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
6
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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