Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials

Table 1

Characteristics of studies included in systematic review.

Number	Study	Study design	Intervention (dose/day)	Characteristics of patients				Duration (weeks)	Jadad score
				Number of samples	Female (%)	Age (mean ± SD); (years)	Indication
1	Buxton et al. 1978 [16]	A crossover, double-blind, two cycles of four-week treatment study	Indomethacin 75 mg	20	70.0	64	OA	2 wk fenbufen; 2 wk placebo; 2 wk indomethacin	3
			Fenbufen 600 mg	20
2	Verbruggen et al. 1982 [17]	A crossover, double-blind study	Naproxen 500 mg	11	90.0	66 (median)	OA	2	3
			Nabumetone 1000 mg	10	64.0	62.5 (median)
3	Turner 1988 [18]	Two randomized, double-blind studies	Naproxen 750 mg	286	N/A	52.3 (all)	RA	24	3
			Naproxen 1500 mg	300
4	Eversmeyer et al. 1993 [19]	A randomized, open-label,  multicenter study	Diclofenac 100–200 mg	296	N/A	N/A Age > 18	OA and RA	12	2
			Nabumetone 1500–2000 mg	3315
			Naproxen 500–1500 mg	279
			Ibuprofen 1200–3200	296
			Piroxicam 10–20 mg	286
5	Kennedy et al. 1994 [20]	A randomized, double-blind, parallel,  multicenter study	Diclofenac 150 mg	121	70.0	64.6 ± 9.7	OA	16	5
			Ketoprofen ER 200 mg	118	70.0	63.3 ± 10.8
6	Schmitt et al. 1999 [21]	A randomized, double-blind, multicenter study	Diclofenac, enteric coated 150 mg	112	98.9	60 ± 9	OA	12	5
			Diclofenac dual release capsule 150 mg	111	82.9	61 ± 9
			Diclofenac capsule 75 mg	114	85.1	61 ± 10
			Placebo	56	82.1	62 ± 9
7	Morgan et al. 2001 [22]	A randomized, double-blind, parallel, multicenter study	Diclofenac 100–150 mg	168	70.0	72 ± 6	OA	12 wk	3
			Nabumetone 1000–2000 mg	167	71.0	72 ± 6
8	McKenna et al. 2001 [23]	A placebo-controlled, randomized, double-blind comparison study	Celecoxib 200 mg	201	68.0	61.9	OA	6 wk	4
			Diclofenac 150 mg	199	62.0	62.7
			Placebo	200	66.0	60.4
9	Furst et al. 2002 [24]	A randomized, double-blind, double-dummy, parallel study	Diclofenac 150 mg	181	77.9	54.7 ± 12.8	RA	12 wk	4
			Meloxicam 7.5 mg	175	78.9	56.3 ± 11.5
			Meloxicam 15 mg	184	75.5	55.6 ± 12.1
			Meloxicam 22.5 mg	177	73.4	56.7 ± 11.8
			Placebo	177	75.1	56.0 ± 12.1
10	Tugwell et al. 2004 [25]	A randomized, double-blind, double-dummy, equivalence study	Diclofenac 150 mg	311	57.0	63 ± 10	OA	12 wk	5
			Topical diclofenac 1.5% w/w 1.55 ml	311	57.0	64 ± 10
11	Temper et al. 2006 [26]	A randomized, double-blind,  single-dummy, control parallel, multicenter study	Naproxen 750 mg	Group 1, 239; and group 2, 52	71.8	59.5	OA	group 1, 52 wk; and group 2, 42 wk	5
			Acetaminophen 4 g	Group 1, 237; and group 2, 53	66.6	59.1
12	Laine et al. 2009 [27]	Three randomized, double-blind studies:   the MEDAL study, EDGE study, and EDGE II study	Diclofenac 150 mg	17,289	74.2	63.2 ± 8.5	OA and RA	72	3
			Etoricoxib 60 or 90 mg	17,412	74.2	63.2 ± 8.5
13	Dahlberg et al. 2009 [28]	A randomized, double-blind, parallel, multicenter study	Celecoxib 200 mg	463	68.0	71	OA	52	5
			Diclofenac 100 mg	462	69.0	71
14	Sampalis and Brownell 2012 [29]	A randomized, double-blind, placebo, and active comparator controlled pilot study	Celecoxib 200 mg	15	67.0	57.6 ± 12.6	OA	12	4
			UP446 250 mg	15	67.0	62.8 ± 10.8
			UP446 500 mg	15	60.0	54.6 ± 14.8
			Placebo	15	67.0	55.3 ± 14.3
15	Shell et al. 2012 [30]	A randomized, double-blind, controlled study	Naproxen 250 mg	42		18–75	Low back pain	4	3
			Medical food alone	43
			Both medical food and naproxen	44
16	Chopra et al. 2013 [31]	A randomized, double-blind, parallel, multicenter study	Celecoxib 200 mg	110	NA	56.6	OA	24	5
			SGCG & SCG	220		55.5
			Glucosamine 2 g	110		55.3
17	Altman et al. 2015 [32]	An open-label, multicenter study	Low dose SoluMatrix diclofenac 75–105 mg	601	59.7	61.9	OA	52	2
18	Pinsornsak et al. 2015 [33]	A randomized, double-blind, controlled study	Diclofenac 75 mg	33	90.3	58.2	OA	4	5
			Sahastara (SHT) 3000 mg	33	90.0	60.4