Functional constipation in children: What physicians should know

Table 6 Characteristics of randomized controlled trials assessing the effects of herbal medications in children with constipation

Ref.	Country	Age (yr)	Study design	No. case (intervention/ control)	Intervention protocol	Probably pharmacological effect of herbal medicine	Duration of treatment/follow-up/end point and outcome measurement	Treatment effect
Esmaeilidooki et al[99], 2016	Iran	2-15	Open label, RCT, single center	109 (52/57)	CFE 1 mL/kg per day in three-divided doses (equivalent to 0.1 g of dried pulp of fruits of Cassia fistula). PEG 0.7-0.8g/kg per day	Phenolic antioxidants such as flavonoids, flavan-3-ol derivatives and anthraquinones: Stimulant laxative	Treatment for 4 wk. Primary outcome: Frequencies of defecation, severity of pain, consistency of stool, fecal incontinence and retentive posturing. Secondary: The safety and compliance of therapy	After 4 wk: 86.5% of children in CFE group and 77.1% in PEG group exited from the criteria of FC (RR = 1.121, CI95%: 0.939-1.338). Frequency of defecation that in CFE group (10.96 ± 5.7 stools per week) was significantly more than PEG group (6.9 ± 3.5 stools per week) (P < 0.001). No serious adverse effects in both groups (25% diarrhea and 3.8% abdominal pain)
Cai et al[161], 2018	China	1-14	Double-bline RCT, multicenter	480 (120/360)	XEBT: (1) 1-3 years old: 2.5 g, 3 times a day; (2) 4-6 years old: 5 g, 2 times a day; and (3) > 7 years old: 5 g, 3 times a day. Placebo	Seven herbs (Houpo contains magnolol, JueMingZi contain anthraquinones, LuHui contains reactive Aloe-emodin, BaiZhu contains Atractylodes japonica, LaiFuZi, XingRen, ZhiQiao): Promote small bowel peristalsis and work against atropine-induced small intestine suppression in mice	Treatment for 14 daysPrimary outcome: Frequency of SBM for 14 d. Secondary outcomes: Effectual time of defecation, mean symptom scores, disappearance rate of symptoms, recurrence rate and safety outcomes	The mean value of SBM for 14 d were 8.89 and 5.63 in the XEBT and placebo group (P < 0.05). The median effectual time of defecation, main symptom score and disappearance rate of symptoms were significant improved in XEBT group without the significant minor adverse effects between groups
Dehghani et al[101], 2019	Iran	4-12	Double-blind RCT, single center	92 (45/47)	BSM (sugarcane extract) 1 mL/kg per day. PEG 1 g/kg per day	The BSM naturally contained polyphenols (960 μg/mL), potassium (12430 μg/mL), iron (10 μg/mL), calcium (3320 μg/mL), zinc (22 μg/mL), sucrose (296000 μg/mL), triterpenoids (11230 μg/mL), phytosterols (7 μg/mL), flavonoids (2 μg/mL and polysaccharides (1250 μg/mL): Polysaccharide act as bulk forming agent, flavonoids/phytosterols and polyphenolic compounds act as natural antioxidants and anti-inflammatory agents	Treatment for 4 wk: Primary outcome: Response rate improvement in frequency of defecations per week, absence of lumpy or hard stools, abdominal pain and retention, soiling and blood-stained stool, sensation of anorectal obstruction/blockage. Secondary outcome: Patients’ body weigh was measured in every visit and serological parameters (count blood cells, BUN, creatinine, calcium, phosphorus, sodium and potassium)	Defecation per week was significantly improved in both groups. Symptoms including volitional stool retention, large diameter stool, painful or hard stool and large fecal mass in the rectum decreased significantly two and four weeks after intervention (P < 0.05). No significant difference between the groups. No adverse effects were observed
Qiao et al[102], 2021	China	4-14	Double-blind RCT, multicenter study	200 (100/100)	Mixture of 12 herbs1 (XiaojiDaozhi Decoction) and placebo (5% drug ingredients and 95% dextrin). All received fiber 20 g per day and toilet training)	12.5% Raphanus sativus L. (facilitating intestinal motility), 8.33% Areca catechu L. (stimulating gastrointestinal cholinergic receptor), 6.67% Fructus aurantll immaturus (stimulate gastrointestinal smooth muscle), Citrus aurantium L. (stimulate gastrointestinal smooth muscle), 6.67% Crataegus pinnatifida (stimulate gastrointestinal smooth muscle), Magnolia officinalis Rehd (stimulate gastrointestinal smooth muscle), Cannabis sativa L. (moistening the bowel and purging the stools), Atractylodesmacrocephala Koidz. (stimulate gastrointestinal smooth muscle), Semen armeniacae amarum (purgative effect), Paeonia lactiflora Pall, Radix et rhizoma rhei, (purgative stool)0 and honey (moistening the bowel and purgative effect)	Treatment for 8 wk and follow-up for 12 wk. Primary outcome: Complete SBM (≥ 3 per week) and satisfaction with bowel function. Secondary outcome: Safety and adverse effect (blood measurement of liver and kidney function and lead level)	After 8 wk: 56% of CHM group and 25% of placebo satified with bowel movement (P < 0.05). 40% of CHM group and 19% of placebo had complete spontaneous bowel movement (P < 0.05). No serious adverse effects in both groups
Tavassoli et al[162], 2021	Iran	4-10	Open label RCT, single center	133 (66/67)	Viola flower syrups 5 mL, 3 times a day. PEG 4000 1 g/kg per day	Viola flower contains crude methanolic extract, butanolic and aqueous extracts the stimulate gastrointestinal motility	Treatment 4 wk. Primary outcome: Response off treatment (ROME III criteria). Secondary outcome: Stool consistency, defecation frequency, hard stools, painful defecation, fecal retention, and fecal soiling	Both groups demonstrated significant improvement in stool consistency, number off defecation, hard stool, painful defecation, fecal retention and fecal soiling at the end of the study compared to baseline (P < 0.001). No significant difference was observed between the two groups at baseline or at the end of the study (P > 0.05)
Nasri et al[163], 2021	Iran	2-15	Open-lable RCT	120 (60/60)	LaxaPlus Barij Syrup 1 mL/kg divided into 3 doses. PEG 0.7 g/kg	NA	Treatment and follow-up 8 wk. Primary outcome: Stool consistency, number of defecations, intensity of pain, fecal incontinence. Secondary outcome: Satisfaction rate	After 8 wk follow-up: Bowel movements in the intervention group was significantly higher than in the control group (P < 0.05). Pain intensity, and abdominal pain in the group LaxaPlus Barij® decreased significant than control group. No different about satisfaction rate between 2 group
Saneian et al[103], 2021	Iran	2-15	Double-blind RCT	60 (30/30)	Goleghand (including honey and Rosa damascene) 0.5 g/kg in three divided dose. PEG: 0.7 g/kg	NA	Treatment and follow-up 8 wk. Primary outcome: The number and consistency of stools per day, painful defecation, abdominal pain, and fecal incontinence. Secondary outcome: Adverse effects and parental satisfaction	After 8 wk: The number of fecal defecations in Goleghand group was higher than PEG (P < 0.05). The decrease of defecations after following was more significant in the PEG group than in the Goleghand® group (P = 0.001). Parental satisfaction scores did not change in either group (P > 0.05)
Imanieh et al[104], 2022	Iran	1-18	Double-blind RCT	100 (50/50)	Rosa damascena + brown sugar 1-2 mL/kg (1 mL composed of 0.1 g damask rose and 0.85 g brown sugar). PEG 1-2 mL/kg. All received high fiber diet and hydration	Damask rose: Osmotic laxatives and prokinetic effect. Brown sugar: Osmotic laxatives effect. Possible active ingredients might be phenolic compounds and aqueous fraction (terpenes, glucosides, flavonoids, anthocyanins, kaempferol and quercetin)	Treatment and follow-up 4 wk. Primary outcome: the effective of herbs with PEG. Secondary outcome: Adverse effects	After 4 wk: The cure rate was 100% in the R. damascena group and 91.7% in the control group. Adverse effect of intervention group was the taste which was too sweet

¹LaxaPlus Barij^® Syrup- an herbal medicine that includes jujube, rose, asparagus, violet flower, borage, quince seeds, and Cordia myxa fruit. CFE: Cassia fistula emulsion; PEG: Polyethylene glycol; FC: Functional constipation; RR: Risk ratio; RCT: Randomized controlled trial; XEBT: Xiao’er Biantong granules; SBM: Spontaneous bowel movements; BSM: Black strap molasses; BUN: Blood urea nitrogen; CHM: Chinese herbal medicine.