Overview of Genetics and Pain

10/17/2013 Overview of Genetics and Pain Kathleen Broglio, DNPc, MN, ANP-BC, ACHPN, CPE New York University School of Nursing [email protected]...
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10/17/2013

Overview of Genetics and Pain Kathleen Broglio, DNPc, MN, ANP-BC, ACHPN, CPE New York University School of Nursing [email protected] 808-561-6994

Conflict of Interest Disclosure • Advisory Board- Quest Diagnostics, Purdue Pharma • Speaker- Mundi Pharmaceuticals • Honorarium - UPTODATE

Objectives • Discuss the current state of pain genetics

research • Describe the role of genetics in pain

assessment and management • Discuss drug metabolism through CYP450 system and its effect on response to analgesics • Utilize pharmacogenetic testing to assess for potential response to analgesics

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Some basic definitions….. • Genotype – combination of the two set of chromosomes at

fertilization; an individual genetic constitution • Phenotype- the outward appearance of the individual; part of

genetic inheritance (predisposition) and influence of environment • Genomic Variation -only use 5% genes to generate proteins; 1. Decipher population history 2. Track somatic changes 3. Predict response to therapy 4. Identify genes for complex disease • Allele- different forms or DNA sequence of a gene • Genetic variations - DNA sequence variants that are more common in populations; Single nucleotide polymorphisms account for 3 million differences between individual pairs; significance - influence risk for complex common diseases

If it were only that easy…. • Science Daily News, Sept 9, 2011

Gene That Controls Chronic Pain Identified

Patient Profile • 62 y.o. Caucasian woman • Postthoracotomy neuropathic pain • Constant severe burning pain left posterolateral

surgical scar • Hyperalgesic along scar and dermatome

• Chronic low back pain, migraines • PMH: COPD - Oxygen

dependent/wheelchair bound

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What’s Genetics Have to do with Pain?

Genotype • Over 350 genes in pain database • Chronic Pain – multifactorial - polygenic

and environmental • Variation implicated in pain development,

characteristic, intensity, frequency, and analgesic responses • Mechanisms • Neurotransmitter system • Sodium/potassium/calcium channels • Opioid metabolism Mogil, 2012

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Young et al., 2012

Selected genes (variation) implicated in pain and response to analgesia Gene

Full name

Pain effect

Neurotransmitter

COMT1

Catechol-o-methyltransferase

Inactivates dopamine, epinephrine, norepinephrine

Changes in effects analgesics; variable response to painful stimuli

ABCB1

ATP-binding cassette, sub-family B (MDR/TAP), member 1

Transport drugs from intracellular to extracellular domains including CNS

Polymorphisms can effect efficacy and safety

Gene

Full Name

Ion Channel function

Pain effects

SCN9A

Sodium channel voltage gated type IX, alpha subunit

Voltage gated Na+

Increase chronic pain (mixed cohort); Alteration pain perception; Erythermalgia, paraxysmal extreme pain, congenital inability experience pain

KCNS1

Potassium voltage gated channel, delayed rectifier, subfamily s, member 1

Voltage gated K+

Increased risk neuropathic pain; sciatica, post-discectomy, amputation, phantom limb; experimental pain

HCN2

Hyper-polarization activated cyclic nucleotide gated ion channel 2

K+, NA+

Inflammatory and neuropathic pain

TRPV1

transient receptor potential cation channel, subfamily V, member 1

Non-selective calcium permeant cation channel

Thermal stimulation- neuropathic pain?

Gene OPRM1

Full name

Miscellaneous

Pain effect

Opioid receptor mu

Receptor functions endogenous opioids

Changes effects opioids- may work synergistically COMT

CYP450

Cytochrome p450

Catalyzes many reaction drug metabolism

Changes in metabolism of to analgesics/side effects

CCT52, FAM173B

Chaperonin-containing-TCP1-complex-5 gene, family with sequence similarity 173, member B

Unfolding proteins

Increased chronic widespread pain

Costigan et al., 2010; Jannetto & Bratanow, 2011; Mogil, 2005; Peters et al., 2012; Tammimaki & Mannisto, 2012; Young et al., 201;

ABCB1 • ATP-binding cassette, sub-family B

(MDR/TAP), member 1(ABCB1) • Drug transporter • Moves drugs from intracellular to extracellular

and CNS • Genetic polymorphisms may affect fentanyl,

methadone, and morphine • May affect the clinical efficacy and safety

Jannetto & Bratanow, 2011

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COMT • Catechol-O-methyltransferase (COMT)1 • Modulate nociception • Has been associated with chronic widespread pain, • Influence on analgesic (opioid) efficacy • May affect efficacy/work in synergy OPMR1 • Inconsistencies study replication, heterogeneity

of studies with only weak associations2 • Implications • Genetic testing may influence analgesic choice,

more studies needed Tammimäki & Männistö, 2012, Walter and Lötsch, 2009

HCN2 • Hyper-polarization activated cyclic

nucleotide gated ion channel 2 (HCN2) • Associated with action potential firing • Affects Na+ and K+ channels- ?pain intensity

• Implications • ? Novel analgesics target these channels

Emery et al., 2011

SCN9A (NAV1.7) • Sodium channel voltage gated type IX,

alpha subunit (SCN9A) • Expressed in peripheral somatic and visceral

sensory neurons • Loss or gain of function mutation pain

perception – Mendelian inheritance pattern • Erythermalgia, Paroxysmal extreme pain disorder

(PEPD), Congenital inability to experience pain (CIP)

• Implications • Development novel agents voltage gated sodium channel for neuropathic pain Dib-Hajj et al., 2013

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KCNS1 • Potassium voltage gated channel, delayed

rectifier, subfamily s, member 1 • Voltage gated K+ ion Channel • Variations possibly implicated in neuropathiic

pain • Implications: Nerve injury could lead to

increased risk neuropathic pain; sciatica, post-discectomy, amputation, phantom limb; experimental pain Costigan et al., 2010

TRPV1 • Transient receptor potential cation channel,

subfamily V, member 1 (TRPV1) • Function transduction painful thermal stimuli • Mouse model capsaicin effect for analgesia • Block the nociceptive sodium channels of TRPV1

• Implications • Analgesic target for therapy

Zakir, et al., 2012

OPMR1 • Opioid receptor mu (OPMR1) • Responsible opioid receptor function • Linked to opioid responsiveness • Caveat: Metanalysis failed to find clinical relevance1 • ? May not have taken into account all SNPS of mu opioid receptor

• Implications • Identifying variants may affect therapy decisions

1Walter

& Lötsch, 2009,

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Miscellaneous • SNP identified (rs2952768 on chromosome 

2q33.3‐2q34) • Function unknown • Associated with sensitivity to opioids, • Associated with liability to substance abuse1

1Nishizawa,

et al., 2012

Cytochrome P450 (CYP450) • Enzymes play role synthesis metabolism • Five human CYPs that have

been identified contributing most to drug metabolism • CYP1A2, CYP2C9, CYP2C19, CYP2D6, and

CYP3A4 • Implications • Testing for genetic variations may affect treatment decisions De Gregori et al., 2010

Implications for nursing • Excellent assessment of pain • Understand the potential for genetic etiology

• Ability to communicate with colleagues in

other disciplines with basic understanding of possible contribution of genetic variation • Treatment decisions based on pharmacogenetic testing

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Patient Profile • Developed chronic low back pain after work

injury 30 years ago • Developed severe post-thoracotomy pain after surgery and extensive hospitalization which included cardiopulmonary resuscitation and prolonged ventilatory support

Epigenetics • Interaction between genes and

environment • Affects gene expression – phenotype

• Challenges use of individualized medicine

based on genetic variation • Unquantifiable environmental effects

Buchheit et al., 2012

Role of epigenetic modification • Transition from acute to chronic pain under

epigenetic control • Immunologic response • Inflammatory cytokine expression • Glucocorticoid receptor function (pain sensitivity) • Pain regulatory genes downregulated • Opioid receptor regulation and function • Epigenetic alterations DNA methylation, histone

acetylation, and RNA interference Buchheit et al., 2012

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Prevention Chronic Pain • Epigenetic intervention • Possible medications interacting at level of

epigenetic changes • Valproic acid – (histone deactylase inhibitor/DNA

methlylation) • Glucosamine (DNA methylation)

• Multiple experimental modalities in process

Buchheit et al., 2012

Patient Profile • Reports migraine headaches since

childhood • Reports family history of pain in ancestors and in children

Heritability • Extended family study - any chronic pain

about 16% and severe chronic pain 30%1 • Twin studies • Low back/neck pain 35%2 • Systematic review low back pain 21-67%3 • Migraine and tension headaches 50%2 • Irritable bowel syndrome 25%2

• Neuropathic pain – assumed4 • Basic science models 1Hocking

et al., 2012, 2Nielsen et al., 2012, 3Ferreira et al, 2013 4Mogil et al., 1999

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Pedigree - American Caucasian n

n 83y DM Arthritis Migraine

20’s killed

5

98y DM Migraine HTN

98y DM

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6 60’s y HTN Migraine

Health Status unknown

60s y DM Migraine CLBP

5 Health Status unknown

Legend

58y Asthma CLBP DM arthritis

60y CLBP/surgery 50 Migraine HA

62y CPTS 2008 Migraine- childhood CLBP(fall) 30’s COPD 30’s (O2 2008)

CLBP- chronic low back pain COPD- chronic obstructive pulmonary disease CPTS- chronic Postthoracotomy pain syndrome DM- diabetes mellitus 64y HTN- Hypertension 80% body burn 7yo Arthritis Migraine

Patient Profile • Heritability- chronic pain consistent with

studies, lack studies neuropathic pain • Migraine • Low back pain

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Implications for nursing • Explore family history • May help with understanding of pain conditions • Patient education

• Stay abreast of possible development of

agents that may prevent evolution from acute to chronic pain

Patient Profile • Multiple trials of analgesics in past • Side effects from codeine • Excessive somnolence from methadone • Inefficacy from fentanyl • Adverse effects from multiple tricyclic

antidepressants • Adverse effects SNRIs

PHARMACOGENETIC TESTING

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Targets for Pain Management Effect of Genetic variation Gene Analgesic (with variant) affected

Consequence of variation

ABCB1

Morphine

Homozygous variants increased efficacy

CYP2D6

Codeine, oxycodone, tramadol

Poor metabolizers more adverse drug reactions, less efficacy

UGT2B7

morphine

Homozygous variants require lower doses; UGT2B7*2 variants less nausea

COMT

Morphine

Homozygous variants decrease in COMT activity; wild-type require higher doses than variant type

OPRM1

Morphine, M6G

Homozygous variants decreased efficacy, increased requirements

Adapted from Jannetto & Bratanow, 2011

Pharmacogenetics • How variations in genomes affect response

to medications • Term often used interchangeably with

pharmacogenomics • Genetic variation can influence

efficacy/toxicity • Pharmacogenetic testing • Can assist with appropriate selection of

medication and dosing Jannetto & Bratanow, 2011

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Selected analgesics – relevant genes Analgesic

Polymorphic Genes

Codeine

CYP2D6

Fentanyl

CYP3A4, CYP3A5, ABCB1, OPRM1

Oxycodone

CYP2D6

Methadone

CYP2B6, CYP3A4, CYP2D6, ABCB1

Morphine

ABCB1, COMT, UGT2B7, OPRM1

Tramadol

CYP2D6

See attached CYP-450 table for comprehensive table or www.drug-interactions.com Adapted from Jannetto & Bratanow, 2011

CYP2D6 • CYP2D6 – 25%prescribed medications • Ex. Codeine metabolized by CYP2D6 to

morphine • Poor metabolizers –little therapeutic effect • Ultra Rapid metabolizers – possible toxicity

• Worldwide variation - examples • Ultra-metabolizers higher percentage in North

Africa • Poor metabolizers – higher Europe Sistonen et al., 2007

CYP2C19 • CYP2C19 – 15% prescribed medications

(includes some SSRIs, benzodiazepines) • Ex. Tricyclic antidepressants (also affected by

CYP2D6) • Ultra-rapid metabolism may need alternative drug • Poor metabolizers may need lower dose

http://www.pharmgkb.org/gene/PA124, http://millenniumlabs.com/services/millennium-pgt-℠/

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CYP3A4 and CYP3A5 • CYP3A enzymes metabolize >40% drugs • Variations linked decreased enzyme activity • Increased drug levels

• Ex. Fentanyl, hydrocodone, buprenorphine,

methadone, clonazepam

Fine & Portenoy, 2007

CYP 2B6 • CYP 2B6 one of most polymorphic CYP

genes (many variants) • Examples of drugs metabolized include

efavirenz, bupropion, cyclophosphamide, ketamine, and methadone • Implications for analgesia – methadone • May require dosing changes • NB – methadone metabolized through other pathways CYP3A4/5, CYP2D6 Zhanger & Klein, 2013

Pharmacogenomic testing • Prediction of codeine toxicity in infants and

mothers • Testing for CYP2D6 and ABCB1 able to predict

87% of infant and maternal CNS depression cases Implications: Genetic markers can be used to improve outcomes of analgesic therapy (possibly beyond just predicting codeine toxicity) Sistonin et al., 2012

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Patient profile • Testing indicated • Poor metabolizer CYP2C19 and CYP2D6 • Variation of CYP3A4 variant showed decreased

metabolism • Medications rotated • Currently optimized on anticonvulsant, topical

anesthetic, morphine

The Caveats • Predicting response to analgesic therapy

with testing one piece of puzzle • Inability to predict precisely influence of genetic variations • Challenges with medications such as methadone where multiple enzymes involved • Cost of testing • Disparities in insurance coverage

Implications for nursing • Excellent history and tracking of

response/lack of response to analgesia • Exploration of the possibility of

pharmacogenetic testing if feasible • Adjusting treatment plans

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Future directions • Identification of clinical relevance of pain

genes • Novel therapies for pain based on genetic variation • Further refinement of pharmacogenetic testing • Treatment algorithms based on pharmacogenetic results

So what does this all mean…. • Despite its delayed entry, pain genetics is now proceeding

at a particularly rapid pace. As is not unusual in science, increasing knowledge has revealed the size of the problem to be far larger than anticipated. At the present time, I am not optimistic about pain geneticists explaining enough trait variance in clinical pain states or analgesic response to serve as a guide to individualized pain therapy any time soon. However, heuristic advances by pain geneticists are likely to accelerate and refine analgesic development efforts, leading ironically perhaps to new pain treatments for some rather than all. J. Mogil, 2012

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References Buchheit, T., Van de Ven, T., Shaw, A. (2012). Epigenetics and the transition from acute to chronic pain. Pain Medicine, 13, 1474-1490. Costigan, M., Belfer, I., Griffin, R. S., Dai, F., Barrett, L. B., Coppola, G., …Woolf, C. J. (2010). Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain, 133, 2519-2527 De Gregori, M. Allegri, M. DeGretori, S. (2010). How and why to screen for CYP2D6 interindvidual variability in patients under pharmacological treatments. Current Drug Metabolism, 11, 276-282. Dib-Hajj, S. D., Yang, Y., Black, J. A., & Waxman, S. G. (2013). The NAv1.7 sodium channel: from molecule to man. Nature Reviews, 14, 49-62. Emery, E. C., Young, G. T., Berrocoso, E., M., Chen, L. & McNaughton, P. A. (2011). HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science, 333, 1462-1466. Ferreira, P. H., Beckenkamp, P., Maher, C. G., Hopper, J., L., & Ferreira, M. L. (2013). Nature or nurture in low back pain? Results of a systematic review of studies based on twin samples. European Journal Of Pain, 17, 957-971. Fine, P. G. & Portenoy, R. K. (2007). A clinical guide to analgesia. US: Vendome Group Healthcare Division. Gottschalk, A., & Ochroch, E. A.(2008). Clinical and demographic characteristics of patients with chronic pain after major thoracotomy. Clinical Journal of Pain, 24, 708-716. Hocking, L. J., Scotland, G., Morris, A. D., Dominiczak, A. F., Porteous, D. J., & Smith, B. H. (2012). Heritability of chronic pain in 2195 extended families. European Journal of Pain, 16, 1053-1063. Jannetto P. J., Bratanow, N. C. (2011). Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring. Expert Opinion Drug Metabolism and Toxicology, 7, 745-752. Hocking, L. J., Scotland, G.Morris, A. D., Dominiczak, A. F., Porteous, D. J., & Smith, B. H. (2012). Heritability of chronic pain in 2195 extended families. European Journal of Pain, 16, 1053-1063.

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