Is Lubiprostone Effective in Treating Symptoms of Chronic Constipation

OBJECTIVE: The objective of this selective EBM review is to determine whether or not lubiprostone is effective in treating symptoms of chronic constipation. STUDY DESIGN: Review of three English language primary randomized controlled trials from 20072010. DATA SOURCES: Three double-blind, randomized, controlled trials were found using PubMed. These studies compared treatment with lubiprostone to a visually matched placebo. OUTCOME MEASURED: The frequency of each patient’s spontaneous bowel movements within the first 24 hours after initial treatment was recorded from the data collected from the patient’s daily diary. RESULTS: All three trails demonstrated a statistically significant improvement in the rates of spontaneous bowel movements in patients with chronic constipation receiving treatment with lubiprostone compared to those receiving the placebo. CONCLUSIONS: Based on theses three trials, lubiprostone is effective in treating symptoms of chronic constipation. KEY WORDS: chronic constipation, lubiprostone MacDonald, Lubiprostone & Constipation 1 INTRODUCTION Chronic constipation is a condition that adversely affects the daily lives of many men and women. The condition is defined as less than 3 spontaneous bowel movements (SBMs) per week, in addition to symptoms of constipation associated with 25% of bowel movements over the past 6 months. Although chronic constipation is more prevalent in the elderly population, it does affect all age groups. In the United States prevalence rates for chronic constipation range from 12–19%, with women being affected twice as often as men. Furthermore, symptoms of constipation result in a decreased quality of life, reduced productivity and an increase in the number of missed work or school days. This leads to constipation being among one of the most frequent patient complaints faced by internists and primary care physicians, in addition to accounting for nearly 50% of referrals to gastroenterologists. As one of the most common digestive complaints in the general population, constipation is also associated with substantial economic costs. Each year more than 2.5 million Americans visit their healthcare provider for relief from constipation. The estimated total medical cost of care for patients with constipation in 2001 was $235 million per year, with 55% from inpatient care, 23% from the Emergency Department, 16% from outpatient physicians and 6% from outpatient hospital settings. Therefore, not only is chronic constipation a burden on patients’ lives, but it is taxing on the healthcare system as well. There are many underlying causes of chronic constipation. However, the condition generally results from inadequate fiber or fluid intake, from impaired colonic transit or anorectal dysfunction. Also, symptoms of constipation can vary from patient to patient making it difficult for practitioners to clinically quantify the severity of the condition. Symptoms generally include difficult or infrequent bowel movements, excessive straining, hard stools, lower abdominal MacDonald, Lubiprostone & Constipation 2 fullness or a sense of incomplete evacuation. Due to the difficulty evaluating constipation, clinicians determine severity by focusing on the quantitative frequency of a patient’s bowel movements via the use of patient daily dairies. The information gathered from the diary does not only help assess the degree of constipation, but can also help guide patient treatment. There are multiple home and pharmacologic remedies for treating constipation. The initial step in treatment usually involves lifestyle and dietary modifications. Lifestyle changes include increasing fluid intake, exercising and establishing a regular bowel movement routine. Dietary changes mainly focus on increasing fiber intake. This can cause stool to bulk leading to colonic dilation that promotes intestinal peristalsis. If lifestyle and dietary modifications fail, bulk laxatives are generally the next choice. Bulk forming laxatives include psyllium, methycellulose, polycarbophil and wheat dextrin. These are polysaccharide or cellulose derivatives that act by absorbing water and increasing fecal mass. If patients have no response to bulk laxatives, osmotic laxatives are the next step in treatment. Osmotic laxatives include polyethylene glycol, lactulose, sorbitol and magnesium hydroxide. If these all fail, lubiprostone has shown considerable promise with patients suffering from chronic constipation. As a side note, stimulant laxatives are effective in relieving acute symptoms of constipation, but should be avoided in cases of chronic constipation due to adverse affects with long term use such as dehydration and electrolyte disturbances. This review evaluates three double blind, randomized, controlled trials comparing the efficacy of lubiprostone in treating symptoms of chronic constipation. As previously stated, lubiprostone may be used as treatment for severe chronic constipation that is not relieved by other treatment alternatives. Lubiprostone has been shown to accelerate small intestine and colonic transit by activating chloride channels in the intestinal epithelial cells. When activated, MacDonald, Lubiprostone & Constipation 3 these cells contribute to the secretion of intestinal fluid causing an increase in luminal water content without significantly accelerating the rate of ascending colon emptying. This ultimately results in relief of constipation. OBJECTIVE The objective of this systematic review is to determine whether or not lubiprostone is effective in treating symptoms of chronic constipation. METHODS Three double-blind, randomized, controlled trials (RCTs) that included healthy men and women greater than 18 years of age with history of chronic constipation, defined as less than 3 SBMs per week, in addition to symptoms of constipation associated with 25% of bowel movements over the past 6 months were selected for study. All three studies showed no significant differences in demographic parameters between the treatment and placebo groups. The population in each study was predominately female Caucasians with the mean age ranging between 46-48 years. Also, the inclusion and exclusion criteria of all three studies were similar. Additionally, discontinuation rates were not substantially different between the treatment and placebo groups for each study used. These demographics and characteristics are demonstrated in Table 1. All three studies compared the experimental group, receiving treatment of lubiprostone 24mcg twice daily, to a control group, receiving a visually matched placebo. The occurrence of a SBM within the first 24 hours of the initial treatment dose was compared among experimental and control groups to determine the outcome of the studies. All three articles used in this review were collected via PubMed database in 2014. The key words used to acquire the articles were “lubiprostone” and “constipation. ” Each article used was published in English by peer reviewed journals between the years 2007 and 2010. All MacDonald, Lubiprostone & Constipation 4 articles were POEMS selected based on their outcome’s relevance and importance to patients’ quality of life. The inclusion criteria were synonymous for each RCT. The defined criteria consisted of males or non-pregnant, non-lactating females over the age of 18 years old with chronic constipation. 1,5,6 Symptoms used to define constipation included abdominal bloating or discomfort, hard or very hard stools, sensation of incomplete evacuation or straining with defecation. Additionally, potential participants less than 50 years old must have had a flexible sigmoidoscopy or colonoscopy performed within the last 5 years and patients over 50 years old were required to have a barium enema with flexible sigmoidoscopy or a colonoscopy to rule out organic disorders of the large bowel prior to being considered. Exclusion criteria were also similar for each article. The exclusion criteria consisted of documented mechanical obstruction, megacolon or a diagnosis of pseudo-obstruction. Also, known or suspected organic disorders of the large or small intestine, secondary causes of constipation, hospitalization for any gastrointestinal or abdominal surgical procedure during the 3 months prior to study initiation and any history of prior bowel resection excluded patients from participating in any of the studies. In addition, the studies performed by Johanson et al and Johanson and Ueno excluded patients with clinically significant cardiovascular disease, liver, lung or other systemic disease. Johanson et al went further to exclude patients with hematologic, urinalysis or blood chemistry abnormalities or diagnosis of cancer within the past 5 years. Furthermore, the study by Johanson and Ueno also excluded HIV positive patients. Statistics were reported based on p-values using dichotomous data. A Cochran-MantelHaenszel test was used to adjust for a pooled center and determine if there was a consistent difference in the percentage of patients who experienced a SBM within 24 hours of initial MacDonald, Lubiprostone & Constipation 5 treatment between the experimental and control groups. Control event rate (CER) and experimental event rate (EER) were used to calculate relative benefit increase (RBI), absolute benefit increase (ABI), relative risk increase (RRI) and absolute risk increase (ARI). ABI was then used to determine number needed to treat (NNT) and ARI was used to determine numbers needed to harm (NNH). Table1: Demographics and characteristics of included studies Study Type # Pts Age (yrs) Inclusion Criteria Exclusion Criteria W/D Interventions Barish (2010) RCT 237 ≥18 History of chronic constipation. Constipation symptoms a/w at least 25% of BM ≥6 months. Sigmoidoscopy or colonoscopy within the last 5 years if <50yrs, required if ≥50 yrs. Mechanical obstruction, megacolon/megarectum or a diagnosis of pseudoobstructio