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Analgesics and the Effects of Pharmacogenomics Disclosures: None Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics Analgesics and the Effects of Pharmacogenomics Disclosures: none Mindy Cohen, MD Learning Objectives 1. Review genetic variations that influence analgesic pharmacotherapy in children. 2. Identify the most common Before there was the need for polymorphisms in drug-metabolizing enzymes that influence analgesics. analgesia, there was… 3. Describe strategies for modifying analgesic regimens based on pharmacogenomics. PAIN Multifactorial Influences Genetic influence on Personality pain sensitivity Secondary Socio-economic gain status Pain Genetic influence on Genetics Environment analgesic medications Prior stress or trauma Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics Genetic Influences on Pain Genetic Influences on Pain - Cases of Absent Pain - Twin Studies • Some rare cases explained by genetics • 2007- Thermal & chemical noxious stimuli • Loss-of-function mutations . 98 pairs of twins . α-subunit of voltage-gated sodium channel . 22-55% of variability was genetic . Other components that regulate functioning • 2008- Thermal noxious stimuli and homeostasis of nervous system . 96 twins . Cold-pressor pain • 7% of variability was genetic . Heat pain • 3% of variability was genetic Smith M et al. Clinical Genetics 2012 Norbury T et al. Brain 2007 Lotsch J et al. Trends in Pharm Sci 2010 Nielsen C et al. Pain 2008 Genetic Influences on Pain - Twin Studies • 2012- Thermal noxious stimuli, μ-agonists Analgesics and Genetics: . 112 pairs of twins . Pain tolerance and opioid analgesia Pharmacokinetics and . 24-60% of the response was influenced by Pharmacodynamics genetic makeup Angst M et al. Pain 2012 Genetic variation affects Genetic variation affects Pharmacokinetics Pharmacokinetics Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics Pharmacokinetics Pharmacokinetics - Phase I Enzymes - Phase I Enzymes • Cytochrome P450 superfamily • Alter the chemical structure of drugs . Six most significant CYPs • 3A4/5 37-60% of drugs • 2D6 15-25% of drugs *CODEINE* • 2C19 10% • 1A2 9% • 2E1 2% • 2B6 4% Zanger et al. Analytical and Bioanalytical Chem 2008 Pharmacokinetics - Phase I Enzymes CYP 2D6 • 2D6 is highly polymorphic • Alleles defined as . Normal, Reduced, Non-functional Metabolizer Activity Active Reduced Non- Phenotype Score alleles function functional alleles Ultrarapid > 2 > 2 Extensive 1-2 1-2 0-1 0-1 Intermediate 0.5 1 1 Poor 0 2 Zanger et al. Analytical and Bioanalytical Chem 2008 CYP 2D6 CYP 2D6 - Ultrarapid Metabolizers (UMs) Frequency of 2D6 metabolizer phenotypes in Caucasians 30 Metabolizer Activity Phenotype Score 20 Ultrarapid (UM) 1-2% 29 Extensive (EM) 77-92% Phenotype (%) 10 Intermediate (IM) 2-11% Mean Prevalence of UM of Prevalence Mean 7 7 Poor (PM) 5-10% 2 2 0 Afr A N Asian C Eth A fr au Europeano ica m ica rt i e c her opi n r n as / ican n a ian n Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics CYP 2D6 Pharmacokinetics - selected drug targets - Phase II Enzymes • Oxycodone • UGT enzymes • Hydrocodone . Glucuronidation of drugs • Tramadol pro-drug, requires activation . UGT2B7 has genetic polymorphism • Codeine pro-drug, requires activation • Many opioids have –OH (hydroxyl) group . Morphine, M3G, M6G . Codeine . Hydromorphone . Oxymorphone . Naloxone and Naltrexone Case report: Case report: Codeine & Tonsillectomy Codeine & Tonsillectomy • 4 year-old boy (27.6 kg) with obstructive sleep apnea and recurrent tonsillitis • Underwent adenotonsillectomy • Discharged on POD #1 • Prescribed codeine 8 mg/dose q 4-6 hrs . Received a total of 4 doses Figure adapted from Kelly, L. et al. Pediatrics 2012 http://PharmGKB.org Case report: Case report: Codeine & Tonsillectomy Codeine & Tonsillectomy • POD #2 Drug/Metabolite Measured Blood Concentration . Parents found him pulseless Codeine Within expected range • Postmortem analysis suggested respiratory arrest Morphine 17.6 ng/mL • Codeine and Morphine blood levels were measured… Therapeutic morphine concentration is 4.5 +/- 2.1 ng/mL Kelly, L. et al. Pediatrics 2012 Kelly, L. et al. Pediatrics 2012 Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics Case report: Genetic variation also affects Codeine & Tonsillectomy Pharmacodynamics Genotyping revealed a gene duplication that led to an Kelly, L. et al. Pediatrics 2012 μ-Opioid Receptor κ-Opioid Receptor • OPRM1 encodes μ-Opioid Receptor • MC1R encodes Melanocortin-1 receptor • G protein-coupled K+ channel • Improved analgesia of κ-opioid agonists in • 118A>G SNP influences binding of opioids red-haired, fair-skinned women and activation . 75% carry 2 or more inactive variants . G/G genotype has less benefit from opioids . Consider incorporating κ-opioid analgesics . However, less adverse effects as well in these patients (e.g. pentazocine) • Non-gender specific μ-opioid agonist pain modulation . Potency of morphine increased in inactive variants Mogil, J et al. Proc Natl Acad Sci USA 2003 Oertel, B. et al. Pharmacogenet Genomics 2006 Mogil J et al. J Med Genet 2005 Chou, w. et al. Anesthesiology 2006 Genetic variation also affects ABCB1/MDR1 transporter Pharmacodynamics • Removes drugs from intracellular compartment • 3435 C>T SNP, T/T genotype has 4-fold less protein expression . Require less oral opioids for analgesia . Possibly due to increased drug absorption and concentration at site of action • 2677 G>T/A SNP . A allele protective of central side effects Campa D et al. Clin Pharm Ther 2008 Ross J et al. Cancer 2008 Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics Genetic variation also affects Catechol-O-methyltransferase Pharmacodynamics • Metabolizes and inactivates catecholamines • Regulator of Dopamine, Epinephrine, and Norepinephrine in the pain pathway • 472 G>A SNP . Patients require less morphine . Perhaps low-function COMT leads to up- regulation of μ-opioid receptor Rakvag T et al. Pain 2005 Berthele A et al. Neuroimage 2005 OPRM1 and COMT likely ABCB1 & OPRM1 interaction interact • Morphine analgesia COMT OPRM1 genotype • ABCB1 transporter genotype Pain • T allele = less function • OPRM1 mu-opioid receptor • G allele = less affinity of receptor for morphine ABCB1 genotype Campa D. et al. Clin Pharm Ther 2008 Non-Opioid Analgesics and Genetics Group 1 Group 2 Group 3 OPRM1 Normal Normal Decreased receptor response ABCB1 Decreased Normal Normal pump activity Campa D. et al. Clin Pharm Ther 2008 Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics NSAIDs CYP2C9 Genotype and NSAID clearance • Example: Ibuprofen • Major metabolic enzyme is CYP2C9 . Some 2C9 polymorphisms decrease enzyme function *3/*3 genotype has only 25% of the clearance as compared to *1/*1(wild type) genotype Mazaleuskaya L et al. Pharmacogenet Genomics 2015 CPIC Guidelines for Codeine Therapy in Translational Potential of Genetics the Context of CYP2D6 Genotype • More important than dose adaptations could Phenotype Implications for Recommendations for Classification of be genetic guidance on the choice of Codeine codeine therapy recommendation analgesic Ultrarapid Increased formation Avoid codeine. Consider Strong metabolizer of morphine, risk of morphine or nonopioid. • Genetics‐based dosing regimens? toxicity Consider avoiding tramadol Chronic pain population…large potential for • Extensive Normal morphine 15-60 mg q4 hrs Strong benefit metabolizer formation Intermediate Reduced morphine 15-60 mg q4 hrs. If no Moderate metabolizer formation response, consider alternative Poor Greatly reduced Avoid codeine. Consider Strong metabolizer morphine formation, morphine or nonopioid. insufficient pain relief Consider avoiding tramadol Crews K et al. Clin Pharm Ther 2012, Crews K et al. Nature 2014. FDA Black Box Warning What are graduating ENT residents planning to use in their practice? Analgesic Regimen Percent of ENT Post-tonsillectomy Residents Acetaminophen/Hydrocodone 25.5% Acetaminophen 19% Ibuprofen 17% Acetaminophen/Oxycodone 14.9% Acetaminophen/Codeine 8.5% Hydrocodone 8.5% Oxycodone 4.3% Cheng et al. Otolaryngol Head Neck Surgery 2013 Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics The Individual Patient.. Adjustment of Morphine Dose? • Better therapeutic outcome • Successful management of “condition” in real world might increase from 60% to 90+% • Futile therapeutics would decrease • Cost-benefit across drugs and conditions would improve “Imagine if we could readily evaluate the opioid metabolism or receptor function of patients during their preoperative assessments and develop perioperative pain treatment plans targeted specifically to each one.” - Mark Warner, M.D. Rovenstine Lecture 2006 Lotsch J & Geisslinger G Pain 2006 Resources References • Angst, M. S., et al. (2010). "Opioid pharmacogenomics using a twin study • Pharmacogenomics Knowledge Base paradigm: methods and procedures for determining familial aggregation and heritability." Twin research and human genetics : the official journal of . www.pharmgkb.org the International Society for Twin Studies 13(5): 412. • Angst, M. S., et al. (2012). "Pain sensitivity and opioid analgesia: a pharmacogenomic twin study." Pain 153(7): 1397. • Argoff, C. E. (2010). "Clinical implications of opioid pharmacogenetics." • Pharmacogenomics Research Network The Clinical journal of pain 26 Suppl 10: S16. (PGRN) • Berthele, A., et al. (2005). "COMT Val108/158Met genotype affects the mu- opioid receptor system in the human brain: evidence from ligand-binding, . www.pgrn.org G-protein activation and preproenkephalin mRNA expression."
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