EFFICACY AND SAFETY OF INTESTINAL SECRETAGOGUES FOR CHRONIC CONSTIPATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

LASA, Juan Sebastian; ALTAMIRANO, María Josefina; BRACHO, Luis Florez; PAZ, Silvina; ZUBIAURRE, Ignacio

doi:10.1590/S0004-2803.201800000-41

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ORIGINAL ARTICLE • Arq. Gastroenterol. 55 (Suppl 1) • Nov 2018 • https://doi.org/10.1590/S0004-2803.201800000-41 copy

EFFICACY AND SAFETY OF INTESTINAL SECRETAGOGUES FOR CHRONIC CONSTIPATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Eficiência e segurança de secretagogos intestinais para constipação crônica: uma revisão sistemática e meta-análise

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND:

Intestinal secretagogues have been tested for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome. The class-effect of these type of drugs has not been studied.

OBJECTIVE:

To determine the efficacy and safety of intestinal secretagogues for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome.

METHODS:

A computer-based search of papers from 1966 to September 2017 was performed. Search strategy consisted of the following MESH terms: intestinal secretagogues OR linaclotide OR lubiprostone OR plecanatide OR tenapanor OR chloride channel AND chronic constipation OR irritable bowel syndrome. Data were extracted as intention-to-treat analyses. A random-effects model was used to give a more conservative estimate of the effect of individual therapies, allowing for any heterogeneity among studies. Outcome measures were described as Relative Risk of achieving an improvement in the symptom under consideration.

RESULTS:

Database Search yielded 520 bibliographic citations: 16 trials were included for analysis, which enrolled 7658 patients. Twelve trials assessed the efficacy of intestinal secretagogues for chronic constipation. These were better than placebo at achieving an increase in the number of complete spontaneous bowel movements per week [RR 1.87 (1.24-2.83)], at achieving three or more spontaneous bowel movements per week [RR 1.56 (1.31-1.85)] and at inducing spontaneous bowel movement after medication intake [RR 1.49 (1.07-2.06)]. Similar results were observed when assessing the efficacy of intestinal secretagogues on constipation-predominant irritable bowel syndrome based on the results of six trials.

CONCLUSION:

Intestinal secretagogues are useful and safe therapeutic alternatives for the treatment of constipation-related syndromes.

HEADINGS:
Constipation; Irritable bowel syndrome; Colon

Author (Year)	Countrie	Age (median), Gender (%F) and Diagnosis	Outcome Measures	Number of Patients	Interventions	Co-Interventions
LINACLOTIDE
Johnston 2010	USA/Canada	44.4/92%; CIC+IBS-C	% of patients with CBM; % of patients with >3 BM during 75% of treatment period; % of patients with Bristol Score >3; % of patients without significant constipation; abdominal pain severity; abdominal bloating severity; % of patients with global relief	85 patients on placebo; 79 on linaclotide 75 ug; 82 on linaclotide 150 ug; 84 on linaclotide 300 ug; 89 on linaclotide 600 ug	Linaclotide once per day or placebo for 12 weeks	Bisacodyl or phosphate enema as rescue medication
Lembo 2010	USA	47.3/92%/ CIC	% of patients with CBM; % of patients with SBM; % of patients with Bristol Score>3; % of patients without significant straining; abdominal pain and bloating severity; % of patients with global relief	68 patients on placebo; 59 on linaclotide 75 ug; 56 on linaclotide 150 ug; 62 on linaclotide 600 ug	Oral linaclotide once daily or placebo for 4 weeks	Bisacodyl or phosphate enema as rescue medication
Lembo 2011	USA and Canada (2 clinical trials)	47.8/89.7%/ CIC	% of patients with >3 CSBM in 9 out of 12 weeks and/or increase in >1/week; % of patients with SBM after medication intake; % of patients with >2 SBM/week; % of patients with global relief	424 patients on placebo; 430 on linaclotide 145 ucg; 418 on linaclotide 290 ucg	Linaclotide or placebo for 12 weeks	Not clear
Chey 2012	USA	44.3/ 89.55%/ IBS-C	% of patients with pain severity improvement of >30% for at least 6 out of 12 weeks; % of patients with >1 CSBM/week for at least 6 out of 12 weeks; % of patients with >3 CBM/week; % of patients with CSBM after medication intake; % of patients with >2 SBM/week; % of patients with Bristol Score>3; % of patients with global relief	403 patients on placebo; 402 on linaclotide 290 ucg	Linaclotide or placebo for 26 weeks (assessment after 12 weeks of completion)	Not clear
Rao 2012	USA and Canada	43.5/90.5%/ IBS-C	% of patients with pain severity improvement >30% for at least 6 out of 12 weeks; % of patients with >1 CSBM/week for 6 out of 12 weeks; % of patients with >3 CBM/week; % of patients with SBM after medication intake; % of patients >2 SBM/week; % of patients with Bristol Score >3; % of patients with global relief	395 patients on placebo; 405 patients on linaclotide 290 ucg	Linaclotide or placebo for 12 weeks	Oral or rectal bisacodyl as rescue treatment
LUBIPROSTONE
Johanson 2008	USA	48.27/90.55%/ CIC	% of patients with SBM; straining severity score; Bristol score; bloating and abdominal discomfort severity; % of patients who required rescue treatment	33 patients on placebo; 30 on lubiprostone 24 mcg; 32 on lubiprostone 48 mcg; 34 on lubiprostone 72 mcg	Lubiprostone or placebo T.I.D. for 3 weeks	Oral bisacodyl or sodium phosphate enema as rescue treatment
Drossman 2008	USA	46.6/91.6%/ IBS-C	% of patients with global improvement of IBS symptom severity: SBM, abdominal pain and bloating	385 patients on placebo; 769 on lubiprostone 8 mcg	Lubiprostone or placebo T.ID. for 12 weeks	Oral bisacodyl or sodium phosphate enema as rescue treatment
Fukudo 2011	Japan	39.4/90.58%/ CIC+IBS-C	P% of patients with SBM after medication intake; % of patients with global relief	42 patients on placebo; 41 on lubiprostone16 mcg; 43 on lubiprostone 32 mcg; 44 on lubiprostone 48 mcg	Lubiprostone or placebo for 2 weeks	Bisacodyl suppositories or glycerol enema as rescue treatment
Ondo 2012	USA	67.3/24.59%/ Constipation on Parkinson patients	% of patients with global relief; number of SBM/week with medication	31 patients on placebo; 30 on lubiprotsone 24 mcg	Lubiprostone or placebo B.I.D. for 4 weeks	Not clear
Cryer 2014	USA and Canada	50.4/64.35%/ opiod-induced constipation	% of patients with SBM after medication intake; % of patients with >3 SBM/week for at least 50% of treatment duration	208 patients on placebo; 210 patients on lubiprostone 24 mcg	Lubiprostone or placebo B.I.D. for 12 weeks	Oral bisacodyl or sodium phosphate enema as rescue treatment
Fukudo 2015	Japan	42.1/87.9%/ CIC	% of patients with SBM after medication intake; % of patients with >4 SBM/week; constipation severity	62 patients on placebo; 62 patients on lubiprostone 48 mcg	Lubiprostone or placebo for 4 weeks	Bisacodyl suppositories or glycerol enema as rescue treatment
Jamal 2015	USA and Europe	51.7/63.11%/ opioid-induced constipation	% of patients with SBM after medication intake	217 patients on placebo; 214 on lubiprostone 24 mcg BID	Lubiprostone or placebo B.I.D. for 12 weeks	Oral bisacodyl or sodium phosphate enema as rescue treatment
Christie 2017	USA	56.7/65.5%/ constipation on diabetic patients	% of patients with CSBM; average number of SBM/week	39 patients on placebo /37 patients on lubiprostone 24 mcg BID	Lubiprostone or placebo B.I.D. for 8 weeks	Laxatives (including PEG) as rescue treatment
PLECANATIDE
Miner 2017	USA and Canada	45.4/80.75%/ CIC	% of patients with >3 CSBM and/or increase in SBM/week in 9 out of 12 weeks of treatment; % of patients with SBM after medication intake	452 patients on placebo; 452 on plecanatide 3 mg; 441 on plecanatide 6 mg	Plecanatide or placebo once daily for 12 weeks	Bisacodyl as rescue treatment
TENAPANOR
Chey 2017	USA	45.7/ 86.8%/ IBS-C	% of patients with >SBM/week for at least 50% of the treatment duration; % of patients with >30% decrease of abdominal pain severity for at least 50% of the treatment duration	89 patients on placebo; 85 on tenapanor 5 mg; 87 on tenapanor 20 mg; 84 on tenapanor 50 mg BID	Tenapanor or placebo B.I.D. for 12 weeks	Bisacodyl or suppositories as rescue treatment

Study ID	Concealed allocation	Blinding of patients and healthcare personnel	Equalco-interventions between groups	Follow up report	Intention to treat analysis	Jadad score
LINACLOTIDE
Johnston 2010	Yes	Yes	Yes	Yes	Yes	7
Lembo 2010	Yes	Yes	Yes	Yes	Yes	7
Lembo 2011	Yes	Yes	Yes	Yes	Yes	7
Chey 2012	Yes	Yes	Yes	Yes	Yes	7
Rao 2012	Yes	Yes	Yes	Yes	Yes	7
LUBIPROSTONA
Johanson 2007	Not clear	Yes	Yes	Yes	Yes	6
Drossman 2008	Not clear	Yes	Yes	Yes	Yes	6
Fukudo 2010	Not clear	Yes	Yes	Yes	No	6
Ondo 2012	Yes	Yes	Yes	Yes	No	6
Cryer 2014	Yes	Yes	Yes	Yes	Yes	7
Fukudo 2014	Not clear	Yes	Yes	Yes	No	6
Jamal 2015	Yes	Yes	Yes	Yes	Yes	7
Christie 2017	Not clear	Yes	Yes	Yes	Not clear	6
PLECANATIDE
Miner 2017	Yes	Yes	Yes	Yes	Yes	7
TENAPANOR
Chey 2017	Yes	Yes	Yes	Yes	Yes	7

AE	Number of studies	Number of patients on experimental drug	Number of patients on experimental drug and AE (%)	Number of patients on placebo	Number of patients on placebo and AE (%)	RR	CI 95%
LINACLOTIDE
Diarrhea	6	2235	722	1377	47	9.46	7.1-12.61
Abdominal pain	6	2235	106	1377	45	1.45	1.03-2.04
Flatulence	5	1900	89	1292	41	1.47	1.02-2.18
LUBIPROSTONE
Diarrhea	8	1691	131	1055	14	5.83	3.38-10.1
Nausea	7	1663	162	1029	42	2.38	1.71-3.32
Abdominal pain	6	779	51	626	19	2.15	1.28-3.61
PLECANATIDE
Diarrhea	1	931	54	458	6	4.42	1.91-10.21
Nasopharyngitis	1	931	15	458	8	0.92	0.39-2.15
Sinusitis	1	931	13	458	3	2.13	0.61-7.44
TENAPANOR
Diarrhea	1	266	28	90	0	N/A	N/A
Nausea	1	266	13	90	1	4.39	0.58-33.15
Abdominal pain	1	266	11	90	2	1.86	0.42-8.23

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[1] Corresponding author: Juan Sebastian Lasa. E-mail: juanselasa@gmail.com