We must all die' But that I can spare a person from days of torture, that is what I feel is my great

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• We must all die. But that I can spare a person
  from days of torture, that is what I feel is my
  great and ever new privilege. Pain is a more
  terrible lord over mankind than even death
  itself.
• Albert Schweitzer 1953

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Pain and AddictionCommon Etiologies,
Co-Morbidities and Treatment

• Kevin Kunz, M.D., FASAM
• Kona Community Hospital
• November 7, 2005

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Molecules Spirit

• Molecules
• we are a stack of matter interacting with
  other matter
• Spirit Spirituality
• Relationship with self
• Relationship with others
• Relationship with the powers of universe
  whatever we conceive these to be

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Overview of Todays Talk

• Definitions - Morphing
• Shared Bio-Psycho-Social Features
• Epidemic of Prescription Drug Abuse
• Shared Treatment Approaches
• Opioids, Buprenorphine
• Treatment Strategies
• - Molecules and Spirit

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Webster Defines Pain

• a sensation of hurting or a strong discomfort
  caused by injury or disease or dysfunctional
  disorder and transmitted through the nervous
  system.
• Websters New World Dictionary

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IASP Defines Pain

• an unpleasant sensory and emotional experience
  associated with actual or threatened tissue
  damage, or described in terms of such.
• International Association for the Study of
  Pain

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Hospice Defines Pain

• Pain can be timeless, endless, meaningless,
  (and) bring a sense of isolation and despair.
• Cicely Saunders, M.D. Founder of Hospice

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Addiction

• A primary, chronic, neurobiologic disease, with
  genetic, psychosocial and environmental factors
  influencing its development and manifestations.
  Characterized by behaviors that include one or
  more of the following impaired control over
  drug use compulsive use continued use despite
  harm and craving. APS, ASAM, AAPM
• Addiction is a brain disease, expressed as
  behaviors. NIDA

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Chronic Pain or Addiction?

• Primary, chronic neuobiologic disease
• Genetic, psychosocial, environmental factors
  influencing its development, physical and
  behavioral manifestations
• Caused by an actual or perceived injury,
  disease or dysfunctional disorder
• Leading to unpleasant, uncomfortable, hurting,
  emotions and sensations
• It is often timeless, endless and meaningless,
  engendering isolation and despair.
• Core issues of control, pre-occupation,
  consequences, craving/relief

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More Definitions

• Misuse Use leads to impairment/distress
• Abuse A maladaptive pattern of substance use
• Therapeutic Dependence
• Physically dependence but pt. not seeking
  psychic effects as misusers, abusers, addict
• Pseudo-addiction
• Pre-occupation with obtaining meds
  reflects need to control pain or withdrawal
• Tolerance
• increased dosage to maintain effect

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Definition Dependence

• DSM IV criteria (need 3 in one year)
• Tolerance
• Withdrawal (within minutes to several days)
• Larger amounts/longer period than intended
• Inability to/persistent desire to cut down,
  control
• Social, occupational, recreation reduced, given
  up
• Continued desire to use opioids despite adverse
  consequences
• Using to avoid unpleasant feelings caused by
  stopping
• Profound and enduring changes in neurocircuitry

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• Dependence is a chronic relapsing medical
  condition.
• And for the record
• Addiction is a chronic
• relapsing medical condition.

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Dependence or Addiction?

• Physical dependence is a normal physiologic
  response to the medical use of opioids
• Addiction involves the non-medical use of opioids
  (and other molecules), and a constellation of
  abnormal behaviors.
• Addiction is psychological dependence
• Addiction does not equal dependence
• DSM IV no such thing as addiction
• you can be dependent without being addicted and
  you can be addicted without being dependent

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Term Merge

• Non-medical use
• Misuse
• Inadvertent use
• Abuse
• Therapeutic Dependence
• Current use
• Lifetime use
• Habit
• Problem Use

• Illicit use
• Licit use
• Addiction
• Pseudo-addiction
• Comfort use
• Innocent use
• Doesnt meet criteria
• Medical use
• Dependence

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Common Etiologies

• Environmental, trauma
• Psychological
• Genetic
• Social
• Neurophysiologic

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Host, agent. Environment
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Setgenetics, age,sex, expectations,motivations,
medical status, past historySetting
Drug and/orPain

• An idiosyncratic response will occur when a
  susceptible person is drug or pain exposed

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CommonalitiesSpectrum of Disease

• Pain
• mild, intermittent.severe, intractable
• Dependence
• mild, intermittent.severe, intractable

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Common Components

• PAIN
• Sensory
• Emotional
• Cognitive

• ADDICTION/
• DEPENDENCE
• Sensory
• Emotional
• Cognitive

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Common Vulnerability

• Genetically vulnerable
• Drug addiction 60/40
• Pain ?
• Vulnerable by history
• Past problems/consequences with any drugs,chronic
  pain
• Present problems with any drug (even nicotine),
  pain
• Family history of substance abuse, chronic pain
• Family history of mental health issues?
• Mental Health Co-morbidity
• Untreated mood disorders (i.e.anxiety,
  depression, PTSD) PDs
• Psychosocial, Environmental Problems (Axis IV)
• GAF Global Assessment of Functioning (Axis V)

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Common Maladaptive Behaviors

• Loss of control (over drug use, or pain)
• Toxic at important family events, external locus
  of control
• Unable to take pain medications as directed
• Continuing preoccupation (with drug use, or pain)
• Works side job to pay for marijuana, cocaine
• Seeks new cures, hopeful of cure, seeks extra
  meds, victim script
• Adverse consequences (of drug use, or pain)
• Declining function despite stable drug use
• Declining function despite analgesia
• All spheres of life decaying, patient cant
  discern
• Craving
• For relief

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Common Biology

• Neurophysiologic
• common brain pathways
• common neurotransmitter systems
• common perturbations in neural circuitry and
  neurohormones

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Mesolimbic Dopamine System

• Circuit 1
• Relief/Like
• Pleasure/Pain circuit
• Meso-accumbens
• Circuit 2
• Repeat/Want
• Desire and urge circuit
• Basolateral n. of amygdala
• Circuit 3
• Need
• Pathologic desire demand circuit
• Periaqueducal gray of brain stem

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Mesolimbic Dopamine SystemModulates

• Tolerance
• Withdrawal
• Craving
• Self-administration

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Pain Reinforcement

• Opioids stimulate dopamine release
• Produce euphoria, and a sense of comfort in most
  people
• Opioid use thus reinforcing, opioids are freely
  self-administered by most animal species
• Learned association between opioid taking and
  pain relief, which could perpetuate pain in the
  absence of opioid administration
• The experience of chronic pain is complex, shaped
  by a variety of cognitive, behavioral,
  psychological and other variables, all of which
  can be modulated with opioids neurophysiologically
  

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More Commonalities

• Both are diseases, not volitional states
• Patients can become powerless to eliminate their
  pain or their drug problem
• Both groups must eventually relinquish the quest
  for a cure
• Both must accept responsibility and be empowered
  to do what is necessary to recover

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Common Co-Morbidities

• Anxiety Disorder ( 3 of 6)
• Restless/on edge
• Fatigue
• Difficulty concentrating
• Irritable
• Muscle tension
• Sleep disturbance
• Depression (5 of 9)
• Depressed mood
• Diminished interest or pleasure
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue/loss of energy
• Diminished ability to think/concentrate /
  indecisiveness
• Thoughts of death
• Insomnia
• PTSD, Functional Disability, Medical Illnesses,
  Relationships, Occupation, Recreation,
  Self-identity, SA, Pain

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Common Treatments

• Non-pharmacologic
• Education, relaxation, individual family
  therapy, biofeedback, cognitive behavioral
  therapy, Rx mood disorder, distraction,
  accupuncture, active movement, CAM, etc.
• Interventional
• Intervention procedures/surgery
• Medications

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Common Molecules

• Opioids
• Sedative-Hypnotics
• Stimulants
• Anti-depressants, anti-anxiety agents
• Anti-seizure medications
• Adjunctives
• OTC, Current Fad Drug, Hot Rx Drug

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Commonalities Licit and Illicit Drugs

• Psychoactive potential
• Reinforcement potential
• Decrease negative symptoms
• Increase positive symptoms
• Tolerance and withdrawal potential

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Impending Disasters?

• Opioids
• Benzodiazepines
• including Ambien, Sonata, Lunesta
• Barbiturates
• Including Soma, Fioricet
• Stimulants
• Including Adderal, Ritalin, etc.

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How significant a problem is prescription drug
abuse today?
A Major Problem!
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How Many Americans Have a Drug Problem?

• Nicotine 20-30
• Marijuana 14
• Alcohol 6-12
• Opioids ?
• Any illicit drug 8
• Prescription drugs 3
• Perspective 45 take a RX qd there are
  gt150,000 OTCs
• 1965 300 Rx drugs 2005 9,000 Rx drugs
  (RxList.com)

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Generation Rx

• 18 of teens have abused Vicodin
• 20 tried Ritalin or Adderall without Rx
• 9 abused OTC cough syrup to get high
• Equal or greater abuse of OTC/Rx than cocaine,
  Ecstasy, LSD, ketamine, heroin, GHB, ice
• Rx Meds safer (50), less addictive (33)
• Ease of access medicine cabinets
• Drugs are fun vs Drugs help kids when they are
  having a hard time
• Rx/OTC med abuse has penetrated teen culture
• April 21, 2005. Partnership for a Drug Free
  America. 17th annual study of teen drug abuse.
  N 7,300, error margin /- 1.5

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Why Has the Abuse of Prescription Drugs Been
Increasing?

• Pain and DSM relief
• Production and availability increased
• Marketing and media attention
• Molecular factors
• User characteristics
• Physician factors

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Increased Production DEA Quotas,1990-2000

• Morphine 300
• Hydrocodone 500
• Hydromorphone 600
• Oxycodone 1200
• Fentanyl 1700

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Drug
2003 Rx
Revenue

• Hydrocodone 84M
• Lipitor 69M 6.7B
• Synthroid 49M
• Norvasc 36M
• Zoloft 33M 2.9B
• (Others in the top 130 Xanax, Ambien, Ativan,
  Klonipin, Soma
• Valium, oxycodone, Oxycontin, Darvocet, Ultracet,
  Concerta, Adderal)

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Rx Opioids In Hawaii(Source K. Kamita, Chief,
NED, State of Hawaii. 11/7/03)

• Drug
• APAP/hydrocodone
• Tussionex
• Endocet
• OxyContin
• Morphine sulfate
• Methadone

• Prescriptions
• 2,310,398
• 564,258
• 561,658
• 506,408
• 335,502
• 326,446

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Physician Factors

• Dated
• Duped
• Disabled
• Dishonest
• Medication Mania

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Confused Physicians

• The use of narcotics in terminal cases is to be
  condemnedundesirable side effects. Dominant on
  the list of these unfortunate effects is
  addiction.
• AMA Consensus Paper, 1940
• Physicians told not to feardiscipline for pain
  treatment
• amednews.com 6/16/03

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Medication Mania

• Societal phenomenon, perception of safety
• High efficacy of certain meds
• Patient expectation, pressure to prescribe
• Difficult access, payment for non-pharm Rx

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Whos Fault?

• Physicians?
• Pharmaceutical Industry?
• Society Culture?
• Consumer/Patient?

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Molecular Factors

• .

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.morphine molecule

• .

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Opioids can increase pain!

• 30, of patients feel better after withdrawal
  from chronic opioids
• Can cause hyperalgesia, allodynia
• Prolonged use increases expression of dynorphin,
  associated with increased pain sensitivity

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• Recent studies have shown that continuous opioid
  exposure produces exaggerated pain and,
  importantly, such pain occurs while the opioid is
  continuously present in the system
• Vanderah, et al., Pain 925-9, 2001

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• Strong Opioid consensus
• Use aggressively for severe acute pain
• Use aggressively for terminal pain (cancer, AIDS)
• Trial for severe CNMP
• Weak or no Opioid consensus
• Use in less well-defined syndromes (CRPS, PPS,)
• Use in pain syndromes with moderate pain and
  complex psychosocial components ( FM, LBP)

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Opioid Withdrawal

• Acute
• Autonomic
• Rebound increased NE activity from locus
  coeruleus
• Increase BP, HR, peristalsis, diaphoresis, CNS
  irritability, etc.
• Affective
• Suppressed in the dopaminergic reward pathways
• Depression, anxiety, anhedonia, craving, anergia
• Protracted
• 3-6 months or longer
• Anxiety, insomnia, craving, cyclic changes in
  wgt, pupil size

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Acute Opioid Withdrawal

• 5-7 days in length
• Runny nose, sneezing,
• sweating, yawning,
• restless, insomnia
• Piloerection, twitching,
• myalgia, arthralgia,
• abdominal cramps
• Tachycardia,fever,
• hypertension,tachypnea,
• anorexia, diarrhea,
• vomiting, dehydration

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Protracted Opioid Withdrawal(and/or Chronic
Pain?)

• Anergia
• Anhedonia
• Sleep disturbance
• Emotional lability/dysphoria
• Stress incompetence
• Craving (for relief)
• Can persist for months

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Opioids Decrease D2 Receptors
Source Wang, G-J et al., Neuropsychopharmacology,
16(2), pp. 174-182, 1997.
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Detox vs. Medical Withdrawal

• Detoxification
• A term referring to the return of alcoholics
  and addicts to a drug free state with or without
  medical supervision
• Medical Withdrawal
• Is the medically supervised process of safely
  and comfortably taking a dependant person off
  controlled medications

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Opioid Withdrawal Options

• 1. Taper by 50 every several days
• Transition to longer acting analgesic
  (propoxyphene, methadone) and taper
• Symptomatic Rx
• Buprenorphine safe, easy, effective
• Rapid Opioid Detox, UROD

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Opioid Categories

• Agonist Relieve pain and alter mood
• Natural opium, morphine, codeine
• Semi-syn. hydrocodone, oxycodone, heroin
• Synthetic fentanyl, meperidine, methadone
• Antagonist Displace agonist/block receptor
• Naloxone, naltrexone
• Mixed/Partial Agonist and antagonist actions
• Butorphanol (Stadol), Pentazocine (Talwin),
  buprenorphine (Buprenex, Suboxone,Subutex)

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Bup Diss curve
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Buprenorphine

• Analgesic with 20 years world wide use
• NIDA/Industry Orphan drug in US
• Moderate to severe pain
• High activity bupmorphine 130/40 (IV/IM)
• Temgesic sublingual, IM/IV, transdermal
• Rx for opioid withdrawal/maintenance
• First evidence of efficacy in dependence 1978
• world wide use 10 years, 3 years in US
• Excellent safety profile

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Buprenorphine

• High affinity, low dissociation
• Displaces/blocks other opioids, long duration of
  action
• Partial agonist at mu receptor (MS is full
  agonist)
• Ceiling effect (increase dose effect peaks)
• Low abuse, diversion potential
• Pain dose .2 - .4 mg SL q 6 hours
• Addiction dose 2 8mg q.d.
• Off-label/controversial pain use in US
• NIDA study underway

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Office-Based Treatment for Opioid Addiction
Achieving GoalsJAMA, August 17, 2005 Vol 294,
No. 7, p784-786

• Safe
• Effective
• Minimal Diversion
• Hundreds of the physicians who have responded to
  our survey have said that the medication has been
  an absolute life-saver for many of their
  patients.
• Caroline McLeod, PhD
• Evaluation Project Manager, SAMHSA

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94 to 98
85 to 92
100
90
80
70
27 to 47
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Receptor Occupancy
50
40
30
20
10
0
2 mg
16 mg
32 mg
Dose
Source Greenwald, MK et al, Neuropsychopharmacol
ogy 28, 2000-2009, 2003.
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Bup Patient Series

• Practice setting Kona, Hawaii
• Practice Mix 30 addiction, 25 pain, 45
  primary care
• All pain or addiction patients referred
• Outpatient practice with immediately available
  access to hospitalization, counseling, drug
  rehab, medical specialists
• MD credentialed in addiction pain management

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108 Consecutive Bup Patients

• Addiction patients 64
• Pain patients 44
• Pain and Addiction 10
• Current patients 20 addiction, 25 pain
• Induced, but not all currently in KK practice
• Insurance Mix 75 commercial insurance
• The data on this series of pts. is preliminary

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64 Addiction Bup Patients

• M 46 F 18 Age 19-66
• Heroin 30 Prescription Rx 16 IDU 24
• Psychiatric Co-morbidity 50 initally
• Using other illicit drugs 50 initially
• Status
• 26 detoxed (70 still clean)
• 42 left care (16 relapse, 4 jail, 2 move, 2 ?,
  1 killed)
• 31 still on Bup, from 2 weeks to 2 ½ years
• None using controlled or illicit drugs
• All employed
• 25 with co-morbid psych Rx

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44 Pain Bup Patients

• Detoxed 10
• Were taking no other illicit/controlled drugs
• Length of detox 4-8 weeks
• Return to opiates 1
• Co-occurring psych disorder 4
• Terminated Bup Induction 4
• All taking other controlled drugs (Ambien, Soma,
  Ritalin)
• All had unstable medical conditions
• All returned to mu opioid agonists
• Co-Morbid Pain and Addiction 10
• Detoxed 3, 2 returned to mu opioids, 5 current
• Pain Only, Current 20
• Overall rotation/succesful detox 76

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20 Current Pain Bup Patients(Pain and Addiction
Pts. Omitted)

• F 11, M 9 Age 32 88
• Length on mu opioids 3-25 years
• Length on Bup 2 weeks 2 ½ years
• Procedures for pain 17/20
• Surgery for pain 12/20
• Criteria for Bup dependence, request transfer
  from mu opioid secondary to insurance, adverse
  effects, inadequate pain relief, unable or
  unwilling to detox off all opioids
• Buprenorphine dose range 232 mg/d, 10mg ave

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20 Current Pain/Bup Patients
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The French Patientn 749

• Means
• age 33 duration on Bup 11 months
• Mean dose 11mg/day
• Daily dose 56 split dose 43
• AE 4 IV Bup 8
• Improvements
• Relationships 95
• Physical activity 77
• Life habits 94
• Employment 74
• The French Experience. European Addiction
  Research. 4 S1 98, Oct. 1998, pp. 19-23

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All Current Bup Patients

• Gender equal at about 50/50
• Psych Co-morbidity equal at 25
• Satisfaction equally high
• Adverse effects equally low
• Function equally improved
• Employment, family, spirit, life equally
  improved and acceptable to Pt and MD

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Bup Ideal patient

• Treatment seeking wants off mu opioids
• Opioid dependent, no other substance issues
• No acute medical conditions
• No untreated Axis II Disorders
• Transaminases less than 3X normal
• Willing to enter and persevere with substance
  abuse treatment ( addiction pts)
• PCP delegates/co-manages pain/addiction
• Must able to follow instructions
• Manageable environmental stressors

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OPIOID THERAPY FOR CHRONIC PAIN ?

• evidence now suggests that prolonged, high-dose
  opioid therapy may be neither safe nor
  effective.It is therefore important that
  physicians make every effort to control
  indiscriminate prescribing, even when they are
  under pressure by patients to increase the dose
  of opioids.
• BALLANTYNE MAO, NEJM, 3491943-53, 2003

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New Paradigm

• I just minimized or dismissed the issues of
  abuse, addiction and diversion
• ten years later, and we recognize that was a
  big error..we need to talk about the use of
  opioids and other prescription drugs from the
  perspective of two skill setshow to prescribe,
  but at the same time, (doctors) have to have a
  skill set in addiction medicine, how to assess
  the risk of abuse and diversion and addictionor
  they shouldnt use them.
• Dr. Russell Portenoy, ABC National Radio
  12/5/04

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Bup Downside

• 30 patient limit
• High acuity patients, office must gear-up
• Drug interactions (3A4)
• Patients will also need non-pharmacologic
  treatments
• Insurance coverage not yet universal
• Diversion?
• Still new Use it while it works

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Buprenorphine Waiver/Training

• Waiver eligible
• Physicians Boarded in Addiction Psychiatry
• ASAM Certified physicians
• Physicians involved in Bup clinical trials
• Training
• 8 hours of CSAT approved CME
• www.ASAM.org, hhtp//buprenorphine.samsha.gov/
• Online courses available