PERSUADE Study: I Guarantee That It Will …

Peppermint oil (PO) products have been promoted for irritable bowel syndrome (IBS) for quite a long time.  When I have recommended PO as a possible treatment, I frequently say that “I guarantee that it will….give you fresh breath.  It might help your stomach symptoms.”

A recent randomized, double-blind “PERSUADE” study (Zsa Zsa R. M. Weerts et al Gastroenterol 2020; 158: 123-36) shows that PO likely has some efficacy for stomach symptoms in IBS. This trial enrolled 189 patients & 178 completed study (mean age, 34 years, 78% female) from the Netherlands.  Subjects were divided in three groups -instructed to take the study capsule 3/day for 8 weeks:

  • 182 mg small-intestinal release PO-SI
  • 182 mg ileocolonic release PO-IC
  • Placebo

The primary endpoint was at least a 30% decrease in the weekly average of worst daily abdominal pain

Key findings:

  • The primary endpoint did NOT differ significantly between the three groups: PO-SI with 46.8%, PO-IC with 41.3%, and Placebo with 34.4% response.
  • The PO-SI but not PO-IC was associated in secondary improvements compared to placebo in abdominal pain (P=.06), discomfort (P=.02), and IBS severity (P=.02).
  • Adverse events were mild with PO, but more common than placebo. Adverse events included heartburn, belching, and headache.
  • The authors calculate that the number needed to treat with PO-SI would be 8 which is higher than recent ACG monograph which suggested an NNT of 4 (Am J Gastroenterol 2018; 113: 1-18).  Even an NNT of 8 compares favorably with other treatments: linaclotide 6, plecanatide 10, and eluxadoline 12.5.


  • the studied population was mainly young adult, predominantly white and female; thus the findings may not be generalized to other groups
  • the peppermint smell could have undermined blinding despite presentation in capsule form
  • relatively short duration study

The associated editorial by BD Cash (pgs 36-37) notes that PO medicinal use began in 1753 by Carl Linnaeus.  PO is thought to work via smooth muscle calcium channel antagonism.  The findings of working in the small intestine and not ileocolonic release could “spur additional therapeutic development.”

My take (borrowed in part from editorial): “These results reaffirm that PO can improve viscerosensory symptoms of IBS …and is well-tolerated… [It is] clearly not a gangbuster as a monotherapy.”  While the findings show modest effect, the findings are supported by a “robust” study as this is the first randomized, double-blind placebo-controlled clinical trial of PO.

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Also, fidaxomicin has received FDA approval for pediatric use for C diff infections:

Irritable Bowel Syndrome (part 2)

A terrific 12 page review of irritable bowel syndrome (IBS): AC Ford, BE Lacy, NJ Talley. NEJM 2017; 376: 2566-78. While yesterday’s post reviewed some of the updated diagnostic and pathophysiology information, today’s will focus on treatment.

The article’s Table 2 outlines the most frequent treatments, their efficacy, side effects, costs, and quality of evidence. I’ve tried to highlight the key points from table and discussion:

  1. Soluble fiber (eg. psyllium). Efficacy: effective -start at low doses. Quality of evidence: Moderate, Cost: $15-30 per month.
  2. Low-FODMAP diet. Efficacy: “May be effective, nutritionist guidance helpful.” While there have been studies showing this diet can be effective, two studies have shown that this diet is not significantly superior to conventional IBS diets (eg. “eating small, regular meals and avoiding insoluble fiber, fatty foods, and caffeine”).Quality of evidence: Very low.
  3. Gluten-free diet.  Efficacy: May be effective.  “No additive effect over that of a low-FODMAP diet in another small RCT.” Quality of evidence: Very low.
  4. Antispasmodic drugs (eg. dicyclomine).Efficacy: May be effective. Quality of evidence: Low, “No high-quality trials.” Cost: $50 per month.
  5. Peppermint oil. Efficacy: Effective, though few RCTs and no FDA-approved end points. Quality of evidence: Moderate. “No high-quality trials.”  Cost: $9-19 per month
  6. Lubiprostone. Efficacy: Effective, though “only a modest benefit over placebo, particularly for abdominal pain.” Quality of evidence: Moderate. Cost: ~$350 per month.
  7. Linaclotide.  Efficacy: Effective.. ” Quality of evidence: High. “No high-quality trials.”  Cost: ~$350 per month.
  8. Alosetron/5-HT3 receptor antagonists.  Efficacy: Effective. ” Quality of evidence: High. “No high-quality trials.”  Cost: ~$350-1100 per month. Alosetron may trigger ischemic colitis.
  9. Eluxadoline.  Efficacy: Effective, though “only a modest benefit over placebo for global symptoms and no benefit over placebo for abdominal pain.”  Quality of evidence: High. “No high-quality trials.”  Cost: ~$1100 per month. May trigger pancreatitis.
  10. Rifaximin. Efficacy: Effective. Quality of evidence: Moderate. “Modest benefit over placebo.”  “Relapse among patients who have a response is usual.” Cost: ~$1500 per month.
  11. Probiotics. Efficacy: May be effective.  Quality of evidence: Low. “Few high-quality trials and no FDA-approved end points.”  Cost: ~$20 per month.
  12. Tricyclic antidepressants. Efficacy: Effective. Quality of evidence: Moderate.  “Few high-quality trials and no FDA-approved end points.”   “A meta-analysis showed that tricyclic antidepressants were more effective than placebo in 11 randomized trials involving a total of 744 patients.” Cost: ~$5-10 per month.
  13. Psychological treatments. Efficacy: Effective. Quality of evidence: Low.  “Few high-quality trials and no FDA-approved end points.” “Their efficacy may be overestimated because of the lack of blinding.” There is also difficulty for many patients in finding an appropriate provider.  Cost: ??
  14. Placebo. In treatment trials, a placebo response is noted in 30-40%.
  15. Complementary/Alternative Therapies.  “Herbal therapies remain unclear.  STW5 (Iberogast) has been tested and “showed superiority over placebo.” Melatonin “has been reported to reduce abdominal pain in patients with IBS.”

The authors recommend judicious testing  “Any reassurance derived from colonoscopy to rule out organic disease in patients with IBS is short-lived.”

The authors outline their typical approach.  “Reassurance, explanation, and a positive diagnosis are essential steps in management. We recommend starting with dietary modification (slowly increasing soluble fiber if the patient has IBS with constipation or instituting a low-FODMAP diet temporarily  if the patient has IBS with diarrhea or the mixed subtype of IBS). We also recommend increased exercise and stress reduction.  A probiotic may be added, especially if bloating is prominent.  Pain may be ameliorated with an antispasmodic agent or a tricyclic antidepressant, diarrhea with loperamide or a bile acid sequestrant (eg. colestipol) and constipation with polyethylene glycol.” The other therapies may be used in those with persistent IBS symptoms.

My take: When a disease has this many treatments, usually this means that none of the treatments are all that great.

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Chattahoochee River

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Herbal Medicines for IBD and IBS

A nice review (Holtmann G, Talley NJ. Clin Gastroenterol Hepatol 2015; 13: 422-32) provides a summary of the experience of herbal medicines for disorders that include irritable bowel syndrome (IBS), functional dyspepsia, and inflammatory bowel disease (IBD).

A recurring theme in the review is that herbal medicines are poorly studied and vary greatly in the quality of their manufacturing.  “Physicians and regulators need to remain very cautious about the use of herbal remedies.” The available trials, with a long list of plant extracts, are summarized in tables in the review.

Specific points:

  • “A meta-analysis also showed that supplementation of peppermint oil, in addition to pharmacologic standard treatments, was of benefit to both constipation-predominant IBS and diarrhea-predominant IBS patients.”
  • “The use os STW5 [iberogast] also has been found to be effective compared with placebo in the treatment of IBS symptoms.”
  • Very small clinical studies have suggested possible efficacy of aloe vera and curcumin in the treatment of IBD.
  • Adverse effects: “there are numerous case reports on adverse events related to herbal medicines.” Some of these have been severe.
  • “The main driver for the use of herbal and complementary medicines is the unmet need of patients.” However, given that these preparations are non patentable, “there is limited investment of producers.”

Bottomline: There is little financial incentive for companies to determine more conclusively whether these agents are effective for functional disorders or for inflammatory bowel disease.

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How Effective are the Treatments for Functional Abdominal Pain?

According to a recent systematic review (Korterink JJ et al. J Pediatr 2015; 166: 424-31), “there is no evidence to support routine use of any pharmacologic therapy” for pediatric functional abdominal pain (FAP).  How many pediatric gastroenterologists want to discuss this conclusion with their patients?

How did the authors reach their conclusion?

Design: The authors screened 557 articles and ultimately identified only four articles with a total of 6 studies met inclusion criteria which included the following:

  • systemic review or randomized control trial
  • children 4-18 years
  • diagnosis of FAP established with well-defined criteria
  • intervention was compared to placebo or alternative treatment

Results: All of the studies were reviewed –each received an overall quality rating by the authors as “very low.” The particular treatments included amitriptyline, peppermint oil, famotidine, miralax, tegaserod, and cyprohepatadine.  The study with the most patients had only 90 patients and the longest treatment period was 4 weeks.

In the discussion, the authors make several key points:

  • there is a lack of adequately powered, high-quality, placebo-controlled drug trials in children with FAP
  • weak evidence was found in support of peppermint oil, cyproheptadine, and laxatives at reducing pain; amitriptyline and famotidine had weak evidence supporting some improvement in global symptoms or quality of life.
  • problems with the studies: small sample sizes, poorly reported side effects, lack of follow-up, risk of bias
  • “several nonpharmacologic therapies (e.g.. hypnotherapy and cognitive behavioral therapy) have shown their efficacy in treating children with” FAP…with success rates up to 85%.  Moreover, these therapies are not hampered by severe side effects.”

Bottomline: Our office-based psychologist may be more helpful for our patients than all the medications combined.

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