Table 1.

Characteristics of included studies and quality assessment results

Author/Year	Country	Type of study	Population	Total Patients (n)	Age	Intervention arm(s)/N	Control arm/N	Outcome	Adverse events
Bortolotti, M/2000	Italy	RCT	Patients affected by achalasia with an esophageal diameter of < = 5 cm	14	Mean age, 41 years; age range, 21–64 years	A 50-mg tablet of sildenafil	Placebo	Sildenafil inhibits the contractile activity of the esophageal musculature of patients with achalasia, decreasing lower esophageal sphincter tone and residual pressure as well as contraction amplitude.	No side effects were observed, except for headache in one case.
Bortolotti, M/2001	Italy	RCT	Healthy subjects	16	34 years, age range 22–56	A 50-mg tablet of sildenafil	Placebo	Sildenafil markedly inhibits the motor activity of the esophageal musculature by decreasing LES pressure, wave amplitude, and propagation velocity	No side effects were observed, except for headache in one case.
Rhee, P.L./2001	Korea	Before/ After	Healthy male adult volunteers	8	Mean age = 30.5 years	A 50-mg tablet of sildenafil	N.A	LES resting pressure significantly decreased after sildenafil infusion. The body’s peristaltic amplitude gradually decreased and eventually disappeared	No serious side effects were noticed
Bortolotti, M. /2002	Italy	RCT	Patients with symptomatic hypertensive LES	14	Mean age 35 years, range 28–55	A 50-mg tablet of sildenafil	Placebo	Sildenafil inhibits the lower oesophageal sphincter tone and pressure wave amplitude of patients with symptomatic hypertensive LES	No side effects were observed
Eherer, A. J./2002	Austria	Before/ After	Healthy subjects, nutcracker esophagus, hypertensive LES, and achalasia patients	Healthy subjects: 6, Patients with esophageal disorder: 11	Normal subjects: aged 26–30 years, Patients: aged 27–57 years	A 50-mg tablet of sildenafil	Placebo	Sildenafil lowers LOS pressure and propulsive forces in the body of the esophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia.	Two patients experienced side effects and did not want to continue treatment. (Side effects included: headaches, dizziness, fatigue, sleep disturbances, feeling of tightness in the chest at night.)
Mathis, C./2002	USA	Before/ After	Patients diagnosed with hypertensive LES	N.A	N.A	Sildenafil (50 mg) dissolved	N.A	Sildenafil inhibits LES tone and the amplitude of contractions of the distal esophageal body in patients with hypertensive LES.	N.A
Lee, J. I. / 2003	Korea	Before/ After	Healthy subjects, patients with nutcracker esophagus	Healthy subjects: 8, Patients with nutcracker esophagus: 9	Healthy subjects: 24.3 years, Patients with nutcracker esophagus: 44.7 years	0.8 mg/kg sildenafil dissolved in 20 mL of water	distilled water	In both healthy subjects and patients with nutcracker esophagus, sildenafil decreased resting LOS pressure and the amplitude of peristaltic pressure waves at 3, 8 and 13 cm above LOS. Sildenafil also prolonged the duration of LOS relaxation. It had no effect on the velocity of peristalsis or the amplitude of peristaltic pressure waves 18 cm above LOS.	No noticeable side-effects reported
Kim, H. S. / 2006	Korea	Before/ After	Healthy subjects	8	Mean age : 38.5 years	50-mg dose of sildenafil	N.A	Sildenafil decreased the resting lower esophageal sphincter pressure and prolonged the duration of lower esophageal sphincter relaxation for the 45 min following its ingestion, and does not induce gastro-oesophageal reflux.	N.A
Lee, T. H./ 2012	Korea	RCT	Healthy volunteers	16	Mean age : 31.4 years	10 mg vardenafil	Water	Vardenafil decreased resting and residual LES pressures, distal esophageal contraction, and bolus transit.	N.A
Rodriguez, R. / 2013	N.A	Before/ After	Healthy volunteers, patients with type II/III achalasia, and hypertensive peristalsis	20	Healthy group: mean age 27.5 Patients: mean age 45 years	Single dose of 20 mg tadalafil	N.A	Tadalafil is a 5-PDE that induce a prolonged and sustained effect on esophageal contractions, is well tolerated and it could be a promising drug in the management of esophageal motor disorders.	Mild headache
Guevara-Morales /2014	N/A	Before/ After	Achalasic Patients	12	N/A	20 mgs tadalafil	N/A	Tadalafil may significantly reduced LES pressure and IRP in achalasia patients, and patients with Type 2 Achalasia had a better response.	Headache and back pain
Costa, T./2020	Brazil	Before/ After	Healthy volunteers	22	Mean age : 38.1 years	50 mg sildenafil	N.A	Sildenafil caused a significant reduction in distal contractile integral and integrated relaxation pressure in the lower esophageal sphincter. In the proximal esophagus the alteration in distal esophageal contraction caused a significant increase in contraction length, contractile integral, and contraction duration; suggesting an adaptive compensation of the proximal esophagus for the effect of sildenafil on distal esophageal motility.	There was no adverse event after administration of sildenafil.
Wong, M. W. /2020	Taiwan	RCT	Healthy subjects	15	Mean age: 27 years	50 mg sildenafil	Placebo	Sildenafil attenuates esophagogastric junction barrier function, resting LES pressure, and LES relaxation. Both esophageal body contractility and contraction reserve are in- hibited by sildenafil in healthy adults.	Significant adverse effects were not observed in patients.
Wong, M. W. /2021	Taiwan	RCT	Healthy subjects	17	Mean age : 30.2 years	50 mg sildenafil	Placebo	Sildenafil reduces both the success rate and the vigor of secondary peristalsis, similar to that seen with primary peristalsis.	N.A