Introduction

Irritable bowel syndrome (IBS) is one of the most frequent chronic functional gastrointestinal disorders that affects up to 20% of the population of the western countries [1–3] and accounts for 30% of gastroenterologic visits [4]. Although it is not a life-threatening condition, it may render the quality of life very poor [5] and represents a high cost for the society in terms of prescriptions and sick leave [4].

IBS is characterized by abdominal pain, bloating and disordered defecation in absence of evident structural and biochemical alterations. The aetiology is unknown and pathophysiology is not fully understood. Among the proposed pathophysiology mechanisms, there are disturbed gastrointestinal motility, mucosal inflammation, alteration in gut microflora, psychological distress and visceral hypersensitivity. The lack of a well-established and unitary pathophysiology explains why no curative therapy exists and why the treatment is mostly empirical. The only certainty is the presence of symptoms, especially abdominal pain, which, besides bloating and disordered defecations, is an essential symptom of IBS [6], that is correlated with the severity of the disease [7] and is heavily responsible for the poor quality of life of these patients [8].

Abdominal pain of IBS patients has been put in relationship with visceral hypersensitivity to intra-luminal stimuli, such as intestinal distension, normally not perceived as painful [9]. This disturbance in perception has been confirmed by experimental studies [10] and is considered a biological marker of IBS [11]. The origin and the maintenance of visceral hypersensitivity may be due to patho-mechanisms located in the brain or spinal cord, as well as in the primary afferent neurons and in the gut wall [4]. However, there are many observations indicating that peripheral mechanisms may play a predominant role in the genesis of pain [12], at least in patients with a post-infective and “inflammatory” IBS [13–15].

On the basis of these considerations, we believe that it is reasonable to address the therapeutic efforts to decrease the colonic hyperalgesia in patients with IBS, following an emerging trend in the treatment of functional gastrointestinal diseases [16]. Some attempts have already been made to decrease pharmacologically the visceral sensitivity of functional gut disorders with a number of drugs [17], such as fedotozine, octreotide, clonidine, anti-inflammatory compounds, tricyclic antidepressants and antagonists of 5HT3, CRF, CCK and bradykinin, etc. However, most of these substances, although able to increase, at least experimentally, the colonic sensory threshold, are at the moment not commercially available, because being still under investigation or, if commercially available, do not represent a reliable chronic treatment for IBS pain, because of marginal clinical benefits, absence of a predominant selective effect on visceral hypersensitivity, lack of controlled studies and possible dangerous side effects during chronic treatments.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent component of various species of Capsicum annuum (red pepper) can impair selectively the activity of unmielinated nociceptive C-type fibres carrying on pain sensations to the central nervous system from polymodal nociceptors activated by noxious thermal, mechanical or chemical stimuli [18–23]. Capsaicin-sensitive neural elements have been shown in the colon [24] and are implicated in the baseline sensitivity of colon mechanoreceptors [25]. The analgesic properties of this substance were known more than a century ago, and a rich harvest of studies demonstrated that the topical application of capsaicin is able to relieve postherpetic neuralgia of skin and oral cavity, trigeminal neuralgia and cluster headache [26–28], as well as painful diabetic neuropathy and vesical neuropathic pain [29, 30]. In addition, recent experiments demonstrated that repeated exposures of the esophageal mucosa to capsaicin-containing red pepper sauce ingested by patients suffering from heartburn produce an analgesic effect after a first phase of symptom worsening, suggesting the induction of a “sensitization” followed by a “desensitization” of the esophageal mucosa by capsaicin [31]. Similarly, capsaicin administered to patients with functional dyspepsia was found to be able to improve significantly epigastric pain and bloating after an initial period of worsening [32].

On the basis of these considerations, we decided to evaluate the effect of red pepper on symptoms of IBS patients.

Methods

The study was carried out on patients (mean age 44.6 years; 30 males) with IBS diagnosed with Rome II criteria. Only patients between 18 and 65 years were eligible. The following conditions represented a contraindication for the inclusion in the study:

  • organic alterations of the gut,

  • previous surgery of the digestive tract (excluding appendectomy),

  • hepatic, cardiac, renal, neurologic and systemic diseases, in which an involvement of the digestive tract is possible (diabetes, scleroderma, etc.),

  • pregnancy and lactation,

  • alcohol intake >20 g/day,

  • coffee intake >3 cups/day,

  • smoking >10 cigarettes/day,

  • drug addiction,

  • chronic use of anti-inflammatory and anti-hystaminic drugs, as well as the treatments with probiotics and drugs which may interfere with gut motility.

The patients were selected on the basis of history, physical examination, recent lower gut endoscopy-biopsy and abdominal ultrasonography and, when necessary, biochemical tests were performed to exclude general disease that may be responsible for intestinal symptoms. Informed consent was obtained from all patients, as well as the approval of the Ethic Committee of the Hospital.

Drug Composition and Administration

Red pepper powder was obtained by grinding the entire dried fruit of Capsicum annuum, including seeds, produced in the south of Italy. The red pepper powder was administered in pills each of them containing 150 mg of red pepper powder (0.50 mg of capsaicin) and with a coat of a special shellac that dissolves at pH 7.2 in the colon. The enteric-coated pills were chosen to avoid the absorption of capsaicin in the small intestine and to allow the arrival of the whole dose of red pepper in the colon, where the action of capsaicin should take place. After a 2-week washout period, 50 patients were randomized into two parallel groups to receive identical pills of red pepper or placebo in a double blind manner for 6 weeks. A sample size of 25 patients for treatment group guarantees a power of 80% to identify a size effect of 0.8 using the Student t test for independent samples with a two-tailed level of significance of 5%. The patients were asked to take 4 pills/day, 2 of them 1 h before breakfast and the other 2, 1 h before dinner, with a glass of water. No concurrent medications that may influence IBS symptoms were allowed during the study and a 2-week washout of these drugs was performed to assess baseline symptoms of the week preceding the treatment.

Assessment of Symptoms

A diary sheet was given to each patient, for the symptom self-assessment during the basal and treatment periods. In each diary sheet, there was a list of the days of treatment crossed with a list of the following symptoms: abdominal pain and abdominal bloating, being the latter considered related to visceral hypersensitivity [33]. Symptom intensity was scored by the patients and marked on the diary each day during both the basal and treatment periods, on the basis of the 5-point Likert scale (1 = absent, 2 = slight, can be ignored when you do not think about it, 3 = moderate, cannot be ignored, but does not influence the daily activities, 4 = strong, influences your concentration on daily activities, 5 = unbearable, markedly influences your daily activities and/or requires rest) [34]. In addition, the patients indicated each day in the diary the number of defecations, as well as the undesired side effects of the treatment. Side effects assessment was based on spontaneous complaints reported on the diary and on the response to specific questioning at the final visit. In order to assure as high as possible compliance with the treatment, the patients were allowed to contact by phone the doctor for any problem related to the treatment. At the end of treatment, the subjective evaluation on the effectiveness of treatment was ranked by the patients from very bad (1 point) to very good (5 points).

Statistical Study

The statistical evaluation was aimed to look at the effect of the substances on pain intensity (primary end point) and bloating (secondary end point). The study was carried out by an investigator unaware of the meaning of the symptom variations after the administration of the substances. In each patient, the daily scores of abdominal pain and bloating intensity were averaged over a week-long period. To assess the course of the effect of the substances, the mean weekly scores of the two symptom intensity were plotted against time in each group. Then, those of one group were compared with those of the other group and those of each group with the corresponding basal values obtained from the week preceding the treatment, by using Wilcoxon test and Student t test for paired data. We were compelled to choose this kind of statistical analysis, because of the particular mechanism of action of capsaicin that first gives a worsening of symptoms and later an improvement of them. The values of the subjective evaluation of the effectiveness of treatment were compared between the two groups with the chi square test of Mantel–Haenszel.

Results

With the random administration of the two kinds of pills, 23 patients received red pepper pills and 27 placebo. Eight patients discontinued the study: 6 in the red pepper group for the appearance of intense abdominal pain, when starting the treatment, and 2 in the placebo group, for other reasons. In 8 patients, however, the number of pills, presumably of red pepper, was reduced from 4 to 2 a day, because of the appearance of abdominal pain at the beginning of treatment.

The comparisons between groups of all the parameters did not give significant differences. On the other hand, the intra-group comparisons showed that in patients taking red pepper the mean score values of the last 2 weeks of treatment regarding abdominal pain were significantly improved with respect to the pre-treatment values, whereas patients taking placebo showed a transient significant improvement during the first 4 weeks which disappeared during the last 2 weeks (Fig. 1).

Fig. 1
figure 1

Course of the weekly mean abdominal pain intensity scores (mean ± SD) during red pepper (open triangle) and placebo (open circle) administration. Filled triangles and circles indicate values significantly different from the corresponding baseline (B) values

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In addition, we performed a separate statistical analysis regarding the course of abdominal pain of the 8 patients who took a reduced dose of red pepper (2 pills/day instead of 4). These patients showed a significant improvement in the last weeks of treatment similar to that of the whole group treated with red pepper. With regard to bloating, the patients treated with red pepper showed a statistically significant improvement during the last week of treatment, while the placebo group did not show any significant variation (Fig. 2). The mean number of defecations a week did not varied significantly in both groups during the weeks of treatment compared with that of the basal period. The analysis of patient subjective evaluation on the effectiveness of treatments showed that red pepper was considered significantly more effective than placebo (Fig. 3).

Fig. 2
figure 2

Course of the weekly mean bloating intensity scores (mean ± SD) during red pepper (open triangle) and placebo (open circle) administration. Filled triangles and circles indicate values significantly different from the corresponding baseline (B) values

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Fig. 3
figure 3

Comparison between the patient subjective evaluation on the therapeutical effectiveness of red pepper treatment against that of placebo (mean ± SD) (*P < 0.05)

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Discussion

It is necessary to state in advance that it was not possible to comply thoroughly with the currently accepted methodological criteria, because red pepper may cause abdominal pain at the beginning of treatment.

The comparison of pain and bloating scores between the two groups did not give significant differences, whereas the fact that the symptoms at the end of treatments were significantly improved compared to baseline only after red pepper treatment and the fact that the effectiveness of treatments evaluated subjectively by the patients was significantly more effective after red pepper compared to placebo, suggest a type II error that justify the lack of significant differences between the two groups.

However, we believe that the results of this preliminary study considered as a whole, and, in particular, the positive trend observed at the end of treatment, suggest that red pepper powder chronically administered to IBS patients with enteric-coated pills is significantly more effective than placebo in decreasing the intensity of abdominal pain and bloating.

No severe side effects were observed except for six cases, in which the red pepper intake was followed by an abdominal pain that compelled the patients to stop the treatment. In some other patients, red pepper ingestion was followed initially by an abdominal pain, that, although less severe, suggested to us to halve the doses. However, the pain during the treatment showed a progressive and significant improvement that reached a statistical significance at the fifth and sixth weeks of treatment. This phenomenon, that suggests a “sensitization” followed by a “desensitization,” has also been observed after repeated applications of capsaicin not only on the skin but also on the mucous membranes of the oral and nasal cavities, bladder, esophagus, and stomach [21–26], and it is likely related to its mechanism of action. In fact, capsaicin induces an increase followed by a decrease of nociceptive fiber activity, corresponding to an accentuation followed by an attenuation of pain sensation. The mechanism is the following. Capsaicin first binds the transient receptor potential vanilloid receptor type 1 (TPRV1) [35] changing the membrane permeability to Ca++ of the primary sensorial neurons with consequent depolarization and release of many neuropeptides, including substance P (SP) and calcitonin gene related peptide (CGRP). This is the phase of sensitization that is characterized by an increase of pain sensation. Afterward, capsaicin locks the neuronal membrane in a depolarized state that prevents subsequent depolarization and release of neuropeptides, so that the nervous fibers become unresponsive to nociceptive stimuli for a prolonged period of time [19, 21, 22] and the pain sensation no longer takes place. These effects are reversible, except when the treatment is applied during the neonatal period, leading in this case to a complete ablation of the TRPV1 receptors [27]. The course of symptom intensity after treatment with red pepper in our IBS patients suggests that the improvement of symptoms, after a temporary period of worsening, may be related to a desensitizing effect of capsaicin, which renders the colonic nociceptive fibres less responsive to the stimuli that give rise to pain symptoms.

Certainly, the major drawback of this treatment is represented by the occurrence of abdominal pain in the first days of drug administration in some patients with the highest doses of capsaicin, that compelled the patient to stop the assumption or reduce the doses. The appearance or worsening of abdominal pain is due to the phase of sensitization exerted by capsaicin on the nociceptive fibers, that precedes the phase of desensitization, during which the analgesic effect takes place. However, as the low dose of red pepper gave a symptom improvement statistically similar to those of the higher dose, we may conclude that the low dose is sufficient for a therapeutically effective treatment, avoiding or decreasing in the meantime the undesirable effect of initial abdominal pain.

Another shortcoming of this kind of treatment is due to the slowness of the therapeutical effect appearance. This fact is likely due to the difficulty of red pepper powder of spreading on the whole colonic mucosa from the caecum to the rectum with sufficient concentration to act on the nociceptive nerve endings. In addition, the uniform distribution of red pepper powder upon the colonic mucosa may be hampered by a slow colonic transit and by the presence of fecal material. A possible cause of less than optimal abdominal pain improvement may lie in the presence of proximal gut hypersensitivity that may occur in some patients with diarrhea-predominant IBS (36).

Notwithstanding the limitations of this preliminary study, we believe that this kind of treatment could represent a new and rationale approach to manage the visceral hypersensitivity of irritable colon syndrome. In fact, TRPV1 fiber play a pivotal role in the genesis and maintenance of colonic hypersensitivity in IBS patients with a histologic low-grade inflammation caused by various factors, such as infective gastroenteritis, food allergies and alterations in gut microflora, etc. [37]. In fact, the number of TRPV1 immunoreactive sensory fibers are increased in biopsy specimens from patients with rectal hypersensitivity [38] and this increase is in relationship with the production by mast cells, among other inflammatory substances, of nerve growth factor, that is taken up by TRPV1 fibers and transported in a retrograde manner to nerve cell bodies, leading to nerve sprouting and increased expression of the TRPV1 [39]. The TRPV1 fibers are sensitized by several inflammatory mediators [20, 25, 36, 40], including histamine [41], proteases [42], bradykinin, prostaglandins (PG) [43], 5HT [44], etc., released by inflammatory cells, and in particular, by mast cells accumulated around nerve fibers [45, 46].

In addition, it is important to outline the fact that TRPV1 increased expression conditions the genesis and maintenance of the hypersensitivity of colonic mucosa. In fact, in congenic TRPV1 knockout mice that are deprived of TRPV1 fibers and rat neonates chemically deprived of TRPV1 fibers by a treatment with capsaicin, as well as in those given TRPV1 antagonists [47–49], the hyperalgesia is absent or markedly blunted [25, 47]. The hyperalgesia may persist even when the mucosal inflammation is no longer present. In fact, both colonic Zimosan administration in mice and that of acetic acid in rat neonates induce hypersensitivity to colonic distension that persists for several weeks, even when the signs of inflammation have disappeared [25, 47, 50]. These experiments demonstrated that TRPV1 fibers are necessary for settling the hyperalgesia and, although the colonic inflammation triggers an increased expression of TRPV1, the latter may not disappear with the healing of inflammation, disconnecting its existence from that of inflammation.

A possible explanation of the persistence of hyperalgesia after disappearance of signs of inflammation could lie in the neurogenic shifting of the immunogenic kind of inflammation. This shifting may be promoted by a release of inflammatory neuropeptides such as SP and CGRP [51–54] induced by TRPV1 activation [55]. The neurogenic inflammation could explain why there are IBS patients with normal colonic histology [15, 56–58] and why the usual treatments aimed at targeting the immune system and inflammation, that are efficacious in inflammatory bowel diseases, do not express the same effectiveness in IBS. In fact, various attempts to depress or abolish the activity of inflammatory cells, have been made with anti-inflammatory drugs, such as steroids, mast cells stabilizers, aminosalicilates, modifiers of the intestinal flora and drugs with antihistaminic properties, but the results, although interesting, were not impressive, as exhaustively described in a recent review by Barbara et al. [59].

For these reasons, we believe that the most rationale treatment of IBS colonic hyperalgesia consists in counteracting TRPV1 activity, rather than decreasing the substances that sensitize TRPV1 receptors. In fact, once this receptor is sensitized by inflammation, its up-regulation may persist for a long time, even when inflammation has disappeared [25, 47]. This goal may be gained by desensitizing the receptor to TRPV1 agonists, or by blocking the TRPV1 receptor. If the hypothesis of neurogenic inflammation is correct, the intervention on the hyperfunction of TRPV1 fibers, either induced by inflammation or remained after its disappearance, could represent a curative solution for IBS pain.

Capsaicin is well known to desensitize the nociceptive neurons through repeated stimulations of TRPV1 receptors, which induce an excess influx of Ca++ and other cations, with the consequence that sensory neurons are defunctionalized and depleted of their transmitters for a prolonged period of time. However, this result was obtained at the expense of an initial, although temporary, exacerbation of pain in the first weeks of treatment, as already observed in patients with functional dyspepsia treated with red pepper [32]. This problem may be obviated with the use of non-pungent capsaicin-like compounds, such as resineferatoxin [60], that are markedly superior to capsaicin in terms not only of tolerability but also of effectiveness. The other way consists in counteracting the hyperfunction of TRPV1 nocisensors with TRPV1 blockers [61]. This way could be more effective but is also more risky, because it does not keep into consideration that these receptors are also present in the brain and other non-neuronal tissues and are involved in many other physiological functions, such as protection of gastrointestinal mucosa and thermoregulation [22, 62–64]. On the contrary, the defunctionalization of these receptors through chronic administration of specific agonists, such as capsaicin, is surely less dangerous than TPRV1 blockers, considering the fact that millions of persons in the world, especially in south-east Asia, consume large quantities of capsaicin with red pepper every day of their lives without evident adverse consequences. On the contrary, a beneficial effect on functional gut diseases may be inferred considering that these diseases, and in particular IBS, in these countries have a prevalence markedly less than in western countries [65, 66]. In addition, the risk of adverse events in our experimentation is further reduced by the fact that capsaicin is administered with enteric-coated pills, with consequent negligible intestinal absorption, so that it acts only locally on the colonic mucosa and not on the whole body.

In conclusion, the fact that capsaicin contained in red pepper seems to be able to improve the abdominal pain in IBS patients suggests a novel way of dealing with this frequent and distressing functional disease, that to date does not have an effective treatment. We hope that the results of this preliminary research, although with some methodological limitations, may represent a spur to pursue the studies with this kind of treatment based on desensitization of colonic nociceptive neurons, the hyperactivity of which is responsible of abdominal pain in IBS patients, even by using other substances more tolerable and effective than capsaicin.