In the JournalsPerspective

Pregabalin effective for treating pain, bloating, diarrhea in IBS

Pregabalin — a calcium channel alpha 2 delta ligand — helped treat visceral hypersensitivity in patients with irritable bowel syndrome and reduced symptoms of abdominal pain, bloating and diarrhea, according to research published in Alimentary Pharmacology & Therapeutics.

Yuri A. Saito, MD, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minnesota, and colleagues wrote that visceral hypersensitivity is a common symptom of IBS and can be treated with several therapies. However, these treatments do not work for all patients.

“Data on pregabalin’s effects on visceral pain and IBS are limited but suggest the drug does reduce gut visceral hypersensitivity,” they wrote. “Because of its known effects on pain, we postulated that pregabalin would decrease bowel symptoms — particularly IBSrelated abdominal pain or discomfort.”

Researchers conducted a double-blind, placebo-controlled trial to assess the efficacy of pregabalin on gastrointestinal symptoms of IBS. The trial comprised 85 patients that met Rome III criteria with at least three pain attacks per month. Researchers randomly assigned patients to receive either 225 mg of pregabalin (n = 41) or placebo (n = 44) twice daily for 12 weeks.

Patients completed questionnaires weekly, and the primary endpoint was average pain Bowel Symptom Severity Scale (BSS) scores for weeks 9 through 12.

Patients in the pregabalin cohort reported lower average pain-BSS scores for weeks 9 through 12 (25 vs. 42; P = .008) and had lower overall IBD BSS severity scores (26 vs. 42; P = .009).

Investigators also observed differences between diarrhea-BSS (P = .049) and bloating-BSS (P = .016) scores.

Saito and colleagues wrote that the benefit was apparent in patients with diarrhea-predominant and mixed-type IBS. Meanwhile, pregabalin did not appear to effect constipation scores.

“Our study provides novel and important data suggesting a positive effect of pregabalin on IBS symptoms, particularly for mixed-type IBS and diarrhea-predominant IBS patients,” they wrote. “A large multicenter trial of IBSD or IBSM patients utilizing the FDA outcome should be pursued as pregabalin shows promise and treatment options for IBS-related pain and mixed bowel habit IBS remain limited.” – by Alex Young

Disclosures: The authors report no relevant financial disclosures.

Pregabalin — a calcium channel alpha 2 delta ligand — helped treat visceral hypersensitivity in patients with irritable bowel syndrome and reduced symptoms of abdominal pain, bloating and diarrhea, according to research published in Alimentary Pharmacology & Therapeutics.

Yuri A. Saito, MD, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minnesota, and colleagues wrote that visceral hypersensitivity is a common symptom of IBS and can be treated with several therapies. However, these treatments do not work for all patients.

“Data on pregabalin’s effects on visceral pain and IBS are limited but suggest the drug does reduce gut visceral hypersensitivity,” they wrote. “Because of its known effects on pain, we postulated that pregabalin would decrease bowel symptoms — particularly IBSrelated abdominal pain or discomfort.”

Researchers conducted a double-blind, placebo-controlled trial to assess the efficacy of pregabalin on gastrointestinal symptoms of IBS. The trial comprised 85 patients that met Rome III criteria with at least three pain attacks per month. Researchers randomly assigned patients to receive either 225 mg of pregabalin (n = 41) or placebo (n = 44) twice daily for 12 weeks.

Patients completed questionnaires weekly, and the primary endpoint was average pain Bowel Symptom Severity Scale (BSS) scores for weeks 9 through 12.

Patients in the pregabalin cohort reported lower average pain-BSS scores for weeks 9 through 12 (25 vs. 42; P = .008) and had lower overall IBD BSS severity scores (26 vs. 42; P = .009).

Investigators also observed differences between diarrhea-BSS (P = .049) and bloating-BSS (P = .016) scores.

Saito and colleagues wrote that the benefit was apparent in patients with diarrhea-predominant and mixed-type IBS. Meanwhile, pregabalin did not appear to effect constipation scores.

“Our study provides novel and important data suggesting a positive effect of pregabalin on IBS symptoms, particularly for mixed-type IBS and diarrhea-predominant IBS patients,” they wrote. “A large multicenter trial of IBSD or IBSM patients utilizing the FDA outcome should be pursued as pregabalin shows promise and treatment options for IBS-related pain and mixed bowel habit IBS remain limited.” – by Alex Young

Disclosures: The authors report no relevant financial disclosures.

    Perspective

    Brian Lacy 
    Brian E. Lacy
    David Cangemi 
    David J. Cangemi

    Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder (FGID) that significantly impacts our health care system. As defined by the Rome criteria, the key feature of IBS is the presence of abdominal pain, in association with abnormal bowel habits.  Several FDA-approved medications are now available to treat IBS symptoms (eg, linaclotide, rifaximin, eluxadoline), but most target disordered bowel habits of constipation or diarrhea, rather than abdominal pain.

    In the current study, Saito and colleagues evaluated the efficacy and safety of pregabalin for the treatment of IBS abdominal pain. Pregabalin has both analgesic and anxiolytic effects and is FDA approved for the treatment of fibromyalgia and neuropathic pain. Patients were randomly assigned 225 mg pregabalin or placebo twice daily for the 12-week study. The primary endpoint was an improvement in Bowel Symptom Scores (BSS) during weeks 9 to 12.  Patients assigned pregabalin (n = 25) reported lower average pain-BSS scores vs. those who received placebo (n = 42; P = .008). Blurry vision and dizziness were more commonly reported by patients treated with pregabalin. 

    This study is important because it brings attention to another neuromodulator that may improve IBS symptoms by affecting visceral hypersensitivity, akin to tricyclic antidepressants and selective serotonin reuptake inhibitors. Data regarding the use of alpha 2 delta ligands in the treatment of IBS have been limited to date, but both gabapentin and pregabalin have shown to reduce rectal sensitivity. Moreover, gabapentin was recently shown to improve dyspeptic symptoms in patients with functional dyspepsia. The current study provides meaningful data in support of pregabalin for the treatment of IBS pain.

    It should be noted that the majority of patients (68%) in the treatment arm experienced an adverse effect, though none were serious. As such, it will be important to examine different treatment doses in future studies, and to identify whether differences in efficacy and safety exist between pregabalin and gabapentin. That said, the current study by Saito and colleagues provides intriguing evidence for the use of pregabalin in the treatment of IBS. Hopefully this study inspires further research on the use of alpha 2 delta ligands in the treatment of FGIDs like IBS, as they would certainly be a welcome addition to the current treatment armamentarium.

    References

    • Buono JL, et al. Health-related quality of life, work productivity, and indirect costs among patients with irritable bowel syndrome with diarrhea. Health Qual Life Outcomes. 2017; 15: 35.
    • Ford AC, et al. Irritable bowel syndrome. N Engl J Med. 2017; 376: 2566-2578.
    • Houghton LA, et al. Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut. 2007; 56: 1218-1225.
    • Lacy BE, et al. Bowel disorders. Gastroenterology. 2016; 150: 1393-1407.
    • Lee KJ, et al. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2005; 22: 981-988.
    • Saito YA, et al. Randomised clinical trial: pregabalin vs. placebo for irritable bowel syndrome. Aliment Pharmacol Ther. 2019; 00:1-9.
    • Staller K, et al.  Gabapentin improves symptoms of functional dyspepsia in a retrospective, open-label cohort study. J Clin Gastroenterol. 2018; 00: 1-6.

    Brian E. Lacy, MD, PhD
    Professor of Medicine
    Senior Associate Consultant
    Division of Gastroenterology and Hepatology
    Mayo Clinic

    David J. Cangemi, MD
    Senior Associate Consultant
    Division of Gastroenterology and Hepatology
    Mayo Clinic

    Disclosure: Lacy and Cangemi report no relevant financial disclosures.

    Perspective
    Dmitriy Kedrin

    Dmitriy Kedrin

    Pain is a common, often debilitating, symptom experienced by patients with irritable bowel syndrome, and there are no medications available that are specifically approved to treat pain in these patients. Most common target of IBS treatment currently focuses on stool quality and quantity, and when it comes to pain, in clinical practice, anti-spasmodic are widely used with the idea of relieving "spasms," with the hope of alleviating pain as well. However, the evidence for the use of these agents is modest at best. The latest monograph on management of IBS from American College of Gastroenterology recommends trichloroacetic acids and selective serotonin reuptake inhibitors for overall symptom improvement. There is some evidence that these work, specifically from a neuromodulatory angle.

    Part of the problem is large knowledge gaps regarding efficacy of agents used to treat symptoms of irritable bowel syndrome off-label. Evidence for use of neuromodulatory agents to treat visceral hypersensitivity has been largely limited to observational studies and expert opinion. As valuable as those are, they are no substitute for a well conducted randomized blinded trial.

    Pregabalin works by blocking one of the subunits of a voltage-gated calcium channel, leading to reduction in release of excitatory glutamate, which could reduce signal transduction in nociceptive pathways, potentially reducing pain. This is one of the reasons it is used to treat neuropathic pain, probably the most common reason for prescribing this drug today.

    Prior to the abovementioned study, there was only one randomized clinical trial involving pregabalin that was used to show increased threshold (to normal) in patients with rectal hypersensitivity in patients with IBS. So, this new study certainly expands the body of evidence that neuromodulatory agents can serve a useful function in the treatment of patients with IBS, particularly when it comes to treating visceral hypersensitivity/pain.

    In my own practice, several patients with IBS have benefited from pregabalin, and the addition of data from this randomized trial surely will be welcomed by many gastroenterologists. My only wish here was that the study was larger, and a treatment that is currently used in standard practice, such as a fiber supplement was included as a control arm, instead of placebo. It is also important to note that the study was funded by Pfizer, the maker of Lyrica. I certainly hope that more good quality research is produced in the visceral hypersensitivity space.

    References:

    • Saito YA, et al. Aliment Pharmacol Thera. 2019;doi:10.1111/apt.15077.
    • Sobin WH, et al. Am J Gastroenterol. 2017;doi:10.1038/ajg.2017.57.
    • Ford AC, et al. Am J Gastroenterol. 2018;doi:10.1038/s41395-018-0084-x.
    • Drossman DA, et al. Gastroenterology. 2018;doi:10.1053/j.gastro.2017.11.279.
    • Dmitriy Kedrin, MD, PhD
    • Gastroenterologist
      Elliot Hospital

    Disclosures: Kedrin reports no relevant financial disclosures.