Treatment of Substance

Dependence
William R. Yates, M.D.
Professor of Research, OU-Tulsa
Research Psychiatrist, Laureate
 Disclosure
 Research Funding
• Takeda Pharmaceuticals
• Forest Laboratories
 Consultant
• Forest Laboratories
 Psychopharmacology Options
 Alcohol Dependence
• Acamprosate
• Naltrexone
• Topiramate
 Opiate Dependence
• Buprenorphine
 Benzodiazepines Dependence
• Gabapentin and slow tapers
 Nicotine Dependence
• Nicotine replacement
• Bupropion
• Varenicline
 Acamprosate
 Synthetic compound similar to
endogeneous AA homotaurine
 GABA analogue
 Glutamatergic effect
 333 mg caps 2 tid schedule
 Generally well tolerated—slight inc in
diarrhea compared to placebo
 Renal excretion—can be used with
liver disease
 Naltrexone
 Opioid antagonist (synthetic
congener of oxymorphone)
 No opioid agonist effect
 50 mg once daily standard dose
 Hepatic metabolism—safety in
alcholic hepatitis/cirrhosis is unclear
 Can induce acute opioid withdrawal
in patients with opioid dependence
 NIAAA COMBINE Study
 Anton et al JAMA 295:2003-, 2006
 Randomized control trial
 8 groups (placebo, acamprosate,
naltrexone or acamp/naltr combined
with or without cogn behavioral inter
 1383 subjects in 11 centers
 16 week and 1 year outcomes
 % days abstinent/time to 1st hvy drk
 COMBINE Results
 Medical management a potent effect
in alcohol dependence with placebo
 Naltrexone more effective than
placebo
 Acamprosate + naltrexone no better
than naltrexone alone
 No additional effect of adding CBI to
naltrexone with medical
management
 COMBINE Results
80
78
76
74
72
CBI alone
70
Plac/Med Man
68 Plac/MM/CBI
66
64
62
60
Abstinence rates
 Medical Management
 9 sessions over 16 weeks given by
physicians/nurses (20-45 minutes)
 Placebo/medication dispensed
 Abstinence encouraged
 Review of side effects
 Support medication adherence
 Review drinking behaviors since last
visit
 Mu-opioid Receptor-COMBINE
 Asn40 & asp40 90
genotypes 80
 Naltrexone 70

response limited to 60
50
those with asnp40 asn40
40
gentotype 30
asp40

 Anton et al, Arch 20

Gen Psych 65:135, 10

2008 0
% response
Topiramate in Alc Dependence
 Johnson et al, JAMA, 298:1641, 2007
 Randomized placebo controlled
 Up to 300 mg topiramate (171 mg)
 All received weekly behavioral rx
 Key outcome variable-Heavy drinking
days (>=5 drinks per day for men
and >=4 drinks per day for women)
 Percent Heavy Drinking Days
80
70
60
50
Placebo
40
Topiramate
30
20
10
0
2 wks 4 wks 8 wks 14 wks
 Adverse Events
50
45
40
35
30
25 Placebo
20 Topiramate
15
10
5
0
Paresthes Taste Anorexia Cog diff
 Drug Addiction Treatment Act
 DATA 2000
 Allowed qualified physicians to treat
opioid dependence
 Outpatient approval
 Schedule III-V drug use
 Previously required federally
approved methadone treatment
license
 Physician Qualification
 Addiction subspecialty certification from
ABPN, ASIM or other body
 Or complete 8 hour course
• www.buprenorphinecme.com
• 8 hour web-based course/$175
 Ability to appropriately refer for
psychosocial addiction treatment
 Limited to 30 patients
 Requires approval letter from SAMHSA
 Suboxone
 First opioid approved for outpatient
treatment opioid dependence
 Contains:
• Buprenorpine-partial opioid agonist
• Naloxone-opioid antagonist
 Buprenorphine binds tightly to opioid
receptor with partial agonist effect-
reduce withdrawal and blocks high
from other opioid use
 Suboxone vs Methadone
 Advantages of buprenorphine (Subutex)
• Higher doses have lower risk of toxicity.
• Potentially effective at less than recommended daily
dosage.
• Withdrawal symptoms are less severe after
discontinuation.
• Less abuse potential
• More accessible for office-based treatment programs
• Advantages of methadone
• Lower cost
• More effective in patients with higher tolerances
• Treatment retention rates are higher
 Managing Opioid Withdrawal
 Symptom Treatment
 Abdom. cramps Bentyl
 Diarrhea Lomotil
 Insomnia Trazodone
 Muscle aches NSAID
 Hypertension Clonidine

 Source: Donaher, AFP, 73:1573, 2006

Quetiapine & Opioid Withdrawal
 Quetiapine augmentation to usual
outpatient opioid detox
 Eight 25 mg tabs (1-2 tab q 4h prn)
 75% reported reduced craving, 50%
reported reduced anxiety, 20%
reported reduced somatic symptoms
and 18% reported reduced insomnia
with quetiapine
 Pinkofsy, J Clin Psych 66:1285, 2005
 Suboxone Local Resources
 Local Psychiatrists:
• Michael Dubriwny, M.D.
• William Ford, M.D.
• Peter Rao, M.D.
 Local Internists:
• William Yarborough, M.D. OU Internal
Medicine
 Alprazolam Dependence
 Difficulty in discontinuation related to
daily dose and duration of use
 General principles include:
• If attempting alprazolam taper, small
reductions best-may take 6 months to
taper from 3 mg daily dose
• Increased withdrawal symptoms
common when getting down to last 0.5
mg to 1 mg per day
 Alprazolam Dependence
 Consider gradual switch to long acting
benzodiazepine before taper
• i.e. for a patient on 1 mg alprazolam tid
consider switching one dose every 3 days to
0.5 mg to 1 mg of clonazepam
• When completed switched over begin taper by
15% to 20% of daily dose every week or so
• Consider non-benzodiazepine augmentation
(gabapentin, SSRI, CBT) for anxiety
breakthrough symptoms
 Alprazolam Dependence
 Optional Gabapentin substitution
strategy
 Substitute one 400-800 mg dose of
gabapentin for each 1 mg of
alprazolam every 2 to 3 days
 Gabapentin continuation therapy an
option after switch
 Reduces risk of withdrawal seizure
 Option for demanding patient
 Gabapentin in Alcohol Withdrawal
 DB study comparing 4 day fixed dose
taper gabapentin vs lorazepam in Alc
WD
 Focus on effects on sleep
 Gabapentin patients reported better
sleep and less daytime sleepiness
 Suggest gabapentin could be
considered for benzodiazepine
withdrawal
 Nicotine Products
 Nicotine gum
 Nicotine patches
 Nicotine inhaler-prescription
 Nicotine nasal spray-prescription
• Rapid blood levels
• May be more effective for severely
dependent smoker
 Bupropion
 Zyban 300 mg per day 40
 Contraindicated in 35
seizure disorder or 30
eating disorders 25
 Used in conjunction 20 Placebo
with behavioral 150 mg
15
program 300 mg
10
www.cancer.org
5
0
7 weeks 12
weeks
 Varenicline (Chantix)
 Nicotine receptor partial agonist
 Derived from cytisine
 Increases quit rates by threefold
over placebo
 FDA reviewing post-marketing case
reports of increased suicidal ideation
similar to antidepressants
 Varenicline vs bupropion
45
40
35
30
25 Varenicline
20 Bupropion
15 Placebo

10
5
0
Gonzales Jorenby
Genotype & Bupropion Response
35

30

25

20
Bupropion
15 Placebo

10

0
A2/A2 Other
 Cost Issues/Barriers
Drug Monthly Cost
Acamprosate $135
Naltrexone $250
Topiramate $215
Gabapentin $90 (#90 600 mg caps)
Suboxone $250
Bupropion SR $200 (generic $70)
Varenicline $125