The effects of sildenafil on rectal sensitivity and tone in patients with the irritable bowel syndrome

Authors


Correspondence to:

Dr M. Â. Nobre e Souza, Department of Clinical Medicine, Federal University of Ceará, Rua Prof. Costa Mendes 1608 – 4º andar CEP: 60430-040, Fortaleza, Ceará, Brazil.

E-mail: mans@ufc.br

Summary

Background

Visceral tone supposedly affects gut sensitivity in irritable bowel syndrome (IBS). Sildenafil increases nitric oxide and influences visceral compliance.

Aim

To evaluate the effects of sildenafil tone inhibition on rectal sensitivity.

Methods

Eight controls and 21 IBS patients (Rome II) were enrolled in a double-blind study, after dosing with placebo or sildenafil (50 mg p.o.). Thresholds for first sensation, first desire to defecate, pain and supraliminar pain were the sensory endpoints, measured with a barostat and 600-mL rectal bag. Pain (100-mm VAS) and depression-anxiety (Hamilton questionnaire) were scored.

Results

Irritable bowel syndrome rectal compliance and sensory-endpoint thresholds were similar to controls. Five IBS patients had pain threshold lower than controls 95% confidence interval (hypersensitive). Depression score was greater in IBS than controls (11.9 ± 1.3 vs. 6.3 ± 2.5, P = 0.036). In IBS, pain intensity was nonsignificantly higher (37.6 ± 5.3 mm vs. 23.4 ± 8.5 mm, P = 0.064) and supraliminar pain intensity was greater (45.6 ± 5.4 mm vs. 25.9 ± 5.1 mm, P = 0.044) than controls. IBS rectal relaxation increased volume (155.4 ± 41.3 mL vs. 118.8 ± 47.7 mL, P = 0.004) and tension (193.1 ± 118.6 mmHg mL−1 vs. 133.2 ± 98.1 mmHg mL−1, P = 0.019) for triggering first desire to defecate but not for other perceptions. Sildenafil increased volume for both first desire to defecate and pain in the hypersensitive IBS patients. Sildenafil increased rectal compliance only in diarrhoea-IBS. Mixed-IBS obtained higher anxiety (12.9 ± 1.3 vs. 5.9 ± 3.1, P < 0.05) and depression scores (13.9 ± 1.9 vs. 6.3 ± 2.5, P < 0.05) and reported more intense supraliminar pain (53.6 ± 9.8 mm vs. 25.9 ± 5.1 mm, P < 0.05) than controls.

Conclusions

Rectal relaxation following dosing with sildenafil 50 mg increased the first desire to defecate threshold in IBS as a whole, but decreased pain only in the hypersensitive subset. Mixed-IBS presented higher supraliminar pain and anxiety-depression scores.

Introduction

The irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain or distress associated with changes in bowel habits. The pathophysiology of IBS involves visceral hypersensitivity and motility disorders.[1, 2] Early studies showed nitrergic neurons play a role in lower gastrointestinal tract (GIT) diseases. They induce anal channel relaxation in anal fissure patients[3] and play a role in slow-transit constipation.[4] Furthermore, NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, increased the rectal pain threshold to distension in IBS patients with hypersensitivity.[5]

Intracellular guanosine 3′,5′-cyclic monophosphate (cGMP) mediates smooth muscle relaxation induced by NO.[6] Sildenafil is a cGMP-specific phosphodiesterase type-5 inhibitor capable of cleaving GMP and affecting the motor function of various segments of the GIT. In humans, sildenafil induced oesophageal aperistalsis[7] and gastric relaxation.[8] Regarding bowel habit, healthy volunteers reported an increase in the frequency of defecation after sildenafil administration.[9]

Shifting visceral tone is a putative mechanism affecting the sensitivity of the GIT to distension.[10] Accordingly, Gabapentin, a 3-alkylated analogue of γ-amino butyric acid (GABA), increased the threshold pressure for discomfort after rectal distension contemporary to a mild reduction in rectal tone.[11] Also, clonidine-induced relaxation reduced gastric perception to distension in normal volunteers.[12] Fedotozine increased the first sensation and the pain thresholds in IBS patients, although colonic relaxation was minimal.[13] Stress is also known to affect GIT sensorimotor function. Induced anxiety in healthy subjects reduced gastric compliance and accommodation, as well as, yielded significantly higher scores for satiety, fullness and bloating.[14]

Surprisingly, only two studies have dealt with rectal sensorimotor function in IBS, while reducing rectal tone and using a barostat technique. A particular study had shown that sildenafil reduced both the rectal tone and the sensitivity in IBS patients.[15] However, among barostat studies, there are no data regarding IBS sensorimotor function and neither psychosocial factors nor IBS clinical subtypes. In the present study, we aimed at determining whether or not rectal sensitivity of patients with IBS is affected by a reduction in rectal tone induced by sildenafil as measured by an electronic barostat, as well as its relationship to psychosocial factors and IBS clinical phenotype.

Methods

Subjects

This study included 21 subjects (five males; average age 39.9 years; range 26–60 years) with a clinical diagnosis of IBS (according to Roma II criteria) (2) attending the Gastroenterology and Coloproctology outpatient services at Walter Cantídio University Hospital (Federal University of Ceará), and eight control volunteers (six males; average age 32.3 years; range 24–44 years) without any Rome II symptom. A gastroenterologist interviewed both patients and controls for a complete clinical history. All volunteers had a normal clinical examination and no antecedents of abdominal surgery, except for a single case of laparoscopic cholecystectomy in one patient. No subjects had taken medication capable of altering intestinal function within the 15 days preceding the experiments. Complete blood count, blood sedimentation rate, blood concentration of glucose and thyroid hormone and rectosigmoidoscopy with biopsy were normal for all subjects. A negative serum β-HCG test ruled out pregnancy in childbearing age females. Written informed consent was obtained from each participant. The Research Ethics Committee of the University Hospital approved the study protocol prior to the experiments.

The Hamilton Depression and Anxiety Rating Scales

An experienced psychiatrist evaluated all subjects with an open clinical interview using a validated Portuguese version of the Mini International Neuropsychiatric Interview.[16] Symptoms of depression and anxiety were measured with the Hamilton Depression Rating Scale[17] and the Hamilton Anxiety Scale.[18]

Test solution

After randomization and in a double-blind fashion, IBS patients and control volunteers received either 50 mg sildenafil (Pfizer, Guarulhos, São Paulo, Brazil) dissolved in 200 mL standardised orange juice (Tampico, Palmeira dos Índios, Alagoas, Brazil), or just 200 mL orange juice as placebo. Apart from the main experimental protocol, we performed a double-blind, randomized, self-matched survey specifically designed to detect any difference in taste (sourness, bitterness, sweetness or saltiness), odour and appearance between the sildenafil solution and the placebo. Eight volunteers entered this survey. The sildenafil solution was bitterer than the placebo when subjects tasted one solution immediately after the other. Then, an interval of 15–30 days separated the placebo and sildenafil arms, and we maintained the test solutions as described above to ensure a more regular oesophageal transit and drug absorption. Sildenafil solution had been used in another experimental study designed to demonstrate acute effects of the drug.[19]

Study of rectal compliance, tension and sensitivity

Volunteers and system preparations

Rectal compliance, tension and sensitivity were evaluated in a randomized, double-blind, placebo-controlled and self-matched study. After fasting for at least 5 h, the distal bowel was cleared with a 500 mL 12% glycerine enema. One hour later, volunteers took the test solution per os, and after another 40 min, we performed the sensorimotor procedures. The study timeline was in accordance with the biological effects of sildenafil, which last over 8 h in healthy subjects.[20]

The procedures started with a digital rectal examination. Then a 16-F single-lumen polyvinyl catheter with a 9.5-cm wide (600 mL) polyethylene bag at the tip, previously tested for leaks and highly compliant along the volume range tested, was positioned with the distal border at 5 cm from the anal edge. A manual inflation of the bag until mild discomfort prepared the subjects for the sensations experienced during the study. Also, this inflation allowed for a better adjustment of the bag in the rectum. Before any distension protocol, the bag was completely emptied, connected to a visceral stimulator (Synectics Visceral Stimulator/Barostat, Stockholm, Sweden), and the intrabag pressure set to atmospherical pressure. For reasons of safety, the system deflated the bag automatically if higher-than-expected pressures or volumes were reached. This could also be done manually if necessary. The subjects stayed in the right lateral decubitus during the entire procedures.

Linear ascending distension: compliance measurement

After a 10-min rest, continuous ramp distension was initiated at 28 mL/min, starting at 0 mmHg and ending when subjects requested interruption due to pain causing enough discomfort to preclude further distension. This procedure allowed us to calculate the rectal compliance (volume/pressure) and minimal distension pressure (MDP), defined as the point on the pressure vs. volume curve at which an ever-ascending increase in volume was observable.

During ramp distension, subjects reported sensations spontaneously until requesting the interruption of the distension due to pain (maximum pain, i.e. pain requiring discontinuation of distension).

Double random staircase distensions: sensory thresholds

After discontinuation of ramp distension, subjects were allowed to rest for 10 min before starting the double random staircase (DRS-SVS, Synectics, Stockholm, Sweden) distensions designed to determine the thresholds of rectal sensitivity.[10] DRS refer to two ascending staircase distensions with interwoven steps. This protocol prevented the subjects from anticipating the following distension as higher than the immediately previous one. Distensions started with a 4 mmHg increase in relation to MDP. To decrease the experiment time and minimise stress, distension steps were limited to 40 s with 30 s baseline intervals at MDP. Sensorimotor parameters were calculated for the last 15 s of each distension step and baseline interval, allowing for better perception by the subjects. At those moments, the subjects were asked if they were feeling pain or any other symptom. The criteria for threshold determination were the pressures corresponding to the reported sensations. The first sensation (subjective and variable perceptions occurring at least in one staircase, before the desire to defecate, and not described as pain: movements, itching, cold, warm), the first desire to defecate, the first perception of discomfort (pain threshold), and the supraliminar pain (occurring one distension step immediately higher than the pain threshold) were the main sensory endpoints. Desire to defecate and pain sensations were only considered when present in both staircases distensions. During the assessment of sensation, the interaction between the subject and investigators was kept to a minimum. After each manifestation of pain, the subjects scored such perception on a 100-mm visual analogical scale (VAS). For pain thresholds, we only considered perceptions whose VAS values decreased by over 50% during the following baseline. If subjects requested or experienced pain three times in each staircase, the experiment was discontinued.

Study of somatic pain

Ten minutes after the end the barotast procedures, a hand immersion protocol measured somatic pain intensity.[21] Subjects had their hands sunk in warm water to the wrist level during 15 s. This procedure was carried on twice for each water temperatures (45 and 47 °C), in a blind and random order, with 5 min intervals. Volunteers marked pain intensity on a 100-mm long VAS. Individual somatic pain threshold was the mean of the two measurements for each temperature.

Data analysis

Sensorimotor data of control volunteers and IBS patients were analysed after both placebo and sildenafil. The independent sensorimotor variables were pressure, volume, compliance and tension. The dependent variables corresponded to the thresholds for first sensation, first desire to defecate, pain, maximum pain, and intensities of threshold and supraliminar pains. The independent variables were measured at the time of occurrence of the dependent events. For the purposes of analysis the IBS subjects were divided into subtypes according to the predominant pattern of bowel behaviour. The constipation (C-IBS) or diarrhoea (D-IBS) groups presented either constipation or diarrhoea, respectively, with periods of normal bowel movements. Constipation and diarrhoea definitions followed Rome II criteria. A third group of patients could not be categorised into the previous ones, due to a variable bowel behaviour, constipation and diarrhoea emerging apparently at random (mixed-IBS, M-IBS). Pressure vs. volume curves derived from ramp distension data, based on absolute pressure values and their corresponding volumes. Rectal compliance (mL × mmHg−1) was calculated from the rectal volume observed at specific pressure levels during ramp distension. The tension (T) of the rectal wall was calculated based on Laplace's Law, where T = Pressure × Radius; if the radius = (3Volume/4π), then T = Pressure × (3Volume/4π). Since the rectum is an organ of accommodation, a spherical bag was used (10), and the radius was calculated using the formula for the sphere volume. A linear regression model for threshold pain intensity and distending pressure was figured out for IBS patients after placebo and after sildenafil, to predict pain thresholds. Hypersensitivity was defined as a volume pain threshold lower than controls 95% confidence interval, after placebo.

Statistical analysis

The normality of the distribution of the independent variables was tested with the D'Agostino test.[22] When the distribution of a specific variable was not significantly different from the normal ( 0.05), Student′s paired-samples t-test was employed to compare the averages of that variable between each treatment (sildenafil vs. placebo), and Student's unpaired-samples t-test was used to compare IBS vs. controls. On the other hand, when the distribution of a specific variable was significantly different from the normal ( 0.05), Wilcoxon's paired-sample signed-rank test was used to compare the distribution of that variable in relation to treatment regimen. Mann–Whitney test was used to compare anxiety and depression scores between controls and IBS patients. Kruskal–Wallis followed by Dunn's multiple comparison test or anova followed by Bonferroni's test found out whether there were statistical differences or not among three or more independent groups (controls vs. IBS subgroups) of quantitative, discrete variables (anxiety and depression scores), or quantitative, continuous, normal variables (pain intensity, volume, pressure, tension), respectively. Spearman′s correlation coefficient was calculated for testing associations among the scores of pain, anxiety, depression and the independent variables. The level of statistical significance was set at 0.05 for differences in mean values and distributions. A sample size of eight in each group had a 80% power to detect a difference in rectal volume of 30.4 mL with a significance level (alpha) of 0.05 (two-tailed), assuming a standard deviation of 45 mL (JMP Statistical Discovery Software, version 7.0.1, SAS Institute Inc. NC, USA; GraphPad Prism, GraphPad Software, Inc., La Jolla, CA, USA).

Results

We studied 21 patients with IBS, seven with constipation, six with diarrhoea and eight with mixed bowel behaviour. Seventeen (81%) IBS patients reported dyspeptic symptoms and 14 (66.6%) reported symptoms as related to feeding. Fourteen IBS patients (66.6%) reported abdominal pain at least 14 times monthly. Six patients had a clinical diagnosis of major depression, three other had generalised anxiety disorder and 10 had no psychiatric disease. Two control volunteers had a clinical diagnosis of major depression associated with anxiety.

Compliance – ramp distension

After placebo, rectal compliance of IBS patients (16.2 ± 3.9 mL at pressure 4 mmHg, 167.8 ± 12.5 mL at pressure 24 mmHg) was similar to the compliance of control volunteers (19.1 ± 3.6 mL at pressure 4 mmHg, 162.5 ± 22.6 mL at pressure 24 mmHg). After sildenafil treatment, rectal compliances in IBS patients and controls were higher, significantly and nonsignificantly respectively, relative to placebo (Figure 1). Despite that, sildenafil did not change the maximum volume of distension tolerated by IBS patients (placebo: 214.1 ± 16.3 mL, sildenafil: 220.5 ± 12.2 mL, P = 0.553) and controls (placebo: 230.4 ± 22.5 mL, sildenafil: 257.9 ± 13.1 mL, P = 0.185). MDP of the IBS patients was significantly higher than that of the controls, after placebo (3.1 ± 0.6 mmHg, n = 21 vs. 0.9 ± 0.5 mmHg, n = 8, P = 0.008). However, MDP of patients and controls did not change after sildenafil, relative to placebo (IBS patients: 2.6 ± 0.5 mmHg, n = 21, P = 0.394; controls: 1.1 ± 0.4 mmHg, n = 8, P = 0.668).

Figure 1.

Control volunteers and irritable bowel syndrome (IBS) patients yielded similar compliance curves after placebo or sildenafil. IBS patients treated with sildenafil presented a pressure-volume curve significantly shifted to the left, denoting rectal relaxation. Error bars are not shown for Controls. – Sildenafil; – – – Placebo. *P < 0.05, IBS-Placebo vs. IBS-Sildenafil. #,xP = 0.087 and P = 0.082 respectively, Controls-Placebo vs. Controls-Sildenafil.

Sensory thresholds – double random staircase distension

IBS patients vs. control volunteers (after placebo)

Thresholds for the first sensation, first desire to defecate and pain were similar between control subjects and IBS patients (Table 1).

Table 1. Double random staircase distensions of the rectum showed that pressure and volume thresholds for sensations were similar between control volunteers (n = 8) and irritable bowel syndrome (IBS) patients (n = 21) after placebo. However, a subset of hypersentive patients did show a lower volume threshold for all sensations (inside parentheses)
Sensation thresholdsVariablesControlsIBSP value
  1. Data presented as mean ± S.E.M.

First sensationPressure8.0 ± 1.5 mmHg7.8 ± 0.6 mmHg (6.4 ± 1.0 mmHg)0.883 (0.459)
Volume103.4 ± 22.2 mL83.7 ± 12.1 mL (35.0 ± 5.5 mL)0.558 (0.037)
First desire to defecatePressure13.1 ± 1.1 mmHg13.1 ± 0.9 mmHg (12.0 ± 1.3 mmHg)0.642 (0.523)
Volume137.0 ± 24.8 mL118.8 ± 10.9 mL (68 ± 7.2 mL)0.455 (0.047)
PainPressure17.0 ± 3.9 mmHg17.7 ± 1.4 mmHg (12.0 ± 3.8 mmHg)0.509 (0.408)
Volume158.5 ± 25.3 mL158.6 ± 13.4 mL (63.5 ± 13.3 mL)0.903 (0.017)

Effect of rectal relaxation (after sildenafil)

Volume threshold for pain (placebo: 158.4 ± 25.2 mL; sildenafil: 202.5 ± 22.6 mL; P = 0.213) and all the other sensory thresholds did not differ after sildenafil in controls (P > 0.05). Rectal relaxation did not change the thresholds for the first sensation in the IBS patients. This occurred despite rectal compliance at this threshold being higher after sildenafil (P = 0.034). However, rectal relaxation significantly increased the volume (Figure 2) and tension (Table 2) (P = 0.004 and P = 0.019, respectively), but not the pressure (P > 0.05) for triggering the first desire to defecate in the IBS patients (Table 2).

Figure 2.

Rectal relaxation by sildenafil significantly increased the volume threshold for the first desire to defecate in irritable bowel syndrome (IBS) patients. Mean lines with error bars are shown, P = 0.004. Δ Placebo, • Sildenafil.

Table 2. In irritable bowel syndrome (IBS) patients (n = 21), double random staircase (DRS) distensions revealed that rectal relaxation by sildenafil inhibited mainly the thresholds for the first desire to defecate. Sildenafil increased the volume and tension thresholds for pain in a subset of hypersensitive IBS (inside parentheses)
Sensation thresholdsVariablesPlaceboSildenafilP value
  1. Data presented as mean ± S.E.M. Pressure, mmHg; volume, mL; compliance, mL mmHg−1; tension, mmHg mL−1.

First sensationPressure7.8 ± 0.6 (6.4 ± 1.0)7.2 ± 0.6 (4.8 ± 0.8)0.418 (0.178)
Volume83.6 ± 12.1 (35.0 ± 5.5)97.6 ± 9.5 (52.5 ± 17.2)0.274 (0.228)
Compliance10.4 ± 1.1 (5.9 ± 1.1)13.6 ± 1.1 (10.3 ± 2.4)0.034 (0.146)
Tension59.8 ± 12.1(18.2 ± 4.7)63.3 ± 10.0 (23.9 ± 12.2)0.785 (0.513)
First desire to defecatePressure13.1 ± 0.9 (12.0 ± 1.3)14.9 ± 1.6 (13.0 ± 1.0)0.289 (0.718)
Volume118.8 ± 10.9 (68.0 ± 7.2)155.4 ± 9.7 (122.4 ± 12.6)0.004 (0.044)
Compliance9.3 ± 0,7 (5.8 ± 0.7)11.3 ± 0.8 (9.4 ± 0.6)0.039 (0.043)
Tension133.2 ± 22.5 (66.2 ± 11.4)193.1 ± 27.9 (129.2 ± 23.3)0.019 (0.142)
PainPressure17.7 ± 1.4 (12.0 ± 3.8)16.0 ± 1.5 (13.6 ± 2.7)0.297 (0.477)
Volume158.6 ± 13.4 (63.5 ± 13.3)162.1 ± 12.6 (113.0 ± 20.6)0.768 (0.003)
Compliance9.2 ± 0.7 (6.3 ± 0.9)10.7 ± 0.6 (9.2 ± 1.6)0.051 (0.081)
Tension241.8 ± 27.7 (74.7 ± 30.5)230.6 ± 35.5 (137.6 ± 40.9)0.745 (0.021)

Rectal relaxation did not change the pain threshold in the IBS patients (Table 2). Also, the intensity of the threshold pain did not change for IBS patients after sildenafil (placebo: 37.9 ± 5.3 mm vs. sildenafil: 31.9 ± 5.2 mm, P = 0.243). However, rectal relaxation did increase the volume (P = 0.003) and tension (P = 0.021) for triggering pain in the subset of hypersensitive patients (Table 2). Pain intensity correlated significantly with distending pressures in patients with IBS, both after placebo (r = 0.5, P = 0.029, n = 19) and chiefly after rectal relaxation (r = 0.79, P < 0.0001, n = 20). Linear regression models predicted pressure thresholds for pain as low as 5.3 mmHg after placebo (yplac = 2.3– 12), and 8.7 mmHg after sildenafil (ysild = 3– 26). Measured thresholds were 16 and 17.7 mmHg, respectively. Pressures below MDP + 2 SD mmHg were excluded from the analysis above, that is, these models were figured out with pressure above 6 mmHg.

Relationship between bowel behaviour and sensorimotor function

Rectal compliance after sildenafil increased in the D-IBS patients (at distending pressure 12 mmHg: 55.2 ± 16.9 vs. 89.3 ± 9.2 mL, n = 6, P = 0.05; and at distending pressure 16 mmHg: 87.3 ± 16.5 vs. 122.2 ± 11.6 mL, n = 6, P = 0.04), but not in those patients with M-IBS or C-IBS (Figure 3).

Figure 3.

Diarrhoea-IBS patients (triangles, n = 6) treated with sildenafil (closed symbols) presented a pressure-volume curve shifted to the left through distending pressures 8–20 mmHg, denoting rectal relaxation. On the other hand, constipation-irritable bowel syndrome (IBS) (circles, n = 7) and mixed-IBS patients (squares, n = 8) did not present rectal relaxation after sildenafil. – Sildenafil; - - - Placebo. * P = 0.04, # P = 0.05.

In IBS patients, the intensities of pain were nonsignificantly higher for the threshold pain and significantly greater for the supraliminar pain, relative to controls (Table 3). Relative to controls, the supraliminar pain intensity was significantly greater for M-IBS patients (53.6 ± 9.8 vs. 25.9 ± 5.1 mm, P < 0.05, Table 3), and non-significantly for the C-IBS and D-IBS subgroups (Table 3). The intensity of pain correlated with pressure threshold for pain, but only in the M-IBS and after sildenafil (r = 0.76, P = 0.029, n = 8).

Table 3. Pain intensity [mm on a visual analogical scale (VAS), after placebo] reported at the threshold level and at the supraliminar level (one step afterwards along the distending staircase). Intensity of supraliminar pain was significantly more intense for irritable bowel syndrome (IBS) patients as a whole and M-IBS in particular, relative to controls
Pain intensityControls (n = 8)IBS (n = 21)C-IBS (n = 7)D-IBS (n = 6)M-IBS (n = 8)
  1. Data presented as mean ± S.E.M.

  2. a

    IBS vs. Controls, P = 0.064.

  3. b

    IBS vs. Controls, P = 0.044.

  4. c

    M-IBS vs. Controls, P < 0.05 relative to Controls (Bonferroni's test).

Threshold23.4 ± 8.537.6 ± 5.3a29.6 ± 6.142.3 ± 11.241.1 ± 10.1
Supraliminar25.9 ± 5.145.6 ± 5.4b38.9 ± 8.242.8 ± 10.353.6 ± 9.8c

Volume threshold for pain (C-IBS – 176.5 ± 17.0 mL, D-IBS – 134.4 ± 24.8 mL, M-IBS – 161.0 ± 26.3 mL; P = 0.711) and all the other sensory thresholds did not differ among controls and IBS subsets after placebo (P > 0.05). In all subgroups of IBS, the first sensation and the pain thresholds were not different after sildenafil, relative to placebo. However, the first desire to defecate tended to be influenced by sildenafil differently, according to bowel habit. The tension for the first desire to defecate in D-IBS was higher but non-significantly after rectal relaxation (170 ± 29.9 vs. 226.8 ± 30.9 mmHg mL−1, P = 0.084; placebo vs. sildenafil, respectively). However, in D-IBS, sildenafil did not alter the volume or pressure thresholds for the first desire to defecate (114.8 ± 19.5 vs. 143.2 ± 15.0 mL, P = 0.321; 12.2 ± 1.4 vs. 17.4 ± 1.8 mmHg, P = 0.506; n = 6; placebo vs. sildenafil, respectively). On the other hand, sildenafil increased non-significantly the volume for triggering the first desire to defecate relative to placebo in C-IBS (138.8 ± 25.3 vs. 180.7 ± 16.9 mL, P = 0.052, n = 6) and M-IBS patients (105.1 ± 12.5 vs. 142.2 ± 16.2 mL, P = 0.051, n = 6).

Relationship between bowel behaviour and psychiatric attributes

In general, IBS patients were more depressive than control individuals, as appreciated by a higher Hamilton score (Table 4). Anxiety and depression scores did not differ between C-IBS, D-IBS and M-IBS. M-IBS patients, however, obtained higher anxiety and depression scores than controls (Table 4). After sildenafil, the anxiety scores correlated significantly with tension threshold for the first desire to defecate in the M-IBS (r = 0.87, P = 0.024, n = 6).

Table 4. Hamilton's anxiety and depression score in irritable bowel syndrome (IBS) patients and control volunteers. Depression was significantly more intense in IBS patients than in controls
 Controls (n = 8)IBS (n = 21)C-IBS (n = 7)D-IBS (n = 6)M-IBS (n = 8)
  1. Controls vs. C-IBS vs. D-IBS vs. M-IBS tends to be different (Kruskal–Wallis, P = 0.111 for anxiety scores and P = 0.130 for depression scores). Data presented as mean ± S.E.M.

  2. a

    IBS vs. Controls, P = 0.036 (Mann–Whitney).

  3. b

    M-IBS vs. Controls, P < 0.05 (Dunn's Multiple Comparison Test).

Anxiety scores5.9 ± 3.110.6 ± 1.48.4 ± 2.110.0 ± 4.012.9 ± 1.3b
Depression scores6.3 ± 2.511.9 ± 1.3a11.0 ± 2.210.2 ± 2.713.9 ± 1.9b

Somatic pain

Irritable bowel syndrome patients and control volunteers did not differ in relation to intensity of discomfort after hand immersion in hot water (45 °C: 28.9 ± 6.3 mm, n = 12 vs. 29.7 ± 7.1 mm, n = 8, P = 0.877 for IBS vs. controls, respectively; 47 °C: 40.3 ± 5.8 mm, n = 12 vs. 38.2 ± 6.8 mm, n = 8, P = 0.939 for IBS vs. controls, respectively). Sildenafil did not alter these results (45 °C: 24.4 ± 4.3 mm, n = 12, vs. 24.1 ± 4.6 mm, n = 8, P = 0.699 for IBS vs. controls, respectively; 47 °C: 39.1 ± 5.9 mm, n = 12 vs. 39.4 ± 7.7 mm, n = 8, P = 0.939 for IBS vs. controls, respectively).

Discussion

Sensorimotor function of the rectum was evaluated in patients with IBS and in control volunteers. There was no significant rectal tone derangement in IBS volunteers, as shown by our data regarding pressure vs. volume relationship. Importantly, the threshold that triggered pain was the same for IBS patients and controls. However, the amount of perceived pain was larger in IBS, particularly for supraliminar pain. Rectal relaxation did not change either the pain threshold or intensity. In the relaxed state, rectal compliance and the volume threshold for the first desire to defecate increased, indicating the involvement of rectal tone in the defecation mechanism. However, such increase in compliance and volume occurred only for the IBS patients with either diarrhoea or constipation. Patients with a mixed bowel habit (M-IBS) did not respond to sildenafil. Furthermore, IBS patients, particularly the M-IBS subgroup, got greater anxiety or depression scores, relative to controls. As discussed below, pain in IBS is a more complex phenomenon and may depend mainly upon factors related to the central nervous system (CNS). On the other hand, desire to defecate may be a simpler perception, directly related to rectal compliance.

This study was carried out with a state-of-the-art distension method, using a barostat system.[10] A double-blind, randomized, placebo-controlled design minimised bias. Moreover, great care was taken to reduce anticipation when measuring sensory thresholds (DRS distensions). To our knowledge, this design has not previously been used on patients with irritable bowel syndrome, while studying rectal sensorimotor function.

Very few studies have addressed the issue of rectal sensorimotor function while reducing rectal tone. We not only found sildenafil to significantly increase rectal compliance as shown by the volume/pressure ratio at different distension pressures, but the increase was quite relevant (30% rectal volume increase after treatment with sildenafil). Other studies yielded varying degrees of visceral relaxation. IBS patients experienced an increase in rectal volume of approximately 4% with gabapentine[11] and approximately 30% with sildenafil.[15] In another study, sildenafil produced a 40% increase in stomach volume.[8] Likewise, glucagon led to an increase in intragastric volume of 30 ± 9% in healthy volunteers.[23] One of the greatest reductions in visceral tone reported occurred after administration with nitroglycerine and clonidine. These drugs increased gastric volume in healthy subjects by approximately 138% and 60%, respectively.[12] These data validate sildenafil as a pharmacological tool for studying sensorimotor function in a relaxed state of the rectum.

Relaxation is commonly believed to reduce visceral pain; indeed, viscera tone correlates with sensitivity.[23] In the present study, however, the sildenafil-induced increase in rectal volume was not associated with changes in pain perception, except for the subset of hypersensitive patients. The fact that most of our patients did not present visceral hypersensitivity (this was not a selection criterion) may have reduced the sensitivity of our study to detect pain threshold shifts due to tone reduction in the IBS volunteers as a whole. Other studies of different visceral systems found interestingly results similar to ours. Gastric relaxation alone, induced by either clonidine or nitroglycerine, was not sufficient to reduce sensation in general, and pain in particular, in normal volunteers. Marked gastric relaxation with nitroglycerine did not only fail to reduce sensation but increased bloating and nausea.[12] Other data support the view that some visceral sensations may be largely unrelated to tone. Rectal pain in IBS decreased slightly with L-NMMA, although compliance remained unchanged.[5] Also in IBS, fedotozine increased pain thresholds even without a significant increase in colon compliance.[13]

Pain does not depend solely on mechanical factors, but also on mechanisms independent of visceral tone, which may not be influenced by sildenafil. Sildenafil appears to act primarily in the periphery,[8, 15, 24-27] although it may enhance cognitive function.[28, 29] Some authors have also reported sildenafil-induced changes in memory function[28-30] and in neurogenesis.[31, 32] However, its effects on pain in IBS remain largely unclear. We were careful to demonstrate that sildenafil produced no measurable effect on somatic pain under our experimental conditions.

Stress and anxiety alter both perception and gut motor function. Colonic tone during emotional stress increased strikingly in healthy individuals.[33] Also, induction of anxiety in normal subjects reduced gastric compliance and accommodation while significantly increasing the scores for satiety, fullness and bloating.[14] In our study, patients with mixed bowel habit (M-IBS) had higher anxiety and depression scores than control volunteers. Such psychological factors might account for the poor tone inhibition after administration of sildenafil in these patients, at least in part. Bowel habit has been associated with distinct sensorimotor patterns in IBS. Compliance was lower in IBS patients with diarrhoea than in those with constipation,[34] while urgency increased in the former.[34, 35] Our data showed that a variable bowel habit, that is, M-IBS, might be associated with unsatisfactory rectal tone reduction with sildenafil. Awareness of such associations may help optimise clinical decision-making in IBS. A strong correlation between pain intensity and threshold pain pressure was observed for M-IBS patients after sildenafil. In other words, sildenafil did not change the pain threshold, but in M-IBS pain perception increased with increasing stimulation. Such significant correlation did not occur in C-IBS or D-IBS. M-IBS may be associated with a greater elaboration of pain perception. Elaboration means that patients with this syndrome subtype may add more psychosocial factors to their pain reporting, as indicated by higher anxiety and depression scores. Although it could not be explained fully why M-IBS, C-IBS and D-IBS patients respond differently to sildenafil, it can be said that perceptions associated with defecation depend more on rectal mechanical factors. More elaborate perception, such as rectal pain in IBS patients with psychological distress, does not depend so much on tone, and is possibly more related to anxiety and depression.

Our findings suggest a possible contribution of nitrergic mechanisms modulating the rectal sensorimotor function and provide directions for future clinical research. They indicate that rectal defecation symptoms may be controlled by mechanical interventions while mood disorders and other CNS-related factors should be considered when the problem is pain. Patients with greatly variable bowel habits appear to make up a significantly different category of IBS. Such variability may reflect a large amount of pathogenic factors. This study shows the importance of categorising IBS patients, and points to a visceral landmark of psychological distress, that is, bowel habit.

Acknowledgements

Declaration of personal interests: None. Declaration of funding interests: This study was funded in full by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grant number 481098/2009-7.

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