1018 A Questionable Investment for Our Patients: Challenging the Efficacy of New Therapies for Opioid-Induced and Chronic Idiopathic Constipation

Abstract

Introduction. Opioid-induced and chronic idiopathic constipation are common disorders that remain great treatment challenges. Clinical trials of several new, expensive treatments for these conditions have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians, however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms. Methods. We analyzed published data from randomized, placebo-controlled clinical trials of five different treatments for opioid-induced and chronic idiopathic constipation. Active treatments were: Methylnaltrexone (NEJM 358:2332, 2008), Naloxegol (NEJM 370:2387, 2014), Lubiprostone (Am J Gastro 103:170, 2008), Prucalopride (NEJM 358:2344, 2008), and Linaclotide (NEJM 365:527, 2011). We used beta distributions to calculate probability intervals. Results. Across all five studies, the proportion of constipated subjects with active treatment was significantly lower than the proportion with placebo; however, a substantial proportion of patients remained constipated with active treatment (Methylnaltrexone 52%, Naloxegol low-/high-dose 62%/58%, Lubiprostone 42%, Prucalopride low-/highdose 69%/72%, Linaclotide low-/high-dose 81%/80%). Figure 1 displays the proportion of patients who remained constipated with active treatment and placebo. The 95% probability for remaining constipated with active treatment ranged from at least 34% with Lubiprostone to at least 78% with Linaclotide. The proportion of patients experiencing abdominal pain during the study was greater for patients on active treatment compared to placebo across all five studies (Methylnaltrexone vs placebo 18% vs 13%, Naloxegol lowvs high-dose vs placebo 10% vs 16% vs 6%, Lubiprostone vs placebo 5% vs 1%, Prucalopride lowvs highdose vs placebo 19% vs 22% vs 19%, Linaclotide lowvs high-dose vs placebo 4% vs 5% vs 3%). Similar results were seen for diarrhea during the study (Methylnaltrexone vs placebo 6% vs 4%, Naloxegol lowvs high-dose vs placebo 6% vs 9% vs 4%, Lubiprostone vs placebo 5% vs 2%, Prucalopride lowvs high-dose vs placebo 14% vs 19% vs 5%, Linaclotide lowvs high-dose vs placebo 16% vs 14% vs 5%), and flatulence during the study (Methylnaltrexone vs placebo 13% vs 7%, Naloxegol lowvs high-dose vs placebo 3% vs 6% vs 2%, Lubiprostone vs placebo 6% vs 1%, Prucalopride lowvs high-dose vs placebo 11% vs 8% vs 9%, Linaclotide lowvs high-dose vs placebo 6% vs 5% vs 5%). Conclusion. Currently available treatments for opioid-induced or chronic idiopathic constipation are ineffective in a substantial portion of patients. These treatments also fail to relieve accompanying adverse symptoms, and may actually exacerbate them.