Efficacy and palatability of the developed polyethylene glycol-based formula for the treatment of children with functional constipation

Abstract

BACKGROUND

Excipients may improve the palatability of polyethylene glycol (PEG), the first-line treatment for childhood functional constipation (FC), leading to good compliance and improved treatment outcomes.

AIM

To compare the developed PEG-based formula (PEG-Chula) to the commercial formula for treating childhood FC.

METHODS

In this randomized controlled trial, we enrolled children aged < 18 years with FC diagnosed by the Rome IV criteria to receive PEG-Chula [four flavors: (1) Strawberry; (2) Lychee; (3) Apple; and (4) Lychee-rose] or Forlax (orange-grapefruit flavor) for eight weeks. The primary outcomes included changes in stool frequency and consistency measured by the Bristol Stool scale. The secondary outcomes were constipation-related symptom improvement, adverse events, and palatability measured by the facial hedonic scale.

RESULTS

Fifty-two children diagnosed with FC [median age: 4.21 (2.33, 7.88) years; 35 (67.31%) females] were enrolled. After the 8-week treatment, the mean weekly stool frequency increased in both groups, the mean change was 4.02 (95%CI: 3.09–4.95) in PEG-Chula and 3.78 (95%CI: 2.79–4.78) in commercial PEG compared to baseline (P < 0.001). The extent of stool consistency improvement did not differ significantly. The most preferred PEG-Chula flavor was rated more palatable than the commercial PEG. Treatment compliance correlated with medication palatability (r = 0.34, P = 0.013). No significant differences in adverse events were found.

CONCLUSION

Both PEG-based formulas are effective and safe for managing pediatric FC.

Key Words: Constipation; Palatability; Compliance; Polyethylene glycol; Children

Core Tip: Functional constipation (FC), a common functional gastrointestinal disorder in children, affects the quality of life of these children and their families. A combination of osmotic laxatives and toilet training is essential for effective management. Although polyethylene glycol (PEG) is recommended as the first-line treatment, poor palatability often limits patient compliance. This randomized controlled trial compared a newly developed PEG-based formula with the commercialized product, with both formulas being effective and safe. A positive correlation between palatability and compliance was established. Improving taste may be the key to enhancing compliance and improving treatment outcomes in children with FC.

INTRODUCTION

Functional constipation (FC) has been identified as the predominant functional gastrointestinal disorder in children, with a global prevalence of 14.4%[1]. In Thailand, the prevalence of FC was approximately 2.4% in children below five years of age[2] and around 8.1% in adolescents[3]. In addition, up to 3% of children coming to general pediatricians’ appointments have constipation as a presenting complaint, whereas this rate significantly rises to 25% among all children visiting pediatric gastroenterologists[4]. Constipation also imposes a substantial financial burden in many countries[5,6] and also takes a toll on the quality of life of children and their families[7].

In recent years, the Rome criteria have been widely used as a helpful tool to detect FC in children. Although the duration of the symptoms was reduced from 2 months in Rome III to 1 month in Rome IV, to facilitate early detection and prompt treatment[8-10], the prevalence of FC in children is unchanged[11]. Fecal retention behavior is regarded as the primary pathophysiology of FC in infants and young children[12,13]. Therefore, the combination of toilet training and osmotic laxatives is the key to achieving treatment goals, which include establishing normal defecation and preventing recurrence[12,14,15].

Osmotic laxatives—including polyethylene glycol (PEG), lactulose, and milk of magnesium hydroxide (MOM) are recommended as the first-line pharmacological intervention according to the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition guidelines[16]. PEG is the preferred option because it has shown superiority in enhancing the frequency of bowel movements and stool consistency and is receiving greater acceptance among children than lactulose or MOM[17,18].

However, the treatment adherence rate with PEG therapy was reportedly 37%[19] and more than 50% of children had issues with its palatability[20]. The association between adherence and the taste and convenience of medicine has been identified. The unpleasant taste leads patients avoiding the medication, especially in the pediatric population[21,22]. Therefore, taste concealment is essential for increasing medication adherence and treatment efficacy in children[22].

Several PEG-based formulas are currently available on the market. However, there is a paucity of high-quality research assessing the comparative efficacy, safety, and acceptance across these PEG-based products because the inactive ingredients, such as flavorings and sweeteners, can potentially improve the taste and compliance and contribute to the improved management of pediatric FC[23]. Therefore, this study aimed to compare the efficacy, safety, and palatability of a developed PEG-based formula (PEG-Chula) with the commercial formula that is available in Thailand for treating childhood FC.

MATERIALS AND METHODS

Study design and population

This double-blind, randomized controlled trial (RCT) was conducted at The Clinical Research Center, Faculty of Medicine, Chulalongkorn University, from May 2024 to February 2025. The study protocol was approved by the Institutional Review Board of Chulalongkorn University (No. 0093/67) and registered at ClinicalTrials.gov (No. NCT06357897).

Children were included in this study when they met the following criteria: (1) Were aged from 6 months to 18 years old; (2) Were diagnosed with FC according to the Rome IV diagnostic criteria; and (3) Consent forms were signed. Written informed consent was obtained from guardians and patients aged over 12 years old, while informed assent was obtained from patients aged 7–12 years, following the Declaration of Helsinki. Children were excluded from the study if they had an organic cause of constipation (e.g., anorectal malformations, Hirschsprung disease, myelomeningocele, hypothyroidism, etc.), suspected gastrointestinal obstruction, received medication affecting bowel movement, had acute cardiac, liver, pulmonary disorder, and had a history of allergy to the medicine used in this study. Children could be withdrawn from the study when their parents/guardians requested treatment discontinuation for any reason.

Randomization and masking

A list of numbers randomly generated using a computer was prepared by another researcher without clinical involvement in the trial. Eligible patients were enrolled in the study. Then, patients were randomly assigned to the PEG-Chula and commercial PEG groups using a block size of 4 and a 1:1 allocation ratio within each block.

The participants and the doctor were blinded to the type of treatment received during the study. To ensure that the participants were blinded to the study medication, they received all sachets in an identical package.

Medication preparation

We developed the PEG-Chula product based on the PEG 4000 Lavage product, which has been used for colonoscopy preparation and patients with constipation at King Chulalongkorn Memorial Hospital for over 30 years. Under pharmacologist consultations, we used a sugar and flavoring approach to improve the taste of the PEG 4000 Lavage product because it does not require extensive equipment or complex manufacturing processes[22].

We performed experiments with various sweeteners that are accepted for use in medicine and food currently available on the market. We chose stevia because of its advantages such as its natural origin, low-calorie nature, the absence of associated spikes in glycemia levels, and safety[24].

In terms of flavor, we concentrated on the flavors that children preferred. After conducting a pilot study with 24 voluntary participants to select the preferred flavors, we decided on four flavors, including apple, lychee, lychee plus rose, and strawberry, for this RCT study.

For the commercial PEG group, we selected the PEG 4000 available in the Thailand market (Forlax containing PEG 4000, orange-grapefruit flavor, and saccharin sodium). The primary investigator prepared both PEG-Chula and Forlax into sachets labeled A, B, C, and D with 5 g or 10 g of PEG 4000. In the PEG-Chula group, label A was designated as strawberry, B as lychee, C as green apple, and D as a combination of lychee and rose flavors. In contrast, in the commercial PEG group, labels A–D all contained the same flavor.

Intervention

Eligible children were enrolled in the study and randomly assigned to receive PEG-Chula or the commercial PEG formula (Forlax) for eight weeks. The PEG 4000 dose was 0.5–1 g/kg/day for children without fecal impaction and 1–1.5 g/kg/day for children with fecal impaction. The children in each group received the PEG formula in identical packages. Children in both groups received counseling on toilet training, water intake, and fiber intake similarly. During the study, parents were instructed not to administer any laxatives to their children, except for the prescribed medication, and not to add medication to other juice to improve the taste.

Procedure

This study had a total of four visits. At visit 1 (day 0), the physician recorded the demographics, stool habits, and clinical features, and then the patients underwent a physical examination, anal position index measurement, and transabdominal ultrasonography (USG). Caregivers and patients received diary books to record the outcomes, including stool habits, compliance, adverse events, toilet training, and dietary intake. The children received medication labeled A, B, C, and D, with a total number of sachets sufficient for one week of treatment.

At follow-up visits, including visit 2 (week 1), visit 3 (week 4), and visit 4 (week 8), the stool output was identified via the patient diary, and caregivers were asked about the adverse events and medication compliance. From visit 2 (week 1) onward, the children received sachets labeled A, B, C, and D in quantities equal to the total number of days until the next visit. This allowed the children to choose their preferred flavor. The flowchart of the study procedure is shown in Figure 1.

Figure 1 Overview of study procedures. USG: Ultrasonography.

Outcomes

The primary efficacy endpoint was improvement in stool frequency and stool consistency during the intervention period. The weekly stool frequency was recorded in patient diaries, while stool consistency was assessed for each bowel movement using the Bristol Stool scale by patients and caregivers[25]. The secondary outcomes were constipation-related symptom improvement, adverse events, and palatability[26]. Besides, compliance was assessed by recording in the diary and counting the remaining sachets. The palatability of the two formulas was evaluated using a 5-point facial hedonic scale in children aged > 4 years. For children aged ≤ 4 years, caregiver assessments were added to rate the medication’s palatability[27]. Parents reported any adverse events that occurred during the eight-week treatment period. Adverse events such as diarrhea, abdominal pain, nausea and vomiting, or bloating and flatulence were documented only if they did not precede the initiation of treatment.

Statistical analysis

The number of participants in this study was calculated based on the repeated measures design formula.

The significance level was set at 0.05, corresponding to Z_1-α/2 = 1.96, while the power was set at 80% (Z_1-β = 0.84). The pooled standard deviation was calculated as 2.85. The number of repeated measurements in the current study was set at 8. The correlation between time points and stool frequency was assumed to be weak, and a value of 0.25 was chosen. We anticipated that the difference in the number of bowel movements between the PEG-Chula and the commercial PEG would not exceed 1.4 times/week[28]. Accounting for a 10% dropout rate, the final sample size required for each group was determined to be 26 children with FC.

The following three study populations were evaluated: (1) The safety population, comprising patients who received at least one dose of the study medication; (2) The intention-to-treat (ITT) population, which includes all patients in the safety population with at least one post-treatment measure of stool frequency and consistency; and (3) The per-protocol (PP) population, consisting of ITT patients without major protocol deviations. The primary efficacy analysis was performed using the ITT population, while the sensitivity analysis was performed using the PP population. Our safety analysis included the safety population.

Data were managed using REDCap electronic data capture tools[29] hosted at the Chula Data Management Center, Faculty of Medicine, Chulalongkorn University.

For the primary outcomes, stool frequency and consistency were compared between the PEG-Chula and Forlax groups using a mixed-effects model for repeated measures. The model included the intervention group as a fixed effect and used an unstructured covariance matrix to account for correlations within repeated measures of the same subject, assuming independence between patients. The results were illustrated graphically to demonstrate weekly trends in outcomes in the different treatment groups.

For secondary outcomes, continuous variables were reported as the mean ± SD for normally distributed continuous data and the median (interquartile range) for non-normally distributed continuous data. To control for type I error due to multiple comparisons, the Bonferroni correction was applied where appropriate. Group comparisons were conducted using independent t-tests for normally distributed continuous data and the Mann-Whitney U test for non-normally distributed continuous data. Categorical variables were presented as frequencies and proportions, with comparisons made using the χ² test or Fisher’s exact test. Statistical analyses were performed using STATA version 18.

RESULTS

Eighty-one children were screened for eligibility, and 52 were randomized to receive either the PEG-Chula or the commercial PEG formula. One child in the commercial PEG group was excluded due to the unavailability of outcome measurements. Additionally, two patients in the PEG-Chula group were also excluded, one due to missing outcome measurements and another due to protocol deviation. Ultimately, 49 patients completed the study (Figure 2).

Figure 2 Flow of study. ITT: Intention-to-treat; PEG: Polyethylene glycol; PP: Per-protocol.

Of the 52 participants, the median age was 4.21 (2.33, 7.88) years, with 25 children (48.08%) aged under 4 years old. Thirty-five children (67.31%) were female. The median weight and height were 16.10 (11.80, 16.85) kg and 99.50 (88.50, 125.30) cm, respectively. The median duration of FC was 19.50 (12.00, 44.00) months. Additionally, 25 children (48.08%) had received prior treatment, including lactulose (n = 20), PEG (n = 5), enemas (n = 8), and bisacodyl (n = 1). Fecal impaction was detected in one child in the PEG-Chula group and two children in the commercial PEG group. The participants’ demographics and baseline features did not differ significantly between the two groups (Table 1).

Table 1 Patient demographics and baseline characteristics (n = 52).

Variables	PEG-Chula(n = 26)	Commercial PEG(n = 26)
Age (years)	4.38 (2.90, 7.00)	3.92 (2.25, 9.91)
Age group (6 months-4 years)	11 (42.30)	14 (53.80)
Sex, males	11 (42.30)	6 (23.10)
Weight (kg)	16.1 (12.20, 25.20)	15.3 (11.50, 30.10)
Height (cm)	101 (90.00, 124.50)	97.75 (84.50, 135.00)
FC in family	15 (57.70)	16 (61.54)
Previous treatment for FC	14 (53.90)	11 (42.30)
Duration of constipation (months)	21 (12, 48)	16.5 (12, 30)
Frequency of defecation (time/week)	1.96 ± 0.58	2.21 ± 0.74
Stool consistency (Bristol Stool scale)	2.31 ± 0.78	2.08 ± 0.82
Painful defecation (Facial Pain scale)	3.65 ± 1.16	3.48 ± 1.01
Clogged toilet for toilet-trained children (n = 42)	13 (59.09)	10 (50.00)
Presence of fecal mass by examination	2 (7.69)	1 (3.85)
Blood coating the stool	11 (42.31)	8 (30.77)
Anal position index
Male	0.51 ± 0.06	0.5 ± 0.05
Female	0.38 ± 0.09	0.37 ± 0.06

Data were presented by mean ± SD, median (interquartile range) or n (%). FC: Functional constipation; PEG: Polyethylene glycol.

Improvement of stool frequency and stool consistency

The mean stool frequency per week at baseline was 1.96 ± 0.58 in the PEG-Chula group and 2.21 ± 0.74 in the commercial PEG group (P = 0.18). After treatment, the mean stool frequency significantly increased in both groups compared to baseline. The improvement of stool frequency was not significantly different in the PEG-Chula group compared to the commercial PEG group in each week (Table 2, Figure 3A).

Figure 3 Stool frequency and stool consistency between 2 groups at each week. A: Stool frequency; B: Stool consistency. PEG: Polyethylene glycol.

Table 2 Improvement of stool frequency and stool consistency.

Variables	PEG-Chula group		Commercial group		Between group
	mean ± SD	Mean change from baseline (95%CI)	mean ± SD	Mean change from baseline (95%CI)	Mean difference (95%CI)	P value
Stool frequency (time/week)
Baseline (n = 52)	1.96 ± 0.58	-	2.21 ± 0.74	-	-	0.181
Week 1 (n = 51)	6.27 ± 2.97	4.31 (3.39-5.23)	6.16 ± 4.35	3.94 (2.95-4.94)	0.36 (-0.99 to 1.72)	0.597
Week 2 (n = 50)	6.20 ± 2.24	4.22 (3.29-5.15)	6.44 ± 3.98	4.22 (3.23-5.22)	-0.01 (-1.36 to 1.35)	0.993
Week 3 (n = 50)	5.92 ± 2.33	3.94 (3.01-4.87)	6.68 ± 3.8	4.46 (3.47-5.46)	-0.53 (-1.88 to 0.83)	0.448
Week 4 (n = 51)	6.08 ± 2.42	4.12 (3.20-5.03)	6.04 ± 3.88	3.82 (2.83-4.82)	0.29 (-1.06 to 1.64)	0.671
Week 5 (n = 51)	6.50 ± 2.67	4.54 (3.62-5.46)	6.20 ± 3.58	3.98 (2.99-4.98)	0.56 (-0.8 to 1.91)	0.420
Week 6 (n = 51)	6.35 ± 2.81	4.38 (3.47-5.3)	7.08 ± 3.5	4.86 (3.87-5.86)	-0.48 (-1.83 to 0.87)	0.488
Week 7 (n = 51)	6.35 ± 2.42	4.38 (3.47-5.3)	6.04 ± 2.91	3.82 (2.83-4.82)	0.56 (-0.79 to 1.91)	0.415
Week 8 (n = 50)	6.00 ± 2.14	4.02 (3.09-4.95)	6.00 ± 3.07	3.78 (2.79-4.78)	0.23 (-1.12 to 1.59)	0.736
Stool consistency
Baseline (n = 52)	2.31 ± 0.78	-	2.08 ± 0.82	-	-	0.30
Week 1 (n = 51)	4.17 ± 1.02	1.87 (1.55-2.18)	3.53 ± 1.15	1.45 (1.12-1.78)	0.41 (-0.04 to 0.87)	0.075
Week 2 (n = 50)	4.70 ± 0.74	2.40 (2.08-2.72)	4.01 ± 0.96	1.93 (1.61-2.26)	0.47 (0.01 to 0.93)	0.045
Week 3 (n = 50)	4.55 ± 0.92	2.24 (1.92-2.57)	3.96 ± 0.87	1.88 (1.56-2.21)	0.36 (-0.10 to 0.82)	0.123
Week 4 (n = 51)	4.65 ± 0.83	2.34 (2.02-2.66)	4.08 ± 0.78	2.00 (1.67-2.32)	0.34 (-0.11 to 0.80)	0.142
Week 5 (n = 51)	4.48 ± 0.54	2.17 (1.85-2.49)	4.15 ± 0.88	2.07 (1.74-2.40)	0.10 (-0.36 to 0.55)	0.675
Week 6 (n = 51)	4.36 ± 0.57	2.05 (1.73-2.37)	4.23 ± 0.79	2.16 (1.83-2.48)	-0.11 (-0.56 to 0.35)	0.650
Week 7 (n = 51)	4.30 ± 0.49	2.00 (1.68-2.31)	4.00 ± 0.88	1.92 (1.59-2.25)	0.08 (-0.38 to 0.53)	0.740
Week 8 (n = 50)	4.18 ± 0.38	1.87 (1.55-2.2)	4.10 ± 0.73	2.02 (1.69-2.34)	-0.14 (-0.60 to 0.32)	0.546

Data are presented by mean ± SD and mean change with 95%CI. PEG: Polyethylene glycol.

Stool consistency at baseline was 2.31 ± 0.78 in the PEG-Chula group and 2.08 ± 0.82 in the commercial PEG group (P = 0.30). After 8-week treatment, the stool consistency was also significantly increased in both groups compared to baseline (P < 0.001). The stool consistency was significantly higher in the PEG-Chula group compared to the commercial PEG group only at week 2 (P = 0.045). No significant differences were observed during the other weeks (Table 2, Figure 3B).

Improvement of related symptoms

Table 3 presents the improvement of related symptoms after the 8-week treatment period. The dose of PEG 4000 administered during the treatment period did not differ significantly between the groups [0.58 (0.39, 0.63) vs 0.6 (0.38, 0.82), P = 0.62]. Patient compliance in the PEG-Chula group [94.17 (88.60, 100)] was higher than that in the commercial PEG group [90.1 (77.67, 98.10)], although the difference was not statistically significant (P = 0.33). The number of days with defecation per week was similar between the two groups (5.19 ± 1.23 vs 4.95 ± 1.54, P = 0.52). Based on the Facial Pain scale, children in the PEG-Chula group showed a greater reduction in pain during defecation compared to those in the control group, although this difference was not statistically significant (-2.41 ± 1.41 vs -1.87 ± 1.29, P = 0.17). Improvement in the related symptoms of constipation, including withholding behaviors, large-diamater stool, fecal incontinence, abdominal pain, appetite loss, and anal fissures, did not differ significantly between the two groups. By the end of the 8-week treatment period, 98% of the children no longer met the Rome IV criteria for constipation, and one child in the commercial PEG group still met the Rome IV criteria (less than 2 defecations per week, stool retention, and large-diameter stool).

Table 3 Secondary outcome measures (n = 52).

Secondary end points	PEG-Chula	Commercial PEG	P value
Dose of PEG 4000 (g/kg) (n = 51)	0.58 (0.39, 0.63)	0.6 (0.38, 0.82)	0.62
Compliance (n = 51)	94.17 (88.60, 100)	90.1 (77.67, 98.10)	0.33
Days with defecations per week (n = 51)	5.19 ± 1.23	4.95 ± 1.54	0.52
Change from baseline of painful defecation (n = 51)	-2.41 ± 1.41	-1.87 ± 1.29	0.17
Withholding behaviours after treatment (n = 40)	3 (15.79)	8 (38.09)	0.161
Large stool diameter after treatment (n = 36)	2 (10.53)	1 (5.88)	11
Fecal incontinence after treatment (n = 6)	1 (20)	0 (0)	11
Abdominal pain after treatment (n = 13)	0 (0)	1 (16.67)	0.461
Bloating/flatulence after treatment (n = 11)	1 (11.11)	0 (0)	11
Appetite loss after treatment (n = 9)	0 (0)	1 (33.33)	0.331
Anal fissure after treatment (n = 22)	3 (25)	1 (10)	0.591
Fulfill Rome IV criteria for functional constipation after treatment (n = 51)	0	1 (4)	0.301
Fecal contents detected by transabdominal ultrasonography (n = 51)	8 (30.77)	7 (28)	0.82

¹Fisher’s exact test.

Data were presented by mean ± SD, median (interquartile range) or n (%). PEG: Polyethylene glycol.

The palatability of the treatment

The median ratings for PEG-Chula with strawberry, lychee, green apple, and lychee-rose flavors were 3.00 (2.50, 4.00), 4.00 (3.20, 5.00), 3.60 (2.60, 4.00), and 4.00 (3.00, 4.00), respectively. In comparison, the commercial PEG formula received a median rating of 3.90 (3.50, 4.10) (Table 4). The palatability rating of the preferred flavor in the PEG-Chula group was higher than that in the commercial PEG formula group (P = 0.004). The lychee flavor of PEG-Chula was the best favorite flavor chosen by 13 (50%) children. Additionally, a statistically significant positive correlation was observed between treatment compliance and medication palatability (r = 0.35, P = 0.013) (Supplementary Figure 1). There was no statistically significant difference in palatability between children aged less than four years and those aged above four years (Supplementary Table 1).

Table 4 Palatability of the polyethylene glycol formula (n = 52).

Intervention group		Palatability	P value
PEG-Chula group	Strawberry	3.00 (2.50, 4.00)	0.12
	Lychee	4.00 (3.20, 5.00)	0.44
	Green apple	3.60 (2.60, 4.00)	0.27
	Lychee-rose	4.00 (3.00, 4.00)	0.80
	Most preferred flavor	4.30 (4.00, 5.00)	0.004
Commercial PEG group	Orange-grapefruit	3.90 (3.50, 4.10)	1

P value: Comparison between each flavor in polyethylene glycol (PEG)-Chula with the commercial PEG group. Data are presented by median (interquartile range). PEG: Polyethylene glycol.

Safety outcomes

Adverse events were reported in 5 (19.23%) patients in the PEG-Chula group and 3 (11.54%) patients in the commercial PEG group (P = 0.7). Since all reported adverse events were mild, no patient discontinued treatment due to the adverse events (Table 5).

Table 5 Adverse events during the intervention period (n = 52), n (%).

Adverse events	PEG-Chula (n = 26)	Commercial PEG (n = 26)
Number of patients who reported adverse events	5 (19.23)	3 (11.54)
Mild	5 (19.23)	3 (11.54)
Moderate	0	0
Severe	0	0
Any adverse events
Diarrhoea	3 (11.54)	2 (7.69)
Abdominal pain	2 (7.69)	1 (3.85)

PEG: Polyethylene glycol.

DISCUSSION

This study investigated a head-to-head comparison between two PEG 4000-based formulas—the commercially available and the locally produced formulas. PEG was recommended as the first-line treatment because it demonstrated superior effectiveness to other osmotic laxatives[16,17]. Selecting a preferred flavor PEG-based formula for children may provide additional benefits in managing constipation[23]. Therefore, our study was based on the hypothesis that the better-tasting flavor of PEG-based formulas could increase treatment adherence and the effectiveness of constipation management in children.

Per the primary outcomes of this study, stool frequency and consistency improved significantly after an 8-week treatment period. The PEG-Chula was non-inferior and non-superior compared to the commercial PEG formula. At each week, although the stool frequency and consistency in the PEG-Chula group were higher than those in the control group, the differences may not be clinically meaningful. Besides, there were no significant differences in the improvement of symptoms associated with constipation. The dose of PEG 4000 did not differ significantly between the two formulas.

An RCT comparing PEG 4000 without electrolytes and PEG 3350 plus electrolytes showed that children in the PEG 4000 group had superior stool frequency improvement than those in the PEG plus electrolyte group (9.20 ± 3.20 vs 7.80 ± 2.40, P = 0.025). Besides that, the PEG 4000 formula had a better taste than PEG 3350 plus electrolyte (P < 0.001), and the compliance with PEG 4000 was also higher than that with PEG 3350 plus electrolyte[28]. However, in this study, parents of children in the PEG 4000 group were allowed to dissolve the medication in other fluids to improve its taste, and the study outcomes were not adjusted for potential confounders such as sex, age, or medication palatability.

Conversely, the study conducted by Llerena et al[30] also showed that the change in stool frequency and stool consistency did not differ significantly between PEG 4000 and PEG 3350 plus electrolytes. However, to increase compliance in children, parents could dissolve the medication in a different beverage to improve acceptance in both groups. Although the active ingredient used in both studies was the same, the acceptance of children played an important role in the outcomes. These findings suggested that the better palatability formula may have superior efficacy due to increased acceptance and compliance in children.

In our study, there were no significant differences in the palatability of strawberry, lychee, green apple, and lychee-rose in the PEG-Chula group compared to the orange-grapefruit flavor in the control group. However, the rating palatability of the most preferred formula in PEG-Chula was higher than that in the commercial PEG group (P = 0.004). In our study, we observed a weak correlation between treatment compliance and medication palatability (r = 0.35, P = 0.013). This finding suggests a potentially important trend, as poor palatability can negatively affect adherence, while good palatability has been demonstrated to improve compliance[31,32]. A palatable formula may enhance adherence in long-term treatment settings[33]. Although a trend toward better compliance was found in the PEG-Chula [94.17 (88.60, 100) vs 90.1 (77.67, 98.10), P = 0.33], the two groups had the same treatment efficacy. This may be explained by the fact that, in this study, we provided education and compliance reinforcement for guardians. However, in real clinical practice, guardians may be less motivated to adhere to treatment compared to what happens in a controlled clinical trial setting. Notably, cross-sectional studies have demonstrated that the adherence rate to PEG therapy among children with constipation is approximately 30%–40%. Additionally, treatment satisfaction and convenience were found to be associated with compliance in children[19,34].

After eight weeks of treatment, although none of the children exhibited clinical signs of fecal impaction, transabdominal USG detected fecal contents in 8 (30.70%) children in the PEG-Chula group and 7 (28%) children in the commercial PEG group. This finding suggests that the assessment of fecal contents using transabdominal USG could serve as a more sensitive and objective marker to diagnose stool retention in children than abdominal palpation alone. This raises the question of whether fecal contents and rectal diameter detected by transabdominal USG can be utilized as a biomarker for monitoring treatment response or predicting long-term outcomes in pediatric constipation[35,36]. Further studies are warranted to evaluate the diagnostic accuracy and prognostic value of USG assessment in this context.

We observed some adverse events during the 8-week treatment period. The rate of adverse events did not differ significantly between the two groups [5 (19.23%) vs 3 (11.54%)], and all of them were mild. Consistent with findings from other studies, the most commonly reported adverse symptoms associated with PEG were diarrhea or abdominal pain[28,33].

To the best of our knowledge, this is the first study conducted to evaluate the role of inactive ingredients, such as flavor and sweeteners, in PEG 4000 formulas for treating childhood FC. The findings of this study encourage pediatric centers and pharmaceutical companies to develop locally produced PEG formulas with flavors preferred by children in specific regions, potentially optimizing treatment adherence and effectiveness in the management of pediatric FC.

However, this study has some limitations that should be acknowledged. First, although we tried to standardize the external appearance and labeling of both interventions to ensure a double-blind design, some caregivers could still detect differences in smell and taste if they deliberately sampled the medication before administering it to the child. This may have introduced bias in the perception of treatment effectiveness or adherence. Second, we enrolled children across a wide age range (6 months to 18 years), and the relatively small sample size resulted in variability in flavor preferences among different age groups, and the study may be underpowered to detect significant differences in secondary outcomes. Third, while this study assessed short-term efficacy and tolerability, the long-term adherence and effectiveness were not fully explored. Further studies with larger sample sizes, extended follow-up periods, and stricter control of confounders are needed to validate our findings and provide a more comprehensive understanding of the impact of flavoring agents and sweeteners in PEG-based pediatric FC treatments.

CONCLUSION

Both PEG-based formulas are effective and safe in the management of pediatric FC. Palatability aligned with child preference is the key to improving compliance in clinical practice. Therefore, exploring multiple flavor options with the same active ingredient is essential to identifying the most appealing taste for children, ensuring better compliance and reducing their boredom with taking medication daily during long-term treatment.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to the Maha Chakri Sirindhorn Clinical Research Center under the Royal Patronage and Clinical Sciences program, Faculty of Medicine, Chulalongkorn University, for their invaluable support. We are especially thankful to Samsung Thailand for generously providing the ultrasound machine used in this study, and to Insent Company for their assistance in taste testing the formulas. We are also deeply thankful to Assoc. Prof. Rossarin Tansawat and Assoc. Prof. Warangkana Warisnoicharoen for their expert consultation and guidance in developing the polyethylene glycol-Chula formula, and Dr. Yuda Chongpison for her statistical analysis consultation. In addition, we gratefully acknowledge the contributions of our research team—Mr. Santirat Sopee, Ms. Arisa Ama, Ms. Nittikarn Pinyoying, and Ms. Pakpine Phunnoi for their dedication and assistance in data collection.