1. No category

Opioid Dependence:
A Chronic, Relapsing Brain Disease
Presentation Objectives
 Review the evidence that opioid dependence is a
chronic, relapsing disease
 Demonstrate similarities of opioid dependence to other
chronic diseases
 Emphasize the importance of accepting the chronic
disease model as an integral part of providing quality
patient care and protecting access to treatment
Features of a Chronic, Relapsing Condition
 Limited chances of complete ‘cure’ or ‘recovery’
 Relapse common
 Multifactorial
–
–
–
–
Genetic (heritable vulnerability)
Environmental (exposure)
Biological (demonstrated pathophysiology)
Behavioral (lifestyle aspects)
Optimal patient care depends on accepting opioid
dependence as a chronic, relapsing condition
No Universally Accepted Definition
of Addiction
 National Institute on Drug Abuse (NIDA)—A chronic,
relapsing brain disease characterized by compulsive
drug-seeking and use despite harmful consequences and
by long-lasting structural and functional changes in the
brain1
 Other definitions exist, but all agree that addiction is:
–
–
–
–
Chronic2,3
Relapsing3,4
Progressive3,4
Compulsive2,4
1. National Institutes of Health National Institute on Drug Abuse.
http://www.drugabuse.gov/ScienceofAddiction/addiction.html.
Accessed July 7, 2011. 2. Robinson TE, Berridge KC. Brain Res Rev.1993;18(3):247-291. 3. O’Brien CP,
McLellan AT. Lancet. 1996;347(8996):237-240. 4. McLellan AT et al. JAMA. 2000;284(13):1689-1695.
Similarities to Other Chronic Diseases1-3
Drug Dependence
Diabetes, Asthma,
and Hypertension
Well studied


Chronic disorder


Predictable course


Effective treatments


Curable
NO
NO
Heritable


Requires continued care


Requires adherence to treatment


Requires ongoing monitoring


Influenced by behavior


Tends to worsen if untreated


Characteristics
1. McLellan AT et al. Addiction. 2005;100(4):447-458; 2. McLellan AT et al. JAMA. 2000;284(13):1689-1695;
3. McLellan AT. Addiction. 2002;97(3):249-252.
Relapse Rates Are Similar to Other Chronic
Diseases1,2
Patients Who Relapse (%)
80
70
60
50%–70%
50%–70%
Hypertension
Asthma
40%–60%
30%–50%
50
40
30
20
10
0
Drug Addiction Type 1 Diabetes
1. McLellan AT et al. JAMA. 2000;284(13):1689-1695; 2. National Institute on Drug Abuse.
http://www.nida.nih.gov/scienceofaddiction/sciofaddiction.pdf. Accessed June 30, 2011.
Opioid Dependence Causes Changes in Brain
PET scan images
The lack of red in the
opioid-dependent
brain shows that
chronic opioid use
has reduced
dopamine receptor
concentration
Wang GJ et al. Neuropsychopharmacology. 1997;16(2):174-182.
Benefits of the Chronic Disease Model
 Emphasizes comprehensive, sustained treatment to help
retain patients, maintain adherence, and focus on success
 Minimizes stigma associated with opioid dependence
 Promotes continuity of care
 Underscores the importance of ongoing monitoring
 Reinforces the need for a multifaceted, multidisciplinary
treatment approach
van den Brink W et al. Can J Psychiatry. 2006;51(10):635-646.
The Multifaceted Components of
Opioid Addiction
The Multiple Components of Drug Abuse
 Drug abuse has multiple
components:
– Neurobiologic1,2
– Behavioral, cognitive, and affective
 Treatment must address each
component
 Drug abuse is learned3,4
 Long-term drug use alters:
– The way people think about their
own behavior5
– Emotional reactions to
environmental stimuli5
1. Koob GF, Le Moal M. Neuropsychopharmacology. 2001;24(2):97-129; 2. Kalivas PW, Volkow ND.
Am J Psychiatry. 2005;162(8):1403-1413. 3. Hesselbrock MN et al. Addictions, A Comprehensive Guidebook.
New York, NY: Oxford University Press; 1999:50-65. 4. Irvin JE et al. J Consult Clin Psychol.
1999;67(4):563-570. 5. Larimer ME et al. Alcohol Res Health. 1999;23(2):151-160.
Neurobiological Aspects: The Cycle of
Addiction1,2
Tolerance
and
withdrawal
Acute
reinforcing
effects
Craving
and
relapse
1. Koob GF, Le Moal M. Neuropsychopharmacology. 2001;24(2):97-129; 2. Kalivas PW, Volkow ND.
Am J Psychiatry. 2005;162(8):1403-1413.
Chemical Changes: Craving and Relapse1,2
Long-term changes in brain responsivity may remain even
after withdrawal and sustained abstinence
 Drug- and cue-induced craving are associated with
activation of critical brain regions
 Patients may always be at risk for craving and relapse
upon re-exposure to the drug or environmental cues
associated with the drug
Orbitofrontal cortex
Nucleus accumbens
Anterior cingulate
Ventral tegmental area
1. Hommer DW. Alcohol Res Health.1999;23(3):187-196; 2. Volkow ND, Fowler JS. Cerebral Cortex.
2000;10(3):318-325.
Behavioral Components of Addictive Behavior
 Within a behavioral framework, drug use is viewed as a special case of operant
behavior maintained by the reinforcing effects of the drug1
 Learned behavior — Disrupt any element to reduce strength of behavior2
3-Term Contingency
Antecedent
Behavior
Consequence
 Drug reinforcement
– Drugs of abuse function as positive reinforcers in laboratory studies and therapeutic utility of
pharmacotherapies can be demonstrated in laboratory studies3,4
 Extinction2
– When responses no longer produce reinforcement, their rate diminishes
– Initial response to extinction is a rate increase; some behaviors are resistant
1. Bigelow GE et al. Addict Behav. 1981;6(5):241-252; 2. Skinner BF. Science and Human Behavior. New York,
NY: Macmllian; 1953; 3. Katz JL, Goldberg SR. Agents Actions. 1988;23(1-2):18-26; 4. Haney M, Spealman R.
Psychopharmacology (Berl). 2008;199(3):403-419.
Multifaceted Treatment Approach
Treatment Goals
Retain patients
Minimize withdrawal
symptoms and cravings
Provide psychosocial
support
The Components of Treatment:
Pharmacotherapy and Psychosocial Intervention1,2
Pharmacotherapy
Can control symptoms by
normalizing brain chemistry
Psychosocial Intervention
Essential to change behaviors
and responses to environmental
and social cues that so
significantly impact relapse
Both are necessary to normalize brain chemistry, change behavior,
and reduce risk for relapse; neither alone is sufficient
1. McLellan et al. Addiction. 1998;93(10):1489-1499; 2. McLellan et al. JAMA. 1993;269(15):1953-1959.
Buprenorphine and Naloxone Combination
Treatment: Opioid Use
 In a four-week, double-blind placebo-controlled trial, the proportion of
opiate-negative urine samples was significantly greater for patients
on active treatment (17.8%) vs placebo (5.8%; P<.001)
Urine Samples Negative for Drugs (%)
Percentage of NEGATIVE Urine Samples
No. of Samples Tested
For opiates
Opiates
Weeks
943
675
633
564
537
494
449
449
408
383
Fudala PJ et al. N Engl J Med. 2003;349(10):949-958.
Please see Important Safety Information on slides 29-32 and full Prescribing Information available
at this presentation.
361
323
178
Efficacy of Buprenorphine and Naloxone
Treatment: Craving
Opiate Craving Scores
Buprenorphine-naloxone
Placebo
 Mean opiate craving scores were significantly lower for patients
on active treatment vs placebo at all time points (P<.001)
Fudala PJ et al. N Engl J Med. 2003;349(10):949-958.
Please see Important Safety Information on slides 29-32 and full Prescribing Information available
at this presentation.
Long-Term Treatment Is Associated With
Positive Outcomes
 Patients (n=5577) receiving medication-assisted therapy with either
methadone or buprenorphine in the United Kingdom
Probability That Treatment Reduces Overall Mortality
Cornish R et al. BMJ. 2010;341:c5475.
Please see Important Safety Information on slides 29-32 and full Prescribing Information available
at this presentation.
Prolonged Medication-Assisted Treatment
Sustains Improvement
4 Studies of Various Treatment Lengths
After 6 Months1
After 12 Months2
(buprenorphine-only; n=690)
(buprenorphine-only; n=40)
• Heroin use decreased by 81%
• Codeine use decreased by 83%
• Benzodiazepine use decreased
by 48%
• Cocaine use decreased by 74%
• 32% improvement in
occupational problems
• 90% improvement in
drug-related problems
• 90% improvement in
crime-related problems
After 18 Months3
After 2-5 Years4
(buprenorphine/naloxone; n=176)
(buprenorphine/naloxone; n=53)
• Less likely to report using any
substance or heroin
• 91% of urine samples were
opioid negative
• More likely to be employed
• 96% of urine samples were
cocaine negative
• Improved on several
psychosocial parameters
1. Lavignasse P et al. Ann Med Interne (Paris). 2002:153(suppl 3):1S20-1S26; 2. Kakko J. Lancet.
2003;361(9358):662-668; 3. Parran TV et al. Drug Alcohol Depend. 2010:106(1):56-60; 4. Fiellin DA et al. Am J
Addict. 2008;17(2):116-120.
Please see Important Safety Information on slides 29-32 and full Prescribing Information available
at this presentation.
SUBOXONE® (buprenorphine and naloxone)
Sublingual Film (CIII) Label: Psychosocial Counseling
Safety and efficacy data for SUBOXONE® are derived from
studies that all used SUBOXONE® (or buprenorphine/naloxone
combination) in conjunction with psychosocial counseling
as part of a comprehensive addiction treatment program.
In order to qualify to prescribe SUBOXONE®, physicians must
have the capacity to provide or to refer patients for necessary
ancillary services, such as psychosocial therapy.
(FDA Physician Information)
[http://suboxone.com/pdfs/SuboxonePI.pdf]
Please see Important Safety Information on slides 29-32 and full Prescribing Information available at
this presentation.
Counseling Improves Outcomes:
Opioid Dependence
 Most recent updates of Cochrane Database reviews of
pharmacological interventions for opioid dependence and
medical taper with and without psychosocial treatment
– Opioid dependence: Adding psychosocial support to medicationassisted treatments improves the number of participants abstinent
at follow-up1
– Medical taper: Adding psychosocial support to medical taper
improves treatment completion and decreases opioid use2
1. Amato L et al. Cochrane Database Syst Rev. 2008;(4):CD004147. doi: 10.1002/14651858.CD004147.pub3;
2. Amato L et al. Cochrane Database Syst Rev. 2008;(4):CD005031. doi: 10.1002/14651858.CD005031.pub3.
Counseling Improves Outcomes:
Opioid Dependence
 Intravenous opiate users were assigned
to one of three treatments:
– Minimum methadone services (MMS;
drug alone)
– Standard methadone services (SMS;
drug + counseling)
– Enhanced methadone services
(EMS; drug + counseling + onsite
psychosocial interventions)
 Outcomes were significantly better for
the EMS group overall (EMS > SMS >
MMS)
 The figure shows the percentage of
subjects in each group with consecutive
opiate-free urine samples (“dose
response” for psychosocial services)
McLellan AT et al. JAMA. 1993;269(15):1953-1959.
Psychotherapy, Counseling, or Psychosocial Support
Improves Outcomes in Other Chronic Diseases
 Depression
– Addition of psychotherapy following initial pharmacological control of acute
symptoms of major depressive disorder confers advantage in terms of
relapse1-3
 Panic disorder
– Combined pharmacotherapy and psychotherapy is significantly superior to
pharmacotherapy alone4
 Nicotine dependence
– Provision of more intense levels of psychosocial support can facilitate
likelihood of quitting5,6
 Alcohol dependence
– Advantages of combining psychotherapy with pharmacotherapy were not
apparent during active therapy, but emerged after therapy ended6,7
 Obesity
– In the absence of a psychosocial intervention aimed at lifestyle change,
weight loss achieved through pharmacotherapy is not sustained8
1. Petersen TJ et al. J Psychopharmacol. 2006;20(suppl 3):19-28; 2. Nierenberg AA et al. J Clin Psychiatry. 2003;
64(suppl 15):13-17; 3. Trivedi MH et al. Psychopharmacol Bull. 2008;41(4):5-33; 4. Zwanzger P et al. J Neural
Transm. 2008;116(6)767-775; 5. Stead LF et al. Cochrane Database Syst Rev. 2008;(1):CD000146.
doi: 10.1002/14651858.CD000146; 6. Doran CM et al. Addict Behav. 2006;31(11):1947-1958; 7. Donovan DM et al.
J Stud Alcohol Drugs. 2008;69(1):5-13; 8. Woo J et al. J Eval Clin Pract. 2007;13(6):853-859.
Defining Counseling and Behavioral Therapy
for Opioid-Dependence Treatment
 Encompasses several types of treatment modalities
– Counseling/psychotherapy, including cognitive behavioral therapy
– Community-based support (12-step programs, Alcoholics Anonymous
[AA]/Narcotics Anonymous [NA])
– Other social support (financial, housing, life skills)
 Treatment should be individualized to address the unique
constellation of factors that impacts each patient’s condition
– Dependence history
– Comorbidities
– Existing social network
– Socioeconomic status
 Psychosocial support may continue beyond pharmacotherapy
to aid in relapse prevention
1. Marlatt A, Gordon R. Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors.
New York, NY: Guilford; 1985; 2. McKay JR et al. J Consult Clin Psychol. 1997;65(5):778-788.
Summary
 Opioid dependence is a chronic, relapsing disease
similar to other chronic diseases
– Medication-assisted maintenance treatment is the standard
– Treatment is not time limited
 The disease is multifaceted with neurobiologic and
behavioral components
– Requires a multifaceted treatment approach
 Combining pharmacotherapy and psychosocial
interventions is critical to treat the multiple facets of the
disease
Important Safety Information
Important Safety Information
SUBOXONE® (buprenorphine and naloxone) Sublingual Film (CIII) is indicated for maintenance
treatment of opioid dependence as part of a complete treatment plan to include counseling and
psychosocial support. Treatment should be initiated under the direction of physicians qualified under
the Drug Addiction Treatment Act.
SUBOXONE Sublingual Film should not be used by patients hypersensitive to buprenorphine or
naloxone.
SUBOXONE Sublingual Film can be abused in a manner similar to other opioids, legal or illicit. Clinical
monitoring appropriate to the patient’s level of stability is essential.
Chronic use of buprenorphine can cause physical dependence. A sudden or rapid decrease in dose
may result in an opioid withdrawal syndrome that is typically milder than seen with full agonists and
may be delayed in onset.
SUBOXONE Sublingual Film can cause serious life-threatening respiratory depression and death,
particularly when taken by the intravenous (IV) route in combination with benzodiazepines or other
central nervous system (CNS) depressants (ie, sedatives, tranquilizers, or alcohol). It is extremely
dangerous to self-administer nonprescribed benzodiazepines or other CNS depressants while taking
SUBOXONE Sublingual Film. Dose reduction of CNS depressants, SUBOXONE Sublingual Film, or
both when both are being taken should be considered.
Liver function should be monitored before and during treatment.
Please see full Prescribing Information available at this presentation.
Important Safety Information (cont)
Death has been reported in nontolerant, nondependent individuals, especially in the presence of
CNS depressants.
Children who take SUBOXONE® (buprenorphine and naloxone) Sublingual Film (CIII) can have severe,
possibly fatal, respiratory depression. Emergency medical care is critical. Keep SUBOXONE Sublingual Film
out of the sight and reach of children.
Intravenous misuse or taking SUBOXONE Sublingual Film before the effects of full-agonist opioids (eg,
heroin, hydrocodone, methadone, morphine, oxycodone) have subsided is highly likely to cause opioid
withdrawal symptoms.
Neonatal withdrawal has been reported. Use of SUBOXONE Sublingual Film in pregnant women or during
breast-feeding should only be considered if the potential benefit justifies the potential risk. Caution should be
exercised when driving vehicles or operating hazardous machinery, especially during dose adjustment.
Adverse events commonly observed with the sublingual administration of SUBOXONE Sublingual Film are
numb mouth, sore tongue, redness of the mouth, headache, nausea, vomiting, sweating, constipation, signs
and symptoms of withdrawal, insomnia, pain, swelling of the limbs, disturbance of attention, palpitations, and
blurred vision.
Cytolytic hepatitis, jaundice, and allergic reactions, including anaphylactic shock, have been reported.
This is not a complete list of potential adverse events associated with SUBOXONE Sublingual Film. Please
see full Prescribing Information for a complete list.
Please see full Prescribing Information available at this presentation.
Important Safety Information (cont)
To report an adverse event associated with taking
SUBOXONE® (buprenorphine and naloxone) Sublingual Film (CIII),
please call 1-877-782-6966.
You are encouraged to report adverse events of
prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
Please see full Prescribing Information available at this presentation.
Prescribing Information
SUBOXONE® (buprenorphine and naloxone) Sublingual Film (CIII) is indicated for
maintenance treatment of opioid dependence and should be used as part of a
complete treatment plan to include counseling and psychosocial support.
Prescription use of this product is limited under the Drug Addiction Treatment Act
(DATA).
Under the Drug Addiction Treatment Act, prescription use of this product in the
treatment of opioid dependence is limited to physicians who meet certain qualifying
requirements, and who have notified the Secretary of Health and Human Services
(HHS) of their intent to prescribe this product for the treatment of opioid
dependence and have been assigned a unique identification number that must be
included on every prescription.
SUBOXONE Film should not be administered to patients who have been shown to
be hypersensitive to buprenorphine or naloxone as serious adverse reactions,
including anaphylactic shock, have been reported.
Please see Important Safety Information on slides 29-32 and full Prescribing Information available at this
presentation.