The short-term (4-week) effectiveness and safety of lubiprostone had been previously established in two placebo-controlled trials in patients with chronic constipation [16
]. However, chronic constipation typically requires long-term treatment. Therefore, it is important to establish the long-term efficacy and safety profile of lubiprostone.
The mean daily capsule intake of 1.7/day indicated that patients were generally compliant with BID dosing throughout the 48-week study period. The study further demonstrated that lubiprostone 24 mcg BID was generally well tolerated by adult patients with chronic constipation. The results were consistent with those observed during the 4-week chronic constipation trials [16
]. Nearly all treatment-related AEs were of mild (51%) to moderate (42%) intensity. The most common treatment-related AE was nausea (19.8%), followed by diarrhea (9.7%), with event rates of 1.08 and 0.61 per 1,000 patient-days, respectively. Thirty-three patients (13.3%) withdrew from the study due to AEs, of which 13 were due to nausea (5.2%). It is notable that, although the current study comprised 48 treatment weeks, the percentage of patients withdrawing from this study due to nausea (5.2%) was similar to the percentages of patients discontinuing treatment in the 4-week studies (approximately 5%) [16
]. Furthermore, since 70% of discontinuations due to nausea in this long-term study were within the first 12 weeks, these results might suggest that patients who can tolerate the drug initially may demonstrate successful long-term outcomes. The mechanism responsible for nausea is unknown, but has been hypothesized to involve an exaggerated pharmacodynamic effect from secreted fluid in the small intestine or a direct gastric effect resulting from a lubiprostone-related modest delay in gastric emptying (mean t1/2
, 132.4 min lubiprostone vs. 106.1 min placebo) [15
]. In the current study, there were no clinically relevant consequences from the patients who experienced diarrhea.
One SAE (out of 16 total in the trial) was assessed to be possibly related to the study drug. The patient, a 27-year-old female with no relevant medical history (concomitant medications included diphenhydramine, paroxetine hydrochloride, bisacodyl, cortisone, and hydroxyzine) became pregnant, approximately 8-1/2 months after enrollment into the study. Because of her pregnancy, the patient discontinued participation in the study. Seven months later, she gave birth to a healthy infant with bilateral clubfoot.
Including this case, there have been a total of six reported pregnancies in clinical trials with lubiprostone. Five of the six pregnancies were carried to term (the other one was electively terminated) and no other fetal abnormalities were reported.
On average, the changes in serum electrolyte levels were not clinically significant. This finding suggests a more physiologic laxation effect with lubiprostone when compared to reports of clinically significant electrolyte shifts with some commercially available laxatives [7
Long-term, open-label studies have inherent limitations relating to the assessment of treatment efficacy, particularly in the areas of generalizability of the results to unselected populations and patient attrition during the study period. Nevertheless, there is some value in examining the patient-reported outcomes in this long-term study population. Patients reported significant improvements from baseline in constipation severity and abdominal symptoms. Significant relief of these symptoms was observed at the first evaluation and was sustained throughout all 48 weeks of the study, suggesting that lubiprostone provided sustained relief of these symptoms without leading to tachyphylaxis. Furthermore, evaluation of patient satisfaction indicated that most patients rated lubiprostone therapy as moderately effective or quite effective; this result is likely reflected by the fact that a significant proportion of patients appeared satisfied with their treatment as >50% of patients continued treatment for the entire study period. These results are consistent with other lubiprostone trials of shorter duration [16
]. Results from this long-term trial suggest that lubiprostone remains safe and effective and provides consistent symptom relief for 1 year in adult patients with chronic constipation.
A limitation of the current study design was the lack of blinding or a placebo control group. Placebo-controlled studies of long duration are difficult to perform due to the high dropout rate of patients in the placebo arm [22
]. However, despite the absence of a placebo arm, these results indicate that the 48-week safety and effectiveness results were consistent with those reported in the shorter-term (i.e., 4 weeks) double-blinded, placebo-controlled studies [16
In conclusion, the present study demonstrates that lubiprostone may be considered safe and generally well tolerated, with effectiveness consistently maintained across 48 weeks in adult patients with chronic constipation.