Evaluation of the efficacy and safety of an innovative flavonoid lotion in patients with haemorrhoid: a randomised clinical trial

Abstract

Objective

Haemorrhoids are one of the most common gastrointestinal and anal diseases. In olive oil and honey propolis, flavonoids have beneficial effects on improving vascular function and decreasing vascular resistance. In this study, we aimed to produce a combination of these two substances in the form of lotions and assess their healing and side effects in comparison with routine treatment, anti-haemorrhoid ointment (containing hydrocortisone and lidocaine).

Design

In this randomised clinical trial study, 86 patients with grade 2 or more haemorrhoid degrees, diagnosed by colonoscopy, were divided into two groups, the case (n=44) and control (n=42). The case group was treated with flavonoid lotion, and the control group was treated with anti-haemorrhoid ointment two times per day for 1 month. Patients were followed weekly with history and physical examination. The data of the two groups were collected before and after the intervention and statistically analysed.

Results

Post-treatment reduction in haemorrhoid grade was significant in the case group (p=0.02). This ratio was insignificant in the control group (p=0.139). Flavonoid lotion (p<0.05) significantly reduced the signs and symptoms of haemorrhoids more than anti-haemorrhoid ointment.

Conclusion

According to the results, flavonoid lotion can be an excellent alternative to topical chemical drugs, such as anti-haemorrhoid ointment, in treating haemorrhoid disease. Besides its effectiveness and safety, it can be easily manufactured and widely available to patien

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Haemorrhoids are one of the most prevalent gastrointestinal and anal diseases, cause signs including bleeding, prolapse and itching. The processes involved in haemorrhoids are inflammation and tissue destruction; nevertheless, the pathophysiology and aetiology of haemorrhoids are not entirely understood.

WHAT THIS STUDY ADDS

• This study presents a novel flavonoid lotion with natural ingredients as a nominee for haemorrhoids treatments, and furthermore, the efficacy of this product is evaluated in comparison to a commonly used ointment, in a clinical trial study.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Our findings suggested flavonoid lotion could effectively treat haemorrhoidal symptoms and heal complications. Flavonoid lotion also has more rapid efficacy in comparison with routine anti-haemorrhoid ointment. This flavonoid lotion could be introduced as an appropriate, available, inexpensive and compelling candidate for the treatment of haemorrhoids.

Introduction

Haemorrhoids are one of the most common gastrointestinal and anal diseases worldwide. Its overall prevalence is 4.4% of the general population, which is caused by venous insufficiency and abnormal swelling in the anal area due to excessive pressure on the lower part of the rectum. Constipation, obesity, fibre-free diet, sitting or standing for a long time, decreased muscle tone in old age, colon malignancies and surgical or traumatic complications are leading causes of haemorrhoids.¹

Flavonoids, with their flavan nucleus, own multiple effective properties such as anti-inflammatory and antioxidant functions, which make them multitarget drugs with a wide cluster of activities such as antiproliferative and anticancer activity, free radical scavenging capacity, coronary heart disease prevention, antihypertensive effects and anti-immunodeficiency viral functions.^{2 3} These properties are related to the inhibition of nuclear factor-κB-dependent proinflammatory cytokines, vascular endothelial growth factor, intercellular adhesion molecule 1, signal transducer and activator of transcription 3 and activation of antioxidant transcription factor nuclear factor erythroid 2-related factor 2. Flavonoids reduce the severity, frequency and duration of haemorrhoidal attacks compared with single-target drugs. They are effective for improving vascular function and reducing vascular bed resistance. They also reduce acute and recurrent haemorrhoid attacks as well as bleeding after haemorrhoidectomy surgery.^4–6 Olive oil and honey propolis have high contents of valuable and natural flavonoids.^7–11 Olive oil has various flavonoids, such as luteolin, apigenin rutinoside, apigenin, rutin and diosmetin.¹² Some studies confirmed the therapeutic effects of olive oil on haemorrhoids.¹³ Flavonoids are also found in honey propolis, including quercetin, myricetin, chrysin, apigenin, luteolin, pinocembrin and pinobanksin. Some recent studies have shown the efficiency of honey usage in the treatment of haemorrhoids.¹⁴

Considering the high price of synthetic flavonoid drugs and their unavailability to the public, we decided to introduce and study a medicine almost similar and even with a higher percentage of flavonoids by natural compounds and low complication in the form of lotions. Using natural flavonoids in olive oil and honey propolis, we prepared a lotion and evaluated its therapeutic and side effects compared with anti-haemorrhoid ointment (containing hydrocortisone and lidocaine), which is routinely used today as treatment.

Participants

This study was recorded as a national randomised clinical trial in the IRCT database with IRCT Id: IRCT20210325050769N2 and Trial Id: 57 224 (https://en.irct.ir/user/trial/57224/view).

In this study, 101 over 18 years patients (sample size was determined based on previous researches) with second-degree haemorrhoids or above, who had been referred to the colonoscopy ward of Baqiyatallah Hospital were included in the study. All patients had complaints about haemorrhoids and their complications (rectal bleeding, pain, tenesmus, anal discomfort, itching and anal discharge). The degree of haemorrhoids was determined during colonoscopy. According to the standard criteria, a gastroenterology professor performed colonoscopy, and the haemorrhoids were graded as follows: First-degree haemorrhoids, visible during anoscopy, may protrude into the lumen but not below the dentate line. Second-degree haemorrhoids: The anal cushions prolapse through the anus on straining but reduce spontaneously. Third-degree haemorrhoids: The anal cushions prolapse through the anus on straining or exertion and require manual replacement into the anal canal. Fourth-degree haemorrhoids: The prolapse stays out at all times and is irreducible. After obtaining consent through an informed consent form, patients with grade 2 or higher haemorrhoids were included in the study. Before entering the study, a 2-week wash-out period was considered ensuring the non-interference of other drugs effective in treating haemorrhoids. Patients with inflammatory bowel disease, pregnancy, lactation, history of haemorrhoid surgery and other anorectal disorders such as anal fissures, anorectal malignancies, heavy bleeding, general instability, haemorrhoid complications or exacerbation of symptoms (such as bleeding and pain), and occurrence of drugs side effects were excluded from the study.

A total of 101 participants were randomly allocated to either case or control groups. The randomisation sequence was computer generated and stratified by sex using blocks of 10. The randomisation list was kept in a locker accessible to the study secretary, but not any investigators. The allocations were kept in sealed, opaque, consecutively numbered envelopes. The study secretary opened the envelope and wrote the allocated intervention in the electronic patient record the day before the intervention. The study was open-labelled without blinding participants, physicians, hospital or research staff.

Eighty-six people completed a 1-month treatment follow-up period (three people died during the trial period (one in control group and two in case group), and five participants haemorrhoids condition got worse and discontinued the intervention (three in control group and two in case group)). The participants in the case group were 44 people treated with flavonoid lotion. The participants in the control group were 42 people treated with the anti-haemorrhoid ointment of the Iran Najo Company. All patients, history and examination results were recorded, and a questionnaire, approved by the relevant professors, was completed before and after the intervention. This questionnaire collected information through a checklist of the variables (online supplemental file S1). Each variable was given a score from 0 to 5, depending on the quality level described in the questionnaire (depending on each variable).

Study design

Each 100 mg of produced flavonoid lotion has 70% flavonoid content (1/2 honey propolis, 1/2 olive oil) and 30% excipient as the underlying solvent. Iran Najo anti-haemorrhoid ointment is available routinely in pharmacies, and each 100 g of it contains hydrocortisone acetate (0.275 g), lidocaine (5 g), aluminium subacetate (3.5 g) and zinc oxide (18 g). Patients in both groups used the medication dosage similarly (topical/rectal, two times per day, for 1 month).

In both groups, instructions were given to improve constipation and intestinal function, including modifying lifestyles such as a high-fibre diet, daily exercise and physical activity. Patients were followed up weekly for history and information collection.

The participants’ history was retaken at the end of the treatment period, and a physical and anorectal examination was performed (the physician performed the anorectal examination manually with the aid of an anoscope.) It is worth mentioning that in order to omit the possible variation of haemorrhoid grade determination, all the examinations (at the first and end of the trial), including the patient’s haemorrhoid grade determination, were done by a single superspecialist physician.

Evaluation data in both groups before and after the intervention were collected, and the data were analysed by SPSS V.26 software. For this purpose, analysis of variance, t-test, χ² and McNemar tests were used. The level of statistical significance was considered less than 0.05.

Results

At the beginning of the study, 101 patients were included, but 7 patients did not refer for follow-up and were excluded from the study (declined to participate the study), also 3 participants died and failed to follow-up the study; in addition, 8 patients discontinued the study and referred to surgery as their symptoms became serious (treatment failure patients or non-responders) (figure 1). These patients were excluded from the analysis as the secondary data couldnt be collected form them.

Figure 1.

Flow chart of the study population.

Of the 86 patients who completed a 1-month follow-up period, 63.9% were male (N=55) and 36.1% female (N=31). The age range of patients was 18–85 years old (56.25±14.60 and 56.9±15.20, respectively, in the case and control groups). There was no statistically significant difference between the two groups in terms of age, gender, mean body weight and body mass index prior to the start of the study (p>0.05). Basic information of patients in both groups is shown in table 1.

Table 1.

Demographic variable in case and control groups

Demographic variable		Case (n=44)	Control (n=42)	P value
Age (years)		56.25±14.60	56.9±15.20	0.839
BMI (kg/m2)		27.36±4.78	26.59±4.76	0.458
Education (n (%))	Unlettered	4 (9.1)	4 (9.1)	0.589
	Under diploma	11 (9.5)	12 (28.6)
	Diploma	15 (34.1)	7 (16.7)
	Licentiate	8 (18.2)	10 (23.8)
	Master	4 (9.1)	6 (14.3)
	Doctorate	2 (4.5)	3 (7.1)
Gender	male participant (n (%))	25 (45.5)	30 (54.9)	0.118
	female participant (n (%))	19 (43.2)	12 (28.6)

BMI, body mass index.

Evaluation of treatment intervention

According to the statistical analysis, the distribution of patients in terms of the degree of haemorrhoids at the beginning of the study was not significantly different between the case and control groups (p>0.05). Statistical analysis revealed a significant reduction in the degree of haemorrhoids after intervention in the case group (p=0.02). Whereas this ratio was not significant in the control group (p=0.139) (table 2, figures 2 and 3).

Table 2.

Comparison of haemorrhoid grades before and after treatment in case and control groups

Degree of haemorrhoids		Case (N=44)	Control (N=42)	Total
Before treatment	Grade 2	7 (15.9%)	9 (21.4 %)	16 (18.6 %)
	Grade 3	36 (81.8%)	31 (73.8 %)	67 (77.9 %)
	Grade 4	1 (2.3 %)	2 (4.8 %)	3 (3.5 %)
After treatment	Normal	16 (36.4 %)	8 (19 %)	24 (28 %)
	Grade 1	14 (31.8 %)	13 (31 %)	27 (31.4 %)
	Grade 2	8 (18.3 %)	13 (31 %)	21 (24.4 %)
	Grade 3	6 (13.6 %)	8 (19 %)	14 (16.2 %)
	Grade 4	0 (0 %)	0 (0 %)	0 (0 %)
P value		0.020	0.139
Total		44 (100%)	42 (100%)	86 (100%)

Figure 2.

Comparison of haemorrhoid grades before and after treatment in case and control groups. A) the haemorrhoid grades in both studied groups prior to intervention; B) the haemorrhoid grades in both studied groups post to intervention.

Figure 3.

Comparison of patients haemorrhoid grades before and after treatment in control (A) and case (B) groups.

The distribution of patients in terms of haemorrhoid symptoms (bleeding, pain, itching, anal discomfort, and incomplete defecation) at the beginning of the study was not significantly different between case and control groups (p>0.05) (table 3).

Table 3.

Comparison of symptoms and complications of treatment between case and control groups

Symptom	Admission			1 week			2 weeks			3 weeks			4 weeks
	Ctl	Cs	P value	Ctl	Cs	P value	Ctl	Cs	P value	Ctl	Cs	P value	Ctl	Cs	P value
Rectal bleeding	21	26	0.388	19	19	0.772	18	15	0.140	15	13	0.884	12	8	0.622
Incomplete defecation	31	26	0.505	27	24	0.915	25	15	0.007*	21	11	0.075	21	12	0.062
Anal pain	30	21	0.073	28	21	0.391	21	11	0.036*	16	10	0.255	15	6	0.025*
Anal irritation	22	23	0.946	20	18	0.816	13	10	0.411	9	6	0.635	6	5	0.732
Anal discharge	13	13	0.750	11	6	0.501	8	5	0.871	7	4	0.782	4	2	0.418
Anal discomfort	25	22	0.490	24	17	0.058	19	12	0.313	15	8	0.121	13	7	0.395
Complication
Diarrhoea	10	12	0.511	6	4	0.471	4	3	0.512	2	1	0.612	2	0	0.259
Nausea	9	10	0.990	2	3	0.990	0	1	0.512	0	1	0.512	0	0	1
Vomiting	5	4	0.540	0	2	0.209	0	1	0.512	0	1	0.512	0	0	1
Skin rash	12	9	0.230	5	3	0.189	2	2	1	2	0	0.230	1	0	0.512
Pruritus	13	14	0.784	7	5	0.960	2	4	0.616	1	1	1	1	0	0.512
Headache	19	21	0.847	4	11	0.087	1	3	0.242	0	3	0.480	0	0	1
Vertigo	15	18	0.943	4	7	0.492	1	2	0.612	0	1	0.512	0	0	1

Number of individuals in case (Cs) and control (Ctl) groups are 44 and 42, respectively (n_total=86).

*Significant differences between case and control groups.

Improvement in bleeding was significant after the intervention in both groups (p=0.000 and p=0.001, respectively). The feeling of incomplete defecation was significantly obtained after treatment compared with before treatment in both groups (p=0.000). However, in the second week of treatment, the effect of flavonoid lotion was significantly better than anti-haemorrhoid ointment (p=0.007) (tables 3 and 4).

Table 4.

Comparison of symptoms and complications of treatment within case and control groups

Symptom	Control group (n=42)					P value	Case group (n=44)					P value
	Admission	1 week	2 weeks	3 weeks	4 weeks		Admission	1 week	2 weeks	3 weeks	4 weeks
Rectal bleeding	21	19	18	15	12	0.000*	26	19	15	13	8	0.001*
Incomplete defecation	31	27	25	21	21	0.000*	26	24	15	11	12	0.000*
Anal pain	30	28	21	16	15	0.041*	21	21	11	10	6	0.000*
Anal irritation	22	20	13	9	6	0.005*	23	18	10	6	5	0.008*
Anal discharge	13	11	8	7	4	0.000*	13	6	5	4	2	0.220
Anal discomfort	25	24	19	15	13	0.000*	22	17	12	8	7	0.000*
Complication
Diarrhoea	10	6	4	2	2	0.011*	12	4	3	1	0	0.009*
Nausea	9	2	0	0	0	0.024*	10	3	1	1	0	0.029*
Vomiting	5	0	0	0	0	0.560	4	2	1	1	0	0.630
Skin rash	12	5	2	2	1	0.270	9	3	2	0	0	0.067
Pruritus	13	7	2	1	1	0.210	14	5	4	1	0	0.056
Headache	19	3	1	0	0	0.004*	21	11	3	3	0	0.006*
Vertigo	15	4	1	0	0	0.012*	18	7	2	1	0	0.016*

Number of individuals in case and control groups are 44 and 42, respectively (n_total=86).

*Significant differences between case and control groups.

Relief of anal pain after treatment compared with before treatment in both control and case groups was significant (p=0.041 and p=0.000, respectively) (table 4). In the second and fourth weeks of treatment, the effect of flavonoid lotion on anal pain was better than anti-haemorrhoid ointment, and there was a statistically significant difference with p=0.036 and p=0.025, respectively (table 3).

Although the improvement of anal discomfort was significant in both groups after treatment (p=0.000), in the first week of treatment, the effect of flavonoid lotion was better than anti-haemorrhoid ointment, and there was a statistically significant difference (p=0.05). All results obtained between and within the analysis are summarised in tables 3 and 4, respectively.

Evaluation of therapeutic intervention complications

Incidence and changes of side effects of flavonoid lotion and anti-haemorrhoid ointment were compared between case and control groups considering the symptoms of diarrhoea, nausea, vomiting, headache, dizziness, focal/diffuse itchy skin and focal/diffuse skin rash.

Most participants who recorded these symptoms in the questionnaire had these symptoms before starting the intervention; this was primarily due to colonoscopic preparation and laxatives or colonoscopic stress, which later gradually decreased with the reduction of laxatives use, improvement of haemorrhoid symptoms and constipation. According to the study follow-up, no new complaint of itching and skin rash was seen during the treatment of the case group. In the control group, we had only one case with local itching and skin rash in the anal area from the end of the second week of treatment, which was not statistically significant. Eventually, this patient had to discontinue treatment, and this complication was improved entirely over time. The other complications recorded in the questionnaire were not new, and patients had these symptoms before starting treatment (tables 3 and 4).

Discussion

This study is a prospective randomised clinical trial. To the best of our knowledge, no study has evaluated the effect of an utterly herbal lotion with the current composition in the treatment of haemorrhoids. However, in other studies, the flavonoid compounds of plants such as Aesculus hippocastanum L. seed extracts, the bark of Acacia ferruginea DC, Vitis vinifera L. leaf extracts, Graptophyllum pictum extract, have been studied. Even in an experimental study, the positive effects of Graptophyllum pictum extract were significantly greater than the effects of micronised purified flavonoid fraction (MPFF)^15–18 such as Daflon tablet, which has been studied several times and is a semisynthetic product containing MPFF.^19–26

Our study confirms the safety and efficacy of flavonoid lotion in the treatment of all symptoms of haemorrhoids. Improvement of haemorrhoid degree of the case group was significant, unlike the control group. This shows that flavonoid lotion outperforms anti-haemorrhoid ointment in treating haemorrhoids.

Although haemorrhoid symptoms were significantly improved in both groups, notably, some therapeutic effects were observed over a shorter period of time in the case group, such as improvement of incomplete defecation, anal pain and anal irritation.

Recent studies have also shown a reduction in pain, bleeding, tenesmus, oedema, inflammation and itching, and improved chronic venous insufficiency and vascular function with flavonoid compounds; even though they have better effects and fewer side effects than band ligation and sclerotherapy; thus, flavonoid compounds may be a better choice for treating haemorrhoids.^27–33

In a systematic review and meta-analysis study (2020), 11 randomised trial studies (13 article) analysis showed significant and beneficial effects of flavonoids in reducing haemorrhoid symptoms such as bleeding, pruritus and discharge/leaking, and tenesmus and improving overall condition of patients.³³

In several clinical trial studies, the duration and extent of post-haemorrhoidectomy pain and bleeding diminished by combination of MPFF and antibiotics and anti-inflammatory medications; by inhibiting the inflammatory process, reducing oedema, improving venous tone and protecting the microcirculations from the inflammatory mediators.³¹ In a clinical trial study, Chiaretti et al compared the anti-haemorrhoidal effects of flavonoids compared with Centella; 199 patients enrolled in this study, 130 patients with II, III, IV haemorrhoidal grades (with bleeding) allocated to intervention group (73 of them treated by oral flavonoids tablets (Flavonil), and 66 patients by Centella complex tablets, 60 included with routine treatment without phlebotonics), the results indicated that 31 patients with bleeding grade IV, did not respond to the therapies and were reffered to do the haemorrhoidectomy; 38 patients with acute haemmorhoidal thrombosis enderwent anaesthesia. The time-to-stop bleeding of the flavonoid treated group was 2 weeks, and Cetella treated was 3 weeks, that was significant decrease in comparison to control group. Moreover the phlebotonics significantly reduce the irritation of the patients after the first week. In and overall this study findings suggests that, flavonoids are the most effective phlebotonics against bleeding and anal irritation.³⁴

Our study indicated that the flavonoid lotion had no focal or systemic side effects during the 1 month treatment, and it was perfectly tolerable for patients. The safety of this drug can be attributed to the origin of its compounds, which contain natural and non-chemical substances. In the control group, we had only one case of itching and local skin rash in the anal area from the end of the second week of treatment, which was not statistically significant. No other complication was observed. Most similar studies have not evaluated the complications of flavonoid treatment.15 30 35–37

Dewan et al evaluated the anti-haemorrhoidal effects of two flavonoid contained products, Hilo (phlebotonic) and Daflon in an multicentric, randomised study; 200 participants assigned to either Hilo or Daflon treatment groups; the Hilo group displayed better improvement in haemorrhoid symptoms (bleeding, paim, itching, soiling, tenesmus, irritation and constipation) on days 7th and 15th postintervention, compared with Daflon group. Conclusively, Hilo had better reduction in clinical symptoms of patients suffering from haemorrhoids as compared with Daflon.

In an investigion the Daflon usage in treatment of grade 4 internal haemorrhoid were assessed; 50 patients included in the study. The overall findings showed significant improvements in symptoms, such as pain, heaviness, bleeding, pruritus and mucosal discharge. Eight patients had minor side effects of Daflon, which was mainly gastrointestinal symptoms (8%), however, it was not serious to make patients discontinued the study.²⁰ Meshikhes et al evaluated the effects of flavonoid compounds (Daflon) as a prospective clinical trial in which five patients had gastrointestinal side effects after taking Daflon. Unfortunately, the type of these complications has not been stated. Another disadvantage of this study is the lack of a control group, while in our study, the control group was treated with an approved drug.³⁸ They also compared the effects of flavonoid compounds (Daflon) with sclerotherapy, in which the study population consisted only of first-degree haemorrhoids. Those results cannot be generalised to more severe degrees of haemorrhoids. several conducted studies based on an animal model, which are less valuable than randomised clinical trial studies. In these studies, the flavonoid compounds of other plants, such as Aesculus hippocastanum L. seed extracts, the bark of Acacia ferruginea DC, Vitis vinifera L. leaf extracts and Graptophyllum pictum extract have been evaluated. Other disadvantages of these studies are the low population studied and the lack of a control group, and the lack of assessing the side effects of treatment.^16–18 The study conducted byde Souza M das et al was also based on the animal model and compared the effects of flavonoid compounds to the effects of sclerotherapy, in which the study population was small. The side effects of treatment were not studied.³⁰

Conclusion

Our finding suggested that flavonoid lotion could effectively treat haemorrhoidal symptoms and heal its complications. It also has more rapid efficacy in comparison with routine anti-haemorrhoid ointment. Thus, this flavonoid lotion could be introduced as an appropriate, available, economical and compelling candidate for the treatment of haemorrhoids.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).

Ethics approval

This study involves human participants and this study is a prospective randomised clinical trial and has been approved by the Research Ethics Committee of Baqiyatallah hospital, Baqiyatallah University of Medical Sciences, Tehran, Iran with umber code IR.BMSU.BAQ.REC.1398.032 (https://ethics.research.ac.ir/IndexEn.php). Participants gave informed consent to participate in the study before taking part.