Table 2.

Studies investigating the association between pharmacogenetics and the effect and safety of NSAIDs and aspirin in pain in vivo (human studies).

Study	Drug	Ethnicity	Study Design	Outcome	Gene Assessed	Variants	Findings (Effect or Safety)
Martinez et al. (2004) [40]	Celecoxib, diclofenac, ibuprofen, piroxicam	N/A	Patients with GI bleeding (n = 94) and healthy individuals (n = 124)	Adverse effects of different NSAIDs	CYP2C9	CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3	CYP2C9*2allele frequency increased in patients with acute bleeding
Saiz-Rodriguez et al. (2021) [37]	Ibuprofen	White	43 patients with moderate to severe pain after dental surgery	Ibuprofen response	CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A4 PTGS2	CYP2B6 G/G, G/T, T/T CYP2C8 PMs, IMs, and NMs CYP2C9 PMs and IMs CYP2C19 IMs, NMs, and UMs CYP2D6 PMs, IMs, NMs, and UMs	Greater pain reduction 6 h after ibuprofen intake in CYP2C9 PMs compared with IMs/NMs
Weckwerth et al. (2020) [38]	Ibuprofen	Brazil	200 patients with acute pain	Ibuprofen response	CYP2C8 CYP2C9	CYP2C8*1/*1, *1/*2, *1/*3, *1/*4, *2/*3, *3/*4 CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3	CYP2C9 and CYP2C8 IMs and PMs have lower levels of postoperative pain
Jaja et al. (2015) [39]	Ibuprofen, aspirin	African American	50 patients with sickle cell disease	NSAIDs efficacy	CYP2C8, CYP2C9	CYP2C8*1/*1, *1/*2, *1/*3, *1/*4, *2/*2, *2/*3, *2/*4 CYP2C9*1/*1, *1/*2, *1/*3, *1/*5, *1/*6, *1/*8, *1/*9, *1/*11, *2/*3, *5/*9, *6/*8, *8/*9, *9/*11	CYP2C9 NMs visited the hospital more frequently due to severe pain
Hamilton et al. (2020) [49]	Celecoxib	N/A	31 patients with postoperative pain	Celecoxib efficacy and safety	CYP2C9	CYP2C9 NMs and IMs	Concomitant drug intake, no clear conclusion regarding a pharmacogenetic association
Murto et al. (2015) [50]	Celecoxib	Caucasian, African American Hispanic, South and East Asian	93 patients with postoperative pain	Celecoxib efficacy	CYP2C9	CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, *2/*2, *3/*3	Reduced pain recurrence in CYP2C9*3 allele carriers compared to wild-type carriers
Ustare et al. (2020) [51]	Celecoxib	Malay, Malay-Chinese, Malay-Polynesian, Filipinos	99 patients with postoperative pain	Celecoxib efficacy	CYP2C9	CYP2C9*1/*1, *1/*3	Lower pain scores in CYP2C9 IMs after 24 and 48 h compared to NMs
Calvo et al. (2017) [54]	Piroxicam	Brazil	102 patients with postoperative pain	Piroxicam efficacy and adverse effects	CYP2C8, CYP2C9	CYP2C8*1/*1, *1/*3, *3/*3 CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3	Postoperative pain scores and adverse effects were comparable between genotypes
Daly et al. (2007) [68]	Diclofenac	North European	Patients with and without diclofenac-induced hepatotoxicity (n = 28/48) Healthy volunteers (n = 112)	Diclofenac adverse effects	UGT2B7, CYP2C8, ABCC2	UGT2B7*1/*1, *1/*2, *2/*2 CYP2C8*1/*1, *1/*2, *1/*3, *1/*4, 1/*5, *2/*3, *2/*2 ABCC2 C-24/C-24, C-24/T-24, T-24/T-24	UGT2B7*2 allele was associated with a higher risk of diclofenac-induced hepatotoxicity compared with wild-type carriers
Aithal et al. (2000) [65]	Diclofenac	Caucasian	124 patients with diclofenac-induced hepatotoxicity (n = 24); control group (n = 100)	Diclofenac adverse effects	CYP2C9	CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, *3/*3	No association of CYP2C9*2 or CYP2C9*3 with diclofenac-induced hepatotoxicity
Shiotani et al. (2014) [79]	Aspirin	Japanese	638 patients with peptic ulcer (n = 111); patients with GI bleeding (n = 45); control group (n = 482)	Aspirin adverse effects	SLCO1B1, CHST2	SLCO1B1 388 A > G (rs2306283), 521 T > C (rs4149056) CHST2 2082 C > T (rs6664)	SLCO1B1*1b and CHST2 2082 T allele frequency was increased in patients with peptic ulcer and ulcer bleeding compared to the controls
Wang et al. (2019) [81]	Aspirin	N/A	154 patients with coronary heart disease; with (n = 57) or without (n = 97) upper GI bleeding (UGIB)	Aspirin adverse effects	TNF-α gene	-1031T > C TT, TC, CC -863C > A CC, CA, AA -857C > T CC, CT, TT	-1031T > C: C allele and CC genotype carriers and -863C > A: A allele, CA, and CA + AA genotype carriers had increased risk of UGIB -857 C > T had no effect
Groza et al. (2017) [82]	Aspirin	N/A	Patients with UGIB (n = 154); control group (n = 178)	Aspirin adverse effects	VKORC1	VKORC1 -1639 G > A GG, GA, AA	VKORC1 -1639 G > A: AA genotype is associated with an increased risk of UGIB
E. Piazuelo et al. (2008) [83]	Aspirin	White	Patients with UGIB (n = 88); control patients (n = 108)	Aspirin adverse effects	eNOS GP IIIa	eNOS 4b/4b, 4a/4b, 4a/4a GP IIIa PlA1/A1, PlA1/A2, PlA2/A1	eNOS a allele carriers had reduced risk of UGIB
Figueiras et al. (2016) [80]	Multiple drugs	Caucasian	1920 patients with hematemesis, melena; and hematochezia (n = 577); control group (n = 1343)	NSAIDs adverse effects	CYP2C9	CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3	Higher risk of upper GI bleeding in CYP2C9*3 allele carriers CYP2C9*2 allele had no such effect
Lee et al. (2014) [70]	Meloxicam	Korean	22 healthy participants	Meloxicam adverse effects	CYP2C9	CYP2C9*1/*1, *1/*3, *3/*3	CYP2C9*3/*3 carriers have significantly greater TXB2 inhibition compared with CYP2C9*1/*1 and *1/3 (possible differences in the incidence of cardiovascular complications and bleeding)
Mejía-Abril et al. (2021) [58]	Dexketoprofen	Caucasian, Latin-American, Black, Asian	85 healthy participants	Dexketoprofen adverse effects	CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5 ABCB1, ABCC2, SLCO1B, UGT1A1	CYP1A2*1C, *1F, *1B CYP2A6*9 CYP2B6*9, *5, rs4803419, rs2279345, rs2279343 CYP2C8*2, *3, *4 CYP2C9*2, *3 CYP2C19*2, *3, *4, *17 CYP2D6*3, *4, *6, *7, *8, *9, *10, *14, *17, *41 CYP3A4*22, rs55785340, rs4646438 CYP3A5*3, *6 ABCB1 C3435T, G2677 T/A, C1236T ABCC2 rs2273697, rs717620 SLCO1B1*1B, *5, rs4149015, rs11045879 SLC22A1*2, *3, *5 UGT1A1*80	No adverse effects after dexketoprofen intake were reported

N/A = not available, GI = gastrointestinal, NSAIDs = non-steroidal anti-inflammatory drugs, PM = poor metabolizer, IM = intermediate metabolizer, NM = normal metabolizer, UM = ultra-metabolizer, UGIB = upper gastrointestinal bleeding, TXB2 = Thromboxane B2.