D e p a r t m e n t o fV e t e r a n s A f f a i r s f f a i r s

New Drugs for Old Disorders

Psychiatric Disorders, Addiction and Meds

12 October 2010Peter Banys, MD, MScDirector, Substance Abuse Programs, VA Medical Center, San Francisco

Health Sciences Clinical Professor of Psychiatry, UCSF

Past-President, California Society of Addiction Medicine

Lifetime Prevalence of DisordersEpidemiological Catchment Area Study (1990)

Mental Disorder22.5%

Other Drug Disorder6.1%

Alcohol Disorder13.5%

1.5%

1.1%

3.1%

1.7%

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

AnyMental

Anxiety AffectiveDisorder

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

Early onset (teens to twenties) Debilitating life course Impaired social interactions

Positive Symptoms 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 Sensorium

Temporal Relation to Drinking

Autonomic Dysfunction

Alcohol Withdrawal

>30 No After Yes

Alcoholic Hallucinosis

>30 Yes Intoxication No

EarlyWithdrawal

Yes

Schizophrenia <20 Yes Unrelated No

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 PrinciplesRelationship 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 & DrinkingDepression & 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®)

Calcium Carbimide

ALDH blockers May also have efficacy for reducing cocaine use

Naltrexone (ReVia®)

Nalmefene (ReVex®)

Opioid antagonists

Research only

Tiapride Dopamine antagonist Research only

Acamprosate (Campral®) Glutamate stabilizationGABA effects

Reduction of protracted withdrawal ?

Ondansetron (Zofran®)

[not approved]

Serotonin-3-receptor antagonist

May be effective in an early onset, severe subset of alcoholic population

Topiramate (Topamax®)

[not approved]

Dopamine inhibition

Glutamate stabilization

Reward Reduction

Reduction of protracted withdrawal ?

Medications for Relapse Prevention

Mechanism Medication CommentsAlcoholAgonist

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 CarbimideMetronidazole (Flagyl)

Deterrent medication. Disulfiram is no longer used in aversive challenges.

Opioid Antagonist

Naltrexone (ReVia) Relapse preventionCraving 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 co-modulator of dopamine function (via opioid system). Reduces mesocorticolimbic dopamine release.

GABA Glutamate

Topiramate (Topamax) Reduces heavy drinking, Promotes abstinence

Alcohol Relapse-Prevention Disulfiram (Antabuse®)

250 mg qd. Liver Function Tests, EKG

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®) 666 mg TID Recent US approval

Ondansetron (Zofran®) Research Status

Naltrexone StudiesNaltrexone 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 preventionTreatment 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

Mary E. McCaul, Pharmacotherapy Strategies for Alcoholism Treatment, Symposium: New Developments in the Pharmacological Treatment of Alcoholism, 2003.

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

Acamprosate StudyTherapy 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 +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 DependenceBankole 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 &

1677-85.

Topiramate

Other Targets for Medication Catecholamines

(Dopamine, NE)

Voltage-sensitive calcium channels

Corticotropin-releasing factor (CRF) antagonists

Ciraulo, Update on Treatment Approaches for Alcohol Dependence, ASAM Med-Sci Conf., April 23, 2004.

Serotonin Receptor Subtypeand 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

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.

Evidence Report/Technology Assessment: Jan. 1999 Agency for Health Care Policy and Research

OPIATES

Heroin Myths & Facts Opioid withdrawal is dangerous

Symptoms are much like severe flu-syndrome Heroic medical treatments for detox are more dangerous than

‘cold turkey’ (Kleber)

Detox works 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 Historyof Heroin Addiction

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)

48%

Annual Numbers of New Nonmedical Users of Pain Relievers: 1965-2002

Fig5.3

1965 1970 1975 1980 1985 1990 1995 2000

All Ages

Aged Under 18

Aged 18 or Older

Thousands of New Users

At Least One Non-Medical Useof Oxycontin During Lifetime

2002 National Survey on Drug Use and Health (NSDUH), SAMHSA, Sept 5, 2003

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.

Why Crush OxyContin ?

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Medications for Heroin Addiction

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

Attempts at opiate use produce no “high”

Craving Reduction 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:

An almost perfect, long-acting blocker of opiates

Limited Effectiveness: 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

Dole & Nyswander’s opioid deficiency theory (1964). Daily Dosing, Competitive blocking dose usually

> 60 mg qd

LAAM 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

100

90

80

70

60

50

40

30

20

10

0

-10 -9 -8 -7 -6 -5 -4

%Efficacy

Log Dose of Opioid

Full Agonist(Methadone)

Partial Agonist(Buprenorphine

Antagonist(Naloxone)

EFFICACY:

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) Few anecdotal reports, little research

Paranoid Psychosis and Anhedonia are transient effects

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, pre-natal

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)OndansetronTopiramate (Topamax)

DeterrenceReward Blocker?? NMDA, GABA 5-HT3 Serotonin

Opiates: Naloxone (Narcan)Naltrexone (ReVia, Trexan)Methadone, LAAMBuprenorphine (Suboxone, Subutex)

Overdose RxReceptor BlockerReplacement (agonist)Replacement

Stimulants: [None to Date]

[? Modafinil under study]

Nicotine: Nicotine Replacement(gum, patches, lozenge, spray, inhaler)Bupropion (Wellbutrin, Zyban)

Varenicline (Chantix)

Replacement

GABA/Glutamate actions

Partial agonist

DiscussionDiscussion