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

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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Sumário

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

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

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

CONTEXTO:

Lubiprostona é um ativador de canal de cloreto tipo 2 que tem se demonstrado eficaz e seguro no tratamento da constipação crônica.

OBJETIVO:

Revisar sistematicamente ensaios clínicos randomizados (ECRs) avaliando a eficácia da lubiprostona para pacientes com constipação idiopática crônica (CIC), síndrome do intestino irritável com constipação predominante (IBS-C) e constipação induzida por opioide (OIC).

MÉTODOS:

Buscas foram conduzidas no PubMed, LILACS, Cochrane Collaboration Database e Centre for Reviews and Dissemination. ECRs de lubiprostona relatando desfechos de movimentos intestinais espontâneos (SBM) e dor ou desconforto abdominal foram considerados elegíveis. Metanálise foi realizada calculando razão de riscos e intervalos de confiança de 95%, utilizando o método de Mantel-Haenszel e modelo de efeitos aleatórios.

RESULTADOS:

As buscas identificaram 109 registros representando 93 publicações não-duplicadas e 11 ECRs (978 pacientes de CIC, 1366 de IBS-C e 1300 OIC, total = 3644) preencheram os critérios de inclusão. Síntese qualitativa mostrou que, para pacientes com CIC, a lubiprostona foi superior ao placebo em termos de desfechos SBM. Metanálise para CIC foi possível para os desfechos de responder completo e taxa de SBM em 24 horas, indicando superioridade da lubiprostona sobre o placebo. Para IBS-C, lubiprostona foi significativamente superior para todos os desfechos de SBM em tempos de seguimento variando de 1 semana a 3 meses. Em termos de dor abdominal, lubiprostona proporciono alívio dos sintomas significativamente melhor, particularmente após 1 mês de tratamento. Para OIC, lubiprostona foi mais efetiva do que placebo tanto para medidas de SBM quando de desconforto abdominal.

CONCLUSÃO:

Nossos achados demonstraram que lubiprostona é superior ao placebo em termos de frequência de SBM para CIC, IBS-C e OIC. Em termos de sintomas abdominais, o efeito mais pronunciado foi visto para dor abdominal em pacientes com IBS-C.

DESCRITORES:
Lubiprostona; Constipação intestinal; Síndrome do intestino irritável; Constipação induzida por opioides

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