Managing Pain in the Midst

of an Opioid Epidemic

Dr. Jerry L. EppsChief Medical Officer

University of Tennessee

Medical Center

Dr. Jim SillimanPresident, CEO

GeneAlign

Disclosures

• The faculty members have a consulting relationship with Pacira

Pharmaceuticals, Inc.

• This program is sponsored and approved by Pacira Pharmaceuticals, Inc.

• This program is not accredited for continuing education (CE), and attendees

will not receive CE credit

• These presentations are reflective of the individual faculty members’

experience and are not intended as recommendations by Pacira

Pharmaceuticals, Inc.

2

Table of Contents

A Potential Gateway to Long-Term Opioid Addiction

Current pain management strategies are overreliant on opioids as

the premier source of pain management

The University of Tennessee Medical Center Case StudyObserving a potential target population and how it may benefit from

a personalized pain management approach

Taking Steps Toward Change

Identifying the effort required to improve pain management

A Potential Gateway to Long-Term Opioid Addiction

Current pain management strategies are overreliant on

opioids as the premier source of pain management

The National Prescription Drug Epidemic

White House Summit on the Opioid

Epidemic1:

• “The abuse of opioids…has a

devastating impact on public health

and safety in this country”

CDC2:

• 46 people in the United States die from an

overdose of prescription painkillers every day

• 259 million prescriptions were written for

painkillers in 2012 by healthcare providers

– Enough for every American adult to have a

bottle of narcotic pills

• 10 of the highest prescribing states for

painkillers are in the South

References: 1. President Barack Obama White House Archive website. https://obamawhitehouse.archives.gov/blog/2014/06/19/white-house-summit-opioid-epidemic.

Accessed March 8, 2017. 2. Centers for Disease Control and Prevention website. https://www.cdc.gov/vitalsigns/opioid-prescribing/. Accessed March 8, 2017.

5

A Lost Middle Ground: Pain Management Has Evolved From

Undertreatment to Overreliance and Overtreatment

References: 1. Porter J et al. N Engl J Med. 1980;302(2):123. 2. Portenoy RK et al. Pain. 1986;25(2):171-186. 3. Pain as the 5th

Vital Sign Toolkit. Washington, DC: Dept of Veterans Affairs; 2000. 4. Federation of State Medical Boards of the United States, Inc.

http://www.fsmb.org/Media/Default/PDF/FSMB/ Advocacy/pain_policy_july2013.pdf. Accessed March 3, 2017. 5. Murthy VH. Public

Health Reports. 2016;131:387-388..

1980s

Published studies and letters

posit that opioids do not carry

significant risks for adverse

events or addiction1,2

1998

Pain is established as a “fifth

vital sign.” Consistent pain

management guidelines that

rely on opioids are created3,4

2016

“Today, more Americans die

because of drug overdoses than

because of car crashes, and most

of these overdoses involve some

form of opioid” 5

-US Surgeon General

6

THE SITUATION

Opioid-Related Adverse Events Are Commonplace

73% 99% 92%

of inpatient surgeries report moderate to extreme pain after surgery1

of patients receive opioids to manage postsurgical pain2

THE CURRENTSTANDARD OF CARE

THE OUTCOME

of postsurgical patients who receive opioids report some sort of adverse events3

References: 1. Gan TJ et al. Curr Med Res Opin. 2014;30(1):149-160. 2. Kessler ER et al. Pharmacotherapy. 2013;33(4):383-391. 3. Gregorian RS et al. J Pain. 2010;11(11):1095-1108. 7

Opioids Provide Pain Management, but at What Cost?

References: 1. Alam A et al. Arch Intern Med. 2012;172(5):425-430. 2. Carroll I et al. Anesth Analg. 2012;115(3):694-702.

1 in 15 patients who receive

postsurgical opioids become

addicted1,2

8

Reliance on Opioids Places a Burden on

Healthcare Resources

References: 1. Kessler ER et al. Pharmacotherapy. 2013;33(4):383-391.2. Oderda GM et al. J Pain Palliat Care Pharmacother. 2013;27(1):62-70. 3. Minkowitz HS

et al. Am J Health Syst Pharm. 2014;71(18):1556-1565. 4. Gan TJ et al. Curr Med Res Opin. 2015;31(4):677-686.

Patients experiencing opioid-related adverse events have

higher healthcare resource utilization and costs1-4

47%–86%higher costs

55%–150%longer hospital stays

36%–68%higher readmission rates

9

10

The Operating Room Inadvertently

Becomes a Point of Origin for Long-Term Opioid Addiction

References: 1. Wang M et al. Spine J. 2013; 13(9):S6-S7. 2. Alam A et al. Arch Intern Med. 2012;172(5):425-430.

Patients 1 year after surgery1

18% of opioid-naïve

patients were

still using

narcotics

Patient aged ≥65 years with an opioid

prescription 7 days postsurgery2

44%increased chance

of becoming a

long-term

opioid user

Postsurgical Opioid Utilization Can Lead to Chronic Use

33% of all patients

were still

using opioids

The current hospital pain management strategy suggests

a need for non-opioid solutions

11

10%remained on

opioids

1 year later

► ~ 300 patients, with 92% reporting adequate pain control

► Usually received 30 narcotic pills

► >50% took pain pills for 2 days or less

► Consumed an average of 11 pills per patient

References: 1. Bartels K et al. PLoS ONE. 2016;11(1):e0147972. 2. Rodgers J et al. J Hand Surg Am. 2012;37(4):645-650.

C-SECTION

Proportion of patients taking half or less

of prescribed opioid pills1

THORACIC SURGERY

Outpatient upper extremity surgery2

Common Surgeries Create a Surplus of Opioids That

Flood the “Market” With Product

Initiation of short-term opioid therapy

may lead to long-term use

83% 71%

Almost 5000 leftover tablets

12

Reducing Misuse, Abuse, and Diversion

• Controlled prescription drugs (CPDs) are abused at a

higher rate than any illicit drug except marijuana1

• Pain medications are:

– The most common CPDs used illegally

– Most often involved in incidents of overdose

• Diversion of CPDs costs insurers up to $72.5 billion per year2

References: 1. Drug Enforcement Administration website. https://www.dea.gov/resource-center/DIR-017-13%20NDTA%20Summary%20final.pdf. Accessed March 8,

2017. 2. US Dept of Justice website. https://www.justice.gov/archive/ndic/pubs33/33775/33775p.pdf. Accessed March 8, 2017. 13

The University of Tennessee Medical Center Case Study

Observing a potential target population and how it may benefit

from a personalized pain management approach

Tennessee Department of Health Controlled

Substance Database

51 PILLS OF

HYDROCODONE

Reference: 1. East Tennessee State University website. https://www.etsu.edu/com/cme/documents/119469-staubus-full-page.pdf/ Accessed March 8, 2017.

The number of prescription drugs prescribed annually for every Tennessean older than 12 years1

21 PILLS OF

OXYCODONE

15

Reference: 1. East Tennessee State University website. https://www.etsu.edu/com/cme/documents/119469-staubus-full-page.pdf/ Accessed March 8, 2017.

Comparison of Select Causes of Death

Tennessee Resident Select Causes of Death, 2006-20101

0

200

400

600

800

1000

1200

2006 2007 2008 2009 2010

Assault Suicide Overdose

De

ath

s

16

Observing Opioid Misuse in Tennessee to Identify Specific

Populations That May Benefit From an Individualized Approach1

• For every person who dies, there

are 851 people in various stages

of misuse, abuse, and treatment

• At least 1,074,813 Tennesseans

(1 in 6) misuse or abuse opioids

or are in treatment

Reference: 1. The Tennessean website. http://www.tennessean.com/story/money/industries/health-care/2016/04/02/opioid-abuse-has-death-grip-tennessee/82386402/.

Accessed March 8, 2017.

12,630in treatment

admissions for

abuse

32,838emergency

department

visits for misuse

or abuse

Those who died in 2014

136,404who abuse

opioids or are

dependent

925,779 non-medical

users

17

University of Tennessee Medical Center:

Summary of Changes

• Pain scale

–Emphasis on function

• Pathways: Impact in Cerner

–For pain orders embedded in disease/procedural

pathway for minimal change

–Guidance established for inexperienced clinicians

via 2 new pain pathways

–Experienced clinicians (hospitalists) using general

medicine pathways essentially unaffected

–Multimodal (non-narcotic options) easier to

access in computerized physician order entry

–Pain flowsheet

• “3 Strikes…you’re out” (evaluate)

–Guidance for expected responses for both

nursing and physicians established

• Red flags

–Prompt to identify the accurate diagnosis and

treat the cause of the pain

• Use of sedation scales

• Escalation of nursing or patient concerns

–“Something’s not right!”

• Mandatory attending evaluation

• Morphine milligram equivalents

–Common language of “how much”

• On-site drug disposal receptacle

–Secure and Responsible Drug Disposal Act 2010

• Standardized management of opioid misuse

–Patient compact

–Nursing aid

–Withdrawal

–Addiction treatment

18

The Revised Pain Scale

The pain scale has been revised to incorporate

patient functional abilities. This will help patients to score

their pain more accurately with a reference point

NO PAIN

Activity normal

CAN BE IGNORED

Able to

function

ANNOYING

Affects physical

ability

VERY DISTRACTING

Limits

normal activity

VERY INTENSE

Can only think

about pain

UNBEARABLE

Unable to function

or speak

PAIN ASSESSMENT RULER 1-10 PAIN INTENSITY SCALE

19

Where We Are Going

• Enhanced

recovery after

surgery1

References: 1. Melnyk M et al. Can Urol Assoc J. 2011;5(5):342-348. 2. Boston University Medical Campus website. https://www.bumc.bu.edu/care/files/2010/09/11.-

ALFORD-Chronic-Pain-and-Opioid-Risk-Management.pdf. Accessed March 3, 2017. 3. Beck DE et al. Ochsner J. 2015;15(4):408-412. 4. Sprouse-Blum AS et al. Hawaii

Med J. 2010;69(3):70-71. 5. GeneAlign website. https://www.genealign.com/clinicians-pharmacogenetic-testing/#information. Accessed March 8, 2017.

Personalized medicine

through pharmacogenetics

20

• Opioid risk

management2

• Multimodal pain

management3

• Understanding

the effects of

β-endorphins4

Utilizes the analysis of the genes responsible

for the metabolism of medications and

determined inherited variations that can affect a

patient’s response to certain medications5

Using Pharmacogenetics to Personalize Medicine

May Help Improve Pain Management Strategies

• Personalized (precision) medicine

– National Institutes of Health: “Precision

medicine is an emerging approach for

disease treatment and prevention that

takes into account individual variability

in environment, lifestyle and genes for

each person”1

• Pharmacogenetics

– Testing for an individual’s ability to

respond and process medications

based on DNA2

• Opioid use

– Optimized medication selection may

provide faster and more efficient

symptom relief3

CYP, cytochrome P-450; DNA, deoxyribonucleic acid; OTC, over the counter.

References: 1. National Institutes of Health website. https://www.nih.gov/research-training/allofus-research-program. Accessed March 8, 2017. 2. Scott SA. Genet Med.

2011;13(12):987-995. 3. GeneAlign website. https://www.genealign.com/lab-testing-services/. Accessed March 22, 2017.

PATIENT’S

MEDICATIONS

CYP2C19

CYP3A4

CYP2D6

TARGET

METABOLIC ENZYMES

PROPOSED NEW

MEDICATION

Fluoxetine

(Prozac®)

Hydrocodone

(Vicodin®)

Diphenhydramine

(Benadryl®) (OTC)

Clopidogrel

(Plavix®)

Omeprazole

(Prilosec®) (OTC)

St. John’s Wort

(OTC)

Simvastatin

(Zocor®)

21

22

Pharmacogenetic Guidance in Analgesia Selection Reduces

Opioid Consumption and Improves Pain Management

• A recent study demonstrated that

using pharmacogenetic guidance can

reduce opioid use by 50%, as well

as incidences of analgesia-related

side effects1

– Using genetic testing for pain

management improved the OBAS rating

for patients recovering from surgery

• To improve analgesia assessment, the OBAS

rating takes into consideration distress from

opioid symptoms, analgesia effectiveness,

and patient satisfaction2

OBAS, overall benefit of analgesia score; POD, postoperative day.

References: 1. Senagore AJ et al. Am J Surg. 2017;213(3):467-472. 2. Lehmann N et al. Br J Anaesth. 2010;105(4):511-518.

0

1

2

3

4

5

6

POD 1 POD 5

OB

AS

Sc

ore

Days Postsurgery

Pharmacogenetic Group Historical Group

OBAS SCORE1

P=0.01

Work Flow for Addiction Risk Assessment

23

Report

Addiction Risk

Results

BDNF

OPRM1

DRD2

12

SOAPP® Version 1.0-SF Score

Behavior

Genetics

Toxicology

BDNF, brain-derived neurotrophic factor; DRD2, dopamine receptor D2; OPRM1, opioid receptor mu 1; SOAPP®, Screener and Opioid Assessment for Patients with Pain®.

Health Plan Beta Test—GeneAlign

24

Gene

Extensive

Metabolizer

(Normal)

Intermediate

Metabolizer

(Impaired)

Poor Metabolizer

(Elevated Risk)

Ultra-Rapid

Metabolizer

(Elevated Risk)

Total Impaired

Population

2D6 43% 33% 25% NA 58%

2C19 40% 25% 4% 31% 60%

2C9 65% 31% 4% NA 35%

3A4 94% 6% NA NA 6%

3A5 56% 22% 22% NA 44%

Patients Respond Differently to Medications,

Thus Requiring Personalized Treatment

Good responders

to Drug A

Treatment-resistant or

refractory patients

Good responders

to Drug B

Good responders

to Drug C

DIFFERENT

PRESCRIPTIONS

SAME

DIAGNOSIS

PHARMACOGENETIC

TESTING

25

aBased on 43 patients on opioids with CYP2D6 impairment.

Reduction in Metabolic Opioid Severitya

26

Before After

11% Safe

31% Warning

58%Caution

62% Safe

2% Warning

36%Caution

Opioid Reduction With Multimodal Analgesia in TKA

27

Gabapentinoids4,5

10%-49%

Dexamethasone7

41% IV acetaminophen6

Average reduction

of 9 mg

of morphine

equivalents

NSAIDs2,3

~15%-55%Ketamine1

10%-30%

IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; TKA, total knee arthroplasty.

References: 1. Moodie JE et al. Anesth Analg. 2008;107(6):2025-2031. 2. Kazerooni R et al. J Arthroplasty. 2012;27(6):1033-1040. 3. Rawal N et al.

BMC Musculoskelet Disord. 2013;14:300. 4. Mathiesen O et al. Br J Anaesth. 2008;101(4):535-541. 5. Buvanendran A et al. Anesth Analg. 2010;110(1):199-207.

6. Apfel CC et al. Pain. 2013;154(5):677-689. 7. Backes JR et al. J Arthroplasty. 2013;28(8 suppl):11-17.

Opioid Reduction With Multimodal Analgesia in TKA

28COX, cyclooxygenase; NA, not applicable; PGx, pharmacogenetics; PO, by mouth.

Drugs Dose Before SurgeryRoute of

AdministrationTime Before Surgery PGx Guidance

NSAIDs

Ketorolac

Ibuprofen

15-30 mg

800 mg

PO/IV

PO

1-2 h

1-2 h

Ultra-rapid

metabolizer 1A2

COX-2 inhibitors

Celecoxib 400 mg PO 1 h Normal metabolizer

2C9, 2D6

Antineuropathic

Gabapentin

Pregabalin

1200 mg

150 mg

PO

PO

1-2 h

1 h

Normal metabolizer

3A4, 2D6

Propacetamol

Acetaminophen

2 g

1 g

PO/IV

PO/IV

15 min

15 minNA

Liposomal

bupivacaine

Up to 266 mg Injection into the soft tissues of the

surgical site during surgery

Normal metabolizer

3A4

Please see Important Safety Information on slides 35 and 36. Full Prescribing Information is available at www.EXPAREL.com.

Protocols for Personalized Pain Management

CHARACTERISTICS

• Low genetic risk

• Negative addiction indication

• Negative toxicology screen

PHARM D RECOMMENDATIONS

• Identify best available rescue narcotic based

on patient's genetic profile

• Identify multimodal perioperative pain

management

• RN-assisted transitioning to NSAIDs, ice,

TENS, etc.

NURSING OVERSIGHT

• Education related to opioid addiction

CHARACTERISTICS

• Moderate genetic risk

• Negative addiction indication or mutated opioid genetics

• Negative toxicology screen

PHARM D RECOMMENDATIONS

• Identify best available rescue narcotic based on patient's genetic profile

• Encourage multimodal perioperative pain management

• Limit exposure length to minimum

• RN-assisted transitioning to NSAIDs, ice, TENS, etc.

NURSING OVERSIGHT

• Education related to opioid risk mutations and opioid avoidance

CHARACTERISTICS

• High genetic risk

Or positive addiction indication and mutated

opioid genetics

Or positive toxicology confirmation

PHARM D RECOMMENDATIONS

• Perioperative narcotic avoidance

• Primary: multimodal perioperative pain

management (EXPAREL® [bupivacaine

liposome injectable suspension] or other

multimodal or long-lasting anesthetics)

• RN or MD telemedicine involvement in

postoperative pain management

ADDICTION SPECIALIST OVERSIGHT

• Education specific to narcotics

• Narcotic surveillance

Stratify preoperative patients based on

addiction risk, PGx, DDI, and toxicology

Track II Track IIITrack I

29Please see Important Safety Information on slides 35 and 36. Full Prescribing Information is available at www.EXPAREL.com.

DDI, drug-drug interaction, TENS, transcutaneous electrical nerve stimulation.

Sample Processing and Reporting

Cheek swab

by healthcare

professional

Pharmacist performs

an in-depth analysis

and provides

perioperative

management summary

Swab

sent to

the lab

Lab inputs

data into

GeneAlign

system

Analyst

simplifies

data

After testing, individual data is

analyzed to establish the primary

course of action in pain

management throughout all steps

of a patient’s surgical procedure

30

Avoidance of Prescription Drug Abuse After Surgery:

Protocol-Driven, Nursing-Directed Telemedicine Program

• Presurgical assessment of a patient’s

addiction risk

– SOAPP® Version 1.0-SF

• Genetics panel

– Brain-derived neurotrophic factor

– Dopamine receptor D2

– Opioid receptor mu 1

• Positive/negative toxicology

• Presurgical and postsurgical

pain-control counseling

• Pill dispensing

– Measured prescription amounts

– Unused medications returned

• Postsurgical pain-control monitoring

31

Taking Steps Toward Change

Identifying the effort required to improve pain management

Provide a protocol-based personalized

medicine program to identify patients at risk for

prescription-drug abuse and to manage pain

after discharge from the hospital

Significantly reduce opioid use and addiction

in the United States

Reduce the cost of surgical care and pain

management

Decrease adverse drug events and deaths

from overdoses

Reduce the conversion to heroin and other

illicit drugs

Develop evidence-based national guidelines

Potential Opportunity

1

2

3

4

5

6

33

FUNDING SUPPORT

Nursing

Information technology

Laboratory testing

Counseling

Data analytics

Needs

Commercial and

government payers

Government and

community leaders

Physicians and

other providers

News and other

media

34

35

● EXPAREL is contraindicated in obstetrical paracervical block anesthesia

● In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea,

constipation, and vomiting

● EXPAREL is not recommended to be used in the following patient population: patients <18 years old and/or pregnant patients

● Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in

patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics

normally, are at a greater risk of developing toxic plasma concentrations

Warnings and Precautions Specific to EXPAREL

● EXPAREL is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks, or

intravascular or intra-articular use

● Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if

administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20

minutes or more. Formulations of bupivacaine other than EXPAREL should not be administered within 96 hours following

administration of EXPAREL

Full Prescribing Information is available at www.EXPAREL.com.

EXPAREL® (bupivacaine liposome injectable suspension)

Important Safety Information

36

Full Prescribing Information is available at www.EXPAREL.com.

Warnings and Precautions for Bupivacaine-Containing Products

● Central Nervous System (CNS) Reactions: There have been reports of adverse neurologic reactions with the use of local

anesthetics. These include persistent anesthesia and paresthesias. CNS reactions are characterized by excitation and/or

depression

● Cardiovascular System Reactions: Toxic blood concentrations depress cardiac conductivity and excitability which may lead to

dysrhythmias sometimes leading to death

● Allergic Reactions: Allergic-type reactions (eg, anaphylaxis and angioedema) are rare and may occur as a result of

hypersensitivity to the local anesthetic or to other formulation ingredients

● Chondrolysis: There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local

anesthetics, which is an unapproved use

EXPAREL® (bupivacaine liposome injectable suspension)

Important Safety Information (cont’d)

Thank you

Dr. Epps: JLEpps@utmck.edu

Dr. Silliman: jim.silliman@genealign.com

All trademarks, registered or unregistered, are the property of their respective owners.

©2017 Pacira Pharmaceuticals, Inc.

Parsippany, NJ 07054 PP-NP-US-0399 04/17