Richard B. Riemer, D.O. Medical Director, Schools Insurance Authority

The Unintended Consequences of Compassionate Care

Richard B. Riemer, D.O.Medical Director, Schools Insurance Authority

A historical perspective Data supporting the “epidemic of

prescription drug overdose” Innovations in Neuroscience: what we have

learned about addiction and drugs of addiction including prescription opioids.

The Clinical Dilemma- the “carefully selected patient”

The talk

Eric Kandel, MD

Nobel Prize Recipient in Physiology or Medicine, 2000

New York Times, 9/9/2013

“The new science of mind is based on the principle that our mind and brain are inseparable… it constructs our sensory experiences, regulates thoughts and emotions and controls our actions…our mind is a set of operations carried out by our brain…these same principles of unity applies to mental disorders.”

Scope of the Problem

Profiting From Pain: UDT

2000 2013$0

$500,000,000

$1,000,000,000

$1,500,000,000

$2,000,000,000

$2,500,000,000

800 million

2 Billion

Profiting from Pain: US ED Visits

2004

2013

0 200000 400000 600000 800000 1000000

299498

885340

Monitoring “Doctor Shopping”

2002 20120

5

10

15

20

25

30

35

40

45

16

42

Profiting from Pain: Opioid Costs

In California, workplace insurers spent $252 million on opioids in 2010

This represented ~30% of all prescription costs, twice that of 2002.

2002 20100%

5%

10%

15%

20%

25%

30%

35%

15%

30%

Primary non-heroin opiates/synthetics admission rates, by State(per 100,000 population aged 12 and over)

Source is Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, Treatment Episode Data (TEDS), Data received through 11.3.2010.

“And now my beauty, something with poison in it I think… but attractive to the eye, and soothing to the smell…poppies, poppies, poppies will put them to sleep…now they’ll sleep”. Wicked Witch of the West

The Opium PoppyPapaver Somniferum

Crude opium latex on poppy head

The synthesis of Heroin from Opium

Aktiengesellschaft Farbenfabriken

Reason in Common Sense, p. 284George Santayana

“Those who cannot remember the past are condemned to repeat it.”

Opioid addiction is rare in pain patients. Physicians are needlessly allowing patients to

suffer because of “opiophobia”. Opioids are safe and effective for chronic

pain. Opioid therapy can be easily discontinued.  Dhalla, I.A., N. Persaud, and D.N. Juurlink, Facing up to the prescription

opioid crisis. BMJ, 2011. 343: p. d5142.

Industry-influenced “Education” on Opioids for Chronic Non-Cancer Pain Emphasizes:

Misperception: “drugs are safe” Campaign: “under-treatment of pain”- new

standard of care. Joint Commission: Pain the 5th Vital Sign Since 2001: 12 units CME in Pain

Management Perceived safety of long term opioids, No

Ceiling Dose and new extended release formulations.

Factors contributing to the Epidemic

Protection from and relief of pain and suffering are a fundamental feature of the human contract we make as parents, partners, children, family, friends, and community members, as well as a cardinal underpinning of the art and science of healing. Pain is part of the human condition; at some point, for short or long periods of time, we all experience pain and suffer its consequences. While pain can serve as a warning to protect us from further harm, it also can contribute to severe and even relentless suffering, surpassing its underlying cause to become a disease in its own domains and dimensions. We all may share common accountings of pain, but in reality, our experiences with pain are deeply personal, filtered through the lens of our unique biology, the society and community in which we were born and live, the personalities and styles of coping we have developed, and the manner in which our life journey has been enjoined with health and disease.IOM-Relieving Pain In America (2011)

Universal Contract

>100 million Americans 1

Mean Prevalence of 35.5% for chronic pain of any kind 2

Weighted mean prevalence of 11% for severe chronic pain 2

Epidemiology of Chronic Pain

1. Institute of Medicine Relieving Pain in America: A blueprint for transforming prevention, care, education and research, 2011.

2. Opina M, Hartstall C. 2002. Prevalence of chronic Pain: An Overview. Alberta Heritage Foundation for Medical Research. Alberta, CA.

$8.4 billion spent on narcotic analgesics in 2010.

Narcotics: 11th most prescribed drug Oxycontin accounted for $3.1 billion in sales Hydrocodone/APAP was the most dispensed

medication in the U.S.- 131.2 billion dispensed.

Enough Hydrocodone to give every US Adult one 5 mg tablet every 4 hours for six weeks.

2010 Data

Behavior Percentage

Addicted to opioids 3.3

Engaged in misuse behaviors

11.5

Illicit Drug Use 14.5

Opioid misuse and abuse in CNCP patients (Fishbain DA, 2007)

Motor vehicle traffic, poisoning, drug overdose rates, US, 1980-2009

Unintentional Drug OD Deaths in US, 1970- 2009

28,578 deaths in US in 2009

Opioid Epidemic Facts

For every one overdose death from opioids: ◦ 9 treatment admissions◦ 30 Emergency Department Visits◦ 118 met criteria for addiction◦ 785 people over the age of 12 using drugs for

non-medical reasons From 1971 to 2007: an 8-fold increase in

drug overdoses.

Physician Prescribing Practices

National Survey: 2006-2008- users of opioids for non-health-related purposes revealed they obtain drugs from physicians 31% of the time.

Overdoses: ◦ 40% see multiple doctors◦ 40% see one doctor, prescribed high doses◦ 20% see one doctor, prescribed low dose

Risk of OD 4-12 fold higher >100 MED’s ~50% of OD’s occur when opioids are

combined with other drugs (especially BZDP’s).

In California

Many of the Rx opioids are high risk preparations:◦3% fentanyl immediate release◦17% fentanyl patches◦10% methadone

Methadone: 2% of all opioids nationally, but 1/3rd of all deaths due to OD

45% of prescriptions in California WC were for oxycodone- one of the most abused drugs.

Unpublished-Nickols, T., et al. 2012, RAND-David Griffen College of Medicine/UCLA

In California Small number of physicians represent

outliers with high-risk prescribing practices. One percent of physicians who prescribed

opioids within CA WC were the source of 33% of all opioid prescriptions.

Swedlow A, Ireland J, Johnson, G. Prescribing Patterns of Schedule II Opioids in California Workers’ Compensation: California WC Institute 2011.

Is there any role for chronic opioid analgesia (COT) in the treatment of chronic noncancer pain (CNCP)?

Does the prescription of opioids to an injured worker with noncancer pain worsen outcomes?

Does the Rx of Opioids effect outcomes (disability, pain severity, surgical risk, etc.)

How to determine the “carefully selected patient”?

Questions to ponder:

?Acute Pain Chronic Pain

How do we go from here to there?

OpioidsAcute Pain Chronic Pain

How do we go from here to there?

At what point are the conditions indistinguishable?

CNCPCOT

Predicting Opioid Misuse by Chronic Pain Patients Experts advocate use of COT for carefully

selected patients- how good are you? Is it possible to identify patients with

predisposing factors that place them at risk for Substance Abuse Disorder (SAD)?

Gut feelings- Physicians judged only 13.9% of CPP prescribed opioids having aberrant drug behaviors when 50% had positive UDT for illicit drugs and 8.7% had no evidence of opioid in their urine.

(Wassan, A.D. et al. Psychiatric history and psychological adjustement or risk fractors for aberrant drug-related behavior among patients with chronic pain. Clin. J. Pain, 2007: 23(4): 307-15.

Predicting Opioid Misuse by Chronic Pain Patients Patient self-report: notoriously unreliable. Berndt et al found that 32% of patients

reports of prescription medication use did not correspond with UDT.

Cook et al. found that self-reports compared to urine tests, up to 50% of substance abusers report falsely.

Predicting Opioid Misuse by Chronic Pain Patients-Systematic Review and Literature Synthesis (Turk, 2008) Mixed predictors (+) in some

studies and (-) in others:◦ Male sex, hx anxiety d/o; hx

of Rx drug abuse and race (non-white)

Variables rarely examined but when they were, there was some predictive value:◦ (+) FHx of drug/illicit drug use◦ Hxchildhood sexual abuse◦ Hx of DUI or drug convictions◦ Lost or stolen Rx◦ Supplemental sources of

drugs Not predictive:

socioeconomic status and disability level.

No one interview format or instrument is superior to any other in predicting opioid misuse among CPP.

Strongest predictor: personal hx of alcohol and illicit drug use.

2 variables not predictive: severity of pain and female sex

Younger age, hx of legal problems, (+) UDT moderately positive predictors

Predicting Opioid Misuse by Chronic Pain Patientsor- despite our best attempt to “profile” those at risk, it may merely be the prescription and use of opioids themselves which best predicts poor outcomes!

  Does health care utilization and the physicians

initial management of work-related LBP associate with the length of disability.

Subtext: Does the prescription of opioids affect total cost and length of disability.

Mahmud, M.A., et al., Clinical management and the duration of disability for work-related low back pain. J Occup Environ Med, 2000. 42(12): p. 1178-87.

Does the Doctor make a difference?

  An association between the avoidance of

prolonged opioid use (>7 days) and going off disability was observed.

Mahmud, M.A., et al., Clinical management and the duration of disability for work-related low back pain. J Occup Environ Med, 2000. 42(12): p. 1178-87.

Does the Doctor make a difference?

Opioids: Early Management

Duration of Opioids

0

10

20

30

40

50

</=7 days

>7 days

13

45

</=7 days>7 days

Opioids and Imaging Combined

Imaging and Opioids

Imaging only No imaging or opiods

0

5

10

15

20

25

30

35

40

45

5045

28

10

Days of Disability

Is there a relationship between early opioid prescribing and Disability?

Prospective observational study correlated that prescription of more then 7 days of opioids in the first 6 weeks after acute low back injury was associated with increased risk (OR 2.2) of long-term (one year) work disability.

Receipt of at least 2 opioid prescriptions in 6 weeks was associated with increased risk (OR >/= 1.8) of long term disability.

Receipt of >150 MED in six weeks associated with doubling of 1-year disability.

Franklin, G.M., et al., Early opioid prescription and subsequent disability among workers with back injuries: the Disability Risk Identification Study Cohort. Spine (Phila Pa 1976), 2008. 33(2): p. 199-204.

Correlation of #RX and 1-year Disability

0 1 2 3 >3

1

1.8

2.9

5.6

6.2

Number of days opioids prescribed during the first 6 weeks of care correlates with 1 year disability.

0 1 to 7 >7

0.74%

4.78%

9.20%Percentage

Disability Duration Medical Costs Late Opioid Use Subsequent back surgery

Webster, B.S., S.K. Verma, and R.J. Gatchel, Relationship between early opioid prescribing for acute occupational low back pain and disability duration, medical costs, subsequent surgery and late opioid use. Spine (Phila Pa 1976), 2007. 32(19): p. 2127-32.

What is the relationship between early opioid prescribing for ACUTE low back pain and

January 2002-December 2003 Only acute LBP cases N= 8443 cases (1/1/2002-12/31/2003) Excluded CLBP, Tx within the past year, no

concurrent or serious injury, i.e. fx The MEA (morphine equivalent

amount) within the first 15 days after onset of injury was calculated.

Study

Group I: (No opioids within the first 15 days) Group II: 1-141 MEA Group III: 141-225 Group IV: 226-450 Group V: >450

Five Groups Identified:

0 1-140 141-225 226-450 450+

121.1 124.1149.6

175.5204.2

Disability Days

MEA vs. Disability Duration (days)

0 1-140 141-225 226-450 450+0

5,000

10,000

15,000

20,000

25,000

30,000

Medical Costs

Medical Costs

MEA and Medical Costs

0 1-140 141-225 226-450 450+

7.9

10.511.9

15.6

23.5

Surgery %

MEA and Risk of Subsequent Surgery

0 1-140 141-225 226-450 450+

7.2

13.5

18.8

23.4

34.3

Late Opioid

MEA and “late opioids”

After controlling for age, gender, job tenure, and injury severity, the findings indicate that receipt of higher amount of morphine equivalent medications in early treatment was significantly associated with adverse outcomes including higher medical costs and prolonged disability, higher risk of surgery, and continued use of opioids.

Conclusions

Drugs of Addiction and the Brain

Innovations in Science- A window into the living brain

Some of the key players

Neuroanatomy 101

Amygdala“The heart and soul of the brain’s emotional network.” (Joseph LeDoux, 1992, Professor of Neuroscience and Psychology, NYU)

Insula: “I just don’t feel right, but can’t tell you why.” (miscellaneous patient)

Neuronal Pathways for chronic pain-Nucleus Accumbens

Plays a central role in reward circuit relying on dopamine and serotonin.

Close relationships to the VTA (s. nigra) which is targed by opiates; prefrontal cortex, locus ceruleus (drives aberrant drug seeking behaviors), hippocampus, prefrontal cortex, insular cortex.

Signals anticipation of pain perception.

Prefrontal Cortex

Major brain regions with roles in Addiction

Cocaine MOA

MRI ScanFunctional MRI Scan (fMRI)DTI- Diffusion tensor imagingSPECT Scan (single-photon emission computed tomagraphy)

PET (positron emission tomography)

Neuroimaging

Speed matters

Speed matters

Expectation Matters

Volkow N D et al. J. Neurosci. 2003;23:11461-11468

©2003 by Society for Neuroscience

Cues stimulate brain

Age Matters

Family MattersSimilar Gray matter abnormalities in dependent and nondependent siblings

Stimulant Dependent siblings vs. Healthy

Non-dependent siblings vs. healthy

Amygdala

Putamen

Post-central gyrus, insula and superior temporal gyrus

Addiction is “polygenic” Genes influence:

◦ Brain development◦ Relevant neurotransmitter systems◦ Drug metabolic pathways◦ Neural circuitry◦ Cellular physiology◦ Behavioral patterns◦ Response to environmental stimuli◦ Individual’s personality traits

Genetics Matter

Genetics Matter MAO’s

◦ Deaminates NE, Epi, Serotonin, dopamine

◦ Adult carriers of “low-activity” MAOA, exposed to child abuse, more likely to develop conduct D/O, antisocial PD, violent behaviors.

◦ MAO-L: reduced volume of ACC (pathway disrupted in SUD)

Genetics Matter BDNF-Brain-derived

neurotrophic factor BDNF (Val(66) Mety

genotype may provoke drug seeking behavior in heroin users.

Low levels BDNF impede development of serotonin neurons

Example: “Gateway theory”- how early exposure to a chemical or drug, may increase risk for subsequent addiction (by increasing gene transcription in brain circuits that underlie addiction)

Example: prenatal exposure to cigarette smoke associated with specific brain changes and behaviors later in adolescence (methylation of BDNF)

Hypothetical example: Injured worker with pain.

Epigenetics matters

Dopamine and other neurotransmitters Learning- synaptic plasticity and long-term

potentiation (LTP) and long-term depression (LTD)

Molecules matter

The neuron

Conditioned Place Preference Chamber: will the mouse love it or list it?

Cocaine reduces metabolism (PET)

Methamphetamine reduced gray matter

Do Opioids change your brain? Most research on neurobiological aspects of opioid

dependence on brain systems focused on illicit opioids (e.g. heroin).

This study was unique: examines impact of long-term prescription opioids, since this may cause a different illness (pure, pharmacologically bred).

n=10: small, homogeneous population of patients without dependence on alcohol, other drugs, comorbid psychiatric or neurologic disease and NO Pain.

Compared morphologic and functional imaging (MRI, DTI and fMRI)

Upadhyay, J., et al., Alterations in brain structure and functional connectivity in prescription opioid-dependent patients. Brain, 2010. 133(Pt 7): p. 2098-114.

Do Opioids change your brain? Results:

◦3T MRI: Reduced amygdala volume (bilaterally)

◦MRI/Diffusion weighted imaging: Reduced FA in white matter tracts connected to amygdala, corpus callosum, and internal capsule.

◦Functional MRI: Reduced FA correlated with fMRI that showed reduced connectivity between corresponding structures: insula, amygdala and nucleus accumbens.

Significant group-level FA decreases in white matter pathways.

Upadhyay J et al. Brain 2010;133:2098-2114

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resting-state functional connectivity changes in opioid-dependent subjects in insula.

Upadhyay J et al. Brain 2010;133:2098-2114

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resting-state functional connectivity in opioid-dependent subjects in amygdala.

Upadhyay J et al. Brain 2010;133:2098-2114

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resting-state functional connectivity in opioid-dependent subjects in nucleus accumbens.

Upadhyay J et al. Brain 2010;133:2098-2114

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prescription Opioids Change Human Brain: “before & after”Only longitudinal study (n=10)CLBP w/o Radiculopathy vs. Placebo13 areas with changes in brain volume, 6

correlate with doseDesign: MRI volumetric study- pre-MS,

after one month of MS and ~4-6 months after discontinuation of MS.

Younger, J.W., et al., Prescription opioid analgesics rapidly change the human brain. Pain, 2011. 152(8): p. 1803-10.

Prescription opioids-how rapidly do they change the brain This group of patients with CLBP (n=10)) w/o

radiculopathy, SOD, prior opioids, ψ, neuropathic pain compared to placebo group (n-9)

A before and after study, prospective, with imaging prior to, after one month and on average 6 months post treatment with escalating doses of opioids up to 120 MED/day ceiling.

Morphologic study-volumetric changes measured.

Younger JW, et al. Prescription Opioid analgesics rapidly change the human brain.

Prescription opioids-how rapidly do they change the brain-results A total of 13 structures demonstrated

significant regional volumetric gain or loss over the 1-month of treatment.

Volumetric change in 6 of those regions correlated with morphine dose, in particular the right amygdala. (see next slide)

Other areas with significant reduction in size (not dose related) were the right hippocampus, b/l rostroventral pons and right medial orbital gyrus of the orbitofrontal cortex.

GM Volume Decrease (1 month)in the right Amygdala

GM Volume Increase (1 mo.)

Reversibility? This study measured changes up to 4.7

months on average (3.8-6.1 months after cessation of the drug).

A quick and robust return to pre-opioid volume levels would suggest that the drugs impacts were transient and easily negated by discontinuation of the drug.

HOWEVER, drug induced changes were PERSISTENT!

This may underlie the difficulty with fully recovering from adverse affects of opioids.

No RCT examine pain control with doses >180 to 200 MED

Dose-Response relationship observed: higher doses assoc. with greater risks.

Even low doses are associated with increased risk (one study as low as 50 MED/day.

Risk greatest above 100 MED/day: fatal OD ~20 t0 200% increased risk and 1100% increased risk of serious or fatal OD.

Opioid: Maximum Daily Dose

Vaccines to prevent opioid addiction Medications that inhibit pain only in the

peripheral nervous system Opioids that treat only pain without

addiction or side-effects

On the horizon globally

Martin Brady, Executive Director and Debra Russell, Schools Insurance Authority, Sacramento, CA (www.sia-jpa.org)

National Institute of Drug Abuse (www.drugabuse.gov)

Substance Abuse and Mental Health Services Administration (www.samhsa.gov)

Physicians for Responsible Opioid Prescribing (www.supportprop.org)

Centers for Disease Control (www.cdc.gov) National Rx Abuse Summit (

www.nationalrxdrugabusesummit.org)

Thanks to:

The EndQuestions?

Downward spiral of chronic pain and opioid addiction RECURRENT PAIN ATTENTIONAL FIXATION/RUMINATION STRESS NEGATIVE EMOTION TEMPORARY RELIEF FROM OPIOIDS CONDITIONED REINFORCEMENT OF

OPIOID USE OPIOID ATTENTIONAL BIAS OPIOID CRAVING TEMPORARY RELIEF FROM OPIOID

USE HYPERALGESIA INSENSITIVITY TO NATURAL REWARD LOSS OF CONTROL OVER OPIOID

USE

Downward Spiral of Chronic Pain and Opioid Addiction