Targeted therapies for diarrhea-predominant irritable bowel syndrome

Figures & data

Table 1 Characteristics of randomized controlled trials of tricyclic antidepressants in irritable bowel syndrome ± diarrhea and efficacy outcomes

Study	Treatment	Study duration	N	Population	Relief of abdominal pain	Relief of bloating	Global/overall IBS improvement	Stool frequency	Stool consistency	Urgency	Other efficacy assessments
Amitriptyline vs placebo
Rajagopalan et al^Citation28	25–75 mg (titrated)	12 wk	40	Adults with IBS (Rome criteria)	++	NA/NR	++	0	NA/NR	NA/NR	+++ for days felt well + for days with satisfactory bowel movements
Vahedi et al^Citation29	10 mg qhs	2 mo	50	Adults with IBS-D (Rome II)	0	NA/NR	++ for complete response	NA/NR	+	NA/NR	++ for degree of symptom improvement 0 for passage of mucus + for feeling of incomplete defecation 0 for diarrhea
Desipramine vs placebo
Greenbaum et al^Citation30	50–150 mg qhs vs placebo	Three 6 wk periods	41	Adults with IBS*		NA/NR	15/26 patients improved on desipramine	+		NA/NR	0 for diarrhea
				Overall completers	++				0		++ for reduction in slow contractions
				I BS-D	+		87% of patients who improved on desipramine had IBS-D	+	0	NA/NR	++ for diarrhea + for slow contractions
Drossman et al^Citation31	50–150 mg (titrated)†	12 wk	431	Women with functional bowel disorder	0	NA/NR	0 for responder analysis				+ for post-treatment satisfaction
							++ for patients with detectable desipramine	NA/NR	NA/NR	NA/NR	0 for IBS-QOL
Imipramine vs placebo
Talley et al^Citation33	25–50 mg/d‡	12 wk	34	Adults with IBS (Rome II)	0	NA/NR	0 for IBS symptom relief at last wk, for adequate relief at ≥50% of wk, and for CGI	NA/NR	NA/NR	NA/NR	0 for anxiety and 0 for depression on HADS 0 for mental score and 0 for physical score on SF-36
Abdul-Baki et al^Citation32	25 mg qhs	12 wk	107	Women with IBS (Rome II)	NA/NR	NA/NR	0	NA/NR	NA/NR	NA/NR	0 for QOL score on SF-36

Notes:

* IBS defined as ≥3 months of abdominal pain or distress, occurring at least biweekly for which no organic cause is evident.

† Study included 12-week treatment with cognitive behavioral therapy vs education and desipramine vs placebo comparisons; however, only desipramine vs placebo results are presented in this table.

‡ Treatment in this study included a citalopram 20–40 mg/d arm as well; only the imipramine vs placebo results, including number of patients, are presented in this table.

Positive signs indicate significant improvement over placebo: + for P ≤ 0.05; ++ for P ≤ 0.01; +++ for P ≤ 0.001; ++++ for P ≤ 0.0001; 0 represents no statistically significant difference between active treatment and placebo.

Abbreviations: CGI, Clinical Global Impression scale; HADS, Hospital Anxiety and Depression Scale; IBS, irritable bowel syndrome; IBS-D, diarrhea-predominant IBS; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; NA/NR, not assessed or not reported; QOL, quality of life; SF-36, Medical Outcomes Study Short Form.

Table 2 Characteristics of randomized controlled trials of selective serotonin-reuptake inhibitors in irritable bowel syndrome ± diarrhea and efficacy outcomes

Study	Treatment	Study duration	N	Population	Relief of abdominal pain	Relief of bloating	Global/overall IBS improvement	Stool frequency	Stool consistency	Urgency	Other efficacy assessments
Fluoxetine vs placebo
Kuiken et al^Citation35	20 mg qhs	6 wk	40	Adults with IBS (Rome I)	0	0	0	NA/NR	NA/NR	0	0 for flatulence 0 for incomplete evacuation
Paroxetine vs placebo
Tabas et al^Citation36	HFD ± 10 mg qd; titration at wk 4, 8, and 11 prn; 40 mg qd maximum dose	12 wk	81	Adults with IBS (Rome I)	0	0	++*	NA/NR	NA/NR	NA/NR	+ improvement in stool passage
Masand et al^Citation37	12.5 mg qd of the controlled release form; titrated biweekly to response and tolerability; 50 mg qd maximum dose	12 wk	72	Adults with IBS (Rome II)	0	0	++	NA/NR	NA/NR	NA/NR	++ for CGI-severity improvement 0 for constipation, diarrhea, and distress
Citalopram vs placebo
Tack et al^Citation38	20 mg qd for first 3 wk then 40 mg qd for wk 4–6	6 wk	23	Adults with IBS (Rome II)	+ for number of days per wk with abdominal pain	+	NA/NR	NA/NR	NA/NR	NA/NR	+ for number of days with loose stools, straining, and incomplete evacuation
Talley et al^Citation33	40 mg qd†	12 wk	33	Adults with IBS (Rome II)	0	NA/NR	0 for adequate IBS symptom relief at last wk, adequate relief for ≥50% of wk, and for CGI	NA/NR	NA/NR	NA/NR	0 for anxiety and 0 for depression on HADS 0 for mental score and 0 for physical score on SF-36

Notes:

* Endpoint measured was “improvement in overall well-being”.

† Treatment in this study included an imipramine 25–50 mg/d arm as well; only the citalopram vs placebo results, including number of patients, are presented in this table.

Positive signs indicate significant improvement over placebo: + for P ≤ 0.05; ++ for P ≤ 0.01; +++ for P ≤ 0.001; ++++ for P ≤ 0.0001; 0 represents no statistically significant difference between active treatment and placebo.

Abbreviations: CGI, Clinical Global Impression scale; HADS, Hospital Anxiety and Depression Scale; HFD, high fiber diet; IBS, irritable bowel syndrome; NA/NR, not assessed or not reported; SF-36, Medical Outcomes Study Short Form.

Table 3 Characteristics of randomized controlled trials of nonabsorbable antibiotics in IBS and efficacy outcomes

Study	Treatment	Study duration	N	Population	Relief of abdominal pain	Relief of bloating	Global/overall IBS improvement	Stool frequency	Stool consistency	Urgency	Other efficacy assessments
Neomycin vs placebo
Pimentel et al^Citation21	500 mg bid	10 d treatment, 7 d follow-up	111	Adults with IBS (Rome I)	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	CS:† + for reduction of CS and ≥50% improvement in CS
Rifaximin vs placebo
Pimentel et al^Citation44	400 mg tid	10 d treatment, 10 wk follow-up	87	Adults with IBS without underlying predisposition to SIBO (Rome I)	0	++	+	NA/NR	NA/NR	NA/NR	0 for diarrhea
Sharara et al^Citation51	400 mg bid	10 d treatment, 10 d follow-up	124	Men with bloating/ flatulence and abdominal discomfort or bowel disturbance or abnormal stool consistency
				All patients	NA/NR	+	+ for symptom relief at end of treatment; + at end of follow-up	NA/NR	NA/NR	NA/NR	+ for mean symptom score at end of treatment; 0 for mean symptom score at end of follow-up
				70 with IBS-D, -A, or -C (Rome II)	NA/NR	NA/NR	+ for symptom relief at end of treatment; + at end of follow-up	NA/NR	NA/NR	NA/NR
				54 who did not meet Rome II criteria	NA/NR	NA/NR	0 for symptom relief at end of treatment	NA/NR	NA/NR	NA/NR	NA/NR
IBS-D phase II study:* Lembo et al^Citation54	550 mg bid	14 d treatment, 12 wk follow-up	388	Adults with IBS-D (Rome II)	NA/NR	+ at end of treatment; + at end of follow-up	+ at end of treatment; + at end of follow-up	NA/NR	NA/NR	NA/NR	NA/NR
IBS-D phase II study:* Ringel et al^Citation55	550 mg bid	14 d treatment, 12 wk follow-up	388	Adults with IBS-D (Rome II)	NA/NR	0 in patients with mild–moderate pain at baseline; 0 in patients with severe pain; + in patients with mild–moderate bloating at baseline; 0 in patients with severe bloating	+ in patients with mild–moderate pain at baseline; 0 in patients with severe pain; ++ in patients with mild–moderate bloating at baseline; 0 in patients with severe bloating	NA/NR	NA/NR	NA/NR	Most substantial confounders of clinical response: daily bloating, abdominal pain, and use of rescue medications
IBS-D phase II study:* Pimentel et al^Citation56	550 mg bid	14 d treatment, 12 wk follow-up	388	Adults with IBS-D (Rome II)	NA/NR	0 in patients with mild–moderate pain at baseline; 0 in patients with severe pain; + in patients with mild–moderate bloating at baseline; 0 in patients with severe bloating	+ in patients with mild–moderate pain at baseline; 0 in patients with severe pain; ++ in patients with mild–moderate bloating at baseline; 0 in patients with severe bloating	NA/NR	NA/NR	NA/NR	Most substantial confounders of clinical response: daily bloating, abdominal pain, and use of rescue medications
IBS-D phase II study:* Chey et al^Citation57	550 mg bid	14 d treatment, 12 wk follow-up	388	Adults with IBS-D (Rome II)	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	+ for IBS-QOL total score; + for dysphoria, body image, health worry, social reaction, and relationship improvements
TARGET 1 and 2 studies; Pimentel et al^Citation58	550 mg tid	2 wk	1260	Adults with nonconstipated IBS
				623 in TARGET 1	+	++	++	NA/NR	++	NA/NR	+ for relief during all 3 mo;
				637 in TARGET 2	+	+	+	NA/NR	++	NA/NR	++ for relief during all 3 mo;
				1260 in total	++	+++	+++	NA/NR	+++	NA/NR	+++ for relief during all 3 mo

Notes:

* Reanalysis of the data from one phase II study.

† Composite score based on abdominal pain, diarrhea, and constipation (0–5 scale for each); higher scores denote more severity.

Positive signs indicate significant improvement over placebo: + for P ≤ 0.05; ++ for P ≤ 0.01; +++ for P ≤ 0.001; ++++ for P ≤ 0.0001; 0 represents no statistically significant difference between active treatment and placebo.

Abbreviations: CS, composite score; IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome with alternating diarrhea and constipation symptom predominance; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; SIBO, small intestinal bowel overgrowth.

Table 4 Characteristics of randomized controlled trials of alosetron in irritable bowel syndrome and efficacy outcomes

Study	Treatment	Study duration	N	Population	Relief of abdominal pain	Relief of bloating	Global/overall IBS improvement	Stool frequency	Stool consistency	Urgency	Other efficacy assessments
Alosetron vs placebo
Camilleri et al^Citation66	1, 2, 4, or 8 mg bid	12 wk	370	Adults with IBS-D or -A (Rome I)
				Women	1 mg: +	NA/NR	NA/NR	All doses: +	All doses: +	All doses: +	NA/NR
					2 mg: +
					4 mg: 0
					8 mg: 0
				Men	All doses: 0	NA/NR	NA/NR	All doses: 0	All doses: 0	All doses: 0	NA/NR
Bardhan et al^Citation67	0.1, 0.5, or 2 mg bid	12 wk	462	Adults with IBS-D, -A, -C, or other IBS (Rome I)
				All patients	0.1 mg: 0	NA/NR	NA/NR	0.1 mg: 0	NA/NR	NA/NR	2 mg: + for diarrhea
					0.5 mg: 0			0.5 mg: + in wk 1–2, 9–12
					2 mg: + in wk 5–8, 9–12			2 mg: + 1 in wk 1–2, 9–12
				Women	0.1 mg: 0	NA/NR	NA/NR	0.1 mg: 0	0.1 mg: ++	NA/NR	2 mg: + for diarrhea
					0.5 mg: 0			0.5 mg: + in wk 1–2	0.5 mg: ++
					2 mg: + in wk 9–12			2 mg: + in wk 1–2	2 mg: ++; all at wk 1–2, 9–12
				Men	All doses: 0	NA/NR	NA/NR	0.1 mg: 0	0.1 mg: 0	NA/NR	All doses: 0 for diarrhea
								0.5 mg: 0	0.5 mg: ++ in wk 1–2, 9–12
								2 mg: + in wk 1–2	2 mg: ++ in wk 1–2, 9–12
Camilleri et al^Citation68	1 mg bid	12 wk	647	Women with IBS-D or -A (Rome I)
				All patients	+ overall and weekly in wk 2–12	NA/NR	NA/NR	+++ weekly in wk 1–12	+++ weekly in wk 1–12	+++ weekly in wk 1–12	NA/NR
				IBS-D	+ overall	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR
				IBS-A	0	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR
Camilleri et al^Citation69	1 mg bid	12 wk	626	Nonconstipated womenwith IBS-D or -A (Rome I)
				All patients	+++ overall	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR
				IBS-D	+++ overall	0	NA/NR	+++ in wk 1–12	+++ in wk 1–12	++ in wk 1–2; +++ in wk 3–12	+ for reduction of days with sensation of incomplete evacuation in mo 2, ++ at mo 3
Watson et al^Citation71,*	1 mg bid	12 wk	1273	Women with IBS-D or -A (Rome I)	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	+ in IBS-D on all QOL subscales† in both studies* (except mental health subscale in Camilleri^Citation69)
Lembo et al^Citation70	1 mg bid	12 wk	801	Nonconstipated women without satisfactory control of bowel urgency (Rome II)	NA/NR	NA/NR	+++ in wk 4, 8, and 12	+++	+++	+++	+++ for reduction of days with sensation of incomplete evacuation
Olden et al^Citation73 (Same cohort as Lembo et al^Citation70)	1 mg bid	12 wk	801	Nonconstipated women without satisfactory control of bowel urgency (Rome II)	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	+++ for overall satisfaction with treatment at 12 wk
Chey et al^Citation74	1 mg bid	48 wk	714	Women with IBS-D or -A (Rome I)
				IBS-D	++ for 48 wk average	0	NA/NR	++	+	+++	NA/NR
				IBS-D with greater urgency	++ for 48 wk average		NA/NR	++	+	+++	NA/NR
Lembo et al^Citation75,‡	1 mg bid	12 wk	492	Women with severe IBS-D (Rome II)	NA/NR	NA/NR	+++ at wk 4, 8, 12	+++	+++	+++	+ for reduction of days with sensation of incomplete evacuation for 11 of 12 wk
			711	Women with IBS-D without satisfactory control of bowel urgency (Rome II)	NA/NR	NA/NR	+++ at wk 4, 8, 12	+++	+++	+++	++ for the % of subjects with ≤1 d of uncontrolled urgency at wk 1–2; +++ for wk 3–12
Chang et al^Citation76	0.5, 1, 2, or 4 mg bid	12 wk	662	Men with IBS-D (Rome I)	0.5 mg: 0 1 mg: + at wk 5–12 2 mg: 0 4 mg: 0	All doses: 0	NA/NR	All doses: 0	All doses: +++	All doses: 0	0 for reduction of days with sensation of incomplete evacuation
Krause et al (efficacy and safety)^Citation77	0.5 mg qd, 1 mg qd, or 1 mg bid	12 wk	705	Women with severe IBS-D who had failed conventional therapy (Rome II)	All doses: + at each 4 wk interval (1–4, 5–8, 9–12)	NA/NR	All doses: + at wk 12	All doses: ++ at each 4 wk interval (1–4, 5–8, 9–12)	All doses: +++ at each 4 wk interval (1–4, 5–8, 9–12)	0.5 mg: + at wk 9–12 1 mg qd: + at wk 9–12 1 mg bid: 0	All doses: ++ at each 4 wk interval (1–4, 5–8, 9–12) for normalization of bowel patterns
Nicandro et al (QOL)^Citation78 (same cohort as Krause et al^Citation77)	0.5 mg qd, 1 mg qd, or 1 mg bid	12 wk	705	Women with severe IBS-D who had failed conventional therapy (Rome II)	NA/NR	NA/NR	++ all alosetron-treated subjects on overall treatment satisfaction	NA/NR	NA/NR	NA/NR	IBS-QOL 0.5 mg qd: + in 8/9 domains 1 mg qd: + in 5/9 domains 1 mg bid: + in 7/9 domains Reduction in lost work productivity 0.5 mg qd: + 1 mg qd: 0 1 mg bid: ++++

Notes:

* Primary efficacy reported in Camilleri et al,^68,69 respectively.

† QOL subscales: emotional health, sleep, energy, physical and social functioning, food/diet, role-physical, sexual relations, and mental health.

‡ Counted as a reanalysis of Lembo et al.⁷⁰ Positive signs indicate significant improvement over placebo: + for P ≤ 0.05; ++ for P ≤ 0.01; +++ for P ≤ 0.001; ++++ for P ≤ 0.0001; 0 represents no statistically significant difference between active treatment and placebo.

Abbreviations: IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome with alternating diarrhea and constipation symptom predominance; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; NA/NR, not assessed or not reported; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; QOL, quality of life.

Table 1 Randomized controlled trials of tricyclic and selective serotonin-reuptake inhibitor antidepressants in irritable bowel syndrome: study characteristics and efficacy outcomes

Study	Diagnostic criteria	Sample size, type of IBS,* dosage, analysis population	Study type and duration	Relief of abdominal pain with or without discomfort	Relief of bloating and/or distension	Effect on stool frequency	Effect on stool consistency	Effect on urgency	Global or overall IBS improvement	Other efficacy assessments
Tricyclic antidepressant: amitriptyline
Rajagopalan et al^Citation1	Rome	Patients: 40, age 21–65 yr, with IBS and symptoms for ≥1 yr Treatment: amitriptyline 25–75 mg (titrated) vs placebo	Randomized, DB, PC design; 12 wk treatment	Reduction in days per wk with abdominal pain: +, P < 0.01	NA/NR	0	NA/NR	NA/NR	+, 63.6% with amitriptyline vs 25.9% with placebo, P < 0.01	Days felt well: +, P < 0.001 Days with satisfactory bowel movements: +, P < 0.05
Vahedi et al^Citation2	Rome II	Patients: 50, mean age 36 yr, with IBS-D and symptoms for ≥12 wk during the preceding yr, 42% women Treatment: amitriptyline 10 mg qhs vs placebo	Randomized, DB, PC design; 2 mo treatment	0	NA/NR	NA/NR	Number of loose stools per day: +, P < 0.05	NA/NR	Complete response: ITT +, P = 0.01	Degree of symptom improvement: +, P = 0.01; Passage of mucus: 0; Feeling of incomplete defecation: +, P < 0.05; Diarrhea: 0
Tricyclic antidepressant: desipramine
Greenbaum et al^Citation3	Clinical diagnosis (history, PE, labs, stool studies, proctosigmoidoscopy, and barium enema at screening or within previous yr)	Patients: 41 (27 women) with IBS defined as ≥3 mo of abdominal pain or distress not attributed to menstruation, with diarrhea, constipation, or alternating symptoms occurring at least biweekly with no organic cause; concomitant meds allowed, including analgesics and antibiotics Treatment: desipramine 50–150 mg qhs, atropine 0.4–1.2 mg qhs, or placebo Analysis population: Overall completers (n = 28) IBS-D (n = 19) IBS-C (n = 9) IBS-D vs IBD-C	DB, PC, crossover design; 3 6 wk test periods	Pain index: +, P < 0.0025 +, P < 0.025 N too small for meaningful comparison Significant differences favoring IBS-D (P < 0.01) over IBS-C	NA/NR	Mean frequency of stools: +, P < 0.025 +, P < 0.025 N too small for meaningful comparison No significant differences between IBS-D and IBS-C	Mean frequency of loose stools: 0 0 N too small for meaningful comparison No significant differences between IBS-D and IBS-C	NA/NR	15 of 26 patients with improvement while receiving desipramine 87% of patients who reported global improvement had IBS-D	Reduction in diarrhea: 0 +, P < 0.005 0 Significant differences between IBS-D; (P < 0.025) and IBS-C; Reduction in slow contractions: +, P < 0.01 +, P < 0.05 N too small 0 No significant differences for number of fast contractions or motility indices; Other assessments included Brief Psychiatric Rating Scale and HAM-D
Drossman et al^Citation4	Rome I and physicians’ clinical diagnosis	Patients: 431 women aged >18 yr with functional bowel disorder with moderate to severe abdominal pain with or without altered bowel habit; 78% of whom had IBS on Rome I criteria; 87% had IBS diagnosis by physician Treatment: desipramine 50–150 mg (titrated) vs placebo	Randomized (variable-sized blocks of 6 and 12), comparator-controlled design; 12 wk treatment with CBT vs education and desipramine vs placebo (only desipramine vs placebo results presented here)	McGill average daily pain: ITT: 0	NA/NR	NA/NR	NA/NR	NA/NR	Responder analysis: ITT: 0 PPP: +, P = 0.02; Patients with detectable desipramine: +, P = 0.006; Global well-being: ITT: 0	Post-treatment satisfaction: ITT: +, P = 0.011; IBS-QOL: ITT: 0; Composite score: ITT: 0 PPP: +, P = 0.03; Patients with detectable desipramine: +, P = 0.01
Tricyclic antidepressant: imipramine
Talley et al^Citation5	Rome II	Patients: 34 with IBS (IBS-D 73%) Treatment: imipramine 25–50 mg/d, citalopram 20–40 mg/d, vs placebo (“n” represents imipramine vs placebo results presented here)	Randomized, DB, PC, PG, pilot study; 12 wk treatment	0	NA/NR	0	NA/NR	NA/NR	Adequate relief of IBS symptoms at last wk: 0; Adequate relief of IBS symptoms ≥ 50% of wk: 0; CGI: 0; BSSRS: Disability +, P = 0.05 Distress: +, P = 0.02	HADS: anxiety 0 and depression 0; SF-36: menta 0 and physical 0
Abdul-Baki et al^Citation6	Rome II	Patients: 107 patients with IBS (42% female) Treatment: imipramine 25 mg qhs vs placebo	Randomized, DB, PC study; 12 wk treatment	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	Global symptom relief: ITT: 0 PPP: +, P < 0.05	QOL using SF-36: 0
SSRI: fluoxetine
Kuiken et al^Citation7	Rome I	Patients: 40 adults with IBS (IBS-D 40%) Treatment: fluoxetine 20 mg qhs vs placebo	Randomized, DB, PC study; 6 wk treatment	0	0	NA/NR	NA/NR	0	0	Flatulence: 0 Incomplete evacuation: 0
SSRI: paroxetine
Tabas et al^Citation8	Rome I	Patients: 81 adults with IBS Treatment: HFD ± paroxetine 10 mg qd vs placebo; titration at wk 4, 8, and 11 prn; maximum dose 40 mg qd	Randomized, DB, PC study; 12 wk treatment	0	0	NA/NR	NA/NR	NA/NR	++†, P = 0.01	Stool passage: +
Masand et al^Citation9	Rome II	Patients: 72 adults with IBS (women 87.5%) Treatment: paroxetine CR 12.5 mg qd titrated biweekly to response and tolerability; maximum dose 50 mg qd	Randomized, DB, PC study; 12 wk treatment	0	0	NA/NR	NA/NR	NA/NR	NA/NR	CGI-Severity improvement: ++, P < 0.01; Constipation, diarrhea, distress: 0
SSRI: citalopram
Tack et al^Citation10	Rome II	Patients: 23 adults with IBS (women 78.3%) Treatment: citalopram 20 mg qd for 3 wk then 40 mg qd for 3 wk	Crossover study; 6 wk treatment	No. days per wk with abdominal pain: +, P < 0.05	+; P < 0.05	NA/NR	NA/NR	NA/NR	NA/NR	No. days with loose stools, straining, and incomplete evacuation: +, P < 0.05
Talley et al^Citation5	Rome II	Patients: 33 adults with IBS (IBS-D 76%) Treatment: citalopram 20–40 mg/d, imipramine 25–50 mg/d, vs placebo (“n” represents citalopram vs placebo results presented here)	Randomized, DB, PC, PG, pilot study; 12 wk treatment	0	NA/NR	0	NA/NR	NA/NR	Adequate IBS symptom relief at last wk: 0; CGI: 0; BSSRS: Disability: 0 Distress: 0	Adequate symptom relief for ≥50% of wk: 0

Notes:

* According to predominant stool pattern, if available;

† Endpoint was “improvement in overall well-being.” + Indicates significant improvement over placebo; 0 represents no statistically significant difference between active treatment and placebo. If a study did not report on a particular assessment, it was noted as “not assessed.” If more than one population is assessed for a particular parameter, the populations are numbered (see sample size, type of IBS, dosage, analysis population column); subsequent efficacy values are presented to correspond to the population so designated.

Abbreviations: BSSRS, bowel syndrome severity rating scale; CBT, cognitive behavioral therapy; CGI, Clinical Global Impression scale; CR, controlled release; DB, double-blind; HADS, Hospital Anxiety and Depression Scale; HAM-D, Hamilton Rating Scale for Depression; HFD, high-fiber diet; IBS, irritable bowel syndrome; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; ITT, intent-to-treat population; NA/NR, not assessed or not reported; PC, placebo-controlled; PE, physical exam; PG, parallel group; PPP, per-protocol population; QOL, quality of life; SF-36, Medical Outcomes Study Short Form; SSRI, selective serotonin-reuptake inhibitor.

Table 2 Randomized controlled trials of rifaximin in irritable bowel syndrome: study characteristics and efficacy outcomes

Study	Diagnostic criteria	Sample size, type of IBS,* dosage, analysis population	Study type and duration	Relief of abdominal pain with or without discomfort	Relief of bloating and/or distension	Effect on stool frequency	Effect on stool consistency	Effect on urgency	Global or overall IBS improvement	Other efficacy assessments
Pimentel et al^Citation11	Rome I	Patients: 87, aged 18–65 yr, with IBS without an underlying condition predisposing to SIBO, 66% women Treatment: rifaximin 400 mg tid vs placebo for 10 days in 1:1 ratio in blocks of 4 patients (rifaximin = 43, placebo = 44)	Randomized, DB, PC design; 10-d treatment. 10 wk follow-up	VAS-abdominal pain: 0	VAS-bloating: +, P = 0.010	NA/NR	NA/NR	NA/NR	Overall improvement: +, P = 0.020	VAS-diarrhea: 0, diarrhea common AE
Sharara et al^Citation12	Intestinal gas-related symptoms Rome II Patient not meeting Rome II	Patients: 124, 54% men Treatment: rifaximin 400 mg bid vs placebo Analysis population: History of bloating and/or excessive flatulence for >12 wk and any of the following: chronic abdominal pain or discomfort, disturbances in bowel movements including feeling of incomplete evacuation, or abnormal stool consistency 70 IBS patients met Rome II criteria with 20% IBS-D, 42% IBS-A, 38% IBS-C 54 patients did not meet Rome II criteria	Randomized, DB, PC design; 10 d treatment, 10 d follow-up	NA/NR	+, P = 0.02 NA/NR	NA/NR	NA/NR	NA/NR	Subjective feeling of symptom relief at end of treatment: +, P = 0.03 +, P = 0.04 0; Subjective feeling of symptom relief at end of follow-up: +, P = 0.02 +, P = 0.05	1. Mean symptom score at end of treatment: +, P = 0.03; At follow-up: 0
IBS-D phase II study Lembo et al^Citation13 Ringel et al^Citation14 Pimentel et al^Citation15 Chey et al^Citation16	Rome II	Patients: 388 with IBS-D Treatment: rifaximin 550 mg bid for 14 d vs placebo	DB, multicenter design; 14 d DB treatment, 14 d placebo, followed by 12 wk follow-up	NA/NR NA/NR NA/NR NA/NR	Adequate relief of IBS-related bloating symptoms: At end of treatment: +, P = 0.04; At end of follow-up: +, P < 0.05 and/or In patients with baseline abdominal pain mild-moderate: 0 or severe: 0; Relief of bloating symptoms in patients with baseline bloating mild to moderate: +, P = 0.03, or severe: 0. NA/NR	NA/NR NA/NR NA/NR NA/NR	NA/NR NA/NR NA/NR NA/NR	NA/NR NA/NR NA/NR NA/NR	Adequate relief of global symptoms: At end of treatment: +, P = 0.03; At end of follow-up: +, P < 0.05 and/or Relief of global symptoms in patients with baseline abdominal pain mild-moderate: +, P = 0.04, and severe: 0; Relief of global symptoms in patients with baseline bloating mild to moderate: +, P = 0.006, and severe: 0 NA/NR	NA/NR and/or The most substantial confounders of clinical response were daily bloating, abdominal pain, and use of rescue medications IBS-QOL total score: +, P = 0.02; also +, P < 0.05 for dysphoria, body image, health worry, social reaction, and relationship improvements
Pimentel et al^Citation17 TARGET 1 and TARGET 2 studies^Citation17	Rome II	Patients: 1260 with nonconstipated IBS enrolled in 2 identically designed TARGET 1 (n = 623) and TARGET 2 (n = 637) studies Treatment: rifaximin 550 mg tid vs placebo: TARGET 1 TARGET 2 Total from both trials	Randomized, DB, PC, PG design; 2 wk treatment, 10 wk follow-up	Daily abdominal pain improvement (for at least 2 of first 4 wk after treatment): +, P = 0.02 +, P = 0.02 +, P < 0.001	Defined as for at least 2 of first 4 wk after treatment (weekly assessment): +, P = 0.005 +, P = 0.02 +, P < 0.001	NA/NR	Daily symptoms +, P < 0.001 +, P = 0.01 +, P < 0.001	NA/NR	Defined as relief for at least 2 of first 4 wk after treatment (weekly assessment): +, P = 0.01 +, P = 0.03 +, P < 0.001	Relief of IBS-related abdominal pain and loose or watery stools for at least 2 of first 4 wk after treatment based on daily assessments: +, P = 0.04 +, P = 0.008 +, P < 0.001

Notes:

* According to predominant stool pattern, if available. + Indicates significant improvement over placebo; 0 represents no statistically significant difference between active treatment and placebo. If a study did not report on a particular assessment, it was noted as “not assessed.” If more than one population is assessed for a particular parameter, the populations are numbered (see sample size, type of IBS, dosage, analysis population column); subsequent efficacy values are presented to correspond to the population so designated.

Abbreviations: AE, adverse event; DB, double-blind; IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome with alternating diarrhea and constipation symptom predominance; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; IBS-QOL, Irritable Bowel Syndrome Quality of Life Questionnaire; NA/NR, not assessed or not reported; PC, placebo-controlled; PG, parallel group; SIBO, small intestinal bowel overgrowth; VAS, visual analog scale.

Table 3 Randomized controlled trials of alosetron in irritable bowel syndrome: study characteristics and efficacy outcomes

Study	Diagnostic criteria	Sample size, type of IBS,* dosage; analysis population	Study type and duration	Relief of abdominal pain with or without discomfort	Relief of bloating and/or distension	Effect on stool frequency	Effect on stool consistency	Effect on urgency	Global or overall IBS improvement	Other efficacy assessments
Camilleri et al^Citation18	Rome I	Patients: 370 adults aged ≥ 18 yr with IBS-D or IBS-A; 67% women Treatment: alosetron 1, 2, 4, 8 mg bid vs placebo Analysis population: Women Men	Randomized, DB, PC, dose-ranging, PG design; 12 wk treatment	Relief of pain and discomfort +, for 1 mg bid (P = 0.015) and 2 mg bid (P = 0.023) in women; 0 for 4 or 8 mg bid in women 0, for all dosage strengths in men	NA/NR	All doses: +, P < 0.05 0	All doses: +, P < 0.05 0	All doses: +, P < 0.05 0	NA/NR	NA/NR
Bardhan et al^Citation19	Rome I	Patients: 462 adults aged >18 yr with IBS-D (32.9%), IBS-A (32.3%), IBS-C (31.3%), or IBS other (3.5%), 73% women Treatment: alosetron 0.1, 0.5, 2 mg bid vs placebo Analysis population: Total Women Men	Randomized, DB, PC, PG, design; 12 wk treatment	Mean % of pain-free days (diary cards): 1. 2 mg bid: +, P < 0.05 in wk 5–8 and 9–12 2. 2 mg bid: +, P < 0.05 in wk 9–12 3. 0; VAS for pain and discomfort: + for 2 mg bid, P = 0.04 0 0	NA/NR	Diary cards: 0.5 and 2 mg bid: +, P < 0.05 in wk 1–2 and 9–12 0.5 and 2 mg bid: +, P < 0.05 in wk 1–2 2 mg bid: +, P < 0.05 in wk 1–2	and 0.1, 0.5, and 2 mg bid: +, P < 0.002 in wk 1–2 and 9–12 0.5 and 2 mg bid: +, P < 0.002 in wk 1–2 and 9–12	NA/NR	NA/NR	VAS for diarrhea: 2 mg bid: +, P = 0.03 2 mg bid: +, P = 0.033 0
Camilleri et al^Citation20	Rome I for last 6 mo	Patients: 647 women aged ≥ 18 yr with IBS-D (71%), IBS-A (28%) for ≥ 6 mo; IBS-C (1%) although exclusionary Treatment: alosetron 1 mg bid vs placebo	Randomized, DB, PC, PG design; 12 wk treatment	Proportion with adequate relief of pain and discomfort: Overall: +, 41% alosetron, 29% placebo, CI 4.7–19.2; IBS-D +; IBS-A 0; Weekly results: +, P < 0.05 from wk 2–12; Change in pain severity scores: +, P < 0.05 at mo 2 and 3	NA/NR	+, P < 0.001 each wk, wk 1–12	+, P < 0.001 each wk, wk 1–12	+, P < 0.001 each wk, wk 1–12	NA/NR	NA/NR
Camilleri et al^Citation21	Rome I for last 6 mo	Patients: 626 nonconstipated women aged ≥ 18 yr with IBS-D (71%), IBS-A (27%) for ≥ 6 mo; IBS-C (2%) although exclusionary Treatment: alosetron 1 mg bid vs placebo Analysis population: All patients IBS-D patients	Randomized, DB, PC, PG, design; 12 wk treatment	Proportion with adequate relief of pain and discomfort: Overall: 41% alosetron vs 26% placebo, P < 0.001; CI 7.8–22.5 Overall: 43% alosetron vs 26% placebo, patients were responders for all 3 mo, P < 0.001; For each mo: +, P < 0.05; Weekly with significant benefit achieved by wk 4–12 +, P < 0.01	NA/NR 0	Weekly from wk 1–12 NA/NR +; P < 0.001	Weekly from wk 1–12 NA/NR +, P < 0.001	Weekly from wk 1–12 NA/NR +, P < 0.01	NA/NR NA/NR	No significant differences in alosetron efficacy between IBS-D and IBS-A incomplete evacuation: NA/NR For mo 1: 0; For mo 2: +, P = 0.02; For mo 3: +, P = 0.009
Watson et al^Citation22	Rome I	Patients: 1273 women aged ≥ 18 yr with IBS-D (71%) or IBS-A (27%) for ≥ 6 mo; IBS-C (2%) although exclusionary Treatment: alosetron 1 mg bid vs placebo *Primary efficacy reported in Camilleri et al, 2000 and 2001	Randomized, DB, PC, PG design; 12 wk treatment	See individual trials (Camilleri et al, 2000 and 2001) above	See individual trials (Camilleri et al, 2000 and 2001) above	See individual trials (Camilleri et al, 2000 and 2001) above	See individual trials (Camilleri et al, 2000 and 2001) above	See individual trials (Camilleri et al, 2000 and 2001) above	NA/NR	QOL: across both studies, alosetron resulted in significant improvement in IBS-D +, P < 0.05 on all scales (emotional health, sleep, energy, physical and social functioning, food/ diet, role-physical, and sexual relations), except mental health was improved for Camilleri et al, 2001 only
Lembo et al^Citation23	Rome II	Patients: 801 women aged ≥ 18 yr, nonconstipated with IBS-D (98%) or IBS-A (2%), with lack of satisfactory control of bowel urgency (required to occur on ≥ 50% of days during 2 wk screening) Treatment: alosetron 1 mg bid vs placebo Randomized (2:1 ratio), DB, PC design; 12 wk treatment	NA/NR	NA/NR	Median stool frequency: +, P < 0.001	Median stool consistency: +, P < 0.001	Median proportion of days with satisfactory control of urgency: +, P < 0.001	Proportion of responders: +, P < 0.001 at wk 4, 8, 12	Percentage of days with incomplete evacuation (lower): +, P < 0.001
Wolfe et al^Citation24	Rome I for at least 6 mo	Patients: 859, aged ≥ 18 yr, with IBS-D or IBS-A for ≥ 6 mo, 74% women Treatment: alosetron 1 mg bid vs placebo	Randomized (3:1 ratio), DB, PC design; 48 wk treatment	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	NA/NR	Safety only
Olden et al^Citation25	Rome II	Patients: 801 women aged ≥ 18 yr nonconstipated with IBS-D (98%) or IBS-A (2%) with lack of satisfactory control of bowel urgency (required to occur on ≥ 50% of days during 2 wk screening) Treatment: alosetron 1 mg bid vs placebo	Randomized (2:1 ratio), DB, PC design; 12 wk treatment	See Lembo et al, 2001 above	See Lembo et al, 2001 above	See Lembo et al, 2001 above	See Lembo et al, 2001 above	See Lembo et al, 2001 above	See Lembo et al, 2001 above	Overall satisfaction with treatment 12 wk: 69% alosetron, 45% placebo +, P < 0.001; significantly more patients taking alosetron were satisfied or very satisfied across 11 distinct medication attributes +, P < 0.001
Chey et al^Citation26	Rome I	Patients: 714 women aged ≥ 18 yr with IBS-D (80%) or IBS-A (20%); same patients in Lembo et al, 2001 Treatment: alosetron 1 mg bid vs placebo Analysis population: 1. IBS-D subgroup (n = 569) 2. IBS-D with more frequent urgency (urgency on ≥ 10 d of 14 d screening; n = 417)	Randomized, DB, PC, PG design; 48 wk treatment	48 wk adequate pain and discomfort relief: +, P = 0.01 +, P = 0.005	0 NA/NR	Rate of satisfactory control of stool frequency: +, P = 0.004 +, P = 0.009	Rates of satisfactory control of stool consistency: +, P < 0.014 +, P < 0.012	48 wk average satisfactory control of urgency: +, P < 0.001 +, P < 0.001	NA/NR	NA/NR
Lembo et al^Citation27†	Population A: Rome II Population B: Rome II	Patients: Population A: 492 women aged >18 yr with severe IBS-D (>3 mo of IBS symptoms); 89% IBS-D and 11% IBS-A Population B: 711 women aged >18 yr (257 from Population A and 454 from Lembo et al, 2001) with IBS-D who lacked satisfactory control of bowel urgency ≥ 71% of the time during screening (≥ 10 of 14 d); 95% IBS-D and 5% IBS-A Treatment: alosetron 1 mg bid vs placebo	1. and 2. Randomized, DB, PC design; 12 wk treatment	NA/NR	NA/NR	+, P < 0.001 +, P < 0.001	+; P < 0.001 +, P < 0.001	Satisfactory control of urgency: +, P < 0.001 +, P < 0.001	GIS responders: +, P < 0.001 at wk 4, 8, 12 +, P < 0.001 at wk 4, 8, 12	Sense of incomplete evacuation improved: At 12 wk: +, P = 0.018 For 11 of 12 wk: +; Diarrhea: Similar between treatment groups
Chang et al^Citation28	Rome I	Patients: 662 men aged >18 yr with IBS-D (≥ 6 mo of IBS symptoms) Treatment: alosetron 0.5, 1, 2, or 4 mg bid vs placebo	Randomized, DB, PC, dose-ranging study; 12 wk treatment	Average adequate relief of pain and discomfort in wk 5–12: +, P = 0.04 for alosetron 1 mg bid; 0 for other doses	All doses: 0	All doses: 0	All doses: +, P < 0.001	All doses: 0	NA/NR	Incomplete evacuation: 0 Pain-free days: 0
Krause et al (efficacy and safety)^Citation29 Nicandro et al (QOL)^Citation30	Rome II	Patients: 705 women aged ≥ 18 yr with severe IBS-D (≥ 6 mo of symptoms of IBS) who had failed conventional therapy Treatment: alosetron 0.5 mg qd, 1 mg qd, and 1 mg bid vs placebo	Randomized, DB, PC design; 12 wk treatment	Average adequate relief of pain and discomfort: +, for all 3 alosetron doses at each 4 wk interval (1–4, 5–8, and 9–12), P ≤ 0.038) NA/NR	NA/NR NA/NR	All alosetron doses: +, P ≤ 0.006 for each dose at each 4 wk assessment NA/NR	All alosetron doses: +, P ≤ 0.001 for each dose at each 4 wk assessment NA/NR	At wk 9–12: + for alosetron 0.5 and 1 mg qd, P < 0.05 NA/NR	Proportion of responders for IBS-GIS + for all 3 alosetron doses at wk 12: P ≤ 0.02; at wk 4: P ≤ 0.028; at wk 8: P ≤ 0.009 Overall treatment satisfaction: +, P ≤ 0.003	Normalization of bowel patterns: +, P ≤ 0.004 for all alosetron doses at each 4 wk assessment IBS-QOL questionnaire (9 symptom domains): improvements: +, except for domains of emotional and sleep with alosetron 1 mg qd; physical functioning with alosetron 1 mg qd and 1 mg bid; and sexual relations all alosetron groups; Work productivity time reductions: +, for alosetron 0.5 mg qd (P = 0.02) and 1 mg bid (P = 0.0001)

Notes:

* According to predominant stool pattern, if available.

† Counted as a reanalysis of Lembo et al, 2001. + Indicates significant improvement over placebo; 0 represents no statistically significant difference between active treatment and placebo.

If a study did not report on a particular assessment, it was noted as “not assessed.” If more than one population is assessed for a particular parameter, the populations are numbered (see sample size, type of IBS, dosage, analysis population column); subsequent efficacy values are presented to correspond to the population so designated.

Abbreviations: CI, confidence interval; DB, double-blind; GIS, global improvement scale; IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome with alternating diarrhea and constipation symptom predominance; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; NA/NR, not assessed or not reported; PC, placebo-controlled; PG, parallel group; QOL, quality of life; VAS, visual analog scale.

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VahediHMeratSMomtahenSClinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndromeAliment Pharmacol Ther20082767868418248658

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GreenbaumDSMayleJEVanegerenLEEffects of desipramine on irritable bowel syndrome compared with atropine and placeboDig Dis Sci1987322572663545719

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DrossmanDATonerBBWhiteheadWECognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disordersGastroenterology2003125193112851867

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TalleyNJKellowJEBoycePTennantCHuskicSJonesMAntidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trialDig Dis Sci20085310811517503182

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Abdul-BakiHEl HajjIIElzahabiLA randomized controlled trial of imipramine in patients with irritable bowel syndromeWorld J Gastroenterol2009153636364219653341

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MasandPSPaeCUKrulewiczSA double-blind, randomized, placebo-controlled trial of paroxetine controlled-release in irritable bowel syndromePsychosomatics200950788619213976

 PubMed Web of Science ®Google Scholar

TackJBroekaertDFischlerBVan OudenhoveLGeversAMJanssensJA controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndromeGut2006551095110316401691

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 PubMed Web of Science ®Google Scholar

WatsonMELaceyLKongSAlosetron improves quality of life in women with diarrhea-predominant irritable bowel syndromeAm J Gastroenterol20019645545911232690

 PubMed Web of Science ®Google Scholar

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CheyWDCheyWYHeathATLong-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndromeAm J Gastroenterol2004992195220315555002

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