Table 2.

Commonly used opioids and genetic variants reported to modulate response. Bold text refers to studies in cancer patients.

Gene (protein)	Drugs Involved	Function	Available Data
CYP2D6 (Cytochrome P450 2D6 isoenzyme)	Codeine Oxycodone Hydrocodone Methadone Tramadol	Activation of prodrugs De-activation of the active drug	CYP2D6 genotype impacts on plasma concentrations of tramadol and its demethylated metabolites, as well as drug tolerability [21]. CYP2D6 genotypes had clear effects on oxycodone PK but lack of clinical difference (pain/adverse events) between classes of metabolizers [22].
CYP3A4 (Cytochrome P450 family 3 subfamily A members 4)	Fentanyl Sufentanyl Alfentanyl Oxycodone Hydrocodone	Inactive metabolites are formed via N-de-alkylation Oxycodone: 80% of this drug is converted by CYP3A4 to the non-active metabolite nor-oxycodone	*22 allele mutation encodes decreased CYP3A4 enzymatic activity [29]. Fentanyl (n = 620) showed that genetic variability in CYP3A4*22 influenced transdermal fentanyl metabolism [31]. CYP3A4*1G carriers consumed less opioids [32]
CYP3A5 (Cytochrome P450 family 3 subfamily A members 5)	Fentanyl Sufentanyl Alfentanyl	Inactive metabolites are formed via N-de-alkylation	Most frequent genetic variant in white individuals is the inactive CYP3A5*3 allele 80% of white individuals are homozygous carriers of this allele = do not express (non-expressers [28]) CYP3A5 expressers who carry at least one *1 allele may require lower doses CYP3A5*3 allele = more adverse effects [33]
OPRM1 (μ-opioid receptor)	Opioids		OPRM1 SNPs were not significantly different in patients with higher pain and side effects [34] OPRM1 SNPs were associated with increased opioid requirements in cancer patients [35,36,37] OPRM1 A/A + COMT Met/Met genotype = lower dose of morphine [38] OPRM1 variants were associated with increased opioid requirements for postoperative pain, while other gave opposite results or failed to demonstrate any association in the postoperative period [39]
COMT (Catechol-O-methyltransferase)	Opioids		COMT Val/Val genotype = higher dose of analgesics [37] OPRM1 A/A + COMT Met/Met genotype = lower dose of morphine [38]
ABCB1 (ATP binding cassette subfamily B member 1)	Fentanyl Oxycodone Morphine	Efflux pump in the intestine and at the blood–brain barrier	The 3435C > T SNP is mostly studied In 3435TT genotyped individuals = higher expression = higher morphine concentrations in the cerebrospinal fluid [40]. Lower opioid doses might be needed in these patients (risk of side effects on normal dosages), but results are contradictory [32] Morphine equivalents decreased in a gene dose-dependent manner with the variant ABCB1 3435C > T [41].
ABCC3 (ATP-binding cassette subfamily C member 3 transporter)	Morphine	Transporter involved in the efflux of M3G and M6G from the liver to the bloodstream	The promoter SNP-211C>T (rs4793665) was associated with decreased ABCC3 mRNA expression [42] Children—postoperative pain: 211C > T polymorphism was associated with lower M3G and M6G plasma concentrations [43]
SLC22A1 (Organic Cation Transporter 1)	Tramadol Codeine Morphine	Present on the sinusoidal membrane of hepatocytes. Uptake of positively charged compounds at physiological pH (morphine, active metabolite of tramadol)	Tramadol: increased plasma concentrations of O-desmethyltramadol [44] and lower tramadol consumption during the first 24 h after surgery [45] Increase of 56% in morphine AUC after codeine administration and lower clearance in children [43,46] These genetic variants could explain why children with a white background experienced more adverse events than African American children, in whom the variant alleles are less frequent [43]. SLC22A1deficient alleles may be especially relevant for patients carrying the CYP2D6 ultra-metabolizing status
KCNJ6 (G protein–activated inwardly rectifying potassium 2 channel- GIRK2)	Opioids	The encoded channel is one of the downstream signaling effectors of the MOR.	Several SNPs in the KCNJ6 gene were related to opioid response but negative findings have been published as well.

AUC: area under the curve; SNPs: Single Nucleotide Polymorphisms; MOR: μ-opioid receptor.