Transcript Varenicline for Meth Dependence?

Pilot Study of Varenicline
for Meth Dependence
Todd Zorick
October 9, 2008
Seminars in Addiction Psychiatry
Study History
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Protocol originally designed by Dr. Rich De La
Garza and Dr. Tom Newton as part of Dr. Steve
Shoptaw’s P50 grant for Stimulant Medication
Development.
Submitted 9/07, approved by IRB.
3/08- Drs. Newton and De La Garza moved to
Baylor.
Protocols transferred to London Lab.
IRB approval 6/08 for transfer.
TZ hired 7/1/08.
Varenicline(Chantix®)
 partial
agonist at α4β2 nicotinic
acetylcholine receptors (nAChRs)
 full agonist at α7 nAChRs
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Mihalak et al. 2006
 Approved
for smoking cessation August
2006- priority review.
 12 week Tob. abstinence rates: 44%
Varenicline, 30% Buproprion, 18% PLA
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Nides et al, 2008
Varenicline Pharmacology
 Common
Side Effects: nausea, headache,
insomnia, abnormal dreams.
 No CV side effects (bp, pulse, etc.)
 Metabolism: 92% renal excretion
 Half-Life: 24 hours.
 Original Phase III Study: 352 healthy
smokers- no psychiatric/medical
sequellae.
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Gonzalez et al, 2006 JAMA
Varenicline Doubts
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As of June 2008, 3.5 Million scripts of Varenicline written
in US!
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ISMP, 2008.
Case reports of SI/ agitation/ psychotic symptoms- no
RTCs or systematic reviews.
 February 2008: FDA Alert- “it appears increasingly likely
that there is an association between Chantix and serious
neuropsychiatric symptoms.”
 May 2008: FAA banned use of VA in pilots, ATC due to
reports of VA-associated accidents (seizure risk?).
 Definitive studies pending (hopefully).
Varenicline Mechanism
α4β2 nAChR Partial
Agonist- blocks
nicotine activation,
and Produces moderate
sustained release of
DA at NAc.
 Both contribute to
anti-smoking efficacy.
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Coe et al J Med Chem
2005
nAChRs
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Acetylcholine-gated Na+/K+/Ca++ channel
receptors.
17 different subunits can combine to form a
variety of different subtypes of nAChR.
α4β2- EPSP primarily.
α7- Ca++/2nd messenger activation primarily.
Schizophrenics- deficient in α7- heavy smoking
reverses PPI defects- improved information
processing/gating.
Acetylcholine NT system
 Originating
from Nucleus Basalis of
Meynert, RAS- diffusely projecting to many
parts of brain.
 Related to attention/arousal/memory.
 Degeneration in AD- decreased
memory/arousal.
 Tonically Active during wakefulness,
inactive during sleep.
nAChR – DA Circuitry
-Funk et al, 2006, Alc. Res. Health
Note: PPT- Pedunculopontine Tegmental Nucleus,
Reticular Activating System
Areas in the brain involved in nicotine addiction
Le Foll, B. et al. CMAJ 2007;177:1373-1380
Copyright ©2007 Canadian Medical Association or its licensors
Methamphetamine Dependence
 Potent
CNS stimulant with high abuse
potential.
 Causes reversal of flow of DAT, NAT, 5HTT- toxic increase in monoamine conc.
In synaptic clefts.
 T1/2- 9-14 hours in humans.
 Methyl group- causes increased BBB
permeability, decreased breakdown
compared to amphetamine (Adderall).
Meth in the World
 Synthesized
1891- First used medicinally
for depression/fatigue.
 Given to Japanese and German soldiers in
WWII to decrease fatigue.
 Hitler was given MA injections by his MD
from 1942-1945.
 Military supply in Japan sold OTC in 19461950- first MA epidemic in world- over
500,000 Japanese users in 1954.
Meth in the US
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Distributed by biker gangs in CA in 1960s via
“kitchen” Meth labs.
 Use still most prevalent in Western US- now
made in Mexico in large labs and distributed by
Mexican Drug Cartels.
 Prevalence- declining slightly- 0.7% of US
population >12 years old using in 2002 vs. 0.5%
in 2005.
 1.2% in Western US vs. 0.1% in Northeast.
US Meth Epidemic
 2005
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SAMHSA Data
100-200,000 MA-dependent individuals in
US.
~80,000 received treatment for MA
Dependence at a facility (hospital, rehab,
treatment center, etc).
Still Endemic in West: 2002-2005 prevalence
2.0% in NV, 1.5% in WY, MT, 1.2% in OR,
1.1% in CA; vs. <0.1% in NY, CT.
Spreading?
Treatment for MA Dependence
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No FDA approved Medications.
 Limited evidence for Modafinil, Buproprion,
Baclofen, others.
 Primary EBT includes CBT, relapse prevention,
MI, structured rehabs- MATRIX Model.
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Problem: MA dependence associated with cognitive
deficits- ↓ ability to learn new behaviors.
N=230, 1 year post 16 weeks intensive OP MATRIX
Rx, days of MA use/month ↓ from 12.55 to 3.96.
• Marinelli-Casey et al, 2008 J Subst Abuse Treat
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Nature vs. Neural Toxicity
Varenicline for MA dependence?
 Varenicline
causes sustained release of
DA in NAc- may assist MA withdrawal
(hypodopaminergic state).
 Therefore, may block craving/desire for
MA.
 Primary
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question: Is It Safe?
Phase I Safety data needed to take to Phase
II Clinical trials per P50/ Shoptaw Group.
Study Design
 Double-blind,
placebo-controlled, inpatient
study using MA-dependent subjects.
 N=6 for usable safety data, N=8-13 for
publication-quality data.
 SCID to rule out comorbid Axis I
psychiatric disorder.
 Safety Labs, Medical History and Physical,
EKG to rule out comorbid medical
conditions
Study Design 2
 Outpatient
screening- labs, PE, EKG,
SCID, Utox MA+.
 If qualify, come to CRC Utox MA-.
 2 Phases- I is 10 days, II is 8 days, at least
14 days between conditions (VA vs. PLA).
 Phase I, day 1- 3mg IV MA x 10 (30mg
total)- safety evaluation of MA alone.
 Day 2- start with Varenicline/PLA Rx.
Study Design 3
 Varenicline
(or PLA) 0.5 mg nightly for 3
days, then 0.5 mg twice daily for 2 days,
then 1.0 mg twice daily for 2 days.
 Slow titration as in OP to avoid nausea,
headache.
 Day 7 of VA Rx- re-challenge with IV MA
3mg x 10 (30mg total).
 Day 8 of VA Rx- choice session IV MA vs
PLA 3mg or $1 x 10 choices.
Outcome Measures
 EKG
changes, HR, BP, subjective effects
(high, crave, desire, etc) with MA and VA
vs. PLA.
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Hyp: VA will have <10% ↑ in HR/BP with MA
compared to PLA.
 VA
effect on choice for Self-Administered
MA in choice session?
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Hyp: VA will reduce number of SA MA
infusions on choice day compared to PLA.
Additional Safety Data
 Original
study design- take-home
varenicline.
 2/08- FDA Alert- protocol re-designed: all
inpatient.
 Check BDI daily. Check POMS, ARCI
during infusion days to rule out ↑
psychiatric symptoms during VA Rx.
 F/U visit 2 weeks after 2nd Phase for AEs.
Progress To Date
 19
Subjects gave IC to Date.
 1 Subject Finished both Phase I and II,
pending 2 week F/U.
 2 Subjects finished Phase I- one moved to
Brooklyn, the other pending Phase II.
 Still active Enrollment.
 Blind not broken, but to the eye appears to
be safe so far (<10% ↑ in HR, BP).
 No SAEs to date!
Thanks!!
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Dr. Edythe London
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Thomas Hanson
Clayton Clement
Bahar Ebrat
Sarah Wilson
Theresa Caban
Students and RAs who
are helping out!!
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Dr. Steve Shoptaw
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Dr. K. Heinzerling
Dr. Aimee-Noelle
Swanson
CRC Staff
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Heather Barber
Debra Flott
All the RNs