Table 5.

Recommendations and Evidence of Drugs/Probiotics Suggested for Chronic Constipation According to the Different Guidelines

	European GL	French GL	Spanish GL	Korean GL
Osmotic laxatives	Positive effect, PEG is superior to lactulose. ● Evidence: Strong ● Recommendation: Strong ● Agreement:100% Lactulose is effective ● Evidence: Low ● Recommendation: Weak ● Agreement:100%	Positive effect as first line therapy ● Level II, Grade B ● Magnesium. Positive effect ● Level I, Grade A ● PEG is more effective than lactulose ● Level I, Grade A	PEG is recommended ● Evidence: Moderate ● Recommendation: strong ● Lactulose is recommended ● Evidence: Low ● Recommendation: Strong ● PEG is preferred over lactulose ● Evidence: Moderate ● Recommendation: weak	Magnesium. Positive effect, even if there are few studies ● Evidence: C ● Recommendation: 1 ● Experts’ agreement: completely agree: 57.1%, mostly agree: 39.3%, partially agree: 3.6% Magnesium: careful attention in patients with impaired renal function for the risk of hypermagnesemia. ● Evidence: C ● Recommendation: 1 ● Experts’ agreement: completely agree: 44.4%, mostly agree: 51.9% partially agree: 3.7% Positive effect of nonabsorbable carbohydrates, such as sorbitol and lactulose. ● Evidence: B Recommendation: 1 ● Experts’ agreement: completely agree: 53.9%, mostly agree: 46.1% Long-term administration of nonabsorbable carbohydrates is allowed because serious adverse reactions are rare. ● Evidence: A ● Recommendation: 1 ● Experts’ agreement: completely agree: 39.3%, mostly agree: 60.7% Positive effect also in elderly patients. ● Evidence: C ● Recommendation: 2 ● Experts’ agreement: completely agree: 10.7%, mostly agree: 82.2%, partially agree: 7.1% Positive effect of PEG ● Evidence: A ● Recommendation: 1 ● Experts’ agreement: completely agree: 73.1%, mostly agree: 26.9% In long-term administration of PEG serious adverse reactions are rare. ● Evidence: A ● Recommendation: 1 ● Experts’ agreement: completely agree: 50.0%, mostly agree: 50.0% PEG have positive effect also in elderly patients Evidence: C ● Recommendation: 2 ● Experts’ agreement: completely agree: 23.1%, mostly agree: 69.2%, partially agree: 7.7%
Bulking agents	Positive effect as first line therapy, soluble fibers, as psyllium, are preferred to insoluble ones, because of less adverse events ● Evidence: Moderate ● Recommendation: Strong ● Agreement:100%	Positive effect as first line therapy ● Level II, Grade B	Positive effect. Psyllium is suggested as a first line treatment ● Evidence: Low ● Recommendation: weak Methylcellulose is recommended as an alternative ● Evidence: Low ● Recommendation: Strong	Positive effect as first line treatment. ● Evidence: A ● Recommendation: 1 ● Experts’ agreement: completely agree: 70.4%, mostly agree: 29.6% Bulking agents can be effective in patients with inadequate fiber intake. ● Evidence: C ● Recommendation: 2 ● Experts’ agreement: completely agree: 15.4%, mostly agree: 80.8%, partially agree: 3.8%
Lubricant laxatives	NA	Positive effect as second line therapy ● Level III, Grade C	Positive effect of paraffin oil and docusate sodium ● Experts recommendation	NA
Stimulant laxatives	Positive effect. Bisacodyl is well-tolerated ● Evidence: Moderate ● Recommendation: Strong ● Agreement:100% Sodium picosulfate is efficacious and well tolerated ● Evidence: Moderate ● Recommendation: Strong ● Agreement:100% Anthraquinones are effective ● Evidence: Low ● Recommendation: Weak ● Agreement:100% Anthraquinones are well tolerated ● Evidence: Moderate ● Recommendation: Weak ● Agreement:100%	Positive effect as second line therapy ● Level II, Grade B They can be proposed if patients have not had stools for several days ● Level III, Grade C	Positive effect, recommended as rescue therapy ● Evidence: Moderate ● Recommendation: Strong Their use is suggested in patients who have not responded to bulking and osmotic laxatives ● Evidence: Moderate ● Recommendation: weak	Positive effect as second line therapy. ● Evidence: B ● Recommendation: 2 ● Experts’ agreements: completely agree: 22.2%, mostly agree: 70.4%, partially agree: 7.4%
Local laxatives	Positive effect of rectal suppositories and rectal enemas ● Evidence: Low ● Recommendation: Strong ● Agreement:100%	Positive effect. CO2 releasing suppositories are a first line approach in outlet obstruction constipation and in association with biofeedback ● Level I, Grade A	Positive effect of cleansing enemas, commercial enemas and/or glycerol or bisacodyl suppositorie. ● Expert recommendation	Positive effect of enemas. ● Evidence: C ● Recommendation: 2 ● Experts’ agreement: completely agree: 21.4%, mostly agree: 60.7%, partially agree: 10.7%, mostly disagree:3.6% and not expressed opinion: 3.6% Enemas should be used carefully because there are no standardized guidelines, and it may cause complications ● Evidence: C ● Recommendation: 2 ● Experts’ agreement: completely agree: 42.3%, mostly agree: 38.4%, partially agree: 15.4%, completely disagree: 3.9%
Prokinetics	Positive effect as second line treatment of prucalopride ● Evidence: High ● Recommendation: Strong ● Agreement:100% Acetylcholinesterase inhibitors (distigmina, neostigmina) exert prokinetics effect on gut, but they are currently not used in constipation therapy ● Evidence: Moderate ● Recommendation: Weak ● Agreement:100% Peripherally Acting µ-Opioid Receptor Agonists (PAMORA) are effective in the management of opioid induced chronic constipation ● Evidence: High ● Recommendation: Strong ● Agreement:100% PAMORA may potentially be effective, also in constipation not caused by opioids ● Evidence: Low ● Recommendation: Weak ● Agreement:100%	Positive effect. Prucalopride (2mg/day) is indicated as second line both in women and also men ● Level I, Grade A	Positive effect. Prucalopride is a treatment option in women ● Evidence: Moderate ● Recommendation: weak	Positive effect of Prucalopride (2mg/day) ● Evidence: A ● Recommendation: 1 ● Experts’ agreement: completely agree: 57.7%, mostly agree: 42.3%
Secretagogues	Positive effect as second line treatment. Linaclotide is effective and safe in the chronic constipation and IBS-C. Lubiprostone is also effective, but has limited availability in Europe ● Evidence: High ● Recommendation: Strong ● Agreement:92%	Not available in France when guidelines had been published ● No practical recommendations	When guidelines had been published Lubiprostone was not marketed in Spain and Linaclotide was approved in Spain only for the treatment of irritable bowel syndrome with constipation (IBS-C)	Positive effect of Lubiprostone ● Evidence: A ● Recommendation: not applicable ● Experts’ agreement: completely agree: 29.2%, mostly agree: 58.3%, partially agree: 4.2% and not expressed opinion: 8.3% Linaclotide, may be effective in patients refractory to conventional laxatives. ● Evidence: B ● Recommendation: not applicable ● Experts’ agreement: completely agree: 7.2%, mostly agree: 71.4%, partially agree: 14.3%, and not expressed opinion: 7.1%
Modulation of microbiota (microbiota transfer or probiotics)	Insufficient evidence to recommend fecal microbiota transfer or probiotics for routine treatment of functional constipation, (even if some positive effects were described) ● Evidence: Low ● Recommendation: Weak ● Agreement:100%	Not positive not negative effect of probiotics, not recommended Expert Recommendation	NA	Positive effect of probiotics in conjunction with other drugs. ● Evidence: C ● Recommendation: 2 Experts’:agreement completely agree (14.8%), mostly agree (63.0%), partially agree (18.5%), mostly disagree (3.7%)

Abbreviation: NA, not assessed.