2742-2751-Tribenoside and Lidocaine in the Local Treatment Of

Home , Tribenoside

European Review for Medical and Pharmacological Sciences 2016; 20: 2742-2751 Tribenoside and lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence

Z. LORENC1, Ö. GÖKÇE2

1General, Colorectal and Trauma Surgery Silesian Medical University Katowice, Poland 2Department of Surgery, Yeditepe University, Istanbul, Turkey

Abstract. – OBJECTIVE: The combination of Key Words: tribenoside+lidocaine (Procto-Glyvenol®) is a Tribenoside, Lidocaine, Hemorrhoids. medical preparation for the local treatment of hemorrhoids, delivered as a suppository or rectal cream. This product has been used for decades in the therapy of hemorrhoids. This re- Introduction view discusses available evidence on the use of tribenoside/lidocaine in clinical practice. Hemorrhoid disease is one of the most common MATERIALS AND METHODS: Papers were re- proctological conditions in Western countries1. Its trieved by a PubMed search, using different com- prevalence is as high as 36% of the general pop- binations of pertinent keywords (e.g. tribeno- ulation, with a higher incidence in middle-aged side AND hemorrhoids), without any limitations 1,2 in terms of publication date and language. Docu- people of high socioeconomic status . It has been ments from Authors’ personal collection of liter- estimated that about 50% of the general popula- ature could also be considered. Papers were se- tion will experience symptomatic hemorrhoids lected for inclusion according to their relevance at some points in their life3. In addition, pregnant for the topic, as judged by the Authors. women are at high risk of developing hemorrhoid RESULTS: The efficacy of the combination of disease4,5. The prevalence of hemorrhoids in preg- tribenoside+lidocaine in relieving symptoms nant woman ranges from 25% to 35%, and up to caused by hemorrhoids and its safety have been assessed in several clinical studies on 85% of pregnant women experience hemorrhoids 6 patients of either gender, either versus its two in the third trimester . Other subjects at particu- individual components (tribenoside and lido- lar risk of developing hemorrhoids are elderly and caine) or versus steroids in the same setting. those with high body mass index7,8. Five studies compared the combination treat- For what concerns clinical presentation and ment with each of its single components, and symptoms, hemorrhoids can cause anal discharge of these, three studies compared tribenoside+ lidocaine with a tribenoside-free semi-place- and itching. Moreover, internal hemorrhoids may bo preparation containing only lidocaine, and cause objective symptoms such as prolapse or rec- two studies compared this combination with tal bleeding, while external hemorrhoids can re- lidocaine-free preparations containing only sult in subjective symptoms including pain, burn- tribenoside. Tribenoside+lidocaine was com- ing and itching due to engorgement and throm- pared with steroid-containing preparations in bosis9. six studies. Last, two studies evaluated the ef- The severity of hemorrhoids is classified into ficacy and tolerability of the tribenoside+lido- 10 caine combination in women with hemorrhoids four stages, according to Goligher . More ad- as a consequence of pregnancy or delivery. vanced stages of disease require surgical treat- All the above-mentioned studies were well- ment, while medical management and lifestyle conducted and can provide a comprehensive interventions are suitable for grade I/II hemor- evaluation of tribenoside+lidocaine in the treat- rhoids, which represent the wide majority (>90%) ment of hemorrhoids. of all reported cases1,8,9. CONCLUSIONS: Enough evidence exists to recommend the use of this combination therapy In particular, dietary and lifestyle changes, as a fast, effective and safe option for the local which require a high patient compliance, are usu- treatment of low-grade hemorrhoids. ally considered the first step for any conservative

2742 Corresponding Author: Özcan Gokçe, MD; e-mail: [email protected] Tribenoside+lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence strategy; however, evidence supporting these system. Tribenoside seems to share the positive interventions is anecdotal1. Fiber supplemen- pharmacological properties ascribed to gluco- tation can play a role as a supportive treatment corticoids and non-steroidal anti-inflammatory of hemorrhoids, in particular as stool softeners, agents, yet is free from the undesirable effects on when combined with other therapies11,12. Phyto- the gastro-intestinal system, the connective tis- therapy has been widely tested for the therapy of sue or the body’s defence system15. Remarkably, low-grade disease, but studies supporting these tribenoside exhibits anticoagulant and inhibito- interventions are of modest methodological qual- ry activity against inflammatory mediators such ity1. Medical treatment is mainly based on the use as histamine and prostaglandins, thus providing of topical preparations, containing anti-inflam- benefit to microcirculation, reducing capillary matory drugs including steroids, anesthetics, as- permeability and improving vascular tone14. An tringents, and/or antiseptics9. However, in most in vitro study, specifically aimed at investigating cases no randomized trials have been conducted the molecular bases of the efficacy of tribenoside to assess the efficacy and safety of different in- in the treatment of hemorrhoids, showed that the terventions which in some cases – e.g., steroids – expression of laminin α5, a major component of are associated with the potential onset of adverse the basement membrane disrupted in this disease, events1,9. was four times higher in the tribenoside-treated The combination of tribenoside+lidocaine cells than in controls14. Collectively, these findings (Procto-Glyvenol®, Recordati, Italy) is a medical suggest that tribenoside interacts with epidermal preparation for the local treatment of hemorrhoids, cells and regulates the expression and localization delivered as a suppository or rectal cream13. This of laminins, thus helping reconstruct basement product has been used for decades in the thera- membrane in wound healing of hemorrhoids. py of hemorrhoids, and its efficacy and safety are On the other hand, lidocaine is a widely-used supported by a number of well-conducted studies local anesthetic which relieves pain, burning and and broad clinical experience. itching caused by hemorrhoids1,16. This molecule This review discusses available evidence on the use is characterized by a fast (few minutes) onset of of tribenoside/lidocaine in patients with hemorrhoids. its surface anesthetic action, providing rapid relief from pain and itching16. Selection of Evidence Therefore, this combination therapy combines Papers for consideration for the present review the rapid local anesthetic action exerted by lido- were retrieved by a PubMed search, using dif- caine with the efficacy of tribenoside in promot- ferent combinations of pertinent keywords (e.g. ing local healing and favoring the recovery of tribenoside AND hemorrhoids), without any lim- local vessels to normal conditions. This double itations in terms of publication date and language. mechanism of action allows to control both sub- Documents from Authors’ personal collection of jective (e.g., pain and discomfort) and objective literature could also be considered. Papers were (e.g., prolapse and bleeding) symptoms of hem- selected for inclusion according to their relevance orrhoids reducing inflammation and improving for the topic, as judged by the Authors. vascular tone.

Clinical Pharmacology Overview of Clinical Evidence Tribenoside is a saccharide derivative which has The efficacy of the combination of tribeno- been extensively used for the treatment of hemor- side+lidocaine in relieving symptoms caused by rhoids14. Several studies have shown that tribeno- hemorrhoids and its safety have been assessed in side possesses a unique spectrum of pharmaco- several clinical studies on patients of either gen- logical activities, and in particular anti-inflam- der, either versus its two individual components matory, mild analgesic, antitoxic, wound-healing, (tribenoside and lidocaine) or versus steroids in fibrinolysis-promoting, anti-arthritic, amine-re- the same setting17-27. lease-inhibitory, membrane-stabilizing and veno- Table I provides an overview of those studies. tropic properties have been reported15. Notewor- Of note, 5 studies compared the combination treat- thy, unlike corticosteroids or nonsteroidal anti-in- ment with each of its single components. Of these, flammatory agents, tribenoside does not present 3 studies compared tribenoside+lidocaine with a untoward effects on the gastrointestinal system, tribenoside-free semi-placebo preparation contain- the connective tissue or the immune system, ing only lidocaine17-19, and 2 studies compared this and does not affect the prostaglandin-synthetase combination with lidocaine-free preparations con-

2743 Z. Lorenc, Ö. Gökçe <0.01). p Continued =0.01). p <0.01). p =0.01). =0.01). p <0.001) p Clinical efficacy rated “good”as in patients13 on tribenoside + lidocaine, compared with 4 patients on lidocaine only ( Treatment was judged as “ineffective” in no patients on TL, vs. 4 subjects in the other group ( Both formulations TL of resulted in mins) 30 a rapid symptom (about TL was significantly preferredover ( steroids TL was significantly superiorover lidocaine in providing rapid relief on both subjective and objective symptoms ( Clinical efficacy was rated as “very good local and systemic tolerability” patientsin 15 on TL and 3 subjects on lidocaine ( TL had very good local and ystemic tolerability TL significantly improved both subjective and objective symptoms, while lidocaine resulted in an improvement subjective of symptoms only. Significantly moreeffective improvement subjective of symptoms with TL compared with Excellent tolerability.

• • • improvement • • • • • • steroid. • Main outcomes - -

Treatment All applied days: up to 10 I. Tribenoside + lidocaine 5% cream 2% vs. lidocaine 2% II. Tribenosidelidocaine + 5% cream2% III. Tribenoside 400 mg + lidocaine 40 mg suppositories Tribenoside 400IV. mg + lidocaine 40 mg suppositories vs. hydrocortisone or triamcinolone prednifluocortolone or or solone Tribenoside and 5% lidocaine cream 2% versus semi-placebo creamcontaining li docaine days up for to 2% 10 I. Tribenoside 400 mg + lidocaine 40 mg suppositories vs. lidocaine 40 mg only days upfor to 10 II. Tribenoside 400 mg + lidocaine 40 mg suppositories vs. hydrocortisone up 1% days to 10 28 60 44 45 Total numberTotal of patients 177 I. II. III. I V. 48 women 67 suffering from hemorrhoids as a consequence of pregnancy or delivery -

Double blind study comparing TL cream with semi-placebo cream with lidocaine only Open label analysis on TL cream only Open-label analysis on TL TL vs. steroid-containing Randomized, double-blind study TL of suppositories vs. lidocaine only study TL of suppositories vs. Randomized, double-blind

Design I. II. III. suppositories IV. preparations Randomized, double-blind study lidocainevs. Analysis two of different stud ies: I. II. hydrocortisone 18

17 Overview of the identified studies on the combination of tribenoside + lidocaine (TL). Overview of the identified studies on combination tribenoside Study Rizzi et al Analysis 4 different of studies: Fontana et al Table I.

2744 Tribenoside+lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence Continued Similar efficacyof four the TL of Use recommended thanks to its favorable safety profile itsand rapid and effective action. Similar efficacyof the different adverseNo events reported with TL A trend to an advantage in terms of nodules improvement was observed TL.for bothFor groups, treatment effect was rated as “Good” the by majority of patients and physicians. Faster onset action of with TL. Good tolerability TL. of Similar efficacyof the two Adverse events associated with steroids potentially with avoided TL. Main outcomes • preparations • • preparations. • • • • • • preparations. • - - - - - Treatment TL (cream or suppository) vs. prednisolone alone, side tribeno trimethylace tate + 0.1% vioform 5% or fluocinolone + bismuth gallateacetonide + 5% 0.01% lidocaine 2% TL cream, tribenoside 5% cream, pred + vioform 5% nisolone pivalate 0.1% 0.01% acetonide fluocinolone and cream, + lidocaine cream. 2% All treatments were administered days up for to 10 Tribenoside 400 mg + lidocaine 40 mg prednisolone supposito suppositories vs. daysries up for to 14 Tribenoside + lidocaine suppositories mg) or cream mg bid) (400/40 (5%/2% versushydrocortisone-containing prepa ration, either as cream or suppositories Total numberTotal of patients 462 40 289 52 Design Randomized, double-blind study Single-blind study Double-blind study Randomized, double-blind study 21 20 22 23 Overview of the identified studies on the combination of tribenoside + lidocaine (TL). Overview of the identified studies on combination tribenoside Study Marques et al Angriman et al Berson et al Holzer Table I.

2745 Z. Lorenc, Ö. Gökçe

taining only tribenoside20,21. Tribenoside+lidocaine was compared with steroid-containing preparations in 6 studies17,19-23. Last, two studies evaluated the efficacy and tolerability of the tribenoside+lidocaine combination in women with hemorrhoids as a consequence of pregnancy or delivery19,24. All the above-mentioned studies were well- conducted and can provide a comprehensive evaluation of tribenoside+lidocaine in the treatment of hemorrhoids. However, they were often local studies, published in languages other than English and, therefore, clinicians and research- Main outcomes Efficacy rated as ‘Excellent’ in 15 Efficacy rated as ‘Excellent’ Fast relief from symptoms. No adverse events. “Excellent” as rated efficacy Treatment and “Good“ in 13 subjects, in 11 Excellent tolerability. Anal itching disappeared in 75%, smarting in 72% and pain 57% of cases. 50% rated efficacy as ‘Excellent’. No adverse events related to treatment.

• patients. • • • • • • ers may not be immediately familiar with their results. Thus, a short summary of the key as- - - - pects of each study is reported here.

Rizzi et al17 Rizzi et al have published, in a single paper, the results of different analyses on the combination of tribenoside+lidocaine: (i) a double-blind study comparing tribenoside 5% + lidocaine 2% cream (n=14) with a semi-placebo cream (excipients + lidocaine 2%; n=14); (ii) an open-label investigation on tribenoside+lidocaine cream only (n=60); (iii) an open-label investigation on tribenoside+-

Treatment lidocaine suppositories (n=44); (iv) a comparison

All patients received oral tribenoside 400 oral tribenoside received All patients for 10 days (post-par daily mg 2-6 times tum) or 20 days (pregnancy). twice suppositories TL with treatment Local daily was administered for 5 days in 19 wo men who compelled bothersome pain mg 40 lidocaine + mg 400 Tribenoside suppositories tid for 14 days Oral tribenoside (200 mg tid) and local bid, 2% cream 5% + lidocaine tribenoside for 14 days 40 suppo 400 mg + lidocaine Tribenoside sitories tid for 28 days of the study combination with steroids-containing preparations (hydrocortisone or triamcinolone or fluocortolone or prednisolone (n=45). All tribenoside+lidocaine preparations were applied twice daily for up to ten days. A global assessment of treatment efficacy (good, medium, ineffective) was performed. Clinical evaluation of each ob- Total numberTotal of patients 40 women with hemorrhoids as a consequence of pregnancy or delivery 30 30 30 jective (secretion, hemorrhage, nodules) and subjective (pain, burning, pruritus) symptoms was also carried out using a 4-point scale (0=absent, 1=mild, 2=moderate, 3=severe). Results from the double-blind investigation (i) showed that the overall clinical efficacy was rated as “good” in 13 patients on tribenoside+lidocaine, compared with 4 patients on lidocaine only (p<0.01); (Figure 1) treatment was judged Design Observational study Observational study Observational study Observational study as “ineffective” in no patients on the combination treatment, versus 4 subjects in the other group (p<0.01). Both formulations of tribenoside+lidocaine resulted in a rapid symptom improvemen, with effect on subjective symptoms being already evident before a maximum of 30 minutes since 25 27 administration. Notably, a statistically-significant superiority (p<0.001) was also observed when 26 24 evaluating the number of preferences in favor of Overview of the identified studies on the combination of tribenoside + lidocaine (TL). Overview of the identified studies on combination tribenoside tribenoside+lidocaine compared with those for steroid-containing preparations (Figure 2). Toler- Study Delarue Vargas-Lozano Da Silva Zurita-Briceno

Table I. ability, both general and local, proved very good.

2746 Tribenoside+lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence

Figure 1. Results from the double-blind investigation (i) showing the proportion of cases in which the therapeutic effect of the combination or lidocaine semi-placebo was rated as “good”, “moderate” or “ineffective”. Differences between the two preparations were statistically significant (p<0.01)17.

Fontana18 in 24 pairs of patients (34 males; mean age 49 A double-blind comparative study of tribeno- years) suffering from hemorrhoids. Both prepa- side 5% and lidocaine 2% cream versus semi-pla- rations were applied for up to 10 days. Overall, cebo cream containing lidocaine only, using a tribenoside+lidocaine cream was significantly su- scheme of sequential analysis, was performed perior over semi-placebo in providing rapid relief

Patients’ preferences among topical hemorrhoid preparations

Figure 2. Patients’ preferences for tribenoside+lidocaine preparations (suppository and cream) or other standard care steroid-containing preparations17.

2747 Z. Lorenc, Ö. Gökçe

Improvement of symptoms

Figure 3. Improvement of subjective and objective symptoms of hemorrhoids with tribenoside + lidocaine and hydrocortisone containing preparation, expressed as difference in the score reported after treatment and the score reported at baseline. p<0.001 for both preparations vs. baseline; p<0.01 for tribenoside+lidocaine vs hydrocortisone 1% in the effect on subjective symptoms19. on both subjective (pain, itching, sense of weight baseline: 4.62; mean score after treatment: 0.24; and tenesmus) and objective (inflammation, hem- p<0.01) and objective (2.86 vs. 0.91; p<0.01) symp- orrhage, secretion) symptoms of hemorrhoids toms of hemorrhoids, likely because the presence (p=0.01 vs. placebo). Local and general tolera- of both lidocaine – with a fast action on subjective bility were excellent, no adverse reactions were symptoms – and tribenoside – able to ameliorate observed in any of the 48 treated patients. Clinical objective symptoms and improve vascular tone. efficacy was rated as “Very good” in 15 patients On the other hand, patients on lidocaine only ex- assigned to the study combination and 3 subjects perienced a relief of subjective symptoms (5.75 on lidocaine only (p=0.01). vs. 3.25; p<0.01), but no effect on objective symptoms was reported (3.30 vs. 1.90). Moggian19 The comparison with hydrocortisone prepa- In another randomized, double-blind study, ration showed a significant effect on the subjec- tribenoside 400 mg + lidocaine 40 mg suppos- tive and objective symptomatology (p<0.001). itories (n=21), administered for up to 10 days’ Notably, a significant difference in favor of treatment, were compared with a semi-placebo tribenoside+lidocaine over steroid-containing (excipient + lidocaine 40 mg only; n=20); in a par- preparations was observed in the improvement allel double-blind evaluation, tribenoside+lido- of subjective symptoms (tribenoside+lidocaine: caine suppositories (n=13); all preparations were -4.23 vs. baseline; steroids: -2.53 vs. baseline; compared with hydrocortisone 1% suppositories p<0.01) (Figure 3). The tolerability of tribeno- (n=13) all preparations in the study were admin- side+lidocaine was judged as excellent. istered b.i.d.. All patients were women (mean age, 33 years) suffering from hemorrhoids as a conse- Marques et al20 quence of pregnancy or delivery. Both objective This was a controlled, double-blind, multi- (secretion, hemorrhage, nodules) and subjective center investigation in which tribenoside+li- (pain, burning, itching) symptoms were assessed docaine, either as cream or suppositories, was according to a 4-point scale for each symptom (0= compared with tribenoside alone, prednisolone absent, 1=mild; 2=moderate; 3=severe).. trimethylacetate 0.1% + vioform 5% or fluocino- Tribenoside+lidocaine suppositories signifi- lone acetonide 0.01% + bismuth gallate 5% + lido- cantly improved both subjective (mean score at caine 2% (all comparators were administered in

2748 Tribenoside+lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence either cream or suppository formulation). In total, ferences were observed between the study com- 462 patients of either gender were evaluated. bination and hydrocortisone treatment; howev- The results demonstrated the similar effica- er, the Author of this study stated that adverse cy of the four preparations, as assessed using a events associated with corticoid-treatments 4-point scale. In particular, the Authors of this could be avoided using tribenoside+lidocaine study recommended the use of tribenoside+lido- preparations. caine, thanks to its favorable safety profile and its rapid and effective action. Delarue24 40 women with hemorrhoids as a conse- Angriman and Neumayer21 quence of pregnancy (n=33) or delivery (n=7) Angriman and Neumayer conducted a sin- were treated with oral tribenoside 400 mg gle-blind investigation on tribenoside+lidocaine 2-6 times daily for 10 days (post-partum) or cream (n=8), tribenoside 5% cream (n=8), pred- 20 days (pregnancy). Local treatment with nisolone pivalate 0.1% + vioform 5% cream (n=8), tribenoside+lidocaine suppositories twice daily and fluocinolone acetonide 0.01% + lidocaine 2% was administered for 5 days in 19 women who cream (n=16). All treatments were administered compelled bothersome pain. Efficacy was rated for up to 10 days. Overall, tribenoside+lidocaine as “Excellent” in 15 patients, “Good” in 18 and cream showed an efficacy comparable with that “Minimal” in 7 subjects, with positive results of controls – as expressed in terms of subjective in 82.5% of cases, and a fast onset of symptom and objective symptoms improvement – and an relief was reported, from 10 minutes since ad- excellent tolerability, since it did not share the ministration up to 10-12 hours. Tolerability was side-effects reported with steroid-containing excellent in all patients: no systemic or local preparations. adverse effects were observed.

Berson et al22 Vargas Lozano25 In this double-blind investigation, tribenoside In this study, 30 patients (14 men, mean age: 400 mg + lidocaine 40 mg suppositories (n=147) 37 years) were treated with tribenoside+lidocaine were compared with prednisolone-containing suppositories tid for 2 weeks. Treatment efficacy suppositories (n=142). Patients (mean age: 43 was rated as “Excellent” in 11 and “Good“ in 13 years) were treated once daily for a maximum of subjects, with 80% of patients, therefore, show- 14 days. Symptoms improvement and global as- ing favorable results. In particular, most evident sessment of treatment effect were evaluated. symptom improvements were observed for pain, The excellent anti-phlogistic effect of the bleeding, burning and pruritus. Tolerability was tribenoside+lidocaine combination was con- excellent in all cases. firmed also in this study. The frequency of improvement of each symptom of hemorrhoids was Da Silva26 similar in the two groups; however, a trend to an 30 patients with hemorrhoids received com- advantage in terms of nodules improvement was bined treatment with oral tribenoside (200 mg observed for tribenoside+lidocaine, compared tid) and local tribenoside+lidocaine cream bid, with prednisolone (patients improved: 10/14, for two weeks. 71.4% vs. 7/21, 33.3%). The onset of action with The treatment was “excellent” in the reduction tribenoside+lidocaine was also faster. The major- of bleeding in 93% of cases. Anal itching dis- ity of both physicians and patients rated the effi- appeared in 75%, smarting in 72% and pain in cacy of the tribenoside +lidocaine combination as 56% of cases, while considerable improvement in “good” (59.7% and 62.5%, respectively). those symptoms occurred in 8%, 22% and 30%, respectively. Holzer23 In this randomized, double-blind study, Zurita-Briceno27 tribenoside+lidocaine suppositories (400/40 mg In this single-arm study, 30 patients (5 men, bid) or cream (5%/2% mg) was compared with mean age: 46 years) were treated with tribeno- an hydrocortisone-containing preparation, ei- side+lidocaine suppositories tid for 4 weeks. ther in cream or suppository form. 53 patients Efficacy was judged as “Excellent” in 15 (50%), (27 males) were treated for 21 days. In line with “Good” in 10 (33%), “Moderate” in 4 (13%) and the above-mentioned studies, no statistical dif- “Insufficient” in 1 (3.3%) patients. Only few ad-

2749 Z. Lorenc, Ö. Gökçe verse events were reported, and all of them were fectively used for up to 20 days without being considered poorly related to treatment. associated with any relevant adverse event and showing an excellent tolerability. With respect Implications for Clinical Practice to other preparations used in clinical practice, Hemorrhoids are a widespread condition asso- the tribenoside+lidocaine combination shows a ciated with a number of bothersome symptoms, long-lasting effect, likely due to the presence either of subjective (e.g. pain, burning and itch- of the anti-inflammatory tribenoside. This long ing) or objective (e.g. bleeding, swelling and nod- lasting-effect allows a twice daily administra- ules) nature. tion until acute symptoms diminish, after which At present, available medical treatments the dosage can be reduced to once a day13. The for low-grade hemorrhoids are supported by observed efficacy with this limited number poor-quality evidence, and the pharmacological of administrations/day is dependent upon the rationale behind at least some treatment is ques- long-lasting pharmacological effect of the com- tionable1. The standard treatment is represented by bination. In all available study, the combination steroids; however, these molecules are burdened of tribenoside+lidocaine was characterized by with a not-completely favorable toxicity profile an excellent tolerability, with only negligible also because of the risk of systemic adsorption, adverse events being reported. which may limit their application over the mid- The combination of tribenoside+lidocaine was dle-term period or in some particular populations at least equally effective as the gold standard of patients such as pregnant/breastfeeding wom- treatment for hemorrhoids, i.e. steroid-based en (a population at high risk of developing hem- preparations, and sometimes superior in pro- orrhoids), elderly, patients with some infections viding a prompt relief of the bothersome symp- (e.g. mycoses, HSV, local viral infections, TBC) toms such as pain and itching. Since the use of or athletes. steroids is not recommended for prolonged pe- The combination of tribenoside+lidocaine is a riods due to the possible steroid-related side-ef- single formulation (cream or suppositories) con- fects, tribenoside+lidocaine can represent. A taining two different molecules characterized by fast, effective and safe option to treat hemor- complementary actions. Tribenoside has the po- rhoids. Noteworthy, this combination can be tential to ameliorate microcirculation, promote particularly suitable for some populations of the healing of basement membrane and improve patients at high risk of hemorrhoids in whom local microcirculation and vascular tone, thus im- steroids could be contraindicated. In particu- proving the objective symptoms of hemorrhoids. lar, tribenoside+lidocaine can be safely admin- On the other hand, lidocaine is a widely-used local istered in pregnant women after the first tri- anesthetic, able to induce a rapid relief of subjec- mester of pregnancy (although no randomized tive symptoms such as local pain and discomfort studies have been conducted in this specific which may be perceived as the most bothersome population) and during breastfeeding. Also, the by patients. combination of tribenoside+lidocaine can be Given its rapid comprehensive efficacy on suitable for athletes or patients carrying some all different symptoms of hemorrhoids, the types of infections, in whom steroids cannot be tribenoside+lidocaine combination can find administered. a place in the treatment of this condition. Im- Of note, the efficacy and safety of tribeno- portantly, its efficacy and safety have been for- side+lidocaine were consistent regardless of the mally evaluated in a number of well-conducted specific formulation and dosing regimen, and studies, mostly of which included a comparator were also observed in women with hemorrhoids arm using a reference treatment for the thera- due to recent delivery or pregnancy. It is worth py of hemorroids. Overall, the combination of notice that the dosage of the combination was tribenoside and lidocaine was superior over the optimized for the specific formulations (cream single components in symptoms improvement, or suppository) during the development phase of likely thanks to its ability to ameliorate both the product. subjective and objective symptoms at the same It must be acknowledged that all the studies time. The effects on subjective symptoms were evaluating tribenoside+lidocaine were conducted rapidly (10-30 minutes) observed after the ad- in the ’70s of the last century. However, the de- ministration of the combination. Moreover, in sign of these trials was robust, and the total num- the reported studies, the treatment has been ef- ber of evaluated patients exceed 1,000.

2750 Tribenoside+lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence

Conclusions treatment of hemorrhoids complications: a sys- tematic review and meta-analysis. Am J Gastro- We believe that enough evidence exists to rec- enterol 2006; 101: 181-188. ommend the use of this combination therapy as a 12) Moesgaard F, Nielsen ML, Hansen JB, Knudsen JT. fast, effective and safe option for the local treat- High fiber diet reduces bleeding and pain in patients with hemorroids: a double blind trial of ment of low-grade hemorrhoids. Vi-Siblin. Dis Colon Rectum 1982; 25: 454-456. 13) Procto-Glyvenol SPC. 14) Kikkawa Y, Takaki S, Matsuda Y, Okabe K, Taniguchi M, Acknowledgement Oomachi K, Samejima T, Katagiri F, Hozumi K, Nomizu Editorial assistance for the preparation of this manu- M. The influence of Tribenoside on expression script was provided by Luca Giacomelli, PhD, on be- and deposition of epidermal laminins in HaCaT half of Content Ed Net; this assistance was funded by cells. Biol Pharm Bull 2010; 33: 307-310. Recordati. 15) Jaques R. The pharmacological activity of tribenoside. Pharmacology 1977; 15: 445-460. 16) Barkin RL. The pharmacology of topical analge- Conflicts of interest sics. Postgrad Med 2013; 125(4 Suppl 1): 7-18. The authors declare no conflicts of interest. 17) Rizzi B, Giacomini F, Bandini V. Terapia locale della sindrome emorroidaria con etil-3,5,6-tri-o-ben- zil-d-glicofuranoside: risultati clinici. Gazz Int Med References Chirur 1972; 77: 1598-1606. 18) Fontana G. Trattamento della sindrome emorroidaria con un derivato glicofuranosidico in cre- Altomare DF, Giannini I. 1) Pharmacological treat- ma associato ad un anestetico. Gazz Med Ital ment of hemorrhoids: a narrative review. Expert 1973; 132: 32-35. Opin Pharmacother 2013; 14: 2343-2349. 19) Moggian G. Sperimentazione clinica controllata di Johanson JF, Sonnenberg A 2) . The prevalence of un derivato glicofuranosidico anti-emorroidario, hemorrhoids and chronic constipation. An epide- per uso locale. Minerva Med 1973; 64: 215-218. miologic study. Gastroenterology 1990; 98: 380- 20) Marques JR, Da Silva JH, Galizia I, Kerzner A, Net- 386. to GM, Moreira GO, Da Cruz GMG, Zerbini JC, Ganz RA. 3) The evaluation and treatment of hem- D’Araujo MA, Simonsen OS, Jatopa PP, De Souza CE.. orrhoids: a guide for the gastroenterologist. Clin Ensaio controlado com Procto-Glyvenol no trat- Gastroenterol Hepatol 2013; 11: 593-603. amento das hemorroides. Rev Bras De Cirurgia 4) Abramowitz L, Sobhani I, Benifla JL, Vuagnat A, Daraï 1972; 62: 7-8. E, Mignon M, Madelenat P. Anal fissure and throm- 21) Angriman J, Neumayer F. Tratamiento de las hem- bosed external hemorrhoids before and after de- orroides con glucofuranosido crema. Orientación livery. Dis Colon Rectum 2002; 45: 650-655. Médica 1972; 31: 353-354. Quijano CE, Abalos E. 5) Conservative management 22) Berson I, Geiser JD. Utilisation d’un nouveau pro- of symptomatic and/or complicated haemorrhoids duit: le procto-glyvenol en pratique proctologique. in pregnancy and the puerperium. Cochrane Da- Revue Suisse de Médecine (Praxis) 1975; 63: 19- tabase Syst Rev 2005: CD004077. 22. Staroselsky A, Nava-Ocampo AA, Vohra S, Koren G. 6) 23) Holzer A. Betrachtungen über ano-rektale Hemorrhoids in pregnancy. Can Fam Physician leidenszustände und ihre behandlung. Der Prak- 2008; 54: 189-190. tische Arzt 1976; 30: 662-672. Lohsiriwat V. 7) Treatment of hemorrhoids: A colo- 24) Delarue T. Traitement de la maladie hemorroidaire proctologist’s view. World J Gastroenterol 2015; pendant la grossesse et le post partum par le gly- 21: 9245-9252. venol. Arch Med Ouest 1977; 9: 637-641. Riss S, Weiser FA, Schwameis K, Riss T, Mittlböck M, 8) 25) Vargas Lozano R. Tratamiento sintomatico en hem- Steiner G, Stift A. The prevalence of hemorrhoids orroides con glucofuranosidos topicos. Medicina in adults. Int J Colorectal Dis 2012; 27: 215-220. (Rev. Mex.) 1972; 52: 575-578. Mounsey AL, Halladay J, Sadiq TS. 9) Hemorrhoids. 26) Da Silva A. Doença hemorroidaria – tratamento Am Fam Physician 2011; 84: 204-210. clinico com o tribenosido. Folha Méd 1976; 73: 10) Goligher JC. Surgery of the anus, rectum and co- 531-536. lon. Balliere Tindal, London, 1980; pp. 93-135. 27) Zurita-Briceno L. Tratamiento topico de hemorroi- 11) Alonso-Coello P, Mills E, Heels-Ansdell D, López-Yar- des con glucofuranosido. Medicina (Rev. Mex.) to M, Zhou Q, Johanson JF, Guyatt G. Fiber for the 1972; 52: 229-232.

2751