Lubiprostone

Lubiprostone

PEP Topic 
Constipation
Description 

Lubiprostone is a locally acting chloride channel activator with a similar mechanism of action to bulking agents and osmotic laxatives on intestinal fluid. Lubiprostone increases intestinal fluid volume and motility, resulting in stool softening and ease of passage. Although the U.S. Food and Drug Administration approved the use of lubiprostone in January 2006 for chronic idiopathic constipation, no studies in patients with cancer have been published.

Effectiveness Not Established

Research Evidence Summaries

Baker, D.E. (2007). Lubiprostone: A new drug for the treatment of chronic idiopathic constipation. Reviews in Gastroenterological Disorders, 7, 214–222.

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Intervention Characteristics/Basic Study Process:

In phase III, placebo-controlled studies, lubiprostone 24 mcg twice daily was compared to placebo. Studies 1, 2, and 3 comprised a two-week drug-free period followed by treatment with lubiprostone 24 mcg twice daily for four weeks, followed by randomization to continue lubiprostone or placebo.

Open-label studies used lubiprostone 24 mcg twice daily. Three studies of long-term clinical safety assessed lubiprostone administered for 12 months in patients with chronic idiopathic constipation.

Sample Characteristics:

Phase III Studies

  • Patients were included in the study if they had constipation, defined as fewer than three spontaneous bowel movements per week plus a six-month history of at least one other Rome II criteria for functional constipation.
  • Study 1 reported on a sample of 242 patients. Mean patient age was 48.6 years. The sample was 90% female and 86% Caucasian.
  • Study 2 reported on sample of 237 patients who were predominantly female and Caucasian.
  • Study 3 reported on a sample of 128 patients with chronic constipation.

Open-Label Studies

  • Three studies reported on a sample of 871 patients with chronic idiopathic constipation.
  • Mean patient age was 51 years. Nineteen percent of the sample (n = 163) was aged 65 years or older.
  • The sample was 86% female and 87% Caucasian.

 

Study Design:

  • Phase III studies
    • Studies 1 and 2: double-blind, placebo-controlled
    • Study 3: placebo-controlled randomized controlled trial (RCT)
  • Open-label studies

Measurement Instruments/Methods:

  • In studies 1 and 2, the primary endpoint was frequency of spontaneous bowel movements (BMs) after initiation of double-blind treatment.
  • In study 3, a responder was defined as having three or more spontaneous BMs per week during lubiprostone therapy and was converted to nonresponder status (fewer than three spontaneous BMs per week) during the randomized phase for the placebo group.

Results:

Study 1 and 2

  • Spontaneous BMs increased during all four weeks of lubiprostone treatment in both studies. In study 1, frequencies ranged from 5.1 to 5.7 in the lubiprostone group and 2.8 to 3.5 in the placebo group (p < 0.002 at all weeks). Results were similar for study 2.
  • Time to spontaneous BM was shorter in the lubiprostone group. In study 1, spontaneous BM occurred in 56.7% of patients in the lubiprostone group within 24 hours of the first dose compared to 36.9% in the placebo group (p= 0.0024). In study 2, spontaneous BMs occurred in 69.9% of patients in the lubiprostone group within 24 hours of the first dose compared to 31.9% in the placebo group (p < 0.0001).

Study 3

  • Spontaneous BMs increased from 1.36 per week at baseline to 6.25, 5.94, 5.52, and 6.2 per week during weeks 1, 2, 3, and 4, respectively (p < 0.0001 at all weeks).
  • During the randomization phase, spontaneous BMs progressively declined for the placebo group. At week 7, frequency of spontaneous BMs was 5.59 for the lubiprostone group (p = 0.0223 ) versus 3.04 in the placebo group (p = 0.0223) compared to baseline.

Open-Label Studies

  • Lubiprostone reduced abdominal bloating, abdominal discomfort, and severity of constipation over six to 12 months of treatment, and significant improvements were reported for constipation severity, bloating, and abdominal discomfort scores (p < 0.001).
  • Although the incidence of adverse events was low overall, incidence of nausea was higher. Older adults had fewer adverse events.

Conclusions:

Placebo-controlled RCTs demonstrated lubiprostone was well tolerated and not associated with severe adverse effects. However, incidence of nausea was higher. Comparative studies with other therapies are needed.

Limitations:

  • The duration of constipation was not described.
  • Information related to history of previous types of therapies used to treat constipation was lacking.
  • The studies lacked a control group.
  • Data were from publications of abstracts only. No peer journal articles were reviewed.
  • No studies included patients with cancer.

Barish, C.F., Drossman, D., Johanson, J.F., & Ueno, R. (2010). Efficacy and safety of lubiprostone in patients with chronic constipation. Digestive Diseases and Sciences, 55, 1090–1097.

doi: 10.1007/s10620-009-1068-x
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Study Purpose:

To assess the efficacy and safety of lubiprostone in the treatment of patients with chronic constipation.

Intervention Characteristics/Basic Study Process:

Patients had a washout period, followed by a two-week prerandomization period. Patients were randomized to receive either oral lubiprostone 24-mcg capsules (n = 119) or placebo (n = 118) twice daily with food and at least 8 oz of water. Patients were instructed to keep daily diaries to record their medication administration, use of medication rescues, and occurrences of bowel movements (BMs) (date and time). Study assessments were scheduled after one week (office visits), two weeks (telephone evaluation), four weeks (end-of-treatment office visit), and two weeks following the end of treatment.

Sample Characteristics:

  • The study reported on a sample of 237 patients who met the Rome II criteria for functional constipation.
  • Mean patient age was 46.2 years (SD = 12.13) for the lubiprostone group and 45.4 years (SD = 13.24) for the placebo group.
  • The study comprised 104 women and 15 men in the lubiprostone group, and 105 women and 13 men in the placebo group.
  • Constipation severity was 3 (SD = 0.82) in the lubiprostone group and 3 (SD = 0.76) in the placebo group. 
  • Stool consistency was 2.7 (SD = 0.83) in the lubiprostone group and 2.8 (SD = 0.77) in the placebo group.
  • All were normal patients with constipation.

Setting:

  • Multi-site
  • United States

Study Design:

This was a randomized, double-blinded, placebo-controlled study.

Measurement Instruments/Methods:

  • Daily BM diary
  • Five-point scale of stool consistency
  • Five-point scale of stool straining

Results:

  • Lubiprostone was an effective treatment for chronic constipation, with more than 60% of patients having a spontaneous BM within 24 hours of their first dose.
  • Patients taking lubiprostone also experienced significant improvement in spontaneous BM frequency, stool consistency, straining, severity, and abdominal bloating.
  • Patients' global treatment effectiveness was significantly higher in the lubiprostone group compared with the placebo group.
  • Fewer patients receiving lubiprostone required rescue medication.
  • Nausea was the most common adverse side effect reported, occurring in 25 patients in the lubiprostone group compared to five patients in the placebo group.

Conclusions:

Lubiprostone was an effective treatment for chronic constipation.

Limitations:

  • The sample comprised more women than men.
  • Nausea was reported as toxicity to the drug, but also was reported in the placebo group. In addition, nausea may also be seen in patients who have issues with constipation.
  • The sample did not include patients specifically with cancer or related opioid-induced constipation. Therefore, applicability to that population is unclear.

Nursing Implications:

Lubiprostone has been shown to be effective in the management of chronic constipation and is used for patients with chronic constipation related to irritable bowel syndrome. However, additional studies are warranted in patients with cancer, as well as the palliative care population, in which patients are receiving chemotherapy agents, antiemetics, and narcotics that contribute to their constipation.

Johanson, J.F., Morton, D., Geenen, J., & Ueno, R. (2008). Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. American Journal of Gastroenterology, 103, 170–177. 

doi: 10.1111/j.1572-0241.2007.01524.x
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Study Purpose:

To assess the efficacy and safety of lubiprostone 24 mcg BID in patients with chronic constipation.

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either oral lubiprostone 24-mcg capsules or placebo capsules. Patients continued to record information regarding bowel movements (BMs), use of rescue medications, and symptoms on a daily basis. Study drug capsules were counted to assess compliance every two weeks. Rescue medication comprised bisacodyl suppository and fleet enema if the suppository was not effective. Efficacy was defined as the frequency of spontaneous BMs during the first and subsequent study weeks. Patients were followed for four weeks.

Sample Characteristics:

  • The study reported on a sample of 224 patients.
  • Mean patient age was 48 (SD = 12.28) to 49 years (SD = 12.93) across study groups.
  • The sample was 89% female and 11% male.
  • Patients were excluded if they had mechanical obstruction. No other diagnosis information was provided.

Setting:

  • Multi-site
  • Outpatient
  • Midwestern United States

Study Design:

This was a double-blind, placebo-controlled randomized trial.

Measurement Instruments/Methods:

  • Four-point Likert-type scales for symptoms of bloating, straining, and discomfort; stool consistency; and global treatment effectiveness
  • Patient diary

Results:

  • Patients in the lubiprostone group reported significantly more spontaneous BMs than those in the control group (p = 0.0001) during the first and subsequent weeks.
  • Fifty-seven percent of patients in the lubiprostone group experienced a spontaneous BM within 24 hours of taking the first dose compared to 37% in the placebo group (p = 0.0024).
  • Use of rescue medication was significantly lower in the lubiprostone group ( p = 0.036).
  • Patients in the lubiprostone group reported significant improvement in all related symptoms compared to those in the placebo group (p < 0.05).
  • No significant differences existed between groups in reported events. The most frequent event was nausea. Eight percent of patients in the lubiprostone group were discontinued from the study because of adverse events including nausea, headache, flatulence, and diarrhea.

Conclusions:

Taking lubiprostone improved frequency of spontaneous BMs and constipation-related symptoms, with low incidence of treatment-related adverse events.

Limitations:

  • Patient diagnoses were not provided, and whether any patients had issues such as opioid-induced constipation is not known.
  • Use of rescue medications was stated to decline, but actual use was not reported and the definition of primary treatment efficacy did not specify spontaneous BM without rescue medication.
  • Applicability to patients with cancer is not clear.

Nursing Implications:

Lubiprostone effectively improved constipation in this study; however, applicability to patients with cancer is not clear. Nausea was the most common side effect, which could limit its use in patients with cancer, who may be on other medications and treatments that also cause nausea. Research involving patients with cancer-related constipation should be considered.


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