Title:  Vaccination For The Treatment of Cocaine Dependence

Thomas A. Nguyen, MD

Department of Psychiatry and Behavioral Neuroscience

University of Cincinnati, College of Medicine

Alcohol Medical Scholars Program

© AMSP 2011

 

 

 

I.       Introduction

A.    Substance use disorders (SUD) = major public health problem1 (Slide 2)

1.      Cost $67 billion/yr in crime & lost productivity

2.      Affect many people- rates past year:

a.    Alcohol (ETOH)- 8%

b.      Cocaine ~ 1%

c.    Opiates- 1%

3.      Cocaine especially problematic:  (Slide 3)

a.     >2 million Americans are cocaine dependent

b.      Can cause serious consequences2

i.              Medical:  heart attack, cardiac arrhythmia, stroke, seizure

ii.            Psychological:  hallucinations (see/hear things not there), paranoia (believe others want to harm), mood disturbance

iii.          Legal & criminal:  possession, trafficking, theft

iv.          Cocaine-related ER visits ↑ by ~ 50% in past 10 yrs

B.     This lecture reviews:  (Slide 4)

1.      Definitions (abuse & dependence [dep])

2.      Overview of  tx options & limitations

3.      Neurobiology of cocaine use disorder (CUD)

4.      How vaccines (vax) work  & application to CUD

II.    Definitions3  (Slide 5)

A.    Abuse- repeated problems in same 12 months with ≥ 1 of :

1.      Failure to fulfill major obligations

2.      Recurrent use in hazardous situations

3.      Recurrent legal problems

4.      Continued use despite social or interpersonal problems

B.     Dependence- repeated problems in same 12 months with ≥ 3 of:

1.      Tolerance:  ↑ use to get same effect; ↓ effect with the same amount used

2.      Withdrawal

3.      Unable to cut down or quit

4.      ↑ time looking for, using, & recovering from use

5.      Using more & longer than intended

6.      Giving up important activities

7.      Continued use despite consequences

C.     Clinical vignette to apply definitions:  (Slide 6)

1.      38 yo, married, white male attorney in ER with suicidal thoughts (e.g., withdrawal)

a.       Using $30 crack cocaine/day

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b.      Binges $1000/weekend (e.g., tolerance)

c.       Paranoia after binge (e.g., consequence)

d.      Uses cannabis (1-2 joints/day &  2-4 beers/day)

e.       Family hx of alcohol dep

2.      Diagnosis- cocaine dep as: (Slide 7)

a.       Tolerance

b.      Withdrawal

c.       Continued use despite psychological problems (paranoia)

III. Limited medication options for4:

A.    ETOH

1.      Disulfiram (Antabuse 250mg/d)  (Slide 9)

a.       Sensitizing agent to ETOH- inhibits enzyme in ETOH metab (aldehyde dehydrogenase)

b.      Causes physical sx (e.g., nausea & vomiting)

c.       ↓ ETOH use in highly motivated patients (pts)

d.      Many side effects

e.       Placebo controls hard (everyone expects to get ill if drink)

2.      Naltrexone (Revia 50mg/d)  (Slide 10)

a.       Opioid receptor antagonist

b.      These receptors key in feel reward

c.       May ↓ reward of drink

d.      ↓ heavy ETOH use

3.      Acamprosate (Campral 1-2g/d)  (Slide 11)

a.       NMDA receptor antagonist

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b.      These ↑ activity for months after abstinence

c.       Causes anxiety & insomnia

d.      ↓ start of alcohol use & ↓ quantity of ETOH

e.       Meds ↑ outcome ~ 15%

B.     Opioids

1.      Methadone (Methadone ≥ 80mg/d)  (Slide 12)

a.       Long acting opioid receptor agonist

b.      Daily dosing → no withdrawal

c.       Blunts euphoria if take opioids

d.      ↑ abstinence, ↑ employment & ↓ crime

e.       ↓ relapse

2.      Buprenorphine (Subutex 16-20mg/d)  (Slide 13)

a.       Long acting opioid receptor partial agonist

b.      ↑ abstinence & ↓ relapse

3.      Naltrexone (Revia 50-100mg/d) (Slide 14)

a.       Opioid receptor antagonist

b.      Blocks opioid high

c.       ↑ abstinence & ↓ relapse in highly motivated pts

4.      All need motivation to take; only modest ↑ outcome

C.     Nicotine  (Slide 15)

1.      Nicotine replacement (gum, patch, spray, inhaler, lozenge)- 2X quit rate

2.      Buproprion SR (Zyban 150mg/twice per day [BID])

a.       Inhibits dopamine (DA) & norepinephrine (NE) reuptake

b.      2X quit rate

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3.      Varenicline (Chantix 1mg BID)

a.       Selective nicotine receptor partial agonist

b.       3X quit rate

IV. Current tx options & limitations for CUD

A.    No effective medications for CUD2 (Slide 16)

B.     High rates of tx noncompliance & relapse

1.      Compliance4- dropout rates 50% from tx programs

2.      Relapse5- 52% w/i 1 yr after tx

C.     Behavioral interventions:  essential core of SUD tx (Slide 17)

1.      Cognitive behavioral therapy (CBT)6

a.       Emphasizes skills training (relapse prevention)

b.      Helps pts recognize consequences of continued drug use

                                                                                    i.         Legal (possession)

                                                                                  ii.         Medical (heart attacks)

                                                                                iii.          Occupational (absenteeism, impaired performance)

c.       Challenge thoughts about drug use (Slide 18)

                                                                                i.            Recognize dysfunctional thinking (denial, rationalization [constructing justification for an action])

                                                                              ii.            Substitute w/ rational thoughts (e.g., using → consequences)

d.      Develop coping skills for high risk situations

                                                                                  i.           Anticipate possible triggers (people, places, or things which evoke cravings for drugs)

       a’.  Meet with friends who use

       b’.  Stress

                                                                                ii.            Incorporate strategies to cope with triggers

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e.       ↑ abstinence @ 17 wks6:  CBT (40%) vs. tx as usual TAU (23%)

2.      Contingency management (CM)- used in formal tx programs7(Slide 19)

a.       Reinforced behaviors are more likely repeated

b.      Receive vouchers for goods & services for ↓ cocaine use

c.       ↑ patient acceptance, retention & abstinence

i.                    12 wk retention8:  CM  (55%) vs. TAU  (38%)

ii.                  8 wk abstinence6:  CM (73%) vs. TAU (12%)

d.      ↑ compliance7:  CM  (50%) vs. no tx  (5%)

e.       Continued use ↓ @ 12 months7- CM (52%) vs. TAU (27%)

3.      Combining CBT + CM → improved abstinence @ 3 wks9:  CBT (35%); CM (60%); CBT + CM (70%)  (Slide 20)

D.    Novel tx approaches needed

1.      Understanding CUD impact on CNS → new targets for tx

2.      Technological advances → new approaches (e.g., vaccines)

V.  Neurobiology of CUD10 (Slide 22)

A.    Coke↑ DA in the brain

1.      Blocks DA reuptake transporter

2.      ↑ DA →  reinforcing effects

B.     Coke a small molecule & crosses blood-brain-barrier (BBB)

C.     Route of administration determines onset of CNS effect (Slide 23)

1.      Smoking- 6-8 secs in modest amts

2.      IV- 15 secs in large amts

3.      Intranasal- minutes in lower amts

4.      More delay & ↓ amts → ↓ reinforcing

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VI.   How vaccines (vax) work & application to CUD

A.    Important definitions for understanding vax  (Slide 25)

1.      Antigens (Ags):  foreign substances →  immune response

2.      Antibodies (Abs):  proteins produced in antigen response

B.     Immunology of vax development11 (Slide 26)

1.      Active Immunity (AI) → specific Ab production

a.       Confers longer immunity (immunologic memory)

b.      Lower cost than monoclonal Abs (mAbs) production

c.       Requires exposure time for Ab production (delayed onset)

d.      Inter-individual variability

2.      Passive Immunity (PI)- mAbs made outside host  (Slide 27)

a.       Immediate onset (useful in drug overdose)

b.      More expensive than AI

c.       Shorter immunity than AI (dependent on amount and half-life [t1/2] of mAbs)

d.      Minimizes inter- individual variability

3.      To be efficacious, both types of immunotherapy must:

a.       Last long enough to elicit immune response

b.      Produce Abs highly specific to coke

C.     Vax strategies for treating cocaine dep2  (Slide 28)

1.      Goal:  prevent cocaine from entering CNS

2.      Induce immune response to produce Ab

3.      Abs attach to coke

4.      Ab-coke complex very large

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a.       Cannot cross BBB

b.      Cannot cross placenta → protects fetus

D.    Development of AI vax for cocaine dep5  (Slide 29)

1.      Produce a lot of Abs

a.       Eg:  (tetanus vax) 1µg/mL of Ab vs. (cocaine vax) 40µg/mL

b.      ↑ Ab concentration = ↑ coke binding → ↓ coke in CNS

c.       Efficacy- requires 80% binding

d.      Blunted drug response – requires 50% binding

2.      Binding should not interfere with coke metabolism

a.       If binding ↓ metabolism →  ↑ coke’s peripheral fx

b.      → ↑ BP, ↑ HR

E.     Types of clinical trials in developing vax12

1.      Preclinical trials are first step  (Slide 30)

a.       Done in vivo (animal or cell culture) or in vitro

b.      Gives info on mechanism of action, toxicity & metabolism

2.      Phase 0- (establish vax behavior in humans)

a.       Efficacy not a goal = use subtherapeutic dose

b.      Assess:

i.                    Pharmacokinetics- absorption & distribution

ii.                  Pharmacodynamics- fx of drug on body

3.      Phase I (assess tolerability in humans)  (Slide 31)

a.       Give single or multiple ascending doses

b.      ↑ dose if tolerated

c.       Observe reaction

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4.      Phase II (larger groups of subjects)

a.       Groups are selected or randomized with control

b.      Phase IIa- assess dosing requirements

c.       Phase IIb- assess efficacy

5.      Phase III- randomized controlled multicenter trials on large groups  (Slide 32)

a.       Phase IIIa (determines effectiveness)

i.                    Vs.  placebo

ii.                  Vs.  “gold standard” tx (e.g., naltrexone)

b.      Phase IIIb- effectiveness beyond original use of approval

c.       Two successful Phase III trials for FDA approval  (Slide 33)

6.      Phase IV- post marketing surveillance to detect rare or long-term adverse fx

F.      Results of studies of vax treating cocaine dep

1.      Phase I (human tolerability)13  (Slide 34)

a.       Significant Ab response to coke

b.      Well tolerated

c.       No serious adverse fx

2.      Phase IIa (18 pts over 14 wks) (doses)13  (Slide 35)

a.       Two dose levels

i.                    100µg X 4 injections

ii.                  400µg X 5 injections

b.      Well tolerated

c.       No allergy

d.      Individual variability in Ab production (30%- low Ab)

e.       Subjects w/ higher dose → ↑ clean urine drug screens & ↓ euphoria

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3.      Phase IIb (115 pts over 24 wks) (efficacy)14  (Slide 36)

a.       Randomized pts-  five 360µg injections

b.      Controlled pts- five saline injections

c.       All pts received CBT

d.      Pts w/ Ab levels ≥43µg/mL (38%) → ↓euphoria

e.       Pts w/ ↑ Ab levels = ↓ coke use

i.                    53% w/ high Ab (≥43µg/mL) abstinent during wks 8-20

ii.                  23% w/ low Ab (≤43µg/mL) abstinent during wks 8-20

G.    Limitations of coke vax15  (Slide 38)

1.      Inter-individual variability in Ab response (etiology unknown)

2.      Ab titers↓ over time ~ 6 mos

3.      Requires boosters to sustain Ab titer

4.      Override vax w/ ↑ cocaine use (possible lethal consequences)

5.      Can use other forms of stimulants

6.      Vax do not address cravings or withdrawal sx

7.      No long term data (vax currently in phase IIb)

8.      Vax available possibly by 2015

H.    Clinical vignette revisited- benefits of vax in pt  (Slide 40)

1.      Pt may benefit from first line tx = behavioral interventions

2.      Pt likely to relapse b/c of cravings

3.      Crack’s route of administration → rapid & intense euphoria

4.      Vax attenuates euphoria

5.      ↓ euphoria = ↓ reinforcement

6.      ↓ reinforcement prevents full relapse

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7.      ↑ vax effectiveness if pt well motivated

8.      Goal may be ↓ use rather than abstinence

VII.          Conclusions  (Slide 41)

A.    CUD costly to individuals & society

B.     CUD no effective pharmacotherapy

C.     Coke’s properties (i.e., short t1/2, metabolized by simple hydrolysis & no active metabolites) allow for vax development

D.    Vax blocks coke’s reinforcing fx

E.     Early clinical data support potential effectiveness of vax

F.      Vax has limitations

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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References

 

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3.      Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision.  Washington DC:  American Psychiatric Press Inc;  2000.

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12.  Van Spall HG, Toren A, Kiss A, et al.  Eligibility Criteria of of Randomized Controlled Trials Published in High-Impact General Medical Journals:  a systematic sampling review.  JAMA 2007;297(11):1233-1240.

13.  Martell BA, Orson FM, Poling J, et al.  Vaccine pharmacotherapy for the treatment of cocaine dependence.  Biol Psychiatry  2005;58:158-164.

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