Update on the pharmacogenomics of pain management

Figures & data

Table 1 Gene nomenclature explanation

CYP2C19*17
CYP	Superfamily
2	Family
C	Subfamily
19	Gene
*17	Allelic variant

Figure 1 Types of chronic pain.

Table 2 Ethnic differences in CYP2D6 activity

CYP2D6 genetics
Type	Activity	Ethnic differences
Poor metabolizer	None	Asian: 0-1.2%, African American: 2–5%, Ethiopian/Nigerian: 1.8-8.1%, Caucasians: 3–10%, Mexican American/Hispanic: 2.2–6.6%
Intermediate metabolizer	Low	Asian: 51%, Caucasian: 1-2%, Ethiopian/Nigerian: NA, Mexican American/Hispanic: NA
Extensive metabolizer	Normal	Most individuals fall into this category
Ultrarapid metabolizer	High	Asian: 0.9%, Danes and Finns: 1%, Ethiopian/Nigerian: 29-30%, Greeks: 10%, Mexican American/Hispanic: 1.7%, North Americans (white): 0.8-4.3%, Portuguese: 10%, Saudis: 20%

Notes: Data from these studies.^81,82

Table 3 Phenotypic effects of SNPs on drug metabolism

Drug given	Prodrug		Active drug
Metabolizer level	Poor	Rapid	Poor	Rapid
Drug exposure	Decreased conversion	Increased conversion	Decreased inactivation	Increased inactivation
Drug activity	Decreased efficacy	Increased efficacy	Increased efficacy	Decreased efficacy
Adverse effects	Increased if prodrug is toxic	Increased if active compound is toxic	Increased if drug is toxic	Decreased if drug is toxic Increased if drug is toxic

Figure 2 Biological polymorphisms involved in pain.

Table 4 A list of drugs, their clinical utility, associated polymorphisms and phenotypic effect of the genetic variant

Drug	Clinical utility	Genes	Phenotypic effect of the genetic variant
Codeine	Management of mild- to moderately-severe pain	CYP2D6 UGTB7	Poor metabolizers may fail to reach adequate analgesia Ultrarapid metabolizers may reach high levels of morphine following low to standard dosing leading to increased risk of toxic systemic concentrations of morphine^Citation87,Citation88,Citation108 Loss of function mutation in UGTB7 is associated with decreased metabolism of morphine, resulting in increased risk of toxicity^Citation86
Tramadol	Management of pain severe enough to require an opioid analgesic and for which alternative nonopioid treatments are inadequate	CYP2D6	Poor metabolizers fail to reach adequate analgesia^Citation87 Ultrarapid metabolizers may experience life-threatening serotonin or opioid receptor-mediated adverse events^Citation89
Hydrocodone	Management of pain severe enough to require daily around-the-clock opioid, long-term treatment and for which alternative treatment options are inadequate	CYP2D6 CYP3A4	CYP2D6 enzyme demethylates hydrocodone into hydromorphone, which has stronger mu receptor binding activity. Ultrarapid metabolizers may reach higher levels of hydromorphone from conversion of hydrocodone and thus be at higher risk of toxicity^Citation87,Citation90 Poor CYP2D6 metabolizers may not reach desired analgesic effect with standard dosing
Oxycodone	Pain management in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain	CYP3A4 CYP2D6	Patients designated as PMs have been reported to need more oxycodone to achieve adequate analgesia Complex phenotypic effects impacted by parent drug’s inherent analgesic effect^Citation94,Citation95 Weak evidence suggests a higher risk of side effects such as respiratory depression, tiredness, or nausea
Morphine	Management of pain severe enough for which alternative treatments are inadequate that require an opioid analgesic	ABCB1 OPRM1	Associations between ABCB1 polymorphisms and prolonged recovery room stays and postoperative morphine requirement^Citation83,Citation85 GG genotype for OPRM1 associated with increased requirement for postoperative opioids^Citation85
Diamorphine	Not recommended clinical utility to date	hCE-1 hCE-2	Variation in OPRK1 and OPRD1 may be connected to potential for addiction^Citation80,Citation96
		OPRK1
		OPRD1
Fentanyl	Surgery: adjunct to general or regional anesthesia; preoperative medication; analgesic during anesthesia and in the immediate postoperative period Transdermal device: acute postoperative pain Transdermal patch: management of pain in opioid-tolerant patients Transmucosal: management of breakthrough cancer pain in opioid-tolerant patients	OPRM1	Variations in median effective dose required to exhibit analgesia among polymorphisms such as ABCB1^Citation97
	ABCB1
Buprenorphine	Use for moderate to severe pain Opioid dependence	CYP3A4	OPRD1 SNPs such as rs58111 and rs529520 may help predict outcomes of buprenorphine use in treating opioid dependence^Citation98
		OPRD1
NSAIDS	Pain for which an opioid analgesic is not required	CYP2C9	Two variants of CYP2C9, CYP2C9*2 and CYP2C9*3, result in decreased inactivation of NSAID, increasing risk for side effects such as GI bleed^Citation100 Mutations resulting in varying concentrations of PTGS1/2 associated with variable response based on selectivity of NSAID for COX1 or COX2^Citation100
		PTGS1, PTGS2
Ketamine	Induction and maintenance of general anesthesia and procedural sedation/analgesia	CYP2B6, CYP3A4, CYP2C	Decreased enzyme binding and reduced drug clearance in polymorphisms have been noted, but clinical significance has yet to be identified.^Citation101
Lidocaine	Local and regional anesthesia by infiltration, nerve block, epidural, or spinal techniques	SCN9A MCR1	Reduced efficacy in polymorphisms^Citation102

Abbreviations: PM, poor metabolizer; NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase.

Figure 3 Predictive factors for personalized medicine.

Table 5 Evidence for correlations between ethnicity or gene polymorphisms based on metabolizer status

	Poor metabolizer/none	Intermediate metabolizer/low	Extensvine metabolizer/normal	Ultrarapid metabolizer/high
Bijl et al, 2007^Citation115	*3, *4, *5, *6	*10, *41	*1, *2	“Ultrarapid metabolizers” (UMs) have >2 functional copies of the CYP2D6 gene and exhibit extremely high enzyme activity. Many genotyping assays determine the duplication of any CYP2D6 gene, including nonfunctional genes, leading to false positive UM assignment. In this way, genotyping will only detect 10–30% of CYP2D6 UMs.
Bernard et al, 2005^Citation116	*3, *4	*9, *10, *17, *41	n/a	n/a
Zhou 2009^Citation117	*3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62	*10, *17, *36 and *41	*2	n/a
Dean 2012^Citation118	*4/*4, *4/*5, *5/*5, *4/*6	*4/*10, *5/*41	*1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *1/*10	*1/*1xN *1/*2xN
Gaedigk et al, 2017^Citation119	*3, *4, *4xN,*5, *6, *7, *8, *11, *12, *36, *40, *42, *56	*9, *10, *17, *29, *41, *44, *49	*2, *35, *43, *45	*1xN, *2xN
Del Tredici et al, 2018^Citation120	*3, *3xN, *4, *4xN, *4N, *5, *6, *6xN, *36, and *36xN	*9, *9xN, *10, *10xN, *17, *17xN, *29, *29xN, *36-*10, *36-*10xN, *36xN-*10, *36xN-*10xN, *41, and *41xN	*1, *1xN, *2, *2xN, *2A, *2AxN, *35, and *35xN	n/a

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