Systematic review with meta-analysis: lubiprostone efficacy on the treatment of patients with constipation

PASSOS, Maria do Carmo F; TAKEMOTO, Maira Libertad Soligo; CORRADINO, Gabriel Cyrillo; GUEDES, Luciana S

doi:10.1590/S0004-2803.202000000-83

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REVIEW • Arq. Gastroenterol. 57 (04) • Oct-Dec 2020 • https://doi.org/10.1590/S0004-2803.202000000-83 copy

Systematic review with meta-analysis: lubiprostone efficacy on the treatment of patients with constipation

Revisão sistemática com metanálise: eficácia da lubiprostona no tratamento de pacientes com constipação

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND:

Lubiprostone is a type 2 chloride channel activator that has been shown to be efficacious and safe in the treatment for chronic constipation.

OBJECTIVE:

To systematically review randomized clinical trials (RCTs) assessing efficacy of lubiprostone for patients with chronic idiopathic constipation (CIC), irritable bowel syndrome with predominant constipation (IBS-C) and opioid-induced constipation (OIC).

METHODS:

Searches were conducted in PubMed, LILACS, Cochrane Collaboration Database, and Centre for Reviews and Dissemination. Lubiprostone RCTs reporting outcomes of spontaneous bowel movements (SBM) and abdominal pain or discomfort were deemed eligible. Meta-analysis was performed calculating risk ratios and 95% confidence intervals, using the Mantel-Haenszel method and random effects model.

RESULTS:

Searches yielded 109 records representing 93 non-duplicate publications, and 11 RCTs (978 CIC, 1,366 IBS-C, 1,300 OIC, total = 3,644) met inclusion criteria. Qualitative synthesis showed that for CIC patients, lubiprostone is superior to placebo in terms of SBM outcomes. Meta-analysis for CIC was feasible for full responder and SBM within 24h rates, indicating superiority of lubiprostone over placebo. For IBS-C, lubiprostone was significantly superior for all SBM outcomes in follow-ups ranging from 1 week-3 months. In terms of abdominal pain, lubiprostone provided significantly better symptoms relief, particularly after 1 month of treatment. For OIC, lubiprostone was more effective than placebo for both SBM and discomfort measures.

CONCLUSION:

Our findings demonstrated that lubiprostone is superior to placebo in terms of SBM frequency for CIC, IBS-C and OIC. In terms of abdominal symptoms, the most pronounced effect was seen for abdominal pain in IBS-C patients.

HEADINGS:
Lubiprostone; Constipation; Irritable bowel syndrome; Opioid-induced constipation

Population	Author, year	Country	Sample size	Intervention	Comparator	Outcomes
CIC	Johanson, 2007³⁸38. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther . 2007;25:1351-61.	USA	129 CIC patients	Lubiprostone 24 (n=30), 48 (n=32) or 72 mcg (n=34)	Placebo (n=33)	Mean number of SBMs per week
	Johanson, 2008³²32. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-Week, Double-Blind, Randomized, Placebo-Controlled Trial of Lubiprostone, a Locally-Acting Type-2 Chloride Channel Activator, in Patients With Chronic Constipation. Am J Gastroenterol . 2008;103:170-7.	USA	242 CIC patients	Lubiprostone 48 mcg (n=120)	Placebo (n=122)	Number of SBMs after 1 week
	Barish, 2009¹⁹19. Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and Safety of Lubiprostone in Patients with Chronic Constipation. Dig Dis Sci. 2010;55:1090-7.	USA	237 CIC patients	Lubiprostone 48 mcg (n=119)	Placebo (n=118)	Number of SBMs after 1 week
	Fukudo, 2011²⁰20. Fukudo S, Hongo M, Kaneko H, Ueno R. Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. Neurogastroenterol Motil . 2011;23:544-e205.	Japan	170 constipation patients with or without IBS	Lubiprostone 16 (n=41), 32 (n=43) or 48 mcg (n=44)	Placebo (n-42)	Change from baseline in the weekly average number of SBMs at week 1
	Fukudo, 2015³¹31. Fukudo S, Hongo M, Kaneko H, Takano M, Ueno R. Lubiprostone Increases Spontaneous Bowel Movement Frequency and Quality of Life in Patients With Chronic Idiopathic Constipation. Clin Gastroenterol Hepatol . 2015;13:294-301.e5.	Japan	124 CIC patients	Lubiprostone 48 mcg (n=62)	Placebo (n=62)	Change from baseline in the weekly mean number of SBMs after 1 week
	Christie, 2016³⁰30. Christie J, Shroff S, Shahnavaz N, Carter LA, Harrison MS, Dietz-Lindo KA, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Examine the Effectiveness of Lubiprostone on Constipation Symptoms and Colon Transit Time in Diabetic Patients. Am J Gastroenterol . 2017;112:356-64.	USA	76 CIC patients	Lubiprostone 48 mcg (n=37)	Placebo (n=39)	Difference in number of SBMs per week from baseline
IBS-C	Johanson, 2008²⁹29. Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2008;27:685-96.	USA	195 IBS-C patients	Lubiprostone 16 (n=51), 32 (n=49) or 48 mcg (n=45)	Placebo (n=48)	Change from baseline in mean abdominal pain score (1 month)
	Drossman, 2009³³33. Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome - results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther . 2009;29:329-41.	USA	1171 Rome II IBS-C patients (pooled results of 2 RCTs) Study 0431 n=590 Study 0432 n=581	Lubiprostone 48 mcg (n=769)	Placebo (n=385)	Overall responder rate
OIC	Cryer, 2014²¹21. Cryer B, Katz S, Vallejo R, Popescu A, Ueno R. A Randomized Study of Lubiprostone for Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Med . 2014;15:1825-34.	USA and Canada	418 chronic noncancer pain patients	Lubiprostone 48 mcg (n=210)	Placebo (n=208)	Change from baseline in the frequency of SBMs at week 8
	Jamal, 2015³⁶36. Jamal MM, Adams AB, Jansen J-P, Webster LR. A Randomized, Placebo-Controlled Trial of Lubiprostone for Opioid-Induced Constipation in Chronic Noncancer Pain. Am J Gastroenterol . 2015;110:725-32.	USA and EU	431 chronic noncancer pain patients using non-methadone opioid	Lubiprostone 48 mcg (n=214)	Placebo (n=217)	Overall SBM response rate
	Spierings, 2017³⁹39. Spierings ELH, Drossman DA, Cryer B, Mazen Jamal M, Losch-Beridon T, Mareya SM, et al. Efficacy and Safety of Lubiprostone in Patients with Opioid-Induced Constipation: Phase 3 Study Results and Pooled Analysis of the Effect of Concomitant Methadone Use on Clinical Outcomes. Pain Med . 2018;19:1184-94.	USA	451 chronic noncancer pain patients	Lubiprostone 48 mcg (n=224)	Placebo (n=213)	Change from baseline in frequency of SBMs at week 8

	Outcomes	Studies	Results (lubiprostone vs placebo)	P -value
CIC	Mean change in the number of SBMs from baseline (4 weeks)	Fukudo, 2015	2.56 vs 1.62	0.042
	Mean SBM per week (8 weeks)	Christie, 2016	7.00 vs 5.27	0.02
	Mean SBM per week (4 weeks)	Johanson, 2008	5.30 vs 2.91	0.002
		Barish, 2009	5.37 vs 3.46	0.0068
		Christie, 2016	5.77 vs 4.78	NR
	Mean SBM per week (1 week)	Johanson, 2007	Point estimates NR, higher mean for Lubiprostone (chart)	0.02
		Johanson, 2008	5.69 vs 3.46	0.0001
		Barish, 2009	5.89 vs 3.99	0.0001
	Change in mean SBM in the first week	Fukudo, 2011	6.8 vs 1.5	0.0001
		Fukudo, 2015	3.7 vs 1.3	0.001
	SBM within 24 hours	Johanson, 2007	59.4% vs 27.3%	0.009
		Johanson, 2008	56.7% vs 36.9%	0.0024
		Barish, 2009	61.3% vs 31.4%	0.0001
		Fukudo, 2011	75.0% vs 26.2%	0.0001
		Fukudo, 2015	58.1% vs 34.6%	0.004
	Weekly full responder rate (≥ 3-4 SBM per week) (4 weeks)	Johanson, 2008^†	57.8% vs 27.9%	0.004
		Barish, 2009	60.0% vs 39.0%	0.0022
		Fukudo, 2015	54.2% vs 36.7%	0.066
	Mean abdominal discomfort score (4 weeks)	Johanson, 2008	1.23 vs 1.52	0.045
		Barish, 2009	1.24 vs 1.47	0.1383
	Mean abdominal discomfort rate (4 weeks)	Christie, 2016	53.0% vs 67.0%	0.86
	Mean abdominal discomfort rate (8 weeks)	Christie, 2016	50.0% vs 52.0%	0.86

	Outcomes	Studies	Results (lubiprostone vs placebo)	P-value
IBS-C	Overall responder rate^†	Drossman, 2009	17.9% vs 10.1%	0.001
	Monthly responder rate (month 3)	Study 0431 in Drossman, 2009	21.3% vs 14.5%	0.026
		Study 0432 in Drossman, 2009	22.7% vs 14.6%	0.026
		Drossman, 2009 (pooled results)	22.0% vs 14.5%	0.003
	Weekly responder rate (weeks 2, 4, 5, 6, 10 and 12)	Drossman, 2009	Point estimates NR, higher rate for Lubiprostone (chart)	0.030
	Mean change from baseline in weekly SBM rate (month 3)	Johanson, 2008b	Point estimates NR, higher rate for Lubiprostone (chart)	0.033
	Mean improvement in abdominal pain score (month 1)	Johanson, 2008b	Point estimates NR, higher mean for Lubiprostone (chart)	0.023
		Drossman, 2009	Point estimates NR, higher mean for Lubiprostone	> 0.05
	Mean improvement in abdominal pain score (month 2)	Johanson, 2008b	Point estimates NR, higher mean for Lubiprostone (chart)	0.028
		Drossman, 2009	-0.43 vs -0.35	0.039
	Mean improvement in abdominal pain score (month 3)	Johanson, 2008b	Point estimates NR, higher mean for Lubiprostone (chart)	0.260
		Drossman, 2009	-0.45 vs -0.36	0.028

	Outcomes	Studies	Results (lubiprostone vs placebo)	P-value
OIC	Mean change from baseline in SBM frequency (week 8)	Cryer, 2014	3.3 vs 2.4	0.005
		Spierings, 2017	2.6 vs 2.4	0.842
	Mean change from baseline in SBM frequency (week 12)	Cryer, 2014	Point estimates NR, higher mean for Lubiprostone (chart)	0.091
		Jamal, 2015	Point estimates NR, higher mean for Lubiprostone (chart)	0.040
		Spierings, 2017	2.5 vs 2.6	0.956
	Mean change from baseline in SBM frequency (overall)	Cryer, 2014	2.2 vs 1.6	0.004
		Jamal, 2015	3.2 vs 2.4	0.001
		Spierings, 2017	2.6 vs 2.3	0.224
	SBM within 24 hours	Cryer, 2014	38.8% vs 27.8%	0.018
		Jamal, 2015	50.9% vs 38.2%	0.008
		Spierings, 2017	33.2% vs 30.2%	0.502
	Overall responder rate	Jamal, 2015	27.1% vs 18.9%	0.030
	Median time to first SBM	Cryer, 2014	28.5 vs 46.0 hours	0.053
		Jamal, 2015	23.5 vs 37.7 hours	0.004
	Mean improvement in abdominal discomfort scales (overall)	Cryer, 2014	Point estimates NR, higher mean for Lubiprostone (chart)	0.047
		Jamal, 2015	Point estimates NR, higher mean for Lubiprostone (chart)	0.127
		Spierings, 2017	-0.5 vs -0.4	0.027

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[1] Corresponding author: Luciana S Guedes. E-mail: luciguedes@uol.com.br