Clinical efficacy of pharmacological and non-pharmacological interventions for constipation-predominant irritable bowel syndrome

Table 1 Clinical and demographic characteristics of studies included in network meta-analyses (n = 39 studies)[11-48]

Ref.	Year	Country	Study type	Intervention mode		Number of cases		Age (years)		Gender (male/female)		Inclusion criteria	Outcome indicators
				Experimental group	Control group	Experimental group	Control group	Experimental group	Control group	Experimental group	Control group
Chapman et al[11]	2013	Poland	RCT	PEG	Placebo	68	71	43.6 ± 14.9	39.1 ± 14.5	10/57	13/57	Aged 18-80 years; IBS-C diagnosed according to Rome III criteria	CSBM, SBM, BSFS, adverse events
Brenner et al[12]	2024	United States	RCT	Plecanatide	Placebo	560	544	43.7 ± 13.7	43.2 ± 14.2	142/418	131/413	Adults aged ≤ 85 years with IBS-C (Rome III criteria)	CSBM, SBM, adverse events
Brenner et al[12]	2024	United States	RCT	Plecanatide	Placebo	159	173	43.0 ± 15.7	46.7 ± 14.0	47/112	52/121	Adults aged ≤ 85 years with IBS-C (Rome III criteria)	CSBM, SBM, adverse events
Chey et al[13]	2021	United States	RCT	Linaclotide	Placebo	67	66	44.8 ± 14.9	45.4 ± 14.7	8/59	13/53	Patients aged 18 years or older who met the Rome III criteria for IBS-C	SBM, BSFS, adverse events
Chey et al[13]	2021	United States	RCT	Linaclotide	Placebo	67	66	44.7 ± 13.7	45.4 ± 14.7	8/59	13/53	Patients aged 18 years or older who met the Rome III criteria for IBS-C	SBM, BSFS, adverse events
Chey et al[13]	2021	United States	RCT	Linaclotide	Placebo	67	66	46.5 ± 12.7	45.4 ± 14.7	12/55	13/53	Patients aged 18 years or older who met the Rome III criteria for IBS-C	SBM, BSFS, adverse events
Peng et al[14]	2022	China	RCT	Linaclotide	Placebo	327	332	39.6 ± 12.8	40.5 ± 13.9	63/264	45/287	Patients aged 18 years or older who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Brenner et al[15]	2018	United States	RCT	Plecanatide	Placebo	351	354	43.0 ± 13.8	43.0 ± 13.8	84/267	82/272	Adults aged 18-85 years who met Rome III criteria for IBS-C	CSBM, BSFS, adverse events
Brenner et al[15]	2018	United States	RCT	Plecanatide	Placebo	349	354	43.2 ± 13.3	43.0 ± 13.8	83/266	82/272	Adults aged 18-85 years who met Rome III criteria for IBS-C	CSBM, BSFS, adverse events
Brenner et al[15]	2018	United States	RCT	Plecanatide	Placebo	377	379	44.0 ± 14.6	44.8 ± 14.7	107/270	107/272	Adults aged 18-85 years who met Rome III criteria for IBS-C	CSBM, BSFS, adverse events
Brenner et al[15]	2018	United States	RCT	Plecanatide	Placebo	379	379	43.1 ± 14.2	44.8 ± 14.7	106/273	107/272	Adults aged 18-85 years who met Rome III criteria for IBS-C	CSBM, BSFS, adverse events
Chey et al[16]	2012	United States	RCT	Linaclotide	Placebo	401	403	44.6 (19-82)	44.0 (18-87)	33/368	51/352	Men and women aged 18 years or older who met modified Rome II criteria for IBS-C	Adverse events
Cash et al[17]	2023	United States	RCT	Plecanatide	Placebo	188	168	43.0 (20-80)	42.9 (19-78)	41/147	37/131	Age ≥ 18 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Cash et al[17]	2023	United States	RCT	Plecanatide	Placebo	171	168	41.3 (18-76)	42.9 (19-78)	43/128	37/131	Age ≥ 18 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Fukudo et al[18]	2018	Japan	RCT	Linaclotide	Placebo	116	112	41.5 ± 11.3	41.6 ± 10.8	7/109	12/100	Male and female outpatients aged 20-64 years with IBS-C based on the Rome III diagnostic criteria	Adverse events
Fukudo et al[18]	2018	Japan	RCT	Linaclotide	Placebo	111	112	41.7 ± 11.9	41.6 ± 10.8	9/102	12/100	Male and female outpatients aged 20-64 years with IBS-C based on the Rome III diagnostic criteria	Adverse events
Fukudo et al[18]	2018	Japan	RCT	Linaclotide	Placebo	112	112	41.8 ± 9.8	41.6 ± 10.8	13/99	12/100	Male and female outpatients aged 20-64 years with IBS-C based on the Rome III diagnostic criteria	Adverse events
Fukudo et al[18]	2018	Japan	RCT	Linaclotide	Placebo	107	112	38.9 ± 11.0	41.6 ± 10.8	8/99	12/100	Male and female outpatients aged 20-64 years with IBS-C based on the Rome III diagnostic criteria	Adverse events
Fukudo et al[19]	2018	Japan	RCT	Linaclotide	Placebo	249	251	41.6 ± 10.7	42.2 ± 11.3	37/212	24/227	Male and female outpatients aged 20-79 years diagnosed as having IBS-C based on the Rome III diagnostic criteria	Adverse events
Rao et al[20]	2020	United States	RCT	Linaclotide	Placebo	26	13	40.1 ± 2.6	46.4 ± 2.1	1/25	0/13	Adults aged 18-85 years who met Rome III criteria for IBS-C	BSFS, IBS-QOL, adverse events
Chang et al[21]	2021	United States	RCT	Linaclotide	Placebo	306	308	46.5 (19-85)	46.8 (18-79)	65/241	53/255	Men or women; ≥ 18 years; met Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Yang et al[22]	2018	China	RCT	Linaclotide	Placebo	417	422	41.0 (18-77)	41.3 (18-80)	84/333	67/355	Men and women ≥ 18 years of age were eligible if they met the Rome III criteria for IBS-C	Adverse events
Chey et al[23]	2017	United States	RCT	Tenapanor	Placebo	88	90	45.8 ± 12.7	46.0 ± 13.8	12/76	13/77	Adults 18-75 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Chey et al[23]	2017	United States	RCT	Tenapanor	Placebo	89	90	45.3 ± 14.1	46.0 ± 13.8	12/77	13/77	Adults 18-75 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Chey et al[23]	2017	United States	RCT	Tenapanor	Placebo	89	90	45.8 ± 12.2	46.0 ± 13.8	10/79	13/77	Adults 18-75 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Chey et al[24]	2020	United States	RCT	Tenapanor	Placebo	307	299	45.0 ± 13.4	44.9 ± 13.0	63/244	50/249	Men and women aged 18-75 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Nasab et al[25]	2025	Iran	RCT	Traditional Chinese medicine	Placebo	30	30	39 ± 4.38	38.77 ± 4.22	13/17	14/16	Patients aged 18-50 years who met modified Rome IV criteria for IBS-C	IBS-QOL, IBS-SSS
Yu and Xuan[26]	2017	China	RCT	PEG	Placebo	48	48	56.95 ± 5.43	56.45 ± 5.62	26/22	25/23	Diagnosed with IBS-C according to the Rome III diagnostic criteria for IBS	Adverse reactions
Li et al[27]	2025	China	RCT	Traditional Chinese medicine	Lactulose oral solution	36	36	43.28 ± 14.76	43.03 ± 14.84	20/16	12/24	Age 18-70 years; meeting Rome IV diagnostic criteria for IBS-C	BSFS, IBS-SSS, adverse events
Hao et al[28]	2025	China	RCT	Traditional Chinese medicine	Linaclotide	51	46	42.87 ± 10.18	45.42 ± 9.29	22/29	18/28	Age > 18 years who met the Rome IV criteria for IBS-C	BSFS, IBS-SSS, IBS-QOL, adverse events
Chey et al[29]	2020	United States	RCT	Tenapanor	Placebo	293	300	46.1 ± 13.1	44.8 ± 13.8	53/240	53/247	Men and women aged 18-75 years who met the Rome III criteria for IBS-C	CSBM, SBM, BSFS, adverse events
Rao et al[30]	2012	United States	RCT	Linaclotide	Placebo	405	395	43.3 (19-81)	43.7 (18-84)	38/367	38/357	At least 18 years of age; met modified Rome II criteria for IBS-C	Adverse events
Andresen et al[31]	2007	United States	RCT	Linaclotide	Placebo	12	12	43.4 ± 2.8	38.5 ± 2.8	0/12	0/12	Female, nonpregnant, non-breastfeeding participants aged 18-65 years with IBS-C, based on Rome II criteria	BSFS
Andresen et al[31]	2007	United States	RCT	Linaclotide	Placebo	12	12	35.4 ± 2.3	38.5 ± 2.8	0/12	0/12	Female, nonpregnant, non-breastfeeding participants aged 18-65 years with IBS-C, based on Rome II criteria	BSFS
Rao et al[32]	2014	Not explicitly stated	RCT	Linaclotide	Placebo	805	797	NA	NA	NA	NA	Patients were eligible to participate if they were at least 18 years of age and met modified Rome II criteria for IBS-C	Adverse events
Chang et al[33]	2016	United States	RCT	Lubiprostone	Placebo	325	180	45.4 ± 12.4	46.4 ± 12.2	21/304	6/174	Meeting the Rome II Modular Questionnaire criteria for IBS-C	Adverse events
Johanson et al[34]	2008	United States	RCT	Lubiprostone	Placebo	51	48	46.5 ± 10.1	44.6 ± 11.1	4/47	4/44	Men and women aged 18-80 years or older who met modified Rome II criteria for IBS-C	Adverse events
Johanson et al[34]	2008	United States	RCT	Lubiprostone	Placebo	49	48	48.3 ± 11.9	44.6 ± 11.1	3/46	4/44	Men and women aged 18-80 years or older who met modified Rome II criteria for IBS-C	Adverse events
Johanson et al[34]	2008	United States	RCT	Lubiprostone	Placebo	45	48	43.9 ± 11.6	44.6 ± 11.1	7/38	4/44	Men and women aged 18-80 years or older who met modified Rome II criteria for IBS-C	Adverse events
Drossman et al[35]	2009	United States	RCT	Lubiprostone	Placebo	769	385	46.1 (19.0, 83.0)	47.7 (18.0, 85.0)	71/698	26/359	Eligible patients being at least 18 years of age and meeting the Rome II Modular Questionnaire Criteria for IBS-C	Adverse events
Kwon et al[36]	2024	Republic of Korea	RCT	Probiotics	Placebo	15	15	36.4 ± 13.6	37.1 ± 13.7	NA	NA	Participants qualified for randomization had clinical responses based on the Rome IV criteria	IBS-SSS, IBS-QOL
Mourey et al[37]	2022	France	RCT	Probiotics	Placebo	230	226	41.2 ± 13.96	39.9 ± 14.56	28/202	36/190	Females and males aged 18-75 years were eligible to participate if they met the Rome IV criteria for IBS-C	Adverse events
Akçalı et al[38]	2025	Turkey	RCT	Inulin	Placebo	17	17	36.35 ± 11.6	38.23 ± 12.9	4/13	4/13	Aged between 19 years and 65 years, diagnosed with IBS-C according to the Rome IV criteria	IBS-SSS, IBS-QOL
Camacho-Díaz et al[39]	2023	Mexico	RCT	Fiber	Placebo	24	26	50.0 ± 2.0	50.0 ± 2.0	NA	NA	Screening of patients was based on the Rome III diagnostic criteria for IBS-C	IBS-QOL
Rao et al[8]	2021	United States	RCT	Sensory adaptation training	Placebo	26	23	45.0 ± 3.0	47.0 ± 3.1	0/26	4/19	Age ≥ 18 years who met the Rome III criteria for IBS-C	BSFS, adverse events
Huang et al[40]	2022	China	RCT	Acupuncture	Placebo	26	26	51.4 ± 16.2	49.6 ± 17.5	9/17	10/16	Men and women aged 18-75 years who met the Rome IV diagnostic criteria for IBS-C	CSBM, BSFS, IBS-SSS, IBS-QOL
Lu et al[41]	2015	China	RCT	Acupuncture	Moxibustion	19	21	40 ± 12	42 ± 8	NA	NA	The eligibility of the initial IBS-C patients according to the Rome III diagnostic criteria	BSFS
Zhao et al[42]	2018	China	RCT	Acupuncture	Moxibustion	30	30	40.40 ± 12.67	42.33 ± 8.68	NA	NA	Complied with Rome III diagnostic criteria of C-IBS; were 18-65 years old	BSFS, adverse events
Isakov et al[43]	2023	Russia	RCT	Inulin + vitamins	Placebo	20	20	48.7 ± 17.7	47.7 ± 15.9	0/20	0/20	Age ranging from 18 years to 80 years old; diagnosis of IBS-C based on ROME IV criteria	BSFS
Shi et al[44]	2021	China	RCT	taVNS	Placebo	21	21	41.5 ± 15.4	49.6 ± 15.6	4/17	6/15	Aged 18-75 years; met the Rome IV diagnostic criteria for IBS-C	CSBM, BSFS, IBS-SSS, IBS-QOL
Choi et al[45]	2011	Korea	RCT	Fiber	Placebo	16	18	NA	NA	NA	NA	Volunteers between 18 years and 70 years of age who met the Rome III criteria with IBS-C	BSFS
Liu et al[46]	2024	China	RCT	taVNS	Placebo	20	20	48.10 ± 11.54	48.75 ± 12.23	5/15	5/15	Individuals aged 18-70 years diagnosed with IBS-C according to the Rome IV criteria	CSBM, SBM, BSFS, IBS-SSS, IBS-QOL, adverse events
Pei et al[47]	2015	China	RCT	Acupuncture	Lactulose oral solution	30	30	44 ± 12	44 ± 14	11/19	9/21	Age between 18 years and 65 years who meeting the Rome III diagnostic criteria for IBS-C	IBS-QOL
Guo et al[48]	2021	China	RCT	Acupuncture	PEG	92	45	46.3 ± 14.3	47.0 ± 13.6	33/59	17/28	Age between 18 years and 70 years who meeting the Rome III diagnostic criteria for IBS-C	IBS-SSS, IBS-QOL, adverse events

RCT: Randomized controlled trials; PEG: Polyethylene glycol; taVNS: Transcutaneous auricular vagus nerve stimulation; NA: Not available; IBS-C: Irritable bowel syndrome with constipation; CSBM: Complete spontaneous bowel movement; SBM: Spontaneous bowel movement; BSFS: Bristol stool form scale; IBS-QOL: Irritable bowel syndrome quality of life; IBS-SSS: Irritable bowel syndrome severity scoring system.

Table 2 Certainty of evidence

Quality assessment							Summary of findings
Participants (studies) follow up	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Overall quality of evidence	Study event rates (%)		Relative effect (95%CI)	Anticipated absolute effects
							With control	With outcomes		Risk with control	Risk difference with outcomes (95%CI)
CSBM (critical outcome; better indicated by lower values)
8318 (17 studies)	Serious	Serious	No serious indirectness	No serious imprecision	Undetected	Moderate due to risk of bias, inconsistency, large effect	4159	4159			The mean CSBM in the intervention groups was 1.1 higher (1.05 to 1.16 higher)
SBM (critical outcome; better indicated by lower values)
5706 (16 studies)	Serious	Serious	No serious indirectness	No serious imprecision	Undetected	Moderate due to risk of bias, inconsistency, large effect	2848	2858			The mean SBM in the intervention groups was 1.65 higher (1.58 to 1.72 higher)
BSFS (critical outcome; better indicated by lower values)
7689 (28 studies)	Serious	Serious	No serious indirectness	No serious imprecision	Undetected	Moderate due to risk of bias, inconsistency, large effect	3834	3855			The mean BSFS in the intervention groups was 0.97 higher (0.94 to 1.01 higher)
IBS-SSS (critical outcome; better indicated by lower values)
544 (9 studies)	Serious	Serious	No serious indirectness	No serious imprecision	Undetected	Moderate due to risk of bias, inconsistency, large effect	245	299			The mean IBS-SSS in the intervention groups was 37.34 lower (46.23 to 28.45 lower)
IBS-QOL (critical outcome; better indicated by lower values)
617 (11 studies)	Serious	No serious inconsistency	No serious indirectness	No serious imprecision	Undetected	High due to risk of bias, large effect	278	339			The mean IBS-QOL in the intervention groups was 7.27 higher (5.32 to 9.22 higher)
Adverse events (critical outcome)
16725 (36 studies)	Serious	Serious	No serious indirectness	No serious imprecision	Undetected	Moderate due to risk of bias, inconsistency, large effect	2720/8076 (33.7%)	3357/8649 (38.8%)	OR = 1.23 (1.15 to 1.32)	Study population
										337 per 1000	48 more per 1000 (from 32 more to 65 more)
										Moderate
										346 per 1000	48 more per 1000 (from 32 more to 65 more)

CI: Confidence interval; CSBM: Complete spontaneous bowel movement; SBM: Spontaneous bowel movement; BSFS: Bristol stool form scale; IBS-QOL: Irritable bowel syndrome quality of life; IBS-SSS: Irritable bowel syndrome severity scoring system.