Efficacy of indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A comprehensive meta-analysis of randomized controlled trials

Table 1 Characteristics of included studies and outcomes

Ref.	Setting	Intervention	Control	Indication	Patients	Age	Female	PEP
								Overall	Mild	Moderate	Severe
Romano-Munive et al[50], 2021, Mexico	Multicenter, double blinded, unselected patients	100 mg of rectal indomethacin with 10 mL water	100 mg of rectal indomethacin with 1:10000 epinephrine dilution (0.1 mg/mL)	Naïve papilla and indication for ERCP	EI = 275	50.3 ± 21.4	188	10	8	1	1
					WI = 273	51.8 ± 20.3	192	14	9	5	0
Patai et al[22], 2017, Hungary	Single-center, double blinded, unselected patients	100 mg of rectal indomethacin	Placebo	Intact papilla undergoing biliary endoscopic therapy	Indomethacin = 270	66.25	181	18	15	2	1
					Placebo = 269	64.51	181	37	33	3	1
Elmunzer et al[35], 2012, United States	Multicenter, single blinded, selected patients	100 mg of rectal indomethacin suppositories	Placebo	Risk of post-ERCP pancreatitis	Indomethacin = 295	44.4 ± 13.5	229	27	14	13	3
					Placebo = 307	46.0 ± 13.1	247	52	25	27	3
Levenick et al[51], 2016, United States	Single-center, single blinded, unselected patients	100 mg of rectal indomethacin suppositories	Placebo	Patients undergoing ERCP	Indomethacin = 223	64.9	118	16	16	0	0
					Placebo = 226	64.3	118	11	9	1	1
Liu et al[52], 2024, China	Single-center, single blinded, unselected patients	100 mg of rectal indomethacin suppositories	Placebo	Patients undergoing ERCP for bile duct stones	Indomethacin = 58	61.6 ± 15.6	29	4	3	1	0
					Placebo = 109	62.9 ± 15.2	49	22	11	9	2
Li et al[53], 2019, China	Single-center, single blinded, unselected patients	100 mg indomethacin suppositories	Glycerin suppository	Patients undergoing ERCP for bile duct stones	Indomethacin = 50	55.68 ± 13.58	31	6	NA	NA	NA
					Glycerin = 50	58.70 ± 13.60	37	16
Mohammad Alizadeh et al[44], 2017, Iran	Single-center, single blinded, unselected patients	100 mg indomethacin	100 mg diclofenac and 500 mg naproxen	Patients undergoing ERCP	Indomethacin = 122	58.0 ± 16.8	65	7	3	2	2
					Diclofenac = 124	56.5 ± 18.7	66	5	2	1	2
					Naproxen = 126	54.8 ± 13.7	66	20	7	8	5
Alavinejad et al[32], 2022, multiple countries	Multicenter, single blinded, unselected patients	100 mg indomethacin	1200 mg oral N-acetyl cysteine, N-acetyl cysteine plus indomethacin, placebo	Standard indications for ERCP	Indomethacin = 138	55.36	85	24	15	6	3
					N-acetyl cysteine = 84	57.44	49	9	2	7	0
					N-acetyl cysteine + indomethacin = 115	56.11	62	9	3	6	0
					Placebo = 95	61.53	55	19	10	7	2
Guha et al[38], 2023, India	Single-center, single blinded, unselected patients	100 mg indomethacin	Vigorous hydration	Standard indications for ERCP	Indomethacin = 174	43.7 ± 14.4	119	5	NA	5	3
					Aggressive hydration = 178	44.3 ± 14.7	127	1		1	0
Sotoudehmanesh et al[23], 2007, Iran	Single-center, double blinded, unselected patients	100 mg indomethacin	Placebo	Standard indications for ERCP	Indomethacin = 245	58.4 ± 17.1	134	7	NA	NA	NA
					Placebo = 245	58.1 ± 16.8	130	15
Andrade-Dávila et al[33], 2015, Mexico	Single-center, single blinded, selected patients	100 mg indomethacin	Glycerin suppository	Risk of post-ERCP pancreatitis	Indomethacin = 82	51.59 ± 18.55	51	4	3	1
					Glycerin = 84	54.0 ± 17.85	59	17	14	3
Qian et al[54], 2022, China	Single-center, double blinded, unselected patients	100 mg indomethacin	Glycerin suppository	Risk of post-ESWL pancreatitis	Indomethacin = 685	46 (35-54)	194	60	59	1	0
					Glycerin = 685	47 (37-54)	197	84	79	5	0
Wu et al[43], 2023, China	Single-center, single blinded, selected patients	100 mg indomethacin	0.25 mg of somatostatin indomethacin + somatostatin placebo	Risk of post-ERCP pancreatitis	Indomethacin = 366	52.7 ± 14.2	196	76	NA	NA	NA
					Somatostatin = 424	49.3 ± 16.6	163	22
					Somatostatin + Indomethacin = 420	51.9 ± 16.2	196	22
					Placebo = 248	50.4 ± 15.9	116	48
Döbrönte et al[34], 2014, Hungary	Multicenter, single blinded, unselected patients	100 mg indomethacin	Placebo	Risk of post-ERCP pancreatitis	Indomethacin = 347	NA	214	20	16	4	NA
					Placebo = 318		212	22	18	4
Fogel et al[36], 2020, United States	Multicenter, double blinded, selected patients	100 mg indomethacin	200 mg indomethacin	High risk of post-ERCP pancreatitis	Indomethacin = 515	49.3 (15.2)	392	76	48	28	NA
					Placebo = 522	50.4 (15)	421	65	37	28
Norouzi et al[55], 2023, Iran	Single-center, double blinded, selected patients	100 mg indomethacin + somatostatin	100 mg indomethacin + saline	High risk of post-ERCP pancreatitis	Indomethacin = 192	63.03 (16.57)	116	22	9	11
					Control group = 184	62.95 (15.58)	98	28	12	12
Sadeghi et al[56], 2023, Iran	Single-center, unselected patients	100 mg indomethacin	100mg indomethacin + vitamin C	Standard indications for ERCP	Indomethacin = 165	59.0 ± 14.4	96	27	19	4	4
					Control group = 165	62.0 ± 14.1	93	17	14	2	1
Kamal et al[57], 2019, United States, India	Multicenter, double blinded, selected patients	100 mg indomethacin	100 mg indomethacin + 20 mL of 0.02% epinephrine	High risk of post-ERCP pancreatitis	Indomethacin = 482	52.16 (14.3)	275	31	NA	NA	4
					Control group = 477	52.56 (15.6)	276	32			7
Elmunzer et al[20], 2024, Canada	Multicenter, double blinded, selected patients	100 mg indomethacin	100 mg indomethacin + stent	High risk of post-ERCP pancreatitis	Indomethacin = 975	55.6 (16.4)	599	145	67	58	20
					Control group = 975	55.8 (16.3)	596	110	52	44	14
Makhzangy et al[21], 2022, Egypt	Single-center, unselected patients	100 mg indomethacin	100 mg indomethacin + saline	Standard indications for ERCP	Indomethacin = 60	45.27 ± 15.39	29	5	NA	NA	NA
					Control group = 60	42.3 ± 14.28	37	0
Luo et al[58], 2019, China	Multicenter, double blinded, unselected patients	100 mg indomethacin + epinephrine	100 mg indomethacin + saline	Standard indications for ERCP	Indomethacin = 576	62 (50-71)	281	49	45	4	NA
					Control group = 582	61 (49-71)	280	31	29	2
Hosseini et al[40], 2016, Iran	Single-center, double blinded, selected patients	100 mg indomethacin	3 L normal saline. Indomethacin + normal saline 2 g glycerin suppositories	Standard indications for ERCP for CBD	Indomethacin = 100	51.20 ± 12.12	40	11	NA	NA	NA
					Intravenous saline = 100	50.76 ± 13.32	53	10
					Normal saline + indomethacin = 101	47.91 ± 11.06	62	0
					Glycerin = 105	49 ± 14.26	49	17
Abdi et al[31], 2024, Iran	Single-center, double blinded, unselected patients	100 mg indomethacin plus CoQ10	Indomethacin plus placebo	Standard indications for ERCP	Indomethacin = 166	55.0 ± 13.1	92	17	14	2	1
					Placebo = 166	58.0 ± 13.4	87	25	19	3	3
Mok et al[41], 2017, United States	Single-center, double blinded, selected patients	100 mg Indomethacin plus normal saline	Normal saline + placebo LR + placebo LR + India	High risk of post-ERCP pancreatitis	Indomethacin + normal saline = 48	62	33	6	NA	NA	1
					Normal saline + placebo = 48	58	29	10			0
					LR + placebo = 48	58	35	9			0
					LR + indomethacin = 48	63	23	3			0
Sotoudehmanesh et al[59], 2014, Iran	Single-center, double blinded, selected patients	100 mg indomethacin + dinitrate tablet	100 mg indomethacin + placebo	Standard indications for ERCP	Indomethacin = 150	58.4 ± 17.8	74	10	NA	NA	NA
					Placebo = 150	58.6 ± 17.5	80	23
Wang et al[42], 2020, China	Single-center, double blinded, selected patients	Indomethacin + nitroglycerin	Placebo suppository PSP with placebo suppository + tablet	Standard indications for ERCP only female	Indomethacin = 176	66.87 ± 13.04	176	9	5	4	0
					Placebo = 176	63.5 ± 14.4	176	34	14	20	0
					PSP = 174	66.30 ± 12	174	21	13	8	0
Lai et al[37], 2019, Taiwan	Single-center, double blinded, unselected patients	100 mg rectal indomethacin pre-ERCP + 100 post	100 mg rectal indomethacin post-ERCP	Standard indications for ERCP	Indomethacin = 87	60.5 ± 16.9	33	4	NA	NA	NA
					Placebo = 75	59.3 ± 15.7	28	5
Sotoudehmanesh et al[60], 2019, Iran	Single-center, double blinded, unselected patients	100 mg rectal indomethacin + 5 mg isosorbide	100 mg rectal indomethacin + 5 mg isosorbide + pancreatic duct stent	Standard indications for ERCP	Indomethacin = 207	56.8 (17.2)	120	33	27	6	NA
					PSP = 207	53.9 (16.8)	131	26	22	4
Sperna Weiland et al[61], 2021, Netherlands	Multicenter, double blinded, selected patients	100 mg rectal diclofenac or indomethacin	100 mg rectal diclofenac or indomethacin + hydration	Moderate to high risk of post-ERCP pancreatitis	Indomethacin = 425	60 (49-71)	250	39	29	10	NA
					Indomethacin + hydration = 388	57 (44-71)	232	30	27	3
Hatami et al[39], 2018, Iran	Single-center, double blinded, selected patients	100 mg indomethacin	10 mL epinephrine (diluted to 1/10000 in saline) epinephrine + indomethacin	High-risk post-ERCP pancreatitis	Indomethacin = 6	58.06 ± 17.1	27	6	4	1	1
					Epinephrine = 68	59.59 ± 15.68	33	1	1	0	0
					Epinephrine + indomethacin = 58	59.62 ± 15.36	34	0	0	0	0

EI: Epinephrine and rectal indomethacin; WI: Sterile water and rectal indomethacin; LR: Lactated Ringer’s solution; PSP: Prophylactic pancreatic stent placement; NA: Not available; PEP: Post-endoscopic retrograde cholangiopancreatography-pancreatitis; ERCP: Endoscopic retrograde cholangiopancreatography; ESWL: Extracorporeal Shock Wave Lithotripsy; CBD: Common bile duct stones.

Table 2 Outcome of the studies

Ref.	Total adverse events	Abdominal pain	Bleeding	Cholangitis	Mortality
Romano-Munive et al[50], 2021, Mexico	EI = 40	9	9	5	2
	WI = 41	5	3	10	6
Patai et al[22], 2017, Hungary	Indomethacin = 30	NA	9	2	NA
	Placebo = 42		3	2
Elmunzer et al[35], 2012, United States	Indomethacin = 4	NA	4	NA	NA
	Placebo = 9		7
Levenick et al[51], 2016, United States	Indomethacin = 4	NA	4	NA	0
	Placebo = 6		6		3
Liu et al[52], 2024, China	Indomethacin = NA	NA	NA	NA	0
	Placebo = NA				1
Guha et al[38], 2023, India	Indomethacin = 11	43	3	NA	3
	Placebo = 8	40	4		3
Andrade-Dávila et al[33], 2015, Mexico	Indomethacin = 2	NA	2	NA	NA
	Placebo = 3		3
Qian et al[54], 2022, China	Indomethacin = 65	NA	NA	5	NA
	Placebo = 99			13
Wu et al[43], 2023, China	Indomethacin = 62	NA	45	NA	2
	Somatostatin = 21		18		3
	Somatostatin + indomethacin = 25		21
	Placebo = 43		30
Fogel et al[36], 2020, United States	Indomethacin = 6	NA	6	NA	NA
	Placebo = 8		8
Kamal et al[57], 2019, United States, India	Indomethacin = 6	NA	0	NA	3
	Placebo = 8		10		3
Luo et al[58], 2019, China	Indomethacin = 42	NA		4	8
	Placebo = 44			6	9
Mok et al[41], 2017, United States	NA	NA	NA	NA	2
					1
					2
					1
Sotoudehmanesh et al[59], 2014, Iran	NA	1	NA	NA	NA
		2
Wang et al[42], 2020, China	NA	NA	4	4	NA
			6	8
			4	4
Sperna Weiland et al[61], 2021, Netherlands	Indomethacin = 30	NA	NA	NA	12
	Indomethacin + hydration = 24				11

EI: Epinephrine and rectal indomethacin; WI: Sterile water and rectal indomethacin; NA: Not available.

Table 3 Results of the subgroup analysis of multivariance analysis outcomes

Outcomes	Studies	RR	95%CI	P value	Heterogeneity
Age > 40 years	13	0.79	0.59-1.05	0.10	62%
Female patients	14	0.80	0.60-1.07	0.13	56%
Prior cholecystectomy	4	0.42	0.24-0.71	< 0.01	0%
History of pancreatitis	7	0.67	0.47-0.95	0.03	0%
Difficult cannulation	11	0.62	0.44-0.89	< 0.01	59%
Pancreatic sphincterotomy	9	0.29	0.18-0.46	< 0.01	25%
Biliary sphincterotomy	7	0.85	0.74-0.99	0.03	0%
Trainee involvement	6	1.79	0.89-3.60	0.10	84%
Pancreatic duct stent	6	1.41	1.19-1.67	< 0.01	0%

RR: Risk ratios; CI: Confidence interval.