Clinical Challenges when using Antiaddiction Medicines

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Clinical Challenges when using Anti-addiction
Medicines

• Mark Publicker, MD FASAM
• Medical Director, Mercy Recovery Center,
  Westbrook Maine

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Addiction

• Addiction is a cycle of spiraling dysregulation
  of brain reward systems that progressively
  increases, resulting in compulsive drug use and a
  loss of control over drug taking George Koob

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Neural circuitry of reward

• Present in all animals
• Produces pleasure for behaviors needed for
  survival
• Eating
• Drinking
• Sex
• Nurturing

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All drugs of abuse bind to the neural circuitry
of reward
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Drugs of abuse hijack the Reward Center

• Instead of eating, drinking and making love,
  drugs tell you that you need to take them in
  order to survive.
• This is obviously a lie, and one that leads to
  sickness and death.

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Neuroadaptation

• Drugs change the brains balance
• The brain has mechanisms to oppose this change
• The balancing action overshoots
• The stronger the drug, the higher the dosage and
  the longer the use, the more the opposing change

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Neuroadaptation alcoholism

• Long term adaptive changes to the inhibitory
  GABAergic system and to the excitatory
  glutamatergic systems are thought to underlie the
  development and maintenance of alcohol dependence
  

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Neuroadaptation alcoholism

• To compensate for the sedative effects of alcohol
  there occurs an up-regulation of the excitatory
  system and a down-regulation of the inhibitory
  system

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Neuroadaptation alcoholism

• In withdrawal the CNS is left in a hyperexcitable
  state
• anxious
• sleepless
• tremulous
• tachycardic/hypertensive

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Neuroadaptation alcoholism

• Sensitization Sustained increased activity in
  the excitatory system increases the sensitivity
  to context-driven stimuli on the reward system
• Craving

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Clinical Challenges

• Beliefs
• Adherence
• Integration
• Patient selection
• Side effects
• Coverage

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Beliefs

• Rejection of disease concept
• Substitution of one addictive drug for another
• Drug-free state is only valid treatment goal
• Research has shown that this is not achieved nor
  sustained by the majority of heroin addicts

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Belief

• Use of psychiatric medication and other
  medically indicated drugs prescribed by a
  physician and taken under medical supervision is
  not seen as compromising a persons recovery in
  NA. NAWS website

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Beliefs

• I also believe that those who are dependent on
  daily psychotropic medications and believe in
  their use as a form of treatment should be
  encouraged to start their own fellowship, much in
  the same way that the AA fellowship helped us to
  get started, instead of confusing and blurring
  the already proven NA message of complete
  abstinence.
• Believing in the use of psychotropic medications
  as a viable alternative to complete abstinence
  goes beyond ignorance, confusing and blurring our
  proven message to the addict who is still
  suffering. NAWS website
• Smoking, coffee?

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Beliefs

• It becomes clear that just as it is wrong to
  enable or support any alcoholic to become
  re-addicted to any drug, its equally wrong to
  deprive any alcoholic of medication which can
  alleviate or control other disabling physical
  and/or emotional problems.
• The AA member-Medication other Drugs

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Beliefs

• Limited medical education on addiction
• Physician beliefs about addiction reflect those
  of society

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Patient selection

• Chronic alcohol relapse history
• Cocaine dependence
• Opioid dependence

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Patient selection

• Does medication-assisted treatment enhance
  abstinence-based participation?

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Integration

• Contingency management Nancy Petry
• Good research evidence for effectiveness in
  retaining clients, increasing abstinence and
  increasing active participation
• Variable rate reinforcement paradigm
• Benefits have been shown to persist after active
  treatment phase

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Integration

• Combining psychosocial/spiritual practice with
  evidence-based pharmacological treatments
• BRENDA Biopsychosocial assessment, Report to the
  client, Empathic listening, Needs collaboratively
  identified, Direct advice, Assess reaction of
  patient to advice

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Integration

• COMBINE trial NIAAA
• Large multi-site trial of two medications plus
  two behavioral interventions
• Enhancing medication compliance
• Pill taking strategies
• Dealing with side effects
• Counselor support for medication
• Medication groups

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Adherence

• Need to account for stage of change
• Motivational readiness
• Conviction/confidence

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Coverage

• Limited private insurance coverage for
  anti-addiction medication
• CMS did not include a category for anti-addiction
  medication for new Medicare benefit

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Coverage

• Pharmaceutical industry motivation
• Antabuse 1951
• Naltrexone (for opiate addiction) 1968
• Naltrexone (for alcohol dependence) 1994
• Acamprosate 2005

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Medications

• Naltrexone
• Acamprosate
• Buprenorphine
• Topiramate
• Disulfiram
• Rimonabant

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Naltrexone

• Alcohol produces its positive reinforcing effects
  through the opioid system
• Pure opioid antagonist
• Effective in treatment of alcoholism and opiate
  addiction
• Blocks cue-triggered craving
• Blocks the high and increases the negatives

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Naltrexone

• Naltrexone can decrease
• The percentage of days spent drinking
• The amount of alcohol consumed on a drinking
  occasion
• Relapse to excessive and destructive drinking

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Naltrexone

• Great majority of studies show significant
  benefit over placebo
• Antidepressant studies under 50 response
• Works best in patients who have strong craving
  and strong family history
• These patients seem to have a gene variant
  causing increased b-endorphin sensitivity
• Without naltrexone this group did poorly in
  studies
• Genomic differences translate into different
  treatment responses

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Naltrexone

• Oral (Revia) and soon an injectable depot
  formulation (Vivitrol)
• Primary drug-drug interaction Opioids
• Challenges
• Side effects (nausea in small percentage)
• Adherence
• Physician awareness and knowledge
• Integration with psychosocial treatment
• Optimal duration of treatment unknown

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Acamprosate (Campral)

• NMDA receptor antagonist
• Glutamatergic (excitatory) system
• Blocks craving particularly context and
  stress-related cues
• Use in detoxified patients engaged in active
  psychosocial treatment
• Doubles abstinence rates
• Additive with naltrexone (Combine Study)

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Acamprosate

• No liver metabolism or toxicity
• No drug-drug interactions
• Greater rates of complete abstinence
• Longer times to first drink
• May be neuroprotective
• Challenge three time a day dosing

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Buprenorphine/naloxone Suboxone

• Partial agonist pure antagonist
• t/2 24 hours
• Blocks craving and euphoria
• Less physical dependence
• Combo decreases diversion risk

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Suboxone

• DATA 2000 can be prescribed by office-based
  physicians
• DEA waiver
• 30 patient limit
• Adolescent/young adults
• Safety
• Challenges
• Availability

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Suboxone therapeutic effects

• Blocking effect on euphoria with administration
  of opiates
• Blocking effect on withdrawal.
• Relieves craving
• Stabilization of brain function
• Decrease in HPA stress state
• Improvement in mood and behavioral stability

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Suboxone therapeutic effects

• Significant enhancement in treatment retention
  and in the quality of participation
• Opportunity to link office-based medical practice
  with specialized addiction treatment programs
• Both outpatient and residential
• Maine experience

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Suboxone

• Induction inpatient or outpatient
• Detox vs maintenance
• Maintenance
• Best used as component of treatment
• Duration of treatment and treatment retention
  best predictors of outcome

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Topiramate

• Anti-convulsant glutamate antagonist and GABA
  (inhibitory) promoter
• Anti-craving agent for alcohol, cocaine and
  cannabis
• Increases alcohol abstinence rates by 50
• Patients reports enhanced sense of well-being

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Topirmate

• Decreases both the acute reinforcing effects of
  alcohol and cocaine and the longer term
  sensitization that leads to craving and relapse
• Challenges
• Central nervous system
• Metabolic

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Disulfiram (Antabuse)

• Oldest drug treatment for alcohol dependence
  through blockade of aldehyde dehydrogenase
• Increases cocaine-induced dysphoria
• Limited double-blind, placebo controlled studies
• New role treatment of cocaine dependence
• Challenges
• Toxicity
• Adherence

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Disulfiram

• Cocaine mechanism separate from disulfiram effect
• Studies show enhanced abstinence especially with
  combination of cognitive behavioral therapy with
  disulfiram
• Decreased craving and increased dysphoria with
  cocaine use

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Rimonobant

• Cannabinoid receptor antagonist
• Chronic cigarette smoking over activates the
  endocannabinoid system
• The endocannabinioid system modulates nicotine
  reinforcement, food intake and energy balance

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Rimonobant

• Phase III trials
• Benefits
• Smoking cessation promotes initiation of
  abstinence, prevents relapse and weight gain
• Obesity, cardiovascular risk reduction
• Drug addiction

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On the horizon

• Baclofen GABA agonist
• Reduces cocaine self-administration in animal
  models
• Reduces cue-induced craving in humans
• May be most effective in heaviest cocaine users
• Ondansetron
• Early onset drinking
• Blocks serotonin receptors and then to decrease
  in dopamine release

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On the horizon

• Modafinil decreases cocaine high and increases
  abstinence rates
• May also improve executive function in ADHD
  patients
• Cocaine vaccine
• GVG
• Tiagabine GABA uptake inhibitor
• Anti-seizure medication
• Positive study in reducing cocaine use in
  randomized, placebo-controlled study in methadone
  patients

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Conclusions

• Addiction is a treatable brain disease
• Research is edifying the biological mechanisms
  involved

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Conclusions

• Increased understanding of neurobiology is
  allowing for the development of effective,
  targeted pharmacotherapies
• State of the art, evidenced-based treatment must
  integrate behavioral and medical therapies to
  produce the best outcomes.