On-line Supplemental Material
1. eTable 1. A Brief Review of the Clinical Studies on Pinaverium for IBS ...………………2
2. eTable 2. Irritable Bowel Syndrome (IBS-D) Questionnaire ………………………...……3
3. eTable 3. The Bowel Symptom Scale (BSS) for IBS ..……………………………………4
4. eTable 4.Primary and Secondary Efficacy Results (the response rates, odds ratios (OR),
and 95% confidence interval (CI) in the per-protocol population) .…..……………5
5. The Average Inter-item Correlation (r∑) analysis of the six symptoms ……………...……6
6. The Average Inter-item Correlation analysis between the global symptom score and the primary / secondary endpoints ……………………………………………………..…….. 6
7. Additional Introduction, Discussion, and References …………………………………….8
1. eTable 1. A Brief Review of the Clinical Studies on Pinaverium for IBS
Awad et al. 1995 / Jayanthi. et al. 1998 / Defrance & Casini. 1991 / Levy. et al 1977 / Virat & Hueber. 1987 / Delmont. 1981IBS Patient # in Pinaverium group (Completed / Enrolled) / 19/20 / 53 / 61 / 29 / 40 / 25 / 25 / 39 / 39 / 29 / 30
IBS Patient or Healthy subject # in placebo group (Completed / Enrolled) / IBS Patient
19/20 / No placebo / No placebo / IBS Patient
25 / 25 / IBS Patient
39 / 39 / IBS Patient
28 / 30
Described withdrawals or incomplete? / Yes / Yes / Yes / No / No / Yes
Single (S)/Multi (M)-center? / S / S / S / S / S / S
Described as single (S)-/double(D)-blinded? / D / No / S / D / D / D
Treatment period / 3 weeks / 8 weeks / 15 days / 2 weeks / 1 week / 4 weeks
Described as randomized? / Yes / No / No / Yes / Yes / Yes
Total pages (not incl. Ref.) / 6 / 2 / 3 / 3 / 3 / 5
The origin of patients / Mexico / India / Belgium* / France / France / France
Study published in / English / English / English / France / France / France
*: Assuming that the patients were from the first author’s institute.
Original clinical studies on pinaverium are scarce. Only four original clinical studies from Europe1-4, one from Latin America5, and one from Asia6 were found. These studies were either short communications (2 – 3 pages, excluding the Abstract and the References) not adequately addressing the effectiveness of pinaverium1-3,6, or clinical studies not comprehensive enough to cover the safety and tolerate issues related to pinaverium4,5.
- Defrance P and Casini A. A comparison of the action of otilonium bromide and pinaverium bromide: study conducted under clinical control. Ital J Gastroenterol. 1991;23 (Suppl 1): 64-6.
- Levy C, Charbonnier A, Cachin M. [Pinaverium bromide and functional colonic disease (double-blind study] [Article in French]. Sem Hop Ther. 1977;53:372-4.
- Virat J , Hueber D . Colopathy pain and dicetel . Prat Med 1987; 43:32-4 .
- Delmont J. [The value of adding an antispasmodic musculotropic agent in the treatment of painful constipation in functional colopathies with bran. Double-blind study] (Article in French). Med Chir Dig. 1981;10:365-70.
- Awad R, Dibildox M, Ortiz F. Irritable bowel syndrome treatment using pinaverium bromide as a calcium channel blocker. A randomized double-blind placebo-controlled trial. Acta Gastroenterol Latinoam. 1995;25:137-44.
- Jayanthi V, Malathi S, Ramathilakam B, Dinakaran N, Balasubramanian V, Mathew S. Role of pinaverium bromide in south Indian patients with irritable bowel syndrome. J Assoc Physicians India. 1998;46:369-71.
2. eTable 2. Irritable Bowel Syndrome (IBS-D) Questionnaire
Patient ID: .
Name: Gander: M F Age Phone .
Address ZIP .Others .
Treatment history of IBS:- How long have you suffered the symptoms of IBS-D?
- Have you ever received treatment?
No (go to Question 6)
- Name of the drug(s) used for IBS?
- Are you still taking the drugs in Question 3?
No How long stop the drug(s)?______
- Reasons of stopping the drugs:
Effective due to side effects;
Effective but the drugs are expensive;
Somewhat effective, not completely relieve the symptoms;
Not effective;
Others .
Diagnostic Criteria of IBS (symptom onset at least 6 months prior to diagnosis, and in the last 3 months associated with two or more in 7):
- How many months have recurrent abdominal pain or discomfort been?
How many days such symptoms appeared in the past 3 months?
(Inclusion criteria: 3 days)
- Improvement after defecation;
Symptom onset associated with a change in form (appearance) of stool.
(Inclusion criteria: two or more the symptoms)
3. eTable 3.The Bowel Symptom Scale (BSS) for IBS
The Bowel Symptom Scale (BSS) for IBS Patient ID: .
Symptoms / Pretreatment / 2 weeks after treatment / 3 weeks after treatment / 4 weeks after treatmentglobal symptom score / 0 1 2 3 4 / 0 1 2 3 4 / 0 1 2 3 4 / 0 1 2 3 4
Question: “How would you rate your IBS symptoms overall the past 7 days?”
Answer: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.
Abdominal pain / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10
no pain Mild, Nagging, Distressing Intense Worst possible,
annoying uncomfortable, miserable dreadful unbearable,
pain troublesome pain pain horrible pain excruciating pain
Pain frequency / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10
0 = no pain; 1 = 1 pain/day; 2 = 2 pains/day; 3 = 3 pains/day; ...... 9 = 9 pains/day; 10 = ≥ 10 pains/day.
Abdominal discomfort / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10
no discomfort Mild, Nagging, Distressing Intense Worst possible,
annoying uncomfortable, miserable dreadful unbearable,
discomfort troublesome discomfort horrible excruciating
discomfort discomfort discomfort
Discomfort frequency / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10
0 = no discomfort; 1 = 1 discomfort/day; 2 = 2 discomforts/day; 3 = 3 discomforts /day; ...... 9 = 9 discomforts/day; 10 = ≥ 10 discomforts/day.
Daily stool number / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10 / 0 1 2 3 4 5 6 7 8 9 10
0 = no stool; 1 = 1 stool/day; 2 = 2 stools/day; 3 = 3 stools/day; ...... 9 = 9 stools/day; 10 = ≥ 10 stools/day.
Stool consistency
(The # of day with at least one stool of 6 or 7) / 1 2 3 4 5 6 7 / 1 2 3 4 5 6 7 / 1 2 3 4 5 6 7 / 1 2 3 4 5 6 7
Separate Sausage Like a Like a Soft blobs Fluffy pieces Watery, no
hard lumps, -shaped sausage sausage or with clear- with ragged solid pieces
like nuts but lumpy but with snake, smooth cut edges edges, a entire liquid
(hard to pass) cracks on the and soft mushy stool
surface
.
4. eTable 4. Primary and Secondary Efficacy Results (the response rates, odds ratios (OR), and 95% confidence interval (CI) in the per-protocol population)
Week 2 / Week 4Pinaverium / Placebo / P value (X2) / Pinaverium / Placebo / P value (X2)
Primary end points
Single responders / 50.9% / 15.2% / <0.001 / 75.7% / 33.1% / <0.001
OR (95% Cl) / 5.77 / 3.37 / – / 9.86 / 45.1 / 6.31 / 3.87 / – / 10.28 / 58.7
Dual responders / 13.0% / 7.9% / >=0.05 / 43.8% / 20.5% / <0.001
OR (95% Cl) / 1.73 / 0.83 / – / 3.64 / 2.2 / 3.02 / 1.83 / – / 4.96 / 19.6
Abdominal pain / 39.1% / 14.6% / <0.001 / 60.9% / 30.5% / <0.001
OR (95% Cl) / 3.76 / 2.17 / – / 6.50 / 24.0 / 3.56 / 2.62 / – / 5.67 / 29.8
Stool consistency / 25.0% / 8.6% / <0.001 / 58.9% / 23.2% / <0.001
OR (95% Cl) / 3.54 / 1.82 / – / 6.89 / 15.0 / 4.76 / 2.92 / – / 7.74 / 41.8
Secondary end points
Pain frequency / 39.6% / 13.9% / <0.001 / 73.4% / 25.8% / <0.001
OR (95% Cl) / 4.07 / 2.34 / – / 7.08 / 35.8 / 7.91 / 4.80 / – / 13.04 / 96.5
Stool frequency / 40.8% / 19.9% / <0.001 / 55.6% / 33.1% / <0.001
OR (95% Cl) / 2.78 / 1.68 / – / 4.61 / 22.1 / 2.53 / 1.61 / – / 3.99 / 21.9
Abdominal discomfort / 26.0% / 26.5% / >=0.05 / 50.9% / 37.1% / <0.005
OR (95% Cl) / 0.98 / 0.59 / – / 1.61 / 0.0 / 1.76 / 1.12 / – / 2.92 / 8.2
Discomfort frequency / 38.5% / 19.9% / <0.001 / 61.5% / 32.5% / <0.001
OR (95% Cl) / 2.52 / 1.52 / – / 4.18 / 17.8 / 3.33 / 2.10 / – / 5.62 / 36.2
NOTE: Abbreviations: abdoml, abdominal; consist, consistency; freq, frequency; discomft, discomfort. OR, odds ratios; CI, confidence interval.
5. The Average Inter-item Correlation (r∑) analysis of the six symptoms
The Average Inter-item Correlation (r∑) analysis was performed to investigate whether pinaverium tends to relieve some particular IBS symptoms or whether it relieves all the six symptoms simultaneously, i.e., statistically significant correlations existed among these six IBS symptoms relieved. Fifteen Pearson product-moment correlation coefficients (r) were obtained. At both week 2 and week 4, all paired r’s were positive correlated. Strong correlation existed between pain and pain frequency (week 2 / week 4: r = 0.31 / 0.31 , P < 0.01), pain frequency and discomfort frequency (r = 0.27 / 0.28, P < 0.01), discomfort and discomfort frequency (0.23 / 0.39, P < 0.01), discomfort and stool consistence (r = 0.30 / 0.23, P < 0.01). Weak correlation occurred at week 2 between pain and discomfort (r = 0.08, P > 0.05), pain and discomfort frequency (r = 0.13, P > 0.05), pain frequency and discomfort (r = 0.14, P > 0.05), stool frequency and discomfort (r = 0.04, P > 0.05), stool frequency and discomfort frequency (r = 0.09, P > 0.05). At week 4, weak correlation only occurred between stool frequency and discomfort (r = 0.13, P > 0.05). The Average Inter-item Correlation showed that the primary and secondary endpoints are significantly correlated (r∑ = 0.18, P < 0.01 at week 2; r∑ = 0.25, P < 0.01 at week 4), indicating that pinaverium relieved the overall six IBS symptoms simultaneously, not (a) particular IBS symptom(s).
6. The average Inter-item Correlation analysis between the global symptom score
And the primary / secondary endpoints
The Average Inter-item Correlation between the IBS global symptom score and the primary / secondary endpoints is 0.15 (P < 0.05), showing a significant correlation between the global evaluation by patients with the endpoints. Specifically, statistically significant correlations existed in the pinaverium group between the global score and pain (r = 0.28, P < 0.001), stool consistency (r = 0.20, P < 0.05), or stool frequency (r = 0.23, P < 0.01), while no statistically significant correlations existed between the global score and pain frequency (r = 0.14, P > 0.05), discomfort (r = 0.11, P > 0.05), or discomfort frequency (r = 0.11, P > 0.05). In comparison, stronger statistically significant correlations existed in the placebo group between the global score and pain (r = 0.27, P < 0.001), stool consistency (r = 0.27, P < 0.001), or stool frequency (r = 0.22, P < 0.01), while relatively weak correlations existed between the global score and pain frequency (r = 0.20, P < 0.05) and discomfort frequency (r = 0.17, P < 0.05), no statistically significant correlations existed between the global score and discomfort (r = 0.13, P > 0.05). These results indicated that patients judged their global symptoms relief mainly by pain, diarrhea (stool consistency), and the daily stool numbers (stool frequency) while they might have statistically overlooked the other symptoms.
7. Additional Introduction, Discussion, and References
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%-15%.e1
The pathophysiology of IBS has not been fully understood.e2 It was found that IBS patients tend to have an abnormal motility in the gastrointestinal tract,e3 an increased pain sensitivity,e4 an altered gut immune function,e5 abnormal autonomic and central nervous modulation,e6 and psychosocial disturbances.e7
Antispasmodics remain one of the most commonly prescribed groups of medications for the treatment of IBS with few adverse effects.e8, e9
Pinaverium has a quick onset of action and quick offset of action (our clinical observation: onset of action: 1-3 days, offset of action: 3 days to 1 week). Like pinaverium, hyoscyamine has a quick onset of action and quick offset of action (our clinical observation: onset of action: 10-30 minutes, offset of action: 1-3 days). Pinaverium is a calcium channel blocker acting highly selectively on the gastrointestinal tract. In contrast, hyoscyamine is a nonselective muscarinic antagonists, which is used primarily for relieving abdominal pain instead of improving gastrointestinal tract function in IBS patients. Hyoscyamine has extensive anticholinergic side effects.
The relative risk analyses showed that after 4-week treatment with pinaverium, patients still have a 54% RR of having diarrhea, an 80% RR of moderate-severe pain, and an 88% RR of moderate-severe discomfort when compared with placebo (P < 0.01-0.001). It seems that pinaverium was most effective in decreasing the risk of diarrhea. The experimental event rate (EER) for diarrhea is 0.42 and control event rate (CER) is 0.78 (RR = 0.42 / 0.78 = 54%). That means, 6 out of 10 patients would not have diarrhea after being treated with pinaverium for 4 weeks but 2 of them would be cured by itself anyway. On the other hand, although the numeric value of a RR of 88% can be statistically labeled as “significantly” improving discomfort (P < 0.01), such a RR seems to be below the clinical expectation. This high RR might be because of the placebo response rates since the RR was calculated as the event ratio of the drug to placebo. Regardless, pinaverium appeared to be significantly effective in decreasing the risk of having diarrhea, suffering moderate-severe pain and discomfort.
e1.Quigley E, Fried M, Gwee KA, Olano C, Guarner F, Khalif I, Hungin P, Lindberg G, Abbas Z, Fernandez B, Mearin F, Bhatia SJ, Hu PJ, Schmulson M, Krabshuis JH, Le Mair AW. Irritable bowel syndrome: a global perspective. World Gastroenterology Organisation Global Guideline, 2009. Page 3.
e2.Kellow JE, Azpiroz F, Delvaux M, Gebhart GF, Mertz HR, Quigley EM, Smout AJ. Applied principles of neurogastroenterology: physiology/motility sensation. Gastroenterology. 2006;130:1412-20.
e3.Serra J, Azpiroz F, Malagelada JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut 2001;48: 14–19.
e4.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.
e5.O’Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O’Morain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000;12:449–457.
e6.Silverman DHS, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathologic perception of visceral pain. Gastroenterology 1997;112:64–72.
e7.Whitehead WE, Bosmajian L, Zonderman AB, Costa PT Jr, Schuster MM. Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples. Gastroenterology 1988;95:709–714.
e8.Martínez-Vázquez MA, Vázquez-Elizondo G, González-González JA, Gutiérrez-Udave R, Maldonado-Garza HJ, Bosques-Padilla FJ. Effect of antispasmodic agents, alone or in combination, in the treatment of Irritable Bowel Syndrome: systematic review and meta-analysis. Rev Gastroenterol Mex. 2012;77:82-90.
e9.Ruepert L, Quartero AO, de Wit NJ, van der Heijden GJ, Rubin G, Muris JW. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD003460.
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