Antioxidant therapy in acute, chronic and post-endoscopic retrograde cholangiopancreatography pancreatitis: An updated systematic review and meta-analysis

Table 2 Controlled clinical trials of antioxidants in patients with chronic pancreatitis

Ref.	Drug/supplements	Study design	Jadad score	Participants	Treatment (intervention)		Outcome (results)		Adverse effects/events
					Case	Control	Clinical	Laboratory
Dhingra et al[29], 2013	Combined antioxidant (organic selenium, vitamin C, β carotene, vitamin E, methionine)	Randomized; placebo-controlled	3	61 patients with CP	31 patients; 600 Hg of organic selenium, 0.54 g of vitamin C, 9000 IU of β carotene, 270 IU of vitamin E, and 2 g of methionine	30 patients; placebo	Number of painful days per month ↓Number of analgesic tablets per month ↓	Platelet-derived growth factor (PDGF) AA ↓Transforming growth factor β 11Thiobarbituric acid-reactive substances1Ferric-reducing ability of plasma ↑TBARS ↓FRAP ↑
Shah et al[30], 2013	Combined antioxidant (vitamin C, vitamin E, β carotene, selenium, methionine)	Randomized; double blind; placebo-controlled	5	14 patients with CP	7 patients; Antox tablet: vitamin C, vitamin E, β carotene, selenium, methionine (Pharma Nord, Morpeth, United Kingdom); 6 m	7 patients; placebo	Opiate usage1	Serum vitamin C ↑ Serum vitamin E ↑Serum b caroteneSerum vitamin A ↑WCC1Hb1CRP1Serum selenium1IL 1b, 4, 6, and 101TNF-α1
Siriwardena et al[31], 2012	Combined antioxidant (selenium, d-a-tocopherol acetate, ascorbic acid, l-methionine)	Randomized; double blind; placebo-controlled	5	70 patients with CP	33 patients; Antox tablet: 38.5 mg seleniumYeast, 113.4 mg d-a-tocopherol acetate, 126.3 mg ascorbic acid, 480 mg l-methionine; per d; for 6 m	37 patients; placebo	Quality of life1Average daily pain scores1Opiate use1Number of hospital admissions1Outpatient visits1	Serum vitamin C ↑Serum vitamin E ↑Serum beta carotene ↑Serum selenium ↑	Increased frequency of stool, occasional diarrhea, bad taste, and heartburn with nausea
Shah et al[32], 2010	Combined antioxidant (vitamin C, vitamin E, β carotene, selenium, methionine)	Randomized; placebo-controlled	2	137 patients with CP	68 patients; Antox tablet: vitamin C, vitamin E, β carotene, selenium, methionine (Pharma Nord, Morpeth, United Kingdom); at least 6 m	69 patients; placebo	Median visual analogue pain score ↓Cognitive, emotional, social, physical and role function ↑Analgesics and opiate usage ↓	-	-
Bhardwaj et al[33], 2009	Combined antioxidant (organic selenium, vitamin C, β- carotene, α-tocopherol and methionine)	Randomized; double blind; placebo-controlled	5	147 patients with CP	71 patients; combined antioxidants: 600 μg organic selenium,0.54 g ascorbic acid, 9000 IU β- carotene, 270 IU α-tocopherol and 2 g methionine (Betamore G, Osper Pharmanautics, India); per d; for 6 m	76 patients; placebo	Number of painful days per month ↓Numbers of oral analgesic tablets and parenteral analgesic injections per month ↓Hospitalization ↓Percentage of patients become pain-free ↓Number of man-days lost per month ↓	Lipid peroxidation (TBARS) ↓Serum SOD ↓Total antioxidant capacity (FRAP) ↑Serum vitamin A↑Serum vitamin C ↑Serum vitamin E ↑Erythrocyte superoxide dismutase ↓	Headache & Constipation (all during the first month of treatment)
Kirk et al[34], 2006	Combined antioxidant (selenium, β- carotene, L-methionine, vitamins C and E)	Randomized; double-blind; placebo-controlled; crossover	4	72 patients with CP	36 patients; Antox tablet: 75 mg of selenium, 3 mg β- carotene, 47 mg vitamin E, 150 mg vitamin C, and 400 mg methionone; 4 times per day; for 10 wk	36 patients; placebo; 4 times per d; for 10 wk	Quality of life ↑Pain ↓Physical and social functioning ↑Health perception ↑Emotional functioning, energy, mental health:1	Plasma selenium ↑Plasma vitamin C ↑Plasma vitamin E ↑Plasma β-carotene ↑	Two patients complained of nausea and one of an unpleasant taste during treatment with Antox
Durgaprasad et al[35], 2005	Curcumin	Randomized; single blind; placebo-controlled	3	20 patients with tropical pancreatitis (CP)	8 patients; capsule: 500 mg curcumin (95%) with 5 mg of piperine; 3 times per day; for 6 wk	7 patients; placebo (lactose)	Median visual analogue pain score1Severity of Pain1	Erythrocyte MDA ↓GSH level1	-
Banks et al[36], 1997	Allopurinol	Randomized, double-blind, two-period crossover clinical trial	4	26 patients with CP	13 patients; 300 mg/d All opurinol; 4 wk	13 patients, placebo	Pain1	Uric acid level ↓	-
Bilton et al[28], 1994	S- adenosyl methionine (SAMe)Selenium and β-carotene + SAMe	Randomized; double-blind; crossover; placebo- controlled	5	20 patients with AP or CP	20 patients; SAMe 2.4 g/d; 10 wk20 patients; SAMe 2.4 g/d, Selenium 600 μg and β-carotene 9000 IU; 10 wk	Placebo	Attack rate and background pain1	Free radical activity ↓Serum selenium ↓Serum β-carotene ↓Serum vitamin E ↓1Serum vitamin C ↓Serum SAMe ↑Free radical activity ↓Serum selenium ↓Serum β-carotene ↑Serum vitamin E ↑1Serum vitamin C ↓Serum SAMe ↑	-
Salim et al[39], 1991	Allopurinol;dimethyl sulfoxide	Randomized; double-blind; placebo- controlled	4	78 patients with CP	25 patients; allopurinol; 50 mg 4 times per day, with analgesic regimen (IM pethidine hydrochloride; 50 mg every 4 hours, and IM metoclopramide hydrochloride; 10 mg every 8 h)	27 patients; placebo with analgesic regimen	Pain free patients ↑Hospitalization ↓Epigastric tenderness ↓	WBC count ↓Serum amylase ↓ Serum LDH ↓	AllergiesGeneral malaiseHeadacheNauseaVomitingDyspepsiaAbdominal pain
Uden et al[37,38], 1990, 1992	Combined antioxidant (selenium , β-carotene, vitamin C, vitamin E, methionine)	Randomized; double-blind; crossover; placebo- controlled	5	28 patients with CP	26 patients; dimethyl sulfoxide; 500 mg 4 times per day; with analgesic regimen23 patients; daily doses of 600 mg organic selenium, 9000 IU β-carotene, 0.54 g vitamin C, 270 IU vitamin E and 2 g methionine; 10 wk	23 patients; placebo	Pain (Mc Gill) ↓	Free radical activity ↓ Serum selenium ↑Serum β-carotene ↑Serum vitamin E ↑Serum SAMe ↓	-

¹No significant difference between groups. ↑: Significant increase as compared with control; ↓: Significant decrease as compared with control; TBARS: Thiobarbitoric acid reactive substances; FRAP: Ferric reducing antioxidant power; SOD: Superoxide dismutase; AGD: Alanyl-glutamine dipeptide; CRP: C-reaction protein; MDA: Malondialdehyde; LDH: Lactate dehydrogenase; APACHE II: Acute Physiology and Chronic Health Evaluation II; GSH: Glutathione; TPN: Total parenteral nutrition.