Overview of Genetics and Pain

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Overview of Genetics and Pain

• Kathleen Broglio, DNPc, MN, ANP-BC, ACHPN, CPE
• New York University School of Nursing
• Kathleen.broglio_at_nyu.edu
• 808-561-6994

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Conflict of Interest Disclosure

• Advisory Board- Quest Diagnostics, Purdue Pharma
• Speaker- Mundi Pharmaceuticals
• Honorarium UP TO DATE

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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 genetic testing to assess for potential
  response to analgesics

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Some basic definitions..

• Allele- another word for another forms
  different forms or DNA sequence of a gene in a
  population
• Genomic Variation -only use 5 genes to generate
  proteins individual humans differ at about 1 in
  1000 bases 1. Decipher population history 2.
  Track somatic changes 3. Predict response to
  therapy 4. Identify genes for complex disease
• Genetic variations - single nucleotide
  polymorphism (SNP) DNA sequence variants that
  are more common in populations Two or more
  alleles at a locus each have frequencies exceed
  1 - significance - influence risk for complex
  common diseases such as DM, CAD
• Genotype combination of the two set of
  chromosomes (mother and father) at fertilization
  an individual genetic constitution
• Phenotype- the outward appearance of the
  individual something that is physically and
  clinically observed, anything that is
  measured/observed part of genetic inheritance
  (predisposition) and influence of environment

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If it were only that easy.

• Science Daily News, Sept 9, 2011

Gene That Controls Chronic Pain Identified
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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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Whats Genetics Have to do with Pain?
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Genotype

• Over 350 genes in pain database
• Chronic Pain multifactorial - polygenic and
  environmental
• Variability in development, intensity, perception
  and analgesic responses
• Genes involved in
• Neurotransmitter system
• Sodium/potassium/calcium channels
• Opioid metabolism

Mogil, 2012
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Selected genes implicated in chronic pain and
analgesia
Gene Full name Neurotransmitter Pain effect
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 implicated Erythomelagia, paraxysmal extreme pain, insensate
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 Full name Miscellaneous Pain effect
OPRM1 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
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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

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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
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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
• Erythromelagia, 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
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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
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OPMR1

• Opioid receptor mu (OPMR1)
• Receptor function endogenous opioids
• Linked to opioid responsiveness
• Caveat Metanalysis failed to find clinical
  relevance1
• ? May not have taken into account all SNPS of mu
  opioid receptor
• SNP identified (function unknown) associated with
  sensitivity to opioids, liability to substance
  abuse2
• Implications
• Identifying variants may affect therapy decisions

1Walter Lötsch, 2009, 2Nishizawa, et al., 2012
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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 variations may affect treatment
  decisions

De Gregori et al., 2010
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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 about pharmacogenomic 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

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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
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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
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Patient Profile

• Reports migraine headaches since childhood
• Reports family history of pain in ancestors and
  in children

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Heritability

• Extended family study - any chronic pain about
  16 and severe chronic pain 301
• Twin studies
• Low back/neck pain 352
• Systematic review low back pain 21-673
• Migraine and tension headaches 502
• Irritable bowel syndrome 252
• 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

98y DM Migraine HTN
83y DM Arthritis Migraine
98y DM
20s killed
5
6
6
5
60s y HTN Migraine
60s y DM Migraine CLBP
Health Status unknown
Health Status unknown
Legend CLBP- chronic low back painCOPD- chronic
obstructive pulmonary disease CPTS- chronic
Postthoracotomy pain syndrome DM- diabetes
mellitus HTN- Hypertension
58y Asthma CLBP DM arthritis
62y CPTS 2008 Migraine- childhood CLBP(fall)
30s COPD 30s (O2 2008)
60y CLBP/surgery 50 Migraine HA
64y 80 body burn 7yo Arthritis Migraine
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Patient Profile

• Heritability- chronic pain consistent with
  studies, lack studies neuropathic pain
• Migraine
• Low back pain

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Implications for nursing

• Stay abreast of possible development of agents
  that may prevent evolution from acute to chronic
  pain
• Explore family history
• May help with understanding of pain conditions
• Patient education

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Patient Profile

• Multiple trials of analgesics in past
• Side effects from codeine
• Excessive somnolence from methadone
• Inefficacy from fentanyl
• Side effects or adverse effects from multiple
  trycyclic antidepressants

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Pharmacogenomic testing
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Targets for Pain ManagementEffect of Genetic
variation
Gene (with variant) Analgesic 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 UGT2B72 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
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Pharmacogenetic testing

• Pharmacogenomics how variations in genomes
  affect response to medications
• Genetic variation can influence efficacy/toxicity
• 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
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CYP2D6

• CYP2D6 25prescribed medications
• Ex. Codeine metabolized by CYP2D6 to morphine
  tramadol metabolized to O-desmethyltramadol
• Poor metabolizers little therapeutic effect
• Ultra Rapid metabolizers possible toxicity
• Worldwide variation - examples
• Ultra-metabolizers higher percentage in Oceania
  and North Africa
• Poor metabolizers higher Europe

Sistonen et al., 2007
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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 gt40 drugs
• Variations linked decreased enzyme activity
• Increased drug levels
• Ex. Fentanyl, hydrocodone, buprenorphine,
  methadone, clonazepam

Fine Portenoy, 2007
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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 to account for above
• Currently optimized on anticonvulsant, topical
  anesthetic, morphine

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Implications for nursing

• Excellent history and tracking of response/lack
  of response to analgesia
• Exploration of the possibility of pharmacogenomic
  testing
• Adjusting treatment plans

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Future directions

• Identification of clinical relevance of pain
  genes
• Novel therapies for pain based on genetic
  variation
• Routine genetic testing prior to surgery and for
  those with chronic pain
• Treatment algorithms based on pharmacogenomic
  results

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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.
• Mogil, J. S. (2012). Pain genetics past, present
  and future. Trends in Genetics, 28, 258-266.
• Mogil, J. S., Gilson, S. G., Bon, K., Lee, S. E.,
  Chung, K., Raber, P., Devor, M. (1999).
  Heritability of nociception I Responses of 11
  inbred mouse strains on 12 measures of
  nociception. Pain, 80, 67-82. 
• Nielsen, C. S., Knudsen, G. P., Steingrímsdóttir,
  Ó. A. (2012). Twin studies of pain. Clinical
  Genetics, 82, 331-340.
• Nishizawa, D., Fukuda, K., Kasai, S., Hasegawa,
  J., Aoki, Y., Nishi, A., Ikeda, K. (2012).
  Genome-wide association study identifies a potent
  locus associated with human opioid sensitivity.
  Molecular Psychiatry, doi10.1038/mp2012.164.
• Pasternak, G. W. (2010). Molecular insights into
  mu opioid pharmacology From the clinic to the
  bench. Clinical Journal of Pain, 26, S3-S9
• Peters, M. J., Broer, L., Willmen, H. L. D. M.,
  Eiriksdottir, G., Hocking, L. J., Horan, M. A.,
  van Meurs, J. B. J. (2012). Genome-wide
  association study meta-analysis of chronic
  widespread pain evidence for involvement of the
  5p15.2 region. Annals of Rheumatic Disease, 1-10.
  

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References

• Sistonen, J., Sajantila, A. N., Lao, O.,
  Corander, J., Barbujani, G., Fuselli, S.
  (2007). CYP2D6 worldwide genetic variation shows
  high frequency of altered activity variants and
  no continental structure. Pharmacogenetics and
  Genomics, 17, 93-101. 
• Sistonen, J., Madadi, P., Ross, C. J.,
  Yazdanpanah, M., Lee, J. W., Landsmeer, M. L. A.,
  Hayden, M. R. (2012). Prediction of codeine
  toxicity in infants and their mothers using a
  novel combination of maternal genetic markers.
  Nature, 91, 692-699. 
• Tammimäki, A., Männistö P. T. (2012).
  Catechol-O-methyltransferase gene polymorphism
  and chronic human pain a systematic review and
  meta-analysis. Pharmacogenetics and Genomics, 22,
  673-691.
• Walter, C., Lötsch, J. (2009). Meta-analysis of
  the relevance of the OPRM1 118AgtG genetic
  variant. Pain, 146, 270-275.
• Young, E. E., Lariviere, W., R., Belfer, I.
  (2012). Genetic basis of pain variability recent
  advances. Journal of Medical Genetics, 49, 1-9