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.

Related blog posts:

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.

FDA Approves Rifaximin and Eluxadoline for IBS-D

From FDA (5/27/15): Two New FDA-Approved Treatments for adults with IBS-D

Excerpt:

The U.S. Food and Drug Administration today approved Viberzi (eluxadoline) and Xifaxan (rifaximin), two new treatments, manufactured by two different companies, for irritable bowel syndrome with diarrhea (IBS-D) in adult men and women….

“For some people, IBS can be quite disabling, and no one medication works for all patients suffering from this gastrointestinal disorder,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “The approval of two new therapies underscores the FDA’s commitment to providing additional treatment options for IBS patients and their doctors.”

Viberzi, which contains a new active ingredient, is taken orally twice daily with food. Viberzi activates receptors in the nervous system that can lessen bowel contractions. Viberzi is intended to treat adults with IBS-D.

Xifaxan can be taken orally three times a day for 14 days, for the treatment of abdominal pain and diarrhea in patients with IBS-D. Patients who experience a recurrence of symptoms can be retreated with a 14 day treatment course, up to two times. Xifaxan, an antibiotic derived from rifampin, was previously approved as treatment for travelers’ diarrhea caused by E. coli and for reduction of the risk in adult patients of recurring overt hepatic encephalopathy, the changes in brain function that occur when the liver is unable to remove toxins from the blood. The exact mechanism of action of Xifaxan for treatment of IBS-D is not known, but is thought to be related to changes in the bacterial content in the gastrointestinal tract.

The safety and effectiveness of Viberzi for treatment of IBS-D were established in two double-blind, placebo-controlled clinical trials…Results showed Viberzi was more effective in simultaneously reducing abdominal pain and improving stool consistency than placebo over 26 weeks of treatment.

The safety and effectiveness of Xifaxan for treatment of IBS-D were established in three double-blind, placebo-controlled trials.

Related blog posts:

AGA Guidelines on Medicines for Irritable Bowel

New guidelines on the use of medicines for irritable bowel syndrome from Atlanta Gastroenterology Association (AGA) have been published (Gastroenterol 2014; 1146-48, technical review: 1149-72).

Here’s the link: AGA IBS Guidelines.

In brief:

For IBS-C

  • Linaclotide: AGA recommends as better than no drug treatment in adult. This is the only “strong” recommendation with high-quality evidence.
  • Lubiprostone: AGA suggests over no drug treatment.
  • PEG Laxatives: AGA suggests over no drug treatment.

For IBS-D:

  • Rifaximin: AGA suggests over no drug treatment.
  • Alosetron: AGA suggests over no drug treatment.
  • Loperamide: AGA suggests over no drug treatment.

For IBS:

  • Tricyclic antidepressants: AGA suggests over no drug treatment.
  • Selective Serotonin Reuptake Inhibitors: AGA suggests against using for IBS.
  • Antispasmotics: AGA suggests over no drug treatment.

 

Also noted:

Am J Gastroenterol 2014; 109: 1547-61. (Thanks to Ben Gold for this reference.) Meta-analysis of prebiotics/probiotics for IBS.  43 RCTs were eligible for inclusion.  Key finding: IBS symptoms, including pain, bloating and flatulence were improved with RR of 0.79 compared with placebo.  “Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear.”

Related blog posts:

Hepatology Update (Part 2) -Summer 2014

Hepatology 2014; 60: 715-33.  This publication is the AASLD Practice Guideline for Hepatic Encephalopathy in Chronic Liver Disease.  The recommendations are too extensive to summarize.  Here’s one: despite concerns about efficacy, “lactulose is the first choice for treatment of episodic” overt hepatic encephalopathy.  Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence. AASLD Guidelines Website

Hepatology 2014; 60: 679-86. Using the Drug-Induced Liver Injury Network between 2004-2012, the authors identified 22 cases of hepatotoxicity attributed to statins.  Median age was 60 years.  The latency to onset of symptoms varied from 34 days to 10 years with a median of 155 days. Nine patients had a cholestatic hepatitis pattern and 12 had hepatocellular injury, including six with an autoimmune phenotype. Severity: nine required hospitalization, four had evidence of hepatic failure and one died.

Related blog posts:

A C difficile two-fer

Two recent review articles on Clostridium difficile are quite useful:

  • Mezoff EA, Cohen MB. J Pediatr 2013; 163: 627-30.
  • Dupont HL. Clin Gastroenterol Hepatol 2013; 11: 1216-23.

The first publication reviews acid suppression and the risk of C difficile infection (CDI).  It starts off with  a terrific piece of advice from Sir William Osler: “One of the first duties of the physician is to educate the masses not to take medicine.”  The authors note that pH above 4 has been shown to increase bacterial survival, including  C perfringe spores in a mouse model.  In addition, the article notes that there have been concerns as early as 1982 that acid suppression could be a risk factor for CDI.  Several recent studies were summarized, including the following:

  • A recent meta-analysis (Kwok CS et al. Am J Gastroenterol 2012; 107: 1011-9) with 42 studies (N= 313,000 patients) “found an association between PPI use and risk of CDI (OR1.74, 05%CI 1.47-2.85).”
  • A review of the literature (Deshpande A et. Clin Gastroenterol Hepatol 2012; 10: 225-33) between 1990-2010 found an overall increase in CDI risk with PPIs to be OR 2.15 (95% CI 1.81-2.55). No prospective studies were identified.
  • In pediatrics, a study (Turco et al. Alimentary Pharmacol Therapeut 2010; 31: 754-9) with 910 children admitted for abdominal pain and diarrhea identified 68 with CDI.  Compared with control patients, use of PPIs was significantly higher in CDI patients (OR 4.52, 95% CI 1.4-14.4).

The FDA has stated that PPIs may be associated with an increased risk of CDI.  In addition, the use of antibiotics “appear to act synergistically with PPIs.”  Thus, the authors recommend stopping PPIs in those who do not need them.  Periodic ‘holidays’ or dosing step-downs may help assess continued need for PPIs.

The second publication succinctly reviews the diagnosis and management of CDI.  The various diagnostic methods are compared in Table 1.  Therapeutic options for 1st time infection are reviewed in Table 2.  For adults with mild-to-moderate infections, metronidazole (500 mg TID for 10 days) is preferred.  Vancomycin or Fidaxomicin are recommended for more severe infections.

Table 3 lists treatment options for recurrent CDI.  Repeat course of any of the 1st round treatments can be considered depending on patient’s illness severity.  In addition, other potential treatments included the following:

  • vancomycin tapered dose (week 1: 125 mg 4 times/day, week 2: 125 mg 2 times/day, week 3: 125 mg once/day, week 4: 125 mg every other day, week 5 & 6: 125 mg every third day)
  • rifaximin (550 mg BID x 20 days)
  • high-dose vancomycin (250-500 mg 4 times/day for 10 days) followed by S boulardii (2 capsules BID for 28 d)
  • fecal microbiota transfer (FMT) –“although family member stool donors have been used, the current movement is toward volunteer donor pools.”  [I do not think ‘current movement’ was intended as a pun by the authors.]  Volunteer donors could lower the screening costs.
  • intravenous immunoglobulin (small clinical trials have failed to show efficacy)
  • monoclonal antibodies to toxins A/B

Related blog posts:

Rifaximin for Crohn’s disease?

Rifaximin (Xifaxan®) shows promise as a new treatment for Crohn’s disease (Gastroenterology 2012; 142: 473-81).  Rifaximin is an oral medication with minimal systemic absorption; it has a good track record in a number of GI indications, including bacterial gastroenteritis (traveler’s diarrhea), bacterial overgrowth in irritable bowel disease, and hepatic encephalopathy.  There are a few reasons why rifaximin would be considered a good candidate treatment for Crohn’s disease:

  • The pathophysiology of Crohn’s disease involves interaction of adherent bacteria to the intestinal mucosa and with the immune system
  • Other antimicrobials have shown benefit for Crohn’s disease
  • Animal models do not manifest Crohn’s disease when in a bacteria-free environment

In this study of 402 patients with moderate-to-severe Crohn’s disease, a multicenter randomized double-blind trial examined efficacy and safety of rifaximin at doses of 400mg, 800mg, and 1200mg twice daily.  The primary end point was remission based on Crohn’s Disease Activity Index (CDAI).

At the end of the 12-week treatment period, 62% of the 800mg group were in remission compared to 43% of the placebo group.  This difference was maintained 12 weeks afterwards with 45% maintaining remission compared with 43% of patients receiving placebo.  When looking at the other dosing regimens, at 12 weeks, 54% of the 400mg group and 47% of the 1200mg group were in remission based on CDAI.

Clinical response, but not remission, occurred in 56% of placebo patients compared with 63% for 400mg patients, 72% for 800mg patients, and 57% of 1200mg patients.  This trial may have been hampered by patient selection in that the placebo response was high.  This may be due to the fact that ~50% of patients had a low CRP value at baseline.

Safety was good in all patient groups.  However, one rifaximin-treated patient developed C difficile infection.

The fact that a clear dose response was not evident suggests the need for more studies.

Additional Rifaximin References:

  • -NEJM 2011; 364: 22 (pg 81-editorial).  About 10% improvement over placebo in pts with IBS-D.  (see abstract below).  Effects lasted up to 3 months.
  • -JPGN 2009; 49: 400-04. helped symptoms in 61% of IBD pts. n=23 (12 w Crohn). dose 10-30mg/kg/day.
  • -Aliment Pharm Ther 2005; 22: 31-35. Use in SBBO. n=90; 1200mg/day x 7 days. NL glucose breath test in 60% (vs 17% in low dose group); no side effects.
  • -Ann Intern Med 2006; 145: 557-563. double-blind, randomized controlled trial, n=87 for IBS. 400mg tid x 10days. Rx resulted in greater IBS improvement, ~40% improvement vs 20% w placebo during 10 week study
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -J Infect 2011; 62: 34-38. Rx may lead to resistant staphylococci.
  • -Hepatology 2010; 52: 1484. Review.

Additional Crohn’s Antibiotic/Probiotic References:

  • -IBD 2009; 15; 17. 40% response to Cipro in treatment of peranal fistulas. n=25. No response to metronidazole.
  • -IBD 2008; 14: 1597, 1585. No proven role for probiotics and IBD except pouchitis (after Abx)
  • -Clin Gastro & Hep 2008; 6: 145. Pouch problems reviewed -excellent review.
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -Curr Med Res Opinion 2005; 8: 1165-70. Rx for traveler’s diarrhea.  May be useful for Crohn’s as well.
  • -Gastroenterology 2005; 128: 856. Use of ornidazole prophylaxis reduced recurrence p-op from 37.5% to 8%.
  • -IBD 2004; 10: 318-325. antibiotics & IBD review.
  • -Gastroenterology 2004; 127: 412-21. adherent-invasive E. coli associated with ileal mucosa in 22% of Crohn’s (n=63) ileal mucosa vs. 6% of controls (n=16); higher colonization noted in neo-terminal ileums (36%).