Table 5.

Genetic variants associated with methadone treatment adverse events

Ethnicity	Measurement	Gene	Variant/ allele	MAF (minor allele)a	Finding	Reference
European-American (n = 136)	Overdose fatality	CYP3A4	*1B	2% (C)	*1B allele enriched in overdose cases	[99]
European-American (n = 125)	Overdose fatality	CYP2B6	*9	28% (T)	*9 enriched in overdose cases	[100]
			rs8192719	29% (T)	T allele enriched in overdose cases
European (n = 40)	Plasma concentration in fatalities	CYP2B6	*6	38% (–)b,c	*6 allele increased (R,S)-methadone	[101]
European (n = 179)	QTc	CYP2B6	*6	22% (–)b	*6/*6 genotype increased QTc	[106]
European-American (n = 25)	QTc	CYP2C19	*2	13% (A)	*2 allele increased plasma concentration of EDDP, which increased QTc	[107]
Taiwanese (n = 366)	QTc	CYP2C19	*2 *3	33% (A) 4% (A)	Poor metabolism status increased QTc change in patients who continued using illicit opioids	[108]
European (n = 82)	QTc	KCNH2	rs1805123	25% (G)	C allele decreased QTc	[110]
Taiwanese (n = 366)	Reduced libido Insomnia	OPRM1	rs1074287	18% (G)	Minor alleles for all variants associated with changes in libido	[112]
			rs6912029	12% (T)
			rs12209447	12% (T)
			rs510769	17% (T)	Minor homozygous genotypes for all variants associated with insomnia
			rs3798676	12% (T)
			rs7748401	12% (G)
			rs495491	17% (G)
			rs10457090	12% (G)
			rs589046	17% (T)
			rs3778152	12% (G)
			rs563649	12% (T)
			rs2075572	23% (G)
Iranian (n = 202)	Reduced libido	OPRD1	rs2236855	17% (A)	T allele associated with reduced libido	[113]
Iranian (n = 202)	Reduced libido Insomnia	OPRK1	rs997917	30% (T)	C allele associated with reduced libido	[114]
			rs6985606	27% (T)	C allele associated with insomnia

^aEstimates from 1000 Genomes Project

^bFrequency from study population

^cFrequency of CYP2B6*6 carriers

EDDP 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, MAF predicted minor allele frequency in study ethnicity, QTc heart-rate-corrected QT interval