Opioid Dependence: A Chronic, Relapsing Brain Disease

(1)

Opioid Dependence:

(2)

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

(3)

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

(4)

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

brain

1 

Other definitions exist, but all agree that addiction is:

–

Chronic

2,3

–

Relapsing

3,4

–

Progressive

3,4

–

Compulsive

2,4

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,

(5)

Similarities to Other Chronic Diseases

1-3

Characteristics

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



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.

(6)

Relapse Rates Are Similar to Other Chronic

Diseases

1,2

0

10

20

30

40

50

60

70

80 Drug Addiction Type 1 Diabetes

Hypertension

Asthma

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.

Pa

tients W

ho

Re

lapse

(%

)

40%–60%

30%–50%

50%–70%

(7)

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

(8)

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

(9)

The Multifaceted Components of

Opioid Addiction

(10)

The Multiple Components of Drug Abuse



Drug abuse has multiple

components:

–

Neurobiologic

1,2

–

Behavioral, cognitive, and affective



Treatment must address each

component



Drug abuse is learned

3,4



Long-term drug use alters:

–

The way people think about their

own behavior

5

–

Emotional reactions to

environmental stimuli

5

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.

(11)

Neurobiological Aspects: The Cycle of

Addiction

1,2

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.

Tolerance

and

withdrawal

Craving

and

relapse

Acute

reinforcing

effects

(12)

Chemical Changes: Craving and Relapse

1,2

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

1. Hommer DW. Alcohol Res Health.1999;23(3):187-196; 2. Volkow ND, Fowler JS. Cerebral Cortex. 2000;10(3):318-325.

Orbitofrontal cortex

Nucleus accumbens

(13)

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 drug

1



Learned behavior —

Disrupt any element to reduce strength of behavior2



Drug reinforcement

– Drugs of abuse function as positive reinforcers in laboratory studies and therapeutic utility of pharmacotherapies can be demonstrated in laboratory studies3,4



Extinction

2

– 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.

3-Term Contingency

Consequence

Behavior

(14)

(15)

Treatment Goals

Retain patients

Minimize withdrawal

symptoms and cravings

Provide psychosocial

support

(16)

Pharmacotherapy

Psychosocial Intervention

The Components of Treatment:

Pharmacotherapy and Psychosocial Intervention

1,2

Can control symptoms by

normalizing brain chemistry

Essential to change behaviors

and responses to environmental

and social cues that so

significantly impact relapse

1. McLellan et al. Addiction. 1998;93(10):1489-1499; 2. McLellan et al. JAMA. 1993;269(15):1953-1959.

Both are necessary to normalize brain chemistry, change behavior,

and reduce risk for relapse; neither alone is sufficient

(17)

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)

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.

Percentage of NEGATIVE Urine Samples

943 675 633 564 537 494 449 449 408 383 361 323 178

No. of Samples Tested

For opiates Weeks U ri ne S amples N eg ati v e f or D rugs ( % ) Opiates

(18)

Efficacy of Buprenorphine and Naloxone

Treatment: Craving



Mean opiate craving scores were significantly lower for patients

on active treatment vs placebo at all time points (

P

<.001)

Opiate Craving Scores

Fudala PJ et al. N Engl J Med. 2003;349(10):949-958.

(19)

Long-Term Treatment Is Associated With

Positive Outcomes



Patients (n=5577) receiving medication-assisted therapy with either

methadone or buprenorphine in the United Kingdom

Cornish R et al. BMJ. 2010;341:c5475.

(20)

Prolonged Medication-Assisted Treatment

Sustains Improvement

4 Studies of Various Treatment Lengths

• 32% improvement in occupational problems • 90% improvement in drug-related problems • 90% improvement in crime-related problems

After 12 Months

2 (buprenorphine-only; n=40) • Heroin use decreased by 81%

• Codeine use decreased by 83% • Benzodiazepine use decreased

by 48%

• Cocaine use decreased by 74%

After 6 Months

1

(buprenorphine-only; n=690)

• Less likely to report using any substance or heroin

• More likely to be employed • Improved on several

psychosocial parameters After 18 Months3

(buprenorphine/naloxone; n=176)

• 91% of urine samples were opioid negative

• 96% of urine samples were cocaine negative

After 2-5 Years4

(buprenorphine/naloxone; n=53)

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.

(21)

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.

(22)

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

medication-assisted treatments improves the number of participants abstinent

at follow-up

1

–

Medical taper: Adding psychosocial support to medical taper

improves treatment completion and decreases opioid use

2

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.

(23)

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)

(24)

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

relapse

1-3



Panic disorder

–

Combined pharmacotherapy and psychotherapy is significantly superior to

pharmacotherapy alone

4



Nicotine dependence

–

Provision of more intense levels of psychosocial support can facilitate

likelihood of quitting

5,6



Alcohol dependence

–

Advantages of combining psychotherapy with pharmacotherapy were not

apparent during active therapy, but emerged after therapy ended

6,7



Obesity

–

In the absence of a psychosocial intervention aimed at lifestyle change,

weight loss achieved through pharmacotherapy is not sustained

8

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.

(25)

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.

(26)

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

(27)

(28)

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.

(29)

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.

(30)

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.

(31)

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.

(32)