IF:Pain

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Pain Management - OpioidsProblem and Implications • 2% to 40% of adults suffer from chronic pain1

• 90% of patients in the pain management setting receive opioids2

• Prescriptions for opioids have skyrocketed in recent years3

• 178% increase in hydrocodone3

• 556% increase in oxycodone3

• Opioid poisoning increased 91.2% between 1992 and 20024

• 80% of patients with adverse events from opioids had impaired CYP2D6 metabolism5

• Increased regulatory oversight and guidelines

• Codeine has pharmacogenetic language in label

1. Statement of Laxmaiah Manchikanti, MD, CEO, American Society of Interventional Pain Physicians Before the Sub- committee On Criminal Justice, Drug Policy, And Human Resources, July 26, 2006, Prescription Drug Abuse: What Is Being Done To Address This Drug Epidemic?

2. Manchikanti L, Damron KS, McManus CD, Barnhill RC. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial evaluation: A pro- spective, observational study. Pain Physician 2004; 7:431-437.

3. Testimony of Nora D. Volkow, M.D., Director, National Institute On Drug Abuse, National Institutes Of Health, U.S. Department Of Health And Human Services, Before The Subcommittee On Criminal Justice, Drug Policy, And Hu- man Resources Committee, July 26, 2006.

4. Paulozzi LJ, Budnitz DS, Yongli X. In- creasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf 2006; 15:618-627.

5. Utilization of Pharmacogenetics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics 2009;10(7):1157-1167

Pain Management: OpioidsClinical Fact Economic Implication Ref

Response to opioids can very as much as 40 fold among patients. Blood concentrations of opioids does not predict analgesia. Pain medications are involved in 30% of all adverse drug events involve pain medications.

Adverse drug events cost an average of $5.6M per hospital. Patients with adverse drug events average 8-12 additional hospital days at cost of $16,000 to $24,000

1,2

80% of patients reporting adverse drug reactions had impaired 2D6 metabolism

3,2

51% of patients taking oral opioids experience at least one adverse event or adverse effect.

4,2

29% of preventable adverse drug events were associated with analgesics

Increased length of stay by 2.2 days and costs by $3,244

51. Relationships between the measurement of pain using visual score analog and morphine requirements during post operative

intravenous morphine titration. Anesthesiology 2003;98(6):1415-1421.2. Agency for Healthcare Research and Quality. Publication # 01-00203. Utilization of Pharmacogenetics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics

2009;10(7):1157-11674. ACPA Guide to Chronic Pain Medication and Treatment. 2013 Edition5. The cost of drug events in hospitalized patients. Journal of the American Medical Association 1997;277:307-311.

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Biochemical and Physiological Effects of DrugsPharmacokinetics and Pharmacodynamics

Pharmacokinetics• What the body does to a drug

• Think metabolism, bioavailability• Converting Pro-Drug to active agent• Washing the active agent out of the body

Pharmacodynamics• What the drug does to the body

• Think therapeutic, sub-therapeutic or toxic

Distribution

Pharmacogenetics in Pain ManagementLeading pain management drugs are metabolized by genes in the CYP450 Super Family

Cytochrome P450 Enzymes• Enzymes bound to membranes within a cell (cyto)• Contain a heme pigment (chrom and P)• Heme pigment absorbs light at a wavelength of 450nm (450)

More than 50 enzymes in CYP450• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5

• 90% of drugs are metabolized by these 6 enzymes1,2

1. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24.

PhenotypesCategories of people with specific CYP450 variants (polymorphisms)

• Extensive Metabolizer (EM): • Normal Genetics• Two Good Copies of the genetic code required for metabolism

• Intermediate Metabolizer (IM): • Reduced enzymatic activity• 1 Good Copy and 1 Bad Copy of code required for metabolism

• May render the drug a No Go or require a dose adjustment

• Poor Metabolizer (PM): • Complete lack of enzymatic activity• 2 Bad Copies code required for metabolism• Usually renders a drug a No Go

• Ultra Rapid Metabolizer (UM): • Higher than average enzymatic activity• 2 Bad Copies causing much higher than normal metabolism• May render the drug a No Go or require a dose adjustment

Incidence of Variants in the PopulationAre variants rare or common?

Gene EM IM PM UM Total

CYP2D6 53% 35% 10% 2% 47%

CYP2C19 36% 32% 4% 28% 64%

CYP2C9 57% 40% 3% NA 43%

CYP3A4 87% 12% 1% NA 13%

CYP3A5 1% 18% 81% NA 99%

OPRM1 CaucasiansAfrican

AmericansAsians

Normal 60% 80% 30%

Intermediate 30% 19% 50%

Poor 5% 1% 20%

Pharmacogenetics in Pain ManagementPharmacogenetics is only relevant if the drug is metabolized by a CYP450 enzyme

** Prodrug

Consensus RecommendationsOur report will suggest specific actions for these drugs only

Gene Phenotype Drug Consensus Based Action Examples

CYP2D6 Intermediate Metabolizer 35% of the population

oxycodone Avoidhydrocodone Avoidcodeine Dose Adjustmentnortriptyline Dose Adjustmentamitriptyline Dose Adjustmentimipramine Dose Adjustment   

Poor Metabolizer 10% of the population

codeine Avoidhydrocodone Avoidoxycodone Avoidtramadol Avoidamitriptyline Avoidclomipramine Dose Adjustmentimipramine Dose Adjustment   

Ultra Rapid Metabolizer approx 2-6% of

Caucasian population 29% of North African

and Ethiopian populations

6% of African American populations

codeine Avoidhydrocodone Avoidoxycodone Avoidtramadol Dose Adjustmentnortriptyline Dose Adjustmentimipramine Dose Adjustmentclomipramine AvoidAmitriptyline Avoid

Consensus RecommendationsOur report will suggest specific actions for these drugs only

Gene Phenotype Drug Consensus Based Action Examples

CYP2C19 Intermediate Metabolizer25% of the population

Imipramine Dose Adjustment

  Poor Metabolizer2% of the population

Methadone (active portion) Carisoprodol

Possible dose adjustment Avoid, or use with caution

  Ultra Rapid Metabolizer 28% of the population 

Carisoprodol  

OPRM1 Poor Responder Active Opioids (eg, morphine)

Dose Adjustment

  Intermediate Responder Active Opioids Dose Adjustment

IF:PainWe test and report on Kinetics and Dynamics

HydrocodoneOxycodoneCodeineTramadol

MorphineHydromorphone OxymorphoneFentanyl

Common Opioids

Poor Metabolizer = decreased metabolic activity

Prodrug = lack of efficacy from no active metabolite

Active Drug = risk of side effects

Ultrarapid Metabolizer = Super-fast metabolic activity

Prodrug = risk of side effects from active metabolite

Active drug = risk of therapeutic failure

Incorporating PGX into Pain Management

What to do with results?

– CYP2D6 abnormal results (PM, UM): AVOID prodrugs due to potential lack of efficacy/risk ADRs

– CYP2D6 EM or IM results with inhibitor: use caution– OPRM1 G carriers: pts may need higher than average doses

PM = decreased metabolic activity

Prodrug = lack of efficacy from no active metabolite

Active Drug = risk of side effects

UM = fast metabolic activity

Prodrug = risk of side effects from active metabolite

Active drug = risk of therapeutic failure

CODEINE

CYP3A4 CYP2D6

Norcodeine

Morphine

Morphine-6-glucuronide Morphine-3-glucuronide

Active opioid effects (OPRM1)

Renal Excretion

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

CYP2D6 PM: inadequate morphine

CYP2D6 UM: morphine toxicity

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Report

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

**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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IF:PainWe test and report on Kinetics and Dynamics

Pharmacogenetics in OpioidsIn addition to CYP450, we also test for OPRM1

Cytochrome P450 Enzymes• Enzymes bound to membranes within a cell (cyto)• Contain a heme pigment (chrom and P)• Heme pigment absorbs light at a wavelength of 450nm (450)

More than 50 enzymes in CYP450• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5

• 90% of drugs are metabolized by these 6 enzymes1,2

1. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24.3. Reynolds 2008; Reyes-Gibby 2007; Klepstad 2004

• OPRM1: Mu Opioid Receptor• Variant decreases receptor availability3

• May lead to increased dose requirements3