Transcript New Drugs for Old Disorders

New Drugs for
Old Disorders
Psychiatric Disorders, Addiction and Meds
12 October 2010
Peter Banys, MD, MSc
Director, Substance Abuse Programs,
VA Medical Center, San Francisco
Health Sciences Clinical Professor of Psychiatry, UCSF
Past-President, California Society of Addiction Medicine
Department of
Veterans Affairs
ffairs
Lifetime Prevalence of Disorders
Epidemiological Catchment Area Study (1990)
Mental Disorder
22.5%
3.1%
Alcohol
Disorder
13.5%
1.7%
1.5%
1.1%
Other Drug Disorder
6.1%
Regier DA, et al. JAMA 264(19):2511-2518, 1990.
Comorbidity for Persons with
Mental Disorders
Mental Disorders
Substance
Dependence
Odds
Ratio
Antisocial Personality Disorder
83.6%
29.6
Schizophrenia
47.0%
4.6
Affective (Mood) Disorders
32.0%
2.6
Anxiety Disorders
14.6%
1.7
Comorbidity for Persons with
Substance Abuse Disorders
Any
Mental
Anxiety
Affective
Disorder
Antisocial
Personality
Alcohol Disorders
36.6% 19.4% 13.4%
14.3%
Drug Disorders
53.1% 28.3% 26.4%
17.8%
Cocaine
76.1%
33.3%
34.7%
42.7%
Opiates
65.2%
31.6%
30.8%
36.7%
The Chicken or the Egg?

Is addiction caused by an underlying
psychiatric disorder?

Self-medication hypothesis

Mental illness impairs good judgment

Addiction mimics common psychiatric
disorders.

Each disorder is independent but worsens
the other.
Self-Medication Hypothesis
I’m not eating, I’m self-medicating.”
CoMorbid Disorders in Addiction

Psychotic Disorders

Depressive Disorders

Character Disorders

Violence

Suicide
Schizophrenia

NOT “split personality”

Main Characteristics




Positive Symptoms



Early onset (teens to twenties)
Debilitating life course
Impaired social interactions
Hallucinations, Paranoia, Delusions
Disorganized speech & behaviors
Negative Symptoms


Flat affect, lack of presence, poor capacity for humor
Little insight
Delusional Disorders

Unusually stable over time

Types

Erotomania

Grandiose, Messianic

Jealous

Persecutory

Somatic
Psychoses from Addiction



Alcohol

Hallucinosis

Alcoholic Paranoia

Delirium Tremens
Stimulants

Post-Stimulant Paranoia

Auditory Hallucinations
Opiates

Detox Psychoses (rare)
Psychosis:
Differential Diagnosis of Hallucinations
Condition
Age of
Onset
Clear
Temporal
Sensorium Relation to
Drinking
Autonomic
Dysfunction
Alcohol
Withdrawal
>30
No
After
Yes
Alcoholic
Hallucinosis
>30
Yes
Intoxication
No
Early
Withdrawal
Yes
Unrelated
No
Schizophrenia
<20
Yes
Bipolar Disorder

Highs and lows may actually co-exist
as well as alternate

Grandiosity, poor judgment

Superficial insight

Poor listening skills
Post Traumatic Stress Disorder

Two Types

Hyperaroused, over-reactive

Walled-off, numb

Extreme level of trauma, or very
sustained

Disturbed sleep, nightmares,
flashbacks
Depression
Clinical Treatment Problems

Medication or therapy?

How soon?

What if they relapse?
Treatment Principles
Relationship of Alcohol Use and Affective
Disorders

Alcohol produces depressive symptoms
in anyone

Serious, temporary depression may follow
alcohol or drug use

Drinking can escalate during primary
affective episodes, such as mania

Depressive symptoms and alcohol
problems can occur in a variety of
psychiatric disorders
Depression & Drinking

In alcoholism, DSM criteria for
depression can be produced …

by chronic use and

by withdrawal effects

Delay medication trials
for 2-4 weeks into
abstinence if possible

Be aware of increased
suicide rates
Treatment Principles:
Depression in an Addict

2-4 Week Drug-Free
Interval

Conduct Systematic
Medication Trials


One drug at a time

Change from one class to
another

Avoid dangerous O.D.
drugs
Complete Full Therapeutic
Trial

Adequate Doses

Adequate Time Period
(up to 12 weeks)
ALCOHOL
Alcohol’s Effects on
Neurotransmitter Systems
Gilpin & Koob, Neurobiology of Alcohol Dependence,
Alcohol Research & Health, Vol. 31, No. 3, 2008
Medications for Alcoholism:
Disulfiram (Antabuse®)
ALDH blockers
Calcium Carbimide
Naltrexone (ReVia®)
May also have efficacy for
reducing cocaine use
Opioid antagonists
Nalmefene (ReVex®)
Research only
Tiapride
Dopamine antagonist
Research only
Acamprosate (Campral®)
Glutamate
stabilization
GABA effects
Reduction of protracted
withdrawal ?
Ondansetron (Zofran®)
Serotonin-3-receptor
antagonist
May be effective in an
early onset, severe
subset of alcoholic
population
Dopamine inhibition
Reward Reduction
[not approved]
Topiramate (Topamax®)
[not approved] Glutamate
Reduction of protracted
Medications
for Relapse Prevention
Mechanism Medication
Comments
Alcohol
Agonist
Benzodiazepines are cross-reactive but ineffective as
maintenance therapies
Alcohol
Antagonist
Roche has developed an experimental partial antagonist,
but it does not block all alcohol effects, especially not
lethal dose
Acetaldehyde
Metabolism
Blocker
Disulfiram (Antabuse)
Calcium Carbimide
Metronidazole (Flagyl)
Deterrent medication. Disulfiram is no longer used in
aversive challenges.
Opioid
Antagonist
Naltrexone (ReVia)
Relapse prevention
Craving reduction?
Acamprosate (Campral)
Relapse prevention
Serotonin 
SRI’s
Late-onset alcoholics may be less genetically loaded.
5-HT3 Antagonist
Ondansetron
Early-onset (biological) alcoholics. 5-HT3 may be comodulator of dopamine function (via opioid system).
Reduces mesocorticolimbic dopamine release.
GABA 
Glutamate 
Topiramate (Topamax)
Reduces heavy drinking,
Promotes abstinence
Alcohol Relapse-Prevention

Disulfiram (Antabuse®)



Naltrexone (ReVia®, Trexan®)




50 mg qd, Half-dose for 3-4 days at start.
Liver Function Tests
This med blockades ALL opiates, even morphine.
Acamprosate (Campral®)



250 mg qd.
Liver Function Tests, EKG
666 mg TID
Recent US approval
Ondansetron (Zofran®)

Research Status
Mary E. McCaul, Pharmacotherapy Strategies for Alcoholism Treatment,
Symposium: New Developments in the Pharmacological Treatment of Alcoholism, 2003.
Naltrexone Studies
Naltrexone Study
Additional Therapy
Slowed
Relapse
Drinking
Reduction
Craving
Reduction
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Older Studies
Volpicelli et al. 1992 Intensive multimodality
O’Malley et al. 1992 Supportive / Coping Skills
Volpicelli et al. 1997 Relapse prevention
Treatment completers
Anton et al. 1999 Cognitive-behavioral
More Recent Studies
Chick et al. 2000 Compliant patients only
Morris et al. 2001
Guardia et al. 2002
Krystal et al. 2001 TSF Twelve Step Facilitation
Acamprosate in Europe

In 14 of 15 European clinical trials
with more than 3,000 patients,
acamprosate increased abstinence
rates by about 50%

Approved for use in the U.S.

Somewhat weak results in U.S.
COMBINE trial.
Acamprosate Studies
Therapy
Duration
Abstinence
Increase
Craving
Reduction
Paille et al. 1995
12
+
Lhuintre et al. 1990
03
+
+
Sass et al. 1996
11
Whitworth et al. 1996
12
Acamprosate Study
Geerlings et al. 1997
+
+
+
Mary E. McCaul, Pharmacotherapy Strategies for Alcoholism Treatment, Symposium:
New Developments in the Pharmacological Treatment of Alcoholism, 2003.
Acamprosate
Topiramate (Topamax®)

Inhibition of mesocortical dopamine
release via facilitation of GABA activity

Inhibition of glutamate function

Hypotheses:

Decrease mesocorticolimbic dopamine activity
after alcohol intake

Antagonize chronic changes induced by
alcohol in the glutamate system
Oral Topiramate for
Treatment of Alcohol Dependence
Bankole Johnson et al. (2003)

Abstinence-Initiation trial

N=150, Double-blind randomized trial comparing
topiramate to placebo, 12 weeks

Topiramate (up to 300 mg per day)

Outcomes

2.9 fewer drinks per day

3.1 fewer drinks per drinking day

27.6% fewer drinking days

26.2% more abstinent days

Reduced craving
Johnson et al., Lancet, May 17, 2003, Vol. 361, No. 9370, pp. 1666-67 & 1677-
Topiramate
Other Targets for Medication

Catecholamines
(Dopamine, NE)

Voltage-sensitive
calcium channels

Corticotropinreleasing factor
(CRF) antagonists
Ciraulo, Update on Treatment Approaches for Alcohol Dependence,
ASAM Med-Sci Conf., April 23, 2004.
Serotonin Receptor Subtype
and Alcohol Abuse
Serotonin’s Role in Alcohol Effects, in Alcohol Research &
Health, Volume 21, Number 2, p. 114, 1997
Evidence Report/Technology Assessment: Jan.
1999 Agency for Health Care Policy and Research

Disulfiram (Antabuse)

A substantial literature has been generated on the use of
disulfiram in alcoholism, but the number of controlled clinical
trials is limited.

Controlled clinical trials of disulfiram reveal mixed findings.
There is little evidence that disulfiram enhances abstinence,
but there is evidence that disulfiram reduces drinking days.
When measured, compliance is a strong predictor of outcome.

Studies of disulfiram implants are methodologically weak and
generally without good evidence of bioavailability.

Studies of supervised disulfiram administration are
provocative but limited.
Pharmacotherapy for Alcohol Dependence. Summary, Evidence
Report/Technology Assessment: Number 3, January 1999.
Agency for Health Care Policy and Research, Rockville, MD.
http://www.ahrq.gov/clinic/epcsums/alcosumm.htm

Evidence Report/Technology Assessment: Jan.
1999 Agency for Health Care Policy and Research

Naltrexone (ReVia, Trexan)





Trials of naltrexone in the treatment of alcoholism are recent and of
generally good quality.
There is good evidence that naltrexone reduces relapse and number of
drinking days in alcohol-dependent subjects.
There is some evidence that naltrexone reduces craving and enhances
abstinence in alcohol-dependent subjects.
There is good evidence that naltrexone has a favorable harms profile.
Acamprosate (Campral)



There is good evidence that acamprosate enhances abstinence and
reduces drinking days in alcohol-dependent subjects.
There is minimal evidence on the effects of acamprosate on craving or
rates of severe relapse in alcohol-dependent subjects.
There is good evidence that acamprosate is reasonably well tolerated
and without serious harms.
Evidence Report/Technology Assessment: Jan.
1999 Agency for Health Care Policy and Research

Serotonergic Agents




There are several controlled clinical trials of serotonergic agents in
primary alcoholics without comorbid mood or anxiety disorders.
There is minimal evidence on the efficacy of serotonergic agents for
treatment of the core symptoms of alcohol dependence.
There is some evidence on the efficacy of serotonergic agents for the
treatment of alcohol-dependent symptoms in patients with comorbid
mood or anxiety disorders, although the data are limited.
Lithium



There are limited studies on the effects of lithium in primary alcoholics
without comorbid mood disorders.
There is evidence that lithium is not efficacious in the treatment of the
core symptoms of alcohol dependence.
There is minimal evidence for efficacy of lithium for the treatment of
alcohol-dependent symptoms in patients with comorbid depression.
OPIATES
Heroin Myths & Facts

Opioid withdrawal is dangerous



Detox works



Symptoms are much like severe flu-syndrome
Heroic medical treatments for detox are more dangerous than
‘cold turkey’ (Kleber)
The vast majority of heroin detoxes fail, even over 180 days
Death rate increases >8X after detox
Methadone is just another addiction



No “high”
Not injectable,
Does not impair motor performance (Zacny)
40 Year Natural History
of Heroin Addiction
48%
The natural history of narcotics addiction among a male sample (N = 581).
From: Yih-Ing, et. al., 2001. A 33-Year Follow-up of Narcotics Addicts. Archives of General Psychiatry, 58:503-508)
Fig
5.3
Annual Numbers of New
Nonmedical Users of Pain Relievers:
1965-2002
Thousands of New Users
All Ages
Aged 18
or Older
Aged
Under 18
1965
1970
1975
1980
1985
1990
1995
2000
At Least One Non-Medical Use
of Oxycontin During Lifetime
2002 National Survey on Drug Use and Health (NSDUH), SAMHSA, Sept 5, 2003
Why Crush OxyContin ?
Pharmaceutical opioids are usually taken
orally but may also be injected. They may be
crushed to circumvent the mechanisms which
control (delay) the release of the active
ingredients in long-acting formulations.
Triplicate
Review
Medications for
Heroin Addiction


Opioid Addiction

New production of heroin in South America

High purity/potency (smokeable)

Detoxification is of limited long-term efficacy

Most effective treatment for chronic users is Methadone
Maintenance
Medications

Methadone, LAAM
Opioid Agonist Therapy

Buprenorphine
Partial Agonist Therapy

Naltrexone
Opioid Blockade
Opiate Addiction:
Medications

Detoxification

Opioid Substitution



Methadone (Agonist)
[Illegal on outpatient basis]
Buprenorphine (Partial Agonist)
[Requires special DEA license]
Non-Opioid Symptom Relief





Clonidine (Catapres), alpha-2 adrenergic agonist
Lofexadine
Anti-spasmodic, anti-diarrheals
NSAIDS for bone pain and myalgia
Sleep meds
Naltrexone & Opioid Blockade

Extinction Paradigm


Craving Reduction


Attempts at opiate use produce no “high”
Craving is highly situational. It is reduced
when heroin cannot work.
Naltrexone Dysphoria??

Unclear whether the blockade of endogenous
opioids produces dysphoria or a loss of a
sense of wellbeing
Naltrexone:
Efficacy vs. Effectiveness

High Efficacy:


Limited Effectiveness:




An almost perfect, long-acting blocker of opiates
Most effective in monitored treatment of medical or
other professionals, executives, and individuals on
probation
Poor compliance in heroin-using population
Poor treatment retention
Combined Strategies:


Contingency management and family therapy
Criminal Justice leverage
UROD: UltraRapid Opioid Detoxification

Under general anesthesia administered opioid
antagonist

Continue opioid antagonist for several months,
refer to outpatient followup

Cost $5,000 – $20,000

Few long-term clinical trials, none demonstrate
improved results

Potential risks are high (medical co-morbidities
and post-detox overdose deaths)
Clonidine For Opioid Withdrawal
Principle:
Alpha-2 adrenergic agonist,
suppresses activity in locus ceruleus,
Decreases most withdrawal symptoms
Advantages: partial relief of symptoms
Disadvantages:
Requires dose titration, orthostatic hypotension,
Does not treat insomnia, myalgias or craving
Protocol:
0.1-0.2 mg. q 4 hours,
up to 1.2 mg/24 hours for 10 to 14 days
David Fiellin, M.D.
Opiate Addiction:
Maintenance

Methadone



LAAM



Dole & Nyswander’s opioid deficiency theory (1964).
Daily Dosing, Competitive blocking dose usually
> 60 mg qd
Every other day dosing or 2-days a week
Rare prolongation of QTc interval on EKG
Buprenorphine
(formulated with or without naloxone)
 Partial Agonist (high opiate receptor avidity but low
innate activity)
 Daily dosing, 2-32 mg qd
Methadone Maintenance
Outcomes

Gold-Standard for Opioid Treatment




One of the most over-proven treatments in the entire
psychiatry and drug abuse literature
Detoxification methods succeed only < 3% of the time.
Medically safe in pregnant women
Outcomes Measures

Reduction of …





Death rates (8-10X reduction)
Drug use
Criminal activity
HIV spread
Increase in …



Employment
Social stability
Retention, medication compliance, and monitoring
Buprenorphine
The New Kid on the Block
(but not everybody likes him)
Buprenorphine:
Affinity & Dissociation

High Affinity for Mu Opioid Receptor.


Competes with other opioids and blocks
their effects
Slow Dissociation from Mu Opioid
Receptor

Prolonged therapeutic effect
EFFICACY:
100
Full Agonist
(Methadone)
90
80
70
%
60
Efficacy
50
Partial Agonist
(Buprenorphine
40
30
20
Antagonist
(Naloxone)
10
0
-10
-9
-8
-7
Log Dose of Opioid
-6
-5
-4
Buprenorphine Summary

Well accepted maintenance therapy

Mild withdrawal

Decreases opioid use

Greater safety

Lower diversion potential
Opioid Summary:

Heroin remains a lethal drug
48%+ Death Rate / 33 years

Prescription opiate addiction, especially Oxycodone, has been
accelerating since 1995

Opiate withdrawal is uncomfortable (flu-like syndrome) but not
dangerous, per se

Aggressive medical treatments for withdrawal can have serious,
even lethal, consequences.

Efficacy and Effectiveness often diverge in treatment of opiate
addiction

Methadone Maintenance is the Gold Standard for good outcomes

Buprenorphine has a better safety profile, and it may be
prescribed from MD offices.
COCAINE
(Meth) Amphetamine
Discarded
Pseudoephedrine
bottles
Methamphetamine
Laboratory
Crystal
methamphetamine
Stimulant Myths & Facts

Cocaine/Methamphetamine self-medicates ADD
(Attention Deficit Disorder)


Paranoid Psychosis and Anhedonia are transient
effects



Few anecdotal reports, little research
Very long-lasting paranoid thought disorders are seen in
an unknown percent of chronic users
Incomplete therapeutic responses to either neuroleptic
antipsychotics or to antidepressants.
“Crack babies” fail to thrive and develop ADD


No discrete diagnosis or syndrome
Other factors are intermixed (nutrition, smoking, prenatal care, drinking, etc.)
Nicotine
Nicotine
1968
1971
1976
Medications for
Smoking Cessation

NRT’s (Nicotine Replacement Therapy)

Patches, Gum, Lozenges, Inhaler, Nasal Spray

Base = NRT Patches (21-14-07 mg)

Rescue = NRT oral products

Bupropion (Zyban, Wellbutrin)

Varenicline (Chantix)

Partial agonist

Warning: Possible severe mood changes
Lessons from SF VA
Smoking Cessation Clinic



Don’t insist on a quit date for all.
Consider an attrition paradigm for refractory smokers
Go Slow … 6-12 months
Use rescue meds liberally – but keep a rough count to know
when to reduce patch dose

Clean nicotine is better than dirty nicotine

Some patients will need nicotine maintenance

Monthly visits are essential

CO (carbon monoxide) metering is fun and helpful
Medications Today
Alcohol:
Disulfiram (Antabuse)
Naltrexone (ReVia, Trexan)
Acamprosate (Campral)
Ondansetron
Topiramate (Topamax)
Deterrence
Reward Blocker
?? NMDA, GABA
5-HT3 Serotonin
Opiates:
Naloxone (Narcan)
Naltrexone (ReVia, Trexan)
Methadone, LAAM
Buprenorphine (Suboxone, Subutex)
Overdose Rx
Receptor Blocker
Replacement (agonist)
Replacement
Stimulants:
[None to Date]
[? Modafinil under study]
Nicotine:
Nicotine Replacement
(gum, patches, lozenge, spray, inhaler)
Bupropion (Wellbutrin, Zyban)
Replacement
Varenicline (Chantix)
Partial agonist
GABA/Glutamate actions
Discussion