. 2021 Oct 30;27(4):495–512. doi: 10.5056/jnm20210

Table 4.

Adverse Effects of Laxatives From Randomized Controlled Trials

RCTs	Comparison	Intervention	Duration	Adverse events	Drop out
Intra-class comparisons
Ewerth et al¹⁸ (1980), Sweden	Bulk vs Placebo	A: Psyllium 6 g bid B: Placebo	8 wk	Less AEs during bulk laxative treatments Mild abdominal pain and flatulence during placebo	10% (1/10)
Finlay¹⁹ (1988), UK	Bulk vs Placebo	A: Bran 1.5-4.5 g qd B: Regular diet	6 wk	One patient reported difficulty in swallowing bran	14.3% (2/14) (one due to swallowing difficulty and the other due to refusal of bran)
Rajala et al²⁰ (1988), Finland	Bulk vs Placebo	A: Yoghurt + bran 150 mL bid B: Yoghurt bid	2 wk	No significant changes were observed in blood glucose, serum cholesterol or triglyceride, body weights or fecal pH values in either group	Not described
Cheskin et al²¹ (1995), USA	Bulk vs Placebo	A: Psyllium 6 g qid B: Placebo	4 wk	No difference between groups	30.0% (3/10) (cannot tolerate the repeated perfused catheter for anorectal manometry)
Chokhavatia et al²² (1988), USA	Bulk vs Bulk	A: Calcium polycarbophil 2 g qd B: Psyllium 9.5 g qd	3 wk	Not described	7.0% (3/42) (all unrelated to the study medication)
Wesselius-De Casparis et al²³ (1968), Netherland	Osmotic vs Placebo	A: Lactulose 15 mL qd B: Placebo	3 wk	The only AEs sometimes observed was transient gas formation and intestinal bloating	Not described
Sanders²⁴ (1978), USA	Osmotic vs Placebo	A: Lactulose 30 mL qd B: Placebo	12 wk	No adverse clinical and laboratory effects in both groups Results of blood and urine laboratory tests were within normal limits	10.6% (5/47)
Vanderdonckt et al²⁵ (1990), Belgium	Osmotic vs Placebo	A: Lactitol 20 g qd B: Placebo	4 wk	All reported adverse effects were abdominal symptoms, such as bloating and flatulence, compatible with the administration of a non-absorbable sugar	8.7% (4/46)
Dipalma et al²⁶ (2007), USA	Osmotic vs Placebo	A: PEG 3350 17 g qd B: Placebo	6 mo	No treatment emergent safety differences betweenPEG and placebo over the course of the 6-mo study except for gastrointestinal complaints (PEG 39.7%, placebo 25%)^a Most of these events were mild or moderate. There were no clinically significant laboratory changes	0.7% (2/306) (randomization error, noncompliance)
Lederle et al²⁷ (1990), USA	Osmotic vs Osmotic	A: Lactulose 30-60 mL qd B: Sorbitol 30-60 mL qd	4 wk	There were no significant differences between sorbitol and lactulose in any outcome measured except nausea, which increased with lactulose^a	3.2% (1/31 while receiving lactulose)
Seinelä et al²⁸ (2009), Finland	Osmotic vs Osmotic	A: PEG 4000 without electrolyte 12 g qd B: PEG 4000 with electrolyte 12 g qd	4 wk	All AEs: 7 (23.3%) patients in the PEG without electrolyte vs 6 (18.8%) in the PEG with electrolyte group (NS) Serious AEs: 0 patients in PEG without electrolyte vs 3 (9.3%) in PEG with electrolyte group (hospitalization due to hypotension, congestive heart failure, and myocardial infarction) Significant difference in plasma sodium level: 138.8 mEq/L → 137.7 mEq/L in PEG without electrolyte vs 138.6 mEq/L → 138.9 mEq/L in PEG with electrolyte.^a However, none were considered to be clinically significant and none led to intervention	3.3% in PEG without electrolyte group (1/30, for personal reason) 6.3% in PEG with electrolyte group (2/32, 1 due to AE, 1 for personal reason)
Chassagne et al²⁹ (2017), France	Osmotic vs Osmotic	A: PEG 4000 10-30 g qd B: Lactulose 10-30 g qd	6 mo	No clinically relevant or statistically significant changes in the proportion of patients with abnormal values between PEG 4000 and lactulose at Month 6 At least one AEs: 64 (50.4%) patients in lactulose vs 67 (56.8%) in PEG 4000 (NS) Serious AEs: 16 (12.6%) patients in lactulose vs 24 (20.3%) in PEG 4000 (NS) AEs that led to permanent discontinuation: 8 (6.3%) patients in lactulose vs 3 (2.5%) in PEG 4000 (NS)	34.6% (44/127) in lactulose group 24.6% (29/118) in PEG 4000 group
Stern 1966, USA	Stimulant vs Placebo	A: Prucara (162 mg prune concentrate and 162 mg cascarin) 2 tablets bid B: Placebo	3 wk	Watery stool in 1 treated patient (4%, 1/25)	Not described
Hyland and Foran³⁰ (1968), UK	Softener vs Placebo	A: DSS 100 mg tid B: Placebo	4 wk	Not described	13.0% (6/46, 5 unrelated deaths, 1 patient could not tolerate placebo tablet)
Fain et al³¹ (1978), USA	Softener vs Softener	A: DSS 100 mg qd B: DSS 100 mg bid C: DCS 240 mg qd	3 wk	No adverse effect was seen in 3 groups No laboratory abnormalities	2.0% (1/47)
Inter-class comparisons
Kinnunen and Salokannel³² (1987), Finland	Bulk vs Osmotic	A: Magnesiumhydroxide 25 mL qd B: Bulk laxative 8.7 g qd	8 wk	Serum magnesium 2.92 mEq/L in a patient with impaired renal function and 2.74 mEq/L in a patient with normal creatinine but lowered creatinine clearance after the magnesium hydroxide treatment	5.1% (3/59, 3 unable to swallow bulk laxative)
Kinnunen et al³³ (1993), Finland	Bulk + Stimulant vs Osmotic	A: Agiolax 20 mL qd B: Lactulose 30 mL qd	5 wk	No adverse effects and changed in laboratory parameters in both treatments	20.0% (6/30) (1 myocardial infarction, 1 fatal pneumonia in Agiolax group, 1 weakening of general condition and 1 ineffectiveness of medication in lactulose group, 2 referrals to other hospitals)
Passmore et al³⁴ (1993), UK	Bulk+Stimulant vs Osmotic	A: Agiolax 10 mL qd B: Lactulose 15 mL bid	2 wk	24 (31.2%) with Agiolax group and 21 (27.3%) with lactulose group (NS). Flatulence, urgency, and cramps were the most common AEs	9.4% (8/85) (3 withdrawn after first treatment period, 3 unacceptable compliance, 1 deteriorating health, and 1 incomplete data)
Pers and Pers³⁵ (1983), Sweden	Bulk + Stimulant vs Bulk + Stimulant	A: Agiolax 1 sachet qd (15 mg senna) B: Lunelax 1 sachet qd (25 mg senna)	2 wk	No AEs were seen with either of the preparations	5.0% (1/20) (severe diarrhea not related with the medication)
Novel medications
Camilleri et al³⁶ (2009), USA and Belgium	Prucalopride vs Placebo	A: Placebo B: Prucalopride 0.5 mg qd C: Prucalopride 1 mg qd D: Prucalopride 2 mg qd	4 wk	Serious AEs: A: 0 B: 2 (moderate diarrhea and urinary tract infection) C: 0 D: 0 Discontinuation due to AEs: A 0 B 3 (nonsustained ventricular tachycardia, 2 cases as above) C 1 (death d/t lobar pneumonia) D 0 QTc prolongation: A 1 B 1 C 1 D 0	A 22.2% (4/18, 2 other reason, 2 withdrawal of consent) B 14.3% (3/21, 3 due to AEs) C 12.5% (3/24, 1 due to AEs, 1 withdrawal of consent, 1 noncompliance) D 7.7% (2/26, 1 other reason, 1 withdrawal of consent)
Müller-Lissner et al³⁷ (2010), Germany and Belgium	Prucalopride vs Placebo	A: Placebo B: Prucalopride 1 mg qd C: Prucalopride 2 mg qd D: Prucalopride 4 mg qd	4 wk	Total AEs: A 44.4% B 48.7% C 38.7% D 47.5% Severe AEs: A 1 (“arrythmia” and “myocardial infarction” considered not related to the medication) B 1 (“mild drug abuse”) C 0 D 1 (fracture of the left forearm) Discontinuation due to AEs: A 2.9% (2/70) B 2.6% (2/76) C 5.3% (4/75) D 8.8% (7/79)	A 10.0% (7/70) B 9.2% (7/76) C 10.7% (8/75) D 13.9% (11/79)
Ueno et al³⁸ (2006), USA	Lubiprostone vs Placebo	A: Lubiprostone 24 mcg bid B: Placebo	4 wk	AE incidence rates A 12 (46.2%) B 19 (61.3%) (NS)	Not identified
Nakajima et al³⁹ (2019), Japan	Elobixibat vs Placebo	A: Elobixibat 10 mg qd B: Placebo	52 wk	Abdominal pain Patients < 65 yr: 81 (26%) Patients ≥ 65 yr: 1 (4%)^a Diarrhea Patients < 65 yr: 47 (15%) Patients ≥ 65 yr: 3 (12%) (NS)	Not identified
Menees et al⁴⁰ (2020), USA	Plecanatide vs Placebo	A: Placebo B: Plecanatide 3 mg qd C: Plecanatide 6 mg qd	12 wk	Proportions of AEs: A 24.7%, B 35.3%, C 31.9% Proportions of Serious AEs: A 1.9%, B 2.0%, C 1.4%	A 4.3%, B 6.7%, C 7.3%

^aP < 0.05.

bid, 2 times a day; qd, once a day; AEs, adverse effects; RCTs, randomized controlled trials; PEG, polyethylene glycol; mEq/L, milliequivalent per liter; QTc, corrected QT interval.