Key finding: 606 patients were randomized to treatment (placebo: n=202; lubiprostone: n=404). No statistically significant difference in overall SBM (spontaneous bowel movement) response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P=.2245).
A recent systematic review and network meta-analysis (CJ Black, et al. Clin Gastroenterol Hepatol 2020; 18: 1238-39) reviewed the relative efficacy of medications for irritable bowel syndrome with constipation. In total, the 14 trials randomized 9113 patients.
All treatments were significantly more effective than placebo
Linaclotide was ranked most effective; however, indirect comparison of active treatments revealed no significant differences between the individual drugs
A recent study (CJ Black et al. Gastroenterol 2018; 155: 1753-63) examined the effectiveness of secretagogues for constipation-predominant irritable bowel syndrome (IBS-C). The authors conducted a systematic review and network meta-analysis with 15 eligible randomized controlled trials (8462 patients).
Linaclotide (290 mcg per day) was ranked first in efficacy using the end point recommended by the FDA for IBS-C trials
Tenapanor (50 mg twice a day) was ranked first for bloating
Plecanatide (6 mg per day) ranked first for safety
Diarrhea was significantly more common with all of the secretagogues except for lubiprostone; nausea was significantly more common with lubiprostone
The authors acknowledge the limitations in comparing medicines without direct head-to-head trials (which may never occur). They state that linaclotide being superior to other treatments had a probability of 88%.
My take: This study indicates that linaclotide may be more likely to be effective than other IBS-C medications; all of these secretagogues have been shown to be superior to placebo.
In this same issue, pgs 1666-9 (J Ruddy), a patient describes her long journey with abdominal pain/GI symptoms. She describes her initial experiences with physicians who were dismissive and not attentive. Ultimately, a physician listened to her and helped her improve after explaining that she had a postinfectious IBS and provided treatment.
Related study: S Ishague et al. BMC Gastroenterol 2018; 18:71. This randomized controlled trial which compared a multistrain probiotic (Bio-Kult, n=181) to placebo (n=179). The probiotic group had a 69% decrease in abdominal pain compared to a 47% decrease in placebo group.
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:
Soluble fiber (eg. psyllium). Efficacy: effective -start at low doses. Quality of evidence: Moderate, Cost: $15-30 per month.
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.
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.
Antispasmodic drugs (eg. dicyclomine).Efficacy: May be effective. Quality of evidence: Low, “No high-quality trials.” Cost: $50 per month.
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
Lubiprostone. Efficacy: Effective, though “only a modest benefit over placebo, particularly for abdominal pain.” Quality of evidence: Moderate. Cost: ~$350 per month.
Linaclotide. Efficacy: Effective.. ” Quality of evidence: High. “No high-quality trials.” Cost: ~$350 per month.
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.
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.
Rifaximin. Efficacy: Effective. Quality of evidence: Moderate. “Modest benefit over placebo.” “Relapse among patients who have a response is usual.” Cost: ~$1500 per month.
Probiotics. Efficacy: May be effective. Quality of evidence: Low. “Few high-quality trials and no FDA-approved end points.” Cost: ~$20 per month.
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.
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: ??
Placebo. In treatment trials, a placebo response is noted in 30-40%.
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.
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.
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.
Rifaximin: AGA suggests over no drug treatment.
Alosetron: AGA suggests over no drug treatment.
Loperamide: AGA suggests over no drug treatment.
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.
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.”
A recent open-label study of lubiprostone examined its use in children younger than 18 years (2007-2008) at 22 U.S. centers (JPGN 2014; 58: 283-91).
Lubiprostone (Amitiza) activates chloride-channel protein-2 in the gastrointestinal epithelium and promotes secretion of chloride ions and fluid. This results in more frequent bowel movements (BMs) and improved motility. To determine its safety and effectiveness in the pediatric population, the investigators enrolled 127 patients (124 were treated and analyzed and 109 completed the 4-week study). After a 2-week observation period, several doses of lubiprostone were compared: 12 μg QD, 12 μg BID, 24 μg BID. There was no placebo group. The mean age of the participants was 10.2 years.
Mean spontaneous BM frequency increased from baseline: 3.1/week versus 1.5/week. Overall, at each week in treatment ≥ 43% achieved ≥ 3 spontaneous BMs/week.
62% experienced a spontaneous BM within 48 hours of starting treatment.
Common adverse reactions: Nausea (18.5%), vomiting (12.1%), diarrhea (8.1%), abdominal pain (7.3%) and headache (5.6%). Overall, 65% of patients experienced ≥ 1 adverse effect and this was highest (78%) in the subset of patients receiving the highest dosage
Bottomline: Current guidelines recommend osmotic agents like polyethylene glycol (PEG) (Miralax) as first-line treatment. This short-term study shows lubiprostone may be an alternative in nonresponders, though more data on long-term outcomes are needed.
Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59). Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited. Two recent articles do offer some information:
Clin Gastroenterol Hepatol 2011; 9: 577-83.
Gut 2011; 60: 209-18.
The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK. During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week. Stool frequency also increased to 1.9 per week in the placebo group (n=121). All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo. Average age of patients in this study was 55 years. The main adverse effect was diarrhea –mainly during the 1st week of therapy.
A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:
Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data. Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
Long-term prospective studies are not available on the use of stimulant laxatives.
The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation. Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582). All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).
The results showed benefit from both stimulant and osmotic laxatives. Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide. Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.
-J Clin Gastro 2003; 36: 386-389. Safety of stimulants for long-term use.
-Am J Gastro 2005; 100: 232-242. Myths about constipation. Stimulants have not been proven to cause a “cathartic colon”
-J Pediatr 2009; 154: 258. Constipation associated w 3-fold increase in health utilization/cost.
-Clin Gastro Hep 2009; 7: 20. Review of complications assoc c constipation in adults.