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The κ agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome
GASTROENTEROLOGY 1999;116:38–45
The k Agonist Fedotozine Relieves Hypersensitivity to Colonic Distention in Patients With Irritable Bowel Syndrome MICHEL DELVAUX,* DOMINIQUE LOUVEL,* EMMANUEL LAGIER,* BRUNO SCHERRER,‡ JEAN–LOUIS ABITBOL,‡ and JACQUES FREXINOS* *Laboratory of Digestive Motility, Gastroenterology Unit, Centre Hospitalier Universitaire Rangueil, Toulouse; and ‡Jouveinal Research Institute, Fresnes, France
Background & Aims: Visceral hypersensitivity plays a major role in the pathophysiology of inflammatory bowel syndrome (IBS). Opioid k receptors on afferent nerves may modulate it and may be the target of new IBS treatments. The aim of this study was to evaluate the effects of fedotozine, a potent and selective k agonist, on responses to colonic distention and colonic compliance in patients with IBS. Methods: Fourteen patients with IBS (Rome criteria; 50 6 12 years; 6 men and 8 women) were included in a randomized doubleblind, crossover trial comparing the effect of an intravenous infusion of 100 mg fedotozine or saline on sensory thresholds elicited by left colon phasic distention (4–mm Hg steps for 5 minutes) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves built on placebo and on fedotozine. Results: In the fedotozine group, thresholds of first perception (28.7 6 5.9 mm Hg) and pain (34.7 6 5.5 mm Hg) were significantly greater than with placebo (23.3 6 4.5 and 29.0 6 3.5 mm Hg, respectively; P 5 0.0078). Colonic compliance was 9.20 6 3.87 mL · mm Hg21 with placebo and 8.73 6 3.18 mL · mm Hg21 with fedotozine (not significant). Conclusions: Fedotozine increases thresholds of perception of colonic distention in patients with IBS without modifying colonic compliance. Fedotozine seems capable of reversing visceral hypersensitivity observed in these patients and could have some beneficial action on their symptoms.
lthough the pathophysiology of irritable bowel syndrome (IBS) remains largely unknown, a common feature associated with this disorder is abdominal pain or discomfort. A variety of motility disorders have been described, but there is no consensus regarding alterations of colonic motility under basal conditions1,2 during emotional stress,3–5 after a meal,1,6,7 or in response to pharmacological stimulation.6,8 It has become apparent that a decreased threshold for visceral sensitivity may play an important role in the pathophysiology of IBS.9–14 One of the primary events responsible for the generation of abdominal symptoms in IBS might be the passage of a
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gas bolus that stretches the gastrointestinal lumen, stimulating afferent discharge and perception of pain.15 This offers several strategies that may be used in the development of therapeutic agents for the treatment of IBS, agents that increase the compliance of the gut and/or agents targeted at decreasing transmission along the neuronal pain pathway. Several neutrotransmitters play an important role as mediators of the antinociceptive pathways, including serotonin, opioids, vasopressin, substance P, and neurotensin.16 Among these possible targets for new treatments of IBS, fedotozine has shown promising results in both basic and clinical studies. It acts mainly as an agonist of k opiate receptors17 and is able to alter the function of digestive afferent nerve pathways in various animal models.17–20 Clinically, fedotozine has also been shown to improve abdominal symptoms related to functional bowel disorders.21 Recently, it was shown to alter the sensory thresholds elicited by gastric distention in healthy volunteers.22 By contrast, fedotozine showed very few effects on colonic motility in these models.23 Consequently, we designed this double-blind, randomized crossover study to investigate the effects of fedotozine on the perception of isobaric colonic distention by patients with IBS and on the colonic compliance to distention with a barostat. To further investigate the possible effects of fedotozine on colonic tone, we also measured basal and postcibal tone with the barostat in these patients.
Patients and Methods Patients The study was divided into two parts. Part one was designed to evaluate sensory thresholds elicited by colonic distention. Twelve patients were to be included in this part of the study. Six additional patients were to be studied in part
Abbreviation used in this paper: IBS, irritable bowel syndrome. r 1999 by the American Gastroenterological Association 0016-5085/99/$10.00
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two, which evaluated the effect of fedotozine on fasting and postprandial colonic tone. All patients had a clinical diagnosis of IBS based on Rome criteria.24 Patients gave informed consent to participate in the experimental procedures approved by the Regional Ethical Board (CCPPRB Toulouse I). They were required to have a normal physical examination and no antecedent of abdominal surgery (except appendectomy or cholecystectomy). Colonoscopy performed to place the barostat probe in the left colon did not show any abnormality in all patients. No patient was taking medication other than oral contraceptives for at least 15 days before the study. A negative pregnancy test result was recorded for all women included in the study.
Recording Assembly Barostat. The device (Barostat INRA; Toulouse, France) consisted of a sensitive pressure transducer described previously in detail.25 The system could be activated with a lag time of 10 milliseconds, and the maximal air flow was 30 mL/s. The volume of air inside the bag was determined electronically by the computer from the known excursion of the bellows within the reservoir system. The barostat apparatus included a built-in computer system that could be programmed to automatically perform distentions with fixed time lag (5minute duration and 5-minute interval with return to baseline volume between each successive increment) and bag pressure increments (4–mm Hg increments). Distentions could therefore be performed by completely deflating the bag between each pressure increment. Colonic probe. A single-lumen silicone tube (8-mm diameter, Silastic; Dow Corning, Midland, MI) was assembled so that the lumen was located within the barostat bag and the open end of the tube connected to the output of the bellows chamber. A thin-wall polyethylene bag (40 µm) was fastened tightly to the tube. The maximal capacity of the bag (during table-top inflation) was 500 mL with a maximal length of 10 cm. Before placement in the colon, the barostat bag was checked for air leaks at the pressure of 20 mm Hg maintained during 15 minutes. Within the range of volumes used in this study, the barostat bag compliance was considered infinite.14
Conduct of the Study All experimental procedures are summarized in Figure 1. Colonic probe placement. This study was a doubleblind, randomized, placebo-controlled, crossover trial. On the afternoon of the day before the colonoscopy, patients were admitted to the clinical research unit. Preparations started by ingestion of 4 L of polyethylene glycol 4000. On the morning of the next day (day 0), bowel cleansing was completed by repeated tap water enemas until all fecal effluent was clear fluid, free of any particulate matter. Patients came to the endoscopic unit after a 12-hour fast and adequate bowel preparation. Colonoscopy was performed on day 6 at 9 AM with the patients in the left lateral position using minimal air insufflation. Premedication included intravenous propofol (2 mg/kg; ICI-Pharma, Cergy, France), under surveillance of an
Figure 1. Study design, including the phase of selection of patients and the experimental procedures in protocols 1 (distention) and 2 (tone recording).
anesthesiologist. Colonoscopy (CFV100; Olympus, Tokyo, Japan) was performed to the cecum in all patients, and the barostat bag was positioned in the descending colon. Patients were then transported to a recovery room where they were allowed to rest. All experimental procedures began on the day after the colonoscopy to allow a full recovery from anesthesia. Position of the barostat bag was verified fluoroscopically before and after the experimental procedures. Distention protocol. On day 1, the day after the colonoscopy, patients remained fasted. At 10 AM, the barostat bag was used to perform intracolonic isobaric distentions to determine the basal pain threshold that was used as the final inclusion criterion (see above). Patients were requested to remain in a 30° supine position during the entire recording session. Distentions were performed automatically by the computerized barostat to achieve successive increments of 4 mm Hg every 5 minutes preceded by completely deflating the barostat bag for 5 minutes before the next distention until the pain threshold was reached. Using a standardized visceral perception questionnaire, patients were asked when they were first aware of the colonic balloon (threshold of first perception) and then when they first felt abdominal pain (threshold of pain). At the pain threshold or when the maximum pressure of
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48 mm Hg was reached, the bag was deflated, and this completed the distention session. After randomization, a second attempt to distend was performed using the same protocol at 2 PM, but an intravenous infusion was started 30 minutes before the first step of distention, which contained either 200 mL saline (placebo) or 200 mL saline plus 100 mg fedotozine. Treatments were administered in a double-blind, randomized way. The infusion of treatments lasted 90 minutes and, therefore, covered the time at which the pain threshold was reached in all patients. On day 2, the same sequence of experiments was repeated, but treatments were interchanged during the second session of distention. At the end of this last distention attempt, the probe was removed gently from the colon, and this completed the study. Tone measurements. The placement of the probe on day 0 followed exactly the same protocol as in part 1. On days 0 and 1, the barostat was used for the recording of the colonic tone. Patients were requested to remain in a 30° supine position during the entire recording session. The barostat was set up to maintain a constant pressure in the bag that was equal to the pressure allowing the recording of respiratory movements plus 2 mm Hg. Then the volume of the bag was monitored continuously because volume changes are supposed to reflect tone variations of the colon.14 All recordings started at 6 PM. After a basal recording of 30 minutes, an intravenous infusion was started that contained either 200 mL saline (placebo) or 200 mL saline plus 100 mg fedotozine. Treatments were administered in a double-blind, randomized way. The infusion of treatments lasted 90 minutes. Thirty minutes after the beginning of the infusion, the patients were served with a standardized meal of 4200 kJ (40% fat and 60% glucides). The tone recording was continued until the end of tone changes.
Data Analysis Distention thresholds. Pressure and volume of the barostat bag were recorded simultaneously at each distention step by a potentiometric recorder (BS270 Gould; Paris, France). The minimum pressure reported for first sensation and abdominal pain was considered as the only criterion-defining thresholds. Patients reported sensations on a 6-degree verbalrating scale. The statistical analysis was based on pretreatment and posttreatment differences. The pretreatment data were analyzed to exclude a first-order residual effect (Student t test for paired series). A model of analysis of variance involving the treatment effect linked to the period effect, the subject effect linked to the sequence effect, the period effect, and the sequence effect was to be used. In the case of a significant sequence effect, the cause (residual effect or lack of comparability of the groups) and the nature (quantitative and qualitative) would be investigated. An analysis of variance for crossover design was performed on pretreatment values to test comparability of the sequence groups at inclusion and a possible residual effect of fedotozine. The same test based on pretreatment and posttreatment differences was performed to test fedotozine effect.
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Minimum barostat volumes associated with a first sensation and pain were analyzed in the same way. Mean slopes of the pressure-volume curves were estimated by linear regression and compared using analysis of variance between placebo and each fedotozine. All P values of ,0.05 were considered significant in this study. Tone measurements. The volume of the barostat bag was recorded continuously, and variations in colonic tone were calculated according to the following formula: DV 5 [(Vx 2 V0)/V0] p 100, where V0 is the volume of the barostat bag at baseline and Vx is the volume of the bag in the studied condition. Changes in colonic tone reflected by changes in barostat bag volume were compared by the paired Student t test. The duration of observed changes was compared with the same test. All P values of ,0.05 were considered significant.
Results Tolerance of the Treatment, Probe, and Technical Aspects of Recording Sessions Thirty patients were screened for completion of both parts of this study. Twenty-four of them were expected to participate in the first part of the study, evaluating sensory thresholds and the effect of fedotozine on them. After the first attempt of colonic distention was performed, 6 patients were excluded because they had a pain threshold of .32 mm Hg. Four additional patients were withdrawn after randomization because the colonic probe did not stay in the left colon during the whole study. Therefore, 14 patients (6 men and 8 women) were included in the efficacy analysis of the results. Their mean age was 50 6 12 years (range, 23–67 years). In the second part of the study, we evaluated the effect of fedotozine on colonic tone. Six patients (1 man and 5 women) were included in this study. Their mean age was 42 6 12 years (range, 26–51 years). No patient was withdrawn for this part of the study. Data from 24 patients were obtained for assessment of clinical tolerance of fedotozine. No serious adverse event occurred during the study. In all patients, the probe was well tolerated: diarrhea or urgent bowel movement did not occur. At the end of the recording session, the position of the probe was checked on a plain film of the abdomen. The tip of the probe was still in the descending colon in all evaluated patients. Effect of Fedotozine on Barostat Pressure Triggering Visceral Perception in Patients With IBS First sensation threshold. The mean 6 SD distending pressure inducing the first abdominal sensation was 24.3 6 4.7 mm Hg at the baseline distention before
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placebo and 23.7 6 4.0 mm Hg before the distention session during which fedotozine was infused. In the placebo group, the pressure triggering a first abdominal sensation was 23.3 6 4.5 mm Hg with a difference from baseline distention of 21.0 6 3.0 mm Hg. With 100 mg fedotozine intravenously, the pressure triggering a first abdominal sensation increased to 28.7 6 5.9 mm Hg with a difference from baseline distention of 5.0 6 4.6 mm Hg. The difference between responses in the placebo and fedotozine groups was highly significant (P 5 0.0078). Moreover, the curve of cumulative number of patients responding for a given distending pressure clearly shifted to the right on the x-axis, i.e., toward higher distending pressures (Figure 2A). Pain threshold. The mean 6 SD distending pressure inducing a painful sensation in the abdomen was 29.0 6 4.9 mm Hg at the baseline distention before
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placebo and 28.7 6 4.5 mm Hg before the distention session during which fedotozine was infused. On placebo, the pressure triggering a first abdominal sensation was 29.0 6 3.5 mm Hg with a difference from baseline distention of 0.0 6 3.4 mm Hg. On 100 mg fedotozine intravenously, the pressure triggering a painful sensation in the abdomen increased to 34.7 6 5.5 mm Hg with a difference from baseline distention of 6.0 6 5.5 mm Hg. The difference between responses on placebo and fedotozine was highly significant (P 5 0.0078). Moreover, the curve of cumulative number of patients responding for a given distending pressure clearly shifted to the right on the x-axis, i.e., toward higher distending pressures (Figure 2B). Effect of Fedotozine on the Volume of the Barostat Bag at Sensory Thresholds The mean volume of the barostat bag at the time of first sensation was 209.43 6 97.29 mL during dosing with placebo compared with 181.64 6 87.43 mL on 100 mg fedotozine intravenously (Figure 3A). The mean volume of the barostat bag at the time of pain sensation was 243.79 6 102.61 mL during dosing with placebo compared with 224.07 6 91.19 mL on 100 mg fedotozine intravenously (Figure 3B). There was no statistically significant difference between the two treatments for volumes at sensory thresholds. Pressure-Volume Relationship During Isobaric Distentions (Placebo and Alosetron) Pressure-volume curves (compliance curves) were plotted during isobaric distentions on placebo and fedotozine (Figure 4). Compliance, defined as the slope of the pressure-volume curve, was not different on both treatments: 9.20 6 3.87 mL · mm Hg21 on placebo vs. 8.73 6 3.18 mL · mm Hg21 on 100 mg fedotozine intravenously. There was no statistically significant difference between the two treatments for these slopes. Effect of Fedotozine on Colonic Tone and Response to Eating
Figure 2. Cumulative number of patients positively responding for the (A ) first sensation threshold and (B ) pain threshold on placebo (- - - -) and 100 mg fedotozine (—) intravenously.
The mean 6 SD operating pressure was 10.7 6 2.1 mm Hg on placebo and 10.6 6 2.4 mm Hg on fedotozine (not significant). The mean baseline volume of the barostat bag in fasting patients was 83.36 6 33.13 mL on placebo and 107.84 6 47.37 mL on fedotozine. This difference in tone of 222.7% was significant (P 5 0.034), indicating that fedotozine could produce a mild relaxation of the colon in the fasted state (Figure 5). After the meal, the bag volume decreased dramatically and rapidly regardless of the treatment given. In the
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Figure 4. Pressure-volume curve on placebo (N) and 100 mg fedotozine (j) intravenously. Values are expressed as means 6 SD of volumes measured in each patient.
intravenous infusion of fedotozine or placebo, resulting in stable plasma levels of fedotozine at the time when sensory thresholds were measured. However, because of the tight schedule of the protocols, we carefully excluded
Figure 3. Volume measured in the barostat bag at the (A ) first sensation and (B ) pain thresholds. Baseline distention was performed in the morning without any treatment. A second distention session was performed in the afternoon during the random infusion of placebo or 100 mg fedotozine.
placebo group, the bag volume was measured at 9.80 6 8.32 mL, indicating an increase in tone of 88.0%. With fedotozine, the bag volume was measured at 5.92 6 1.51 mL, corresponding to an increase of tone of 94.5% (Figure 5). This hypertonic response of the left colon to eating lasted 76 6 27 minutes on placebo and 77 6 43 minutes on fedotozine. The characteristics of the tonic colonic response to eating were not different when placebo or fedotozine was infused.
Discussion In this study we show that fedotozine, a k opioid receptors agonist, is able to relieve the hypersensitivity characterizing patients with painful IBS, whereas it does not alter colonic compliance and does not modify the characteristics of tonic response of the left colon to eating. All experimental procedures were based on a doubleblind, randomized, crossover protocol using a continuous
Figure 5. Volume of the barostat bag placed in the left colon under a constant operating pressure, defined as the pressure allowing the recording of respiratory movements plus 2 mm Hg. In the fasted state, the bag volume is slightly increased on fedotozine compared with placebo (P 5 0.035), indicating that fedotozine might induce a moderate relaxation of the colon. Variations of the barostat bag volume reflect changes in colonic tone. These changes are characterized by a dramatic decrease of the bag volume in the postprandial period on both placebo (j) and fedotozine (N).
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a carryover effect of experimental procedures on each other by including a baseline distention test in the morning, without any administration of drug, and a second distention test in the afternoon, during which drug or placebo was infused. This protocol allowed us to show an excellent reproducibility of sensory thresholds, as shown in Table 1. On the other hand, it has been claimed in the literature that sensory thresholds are highly sensitive to response bias induced by subjective feelings of studied subjects. To overcome them, sophisticated protocols with repeated distention attempts around the threshold have been proposed to make the stimulus actually random to the subject.26 However, in the present study, the high number of distention sessions performed over 2 days in each patient precluded the use of such long-lasting protocols of distention. The very good reproducibility observed for thresholds when comparing baseline and placebo distentions show that subjects’ perception biases were not interfering with their response to the distention test. Moreover, we recently showed data obtained in healthy volunteers confirming that sensory thresholds were equivalent when elicited with ascending method of limits and tracking or double-random staircase.27 This study design also allowed us to characterize the effect of fedotozine with a careful statistical analysis that took into account the difference induced by the treatment, either placebo or fedotozine from the thresholds elicited during baseline distention rather than by comparing directly the thresholds measured on placebo or fedotozine. Such an analysis was indeed not subjective to a possible carryover effect of the treatment on the first day on thresholds measured on the second day. Using this design, we also eliminated the risk of influence of external factors on sensory thresholds, such as gender and age. Visceral hypersensitivity to luminal distention has been investigated extensively during the last decade and is regarded as one of the main issues for understanding the pathophysiology of IBS. However, it is observed in Table 1. Pressure Determining Sensory and Pain Thresholds Elicited by Isobaric Distention of the Left Colon With a Barostat in Patients With IBS
Before placebo On placebo Difference Before fedotozine On fedotozine Difference Statistics a
First sensation (mm Hg)
Pain (mm Hg)
24.3 6 4.7 23.3 6 4.5 21.0 6 3.0 23.7 6 4.0 28.7 6 5.9 5.0 6 4.6 P , 0.0078
29.0 6 4.9 29.0 6 3.5 0.0 6 3.4 28.7 6 4.5 34.7 6 5.5 6.0 6 5.5 P , 0.0078
NOTE. Values are means 6 SD. performed on differences between baseline distention attempt and distention on placebo or fedotozine.
aComparison
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only two thirds patients with IBS14,28 and correlates over time with the intensity of symptoms.28 Because our study took place during a short period of time, we did not face such a variability of thresholds over time. However, considering the wide variation of sensory thresholds measured during colonic distention in IBS patients in our previous studies, we carefully selected patients who complained of pain at a distending pressure #32 mm Hg, which seemed to be a relevant threshold separating IBS patients and healthy controls.14,29 Moreover, patients were also selected on the basis of the Rome criteria24 and on the intensity of their symptoms during the 2 weeks before inclusion. Only patients with chronic and frequent pain attacks were included. This careful selection of the patients allowed us to evaluate a homogenous set of patients who are representative of hypersensitive patients with IBS. In these experimental conditions, fedotozine was able to significantly increase the pressure thresholds of first sensation and pain triggered by distention. Two of the possible approaches for reduction in abdominal pain associated with IBS are (1) to increase colonic compliance so that adaptation to luminal distention could be increased or (2) to inhibit transmission of the afferent neuronal signal. Considering the results of the present study, we assume that fedotozine acts directly on afferent pathways for relieving hypersensitivity in patients with IBS. Indeed, its effect was marked on sensory thresholds (more than one step of distention difference between treatments). It seems to not result from a pure analgesic effect because fedotozine equally affected the perception of nonnociceptive (first sensation threshold) and nociceptive (pain threshold) stimuli. On the other hand, several arguments support the assumption that the effect of fedotozine also does not result from an alteration of the compliance of the colonic wall: (1) similar pressurevolume relationships during distentions performed on placebo and fedotozine; (2) compliance, defined as the slope of these curves, not different on placebo and fedotozine; and (3) absence of effect of fedotozine on colonic tone. Considering the last point, fedotozine decreased slightly the fasting tone of the left colon (222%). However, this effect was weak, and a similar relaxation of the colon was not observed when comparing the volumes of the bag measured at thresholds. We therefore cannot explain the effect of fedotozine by a relaxation of the colon that would allow it to accommodate larger volumes of distention. It has also been shown that the key factor determining visceral hypersensitivity was the transparietal tension rather than the distending volume.30 Thus, we conclude that the effect of fedotozine is
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caused by its action on peripheral sensory pathways based on the following arguments: (1) k receptors are present on somatic sensory pathways and k agonists are able to relieve pain when locally administered31; (2) k agonists reverse the pain reflex triggered by duodenal distention in rats18; (3) comparison between the effects of morphine and a k agonist administered either centrally or peripherally shows that morphine acts centrally, whereas the k agonist U-50,488H acts on peripheral pathways32; (4) fedotozine reverses the motility disturbances induced by surgery or peritonitis17,20; and (5) fedotozine blocks visceral pain triggered by colonic distention in conscious rats sensitized with previous colonic injection of acetic acid, and this effect occurs only after peripheral administration of fedotozine and is blocked by the k antagonist norbinaltorphimine.33 The receptors for neurotransmitters present on visceral sensory pathways are targets for new treatments of functional bowel disorders. Based on the pathophysiological concept of a diffuse hypersensitivity of the gut in patients with IBS, the question is raised whether distention tests could predict a clinical effect of drugs in treating abdominal pain in IBS patients. Although fedotozine was administered intravenously in the present study, the infusion rate allowed it to reach plasma levels similar to those measured after long-term oral administration of 30 mg fedotozine three times daily. At this dose, fedotozine has been shown effective in relieving symptoms and improving quality of life in patients with IBS.21 Moreover, the analysis of the cumulative curve of positive responses to distention shows that the effect of fedotozine was observed in all patients. The amplitude of the effect induced by fedotozine is also very important from a clinical point of view because the action of fedotozine shifted sensory thresholds up to values observed previously in healthy controls,29 indicating that fedotozine could actually normalize colonic perception of luminal distention in patients with IBS. On the other hand, in the absence of any significant effect on colonic motility, fedotozine could be prescribed indistinctly to patients with either constipation-prone IBS or functional diarrhea because the treatment would be aimed at primarily relieving pain and would not affect bowel habits. We conclude that the clinical effect of fedotozine could be related to its direct action on visceral sensory pathways; this observation reinforces the assumption that visceral hypersensitivity is a determinant causal factor of functional bowel disorders.
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31. Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989;248:1269–1275. 32. Junien JL. Role of peripheral kappa receptors in the modulation of pain. In: Galmiche JP, Fraitag B, eds. Sensitive gastrointestinal disorders: fedotozine contribution to drug therapy. Paris: John Libbey Eurotext, 1995:23–30. 33. Langlois A, Diop L, Friese N, Pascaud X, Junien JL, Dahl SG, Riviere PJ. Fedotozine blocks hypersensitive visceral pain in conscious rats: action at peripheral kappa-opioid receptors. Eur J Pharmacol 1997;324:211–217.
Received March 24, 1998. Accepted September 29, 1998. Address requests for reprints to: Michel Delvaux, M.D., Ph.D., Gastroenterology Unit, CHU Rangueil, F-31403, Toulouse Ce ´dex 04, France. e-mail: [email protected]; fax: (33) 561-3222-29. Supported by a grant from the Jouveinal Research Institute, Paris, France. The authors thank Marcel Caussette and Thierry Hachet for providing the probes and maintaining the barostat and the nurses at the Clinical Unit of Gastroenterology for surveillance recordings.
The k Agonist Fedotozine Relieves Hypersensitivity to Colonic Distention in Patients With Irritable Bowel Syndrome MICHEL DELVAUX,* DOMINIQUE LOUVEL,* EMMANUEL LAGIER,* BRUNO SCHERRER,‡ JEAN–LOUIS ABITBOL,‡ and JACQUES FREXINOS* *Laboratory of Digestive Motility, Gastroenterology Unit, Centre Hospitalier Universitaire Rangueil, Toulouse; and ‡Jouveinal Research Institute, Fresnes, France
Background & Aims: Visceral hypersensitivity plays a major role in the pathophysiology of inflammatory bowel syndrome (IBS). Opioid k receptors on afferent nerves may modulate it and may be the target of new IBS treatments. The aim of this study was to evaluate the effects of fedotozine, a potent and selective k agonist, on responses to colonic distention and colonic compliance in patients with IBS. Methods: Fourteen patients with IBS (Rome criteria; 50 6 12 years; 6 men and 8 women) were included in a randomized doubleblind, crossover trial comparing the effect of an intravenous infusion of 100 mg fedotozine or saline on sensory thresholds elicited by left colon phasic distention (4–mm Hg steps for 5 minutes) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves built on placebo and on fedotozine. Results: In the fedotozine group, thresholds of first perception (28.7 6 5.9 mm Hg) and pain (34.7 6 5.5 mm Hg) were significantly greater than with placebo (23.3 6 4.5 and 29.0 6 3.5 mm Hg, respectively; P 5 0.0078). Colonic compliance was 9.20 6 3.87 mL · mm Hg21 with placebo and 8.73 6 3.18 mL · mm Hg21 with fedotozine (not significant). Conclusions: Fedotozine increases thresholds of perception of colonic distention in patients with IBS without modifying colonic compliance. Fedotozine seems capable of reversing visceral hypersensitivity observed in these patients and could have some beneficial action on their symptoms.
lthough the pathophysiology of irritable bowel syndrome (IBS) remains largely unknown, a common feature associated with this disorder is abdominal pain or discomfort. A variety of motility disorders have been described, but there is no consensus regarding alterations of colonic motility under basal conditions1,2 during emotional stress,3–5 after a meal,1,6,7 or in response to pharmacological stimulation.6,8 It has become apparent that a decreased threshold for visceral sensitivity may play an important role in the pathophysiology of IBS.9–14 One of the primary events responsible for the generation of abdominal symptoms in IBS might be the passage of a
A
gas bolus that stretches the gastrointestinal lumen, stimulating afferent discharge and perception of pain.15 This offers several strategies that may be used in the development of therapeutic agents for the treatment of IBS, agents that increase the compliance of the gut and/or agents targeted at decreasing transmission along the neuronal pain pathway. Several neutrotransmitters play an important role as mediators of the antinociceptive pathways, including serotonin, opioids, vasopressin, substance P, and neurotensin.16 Among these possible targets for new treatments of IBS, fedotozine has shown promising results in both basic and clinical studies. It acts mainly as an agonist of k opiate receptors17 and is able to alter the function of digestive afferent nerve pathways in various animal models.17–20 Clinically, fedotozine has also been shown to improve abdominal symptoms related to functional bowel disorders.21 Recently, it was shown to alter the sensory thresholds elicited by gastric distention in healthy volunteers.22 By contrast, fedotozine showed very few effects on colonic motility in these models.23 Consequently, we designed this double-blind, randomized crossover study to investigate the effects of fedotozine on the perception of isobaric colonic distention by patients with IBS and on the colonic compliance to distention with a barostat. To further investigate the possible effects of fedotozine on colonic tone, we also measured basal and postcibal tone with the barostat in these patients.
Patients and Methods Patients The study was divided into two parts. Part one was designed to evaluate sensory thresholds elicited by colonic distention. Twelve patients were to be included in this part of the study. Six additional patients were to be studied in part
Abbreviation used in this paper: IBS, irritable bowel syndrome. r 1999 by the American Gastroenterological Association 0016-5085/99/$10.00
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two, which evaluated the effect of fedotozine on fasting and postprandial colonic tone. All patients had a clinical diagnosis of IBS based on Rome criteria.24 Patients gave informed consent to participate in the experimental procedures approved by the Regional Ethical Board (CCPPRB Toulouse I). They were required to have a normal physical examination and no antecedent of abdominal surgery (except appendectomy or cholecystectomy). Colonoscopy performed to place the barostat probe in the left colon did not show any abnormality in all patients. No patient was taking medication other than oral contraceptives for at least 15 days before the study. A negative pregnancy test result was recorded for all women included in the study.
Recording Assembly Barostat. The device (Barostat INRA; Toulouse, France) consisted of a sensitive pressure transducer described previously in detail.25 The system could be activated with a lag time of 10 milliseconds, and the maximal air flow was 30 mL/s. The volume of air inside the bag was determined electronically by the computer from the known excursion of the bellows within the reservoir system. The barostat apparatus included a built-in computer system that could be programmed to automatically perform distentions with fixed time lag (5minute duration and 5-minute interval with return to baseline volume between each successive increment) and bag pressure increments (4–mm Hg increments). Distentions could therefore be performed by completely deflating the bag between each pressure increment. Colonic probe. A single-lumen silicone tube (8-mm diameter, Silastic; Dow Corning, Midland, MI) was assembled so that the lumen was located within the barostat bag and the open end of the tube connected to the output of the bellows chamber. A thin-wall polyethylene bag (40 µm) was fastened tightly to the tube. The maximal capacity of the bag (during table-top inflation) was 500 mL with a maximal length of 10 cm. Before placement in the colon, the barostat bag was checked for air leaks at the pressure of 20 mm Hg maintained during 15 minutes. Within the range of volumes used in this study, the barostat bag compliance was considered infinite.14
Conduct of the Study All experimental procedures are summarized in Figure 1. Colonic probe placement. This study was a doubleblind, randomized, placebo-controlled, crossover trial. On the afternoon of the day before the colonoscopy, patients were admitted to the clinical research unit. Preparations started by ingestion of 4 L of polyethylene glycol 4000. On the morning of the next day (day 0), bowel cleansing was completed by repeated tap water enemas until all fecal effluent was clear fluid, free of any particulate matter. Patients came to the endoscopic unit after a 12-hour fast and adequate bowel preparation. Colonoscopy was performed on day 6 at 9 AM with the patients in the left lateral position using minimal air insufflation. Premedication included intravenous propofol (2 mg/kg; ICI-Pharma, Cergy, France), under surveillance of an
Figure 1. Study design, including the phase of selection of patients and the experimental procedures in protocols 1 (distention) and 2 (tone recording).
anesthesiologist. Colonoscopy (CFV100; Olympus, Tokyo, Japan) was performed to the cecum in all patients, and the barostat bag was positioned in the descending colon. Patients were then transported to a recovery room where they were allowed to rest. All experimental procedures began on the day after the colonoscopy to allow a full recovery from anesthesia. Position of the barostat bag was verified fluoroscopically before and after the experimental procedures. Distention protocol. On day 1, the day after the colonoscopy, patients remained fasted. At 10 AM, the barostat bag was used to perform intracolonic isobaric distentions to determine the basal pain threshold that was used as the final inclusion criterion (see above). Patients were requested to remain in a 30° supine position during the entire recording session. Distentions were performed automatically by the computerized barostat to achieve successive increments of 4 mm Hg every 5 minutes preceded by completely deflating the barostat bag for 5 minutes before the next distention until the pain threshold was reached. Using a standardized visceral perception questionnaire, patients were asked when they were first aware of the colonic balloon (threshold of first perception) and then when they first felt abdominal pain (threshold of pain). At the pain threshold or when the maximum pressure of
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48 mm Hg was reached, the bag was deflated, and this completed the distention session. After randomization, a second attempt to distend was performed using the same protocol at 2 PM, but an intravenous infusion was started 30 minutes before the first step of distention, which contained either 200 mL saline (placebo) or 200 mL saline plus 100 mg fedotozine. Treatments were administered in a double-blind, randomized way. The infusion of treatments lasted 90 minutes and, therefore, covered the time at which the pain threshold was reached in all patients. On day 2, the same sequence of experiments was repeated, but treatments were interchanged during the second session of distention. At the end of this last distention attempt, the probe was removed gently from the colon, and this completed the study. Tone measurements. The placement of the probe on day 0 followed exactly the same protocol as in part 1. On days 0 and 1, the barostat was used for the recording of the colonic tone. Patients were requested to remain in a 30° supine position during the entire recording session. The barostat was set up to maintain a constant pressure in the bag that was equal to the pressure allowing the recording of respiratory movements plus 2 mm Hg. Then the volume of the bag was monitored continuously because volume changes are supposed to reflect tone variations of the colon.14 All recordings started at 6 PM. After a basal recording of 30 minutes, an intravenous infusion was started that contained either 200 mL saline (placebo) or 200 mL saline plus 100 mg fedotozine. Treatments were administered in a double-blind, randomized way. The infusion of treatments lasted 90 minutes. Thirty minutes after the beginning of the infusion, the patients were served with a standardized meal of 4200 kJ (40% fat and 60% glucides). The tone recording was continued until the end of tone changes.
Data Analysis Distention thresholds. Pressure and volume of the barostat bag were recorded simultaneously at each distention step by a potentiometric recorder (BS270 Gould; Paris, France). The minimum pressure reported for first sensation and abdominal pain was considered as the only criterion-defining thresholds. Patients reported sensations on a 6-degree verbalrating scale. The statistical analysis was based on pretreatment and posttreatment differences. The pretreatment data were analyzed to exclude a first-order residual effect (Student t test for paired series). A model of analysis of variance involving the treatment effect linked to the period effect, the subject effect linked to the sequence effect, the period effect, and the sequence effect was to be used. In the case of a significant sequence effect, the cause (residual effect or lack of comparability of the groups) and the nature (quantitative and qualitative) would be investigated. An analysis of variance for crossover design was performed on pretreatment values to test comparability of the sequence groups at inclusion and a possible residual effect of fedotozine. The same test based on pretreatment and posttreatment differences was performed to test fedotozine effect.
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Minimum barostat volumes associated with a first sensation and pain were analyzed in the same way. Mean slopes of the pressure-volume curves were estimated by linear regression and compared using analysis of variance between placebo and each fedotozine. All P values of ,0.05 were considered significant in this study. Tone measurements. The volume of the barostat bag was recorded continuously, and variations in colonic tone were calculated according to the following formula: DV 5 [(Vx 2 V0)/V0] p 100, where V0 is the volume of the barostat bag at baseline and Vx is the volume of the bag in the studied condition. Changes in colonic tone reflected by changes in barostat bag volume were compared by the paired Student t test. The duration of observed changes was compared with the same test. All P values of ,0.05 were considered significant.
Results Tolerance of the Treatment, Probe, and Technical Aspects of Recording Sessions Thirty patients were screened for completion of both parts of this study. Twenty-four of them were expected to participate in the first part of the study, evaluating sensory thresholds and the effect of fedotozine on them. After the first attempt of colonic distention was performed, 6 patients were excluded because they had a pain threshold of .32 mm Hg. Four additional patients were withdrawn after randomization because the colonic probe did not stay in the left colon during the whole study. Therefore, 14 patients (6 men and 8 women) were included in the efficacy analysis of the results. Their mean age was 50 6 12 years (range, 23–67 years). In the second part of the study, we evaluated the effect of fedotozine on colonic tone. Six patients (1 man and 5 women) were included in this study. Their mean age was 42 6 12 years (range, 26–51 years). No patient was withdrawn for this part of the study. Data from 24 patients were obtained for assessment of clinical tolerance of fedotozine. No serious adverse event occurred during the study. In all patients, the probe was well tolerated: diarrhea or urgent bowel movement did not occur. At the end of the recording session, the position of the probe was checked on a plain film of the abdomen. The tip of the probe was still in the descending colon in all evaluated patients. Effect of Fedotozine on Barostat Pressure Triggering Visceral Perception in Patients With IBS First sensation threshold. The mean 6 SD distending pressure inducing the first abdominal sensation was 24.3 6 4.7 mm Hg at the baseline distention before
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placebo and 23.7 6 4.0 mm Hg before the distention session during which fedotozine was infused. In the placebo group, the pressure triggering a first abdominal sensation was 23.3 6 4.5 mm Hg with a difference from baseline distention of 21.0 6 3.0 mm Hg. With 100 mg fedotozine intravenously, the pressure triggering a first abdominal sensation increased to 28.7 6 5.9 mm Hg with a difference from baseline distention of 5.0 6 4.6 mm Hg. The difference between responses in the placebo and fedotozine groups was highly significant (P 5 0.0078). Moreover, the curve of cumulative number of patients responding for a given distending pressure clearly shifted to the right on the x-axis, i.e., toward higher distending pressures (Figure 2A). Pain threshold. The mean 6 SD distending pressure inducing a painful sensation in the abdomen was 29.0 6 4.9 mm Hg at the baseline distention before
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placebo and 28.7 6 4.5 mm Hg before the distention session during which fedotozine was infused. On placebo, the pressure triggering a first abdominal sensation was 29.0 6 3.5 mm Hg with a difference from baseline distention of 0.0 6 3.4 mm Hg. On 100 mg fedotozine intravenously, the pressure triggering a painful sensation in the abdomen increased to 34.7 6 5.5 mm Hg with a difference from baseline distention of 6.0 6 5.5 mm Hg. The difference between responses on placebo and fedotozine was highly significant (P 5 0.0078). Moreover, the curve of cumulative number of patients responding for a given distending pressure clearly shifted to the right on the x-axis, i.e., toward higher distending pressures (Figure 2B). Effect of Fedotozine on the Volume of the Barostat Bag at Sensory Thresholds The mean volume of the barostat bag at the time of first sensation was 209.43 6 97.29 mL during dosing with placebo compared with 181.64 6 87.43 mL on 100 mg fedotozine intravenously (Figure 3A). The mean volume of the barostat bag at the time of pain sensation was 243.79 6 102.61 mL during dosing with placebo compared with 224.07 6 91.19 mL on 100 mg fedotozine intravenously (Figure 3B). There was no statistically significant difference between the two treatments for volumes at sensory thresholds. Pressure-Volume Relationship During Isobaric Distentions (Placebo and Alosetron) Pressure-volume curves (compliance curves) were plotted during isobaric distentions on placebo and fedotozine (Figure 4). Compliance, defined as the slope of the pressure-volume curve, was not different on both treatments: 9.20 6 3.87 mL · mm Hg21 on placebo vs. 8.73 6 3.18 mL · mm Hg21 on 100 mg fedotozine intravenously. There was no statistically significant difference between the two treatments for these slopes. Effect of Fedotozine on Colonic Tone and Response to Eating
Figure 2. Cumulative number of patients positively responding for the (A ) first sensation threshold and (B ) pain threshold on placebo (- - - -) and 100 mg fedotozine (—) intravenously.
The mean 6 SD operating pressure was 10.7 6 2.1 mm Hg on placebo and 10.6 6 2.4 mm Hg on fedotozine (not significant). The mean baseline volume of the barostat bag in fasting patients was 83.36 6 33.13 mL on placebo and 107.84 6 47.37 mL on fedotozine. This difference in tone of 222.7% was significant (P 5 0.034), indicating that fedotozine could produce a mild relaxation of the colon in the fasted state (Figure 5). After the meal, the bag volume decreased dramatically and rapidly regardless of the treatment given. In the
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Figure 4. Pressure-volume curve on placebo (N) and 100 mg fedotozine (j) intravenously. Values are expressed as means 6 SD of volumes measured in each patient.
intravenous infusion of fedotozine or placebo, resulting in stable plasma levels of fedotozine at the time when sensory thresholds were measured. However, because of the tight schedule of the protocols, we carefully excluded
Figure 3. Volume measured in the barostat bag at the (A ) first sensation and (B ) pain thresholds. Baseline distention was performed in the morning without any treatment. A second distention session was performed in the afternoon during the random infusion of placebo or 100 mg fedotozine.
placebo group, the bag volume was measured at 9.80 6 8.32 mL, indicating an increase in tone of 88.0%. With fedotozine, the bag volume was measured at 5.92 6 1.51 mL, corresponding to an increase of tone of 94.5% (Figure 5). This hypertonic response of the left colon to eating lasted 76 6 27 minutes on placebo and 77 6 43 minutes on fedotozine. The characteristics of the tonic colonic response to eating were not different when placebo or fedotozine was infused.
Discussion In this study we show that fedotozine, a k opioid receptors agonist, is able to relieve the hypersensitivity characterizing patients with painful IBS, whereas it does not alter colonic compliance and does not modify the characteristics of tonic response of the left colon to eating. All experimental procedures were based on a doubleblind, randomized, crossover protocol using a continuous
Figure 5. Volume of the barostat bag placed in the left colon under a constant operating pressure, defined as the pressure allowing the recording of respiratory movements plus 2 mm Hg. In the fasted state, the bag volume is slightly increased on fedotozine compared with placebo (P 5 0.035), indicating that fedotozine might induce a moderate relaxation of the colon. Variations of the barostat bag volume reflect changes in colonic tone. These changes are characterized by a dramatic decrease of the bag volume in the postprandial period on both placebo (j) and fedotozine (N).
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a carryover effect of experimental procedures on each other by including a baseline distention test in the morning, without any administration of drug, and a second distention test in the afternoon, during which drug or placebo was infused. This protocol allowed us to show an excellent reproducibility of sensory thresholds, as shown in Table 1. On the other hand, it has been claimed in the literature that sensory thresholds are highly sensitive to response bias induced by subjective feelings of studied subjects. To overcome them, sophisticated protocols with repeated distention attempts around the threshold have been proposed to make the stimulus actually random to the subject.26 However, in the present study, the high number of distention sessions performed over 2 days in each patient precluded the use of such long-lasting protocols of distention. The very good reproducibility observed for thresholds when comparing baseline and placebo distentions show that subjects’ perception biases were not interfering with their response to the distention test. Moreover, we recently showed data obtained in healthy volunteers confirming that sensory thresholds were equivalent when elicited with ascending method of limits and tracking or double-random staircase.27 This study design also allowed us to characterize the effect of fedotozine with a careful statistical analysis that took into account the difference induced by the treatment, either placebo or fedotozine from the thresholds elicited during baseline distention rather than by comparing directly the thresholds measured on placebo or fedotozine. Such an analysis was indeed not subjective to a possible carryover effect of the treatment on the first day on thresholds measured on the second day. Using this design, we also eliminated the risk of influence of external factors on sensory thresholds, such as gender and age. Visceral hypersensitivity to luminal distention has been investigated extensively during the last decade and is regarded as one of the main issues for understanding the pathophysiology of IBS. However, it is observed in Table 1. Pressure Determining Sensory and Pain Thresholds Elicited by Isobaric Distention of the Left Colon With a Barostat in Patients With IBS
Before placebo On placebo Difference Before fedotozine On fedotozine Difference Statistics a
First sensation (mm Hg)
Pain (mm Hg)
24.3 6 4.7 23.3 6 4.5 21.0 6 3.0 23.7 6 4.0 28.7 6 5.9 5.0 6 4.6 P , 0.0078
29.0 6 4.9 29.0 6 3.5 0.0 6 3.4 28.7 6 4.5 34.7 6 5.5 6.0 6 5.5 P , 0.0078
NOTE. Values are means 6 SD. performed on differences between baseline distention attempt and distention on placebo or fedotozine.
aComparison
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only two thirds patients with IBS14,28 and correlates over time with the intensity of symptoms.28 Because our study took place during a short period of time, we did not face such a variability of thresholds over time. However, considering the wide variation of sensory thresholds measured during colonic distention in IBS patients in our previous studies, we carefully selected patients who complained of pain at a distending pressure #32 mm Hg, which seemed to be a relevant threshold separating IBS patients and healthy controls.14,29 Moreover, patients were also selected on the basis of the Rome criteria24 and on the intensity of their symptoms during the 2 weeks before inclusion. Only patients with chronic and frequent pain attacks were included. This careful selection of the patients allowed us to evaluate a homogenous set of patients who are representative of hypersensitive patients with IBS. In these experimental conditions, fedotozine was able to significantly increase the pressure thresholds of first sensation and pain triggered by distention. Two of the possible approaches for reduction in abdominal pain associated with IBS are (1) to increase colonic compliance so that adaptation to luminal distention could be increased or (2) to inhibit transmission of the afferent neuronal signal. Considering the results of the present study, we assume that fedotozine acts directly on afferent pathways for relieving hypersensitivity in patients with IBS. Indeed, its effect was marked on sensory thresholds (more than one step of distention difference between treatments). It seems to not result from a pure analgesic effect because fedotozine equally affected the perception of nonnociceptive (first sensation threshold) and nociceptive (pain threshold) stimuli. On the other hand, several arguments support the assumption that the effect of fedotozine also does not result from an alteration of the compliance of the colonic wall: (1) similar pressurevolume relationships during distentions performed on placebo and fedotozine; (2) compliance, defined as the slope of these curves, not different on placebo and fedotozine; and (3) absence of effect of fedotozine on colonic tone. Considering the last point, fedotozine decreased slightly the fasting tone of the left colon (222%). However, this effect was weak, and a similar relaxation of the colon was not observed when comparing the volumes of the bag measured at thresholds. We therefore cannot explain the effect of fedotozine by a relaxation of the colon that would allow it to accommodate larger volumes of distention. It has also been shown that the key factor determining visceral hypersensitivity was the transparietal tension rather than the distending volume.30 Thus, we conclude that the effect of fedotozine is
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caused by its action on peripheral sensory pathways based on the following arguments: (1) k receptors are present on somatic sensory pathways and k agonists are able to relieve pain when locally administered31; (2) k agonists reverse the pain reflex triggered by duodenal distention in rats18; (3) comparison between the effects of morphine and a k agonist administered either centrally or peripherally shows that morphine acts centrally, whereas the k agonist U-50,488H acts on peripheral pathways32; (4) fedotozine reverses the motility disturbances induced by surgery or peritonitis17,20; and (5) fedotozine blocks visceral pain triggered by colonic distention in conscious rats sensitized with previous colonic injection of acetic acid, and this effect occurs only after peripheral administration of fedotozine and is blocked by the k antagonist norbinaltorphimine.33 The receptors for neurotransmitters present on visceral sensory pathways are targets for new treatments of functional bowel disorders. Based on the pathophysiological concept of a diffuse hypersensitivity of the gut in patients with IBS, the question is raised whether distention tests could predict a clinical effect of drugs in treating abdominal pain in IBS patients. Although fedotozine was administered intravenously in the present study, the infusion rate allowed it to reach plasma levels similar to those measured after long-term oral administration of 30 mg fedotozine three times daily. At this dose, fedotozine has been shown effective in relieving symptoms and improving quality of life in patients with IBS.21 Moreover, the analysis of the cumulative curve of positive responses to distention shows that the effect of fedotozine was observed in all patients. The amplitude of the effect induced by fedotozine is also very important from a clinical point of view because the action of fedotozine shifted sensory thresholds up to values observed previously in healthy controls,29 indicating that fedotozine could actually normalize colonic perception of luminal distention in patients with IBS. On the other hand, in the absence of any significant effect on colonic motility, fedotozine could be prescribed indistinctly to patients with either constipation-prone IBS or functional diarrhea because the treatment would be aimed at primarily relieving pain and would not affect bowel habits. We conclude that the clinical effect of fedotozine could be related to its direct action on visceral sensory pathways; this observation reinforces the assumption that visceral hypersensitivity is a determinant causal factor of functional bowel disorders.
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2. Frexinos J, Fioramonti J, Bue´no L. Colonic myoelectrical activity in IBS painless diarrhoea. Gut 1987;28:1613–1618. 3. Whitehead WE, Engle BJ, Schuster MM. Irritable bowel syndrome: physiological and psychological difference between diarrhoeapredominant and constipation-predominant patients. Dig Dis Sci 1980;35:404–413. 4. Welgan P, Meshkinpour H, Beeler M. Effect of anger on colon motor and myoelectric activity in the irritable bowel syndrome. Gastroenterology 1988;14:1150–1156. 5. Camilleri M, Neri M. Motility disorders and stress. Dig Dis Sci 1989;34:1777–1786. 6. Sullivan MA, Cohen S, Snape WJ Jr. Colonic myoelectrical activity in irritable bowel syndrome. Effect of eating and anticholinergics. N Engl J Med 1978;298:878–883. 7. Bazzochi G, Ellis J, Villanueva-Meyer J, Jing J, Reddy SN, Meno I, Snape WJ Jr. Postprandial colonic transit and motor activity in chronic constipation. Gastroenterology 1990;98:686–693. 8. Snape WJ Jr. Irritable bowel syndrome. In: Cohen S, Soloway RD, eds. Functional disorders of the gastrointestinal tract. New York: Churchill Livingstone, 1987:69–83. 9. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973;14:125–132. 10. Swarbrick ET, Bat L, Hegorty JE, Williams CB. Site of pain from the irritable bowel. Lancet 1980;2:443–446. 11. Whitehead WE, Holtkotter B, Enck P, Hoeizi R, Holmes KO, Anthony J, Shasbin HS, Schuster MM. Tolerance for rectosigmoid distension in irritable bowel syndrome. Gastroenterology 1990; 98:1187–1192. 12. Ritchie J. Mechanisms of pain in irritable bowel syndrome. In: Read NW, ed. Irritable bowel syndrome. Philadelphia: Grune & Stratton, 1985:163–172. 13. Dawson AM. Origin of pain in the irritable bowel syndrome. In: Read NW, ed. Irritable bowel syndrome. Philadelphia: Grune & Stratton, 1985:155–162. 14. Bradette M, Delvaux M, Staumont G, Fioramonti J, Bue´no L, Frexinos J. Evaluation of colonic sensory thresholds in IBS patients using a barostat: definition of optimal conditions and comparison with healthy subjects. Dig Dis Sci 1994;39:449– 457. 15. Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med 1975;293:524–526. 16. Bue´no L, Fioramonti J, Delvaux M, Frexinos J. Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology 1997;112:1714–1743. 17. Rivie`re P, Pascaud X, Chevalier E, Le Gallou B, Junien JL. Fedotozine reverses ileus induced by surgery or peritonitis. Action at peripheral kappa opioid receptors. Gastroenterology 1993;104: 724–731. 18. Diop L, Rivie`re P, Pascaud X, Junien JL. Peripheral kappa-opioid receptors mediate the antinociceptive effect of fedotozine on the duodenal pain reflex in rat. Eur J Pharmacol 1994;271:65–71. 19. Langlois A, Diop L, Riviere PJ, Pascaud X, Junien JL. Effect of fedotozine on the cardiovascular pain reflex induced by distension of the irritated colon in the anesthetized rat. Eur J Pharmacol 1994;271:245–251. 20. Rivie`re P, Pascaud X, Chevalier E, Junien JL. Fedotozine reversal of peritoneal-irritation-induced ileus in rats: possible peripheral action on sensory afferents. J Pharmacol Exp Ther 1994;270: 846–850. 21. Dapoigny M, Abitbol JL, Fraitag B. Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study. Dig Dis Sci 1995; 40:2244–2248. 22. Coffin B, Bouhassira D, Chollet R, Fraitag B, De Meynard C, Geneve J, Lemann M, Willer JC, Jian R. Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans. Aliment Pharmacol Ther 1996;10:919–925.
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23. Galmiche JP, Fraitag B. Sensitive gastrointestinal disorders: fedotozine contribution to drug therapy. Paris: John Libbey Eurotext, 1995. 24. Thompson WS, Dotterval G, Drossman DA, Heaton KW, Kruis SW. Irritable bowel syndrome: guidelines for the diagnosis. Gastroenterol Int 1989;2:92–95. 25. Hachet T, Caussette M. A multifunction and programmable computerised barostat. Gastroenterol Clin Biol 1993;17:347– 351. 26. Whitehead WE, Delvaux M. Standardization of barostat procedures for testing smooth muscle tone and sensory thresholds in the gastrointestinal tract. Dig Dis Sci 1997;42:223–241. 27. Blanc C, Delvaux M, Maillot C, Bouin M, Lagier E, Fioramonti J, Bueno L, Frexinos J. Distension protocols for evaluation of rectal sensitivity: the simplest, the best (abstr)? Gastroenterology 1998;114:A722. 28. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 1995;109:40–52. 29. Bradette M, Delvaux M, Staumont G, Fioramonti J, Bue´no L, Frexinos J. Octreotide increases thresholds of colonic visceral perception in IBS patients without modifying muscle tone. Dig Dis Sci 1994;39:1171–1178. 30. Distrutti E, Azpiroz F, Soldevilla A, Malagelada JR. Perception of rectal distension depends on wall tension, but not on expansion (abstr). Gastroenterology 1996;110:A657.
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Received March 24, 1998. Accepted September 29, 1998. Address requests for reprints to: Michel Delvaux, M.D., Ph.D., Gastroenterology Unit, CHU Rangueil, F-31403, Toulouse Ce ´dex 04, France. e-mail: [email protected]; fax: (33) 561-3222-29. Supported by a grant from the Jouveinal Research Institute, Paris, France. The authors thank Marcel Caussette and Thierry Hachet for providing the probes and maintaining the barostat and the nurses at the Clinical Unit of Gastroenterology for surveillance recordings.