CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain: results from a retrospective study in an Italian cohort

Figures & data

Table 1 SNPs detected by xTAG CYP2D6 kit along with their frequencies in USA

*Haplotype	SNPs detected by xTAG CYP2D6 kit v3	Frequency in the US Caucasian population	Frequency in the African-American population	Predicted enzyme activity	References
*1	none	37%-40%	29%-35%	Normal	Kimura et al, 1989^Citation35 Marez et al, 1997^Citation36 Sachse et al, 1997^Citation37
*2	1,584C>G, 1,661 G>C, 2,850C>T, 4,180G>C	26%-33%	18%-27%	Normal	Johansson et al, 1993^Citation38 Panserat et al, 1994^Citation39 Marez et al, 1997^Citation36 Raimundo et al, 2000^Citation40
*3	2,549A>del	1.00%	0.2%-0.6%	None	Kagimoto et al, 1990^4l Marez et al, 1997^Citation36
*4	100C>T, 1,661G>C, 1,846G>A, 2,850C>T, 4,180G>C	18%-20%	6%-9%	None	Gough et al, 1990^Citation42 Hanioka et al, 1990^Citation43 Kagimoto et al, 1990^4l Marez et al, 1997^Citation36 Sachse et al, 1997^Citation37
*5	Deletion	2%-4%	6%-7%	None	Gaedigk et al, 1991^Citation44 Steen et al, 1995^Citation45
*6	1,707T>del, 4,180G>C	1%	0.5%	None	Evert et al, 1994^Citation46 Saxena et al, 1994^Citation47 Daly et al, 1995^Citation48 Marez et al, 1997^Citation36
*7	2,935A>C	Not known	Not known	None	Evert et al, 1994^Citation49
*8	1,661G>C, 1,758G>T,	Not known	Not known	None	Broly et al, 199 5^Citation50
*9	2,613delAGA	2%-3%	0.3%	Reduced	Tyndale et al, 1991^5I Broly et al, 1993^Citation52
*10	100C>T, 1,661G>C,	2%-8%	0.3%-0.4%	Reduced	Sakuyama et al, 2008^Citation53
*11	883G>C, 1,661G>C, 2,850C>T, 4,180G>C	Not known	Not known	None	Marez et al, 1995^Citation54
*15	138insT	Not known	Not known	None	Sachse et al, 1997^Citation37
*17	1,023C>T, 1,661G>C, 2,850C>T, 4,180G>C	0.2%-0.3%	15%-26%	Reduced	Masimirembwa et al, 1996^Citation55 Oscarson et al, 1997^Citation56
*29	1,659G>A, 1,661G>C, 2,850C>T, 3,183G>A,	Not known	Not known	Reduced	Marez et al, 1997^Citation36 Wennerholm et al, 2001^Citation57 Wennerholm et al, 2002^Citation58
*35	1,584C>G, 31G>A, 1,661G>C, 2,850C>T,	7.4%	l%	Normal	Marez et al, 1997^Citation36 Gaedigk et al, 20 03^Citation59
*41	1,661G>C, 2,850C>T, 2,988G>A, 4,180G>C	9%	11%	Reduced	Raimundo et al, 2000^Citation40 Raimundo et al, 2004^Citation60

Notes: Caucasian and African-American population. The column on the far left reports the expected CYP2D6 enzyme activity for each haplotype.

Abbreviation: SNP, single-nucleotide polymorphism.

Table 2 Allelic frequency in the Caucasian population

Genotype or allele	Phenotype	Observed (predicted) frequency (%)	Reference
*1/*1	WT	53.3 (55.0)	^Scordo et al, 2004^Citation63
*1/*3 (*4, *5, *6)	PM	35.0 (32.7)
*3/*4 *4/*4, *4/*5	IM	3.4 (4.2)
*1/*2×2	UM	8.3 (8.1)
*1	WT	22-32	Cavallari et al, 2011^Citation19
*2	EM	22
*4 *5	PM	22-28
*10, *17, *29, *41	IM	1-12
*2 n, *Xn	UM	1-5
*1	WT	33-37	#Haufroid and Hantson, 2015^Citation64
*2	EM	22-33
*3, *4, *5, *6	PM	15-35
*9, *10, *17, *41	IM	2-16
N/R	PM	30-100	§Ting and Schug, 2016^Citation15
N/R	IM	10-20
N/R	UM	8-43

Notes:

^ Calculated according to the Hardy–Weinberg equation in Italian population;

§ reported after a proportional correction of a factor 10 in order to uniform the data;

# EU Caucasian.

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; N/R, not reported; PM, poor metabolizer; UM, ultrarapid metabolizer; WT, wild type.

Figure 1 Patients chronically treated with codeine or oxycodone for the low back pain in each group selected to investigate the onset of the side effects and lack of benefit.

Table 3 Demographic and clinical characteristics of the two groups selected during enrollment of Italian volunteers of the retrospective study in the PainOMICS project

Characteristics of patients		Case (no benefit with side effects)				Control (benefit without side effects)				Total cohort
		n	M	SD	%	n	M	SD	%	n	M	SD	%
Age			68.7	13.1			66.5	14.5			6.8	14.3
Sex	Male	7			28.13	59			34.9	66			35.1
	Female	20			71.9	110			65.1	130			64.9
Weight (kg)			73.1	14.6			74.7	14.4			74.5	14.4
Height (cm)			163.5	8.5			165.9	8.9			165.5	8.8
BMI			27.3	4.7			27.1	5			27.2	4.9
Smoker		8			29.6	46			27.2	54			27.6
Pain generator	Radiculopathy	8			33.3	69			41.1	77			40
	Stenosis	4			13.3	11			6.3	15			7.3
	Sacroiliac joint	4			13.3	14			8.4	18			9.1
	Widespread Degeneration	6			23.3	31			18.4	37			19.1
	Zygapophyseal/facet joint	5			16.7	44			25.8	49			24.5
Pathophysiology of pain	Spinal stenosis				12.9				4.7				5.9
	Facet joint pain				16.1				25.8				24.4
	Sacroiliac joint pain				12.9				8.9				9.5
	Radicular pain				35.5				42.6				41.6
	Widespread pain				22.6				17.9				18.6
Total score of pain detected			12.6	6.2			12.6	7.2			12.6	7
Opioid	Codeine	10			37	87			51.5	97			49.5
	Oxycodone	17			63	82			48.5	99			50.5
Other drugs	No				87.1				82.8				83.4
	Yes				12.9				17.2				16.6

Abbreviation: BMI, body mass index.

Figure 2 Phenotype of patients (in percentage) chronically treated with opioids for the low back pain and split into two groups (Case = side effects without benefit; Control = benefit without side effects) in order to investigate the pharmacokinetics of codeine and oxycodone excluding DDI issues.

Abbreviations: CLBP, chronic low back pain; DDI, drug–drug interaction; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

Table 4 Distribution of CYP2D6 metabolizer phenotypes in the two groups studied according to sex

	WT/EM	IM/PM	UM	Total
Males	55 (83.3%)	10 (15.2%)	1 (1.5%)	66
Case	6 (85.7%)	–	1 (14.3%)	7
Control	49 (83.1%)	10 (17.0%)		59
Females	101 (77.7%)	23 (17.7%)	6 (4.6%)	130
Case	15 (75.0%)	4 (20.0%)	1 (5.0%)	20
Control	86 (78.2%)	19 (17.3%)	5 (4.6%)	110
Total	156 (79.6%)	33 (16.8%)	7 (3.6%)	196

Note: No significant differences between sexes were found (Case, Fisher’s exact test P=0.304; Control, Fisher’s exact test P=0.302).

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

Table 5 CYP2D6 haplotype distribution in the two groups studied (Case and Control) and their association with the no benefit/benefit status

Allele	Case (frequency)	Control (frequency)	OR	95% Lo	95% Hi	χ^2	P-value	Common (frequency >1%)
*1	20 (37%)	129 (38%)	1.000	1.000	1.000	0.092	0.761	+
*4	7 (13%)	66 (20%)	0.730	0.291	1.831	1.157	0.282	+
*2	9 (17%)	61 (18%)	0.973	0.415	2.282	0.077	0.782	+
*41	6 (11%)	38 (11%)	1.045	0.387	2.817	0.001	0.971	+
*35	3 (6%)	20 (6%)	0.921	0.248	3.429	0.040	0.841	+
*5	1 (2%)	8 (2%)	0.678	0.079	5.829	0.159	0.690	+
*9	3 (6%)	4 (1%)	5.760	1.111	29.870	5.358	0.021	+
*10	0 (%)	4 (1%)	0.000	0.000	0.000	0.744	0.389
*2N	2 (4%)	3 (1%)	4.795	0.710	32.380	3.142	0.076	+
*1N	0 (%)	2 (1%)	0.000	0.000	0.000	0.000	1.000
*6	3 (6%)	1 (0%)	81.340	3.356	1,971.000	19.400	0.011	+
*15	0 (%)	1 (0%)	0.000	0.000	0.000	0.000	1.000
*35	0 (%)	1 (0%)	0.000	0.000	0.000	0.000	1.000

Table 6 CYP2D6 diplotype distribution in the two groups (Case and Control) evaluated and their association with the status “no benefit or benefit” and “side effects or not”

Genotype	Case (frequency)	Control (frequency)	OR	95% Lo	95% Hi	χ^2	P-value	Common (frequency >1%)
*1/*1	5 (19%)	28 (17%)	1	1	1	1.682e-05	0.997	+
*1/*4	0 (0%)	21 (12%)	0	0	0	3.757	0.053	+
*1/*2	2 (7%)	24 (14%)	0.4782	0.08255	2.771	1.023	0.312	+
*1/*41	1 (4%)	12 (7%)	0.5818	0.05916	5.721	0.3729	0.541	+
*1/*35	1 (4%)	9 (5%)	0.6507	0.06512	6.503	0.1576	0.691	+
*1/*5	1 (4%)	2 (1%)	2.888	0.2018	41.33	0.6081	0.436	+
*1/*9	2 (7%)	2 (1%)	6.921	0.6521	73.46	2.734	0.098	+
*1/*2N	1 (4%)	2 (1%)	2.236	0.1576	31.73	0.7267	0.394	+
*1/10	0 (0%)	1 (1%)	0	0	0	0	1.000
*1/11	2 (7%)	0 (0%)	5.977e+163	1.69e+152	2.114e+ 175	12.43	0.000	+
*4/*4	1 (4%)	8 (5%)	0.7348	0.07269	7.428	0.1092	0.741	+
*2/*4	3 (11%)	12 (7%)	1.91	0.3676	9.93	0.5443	0.461	+
*4/*41	1 (4%)	10 (6%)	0.5659	0.05744	5.575	0.2826	0.595	+
*4/*35	0 (0%)	4 (2%)	0	0	0	0.6435	0.422	+
*4/*5	0 (0%)	1 (1%)	0	0	0	0	1.000
*4/*10	0 (0%)	1 (1%)	0	0	0	0	1.000
*4/*6	1 (4%)	1 (1%)	25.66	0.2941	2.239	4.656	0.031	+
*2/*2	1 (4%)	7 (4%)	0.8332	0.08038	8.636	0.08367	0.772	+
*2/*41	2 (7%)	7 (4%)	1.729	0.2649	11.29	0.4101	0.522	+
*2/*9	0 (0%)	1 (1%)	8.357e-07	8.357e-07	8.357e-07	0	1.000
*2/*10	0 (0%)	1 (1%)	0	0	0	0	1.000
*2/*9	0 (0%)	1 (1%)	0	0	0	0	1.000
*2/*15	0 (0%)	1 (1%)	0	0	0	0	1.000
*41/*41	0 (0%)	1 (1%)	0	0	0	0	1.000
*41/*35	0 (0%)	3 (2%)	0	0	0	0.5801	0.446	+
*41/*5	0 (0%)	2 (1%)	0	0	0	0.3935	0.531	+
*41/*9	1 (4%)	1 (1%)	9.136	0.3764	221.8	2.495	0.114	+
*41/*2N	1 (4%)	0 (0%)	5.904e+97	7.661e+91	4.55e+103	6.176	0.013	+
*41/*^	0 (0%)	1 (1%)	0	0	0	0	1.000
*35/*35	1 (4%)	1 (1%)	3.485	0.1627	74.63	0.888	0.346	+
*5/*35	0 (0%)	1 (1%)	0	0	0	0	1.000
*35/*3	0 (0%)	1 (1%)	0	0	0	0	1.000
*5/*10	0 (0%)	2 (1%)	0	0	0	0.4365	0.509	+

Notes: The significant results are reported in bold and shading.

Figure 3 Cartoon to summarize the results.

Notes: The alleles *6 and *9 seem to be mainly responsible for the lack of therapeutic effect during chronic treatment with opioids. *2N is responsible of side effects.
Abbreviations: IM, intermediate metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

Table S1 Phenotypes set for the various combinations of CYP2D6 alleles detected by xTAG CYP2D6 Kit v3

	*1	*2	*3	*4	*5	*6	*7	*8	*9	*10	*11	*15	*17	*29	*35	*41
*1	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM
*2		EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM	EM
*3			PM	PM	PM	PM	PM	PM	IM	IM	PM	PM	IM	IM	EM	IM
*4				PM	PM	PM	PM	PM	IM	IM	PM	PM	IM	IM	EM	IM
*5					PM	PM	PM	PM	IM	IM	PM	PM	IM	IM	EM	IM
*6						PM	PM	PM	IM	IM	PM	PM	IM	IM	EM	IM
*7							PM	PM	IM	IM	PM	PM	IM	IM	EM	IM
*8								PM	IM	IM	PM	PM	IM	IM	EM	IM
*9									IM	IM	IM	IM	IM	IM	EM	IM
*10										IM	IM	IM	IM	IM	EM	IM
*11											PM	PM	IM	IM	EM	IM
*15												PM	IM	IM	EM	IM
*17													IM	IM	EM	IM
*29														IM	EM	IM
*35															EM	EM
*41																IM

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

KimuraSUmenoMSkodaRCMeyerUAGonzalezFJThe human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogeneAm J Hum Genet19894568899042574001

 PubMed Web of Science ®Google Scholar

MarezDLegrandMSabbaghNPolymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolutionPharmacogenetics1997731932029241659

 PubMedGoogle Scholar

SachseCBrockmöllerJBauerSRootsICytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequencesAm J Hum Genet19976022842959012401

 PubMed Web of Science ®Google Scholar

JohanssonILundqvistEBertilssonLDahlMLSjöqvistFIngelman-SundbergMInherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquineProc Natl Acad Sci U S A1993902411825118297903454

 PubMed Web of Science ®Google Scholar

PanseratSMuraCGérardNDNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisersHum Genet19949444014067927337

 PubMed Web of Science ®Google Scholar

RaimundoSFischerJEichelbaumMGrieseEUSchwabMZangerUMElucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6Pharmacoge-netics2000107577581

 PubMed Web of Science ®Google Scholar

GoughACMilesJSSpurrNKIdentification of the primary gene defect at the cytochrome P450 CYP2D locusNature199034762957737761978251

 PubMed Web of Science ®Google Scholar

HaniokaNKimuraSMeyerUAGonzalezFJThe human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition siteAm J Hum Genet19904769951001

 Web of Science ®Google Scholar

GaedigkABlumMGaedigkREichelbaumMMeyerUADeletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphismAm J Hum Genet19914859439501673290

 PubMed Web of Science ®Google Scholar

SteenVMMolvenAAarskogNKGulbrandsenAKHomologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of human cytochrome P450 CYP2D6 geneHum Mol Genet1995412225122578634695

 PubMed Web of Science ®Google Scholar

EvertBGrieseEUEichelbaumMCloning and sequencing of a new non-functional CYP2D6 allele: deletion of T1795 in exon 3 generates a premature stop codonPharmacogenetics1994452712747894499

 PubMedGoogle Scholar

SaxenaRShawGLRellingMVIdentification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotypeHum Mol Genet1994369239267951238

 PubMed Web of Science ®Google Scholar

DalyAKLeathartJBLondonSJIdleJRAn inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitutionHum Genet19959533373417868129

 PubMed Web of Science ®Google Scholar

EvertBGrieseEUEichelbaumMA missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteineNaunyn Schmiedebergs Arch Pharmacol199435044344397845481

 PubMed Web of Science ®Google Scholar

BrolyFMarezDLo GuidiceJMA nonsense mutation in the cytochrome P450 CYP2D6 gene identified in a Caucasian with an enzyme deficiencyHum Genet19959656016038530011

 PubMed Web of Science ®Google Scholar

BrolyFMeyerUADebrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 genePharmacogenetics1993331231308101460

 PubMedGoogle Scholar

SakuyamaKSasakiTUjiieSFunctional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57)Drug Metab Dispos200836122460246718784265

 PubMed Web of Science ®Google Scholar

MarezDSabbaghNLegrandMLo-GuidiceJMBoonePBrolyFA novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotypePharmacogenetics1995553053118563771

 PubMedGoogle Scholar

MasimirembwaCPerssonIBertilssonLHaslerJIngelman-SundbergMA novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activityBr J Clin Pharmacol19964267137198971426

 PubMed Web of Science ®Google Scholar

OscarsonMHidestrandMJohanssonIIngelman-SundbergMA combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme functionMol Pharmacol1997526101040

 Web of Science ®Google Scholar

WennerholmAJohanssonIHidestrandMBertilssonLGustafssonLLIngelman-SundbergMCharacterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activityPharmacogenetics200111541742711470994

 PubMedGoogle Scholar

WennerholmADandaraCSayiJThe African-specific CYP2D617 allele encodes an enzyme with changed substrate specificityClin Pharmacol Ther2002711778811823760

 PubMed Web of Science ®Google Scholar

GaedigkARyderDLBradfordLDLeederJSCYP2D6 poor metabolizer status can be ruled out by a single genotyping assay for the -1584G promoter polymorphismClin Chem2003496 Pt 11008101112766015

 PubMed Web of Science ®Google Scholar

RaimundoSToscanoCKleinKA novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjectsClin Pharmacol Ther200476212813815289790

 PubMed Web of Science ®Google Scholar

ScordoMGCaputiAPD’ArrigoCFavaGSpinaEAllele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian populationPharmacol Res200450219520015177309

 PubMed Web of Science ®Google Scholar

CavallariLHJeongHBressARole of cytochrome P450 genotype in the steps toward personalized drug therapyPharmgenomics Pers Med2011412313623226058

 PubMedGoogle Scholar

HaufroidVHantsonPCYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressantsClin Toxicol2015536501510

 PubMed Web of Science ®Google Scholar

TingSSchugSThe pharmacogenomics of pain management: prospects for personalized medicineJ Pain Res201699495626929662

 PubMed Web of Science ®Google Scholar