Chronic Pain and Therapeutics 101

Jeffrey Fudin, PharmD, DAAPM, FCCP, FASHP

Remitigate, LLC

357 Delaware Avenue #214

Delmar, NY 12054

Cell Phone: 518-588-5651

http://www.paidr.com

Topic Areas:

Aspects of chronic and neuropathic pain: etiology; incidence and prevalence; principal

symptoms and signs; nature and range of functional impairments; prognosis; current

therapies; medical, functional, social, environmental

Support issues; Describe areas in which adaptive neurotechnologies could play a role in

diagnosis, treatment, and/or support.

Participants; Mostly neuroscience and engineering grad students. There will be a few med

students and residents.

Suggested Readings in order of importance:

1. Kubotera N, Fudin J. Pain Management for Pharmacists – Concepts and Definitions. CE

Program of The University of Connecticut School of Pharmacy and Drug Topics. Drug Topics. 2013

April; 52-61.

2. Zorn KE, Fudin J. Treatment of Neuropathic Pain: the Role of Unique Opioid Agents. Practical

Pain Management. 2011 May; 11 (4): 26-33.

3. McCarberg B, Bainbridge JL, Fudin J. Optimizing Chronic Pain Management: Integrating

Pharmacokinetics and Pharmacodynamics. (CME: The University of Kentucky College of Pharmacy

is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing

pharmacy education.)

4. Sasu-Tenkoramaa J, Fudin J. Neuropathy in the Cancer Patient: Causes and Cures. Practical Pain

Management. 2013 April; 13(3):53-67.

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Jeffrey Fudin, B.S., Pharm.D., FCCP, FASHPDiplomate, Academy of Integrative Pain Management (AIPM)

President and Director, Scientific and Clinical Affairs, REMITIGATE LLCClinical Pharmacy Specialist & PGY2 Pain Residency Director; Stratton VA Medical Center

Adjunct Affiliations;Albany College of Pharmacy & Health Sciences,

Western New England University College of Pharmacy, UCONN School of Pharmacy

www.paindr.com

Chronic Pain and Therapeutics 101Short Course on Adaptive Neurotechnologies

Topic Areas

Initial Topic Areas

• Aspects of chronic and neuropathic pain: etiology; incidence and prevalence; principal symptoms and signs; nature and range of functional impairments; prognosis; current therapies; medical, functional, social, environmental

• Support issues; Describe areas in which adaptive neurotechnologies could play a role in diagnosis, treatment, and/or support.

Focus

• Pharmacotherapeutics (pros, cons, unmet needs)

Participants

• Mostly neuroscience and engineering grad students. There will be a few med students and residents.

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Learning Objectives

1. Identify the prevalence of pain and understand medication‐related morbidity and mortality.

2. Define acute chronic pain, analgesia, nociceptor, noxious stimulus, and pain threshold.

3. Differentiate neuropathic, somatic, and visceral pain.

4. Categorize medications that are useful for pain including opioids, NSAIDs, antidepressants, anticonvulsants, and others.

5. Summarize medication therapeutic advantages and complexities, and be familiar with political and medical pitfalls of the various medications used to treat pain.

In 2013, the CDC identified approximately this number of persons as dying from prescription opioids:

A. 8,000

B. 9,000

C. 16,000

D. 18,000

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A. 8,000

B. 9,000

C. 16,000

D. 18,000

In 2013, the CDC identified approximately this number of persons as dying from NSAID‐related GI bleeds:

What drug categories are first line agents for neuropathic pain?

A. Antidepressants

B. Anticonvulsants

C. NSAIDs

D. Opioids

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U.S. Prescription Opioid‐Related Deaths

• Approximately 16,000 deaths in 2013 from Rx opioids

• Approximately 9,000 deaths in 2013 from heroin

• According to the CDC:

• ~85% unintentional ≈ 13,600 deaths

• ~37 unintentional deaths/day

• ~1 unintentional death every 40 minutes

• Children/infant deaths

• ~3,300 in 2014 (down from 5,187 in 2004)

Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2015;64(1):32. National Vital Statistics Reports. 2015;64(2). www.cdc.gov/nchs/.Chen LH, et al. QuickStats: Rates of Deaths from Drug Poisoning and Drug Poisoning Involving Opioid Analgesics—United States, 1999–2013. MMWR Morb Mortal Wkly Rep 2015;64:32. (http://origin.glb.cdc.gov/mmwr/preview/mmwrhtml/mm6401a10.htm?s_cid=mm6401a10_w)

Utilization of Healthcare Resource• Over 50% of ED visits for opioid‐induced respiratory

depression (OIRD) and overdose result in admission/hospitalization

• Average length of stay is about 3.6 days• Average hospital charges: $30,000 per patient per

visit• Up to 10% of ED visits for OIRD and overdose result

in near‐fatal events requiring mechanical ventilation• 22% are discharged to another institution (nursing

home or rehabilitation center) following ED stay and admission $$$$

Hasegawa K, et al. Mayo Clin Proc. 2014;89(4):462‐471. Healthcare Cost and Utilization Project (HCUP); Agency for Healthcare Research and Quality. HCUP Databases. www.hcup‐us.ahrq.gov/databases.jsp. Yokell MA, et al. JAMA Intern Med. 2014;174(12):2034‐2037.

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Therapeutic Drug Classes v Pain Type

• Somatic Pain

– NSAIDs, steroids, opioids, SNRIs

• Visceral Pain

– NSAIDs, opioids

• Neuropathic Pain

– Anticonvulsants, antidepressants, opioids (limited)

Multiple Types of Pain

Adapted from: Woolf CJ. Ann Intern Med. 2004;140:441-451.*Chong MS, Bajwa ZH. J Pain Symptom Manage. 2003;25:S4-S11.

A. Nociceptive Pain

B. Inflammatory Pain

C. Neuropathic Pain

D. Noninflammatory/Non-neuropathic pain

Noxious peripheral

stimuli

Peripheral nerve damage

No known tissue or nerve damage

Abnormal central processing

Multiple mechanisms

Brain

Brain

Brain

Brain

Inflammation

• Patients may experience multiple pain states simultaneously*

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Rational PolypharmacyAdvantages

• Reduction in pain intensity• Reduction in RX toxicity & SEs• Improved efficacy• Possible improvement in surgical

outcome & decreased LOS?

Disadvantages

• Requires knowledge of drugs, PK data, & pharmacodynamics

• Every analgesic has its own unique adverse event profile

• May increase drug-drug interactions

1. Sinatra RS. Ann Meeting Cleveland Soc of Anesthesiology. Nov 2010.2. Kehlet H and Wilmore DW. Am J Surg. 2002;183:630‐41.

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assay

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Relative COX-2 Specificity

See http://paindr.com/wp-content/uploads/2012/05/COX-2_specificity.pdf

Abnormal, not unpleasant sensations(eg, tingling)

Paresthesias

Abnormal, unpleasant sensations (eg, shooting, lancinating, burning)

Dysesthesias

Persistent burning pain, shocklike pain

Spontaneous pain

DescriptionSymptom

Spontaneous Symptoms

Baron. Baron. ClinClin J Pain.J Pain. 2000;16(2 suppl):S122000;16(2 suppl):S12--S20; International Association for the Study of Pain S20; International Association for the Study of Pain Website. Website. Available at: Available at: http://www.iasphttp://www.iasp--pain.org/termspain.org/terms--p.htmlp.html. Accessed September 30, 2004.. Accessed September 30, 2004.

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Stimulus-Evoked Symptoms

Explosive response to normally painful stimulus

Hyperpathia

Heightened response to normally painful stimulus

Hyperalgesia

Painful response to nonpainful stimulus

Allodynia

DefinitionSymptom

International Association for the Study of Pain Web site. International Association for the Study of Pain Web site. Available at: Available at: http://www.iasphttp://www.iasp--pain.org/termspain.org/terms--p.htmlp.html. Accessed September 30, 2004.. Accessed September 30, 2004.

Limiting Calcium Influx Can Temper Hyperexcitable Neurons

• Limit amount of Ca2+ entering presynaptic neuron upon excitation

• Allow enough Ca2+ for normal nerve function• Two pharmacologic strategies

− Block Ca2+ channels− Modulate channels without blocking (allosteric)

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Mechanisms of Neuropathic Pain: Central Sensitization

• Peripheral nociceptor inputs trigger molecular changes in central neurons

• Long-lasting changes may result from − Altered receptor expression− Inhibitory interneuron death

Modification of GABA, glycine receptors

NMDA and AMPA receptor activation

Reduce effect of inhibition

Lower firing threshold

GABA = GABA = --aminobutyric acid; NMDA = aminobutyric acid; NMDA = NN--methylmethyl--DD--aspartate; aspartate; AMPA = AMPA = --aminoamino--33--hydroxylhydroxyl--55--methylmethyl--44--isoxazolepropionate.isoxazolepropionate.

Woolf, Salter. Woolf, Salter. ScienceScience. 2000. 2000;288:1765;288:1765--17681768. .

Overview

• Etiology and Pathogenesis

• Tricyclic Antidepressants

• SSRIs, SNRIs, SARIs, MOAIs

• Drug Interactions (iso‐enzyme metabolism)

• Anti‐convulsants

• Anti‐arrhythmic

• Topicals

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Pathogenesis related to DM

• Poorly controlled hypergylcemia.

• Accumulation of sorbitol in nerve cells.

• Decrease in nerve free myoinositol and dcreased activity of nerve sodium‐potassium adenosine triphosphate.

• Increased nonenzymatic peripheral nerve glycosylation.

• Nerve hypoxia.

Other Causes‐1

• Diseases

– A.I.D.S.

– Herpes Simplex Virus

– Syphilis

– Sclerotic/Connective Tissue Disorders

• Back/Tissue Injury

• Iatrogenic Causes

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Differential Diagnosis

• Organic Peripheral Neuropathy

• B‐12

• Porphyria

• Heavy Metal poisoning

• Collagen Disease

• Cancer

• Lymphoma

• Diabetes

Tricyclic Antidepressants• Amitriptyline• Imipramine• Nortriptyline• Desipramine• Clomipramine• Doxepin• Trimipramine• Amoxapine• Protriptyline

BaldessariniBaldessarini. In: . In: Goodman & GilmanGoodman & Gilman’’s The Pharmacological Basis of Therapeuticss The Pharmacological Basis of Therapeutics. 10th ed. 2001.. 10th ed. 2001.

Amitriptyline

CHCH2CH2N(CH3)2

•HCl

Mechanism of Action

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Tricyclic Antidepressants: Positive Controlled Trials

Max et al. Max et al. Neurology.Neurology. 19871987;37:589;37:589--596596; Max et al. ; Max et al. N Engl J Med.N Engl J Med. 19921992;326:1250;326:1250--12561256; ; SindrupSindrup et al. et al. Br J Clin Br J Clin PharmacolPharmacol.. 19901990;30:683;30:683--691691; Max et al. ; Max et al. Pain. Pain. 19911991;45:3;45:3--99; Watson et al. ; Watson et al. Neurology.Neurology. 19821982;32:671;32:671--673673; Max ; Max et al. et al. Neurology.Neurology. 1988;1988;38:142738:1427--14321432; Graff; Graff--Radford et al. Radford et al. ClinClin J Pain. 2J Pain. 2000000;16:188;16:188--192192; ; KishoreKishore--Kumar et al. Kumar et al. ClinClin PharmacolPharmacol Ther.Ther. 19901990;47:305;47:305--312312; Raja et al. ; Raja et al. Neurology.Neurology. 20022002;59:1015;59:1015--10211021..

Pain relief1226Desipramine (12.5-250, PBO)Kishore-Kumar

Raja

Graff-Radford

Max

Watson

PHN

Max

Sindrup

Max

Max

Painful DPN

Study

Nortriptyline (10-160, PBO)

Amitriptyline (12.5-200, PBO)

Amitriptyline (12.5-150, PBO)

Amitriptyline (12.5, PBO)

Desipramine (12.5-250, PBO)

Desipramine (50 or 200, PBO), Clomipramine (50 or 75, PBO)

Desipramine (12.5-150, PBO), Amitriptyline (12.5-150, PBO)

Amitriptyline (25-150, PBO)

Agent (mg/d)

76

49

58

24

20

26

108

29

N

24

8

12

8

12

6

14

12

Weeks

Pain intensity, relief; cognitive function

Pain intensity

Pain relief

Pain relief

Pain relief

Neuropathy symptoms

Pain relief

Pain relief

Primary End Point

Tricyclic Antidepressants: Adverse Effects• Most common adverse effects

− Sedation− Anticholinergic effects

• Dry mouth• Blurred vision• Increased intraocular

pressure• Mydriasis (pupil dilation)• Constipation• Paralytic ileus• Urinary retention• Delayed micturition• Urinary tract dilation• Hyperpyrexia • Sinus tachycardia

• Often have unacceptable side effects in the elderly

Drug Facts & Comparisons. 2004; AGS Panel on Persistent Pain in Drug Facts & Comparisons. 2004; AGS Panel on Persistent Pain in Older Persons. Older Persons. J Am J Am GeriatrGeriatr Soc.Soc.20022002;50(suppl):S205;50(suppl):S205--S224S224..

!

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SE/Problems of TCAs

• adverse behavior effects

• anticholinergic

• seizures (highest w/ maprotiline)

• autonomic side effects

• cardiac side effects

• lag time = 3‐5 days

• troublesome SEs (addressed by SSRIs)

• narrow therapeutic index

Pharmacological tx PN w/ TCAs

Dose [mg] Amine Effects Sedation Anticholinergic

3 Amine TCA

Amitriptyline [Elavil] 25-300 NE > 5HT 3 3

Clomipramine [Anafranil] 25-300 5HT 2 3

Doxepin [Sinequan] 25-300 NE > 5HT 3 2

Imipramine [Tofranil] 25-300 NE > 5HT 2 2

Trimipramine [Surmontil] 25-300 NE > 5HT 3 3

2 Amine TCA

Amoxapine [Asendin] 50-600 NE 1 1

Desipramine [Norpramin] 25-300 NE 0.5 1

Maprotiline [Ludiomil] 25-225 NE 2 2

Protriptyline [Vivactil] 10-60 NE 0.5 2

Nortriptyline [Pamelor] 25-250 NE 1 1

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Serotonin Reuptake Inhibitors

Fluoxetine [Prozac] 5-80 5HT 0.5 0

Fluvoxamine [Luvox] 50-300 5HT 0.5 0

Paroxetine [Paxil] 10-50 5HT 0.5 0.5

Citalopram [Celexa] 10-60 5HT 0.5 0

Sertraline [Zoloft] 50-200 5HT 0.5 0

Escitalopram [Lexapro] 10-20 5HT 0.5 0

Atypical Antidepressants

Venlafaxine [Effexor] 25-375 5HT > NE 0 0

Duloxetine [Cymbalta] 20-120 5HT > NE 0 0

Bupropion [Wellbutrin] 100-450 NE, DA 0 0

Nefazodone [Serzone] 100-600 5HT > NE 3 0

Trazodone [Desyrel] 50-600 5HT > NE 3 0

Mirtazapine [Remeron] 15-45 NE [?] 3 0

MAOIs

Nardil (phenelzine) 45-90mg NE,DA,5-HT 1 0

Selegiline (Eldepryl) 5-20mg NE?,DA?,5-HT 0 0

Parnate (Tranylcypromine) 30-60mg NE,DA,5-HT 1 0

Anti-depressants, continued

TRAMADOL V TAPENTADOL

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Is Tapentadol (Nucynta®) a Glorified Tramadol?

Properties Tramadol Tapentadol

Mu BindingAffinity

6000x less than morphine

18x less than morphine

Metabolism Significant CYP450

Conjugation, O‐Glucuronide

Drug Interactions

See above See above

NeuroamineActivity

5‐HT / NE NE

Boglish P. Fudin J. As The Expert: Is Tapentadol a Glorified Tramadol? Practical Pain Management. 2016 Jan-Feb; 16(1): 19-20.

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Anticonvulsants• First generation

− Phenytoin− Phenobarbital− Primidone− Ethosuximide− Carbamazepine− Valproic acid

• Second generation− Gabapentin− Lamotrigine− Topiramate− Tiagabine− Levetiracetam− Oxcarbazepine− Zonisamide− Felbamate

Carbamazepine Gabapentin

McNamara. In: McNamara. In: Goodman & GilmanGoodman & Gilman’’s The Pharmacological Basis of Therapeutics. s The Pharmacological Basis of Therapeutics. 10th ed.10th ed. 2001; 2001; PhysiciansPhysicians’’ Desk ReferenceDesk Reference®®. 59th ed. 2005; Neurontin. 59th ed. 2005; Neurontin®® (gabapentin) [package insert]. New York, NY: (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004. Pfizer Inc; 2004.

N

CONH2 CH2CO2H

CH2NH2

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Anticonvulsants: Positive Controlled Trials

Wilton. Wilton. S S AfrAfr Med JMed J. 1974. 1974;48:869;48:869--872872; ; RullRull et al. et al. DiabetologiaDiabetologia. 1969. 1969;5:215;5:215--218218; ; BackonjaBackonja et al. et al. JAMA.JAMA.19981998;280:1831;280:1831--18361836; Eisenberg et al. ; Eisenberg et al. NeurologyNeurology. 2001. 2001;57:505;57:505--509509; Rice, ; Rice, MatonMaton. . Pain.Pain. 20012001;94:215;94:215--224224; ; Rowbotham et al. Rowbotham et al. JAMA.JAMA. 19981998;280:1837;280:1837--18421842..

Rowbotham

Rice

PHN

Eisenberg

Backonja

Rull

Wilton

Painful DPN

Study

Gabapentin (300-3600, PBO)

Gabapentin (1800 or 2400, PBO)

Lamotrigine (25-400, PBO)

Gabapentin (900-3600, PBO)

Carbamazepine (600, PBO)

Carbamazepine (600, PBO)

Agent (mg/d)

229

334

59

165

30

40

N

8

7

6

8

6

4

Weeks

Mean daily pain

Mean daily pain

Pain intensity

Daily pain severity

Neuropathy symptoms

Pain relief

Primary End Point

Anticonvulsants: Safety and Adverse Events

*Frequency not specified; †adverse events occurring in 5% of patients and with at least twice the incidence of placebo group; ‡postherpetic neuralgia; §adjunctive therapy in adults with epilepsy.

Physicians’ Desk ReferencePhysicians’ Desk Reference®®. 59th ed. 2005; Neurontin. 59th ed. 2005; Neurontin®® (gabapentin) [package insert]. New York, NY: (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.Pfizer Inc; 2004.

Severe rash including Stevens-Johnson syndrome

NoneAplastic anemia and agranulocytosis

Black box warnings

VomitingDyspepsiaDizzinessAtaxiaSomnolenceIncoordinationInsomniaRashDiplopiaBlurred vision

DizzinessSomnolencePeripheral edema

DizzinessDrowsinessNauseaUnsteadinessVomiting

Most common adverse events

Not currently indicated

PHNTrigeminal neuralgiaNeuropathic pain indication

Lamotrigine†§Gabapentin†‡Carbamazepine*

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Pharmacology: Gabapentin &

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Gabapentin: Mechanism of Action

• Interacts with 2- subunit of voltage-gated Ca2+

channels• In animal models

− Prevents allodynia and hyperalgesia− Prevents pain-related responses in models of

neuropathic pain − Decreases pain-related responses after peripheral

inflammation• Relevance of these models to human pain is

not known

NeurontinNeurontin®® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.(gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.

Pharmacokinetic Properties of Gabapentin• Few drug-drug interactions• Not protein bound or hepatically metabolized• No blood level monitoring or liver function testing required

Dosage adjustment is recommended in patients with compromised reDosage adjustment is recommended in patients with compromised renal function and those undergoing nal function and those undergoing hemodialysis.hemodialysis. See full prescribing information for instructions on proper adjuSee full prescribing information for instructions on proper adjustments. stments. In general, dose selection for an elderly patient should be cautIn general, dose selection for an elderly patient should be cautious, usually starting at ious, usually starting at the lower end of the dosing range, reflecting the greater frequethe lower end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, ncy of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug thor cardiac function, and of concomitant disease or other drug therapy.erapy.

Half-life

5-7 hours

Protein Binding

<3% bound

Bioavailability Metabolism Excretion

Approximately60%

(300 mg TID)

Not appreciably metabolized

Renal

NeurontinNeurontin®® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.(gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.

!

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CO2H

Pregabalin: Predictable Response Versus Gabapentin

High BioavailabilityHigh BioavailabilityHigh BioavailabilityLinear PK ProfileLinear PK ProfileLinear PK Profile

Pregabalin Gabapentin

All doses

90%

900 mg, 60%

1200 mg, 47%

2400 mg, 34%

3600 mg, 33%

1800 mg Recommended

dose

LyricaLyrica®® (pregabalin) Capsules CV [package(pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005insert]. New York, NY: Pfizer Inc; 2005; Neurontin; Neurontin®® (gabapentin) (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004; [package insert]. New York, NY: Pfizer Inc; 2004; WescheWesche, , BockbraderBockbrader. . Presented at: 24th Annual Scientific Presented at: 24th Annual Scientific Meeting of the American Pain Society; 2005.Meeting of the American Pain Society; 2005.

Dose (mg/d)Dose (mg/d)

0 600 1200 1800 2400 3000 3600 4200 48000

2

4

6

8

10

12

14

16

18

Pregabalin

GabapentinSte

ady

Sta

te C

Ste

ady

Sta

te C

ma

xm

ax

(( μμg/

mL)

g/m

L)

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Pharmacokinetics & Drug Interactions

Important Considerations when Prescribing RXs for Neuropathy

Terminology

• Inducer

• Inhibitor

• Substrate

• What is Genetic Polymorphism?

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CYP450 Nomenclature

• Cytochrome is designated CYP

• CYP (#) ‐ # identifying the enzyme family

• CYP (#) (A,C) ‐ Subfamily designation

• CYP (#) (A,C) (#) ‐ Individual enzyme(this is based on when enzyme was discovered

• EXAMPLES:

– CYP3A4, CYP2D6, CYP1A2

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Argoff CE. Clinical implications of opioid pharmacogenetics. Clin J Pain. 2010;26(1):S16‐S20.Belle DJ, Singh H. Genetic factors in drug metabolism. Am Fam Physician. 2008;77(11):1553‐1560.

Individual Response to Treatment

Pharmacogenetics

How the drug affects the

body

How the body alters the drug

Personalizing Medication with Pharmacogenetic

(PGT) Interpretation

48

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PGT Variability & Response

• General population has 40‐60% phenotype variability

• CYP450 enzymes most frequently involved– CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP1A2, CYP2E1

• Genetic differences impact 25% of all drugs

1. Cavallari LH, Limdi NA. Warfarin pharmacogenomics. Curr Opin Mol Ther. 2009 Jun;11(3):243-51. 2. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions and

adverse effects. Am Fam Physician. 2007; 76(3):391-6.3. Ma JD, Lee KC, Kuo GM. Clinical application of pharmacogenomics. J Pharm Pract. 2012

Aug;25(4):417–27.

Phenotypes and Variants

• Allele Variations

– wild:wild vs variant:wild vs wild:variant

• Poor Metabolizer (PM)

– DDDD → M

• Intermediate Metabolizer (IM)

– DDDD → MMm

• Extensive Metabolizer (EM)

– DDDD → MMM

• Ultra Rapid Metabolizer (UM)

– DDDD → MMMMmmm

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Opioid Chemistry and Cross‐sensitivity

51

Medication Metabolism

Phase of Metabolism

Key Enzymes InvolvedExamples: Opioid Medication Metabolized

Phase I Cytochrome P450 (CYP450)Examples: CYP2D6, CYP2C19, CYP2B6, CYP2C9, CYP3A4 & CYP3A5

Codeine, hydrocodone, oxycodone, tramadol, fentanyl, methadone, buprenorphine

Phase II Uridine 5'‐diphospho‐

glucuronosyltransferase (UDP‐glucuronosyltransferase, UGT)Examples: UGT2B7 & 2B15

Morphine, oxymorphone, hydromorphone, tapentadol

Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613‐624.

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http://www.arupconsult.com/assets/graphics/OpiatesAndOpiodMetabolism.jpg

Methadone Statistics(CDC 2012)

2% of prescriptions for opioid analgesics are for methadone

Methadone accounts for nearly 1 in 3 prescription opioid overdose deaths in the U.S., 6X times the number in 2009

http://www.cdc.gov/features/vitalsigns/methadoneoverdoses/

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Important Sub‐pops, Pharmacogenetics

Gerber JG et al. Stereoselective Metabolism of Methadone N‐Demethylation by Cytochrome P4502B6 and 2C19. CHIRALITY 2004;16:36‐44.

CYP3A4

R‐methadoneParent Drug

EDDP inactive metabolite

S: Sorrowing outcome. (Cardiotoxic effects, QT prolongation with potential of Torsade de pointes

CYP2B6

S‐methadoneParent Drug

EDDP inactive metabolite

R: Responsible for analgesia

55

CYP2B6 demonstrates selectively metabalizes S‐enantiomerPotential risk?

(+/‐) % Variation (Compared to Manual Calculation)1

‐33%

‐55%

+100%

+242%

VARIOUSOPIOIDS

FENTA

NYL

METH

ADONE

0%

RISKS:Underdose &Withdrawal

RISKS:Overdose & Death

1. Shaw K, Fudin J. Evaluation and Comparison of Online Equianalgesic Opioid Dose Conversion Calculators. Practical Pain Management. 2013 August; 13(7):61-66. PPM 2013

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Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept. 2012. 46-51.

Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept. 2012. 46-51.

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Met

hado

ne (

mg)

Morphine (mg)

Equianalgesic Dose of Morphine to Methadone

300mg Morphine = 60mg Methadone

302.5mg Morphine = 30mg Methadone

Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. 2012 September; 12(8): 46-51.

Variability in Opioid Equivalence Survey

• Sept 13 thru Dec 31, 2013, 411 Respondents

• RPhs, MD/DOs, NPs, PAs

• Convert to Daily MEQ:

– Hydrocodone 80mg; Fentanyl 75mcg/hr; Methadone 40mg; Oxycodone 120mg; Hydromorphone 48mg

319

Rennick A, Atkinson TJ, Cimino NM, Strassels SA, McPherson ML, Fudin J. Variability in Opioid Equivalence Calculations. (2015) Pain Medicine. Early release version available at http://authorservices.wiley.com/bauthor/onlineLibraryTPS.asp?DOI=10.1111/pme.12920&ArticleID=4251185 (last accessed 9/25/2015).

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The most outrageous conversions

Rennick A, Atkinson TJ, Cimino NM, Strassels SA, McPherson ML, Fudin J. Variability in Opioid Equivalence Calculations. (2015) Pain Medicine. Early release version available at http://authorservices.wiley.com/bauthor/onlineLibraryTPS.asp?DOI=10.1111/pme.12920&ArticleID=4251185 (last accessed 9/25/2015).

Political Unrest & Recent Changes

• Tramadol is now Schedule IV

• Hydrocodone combos change to Schedule II

• VA Opioid Initiative & Opioid Consents

• Oh, so misunderstood!

– Zohydro ER® Blogs on PainDr.com

• ZOHYDRO: What weighs more – A pound of feathers or a pound of hydrocodone?

• Zohydro : Rogue State Politics & A Law Enforcement Perspective

• When Politicians Play Doctor

http://paindr.com/blog/

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http://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose‐a.pdf

Recent CDC Guidelines:Who Should I Target for In‐Home Naloxone?

Opioid Monitoring• Urine Drug Testing (Presumptive v definitive testing)

• Serum testing

• Pharmacogenetics testing

• Opioid Consents

• PDMP monitoring

• Careful titration

• In‐home naloxone education

• etc.

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Conclusions

• Not all “pain medications” are efficacious for neuropathic pain

• Rational Polypharmacy is only rational if benefits outweigh risks

• Most prescribers are grossly under‐educated in pain therapeutics and lack the time to safely initiate and monitor patients

• Alternative pain treatment need to be considered alone and combined with appropriate therapies.