State of Opioid Use for Treatment of

Chronic Pain: Role of Targeted Drug

Delivery

David L. Caraway, M.D., Ph.D.

CEO, Medical Director

Center for Pain Relief, Tri-State

St. Mary’s Regional Medical Center

Huntington, WV

"Life is like riding a bicycle. To keep your balance you must keep moving." - Albert Einstein

Disclosures

Consultant, Investigator, and Faculty, Medtronic Inc.

Consultant, Spinal Modulation, Inc.

Consultant, Vertos Medical, Inc.

Bioness, Inc.

Leadership Positions

NANS

ASIPP

3

Beliefs Common to Americans

and Canadians

We won the War of 1812

We do not stereotype our cross border friends

We think their accent is odd

Our health care system is the best

There is solid evidence for efficacy and safety

supporting use of opioids for chronic non-cancer

pain

Where Were We in 2002?

• Pain is a destructive disease process that should

be treated (2001 JCAHO)

• It is not considered legal, ethical or good

medical practice to withhold opioids from

patients whose lives could be improved with

treatment

Ballantyne, South Med J. 2006;99(11):1245-1255.

Where Are We in 2013?

“American Pain Foundation Shuts Down as Senators

Launch Investigation of Prescription Narcotics”

“The Federation of State Medical Boards, The Joint

Commission (that made pain management a national

priority in 2001) as well as 5 major pain Societies

several prominent doctors , hospitals and

pharmaceutical companies have received demand

letters from the Senate Finance Committee”

(5/08/12 Washington Post)5.

Where Are We in 2012?

"These groups, these pain organizations … helped

usher in an epidemic that's killed 100,000 people by

promoting aggressive use of opioids,"

"What makes this especially disturbing is that despite

overwhelming evidence that their effort created a

public health crisis, they're continuing to minimize

the risk of addiction.”

(Dr. Andrew Kolodny, chairman of psychiatry at Maimonides Medical Center in

Brooklyn, N.Y., and president of Physicians for Responsible Opioid

Prescribing 5/08/12 Washington Post)5.

CDC on Opioids

November 1, 2011 : Dr. Thomas Frieden Director of

the Centers for Disease Control and Prevention

"For chronic pain, narcotics

should be the last resort."

.

8

U.S. with 4.6% of world’s population

Produces 80% of Lawyers (1 lawyer per 1.5

incarcerated) ABA

Consumes almost 30% of Global Oil supply

(CIA)

Consumes 80% of Global Opioid supply

Patricia Good, Division of Drug Diversion Control, DEA

Consumes 99% of Global Hydrocodone supply JAMA, 2007

Canadian Opioid Trends

“Canadians are among the highest users of prescription

opioids in the world, and overall usage of

prescription opioids has more than doubled over the

past decade.”

“As many as 200 000 Canadians are currently addicted

to painkillers, …he’s equally discouraged that

evidence-based best practices for treatment of

medically induced addiction do not exist.”

Benedikt Fischer and Jürgen Rehm, director of the Social and

Epidemiological Research Department at the Centre for

Addiction and Mental Health in Toronto, Ontario

Opioid Prescribing

What is your approach?

Will never prescribe Prescribe without

recognition of risks

Assessment of risk and

benefits guides prescribing

Balance

The Perfect Storm

Overdue recognition of pain as a

medical condition

• 1992 –2002: Population: up 13%, Controlled Rx 154%

• Aggressive marketing including “off-label” and to primary care doctors of potent new preparations

• Overdose Rx deaths exceeded heroin and cocaine first in 2002 . 4000 deaths from methadone in 2005

• 15,000 killed in 2008. 3 times more than in 1999 45% of people who died were Medicaid enrollees

• Nearly half million ED visits. Direct health care costs of up to $72.5 billion

• Nationwide prescription pain pills kills more people than guns (NRA: gun homicide rate)

Rates of prescription painkiller sales, deaths and

substance abuse treatment admissions (1999-2010)

Sources : National Vital Statistics System, 1999-2008; Automation of Reports and Consolidated

Orders System (ARCOS) of the Drug Enforcement Administration (DEA), 1999-2010;

Treatment Episode Data Set, 1999-2009 .

Source Where Pain Relievers Were Obtained for Most Recent Nonmedical Use among Past Year

Users Aged 12 or Older

Note: Totals may not sum to 100% because of rounding or because suppressed estimates are not shown.

1 The Other category includes the sources: “Wrote Fake Prescription,” “Stole from Doctor’s Office/Clinic/Hospital/Pharmacy,” and “Some Other Way.”

Bought/Took

from Friend/Relative

14.8%

Drug Dealer/

Stranger

3.9%

Bought on

Internet

0.1% Other 1

4.9%

Free from

Friend/Relative

7.3%

Bought/Took from

Friend/Relative

4.9%

One

Doctor

80.7%

Drug Dealer/

Stranger

1.6%Other 1

2.2%

Source Where Respondent Obtained

Source Where Friend/Relative Obtained

One Doctor

19.1%

More than

One Doctor

1.6%

Free from

Friend/Relative

55.7%

More than One Doctor

3.3%

Who Prescribes?

National Vital Statistics System. Drug overdose death rates by state. 2008.

Available from URL: http://www.cdc.gov/homeandrecreationalsafety/rxbrief/

CDC (Centers for Disease Control). Vital signs: overdoses of prescription opioid pain relievers—

United States, 1999-2008. MMWR. 2011;60:1-6.

CDC. Vital Signs: Overdoses of Prescription Opioid Pain Relievers—United States, 1999-2008. MMWR 2011; 60: 1-6. 7. Substance Abuse and Mental Health Services Administration.

Results from the 2010 National Survey on Drug Use and Health. Volume 1: Summary of National Findings. Rockville, MD: Substance Abuse and Mental Health Services

Administration, Office of Applied Studies; 2011. Available from URL: http://oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.htm#2.16.

Substance Abuse and Mental Health Services Administration. Substance abuse treatment admissions by primary substance of abuse, according to sex, age group, race, and ethnicity 2009

(Treatment Episode Data Set). Available from URL: http://wwwdasis.samhsa.gov/webt/quicklink/US09.htm.

http://www.cdc.gov/homeandrecreationalsafety/rxbrief

Number ONE!

Huntington, WV:

• Fattest City (CDC 2006 and Jamie Oliver)

• WV number one prescriber of antibiotics (1222 per 1000 CDEEP 12/2011

• Highest Disability (21% SSA 2011,60 minutes 10/06/2013)

• Top 10 Saddest city (USA Today 2/28/2012)

• Cancer and diabetes deaths (CDC 2012)

• Highest Smoking Rate ( 26.8% CDC 2011)

• Highest adult edentulous rate (47.9 % CDC 1999)

WE have slipped to number two in one area

Drug overdose death rates by state per

100,000 people (2008)

SOURCE: National Vital Statistics System, 2008 :

SOURCE: Automation of Reports and Consolidated Orders System (ARCOS) of the Drug

Enforcement Administration (DEA), 2010

Amount of prescription painkillers

sold by state per 10,000 people (2010)

13.6%

12.7%

10.4%8.9%

6.5%

4.9%4.0%

0%

2%

4%

6%

8%

10%

12%

14%

16%

1999 2000 2001 2002 2003 2004 2005

Methadone Related Deaths

(% all Poisoning Deaths)

Source: CDC/NCHS, National Vital Statistics System.

Most abused

• Hydrocodone

– Most prescribed of all drugs

– Largest number of pills diverted

• Oxycontin

– Highest dollar amount of traffic

• Methadone

– Most deaths – Heroin now fast approaching

• Most commonly associated with opioid abuse

– Xanax, Soma

– ED visits for SOMA 15,830, in 2004 to 31,763 in 2009

Opioid Treatment in Nonterminal

Chronic Pain

Efficacy

Safety

Not Lawyers, insurance companies, drug reps

Chronic Pain Patients are Often

Not Satisfied with Opioids

Control Over Chronic Pain Impact on Quality of Life

2006 Voices of Chronic Pain Survey. (American Pain Foundation)

• Chronic pain patients have a “mixed” attitude toward opioids and few patients rated opioids as

“very effective” as way to control their chronic pain

• Many chronic pain patients also question the safety profile of opioids

• Short term efficacy

– Clear efficacy in multiple RCT’s (up to 8 months)

demonstrate improvement in pain

– No evidence to support dosing of higher than 180

mg morphine equivalent per day

• Long term efficacy

– No RCTs for longer than 8 months

– Overall evidence is weak

– Studies mostly look at VAS, little evidence of

improved function

Is Opioid Therapy Effective?

Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J

Med November 13, 2003;349:1943-53

APS /AAPM Opioid Guidelines

• In fact, the panel did not rate any of its 25

recommendations as supported by high quality

evidence.

• Only 4 recommendations were viewed as

supported by even moderate quality evidence.

• Nonetheless, the panel came to unanimous

consensus on almost all of its recommendations

[regarding opioids]

The Journal of Pain Volume 10, Issue 2 Pages

113-130.e22, February 2009

Chronic Non-Malignant Pain

• Moulin et al., Lancet 347:143-147, 1996

• Randomized, DB, crossover study, up to 120mg po MS

• 46 patients, average age 40 yrs.

Oral Opioid Approval

Mean Daily dose of Exalgo arm 37.8 mg Sources : FDA.

Oral Opioid Approval

Sources : FDA.

Dose Escalation

• Tolerance

– Physiological

• Opioid Induced Hyperalgesia

– Solid evidence in animal models

– Emerging clinical data

• Perception

– Goals of therapy

• Disease progression

Age Dependent Opioid Dose Escalation

in Chronic Pain Patients

• Retrospective chart review examined to see if

the age of the patient is related to dose

escalation

• Divided into two groups: < 50 vs > 60

• Younger 452 MMDE

• Older 211 MMDE

• Older VAS reduction from 6.9 to 5.6

• Younger unchanged Palmer et. al. Anesth

Analg 2005; 100:1740-5

Opioid Induced Hyperalgesia

Dose escalation may be a result of tolerance, opioid-induced hyperalgesia or both

• Presentation of Opioid Induced Hyperalgesia

– Associated with high dose and long term use of opioids (animal studies demonstrate single dose induction)

– Increased sensitivity to noxious stimuli

– Paradoxically, as medication is increased to relieve pain, patients experience more pain

– Some patients report decreased pain when taken off of opiates

Mechanisms of OIH• Pharmacological tolerance is a desensitization

• Opioid induced hyperalgesia is a sensitization

• Clinical approaches are different between these two processes

• NMDAr cellular mechanisms are common to both and also are involved in neuropathic pain

• Evidence NMDA receptor antagonists may attenuate OIH

• Opioid administration induces a pronociceptive process mediated in part by increased synthesis of excitatory neuropeptides (through spinal dynorphin which is

increased with opioid infusion)

King et al 2005, Mao 2006, Ossipov et al 2005

Mao J., Pain (100) 2002 213-217

Opioid Induced Hyperalgesia

Angst, MS & Clark, DJ: Opioid-induced hyperalgesia: A

qualitative systematic review. Anesthesiology 2006;

104:570–87

Opioid Induced Hyperalgesia

Conclusions:

• Solid support in animal models of OIH with

various opioids and during withdrawal

• Human data are far more limited and provide

only indirect evidence of OIH

“Conceivably, the long term use of opioids may

exacerbate rather than ameliorate chronic

pain”Angst, MS & Clark, DJ: Opioid-induced hyperalgesia: A qualitative

systematic review. Anesthesiology 2006; 104:570–87

Universal Precautions in Pain

Medicine

• Our understanding and assessment methods to select patient s

that might benefit from opioid therapy are imperfect at best. Lack

of rigorous guidelines

• “Gut” is often incorrect, frequently unfair and stigmatizing

• Standardized approach to the assessment and ongoing

management of all chronic pain patients

Gourlay DL, Heit HA, Almahrezi A. Universal precautions

in pain medicine: a rational approach to the

treatment of chronic pain. Pain Med 2005;6:107-112.

Undue Scrutiny

ASIPP Guidelines 2012

ASIPP Guidelines 2012 Part 1

ASIPP Guidelines 2012 Part 1

ASIPP Guidelines 2012 Part 1

ASIPP Guidelines 2012 Part 1

ASIPP Guidelines 2012 Part 1

ASIPP Guidelines 2012 Part 1

Guidelines for Appropriate

Prescribing

• History

– Obtain and review all records, prior to initiation of

opioid therapy

– Develop a detailed history. Must include any

impairment in function or ADL’s

– Ask specifically if the patient has ever abused or

diverted illicit drugs or prescription medication

– Previous narcotic use

– Caution with self-referred patients

Guidelines for Appropriate Prescribing

Physical Examination

Goal is to establish and document an etiology

reasonably consistent with pain complaints.

Do the findings warrant narcotic analgesia?

Look for warning signs

Establish any functional limitations or deficits

Treatment

Do not start narcotics until detailed history has been

obtained

Document failure of more conservative methods

Determine the minimum dose to maintain function

and ADL’s

Once stable continue to document improvement in

quality of life and compliance

Monthly refills, comprehensive follow-up

Physician remains in control of dosing

Guidelines for Appropriate Prescribing

Create a written narcotics agreement

Informed consent of risks including lack of efficacy

and addiction

Specific office policies, mandatory frequency of

visits

Single source of prescriptions, no changes in

amounts without office visit and rationale

Random DOA screening

Single pharmacy

Delineation of consequences if non-compliant, exit

strategy

Guidelines for Appropriate Prescribing

Summary for Appropriate Prescribing

• Perform and document history and PE, establish diagnosis –prior to initiation of opioids

• Document failure of non-opioid therapy

• Titrate to achieve goals within 6- 8 weeks of initiation of opioid therapy

• Establish and document attainment of goals

• Failure to achieve moderate stable dose warrants re-examination of treatment plan

– Opioid rotation (?)

– Discontinuation

– Surveillance, documentation of 4A’s

Documentation

The “Four A”s

– Analgesia (pain relief, attainment of goals)

– Activities of daily living (ADLs; functional

outcomes)

– Adverse effects (side effects)

– Aberrant drug-related behaviors (appropriate use and

adherence vs misuse or addiction-related outcomes).

Placebo

AVINZA 30 QAM

AVINZA 30 QPM

MSC 15 BID

Double-Blind Study Results: Sleep Measures

Osteoarthritic (OA) Pain

Improved Overall Quality of Sleep

Ch

ang

e fr

om

Bas

elin

e (m

m)

Week 1 Week 40

5

10

15

20* †

*

* †

*

Quality of sleep assessed on a 100 mm scale and duration of sleep each night assessed on a 12-pt scale.Positive changes are improvements from baseline. ANOVA (P<0.05); *Significant difference from placebo (P0.05); †Significant difference from MS Contin®.

16. Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain; results from a randomized placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Management. 2002;23:278-291.

Opioid Therapy: “Rescue Dosing”

• Long-acting opioid “around-the-clock” plus a

short-acting opioid “rescue” dose “PRN”

– Preferred approach for patients with cancer pain

– Rescue dose may or may not be appropriate for

all patients, depending on syndrome and ability

to use the drug responsibly

– Rescue is 5%-15% of total daily dose

Portenoy RK. Opioid prescribing to patients with and without chemical dependency. Presented at: The International Conference on Pain and Chemical Dependency; June 6-8, 2002: New York, NY.

Intermittent Opioids

• Chronic use of opioids leads to tolerance and

possibly opioid induced hyperalgesia

• Intermittent use may reduce this problem (1)

• Allowing three days or more in between opioid

dosing may avoid dose escalation

• Use opioids only for “rescue” and activity

related pain, especially in the younger age

groups

1. Mao J., Pain (100) 2002 213-217

Intrathecal Opioids

• Intrathecal drug delivery devices are not a

therapy: They are a delivery system for a

therapy.

• Opioids are the therapy (for pain)

• How does the intrathecal route of delivery

compare to systemic in terms of safety, efficacy,

side effects and cost?

Ability to Discontinue Multiple Routes of Delivery

Why use the term“TARGETED DRUG DELIVERY”?

Systemic analgesia

• Distributes drug via blood

stream

• High blood levels of drug

• Brain receives highest

proportion of drug

• High dose of drug required

– High elimination load

• Increase in systemic side

effects

Spinal analgesia

• Intrathecal drug distribution

• Low blood levels of drug

• Most drug binds to

TARGET (spinal cord pain

receptors)

• Low dose of drug is effective

– Low elimination load

• Minimal systemic effect on

brain and gut 59

Diversion—Eliminate Easy Access

Intrathecal Opioids

Advantages:

• Achieves steady-state, around the clock dosing

• Reduced side effects (1), Use of intermittent

dosing to reduce tolerance

• Intrathecal Adjuvants

• Compliance : Eliminate systemic opioids

– Can provide patient activated rescue dosing (PCA)

– Reduction in longitudinal costs

1. Smith, T. J Clin Oncology, 2002

Intrathecal Opioids

Disadvantages:

• More invasive

• More difficult to discontinue therapy

• Acquisition costs

• If positioned as a salvage therapy for patients

who have failed but remain on high dose

systemic opioids outcomes are diminished

Practice of David Caraway, MD. St. Mary’s Regional Medical Center

Huntington, WV.

Redefine Patient Selection

Easy first choices for PUMP

• Cancer pain

• Failed Back Pain and extremity pain - non responsive to SCS

• Elderly axial spinal pain

• Good analgesia with systemic opioids but intolerable side effects

Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

Kevin W.

Receiving

Medtronic

intrathecal drug

delivery for

chronic pain.

Redefine Patient Selection

Difficult choices for PUMP

• High oral opioid use with minimal perceived benefit

• Minimal baseline pain with intermittent severe pain may need specialized trialing (PTM?)

• Poorly defined etiology

• Poor compliance to previous therapies

• Young age

Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

Patient Selection for IDD

• Some conditions have not experienced good

outcomes:

– Headache

– Fibromyalgia

– Atypical facial pain

– Non-cancer head-neck pain

– Borderline personality

Typical Dosing

Typical Dosing

Pain Level

Dosing with self administered

PCA

Minimal DosingPain Level

Data Reveals Patient Satisfaction

and Reduction in Oral Opioids

• A prospective registry of 168 patients (92% NMP) using PCA (patient controlled analgesia) found1:

– Patients use device regularly

– Average number of boluses per day = 1.3

– 82% preferred PCA vs their previous method

– 75% more satisfied with PTM compared to their pump alone

– Reduced need for oral opioids

Ilias W, le Polain B, Buchser E, Demartini L; theoPTiMa study group. Patient controlled

analgesia in chronic pain patients: experience with a new device designed to be used with

implanted programmable pumps.Pain Pract. 2008;8(3):164-170.

Requires Same Strategies as

Systemic Delivery • Early titration to achieve

analgesia and therapy goals

• Careful consideration of

dose increases

• Maintain moderate doses

• Monitor for side effects,

efficacy

• Physician remains in control

of dosing

Psychological Evaluation

• Consider recommendations and treat if indicated - prior to trial

• Ability to understand appropriate expectations

• Has patient come to terms with status, expected life span

• Is this someone you are willing to “marry”?

• Major active psychosis, current drug addiction, some personality

disorders, cognitive deficits, progressive organic brain disorders,

suicidal, homicidal behavior

Know

When

To Quit

Dr.

Caraway

And…

When never

to start!

THE END

THANK

YOU