Cohen, Mindy, MD Analgesics and the Effects of ...€¦ · Codeine & Tonsillectomy Kelly, L. et al. Pediatrics 2012 Drug/Metabolite Measured Blood Concentration Codeine Within expected

Analgesics and the Effects of Pharmacogenomics

Mindy Cohen, MD

Disclosures: none

Learning Objectives

1. Review genetic variations that influence analgesic pharmacotherapy in children.

2. Identify the most common polymorphisms in drug-metabolizing enzymes that influence analgesics.

3. Describe strategies for modifying analgesic regimens based on pharmacogenomics.

Before there was the need for analgesia, there was…

PAIN

Multifactorial Influences

Pain

Personality

Socio-economic status

Environment

Prior stress or trauma

Genetics

Secondary gain

Genetic influence on

pain sensitivity

Genetic influence on

analgesic medications

Cohen, Mindy, MD Analgesics and the Effects of Pharmacogenetics

Genetic Influences on Pain- Cases of Absent Pain

• Some rare cases explained by genetics

• Loss-of-function mutations α-subunit of voltage-gated sodium channel

Other components that regulate functioning and homeostasis of nervous system

Lotsch J et al. Trends in Pharm Sci 2010

Genetic Influences on Pain- Twin Studies

• 2007- Thermal & chemical noxious stimuli 98 pairs of twins

22-55% of variability was genetic

• 2008- Thermal noxious stimuli 96 twins

Cold-pressor pain• 7% of variability was genetic

Heat pain• 3% of variability was genetic

Smith M et al. Clinical Genetics 2012Norbury T et al. Brain 2007

Nielsen C et al. Pain 2008

Genetic Influences on Pain- Twin Studies

• 2012- Thermal noxious stimuli, μ-agonists 112 pairs of twins

Pain tolerance and opioid analgesia

24-60% of the response was influenced by genetic makeup

Angst M et al. Pain 2012

Analgesics and Genetics:

Pharmacokinetics and Pharmacodynamics

Genetic variation affects Pharmacokinetics

Genetic variation affects Pharmacokinetics


Pharmacokinetics- 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

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 Phenotype

Activity Score

Active alleles

Reduced function

Non-functional alleles

Ultrarapid > 2 > 2

Extensive 1-2 1-2 0-1 0-1

Intermediate 0.5 1 1

Poor 0 2

CYP 2D6Frequency of 2D6 metabolizer phenotypes in Caucasians

Metabolizer Phenotype

Activity Score

Ultrarapid (UM) 1-2%

Extensive (EM) 77-92%

Intermediate (IM) 2-11%

Poor (PM) 5-10%

CYP 2D6 - Ultrarapid Metabolizers (UMs)

Me

an

Pre

va

len

ce

of

UM

P

he

no

typ

e (

%)

3 0

2 0

1 0

0

7

2 9

722Northern

European

Caucasian

Asian

African

American

African/

Ethiopian


CYP 2D6- selected drug targets

• Oxycodone

• Hydrocodone

• Tramadol pro-drug, requires activation

• Codeine pro-drug, requires activation

Pharmacokinetics- Phase II Enzymes

• UGT enzymes Glucuronidation of drugs

UGT2B7 has genetic polymorphism

• Many opioids have –OH (hydroxyl) group Morphine, M3G, M6G

Codeine

Hydromorphone

Oxymorphone

Naloxone and Naltrexone

Case report: Codeine & Tonsillectomy

Figure adapted from http://PharmGKB.org

• 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


Kelly, L. et al. Pediatrics 2012

• POD #2 Parents found him pulseless

• Postmortem analysis suggested respiratory arrest

• Codeine and Morphine blood levels were measured…



Drug/Metabolite Measured Blood Concentration

Codeine Within expected range

Morphine 17.6 ng/mL

Therapeutic morphine concentration is4.5 +/- 2.1 ng/mL




Genotyping revealed a gene duplication that led to an



Genetic variation also affects

Pharmacodynamics

μ-Opioid Receptor

• OPRM1 encodes μ-Opioid Receptor

• G protein-coupled K+ channel

• 118A>G SNP influences binding of opioids and activation G/G genotype has less benefit from opioids

However, less adverse effects as well

Oertel, B. et al. Pharmacogenet Genomics 2006Chou, w. et al. Anesthesiology 2006

κ-Opioid Receptor

• MC1R encodes Melanocortin-1 receptor

• Improved analgesia of κ-opioid agonists in red-haired, fair-skinned women 75% carry 2 or more inactive variants

Consider incorporating κ-opioid analgesics in these patients (e.g. pentazocine)

• Non-gender specific μ-opioid agonist pain modulation Potency of morphine increased in inactive

variantsMogil, J et al. Proc Natl Acad Sci USA 2003

Mogil J et al. J Med Genet 2005


PharmacodynamicsABCB1/MDR1 transporter

• 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 2008Ross J et al. Cancer 2008



PharmacodynamicsCatechol-O-methyltransferase

• 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 2005Berthele A et al. Neuroimage 2005

OPRM1 and COMT likely interact

PainCOMT

genotype

ABCB1 genotype

OPRM1genotype

ABCB1 & OPRM1 interaction

• Morphine analgesia

• ABCB1 transporter

• T allele = less function

• OPRM1 mu-opioid receptor

• G allele = less affinity of receptor for morphine

Campa D. et al. Clin Pharm Ther 2008

Campa D. et al. Clin Pharm Ther 2008

Group 1 Group 2 Group 3

OPRM1 Normal Normal Decreased receptor response

ABCB1 Decreasedpump activity

Normal Normal

Non-Opioid Analgesics and Genetics


NSAIDs

• Example: Ibuprofen

• Major metabolic enzyme is CYP2C9 Some 2C9 polymorphisms decrease

enzyme function

Mazaleuskaya L et al. Pharmacogenet Genomics 2015

CYP2C9 Genotype and NSAID clearance

*3/*3 genotype has only 25% of the clearance as compared to *1/*1(wild type) genotype

• More important than dose adaptations could be genetic guidance on the choice of analgesic

• Genetics‐based dosing regimens?

• Chronic pain population…large potential for benefit

Translational Potential of Genetics

Crews K et al. Clin Pharm Ther 2012, Crews K et al. Nature 2014.

CPIC Guidelines for Codeine Therapy in the Context of CYP2D6 Genotype

Phenotype Implications for Codeine

Recommendations for codeine therapy

Classification of recommendation

Ultrarapid metabolizer

Increased formation of morphine, risk of toxicity

Avoid codeine. Consider morphine or nonopioid. Consider avoiding tramadol

Strong

Extensive metabolizer

Normal morphine formation

15-60 mg q4 hrs Strong

Intermediate metabolizer

Reduced morphine formation

15-60 mg q4 hrs. If no response, consider alternative

Moderate

Poor metabolizer

Greatly reduced morphine formation, insufficient pain relief

Avoid codeine. Considermorphine or nonopioid. Consider avoiding tramadol

Strong

FDA Black Box Warning What are graduating ENT residents planning to use in their practice?

Analgesic Regimen Post-tonsillectomy

Percent of ENT 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


The Individual Patient..

• 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

Adjustment of Morphine Dose?

Lotsch J & Geisslinger G Pain 2006

Resources• Pharmacogenomics Knowledge Base

www.pharmgkb.org

• Pharmacogenomics Research Network (PGRN)

www.pgrn.org

• FDA genomics resource

http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/

References• Angst, M. S., et al. (2010). "Opioid pharmacogenomics using a twin study

paradigm: methods and procedures for determining familial aggregation and heritability." Twin research and human genetics : the official journal of 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." The Clinical journal of pain 26 Suppl 10: S16.

• Berthele, A., et al. (2005). "COMT Val108/158Met genotype affects the mu-opioid receptor system in the human brain: evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression." NeuroImage28(1): 185.

• Campa, D., et al. (2008). "Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief." Clin Pharmacol Ther 83(4): 559.

• Cheng, J. and Sobol, S. (2013). "Despite warnings, some graduating otolaryngology residents planning to use codeine for posttonsillectomy pain control." Otolaryngol Head Neck Surg 148(2): 356.

• Chidambaran, V. and Sadhasivam, S. (2012). "Pediatric acute and surgical pain management: recent advances and future perspectives." International anesthesiology clinics 50(4): 66.

References• Cohen, M., et al. (2012). "Pharmacogenetics in perioperative medicine."

Current Opinion in Anaesthesiology 25(4): 419.

• Crews, K. R., et al. (2014). "Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update." Clinical pharmacology and therapeutics 95(4): 376.

• Hajj, A., et al. (2013). "Pharmacogenetics of opiates in clinical practice: the visible tip of the iceberg." Pharmacogenomics 14(5): 575.

• Jannetto, P. J. and Bratanow, N. C. (2011). "Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring." Expert opinion on drug metabolism & toxicology 7(6): 745.

• Kelly, L. E., et al. (2012). "More codeine fatalities after tonsillectomy in North American children." Pediatrics 129(5): e1343.

• Kolesnikov, Y., et al. (2011). "Combined Catechol-O-Methyltransferase and μ-Opioid Receptor Gene Polymorphisms Affect Morphine Postoperative Analgesia and Central Side Effects." Anesthesia & Analgesia 112(2): 448.

• Landau, R., et al. (2012). "Pharmacogenetics and anaesthesia: the value of genetic profiling." Anaesthesia 67(2): 165.

• Lotsch, J. and Geisslinger, G. (2006). "Current evidence for a genetic modulation of the response to analgesics." Pain 121(1-2): 1.

References• Lotsch, J. and Geisslinger, G. (2010). "A critical appraisal of human

genotyping for pain therapy." Trends in pharmacological sciences 31(7): 312.

• Mazaleuskaya, L. L., et al. (2015). "PharmGKB summary: ibuprofen pathways." Pharmacogenet Genomics 25(2): 96.

• Mogil, J. S., et al. (2005). "Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans." J Med Genet 42(7): 583.

• Mogil, J. S., et al. (2003). "The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans." Proc Natl Acad Sci U S A 100(8): 4867.

• Muralidharan, A. and Smith, M. T. (2011). "Pain, analgesia and genetics." The Journal of pharmacy and pharmacology 63(11): 1387.

• Nielsen, C. S., et al. (2008). "Individual differences in pain sensitivity: genetic and environmental contributions." Pain 136(1-2): 21.

• Norbury, T. A., et al. (2007). "Heritability of responses to painful stimuli in women: a classical twin study." Brain 130(Pt 11): 3041.

• Oertel, B. G., et al. (2006). "The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers." Pharmacogenet Genomics16(9): 625.


References• Rakvåg, T. T., et al. (2008). "Genetic variation in the Catechol-O-

Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain." Molecular Pain 4(1): 64.

• Ross, J. R., et al. (2008). "Genetic variation and response to morphine in cancer patients: catechol-o-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects." Cancer112(6): 1390.

• Sadhasivam, S. and Chidambaran, V. (2012). "Pharmacogenomics of opioids and perioperative pain management." Pharmacogenomics 13(15): 1719.

• Smith, M. T. and Muralidharan, A. (2012). "Pharmacogenetics of pain and analgesia." Clinical genetics 82(4): 321.

• Somogyi, A. A., et al. (2007). "Pharmacogenetics of opioids." Clinical pharmacology and therapeutics 81(3): 429.

• Webster, L. R. (2008). "Pharmacogenetics in pain management: the clinical need." Clinics in laboratory medicine 28(4): 569.

• Zanger, U. M., et al. (2008). "Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation." Analytical and Bioanalytical Chemistry 392(6): 1093.


Documents

Cohen, Mindy, MD Analgesics and the Effects of ...€¦ · Codeine & Tonsillectomy Kelly, L. et al. Pediatrics 2012 Drug/Metabolite Measured Blood Concentration Codeine Within expected