nutrizione, Ospedale Accreditato “Villa Maria”, Rimini, Italy 3Surgical Coloproctology, University of L’Aquila, Hospital Val Vibrata, L’Aquila, Italy

Abstract. – Hemorrhoidal disease is a wide- th spread proctologic clinical entity. Even if surgi- In the 8 National Congress of the Italian Asso- cal excision is an effective treatment, it only rep- ciation of Colorectal Surgery (SICCR), which was resents the standard procedure for patients with held in Biella (Italy) on 12 November 2019, Ital- high-grade hemorrhoids. Considering that most ian experts met to discuss the clinical evidence cases are grade I or II hemorrhoids, oral or topi- of hemorrhoidal disease during a symposium on cal therapies are widely used despite, currently, practical aspects about the management of this there are no satisfactory options for these kinds common disease, focusing on recent improve- of treatments. The pathology involves the de- generation of the supporting tissue of the anal ments in oral and topical treatment options. cushions, causing venous dilation, blood stag- nation, formation of edematous venous plexus Hemorrhoidal Disease covered by mucosa and inflammation. An effec- Hemorrhoids are normal structures of the hu- tive treatment must, therefore, be multi-target- man body, distinguished internally and externally ed and capable of acting on all the pathological by an anatomical boundary called dentate line3. mechanisms simultaneously. During the 8th Na- tional Congress of the Italian Association of Col- The normal internal hemorrhoidal plexus consists orectal Surgery (SICCR), some clinical evidence of three so-called vascular cushions, or piles, lo- of hemorrhoidal disease has been discussed cated at the left lateral (3 O’clock), right anterior along with new opportunities in oral and topical (11 O’clock) and right posterior (7 O’clock) sec- treatment options. tors of the anus4, and at least three others else- Among these, the effectiveness and the safe- where (at 1, 5 and 9 O’clock)5, whose positions ty of two innovative products, a sublingual na- correspond to the location of the main terminal noemulsion and a liquid bandage, has been reported. arterial branches in the submucosa. They are con- stituted by large arteriovenous shunt, supported Key Words: by elastic tissue. Hemorrhoidal disease, Oral treatments, Topical Hemorrhoidal disease is the result of an abnor- treatments, Liquid bandage. mal enlargement of anal cushions due to different etiologic factors. Although genetic factors con- tribute to developing hemorrhoids, other predis- Introduction posing factors have been claimed. They include obesity, prolonged straining and prolonged stand- Hemorrhoidal disease is a very common proc- ing position. Many dietary factors, including tologic clinical entity, especially in patients who a low-fiber diet, spicy foods and alcohol intake, are >50 years. Even if it is difficult to establish its have been implicated, but reported data are in- real impact since only a minority of the patients consistent6. consults a doctor, it is estimated that hemorrhoidal Approximately four out of ten patients with disease affects nearly 4% of the world’s population, hemorrhoids are symptomatic7. Bleeding is the causing considerable discomfort and worsening the most common symptom and is usually the first patient’s quality of life1. In Italy, the prevalence of complaint of the patient, followed by local swell- hemorrhoidal disease is approximately 1,000,000 ing and anal prolapse. Mucous discharge and con- new cases per year (2% of Italy’s population)2. sequent soiling and itching are both markers of

Corresponding Author: Domenico Tiso, MD; e-mail: [email protected] 9645 C. Ratto, R. Orefice, D. Tiso, G. B. Martinisi, R. Pietroletti advanced disease. A feeling of incomplete evac- Management of Hemorrhoidal uation or rectal fullness is also reported8. Pain is Disease: Improvement of Oral and not a typical symptom, unless in the case of com- Topical Treatments plications, such as edema, thrombosis, ischemia Even if surgical excision is an effective treat- and strangulation. ment, it only represents the standard procedure The diagnosis of hemorrhoids relies mainly for high-grade hemorrhoids. on a thorough history and physical examination The main therapeutic options for low-grade of the patient, obtained by perineal inspection, hemorrhoids can be divided into office-based pro- a digital rectal examination, followed by anos- cedures and medical treatment. copy9. However, colonoscopy is mandatory to Office-based procedures are rubber band liga- rule out colon neoplasia particularly in high-risk tion, injection sclerotherapy, infrared/radiofre- patients10. Differential diagnosis with other anal quency coagulation and cryotherapy19,20. diseases includes anal fissure, abscess, carcino- Medical treatments comprise modern drugs ma, and pudendal neuropathy, particularly in and traditional medicine, available in a variety of the presence of anal pain, which is commonly formulations, including pill, suppository, cream, reported in the mentioned conditions and infre- and wipes. Flavonoids, in a purified preparation quent in hemorrhoidal disease, apart from com- or as part of the derivative of the Ginkgo tree, are plicated ones. widely used for relief of acute symptoms. They The severity of hemorrhoidal disease is graded are able to increase vascular tone, reduce venous into four stages according to Goligher’s classifica- capacity, decrease capillary permeability, and tion, based on the degree of prolapse through the facilitate lymphatic drainage, as well as having anus and its tendency to reduce spontaneously or anti-inflammatory effects21. Calcium dobesilate, manually11. The vast majority of patients (>90%) nitrates and nifedipine are also effective and well present grade I or II, where medical management tolerated as treatment of hemorrhoids. and lifestyle interventions, such as increasing fi- Characteristics of principal hemorrhoids treat- ber and fluid intake, avoiding prolonged standing ment options are summarized in Table I. position and physical activity, are successfully Oral and topical administrations are the most employed12 and can help to prevent hemorrhoidal used for the treatment of low-grade hemorrhoids12 disease. but unfortunately, these kinds of treatment ad- In case of unresponsive disease, ambulatory ministrations present criticism. treatments are available and report up to 90% of Some physiological mechanisms can reduce in- success. Rubber banding13 and, more recently, testinal absorption of the active ingredients of the sclerosing injections14 have shown to be very ef- drugs taken orally. Specifically, the absorption by fective. However, surgical treatment can be effec- the mucous secretions and the cytochrome CY- tive in case of more advanced disease13,15. P3A and P450 activity, or the extrusive activity of SICCR has recently been published a consensus the P glycoprotein, can make the active ingredient statement, with the aim to provide evidence-based unavailable. The peptide nature of the compounds data, allowing a personalized and appropriate can cause their gastric hydrolysis. Finally, a re- management of hemorrhoid treatment16. In addi- duced inflow through enteric tight junctions or tion, it informs patients about the possibility for their biotransformation by the saprophytic flora the management of their condition16. are concurrent factors causing a reduced intesti- A particular condition is represented by the nal absorption of the active ingredients22. occurrence of hemorrhoidal disease during preg- Consequently, only a small percentage of active nancy, where its etiology has been related to spe- compounds is actually absorbed, requiring high cific factors, such as hormones, increased circu- doses of treatment to reach the therapeutic level. lating blood volume, increased pelvic pressure, Considering that a reduction of particle size and pelvic vascular engorgement17. Although has a great impact on the extent of absorption, these factors are different from those reported in as observed with the flavonoid diosmin, which the general population, treatment of hemorrhoidal demonstrated to have a better clinical efficacy disease in pregnancy continues to rely upon ge- with a micronized formulation23,24, a sublingual neric and empiric suggestions, such as increased nanoemulsion formulation has been patented and fiber and fluid intake18. This area warrants further proposed for the administration of different active investigation in order to identify a targeted etio- ingredients, to counteract the main symptoms of logic treatment. hemorrhoids.

9646 Management of hemorrhoidal disease: new generation of oral and topical treatments

Table I. Hemorrhoids therapeutic options. Therapeutic effect/advantages Adverse events/limitations

Office-based procedures Rubber band ligation Cut-off of the blood flow to the hemorrhoid. Pain, bleeding. Contraindicated in Safe, lowest incidence of recurrent patient with anticoagulants or bleeding symptom and need for retreatment27 disorder, and those with concurrent anorectal sepsis27 Injection sclerotherapy Scarring and subsequent fixation of mucosa Low occurrence of pain and bleeding28 to the submucosa Photocoagulation Necrotization of the tissue. Associated with High failure rate27 less pain because there is no mucopexy during the procedure Cryotherapy Creation of submucosal fibrosis to correct Postoperative swelling and lower prolapse and bleeding digestive tract hemorrhage29 Medical treatments Flavonoids Beneficial effects on bleeding, pruritus, Autonomic and mild gastrointestinal discharge and overall symptom improvement symptoms30 Calcium dobesilate Vascular protection and veno-tonic action Fever, arthralgias and gastrointestinal effects31 Nitrates Inhibitory neurotransmitter in the internal Can cause headaches32 sphincterchemical. Can provide sphincterotomy without the risk of permanent incontinence Nifedipine Effective for pain relief No commercially available preparation33

Emortrofine® Oro1* (Boswellia dry extract, di- In a recent observational study, Emortrofine® osmin, hesperidin, lysine, cysteine, ruscus dry ex- Oro demonstrated to be safe and effective as tract, vitamin E, copper and arginine) represents pre-operative treatment in a group of advanced the first sublingual nanoemulsion, which allows hemorrhoid patients. The study demonstrates a a multiple target activity and the maximum bio- significant efficacy in mitigating reported symp- availability of its components in a short time. toms (bleeding, prolapse, itching, pain) and on Moreover, the nanoemulsion in contact with local inflammation signs (dystrophy de-epithe- saliva creates micellar systems, which encapsu- lization, edema), allowing the patient to deal with late the lipophilic components and make possi- surgery in better conditions (Orefice et al, data ble the quick and complete absorption of the ac- not shown). tive ingredients at a sublingual level. Compared Topical treatments may be effective in selected to the traditional tablet administration, this kind groups of hemorrhoidal patients, in particular in of formulation allows a lower dosage of its com- patients with high resting anal canal pressures. ponents because it guarantees a more effective The primary objective of most topical treatment sublingual absorption. This aspect is particular- aims to control the symptoms rather than to cure ly important with regard to the flavonoid compo- it. These topical medications can contain various nent, for which it is necessary to check the daily ingredients, such as local anesthesia, corticoste- dosage. roids, antibiotics and anti-inflammatory drugs25. Emortrofine® Oro also favors a better treat- Main concerns of topical treatments regard ment compliance, because it involves the admin- their prolonged application (>15 days) that can in- istration of three daily doses (reduced to one, af- duce sensitization reactions, immunosuppression ter 6 days of treatment) instead of multiple daily and vessel reactivity (due to cortisone)26, irritation tablets. and habituation (due to lidocaine). An improvement of this kind of treatment is represented by Emortrofine® Gel*, a patented hy- pertonic, viscous and osmotically active solution based on Vitis vinifera, cranberry, omega-3 and ® *The use of commercial name of the product is for descrip- peppermint essential oil. Emortrofine gel is the tive purposes only and does not imply endorsement. first transparent liquid bandage with the charac-

9647 C. Ratto, R. Orefice, D. Tiso, G. B. Martinisi, R. Pietroletti teristics of the ideal topical treatment, as it stays Overall, thanks to their formulation and com- in situ for prolonged time, has film-forming and position, both treatments represent an improve- protective activities and a multi-target action ment of traditional oral and topical treatments (anti-inflammatory, moisturizing, soothing and used for hemorrhoidal disease. healing). In conclusion, even if further clinical studies The clinical effectiveness of Emortrofine® gel are needed to confirm to the clinical evidence col- has been tested in a multicenter, double-blind, lected so far, results suggest a therapeutic poten- randomized controlled clinical study in patients tial of this new generation of treatments, which with grade I-III hemorrhoidal disease. The results should be exploited for other similar topical pa- show that Emortrofine® gel application generates thologies. a robust outflow of the hypotonic liquid accu- mulated inside the hemorrhoidal lesions. Liquid exudation reduces the lesion volume and favors its regression, which, in turn, alleviates the pres- Conflict of Interest sure, reducing pain and improving stool passing. The Authors declare that they have no conflict of interests. Noteworthy, the benefits of treatment persist even 1 week after stopping treatment1. Some clinical experiences suggest that Emor- Funding trofine® gel can be used to replace treatments con- Editorial assistance was funding by Agave SRL, Italy. taining mesalazine, which favors the development of sensitization reactions, even if more evidence is needed to confirm this indication. Disclosure CR, GM, RP, RO have no conflicts of interest to declare. DT The use of this device could be suggested also is a consultant Agave SRL, Italy. for the hemorrhoidal disease related to pregnancy and post-partum. Considering the lack of guidelines for the treatment of this category of patients, Acknowledgements this represents an important novelty. Editorial assistance was provided by Simonetta Papa, Ph.D, and Aashni Shah (Polistudium SRL, Milan, Italy). This assistance was supported by Agave SRL, Italy. Conclusions

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