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Pinaverium Reduces Symptoms of Irritable Bowel Syndrome in a Multicenter, Randomized, Controlled Trial

Published:January 26, 2015DOI:https://doi.org/10.1016/j.cgh.2015.01.015

      Background & Aims

      Pinaverium bromide (pinaverium) is an antispasmodic commonly used to treat irritable bowel syndrome (IBS), but there has been no convincing evidence for its effectiveness and safety. We evaluated these in a prospective, double-blind, placebo-controlled trial.

      Methods

      Patients with IBS, based on Rome III criteria, were assigned randomly to groups given pinaverium (50 mg, 3 times/day; n = 218) or placebo (3 times/day; n = 209) at 4 hospitals in China, from August 2012 through December 2013. The primary end points were reductions in abdominal pain and Bristol stool score. Secondary end points were reductions in pain and stool frequencies and abdominal discomfort and its frequency. We also evaluated changes in IBS global symptom scores and the number of adverse effects.

      Results

      Based on an intention-to-treat analysis, a significantly larger proportion of patients receiving pinaverium met either of the primary end points (50.0% met an end point at week 2, and 77.5% met an end point at week 4), compared with placebo (P < .001). Pinaverium reduced at least 1 secondary end point in significantly more patients receiving pinaverium (76.1% had a reduction at week 2, and 91.7% had a reduction at week 4) than placebo (P < .001). Based on symptom scores, significantly higher percentages of patients receiving pinaverium believed that their IBS symptoms improved (60%) than in the placebo group (34%; P < .001); 29% of patients in the pinaverium group believed that their IBS symptoms stayed the same (29%) and 11% said they worsened. Pinaverium was not associated with severe adverse effects; common side effects included nausea (3.7%), dizziness (3.2%), increased blood pressure (2.3%), and abdominal discomfort (2.3%).

      Conclusions

      Based on a controlled trial, pinaverium reduces symptoms of IBS. It can be considered a first-line treatment for IBS. Trial registration: NCT01641224 (www.ClinicalTrials.gov).

      Keywords

      Abbreviations used in this paper:

      ACG (American College of Gastroenterology), BSS (Bowel Symptom Scale), CI (confidence interval), IBS (irritable bowel syndrome), TEAE (treatment-emergent adverse effect)
      Irritable bowel syndrome (IBS) is the most common chronic (life-long in some patients) and highly recurrent gastrointestinal disorder, with an estimated worldwide prevalence of 10% to 15%.
      • Hungin A.P.
      • Chang L.
      • Locke G.R.
      • et al.
      Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact.
      IBS affects patients physically, psychologically, socially, and economically. IBS patients constantly suffer chronic pain, fatigue, altered bowel habits, and other symptoms as well as work absenteeism.
      • Maxion-Bergemann S.
      • Thielecke F.
      • Abel F.
      • et al.
      Costs of irritable bowel syndrome in the UK and US.
      The economic burden of IBS is huge. The direct costs and indirect costs for IBS care are estimated to be more than $1.7 billion annually

      CDC. Inflammatory bowel disease (IBD). Available: http://www.cdc.gov/ibd/. Accessed: September 28, 2013.

      and $205 million annually,
      • Sandler R.S.
      • Everhart J.E.
      • Donowitz M.
      • et al.
      The burden of selected digestive diseases in the United States.
      respectively, in the United States. There is no cure for IBS, and no gold standard of treatment.
      • Camilleri M.
      • Chang L.
      Challenges to the therapeutic pipeline for irritable bowel syndrome: endpoints and regulatory hurdles.
      A variety of medications were recommended by the American College of Gastroenterology (ACG)
      • Brandt L.J.
      • Chey W.D.
      • et al.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      and have been used to treat IBS such as antispasmodics or antidiarrheal medication (eg, loperamide), 5HT3-receptor antagonists (eg, alosetron and ramosetron), 5-HT4 agonists (eg, tegaserod), probiotics (eg, Lactobacillus, Bifidobacterium), and antidepressants (eg, tricyclic antidepressants and selective serotonin reuptake inhibitors).
      The pathophysiology of IBS has not been fully understood.
      • Camilleri M.
      • Prather C.M.
      The irritable bowel syndrome: mechanisms and a practical approach to management.
      It was found that IBS patients tend to have abnormal motility in the gastrointestinal tract,
      • Kellow J.E.
      • Eckersley G.M.
      • Jones M.P.
      Enhanced perception of physiological intestinal motility in the irritable bowel syndrome.
      increased pain sensitivity,
      • Ritchie J.
      Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome.
      altered gut immune function,
      • Hiatt R.B.
      • Katz L.
      Mast cells in inflammatory conditions of the gastrointestinal tract.
      abnormal autonomic and central nervous modulation,
      • Aggarwal A.
      • Cutts T.F.
      • Abell T.L.
      • et al.
      Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities.
      and psychosocial disturbances.
      • Whitehead W.E.
      • Crowell M.D.
      • Robinson J.C.
      • et al.
      Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared to subjects without bowel dysfunction.
      The rationale for using smooth-muscle relaxants to treat patients with IBS is based on the hypothesis that intestinal dysmotility results in abdominal pain, bloating, and disturbed defecation. Antispasmodics improve IBS symptoms by directly relaxing the colonic smooth muscle cells or antagonizing the excitatory neuromuscular neurotransmission. Antispasmodics remain one of the most commonly prescribed groups of medications for the treatment of IBS, with few adverse effects.
      • Forte E.
      • Pizzoferrato M.
      • Lopetuso L.
      • et al.
      The use of anti-spasmodics in the treatment of irritable bowel syndrome: focus on otilonium bromide.
      Pinaverium bromide (pinaverium), an antispasmodic, is one of the most commonly used IBS medications worldwide. However, original clinical studies on pinaverium are scarce. Only 4 original clinical studies from Europe, 1 from Latin America, and 1 from Asia were found (Supplementary Table 1). These studies were from a single center and had a small sample size (19–53 IBS patients). They were either short communications (2–3 pages) that did not adequately address the effectiveness of pinaverium, or clinical studies that were not comprehensive enough to cover the safety and tolerability issues related to pinaverium. Based on 3 of these small sample studies, the ACG declared that pinaverium “may provide short-term relief of abdominal pain/discomfort in IBS,” but “evidence for safety and tolerability is limited.”
      • Brandt L.J.
      • Chey W.D.
      • et al.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      Therefore, a multicenter, placebo-controlled clinical study with a large sample size on the effectiveness and safety profile of pinaverium is needed urgently.

      Materials and Methods

       Patients and Setting

      Patients were screened, randomized, and treated by either pinaverium or placebo at 4 participating hospitals in China from August 2012 to December 2013. The study protocol was approved by the Institutional Review Boards of the participating hospitals and the University of Minnesota. The Institutional Review Board guidelines for conducting clinical research were strictly followed.

       Study Design

      The inclusion criteria included the following: (1) men or women aged 18 to 70 years; (2) IBS per Rome III criteria for diarrhea-predominant IBS,
      • Drossman D.A.
      Rome III: the functional GI disorders.
      and a weekly average of worst abdominal pain score of greater than or equal to 3.0 on a 0- to 10-point scale
      US Food and Drug Administration
      Guidance for industry irritable bowel syndrome—clinical evaluation of drugs for treatment. Final guidance.
      ; (3) normal liver function, blood cell count, urea, and creatinine level within the past 2 weeks; (4) no diet change during the treatment periods; and (5) agreement to participate in this study. Exclusion criteria included the following: (1) pregnant or breast-feeding women and men who were going to have his sex partner pregnant; (2) digestive system diseases or disorders within the past 3 months; (3) taking IBS medications within the past 10 days, or using anticholinergics, lactulose, smooth muscle relaxants, motility stimulants, pain reliever medicine, or antidepressants within the past 3 months; (4) serious primary heart, liver, kidney, lung, or blood system diseases, asthma, lung or liver dysfunction, current alcoholism, psychiatric illness or dementia, diabetes, or gastrointestinal diseases or disorders; and (5) poor compliance. A questionnaire regarding patients’ medical history was administered to all patients (Supplementary Table 2).
      Patients were randomized by cards prelabeled with “A” or “B.” Each patient was instructed to pick up only one card from a closed bag, which prevented patients from seeing the letter A or B before they took the card out of the bag. Patients with cards A or B would be treated with pinaverium or placebo, respectively. Neither patients nor their evaluators knew which treatment the patients received. The physicians who prescribed either pinaverium or placebo did not share the prescribing information with the patients and the evaluating physicians.
      The treatment period was 4 weeks. A Bowel Symptom Scale (BSS) containing primary and secondary end point questionnaires was developed for the trial (Supplementary Table 3). The BSS was administered at the first visit (pretreatment) and at weeks 2, 3, and 4. Patients received treatment immediately after the first visit. Patients in the pinaverium group took 50 mg pinaverium tablets 3 times a day, and patients in the placebo group took placebo tablets, which were visually identical in appearance to pinaverium, 3 times a day.

       Study Outcomes

      The primary end point was abdominal pain (0 = no pain, 10 = worst pain) and stool consistency (Bristol stool form scale) as recommended by the US Food and Drug Administration (Supplementary Table 3).
      US Food and Drug Administration
      Guidance for industry irritable bowel syndrome—clinical evaluation of drugs for treatment. Final guidance.
      The abdominal pain and stool consistency represented a weekly average of the daily worst abdominal pain and the daily worst Bristol stool form scale, respectively. An abdominal pain responder was defined as a patient who experienced a decrease in the weekly average of the worst daily abdominal pain by at least 30% compared with baseline. A stool consistency responder was defined as a patient who experienced a 50% or greater reduction in the number of bad days per week compared with baseline. A “bad day” was a day that patients had at least 1 stool that had a consistency of type 6 or 7 on the Bristol stool form scale. A patient was categorized as a dual responder to the primary end point if the patient was a responder to both pain intensity and stool consistency.
      The secondary end points (scale, 0–10, with a higher value indicating a worse symptom) included the weekly average frequencies of abdominal pain, daily stool, abdominal discomfort, and the weekly average of the daily worst abdominal discomfort (Supplementary Table 3). A clinical responder to the earlier-described symptoms was defined as a patient who experienced a decrease in the weekly average of the earlier-described symptom scale by at least 30% compared with baseline.
      The tertiary end points included the IBS global symptom relief and the treatment-emergent adverse effect (TEAE) profiles. IBS global symptom relief was evaluated by each patient at week 4 as follows: improved, stayed the same, or worsened in responding to the question, “How would you rate your IBS symptoms overall through the treatment?”

       Statistical Analysis

      The study was powered prospectively based on clinical response at week 4. In accordance with previous studies,
      • Drossman D.A.
      Rome III: the functional GI disorders.
      we assumed that 50% of the patients would respond to pinaverium and 20% of patients would respond to placebo. Including at least 93 patients per group yielded approximately 85% power in comparing pinaverium with placebo using a chi-square power test with a 2-sided α level of .05.
      Demographic and baseline characteristics were summarized using descriptive statistics. Categoric variables were described using the number of patients, frequencies, and/or percentages. Their distributions were compared between treatment groups using the chi-square test or the Fisher exact test when necessary. A 2-tailed t test was conducted to test whether statistical differences existed between baseline and treatment. Odds ratio and 95% confidence intervals (CIs) were used to determine the statistical significance of the treatment effects when compared with placebo.
      The Pearson product-moment correlation or the average interitem correlation (r) analyses were used to test-retest (with 1–2 weeks in-between) the reliability, or the consistency of the measure, of the BSS before it was used, and to test the correlation among the primary and secondary end points, and among the 6 symptoms and the global rating.
      A statistically significant relationship was established when the P value was less than .05.
      The data are presented according to an intention-to-treat protocol, in which missing values were replaced by the last known value (the last-observation-carried-forward method).
      • Unnebrink K.
      • Windeler J.
      Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases.
      All authors had access to the study data and reviewed and approved the final manuscript.

      Results

       Patient Populations and Baseline Measurements

      Among the 716 patients who were screened for this trial, 229 patients were excluded per the exclusion criteria, 60 patients were used to test the reliability of the BSS before this trial, and 427 patients were randomized to the pinaverium and the placebo groups (Supplementary Figure 1). The intention-to-treat population included 218 patients in the pinaverium group and 209 patients in the placebo group. The per-protocol population included 169 patients in the pinaverium group and 151 patients in the placebo group. The baseline of the population is shown in Table 1. There were no significant differences between the baselines of the 2 groups in terms of age, sex distribution, IBS history, and the severity of IBS symptoms before treatment (P > .05).
      Table 1Baselines of Demographics, IBS Medical History, and IBS Symptoms: Intention-to-Treat Population
      CharacteristicPinaverium (n = 218)Placebo (n = 209)P value
      Age, mean ± SD, y36.9 ± 11.836.6 ± 12.6.76
      Men, n (%)103 (47)90 (43).66
      Women, n (%)115 (53)119 (57)(X2 = 0.20)
      IBS history, ± SD, y5.27 ± 4.475.72 ± 5.54.36
      Abdominal pain, mean ± SD4.89 ± 1.915.00 ± 1.96.21
      Stool consistency, mean ± SD6.07 ± 0.845.93 ± 0.76.07
      Pain frequency, mean ± SD5.89 ± 1.905.61 ± 1.60.10
      Stool frequency, mean ± SD4.86 ± 1.344.68 ± 1.56.21
      Abdominal discomfort, mean ± SD4.94 ± 1.675.02 ± 1.81.85
      Discomfort frequency, mean ± SD5.45 ± 2.355.02 ± 1.80.12

       The Reliability of the Bowel Symptom Scale

      A total of 60 patients were used to test–retest the reliability of the BSS measures before this trial. Forty-six patients completed this assessment. The Pearson product-moment correlation between the test and retest of the BSS was high for the total score of the 6 symptoms of the BSS (r = 0.71, P < .001) and for each individual symptom (pain: r = 0.52, P < .001, df = 44; stool consistency: r = 0.59, P < .001, df = 44; pain frequency, r = 0.66, P < .001, df = 44; stool frequency: r = 0.61, P < .001, df = 44; discomfort: r = 0.72, P < .001, df = 44; and discomfort frequency: r = 0.63), suggesting that the measures of the BSS were consistent and reliable.

       Primary End Point Outcomes

      Significantly more patients in the intention-to-treat population receiving pinaverium were clinical responders to either of the primary end points (50.0% at week 2 and 77.5% at week 4, P < .001, compared with placebo) (Table 2). Pinaverium relieved pain in 40.4% of patients at week 2 and in 62.4% of patients at week 4, which was significantly more than the placebo. Pinaverium improved stool consistency in 22.9% of patients at week 2 and in 53.2% of patients at week 4, which was significantly more than the placebo. The Pearson product-moment correlation coefficient analysis found that patients whose abdominal pains were relieved by pinaverium had a 99% chance that their stool consistencies also were improved, and vice versa (r = 0.31 at week 2 and 0.31 at week 4; P = .01 for both).
      Table 2Primary and Secondary Efficacy Results: Response Rates, Odds Ratios, and 95% CI in the Intention-to-Treat Population
      Abbreviations: abdoml, abdominal; consist, consistency; freq, frequency; discomft, discomfort. OR, odds ratios; CI, confidence interval.
      Similar results were seen in the per-protocol population (Supplementary Table 4).

       Secondary End Point Outcomes

      Pinaverium improved at least 1 secondary end point symptom in significantly more patients receiving pinaverium (76.1% at week 2 and 91.7% at week 4, P < .001, compared with placebo). In particular, pinaverium decreased frequencies of pain, stool, and discomfort in significantly more patients at weeks 2 and 4 than placebo (Table 2). When compared with placebo, pinaverium did not reduce the discomfort in significantly more patients at week 2, although the difference was significant at week 4. Similar secondary end point outcomes also were seen in the per-protocol population.
      The r analysis showed that pinaverium relieved the overall 6 IBS symptoms simultaneously, not just a particular IBS symptom (see the Supplemental Materials and Methods section for more detail).
      The mean scales of pain, stool consistency, and discomfort showed a progressive and sustained benefit over 4 weeks when compared with the placebo response (Figure 1). At both weeks 2 and 4, pinaverium relieved the scales of each symptom to a significant extent (P < .05–.001) compared with placebo. Overall, pinaverium relieved the 6 symptoms on average by 25.4% (at week 2) and 38.0% (at week 4), whereas placebo relieved the 6 symptoms on average by 10.6% (at week 2) and 12.2% (at week 4).
      Figure thumbnail gr1
      Figure 1The time course of the mean scales of the primary and secondary end points during the treatment (intention-to-treat population). Mean scales (error bars indicate 95% CIs) of pinaverium (n = 218) and placebo (n = 209). The results of the t test comparing the means of the symptom scales between pinaverium and placebo were indicated by $P < .05 and *P < .001. The P values in the RR tables were results from comparing the percentage of patients receiving pinaverium who suffered abdominal pain, discomfort, or diarrhea with that of placebo (chi-square test). Responses of each end point were normalized using the baseline as 1.0 and nonlinearly regressed by an exponential decay model (bottom right). RR, relative risk.
      At week 4, the relative risk for moderate or severe abdominal pain (pain scale, >3) and discomfort (discomfort scale, >3) in patients receiving pinaverium were 0.80 (95% CI, 0.72–0.88; P = .001) and 0.88 (95% CI, 0.80–0.97; P = .01), respectively, when compared with placebo. The relative risk for diarrhea (Bristol scale, >4) in patients receiving pinaverium was 0.54 (95% CI, 0.45–0.64; P = .001) when compared with placebo.

       Tertiary End Point Outcomes

      A total of 368 patients participated in the IBS global symptom relief survey at the end of their treatment. Sixty percent of the patients receiving pinaverium and 34% of the patients receiving placebo rated their treatment as improved (Table 3). The global ratings by patients who believed that the IBS symptoms had improved, stayed the same, or worsened, showed a significant association by treatment group (X22 = 27.9; P < .001).
      Table 3Perception of Improvement by Treatment Groups
      Patients, n (%)P value (X22)
      Pinaverium (n = 191)Placebo (n = 167)
      Improved115 (60)61 (34)<.001 (27.9)
      Stayed the same56 (29)56 (37)
      Worsened20 (11)50 (28)
      NOTE. Group differences were calculated by using X22.
      The r analysis between the IBS global symptom score and the primary/secondary end points was 0.15 (P < .05), showing a significant correlation between the global evaluation by patients with the end points (see the Supplementary Materials and Methods section for detail).
      No severe adverse effects occurred in this clinical trial. Adverse event rates were similar between the treatment groups. A total of 40 patients receiving pinaverium suffered at least 1 TEAE, and 32 patients taking placebo had at least 1 TEAE (Table 4). The adverse effect profiles of the 2 groups showed a significant difference (the Fisher exact test, P = .016), indicating that the adverse effects in the pinaverium group were caused by pinaverium. In particular, there were 25 TEAEs in the pinaverium group vs only 9 TEAEs in the placebo group including dizziness, increased blood pressure, abdominal discomfort and nausea, indicating that dizziness, increased blood pressure, abdominal discomfort, and nausea are the common side effects of pinaverium.
      Table 4Most Commonly Reported Treatment-Emergent Adverse Effects: Intention-to-Treat Population
      Patients, n (%)
      PinaveriumPlacebo
      Constipation3 (1.4)0 (0)
      Headache4 (1.8)7 (3.3)
      Dizziness7 (3.2)1 (0.5)
      Blood pressure increase5 (2.3)2 (1.0)
      Abdominal pain2 (0.9)2 (1.0)
      Abdominal discomfort5 (2.3)2 (1.0)
      Anxiety4 (1.8)11 (5.3)
      Nausea8 (3.7)4 (1.9)
      Back pain1 (0.5)0 (0)
      Others5 (2.3)12 (5.7)
      At least 1 TEAE40 (18.3)32 (15.3)
      Routine laboratory results, vital signs, physical examinations, and electrocardiograms were unremarkable, showing no treatment-related effects.

      Discussion

      This clinical trial had a large sample size, and was a multicenter, randomized, double-blind, and placebo-controlled study on pinaverium. Antispasmodics work either by their anticholinergic properties (eg, dicyclomine, hyoscyamine), or by a direct effect on intestinal smooth muscle (eg, mebeverine, pinaverium). Pinaverium is one of the most commonly used IBS medications worldwide. Pinaverium improves motility disorders, consequently reducing stool problems as well as relieving abdominal pain in IBS patients with few and nonsevere side effects. Pinaverium is 10 times more spasmolytic than papaverine, with 100 times less anticholinergic than atropine.
      • Bretaudeau J.
      • Foussard-Blanpin O.
      • Baronnet R.
      • et al.
      [Pharmacodynamic study of the spasmolytic properties of pinaverium bromide]. Article in French.
      Pinaverium is used widely in many countries around the world, including European countries, Canada, and Mexico, and is one of the most used IBS medications under different brand names. However, pinaverium has not been approved by the US Food and Drug Administration for use in the United States. It might be because no large-sample, double-blinded, placebo-controlled, randomized clinical trials showed the effectiveness and safety of pinaverium (the ACG determined that the “evidence for safety and tolerability is limited” for pinaverium).
      • Brandt L.J.
      • Chey W.D.
      • et al.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      Hopefully, this clinical trial will contribute to the establishment of a clinically effective, cost-effective, and safe drug as first-line IBS therapy.

       Study Strengths

      First, ideally, the effectiveness of a drug should be evaluated by an objective measurement. Unfortunately, there is no such objective measurement for evaluating the therapeutic effectiveness of IBS drugs. Bearing this in mind, we designed our primary and secondary end points as objectively as possible. For example, regarding the stool frequency, we asked patients about “the number of stools per day” instead of asking patients to assess “how IBS impacts the quality of their daily life.” The results from the test–retest of the reliability of the BSS measures indicated that these measures were consistent and reliable.
      Second, each primary and secondary end point was analyzed in multiple aspects. For example, we analyzed not only the response rates of the pain (Table 2), but also the relative risk for patients still experiencing moderate–severe pain at the end of treatment, as well as the decreases on the pain scales over time (Figure 1). Among the ITT population, 50.0% and 77.5% of the patients either relieved their pain significantly or improved stool consistency significantly (single responders) at week 2 and at week 4, respectively, while 13.3% and 38.1% of the patients both relieved their pain significantly and improved stool consistency significantly (dual responders) at week 2 and at week 4, respectively. The significantly higher single responder rate (P < .001, chi-square) likely was owing to an attentional bias when patients evaluated their treatment.
      • Mohammadi S.
      • Dehghani M.
      • Sharpe L.
      • et al.
      Do main caregivers selectively attend to pain-related stimuli in the same way the patients do?.
      In particular, if pain was the biggest concern to a patient, the pain would carry more weight during the evaluation, whereas if stool consistency was the biggest concern, the stool consistency would carry more weight during the evaluation (selective attention).
      Third, in the past, IBS clinical trials commonly used a single-item, patient-reported global rating as the primary end point, whereas recent clinical trials usually reported both the scaled outcome end points (ie, pain, stool consistency) and the patient-reported global rating.
      US Food and Drug Administration
      Guidance for industry irritable bowel syndrome—clinical evaluation of drugs for treatment. Final guidance.
      In this study, we further investigated the relationship between the subjective patient-reported global ratings and the relatively objective IBS symptoms. Overall, the global ratings showed a statistically significant correlation with the end points (P < .05 in both the pinaverium and placebo groups). Specifically, it seems that pain, diarrhea, and the daily stool numbers carried more weight than pain frequency, discomfort, and frequency did when patients rated their global improvements.
      Finally, the ultra-high placebo response rates of end points
      • Spiller R.C.
      Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials.
      and adverse effects (reportedly 49% in a recent clinical trial
      • Dove L.S.
      • Lembo A.
      • Randall C.W.
      • et al.
      Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.
      ) indicated that the evaluation of IBS treatment is highly influenced by patients’ psychological factors and personalities, as well as social backgrounds. To reduce the nonclinical influence to a minimum, we took 2 measures. We designed the primary and secondary end points to be as objective as possible (see previously), and we analyzed the correlation coefficient between the data from pinaverium and placebo (ie, putting the drug in the context of placebo) (see previously).

       Study Limitations

      First, pinaverium has a quick onset of action and cannot cure IBS. Although our clinical observation indicated that onset of action of pinaverium is 1 to 3 days, we did not collect data until week 2. This made the onset of action look delayed. Furthermore, because of the significant placebo effect in IBS,
      • Spiller R.C.
      Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials.
      symptoms seemed to be improved continuously by pinaverium after week 2, although the quick onset of action of pinaverium masked the placebo effects in the first few days. This explanation matches our data pretty well—for example, the pain scale was reduced by 0.54 during weeks 3 and 4 (15% decreased from week 2) in the pinaverium group while reduced by 0.82 during the 4 weeks (16% decreased from baseline) in the placebo group, indicating that, indeed, placebo effects should be responsible for the continuous symptom relief in weeks 3 and 4 in the pinaverium group.
      Second, pinaverium is an antispasmodic for temporarily relief of IBS symptoms. Although our clinical observation indicated that the treatment effects usually waned within 3 days to 1 week after it was discontinued, we did not provide statistical data in this regard.

      Conclusions

      Every effort was made to minimize bias and to be objective in this clinical trial. Our approach in the 2 treatment groups was indistinguishable. We are convinced that this study was designed and conducted in such a way that possible biases have been reduced to a minimum; the pinaverium effectiveness was evaluated as objectively as possible; and patients, physicians, and evaluators all were blinded successfully. We conclude that pinaverium can be considered as a first-line IBS medication for quick and effective relief of IBS symptoms.

      Acknowledgments

      The authors sincerely thank Thomas W. Shier, PhD, for critically reading and correcting this manuscript, Richard Green, PhD for statistics input, and Ms Camille Lebrec for translating the literature from French to English.

      Supplementary Material

      Figure thumbnail fx2
      Supplementary Figure 1Flow of patients through the trial.

      Supplementary Material

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      Linked Article

      • Pinaverium in Irritable Bowel Syndrome: Old Drug, New Tricks?
        Clinical Gastroenterology and HepatologyVol. 13Issue 8
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          We read with interest the randomized controlled trial by Zheng et al1 that compared the antispasmodic pinaverium with placebo for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). The authors reported that more than 75% of patients receiving pinaverium had either 30% reduction from baseline in abdominal pain or 50% reduction in the number of days with at least 1 stool with a Bristol stool score ≥6 at week 4, compared with 33.5% with placebo (P < .001). The proportion of dual responders, those who achieved both of these end points at week 4, was also significantly higher with pinaverium (38.1% vs 16.7%, P < .001).
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