Copyright 2012-2013 PGXL Laboratories, Louisville KYAll materials herein are the exclusive property of PGXL Laboratories

PGX Applications in Pain Management

Kristen K. Reynolds, PhDVP Laboratory Operations

Panels*Core:

CYP2D6CYP2C9CYP2C19CYP3A4CYP3A5CYP1A2

Panel Add-Ons:

OPRM1 (opioids)

SLC6A4 (SSRIs)

*All genes always orderable a la carte

Generic Brand Metabolic Route

Alfentanil Alfenta CYP3A4/CYP3A5

Carisoprodol** Soma CYP2C19

Celecoxib Celebrex CYP2C9

Codeine** Various brands CYP2D6

Cyclobenzaprine Flexaril CYP1A2, CYP3A4/CYP3A5

Fentanyl Actiq, Duragesic CYP3A4/CYP3A5

Hydrocodone** Lortab, Vicodin CYP2D6

Hydromorphone Dilaudid UGT2B7+

Ibuprofen Advil, Motrin CYP2C9

Lidocaine Various brands CYP1A2

Methadone Various brands CYP2C19, CYP2B6+

Morphine Various brands UGT2B7+

Naproxen Aleve CYP2C9

Oxycodone** Oxycontin, Percocet CYP2D6, CYP3A4/5

Oxymorphone Opana UGT2B7+

Ropivicaine Various brands CYP1A2

Tizanidine Zanaflex CYP1A2

Tramadol** Ultram, various CYP2D6

Zolmipitran Zomig CYP1A2

**prodrug; + test not yet available

Common pain medications with PGXL tests

Opioids

Pharmacokinetic GeneMetabolism

Pharmacodynamic GeneClinical Effect

CYP2D6 - OpioidsHydrocodoneOxycodoneCodeine

PropoxypheneTramadoletc…

CODEINE

CYP3A4 CYP2D6

Norcodeine

Morphine

Morphine-6-glucuronide Morphine-3-glucuronide

Active opioid effects

Renal Excretion

Reynolds KR et al. Clin Lab Med 2008;28:581–598.

CYP2D6 PM: inadequate morphine

CYP2D6 UM: morphine toxicity

Decreased drug metabolism = lack of efficacy– Poor pain control– Mis-interpretation of drug seeking behavior

Ultra-rapid drug metabolism = possible side effects– Over-production of active compound– Mis-interpretation of over-compliance– Possible lower doses required

Effects of CYP2D6

8-15-12 FDA Drug Safety

Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death

• 3 deaths reported in children (2-5yo) who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea

• 3 deaths in children who were CYP2D6 UMs• All children received typical codeine doses• Morphine toxicity signs developed within 1-2 days after starting codeine• Supratherpeutic post-mortem morphine concentrations in the 3 death cases

Morphine Overdose from Codeine

FDA recommendations for Physicians:

• Use the lowest effective codeine dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock)

• Counsel parents:– how to recognize the signs of morphine toxicity– Advise them to stop giving the child codeine– Seek medical attention immediately if child exhibits these signs

• Tests are available for determining CYP2D6 genotype• Consider prescribing alternative analgesics for children

**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.

CYP2D6 Poor Metabolizer (PM): This patient’s genotype is consistent with a lack of CYP2D6 enzymatic activity. PMs are at increased risk of drug-induced side effects due to diminished drug elimination of active drugs or lack of therapeutic effect resulting from failure to generate the active form of the drug, as is the case with pro-drugs.

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CYP2D6 *4/*4 CYP2D6 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Codeine** Morphine, non-opioid Aripiprazole† 10 mg/day maximum Hydrocodone** Hydromorphone, non-opioid Clomipramine† decrease 50% Oxycodone** Oxymorphone, non-opioid Doxepin† decrease 60% Tramadol** Consider active drug, non-opioid Flecainide† decrease 50% Tamoxifen** Anastrozole, exemestane, letrozole Haloperidol† decrease 50% Amitriptyline† Citalopram, sertraline Imipramine† decrease 70% Venlafaxine† Citalopram, sertraline Nortriptyline† decrease 60% Risperidone† Quetiapine, olanzapine, clozapine Propafenone† decrease 70% Metoprolol† decrease 75%, or

atenolol, bisoprolol, carvedilol

Zuclopenthixol† decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine

RESULTS THERAPEUTIC IMPLICATIONS (adapted from published resources) Gene Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment X CYP2D6 *4/*4

Poor Metabolizer

Codeine* Hydrocodone* Oxycodone* Tramadol* Tamoxifen* Amitriptyline† Venlafaxine† Risperidone†

Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, non-opioid Anastrozole, exemestane, letrozole Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine

Aripiprazole† Clomipramine† Doxepin† Flecainide† Haloperidol† Imipramine† Nortriptyline† Propafenone† Metoprolol† Zuclopenthixol†

10 mg/day maximum 50% 60% 50% 50% 70% 60% 70% 75%, or atenolol, bisoprolol, carvedilol 50%, or flupenthixol, quetiapine, olanzapine, clozapine

CYP2D6 *1/*1

Extensive Metabolizer

Normal metabolic clearance expected. Common CYP2D6 medications next page

! CYP2D6 *1/*4

Intermediate Metabolizer

Oxycodone* Hydrocodone* Propafenone† Risperidone† Velafaxine†

Oxymorphone, non-opioid Hydromorphone, non-opioid Sotalol, disopyramide, quinidine, amiodarone Quetiapine, olanzapine, clozapine Citalopram, sertraline

Codeine* Tramadol* Tamoxifen* Amitriptyline† Imipramine† Nortriptyline† Zuclopenthixol† Doxepin† Flecainide† Metoprolol†

15-60 mg/hr titrate to pain relief Avoid CYP2D6 inhibitors, e.g. paroxetine, or consider aromatase inhibitor in post-menopausal women 25% 30% 40% 25% 20% 25% 50%, or atenolol, bisoprolol, carvedilol

X CYP2D6 *1/*1xN

Ultra-Rapid Metabolizer

Codeine* Hydrocodone* Oxycodone* Amitriptyline† Clomipramine†

Paroxetine† Atomoxetine†

Risperidone† Zuclopenthixol† Propafenone†

Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Citalopram, sertraline Citalopram, sertraline Citalopram, sertraline Methylphenidate Quetiapine, olanzapine, clozapine Flupenthixol, quetiapine, olanzapine, clozapine Sotalol, disopyramide, quinidine, amiodarone

Tramadol* Imipramine† Nortriptyline†

Venlafaxine†

Haloperidol† Doxepin†

Metoprolol†

30% 70% 60% 150%, or citalopram, sertraline based on plasma measurement, or pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine 100% up to 250%, or atenolol, bisoprolol, carvedilol

Pharmacokinetic GeneMetabolism

Pharmacodynamic GeneClinical Effect

OPRM1: Mu Opioid Receptor

AnalgesiaSedationEuphoria

Respiratory depressionItching

Morphine

Mu opioid receptor

OPRM1 118A>G GenotypesAG AA

GG

Mean effective analgesic

concentration =

Therapeutic target range

OPRM1: Mu Opioid Receptor

Opioid binds OPRM1 to elicit pain relief

118A>G variant decreases receptor availability and may increase dose requirements

AA AG GG0

50

100

150

200

250Morphine mg/24hr

Reynolds 2008; Reyes-Gibby 2007; Klepstad 2004

OPRM1 helps predict dose of active opioids

MorphineHydromorphoneOxymorphone

Generic Brand Metabolic Route Receptor/Dose

Alfentanil Alfenta CYP3A4/CYP3A5

Carisoprodol** Soma CYP2C19

Celecoxib Celebrex CYP2C9

Codeine** Various brands CYP2D6

Cyclobenzaprine Flexaril CYP1A2, CYP3A4/CYP3A5

Fentanyl Actiq, Duragesic CYP3A4/CYP3A5

Hydrocodone** Various brands CYP2D6

Hydromorphone Dilaudid UGT2B7+ OPRM1

Ibuprofen Advil, Motrin CYP2C9

Lidocaine Various brands CYP1A2

Methadone Various brands CYP2C19, CYP2B6+

Morphine Various brands UGT2B7+ OPRM1

Naproxen Aleve CYP2C9

Oxycodone** Oxycontin, various CYP2D6, CYP3A4/5

Oxymorphone Opana UGT2B7+ OPRM1

Ropivicaine Various brands CYP1A2

Tizanidine Zanaflex CYP1A2

Tramadol** Ultram, various CYP2D6

Zolmipitran Zomig CYP1A2

**prodrug; + test not yet available

OPRM1 Opioid InterpretationsOPRM1 AAOPRM1 Phenotype Therapeutic Implications (adapted from published resources)Normal Opioid Responder

Opioid response: Average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity.

OPRM1 GGOPRM1 Phenotype Therapeutic Implications (adapted from published resources)Poor Opioid Responder

Opioid response: Higher then average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity.

Adjust Dosage Morphine

Adjustment Increase up to 80%

OPRM1 AGOPRM1 Phenotype Therapeutic Implications (adapted from published resources)Intermediate Opioid Responder

Opioid response: Higher then average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity.

Adjust Dosage Morphine

Adjustment Increase 10%

OPRM1 and Naltrexone for Alcohol dependence

OPRM1 and Naltrexone

Naltrexone is a competitive mu opioid receptor antagonist

– Decreases alcohol cravings– Inhibits endorphin “reward”

effects in EtOH/opioid abuse– Decreases relapse risk

EtOH

OPRM1 and risk of alcohol relapse

• 40% of patients treated with naltrexone will relapse

• 80% of those who relapse have AA genotype

Chamorro et al. Addiction Biology 2012;17:505-12.

OPRM1 AA carriers treated with naltrexone have highest risk of relapse

Chamorro et al. Addiction Biology 2012;17:505-12.

AA genotype pts are 2x more likely to relapse that G carriers

OPRM1 Combined Interpretations

OPRM1 AA

OPRM1 Phenotype Therapeutic Implications (adapted from published resources)Normal Opioid Responder / Impaired Naltrexone Responder

Opioid response: Average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity. Naltrexone response: With respect to naltrexone treatment for alcohol dependence, 80% of treated patients who relapse have the OPRM1 AA genotype. Relapse rate among AA genotype patients is 5% higher than the typical on-treatment relapse rate, and is 2-fold greater than for patients with the AG or GG genotypes.

OPRM1 Combined Interpretations

OPRM1 GG

OPRM1 Phenotype Therapeutic Implications (adapted from published resources)Poor Opioid Responder / Normal Naltrexone Responder

Opioid response: Higher then average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity. Naltrexone response: In patients treated with naltrexone for alcohol dependence, those with the GG genotype have a 15% lower average relapse rate compared to the typical on-treatment relapse rate. Overall, relapse rate among G allele carriers is 25% compared to 54% in patients with AA genotype.

Adjust Dosage Morphine

Adjustment Increase up to 80%

OPRM1 Combined Interpretations

OPRM1 GG

OPRM1 Phenotype Therapeutic Implications (adapted from published resources)Poor Opioid Responder / Normal Naltrexone Responder

Opioid response: Higher then average doses of morphine typically required (may also apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on CYP2D6 activity. Naltrexone response: In patients treated with naltrexone for alcohol dependence, those with the GG genotype have a 15% lower average relapse rate compared to the typical on-treatment relapse rate. Overall, relapse rate among G allele carriers is 25% compared to 54% in patients with AA genotype.

Adjust Dosage Morphine

Adjustment Increase up to 80%

NSAIDs

NSAIDs• Non-steroidal anti-inflammatory drugs• Ibuprofen, naproxen, celecoxib, diclofenac, etc• Individual or combination preparations

• Celebrex (celecoxib)• Vicoprofen (hydrocodone + ibuprofen)

NSAID Adverse Events Severe ADRs• Ulcer• GI bleed• Kidney failure• MI• Stroke

Metabolized by CYP2C9

CYP2C9 variants increase risk of NSAID-induced bleeding

CYP2C9 Genotype Risk of GI bleed taking NSAID

*1/*1 1

*1/*2 3.8

*1/*3 7.3

• Case control study: 26 patients taking NSAID <1 month with confirmed GI

bleed vs 52 NSAID users without GI bleeds

• CYP2C9 genotyping performed

Pilotto et al Gastroenterology 2007;133(2):465-71.

CYP2C9 and NSAID use• CYP2C9 genotyping may identify

patient subgroups at increased risk of NSAID-related GI bleeding

• Use with caution based on other clinical factors

Summary Pearls

• Opioid prodrug efficacy/ADR: 2D6• Active opioid dose: OPRM1• Naltrexone efficacy: OPRM1• NSAID ADR: 2C9• Other opioids and muscle relaxers: 3A4/5,

2C19, 1A2