Introduction

Treatment of hemorrhoids depends on the stage of the disorder and the symptoms. Hemorrhoidectomy is considered an effective treatment for third-degree and forth-degree symptomatic hemorrhoids. Many surgical techniques have been proposed; however, open hemorrhoidectomy is still the most commonly performed operation for hemorrhoids [1–6].

Pain is almost a constant feature after hemorrhoidectomy and is the commonest reason for delayed patient discharge. The lining of the anal canal is among the most richly innervated tissues in the digestive tract. Thus, pain after hemorrhoidectomy is certainly an expected outcome which is more intense during defecation [7].

The degree of pain experienced depends on a number of factors, including surgical technique, anesthesia used, postoperative analgesia, early defecation of soft stools, avoidance of dressings, and subjective pain threshold. Various factors are believed to be responsible for the pain after hemorrhoidectomy including spasm of the internal anal sphincter, inflammation of the perianal area, and bacterial colonization at the hemorrhoidectomy site [6, 8].

Opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) have often been administered for pain control, but their use is confined to a short period and is associated with frequent side effects, which might lead to prolonged hospital stay [6–11]. Therefore, the management of postoperative pain after hemorrhoidectomy is crucial, both clinically and economically. Consequently, the introduction of novel methods for the control of post-hemorrhoidectomy pain is required.

Several studies have attempted to identify useful approaches to post-hemorrhoidectomy pain management. Several pharmacological agents with different mechanisms of action have all been tried for such purpose: glyceryl trinitrate; calcium channel blockers, such as diltiazem and nifedipine; metronidazole; botulinum toxin, dextromethorphan; and sucralfate [8, 12–22].

Cholestyramine, a quaternary ammonium chloride anion exchange resin, has been found to be effective in the topical form in the treatment of perianal skin irritation in a number of studies. Cholestyramine ointment has been used to treat skin irritation around enterostomies and after ileoanal anastomosis; it has also been used to treat severe perianal cutaneous lesions, as well as buttocks rash in neonates [23–28]. The effectiveness of this agent has been ascribed to its bile acid-binding activity. Bile acids secreted in the stool are considered to be a major cause of skin irritation and inflammation in the perianal area. Bile acids are powerful detergents that are able to dissolve cell membranes and produce inflammation when injected directly into the tissues [29]. Free bile acids have also been shown to produce intestinal mucosal cell damage when fed to experimental animals [30, 31]. These could be important mechanisms contributing to the inflammation and irritation of the perianal skin following hemorrhoidectomy. Thus, it seems reasonable to suppose that local application of the acid-binding agent cholestyramine might be effective in reducing postoperative pain and pain on defecation following hemorrhoidectomy. To our knowledge, the use of topical cholestyramine in the management of post-hemorrhoidectomy pain has not been reported previously.

In the present study, the efficacy of 15 % cholestyramine ointment in reducing postoperative pain at rest, pain on defecation and analgesic requirement after open hemorrhoidectomy was investigated. Our hypothesis consisted of two assumptions: (1) cholestyramine ointment (15 %) can reduce postoperative pain after open hemorrhoidectomy compared with placebo and cholestyramine ointment (15 %) can reduce pain on defecation after open hemorrhoidectomy compared with placebo; (2) cholestyramine ointment (15 %) can reduce the requirement for analgesics after open hemorrhoidectomy compared with placebo.

Materials and methods

Preparation of the ointments

The cholestyramine and placebo ointments were prepared as two indistinguishable products. From the different types of levigating agents available to prepare the ointment, almond oil was chosen for the final formula for its appropriate physicochemical properties, absence of skin irritating properties, and pleasant appearance of the preparation. The weight ratio of cholestyramine in the ointment was determined according to the clinical application (the pathological condition and the extent of the lesions) and the physical properties (appropriate appearance and smooth texture) of the ointment. In the end, 15 % w/w ointment was found to be appropriate.

Cholestyramine ointment was prepared from cholestyramine powder (15 % w/w), almond oil (21.25 % w/w), and vaseline (63.75 % w/w) by the incorporation method. Simply, the required amount of cholestyramine powder was levigated with the appropriate amount of almond oil, and the required amount of vaseline was then added to this mixture and stirred at room temperature to obtain a homogeneous ointment. The placebo ointment was prepared by mixing almond oil (25 % w/w) and vaseline (75 % w/w) by the same method. The final preparations were tested physicochemically and microbiologically and proved to be suitable for clinical use. The cholestyramine and placebo ointments were filled in identical tubes (each tube containing 30 g of ointment) and labeled with the randomization codes A and B corresponding to placebo and cholestyramine, respectively, by an individual who was not aware of the trial procedure and was not involved in it.

Patient selection

Consecutive newly diagnosed patients with hemorrhoids between 20 and 70 years of age of both sexes were screened for the purpose of enrollment in the study. Those patients with grade three or grade four hemorrhoids were scheduled for open hemorrhoidectomy and were included in the study. Subjects with a history of previous anal surgery, presence of additional anal/perianal disease (including fistula-in-ano, perianal abscess, and anal fissure), history of oral cholestyramine consumption, patients with hepatic cirrhosis, patients addicted to opioids, and pregnant women were excluded from the study.

Trial design

This study was a single-center prospective double-blind placebo-controlled randomized trial conducted in Imam Khomeini Hospital, Sari, Iran, between March and December 2008. The study was approved by the research ethics committee of Mazandaran University of Medical Sciences and registered in the Iranian Registry of clinical trials with registration number IRCT138803091627N2 (the full trial protocol can be accessed at: http://www.irct.ir). The study was performed according to the Declaration of Helsinki, and written informed consent was obtained from all patients before their enrollment in the study. A sample size of 48 in each study arm was calculated to be appropriate with 90 % power and 5 % significance level on the basis of a power analysis. The primary outcomes were as follows: (1) postoperative pain after hemorrhoidectomy as measured by visual analogue scale (VAS) with 0 showing the absence of pain and 10 showing the worst pain imaginable; (2) pain on defecation after hemorrhoidectomy measured by VAS; (3) analgesia requirement measured by tramadol consumption in the first 48 h after hemorrhoidectomy.

Trial procedure

The patients were randomized into two groups following a simple randomization procedure using a computer-generated table of random numbers (the even numbers corresponded to code A and the odd numbers corresponded to code B). The patients were allocated to the intervention by an individual who was not aware of the randomization codes and was not involved in the subsequent therapeutic process. The patients and the investigators (health care providers, data collectors, and those assessing outcomes) were blinded to the allocation, and the randomization code was not available to either investigators or patients until the trial was completed.

All patients underwent the standard Milligan–Morgan technique of open hemorrhoidectomy [32] under general anesthesia by the same surgical team. To ensure uniformity of the surgical technique, all patients were operated on by a single surgeon (F.E.), a uniform anesthesia protocol was used for all patients, and the excision procedure was identical for both groups.

The first dose of the ointment was applied by the surgeon at completion of the surgery, followed by self-administration of the ointment under the supervision of a trained nurse to ensure proper application of the ointment. The patients were advised to apply 1.5 cm of the ointment (equal to 3 g of the ointment, which corresponds to 0.45 g of drug in the case of cholestyramine ointment) on perianal skin (but not inside the anus) 12 h after surgery and then every 8 h for 2 weeks.

All of the patients received opioid analgesic treatment (50 mg tramadol injection) at the end of the surgery and as needed thereafter, up to a maximum of 100 mg per day for a maximum of 48 h. The patients were discharged 48 h after operation and were ordered to take acetaminophen tablets (325 mg) for pain control if required every 6 h for a maximum of 7 days. The patients were visited 12, 24, and 48 h after surgery. Outpatient follow-up was conducted at the second and fourth postoperative weeks.

Statistical analysis

The statistical analysis of the data was performed with SPSS software (SPSS for windows, version 16, SPSS Inc., Chicago, IL). Student’s t test was used to compare the quantitative data and the χ2 test was used to compare the qualitative data between groups. Values of P < 0.05 were considered to show a statistically significant difference.

Results

Of 108 patients recruited for the study, 12 were excluded after irregular use of the ointment (forgot to use the ointment or did not use the ointment on time) and 5 were excluded because of opioid addiction that had not been diagnosed before their enrolment in the trial, leaving 91 patients (44 patients in group A and 47 patients in group B) for analysis (Fig. 1). There were no statistical differences in mean age (P = 0.805), gender distribution (P = 0.34), and degree of hemorrhoids (P = 0.135) between the two groups (Table 1).

Fig. 1
figure 1

Participant flow diagram (according to the CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines)

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Table 1 Demographic characteristics of the patients
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The average postoperative pain scores of patients in group B were significantly lower than group A at the 24th hour (P = 0.001) and the 48th hour (P < 0.001) after hemorrhoidectomy. At the second postoperative week no pain was reported by any of the patients in group B, while a mean pain score of 0.57 ± 1.34 was reported by the patients in group A (Table 2). The average scores of pain on defecation were also lower for group B than for group A at the 48th hour (P = 0.001), during the second week (P < 0.001), and during the 4th week (P < 0.001) after hemorrhoidectomy (Table 3).

Table 2 Average postoperative pain scoresa at different times after hemorrhoidectomyb
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Table 3 Average scoresa of pain during defecation (VAS) at different times after hemorrhoidectomy
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The average amount of tramadol consumption in group B was to a great degree lower than that in group A between the 12th and 24th hours (P < 0.001) and between the 24th and 48th hours (P < 0.001) after hemorrhoidectomy (Table 4). Furthermore, the average amount of acetaminophen consumption per day during the first postoperative week was 892 ± 89.18 mg/day for group A and 585 ± 82.94 mg/day for group B, which shows a considerable difference (P = 0.013, data reported as mean ± SD). No complications were recorded during the trial period except mild pruritus, which started after 48 h.

Table 4 Average tramadol consumption (mg)a at different time intervals after hemorrhoidectomy
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Although the frequency of pruritus was lower in group B throughout the trial period, the difference was not significant until the 4th week (P = 0.001; Table 5). The medication was well tolerated in all patients and no patient discontinued intervention because of adverse events.

Table 5 Number of patients having pruritus at different time points after hemorrhoidectomy
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Discussion

Surgery is the most common treatment for patients with third and fourth degree hemorrhoids. Excisional hemorrhoidectomy is the most effective treatment to reduce recurrent symptoms in patients with grade 3 or 4 hemorrhoids, patients with mixed internal and external hemorrhoids, and those with recurrent hemorrhoids in whom other treatments have been ineffective [33, 34]. There are different surgical procedures for hemorrhoidectomy, but conventional open hemorrhoidectomy is still the most commonly performed operation for hemorrhoids [6].

The most commonly encountered complication after hemorrhoidectomy is postoperative pain, which is usually most intense during the first passage of stools. Pain is the commonest reason for delayed patient discharge. Studies show that, as a result of pain, patients require 4–16 days to return to normal activity. Inadequate pain control also accounts for increased opioid requirements, postoperative nausea and vomiting, urinary retention, and increased readmissions [6]. As a result, the management of postoperative pain after hemorrhoidectomy is crucial, both clinically and economically. Several pharmacological agents with different mechanisms of action have been studied for postoperative pain reduction after hemorrhoidectomy. These agents include ointments of glyceryl trinitrate, diltiazem, nifedipine, metronidazole, sucralfate cream, botulinum toxin injection, and dextromethorphan injection [8, 12–22].

In the present study, we investigated the effects of 15 % cholestyramine ointment on postoperative pain, pain on defecation, and analgesic requirements after open hemorrhoidectomy. Our results showed a marked reduction in postoperative pain in the treatment group compared with the control group at the 24th hour and the 48th hour after hemorrhoidectomy and complete pain elimination by the second postoperative week (Table 2). The results of analgesic consumption in the two groups follow the same pattern (Table 4), which confirms the results obtained by VAS.

Since the action of cholestyramine in reducing pain and skin irritation is mainly through binding to bile acids excreted in the stool and inhibiting their inflammatory effects on perianal skin, the initiation of its effect is determined by the time of first defecation. Before this time no such effect could be observed. The time of first passage of stool for all of the patients in the two groups was between 12 and 24 h after hemorrhoidectomy and none of the patients defecated before this time. Thus, on the first physician visit at the 12th hour after hemorrhoidectomy, no reports of pain on defecation were recorded. There was no significant difference in pain scores on first defecation in the patients of the two groups (between the 12th and 24th postoperative hours), but comparison of the two groups showed a marked reduction in pain on defecation in the treatment group compared with control group between the 24th and 48th hours after hemorrhoidectomy (Table 3). It could be inferred from such data that the bile acid sequestering action of cholestyramine led to a considerable difference in pain on second defecation (between 24th and 48th postoperative hours) between the two groups. This pattern continued in the ensuing days, resulting in considerably less pain on defecation in the treatment group during the second and fourth postoperative weeks (Table 3).

Taking into account all the above-mentioned data, it can be concluded that cholestyramine ointment (15 %) was effective in reducing postoperative pain both at rest and during defecation, consequently decreasing the requirement for analgesic consumption after open hemorrhoidectomy compared with placebo. However, the effects of cholestyramine ointment on wound healing after hemorrhoidectomy was not investigated in this study and should be addressed by further studies.