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IF:Pain © 2009 - 2014 PGXL Laboratories Pain Management - Opioids Problem 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: Opioids Clinical Fact 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. 80% of patients reporting adverse drug reactions had impaired 2D6 metabolism Economic Implication 1,2 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 51% of patients taking oral opioids experience at least one adverse event or adverse effect. 29% of preventable adverse drug events were associated with analgesics Ref 3,2 4,2 Increased length of stay by 2.2 days and costs by $3,244 5 1. 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 # 01-0020 3. Utilization of Pharmacogenetics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics 2009;10(7):1157-1167 4. ACPA Guide to Chronic Pain Medication and Treatment. 2013 Edition 5. The cost of drug events in hospitalized patients. Journal of the American Medical Association 1997;277:307-311. Property of PGxl Biochemical and Physiological Effects Pharmacokinetics and Pharmacodynamics of Drugs 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 Distribution Pharmacodynamics • What the drug does to the body • Think therapeutic, sub-therapeutic or toxic Pharmacogenetics in Pain Management Leading 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. Phenotypes Categories 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 Population Are 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 Caucasians African Americans Asians Normal 60% 80% 30% Intermediate 30% 19% 50% 5% 1% 20% Poor Pharmacogenetics in Pain Management Pharmacogenetics is only relevant if the drug is metabolized by a CYP450 enzyme ** Prodrug Consensus Recommendations Our report will suggest specific actions for these drugs only Gene CYP2D6 Phenotype Intermediate Metabolizer 35% of the population Poor Metabolizer 10% of the population Ultra Rapid Metabolizer approx 2-6% of Caucasian population 29% of North African and Ethiopian populations 6% of African American populations Drug oxycodone hydrocodone codeine nortriptyline amitriptyline imipramine Consensus Based Action Examples Avoid Avoid Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment codeine hydrocodone oxycodone tramadol amitriptyline clomipramine imipramine Avoid Avoid Avoid Avoid Avoid Dose Adjustment Dose Adjustment codeine hydrocodone oxycodone tramadol nortriptyline imipramine clomipramine Amitriptyline Avoid Avoid Avoid Dose Adjustment Dose Adjustment Dose Adjustment Avoid Avoid Consensus Recommendations Our report will suggest specific actions for these drugs only Gene CYP2C19 Phenotype Intermediate Metabolizer Drug Consensus Based Action Examples Imipramine Dose Adjustment Methadone (active portion) Possible dose adjustment Carisoprodol Avoid, or use with caution 25% of the population Poor Metabolizer 2% of the population Ultra Rapid Metabolizer OPRM1 Carisoprodol 28% of the population Poor Responder Active Opioids (eg, morphine) Dose Adjustment Intermediate Responder Active Opioids Dose Adjustment IF:Pain We test and report on Kinetics and Dynamics Common Opioids Hydrocodone Oxycodone Codeine Tramadol Morphine Hydromorphone Oxymorphone Fentanyl Poor Metabolizer = decreased metabolic activity Ultrarapid Metabolizer = Super-fast metabolic activity Prodrug = lack of efficacy from no active metabolite Prodrug = risk of side effects from active metabolite Active Drug = risk of side effects 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 PM = decreased metabolic activity UM = fast metabolic activity Prodrug = lack of efficacy from no active metabolite Prodrug = risk of side effects from active metabolite Active Drug = risk of side effects – CYP2D6 EM or IM Active druguse = riskcaution of therapeutic failure results with inhibitor: – OPRM1 G carriers: pts may need higher than average doses CODEINE CYP2D6 PM: inadequate morphine CYP2D6 UM: morphine toxicity CYP3A4 CYP2D6 Morphine Norcodeine Active opioid effects (OPRM1) Morphine-6-glucuronide Morphine-3-glucuronide Renal Excretion Reynolds KR et al. Clin Lab Med 2008;28:581–598. Property of PGxl Laboratories Report CYP2D6 *4/*4 CYP2D6 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment 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 † 10 mg/day maximum decrease 50% decrease 60% decrease 50% decrease 50% decrease 70% decrease 60% decrease 70% decrease 75%, or atenolol, bisoprolol, carvedilol decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine Zuclopenthixol † **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. Property of PGxl Laboratories IF:Pain We test and report on Kinetics and Dynamics Pharmacogenetics in Opioids In 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 • OPRM1: Mu Opioid Receptor • Variant decreases receptor availability3 • May lead to increased dose requirements3 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