Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome

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1 Aliment Pharmacol Ther 2005; 22: doi: /j x Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome K. J. LEE, J. H. KIM & S. W. CHO Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea Accepted for publication 9 September 2005 SUMMARY Background: Gabapentin has been shown to reduce elements of central sensitization in human experimental hyperalgesia. It remains uninvestigated whether gabapentin has beneficial effects for irritable bowel syndrome associated with visceral hypersensitivity. Aims: To evaluate the effects of gabapentin on sensory and motor function of the rectum in patients with diarrhoea-predominant irritable bowel syndrome. Methods: Forty patients with diarrhoea-predominant irritable bowel syndrome completed this randomized, double-blind, placebo-controlled, parallel-grouped study. All patients received a barostat study and were subsequently randomized for 5-day treatment with gabapentin 300 mg/day and then 600 mg/day or placebo. On day 6, after subjects had their morning dose, the barostat experiment was repeated. Results: The threshold pressures for bloating, discomfort and pain significantly increased after gabapentin, but not after placebo. Significant increase in the pressure and corresponding wall tension inducing discomfort or pain were observed in the gabapentin group, but not in the placebo group. Rectal compliance significantly increased after gabapentin, but not after placebo. The postprandial increase of rectal tone was not affected by gabapentin. Conclusion: Our results show that gabapentin reduces rectal sensory thresholds through attenuating rectal sensitivity to distension and enhancing rectal compliance in diarrhoea-predominant irritable bowel syndrome patients. The clinical efficacy of this drug in irritable bowel syndrome patients warrants investigation. INTRODUCTION Visceral hypersensitivity is considered to be one of the main mechanisms for the functional gastrointestinal disorders. 1, 2 Previous studies evaluating the sensory responses to mechanical distension of the rectum provide evidence that hypersensitivity to luminal distension is a common feature of patients with irritable bowel syndrome (IBS). 3 5 Hypersensitivity to colorectal distension has been demonstrated in 20 80% of IBS patients across Correspondence to: Dr K. J. Lee, Department of Gastroenterology, Ajou University Hospital, Ajou University School of Medicine, San5, Wonchondong, Yeongtong-gu, Suwon, Korea. kjleemd@hotmail.com studies. 6 Different techniques and populations among studies contribute to the wide range of reported hypersensitivity to colorectal distension in IBS patients. Given that gut hypersensitivity may lead to alterations in gut motility and increase the intensity of gut perception, contributing to the genesis of symptoms, restoring normal sensitivity by drugs that reduce visceral sensitivity seems to be an effective treatment for IBS commonly associated with visceral hypersensitivity. However, data on pharmacological treatments targeting visceral hypersensitivity are lacking and clinical application of such concept remains unestablished. Gabapentin, a 3-alkylated analogue of c-amino butyric acid (GABA), has recently been used for the treatment of Ó 2005 Blackwell Publishing Ltd 981

2 982 K. J. LEE et al. neuropathic pain with minimal side-effects. 7 Gbapentin has been shown to attenuate hyperalgesia and allodynia in animal models of neuropathic, inflammatory and surgical pain Although its mechanism of action remains unclear, it has been presumed that gabapentin enhances GABAergic transmission and inhibits a2dsubunits of voltage-gated calcium-channels, 14, 15 resulting in a reduction of centrally mediated nociceptive transmission. 16 In line with those observations, chronic administration of oral gabapentin has recently been shown to reduce elements of central sensitization in human experimental hyperalgesia. 17 In the present study, we hypothesized that gabapentin may have beneficial effects for visceral hypersensitivity which is known to be related to central sensitization. Thus, we evaluated the effects of oral gabapentin on sensory and motor function of the rectum in patients with diarrhoea-predominant IBS, an IBS subgroup that has consistently been reported to commonly exhibit rectal hypersensitivity to distension. MATERIALS AND METHODS Subjects Forty-three patients with diarrhoea-predominant IBS diagnosed by Rome II criteria 18 were enrolled in this study. All patients were recruited from out-patient clinic of the Department of Gastroenterology of Ajou University Hospital, which is a tertiary referral centre. Patients who had previously undergone major abdominal surgical procedures were excluded. The presence of organic disease was also excluded by standard clinical investigations. All patients were instructed to stop any medication, except a study medication, known to affect gastrointestinal function during the study period. The protocol was approved by the Institutional Review Board of the Ajou University Hospital and all subjects provided written informed consent. This was conducted according to the Declaration of Helsinki. 5 days 0 day Gabapentin or placebo Isobaric distensions Operating pressure Meal 15 min 10 min 30 min Figure 1. Study design showing the time of medication and sequence of procedures that were applied in each subject. After 5-day medication, rectal sensitivity to distension and rectal compliance were checked, and then postprandial tonic change of the rectum was evaluated. the inclusion criteria were assigned a unique patient number which encoded the randomization in a 1:1 ratio to one of the two treatment groups: gabapentin (Pfizer Pharmaceuticals Korea, Seoul, Korea) or placebo. The dose of gabapentin was 300 mg/day for the first 3 days and then 600 mg/day for the subsequent 2 days. Before the start of the study medication, patients received a barostat study with assessments of symptoms. All patients were requested to fast from midnight and to evacuate their bowel on the morning of the experimental day. After completion of the barostat study, the study medications were administered in three divided doses for 5 days. On day 6, subjects had their morning dose in the hospital 1 h before a barostat study was conducted. The barostat experiment was repeated in the same manner as the initial study. The five most common adverse events including dizziness, somnolence, peripheral oedema, nausea and headache were assessed before the barostat study. Patients were asked to complete the questionnaire about adverse events occurred throughout the study period with ratings of their severity. Severity of adverse experiences was rated as none, mild (can be ignored, does not influence daily routine or activities), moderate (cannot be ignored and/or occasionally interfering daily routine or activities), severe (frequently or markedly interfering daily routine or activities). Study protocol This was a single centre, randomized, double-blind, placebo-controlled, parallel-grouped trial. Figure 1 depicted the study protocol including the barostat study. Study medications were encapsulated in gelatine capsules, which were identical in appearance, in order to maintain double-blind conditions. Patients meeting Barostat study Barostat device consisted of an infinitely compliant polyethylene bag catheter (10 cm long and 700 ml capacity; Mui Scientific, Mississauga, ON, Canada) connected to a computer-controlled barostat (Distender Series II, G & J Electronics, Toronto, ON, Canada). The technician performing barostat procedure was blinded

3 GABAPENTIN AND VISCERAL SENSITIVITY IN IBS 983 to the treatment medication. A single 500 ml tap water enema was performed to ensure cleansing the rectum. Before each experiment, the barostat bag was checked for air leaks by maintaining a constant pressure of 20 mmhg. With the subject in the left lateral position, the lubricated and tightly folded bag was introduced through the anus and positioned in the rectal ampulla. To unfold the bag, 200 ml air was manually inflated under controlled pressure (<20 mmhg) and the catheter was pulled back carefully until its passage was restricted by the anal sphincter. The catheter was then introduced a further 2 cm and fixed. Subsequently, the bag deflated and the catheter connected to the barostat. During the experiment, subjects were in a prone 10 Trendelenburg position to reduce the gravitational effects of the abdominal organs. The bag was inflated by means of isobaric distension procedure from 5 mmhg with steps of 1 mmhg/min in order to determine the operating pressure. The operating pressure was defined as the first pressure level that provided an intrabag volume continuously above 80 ml. 19 After determination of the operating pressure, the balloon was immediately deflated and subjects were allowed a 5-min rest period while the bag remained deflated. Isobaric phasic distensions were then performed at 2 mmhg intervals. Each step lasted 1 min followed by a 30-s rest period at 0 mmhg. At 30 s during each step distension, subjects were instructed to score their perception of abdominal sensations, using both a graphic rating scale that combined verbal descriptors on a scale graded 0 6 ( none, weak, definite, strong, discomfort, pain ) and 100 mm visual analogue scales (VAS) for desire to defecate, bloating, abdominal discomfort and abdominal pain. The word anchors for VAS were set as weak (1 2), mild (3 4), moderate (5 6), strong (7 8) and intense (9 10). These scales were used to determine defecation, bloating, discomfort and pain thresholds, defined as the first distension to evoke a need to defecate, bloating, discomfort and pain, respectively. Sequential phasic distensions continued until an intrabag pressure of 40 mmhg reached or the subjects reported discomfort of at least moderate intensity or pain. At each pressure increment, intrabag volume was monitored in order to build up pressure volume curves. Rectal compliance was defined as the slope of the linear part of the pressure volume curve. 19, 20 Afterwards, the bag remained completely deflated during 15 min, and then a baseline volume recording was obtained over a period of 10 min during maintaining an operating pressure. Thereafter, subjects were asked to drink a 400 ml nutrient liquid meal (Ensure, Abott Korea, Seoul, Korea; 1 kcal/ml, carbohydrate 64%, protein 14%, fat 22%) over a 5-min period with a straw. Volume of the barostat bag was then continuously recorded during 30 min after the ingestion of meal. Data analysis The mean intrabag volume was measured during each isobaric distension step. Rectal compliance was approximated by calculating the difference in intrabag volume divided by the difference in intrabag pressure. Rectal wall tension was calculated during each pressure distension step by Laplace s law and is expressed in cm mmhg. 19 Rectal volumes measured during the set pressure procedure are represented as average volumes over 5-min periods. The maximum postprandial increase of rectal tone was defined as the maximum decrease in intrabag volume during the 30-min postprandial period compared with the volume recorded during the last 5-min preprandial period. Statistical analysis All values are presented as mean ± S.E.M. A Student s t-test and chi-square test was used for demographic comparison between treatment groups. The slopes of pressure volume curves were compared with a paired Student s t-test. For comparison of sensory thresholds, statistical analysis was performed by a non-parametric test (Wilcoxon signed rank test). The area under the curve for the same numbers of distension steps in the pressure perception curve and the pressure symptom curve was compared before and after the study medication by paired Student s t-test. spss version 10.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical calculations. The P-value below 0.05 was considered to be statistically significant. RESULTS Forty of 43 enrolled patients completed the study. Three patients, two of whom received placebo and one of whom received gabapentin, dropped out because of personal reasons unrelated to the study medication and were not included in the analysis. Thus, data from 20 patients in each treatment group were analysed.

4 984 K. J. LEE et al. Intubation with subsequent positioning of the barostat bag was well-tolerated by all subjects. No significant differences in age (40.6 ± 2.7 vs ± 1.9 years, respectively; N.S.) and sex ratio (11 vs. 9 males, respectively; N.S.) were observed between the gabapentin and placebo groups. The average operating pressure (13.7 ± 0.2 vs ± 0.2 mmhg, respectively; N.S.) and the rectal compliance (7.8 ± 0.1 vs. 7.5 ± 0.2 ml/ mmhg, respectively; N.S.) did not differ between two treatment groups. Rectal compliance Figure 2 displays the pressure volume curves from the sequential isobaric distensions. Rectal compliance significantly increased after the administration of gabapentin (8.1 ± 0.1 vs. 7.8 ± 0.1 ml/mmhg; P < 0.05), whereas it was not altered after treatment with placebo (7.7 ± 0.1 vs. 7.5 ± 0.2 ml/mmhg; N.S.). Sensory thresholds and symptom scores The distending pressure triggering a first sensation of defecation was not altered in both gabapentin and placebo groups. In the gabapentin group, the threshold pressures for bloating, discomfort and pain significantly increased, whereas those were not significantly changed in the placebo group (Table 1). Significant increase in the pressure (17.5 ± 0.5 vs ± 0.6 mmhg; P < 0.005) and corresponding wall tension (72.3 ± 3.4 vs ± 3.4 cm mmhg; P < 0.001) inducing discomfort of at least moderate intensity or pain was observed in the gabapentin group. In contrast, this alteration was not Volume (ml) Pressure (mmhg) Before gabapentin After gabapentin Before placebo After placebo Figure 2. Pressure volume curve during sequential isobaric distensions of the rectum before gabapentin (d) and after gabapentin (s), before placebo ( ) and after placebo (n). Values are mean ± s.d. Rectal compliance was significantly increased by gabapentin (P < 0.05), whereas it was not altered by placebo. Table 1. Pressure thresholds for symptoms during stepwise isobaric distensions before and after the study medication Symptom Gabapentin Placebo Before After Before After Defecation 7.3 ± ± ± ± 0.5 desire Bloating 7.5 ± ± 0.6* 8.9 ± ± 0.4 Discomfort 9.6 ± ± 0.5** 10.1 ± ± 0.5 Pain 14.8 ± ± 0.5** 14.4 ± ± 0.7 Data are given as mean ± S.E.M. (mmhg). * P < 0.05 vs. before the study medication using Wilcoxon signed rank test. ** P < 0.01 vs. before the study medication using Wilcoxon signed rank test. observed in the placebo group (16.1 ± 0.5 vs ± 0.7 mmhg; N.S., 64.3 ± 3.0 vs ± 4.0 cm mmhg; N.S.; Figure 3a,b). Gabapentin reduced the area under the curve for the same number of distension steps in the pressure symptom score curve for bloating, discomfort and pain, (a) 25 Pressure (mmhg) (b) 100 Tension (cm mmhg) * Gabapentin ** Gabapentin Placebo Placebo Before medication After medication Before medication After medication Figure 3. Pressure thresholds and corresponding wall tensions for discomfort of at least moderate intensity or pain. Values are mean ± s.d. Those pressure thresholds (a) and corresponding wall tensions (b) were significantly increased by gabapentin (* P < and ** P < 0.001, respectively), whereas they were not altered by placebo.

5 GABAPENTIN AND VISCERAL SENSITIVITY IN IBS 985 Table 2. The area under the curve for the same number of distension steps in the pressure symptom score curve before and after the study medication Symptom Gabapentin but not for desire to defecate. Whereas, placebo did not affect that of the pressure symptom score curve for all symptoms (Table 2). Postprandial response Placebo Before After Before After Defecation 375 ± ± ± ± 21.1 desire Bloating 253 ± ± 17.2* 274 ± ± 27.6 Discomfort 236 ± ± 11.6** 266 ± ± 10.1 Pain 27 ± ± 2.2* 19 ± ± 3.0 Data are given as mean ± S.E.M. (mm mmhg). * P < 0.05 vs. before the study medication using Wilcoxon signed rank test. ** P < 0.01 vs. before the study medication using Wilcoxon signed rank test. After 10 min of basal volume recording with the distending pressure set at the operating pressure, the liquid nutrient meal was consumed, followed by 30 min postprandial recording. Postprandial change in intrabag volume relative to the volume during the last 5 min of the preprandial period is illustrated in Figure 4. At the initial barostat study before the study medication, the amount of maximum decrease in intrabag volume during the 30-min postprandial period did not differ between the gabapentin and placebo groups Volume (ml) Time after the meal (min) Before gabapentin After gabapentin Before placebo After placebo Figure 4. Postprandial change in intrabag volume relative to the volume during the last 5-min of the preprandial period. Values are mean ± s.d. The amount of maximum decrease in intrabag volume during the 30-min postprandial period was not affected by treatment with gabapentin as well as by treatment with placebo. Table 3. Adverse events in subjects treated with gabapentin and placebo Adverse events Gabapentin (n ¼ 20) Placebo (n ¼ 20) Dizziness 4 1 Somnolence 4 2 Headache 2 2 Nausea 1 1 Peripheral oedema 1 0 (11.1 ± 0.8 vs ± 0.7 ml; N.S.). It was not affected by treatment with gabapentin (10.0 ± 0.8 vs ± 0.8 ml; N.S.) as well as by treatment with placebo (10.4 ± 0.9 vs ± 0.7 ml; N.S.). Adverse effects Three subjects withdrew during the study period, the reason of which was not related to the study medication. The most common adverse events in subjects who received gabapentin were dizziness and somnolence. Table 3 displays the frequency of adverse events in subjects treated with gabapentin and those with placebo. No one dropped out because of adverse events as they were mild. DISCUSSION In the present study, we have demonstrated that gabapentin reduces symptom thresholds in IBS patients through the enhancement of rectal compliance and the attenuation of rectal sensitivity to distensions without altering postprandial tonic response of the rectum. To our knowledge, this is the first demonstration that gabapentin has beneficial effects on hypersensitive rectum or hypertonic rectum commonly observed in patients with IBS. Enhanced visceral sensitivity, represented by reduced thresholds to rectal sensation, may be a hallmark of IBS pathophysiology, particularly in patients with diarrhoea-predominant IBS. 5, However, both hypersensitivity 24 and hyposensitivity 25 have been observed in constipation-predominant IBS patients. Patients with visceral hypersensitivity perceive desire to defecate, bloating, discomfort or pain at lower volumes or pressures. In this study, we enrolled only diarrhoea-predominant IBS patients in order to evaluate whether gabapentin reduces rectal sensitivity as they are more consistently characterized by increased rectal sensitivity than patients with

6 986 K. J. LEE et al. constipation-predominant IBS. Hypersensitivity to rectal distension, defined as the threshold pressure for discomfort or pain below the control mean )2 s.d. (18.4 mmhg in our laboratory), was observed in 68% of our IBS patients. In patients with IBS abnormal sensory responses were reported through the ascending methods of limits. 20, 23, 26 Similarly, the sequential phasic distension protocol was used for measuring sensory thresholds in this study. It may be vulnerable to the response bias because the stimuli are predictable to the subject. Although randomly sequenced distensions or multiple distensions at each pressure step seem to enable more reliable estimation of sensory thresholds, the results of some studies have revealed that practical aspects limit the number of trials and the simple ascending method of limits are equivalent to the more complicated random staircase method to determine sensory thresholds. 23, 27 Data to recommend one of these protocols over another are insufficient yet. In addition, it remains unclear whether the barostat test measures an altered perception or a behavioural response to rectal stimuli. Now, we prefer the ascending method of limits to the random method because progressive distension seems better accepted by the patients, especially for repeated measurements. Furthermore, a simple ascending method of limits may be used provided there is a control group tested in the same way. 28 The rectum plays a role as a dynamic reservoir for the temporary storage of faeces with rectal pressures being maintained at a low level until defecation is initiated. Rectal compliance is a measure of the resistance of the rectal wall to distension reflecting the tone of the rectal wall. Apart from disturbances in rectal sensitivity, significant alterations in rectal tone and compliance may be observed in a subset of IBS patients. Although previous studies have shown controversial results on compliance or wall tone of the rectum in IBS patients, decreased rectal compliance appears to be more frequently observed than increased rectal compliance. 22, 24, 29 Decreased rectal capacity or increased resistance of the rectal wall to distension is an important determinant of defecation sensation. Enhanced rectal sensation and reduced rectal compliance may be therapeutic targets. Our results of the present study showed that gabapentin attenuated rectal sensitivity to distension and raised rectal compliance, providing an evidence that it has a potential as a pharmacological agent for treatment of IBS. Gabapentin is known to be an anticonvulsant or antiepileptic agent whose chemical structure resembles that of GABA. Gabapentin has been shown to attenuate hyperalgesia and allodynia in animal pain models Gabapentin was also found to reduce neuropathic pain in a human model. 7 The mechanism of its antiallodynic action is not fully understood. Gabapentin has been shown to increase extracellular GABA levels, which may be associated with its effectiveness for hyperalgesia or allodynia. 14, 30, 31 In addition, another possible target of gabapentin is the a2d-subunit of voltage-gated Ca 2+ -channels, which are distributed in both peripheral and central nervous system. Studies have supported a role of the a2d-subunit of voltage-gated Ca 2+ -channels in antinociceptive action of gabapentin. 15, 32, 33 Gabapentin modulates voltage-gated Ca 2+ -channels in dorsal root ganglia neurones, inhibiting excitatory neurotransmitter release in the spinal cord dorsal horn. 16 Actually, gabapentin was demonstrated to inhibit central sensitization in a human model of hyperalgesia. 17 The effects of gabapentin on rectal sensitivity, observed in our IBS patients, may be explained by this mechanism. In addition to a centrally mediated mechanism, increased rectal compliance may play a role in reducing rectal sensitivity to distension, indicating a possible peripheral component of antiallodynic action of gabapentin. Given that wall tension of the rectum, calculated by the intrabag pressure and volume, inducing discomfort or pain, increased after treatment with gabapentin, mechanical sensitivity of the rectum seems to be reduced, irrespective of alteration of rectal compliance. The current results showed that gabapentin increased thresholds inducing bloating, discomfort and pain. This observation suggests that IBS symptoms such as bloating, abdominal discomfort and abdominal pain may be improved by the administration of gabapentin. However, gabapentin did not affect thresholds for desire to defecate, suggesting that symptoms related to defecation, including frequent defecation, urgency and incomplete evacuation sense, are less likely to be relieved by it. Thus, the effects of long-term administration of gabapentin on symptoms in IBS patients warrant investigation. In previous human studies on the treatment of neuropathic pain by the administration of gabapentin, the dosing regimen varied among the studies. In general, the recommended way of gabapentin dosing is the stepwise escalation from the initial dose of 300 mg/day to those required to achieve maximum

7 GABAPENTIN AND VISCERAL SENSITIVITY IN IBS 987 7, efficacy (between 1800 mg and 3600 mg/day). The daily dose 1800 mg was found to have analgesic effects for neuropathic pain. However, patients receiving gabapentin reported side-effects, including somnolence and dizziness, more often than those receiving placebo. These side-effects are known to increase patients withdrawal rates. 7, Because our aim of the present study was not to evaluate the effects of chronic administration of gabapentin on symptoms in IBS patients but to evaluate the effects of short-term administration of gabapentin on the motor and sensory function of their rectum, we selected a relatively lower gabapentin dose (600 mg/day) for this trial in order to enhance patients compliance. As study patients were naive to gabapentin, gradual increase of the dose from 300 to 600 mg/day was applied to all subjects in order to decrease adverse effects. Hence, there was no withdrawal due to adverse effects during the study period and our patients were well-tolerated to the study medication. In the result, we found that a relatively lower dose of gabapentin (200 mg three times daily) had beneficial effects for hypersensitive or hypertonic rectum. Because we did not measure the plasma concentration of gabapentin in the present study, the therapeutic level contributing to those effects remains unknown. Although the concept of targeting visceral hypersensitivity as a treatment for IBS remains unestablished, application of pharmacological agents interfering with visceral sensitivity seems to be ideal at least for the treatment of patients with visceral hypersensitivity. The evidence illustrating clinical benefits resulted from normalization of visceral sensitivity by use of visceral analgesics is currently lacking. Therefore, clinical efficacy of gabapentin that reduces visceral mechanosensitivity is required to investigate. 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