Download - Outline of the lecture - NDAFP
12/22/2014
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Treatment of Substance Use
Disorders in Primary and Integrated
Care
Elena Volfson, MD, MPH
Outline of the lecture
• DSM V vs DSM IV substance use disorders
• Current epidemiology of substance use in the
US from NSDUH 2013
• Neurobiology of substance use
• Current review of treatment strategies by
substances : alcohol, tobacco, opiates,
cannabis
DSM-IV and DSM-V Substance Use
Disorders
• Added craving criterion
• Eliminated dependence and abuse distinction
• Eliminated legal problems as criterion
• Mild (2-3), moderate (4-5) and severe (>6) out
of 11
Past month alcohol consumption in
>12 in 2012
Past month alcohol use by race 2012 Past month tobacco use >12 2012
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Tobacco use by women >12 2012Past month cigarette use over age 12
2012
Past month illicit drug use by age 2012Daily or almost daily cannabis use >12
2012
Initiation of use by substances 2012
(excluding tobacco)Goal of Addiction Treatment
• Recovery as "a voluntarily maintained lifestyle
characterized by sobriety, personal health, and
citizenship“ (J Subst Abuse Treat. 2007;33(3):221)
• Restoration of medical and social well-being
• Acquiring or regaining cortical/executive
control over one’s behavior and life
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Proprietary Recipe: Most Effective Treatments
for Any Mental Illness by Dr. Volfson
• Brain transplant
• Re-parenting
• Injection of common sense and perspective
Psychotherapy is the best treatment unless the
patient is actively psychotic, demented or
mentally retarded. Functional frontal lobes are
required for therapy.
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Model of Addiction
CravingReward /
Euphoria
ControlEmotion
Memory
Orbital Prefrontal Cortex
Ventral Tegmentum
Hippocampus
Nucleus Accumbens
Temporal - Parietal
Used with permission from David Oslin, 2012
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Model of Addiction
CravingReward /
Euphoria
ControlEmotion
Memory
12 Step / CBT
Naltrexone
Acamprosate
Naltrexone
Acamprosate
Antidepressants
Mood Stabilizers
Therapy
Used with permission from David Oslin, 2012
Addiction is a Compulsive Relapsing
Disorder
Two essential features:
• impaired ability to regulate the drive to
obtain and use substances
• reduced drive to obtain natural rewards
Change in the reward circuitry : substances
usurp normal learning circuitry to create the
pathology of addiction
Kalivas and O’Brien, 2008
Vulnerabilities in Development of
Addiction
• Genetic
• Developmental
• Social
• Drug-induced brain plasticity
Core Addiction Syndrome
• Common neuroplastic changes in response to chronic administration of different substances of abuse
• Addiction is “overlearned “ with repeated associations between substances and life events mediated by dopamine release
• Addictive behaviors and chronic relapse vulnerability are maintained by glutamatergicneurotransmission
Kalivas and O’Brien, 2008
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Core Addiction Syndrome
• Hypofrontality- subcortical glutamatergic
connections assume primacy and reduce
cortical control over drug-seeking (automatic
behavior)
• Drug-associated stimuli activate PFC
excessively, whereas natural reinforcers (sex,
food, danger etc.) elicit poor response -
maladaptive process
Staged Neuroplasticity of Addiction
• Abstinence
• Social Use
• Chronic Use
• Regulated relapse – conscious choice
• Compulsive relapse- inability to make a
conscious choice(Kalivas and O’Brien 2008)
Neurobiological Changes with Chronic
Substance Use
• Motivation/reward system DA/endorphine
• Glutamate/GABA dysregulation
• HPA axis dysregulation
• Hypofrontality
• Sex hormones dysregulation
• Cravings
• Relapse
Pharmacologic Strategies to Treat
Addiction• Dopaminergic (D1-D5)
• Glutamatergic (NMDA, AMPA, KA, metabotropic)
• GABA ergic (GABA A and B)
• Cholinergic (Ach M and N)
• Noradrenergic (Alpha and beta)
• Serotonergic (14 subtypes)
• Endogenous opioids (mu, delta, kappa, OFQ-N)
• Endogenous cannabinoids (CB1 and CB2)
• Many others (NPY, DARPP-32, galanin, orexin, CRF, substance P, melanocortins, leptin, BDNF etc.)
Most Effective Treatment for
Substance Abuse Disorders
• Combination of medications and therapy
• Treatment of co-morbid mood and anxiety
disorders
• Free up the frontal lobes by quieting
subcortical areas for the therapy
• Therapy: relapse prevention, motivational
interviewing, 12-step facilitation, CBT, family
therapy etc.
Addiction Therapy may be related to activation
of Frontal Cortex
(Boettiger, et.al. 2009)
(Crews and Boettiger et.al. 2009)
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Importance of Simultaneous
Treatment for All Substances Involved
• One craving breeds another
• One addiction drives another (priming effect)
• Very important to address tobacco
dependence
• Stress increases cravings and relapse
Low-risk drinking limits
• If no cardio-vascular disease
• Men: Not more than 2 standard drinks per day
and not more than 4 drinks on an occasion
and not more than 14 drinks per week
• Women and elderly: 1-1.5 drinks per day
Medications for alcohol dependenceMedications for alcohol dependence
Disulfiram
• First medication approved for alcoholism
• Blocks acetaldehyde dehydrogenase
• Works best if dose observed
Medications for Alcohol Use Disorders
• Disulfiram
• Acamprosate
• Naltrexone oral/injectable/implantable
• Topiramate
Disulfiram Reduces Drinking Days
Fuller et al. JAMA. 1986 Sep 19;256(11):1449-55.
*
*p<.05
Acamprosate
• Glutamate antagonist
• Reduced protracted withdrawal
• Reduces cravings
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Acamprosate Promotes Abstinence
Sass et al. Arch Gen Psychiatry. 1996;53(8):673-80
Meta-Analysis of Acamprosate: Abstinence Improved
StudyTreatment
n/NControl
n/NPeto OR
(95% CI Fixed) Weight %Peto OR
(95% CI Fixed)
Besson 1998
Chick 2000
Geerlings 1997
Gual 2001
Ladewig 1993
Paille 1995
Pelc 1997
Poldrugo 1997
Sass 1996
Tempesta 2000
Whitworth 1996
Total (95%CI)
14/55
35/289
14/128
49/141
12/29
45/361
52/126
53/122
54/136
62/164
27/224
417/1775
3/55
32/292
7/134
38/147
7/32
16/177
9/62
37/124
23/136
48/166
11/224
231/1549
3.1
12.6
4.1
12.9
2.8
10.1
7.7
12.1
11.7
15.5
7.4
100.00
4.56 [1.63, 12.76]
1.12 [0.67, 1.86]
2.16 [0.89, 5.27]
1.52 [0.92, 2.52]
2.45 [0.83, 7.18]
1.41 [0.80, 2.48]
3.37 [1.76, 6.44]
1.79 [1.07, 3.01]
3.06 [1.81, 5.18]
1.49 [0.94, 2.35]
2.50 [1.29, 4.87]
1.88 [1.57, 2.25]
Test for heterogeneity: chi-square = 17.00; df = 10; P = 0.074
Test for overall effect: z = 6.87; P < 0.0001
CI = confidence interval; OR = odds ratioBouza et al. Addiction. 2004;99:811.
Outcome: Abstinence Rate
.2.1 1 5 10
Volpicelli et al. , Arch Gen Psychiatry 1992;49(11):876-80
No. of Weeks Receiving Medication
10 2 3 4 5 6 7 8 9 10 11 12
0.0
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.3Naltrexone HCl (N=35)
Placebo (N=35)
Cumulative Rate of Alcohol
Relapse
Medications for alcohol dependence
Naltrexone
• Blocks opiate receptors – prevents
endorphines from binding to GABA-
interneurons
• Blocks subsequent dopamine release
• Effective is a subset of alcoholics
Meta-Analysis: Oral Naltrexone Reduces Relapse
StudyTreatment
n/NControl
n/NPeto OR
(95% CI Fixed) Weight %Peto OR
(95% CI Fixed)
Anton 1999
Chick 2000
Guardia 2002
Heinala 2001
Hersch 1998
Kranzler 2000
Krystal 2001
Latt 2002
Monti 2001
Morris 2001
Oslin 1997
O’’’’Malley 1992
Volpicelli 1995
Volpicelli 1997
Total (95%CI)
26/68
59/90
8/101
49/63
15/31
29/61
142/378
19/56
16/64
19/55
3/21
16/52
10/54
17/48
428/1142
38/63
54/85
19/101
51/58
15/33
31/63
83/187
27/51
19/64
26/56
8/23
31/52
17/45
26/49
445/930
7.5
9.2
5.4
4.0
3.7
7.1
27.4
6.0
5.8
6.1
1.9
5.9
4.5
5.5
100.0
0.42 [0.21, 0.82]
1.09 [0.59, 2.03]
0.39 [0.17, 0.88]
0.50 [0.19, 1.27]
1.12 [0.42, 2.98]
0.94 [0.46, 1.89]
0.75 [0.53, 1.08]
0.46 [0.22, 0.99]
0.79 [0.36, 1.72]
0.61 [0.29, 1.30]
0.34 [0.09, 1.33]
0.32 [0.15, 0.68]
0.38 [0.16, 0.93]
0.49 [0.22, 1.09]
0.62 [0.52, 0.75]
Bouza et al. Addiction. 2004;99:811.
Test for heterogeneity: chi-square = 17.00; df =10; P = 0.074
Test for overall effect: z = 6.87; P < 0.0001
.2.1 1 5 10
Favors Naltrexone Favors Control
CI = confidence interval; OR = odds ratio Arch Gen Psychiatry 1997 Aug;54(8):737-42
Naltrexone is effective in compliant
patients
*
*p = .002
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• Naltrexone embedded in microspheres
• Elimination: polymer eventually metabolized and eliminated as CO2 and H2O
Hydration Diffusion Erosion
Dean. Front Biosci. 2005;10:643.
Extended Release Injectable Naltrexone
• Multicenter study, 624 patients
• 3 groups: placebo, 190 mg, and 380 mg
• All patients received BRENDA
• About 8% of patients were abstinent for
1 week prior to treatment
• 6 months of treatment
Garbutt et al. JAMA 2005;293:1617
Extended-release Injectable Naltrexone: Pivotal Trial
Reductions in Heavy Drinking with
Naltrexone
All Patients
Patients Without Lead-in
Abstinence
Patients With Lead-in
Abstinence
P = 0.02 vs PBO
P = 0.05 vs PBO
P = 0.005 vs
PBO
PBO = placebo
Pe
rce
nt
Re
du
cti
on
Re
lati
ve
to
Pla
ce
bo
Garbutt et al. JAMA. 2005;293:1617
Family History Predicts Naltrexone
Response
Monterosso et al. Am J Addict. 2001;10:258-
68.
Mu Receptor Polymorphism Predicts
Naltrexone Response
Oslin et al. Neuropsychopharmacology 2003;28(8):1546-52..
*
* p=.04
Pharmacology of Topiramate
• Antagonist at AMPA and kainate receptors
• Allosteric agonist at the GABA-A receptor
• Blocks voltage-dependent Na and l-type voltage-gated Ca channels
• Inhibits carbonic anhydrase
• Enhances K+ conductance
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Medications for alcohol dependence
Johnson et al. Lancet. 2003;361(9370):1677-85
Topiramate Promotes
AbstinenceFrom Alcohol
Meta-analysis by Blodgett et al. (2014)
Placebo-Controlled Trial of Topiramate to
Reduce Heavy Drinking
• 12-week study of 138 heavy drinkers whose
goal was to reduce drinking to safe levels
• Topiramate 100 mg twice daily (N=67) or
matching placebo (N=71) with dosage
increased gradually over 6 weeks
• Brief behavioral counseling at each visit
• Moderator analysis of rs2832407 in GRIK1
Kranzler et al., Am J Psychiatry, 2014
Screenin
g
(n=200)
Baseline
(n=138)
12-Week
Treatment
Topiramate
(n=67; 82.1%
completed tx)
12-Week
Treatment
Placebo
(n=71; 87.3%
completed tx)
3-month
Follow-up
Topiramate
(n=60;
90%)
3-month
Follow-up
Placebo
(n=63;
88.7%)
6-month
Follow-up
Topiramate
(n=59;
88.1%)
3-month
Follow-up
Placebo
(n=59;
83.1%)
Study Design
Kranzler et al., Alcohol Clin Exp Res, in press
Within-Treatment Heavy Drinking Days/Week Within-Treatment Abstinent Days/Week
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Genotype Groups
• We genotyped participants for rs2832407 in GRIK1 as a moderator
of topiramate’s adverse effects and effects on drinking behavior.
• The genotypes in European Americans (n=122) were in Hardy-
Weinberg Equilibrium:
• CC (n=51)• AC (n=53)
• AA (n=18)Kranzler et al., Am J Psychiatry, 2014
Heavy Drinking Days by Medication and Genotype Groups
Abstinent Days by Medication and Genotype Groups
Figure : Main effect of medication group (A), and moderating effect of rs2832407 (B and C)
The population of veterans
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Prevention only Heavy
DrinkingAddiction
• Brief Advice/Intervention– Shown to decrease drinking and adverse health
outcomes for non dependent individuals
– Two components:• Advice
• Link drinking to health
• PCMHI staff– Provide training
– Provide Brief interventions
– Assess for comorbidities
Brief Interventions – Heavy Drinking Integrating treatment for addiction
The BHL Model
• Stepped Care Approach
• Strong ties to mental health supervision
• Initial decisions and prescribing in primary care
• Assessment based
• Tracking important – need informatics support
• Emphasis on patient self-management support
• Behavioral Health Provider – facilitates communication and education of team
• Offer telephone contacts – Much appreciated by patients
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• Provider: BHS – nurse, psychologist, SW
• BHS meets with patient for 18 sessions over 6 months either in person or by telephone
• Collaborates with PCP to:– Increase motivation to abstain
– Be supportive and optimistic
– Encourage naltrexone
– Encourage AA attendance
– Provide education (health risks and detrimental outcomes)
Alcohol Care Management -
DependenceDrinking Outcomes
0
10
20
30
40
50
60
70
Su
bje
cts
en
ga
ge
d i
n t
rea
tme
nt
(%)
Alcohol Care
Management
Specialty Addiction care
Relapse to heavy drinking
57
0
10
20
30
40
50
60
Pe
rce
nt
da
ys
of
he
av
y d
rin
kin
g
Alcohol Care
Management
Specialty Addiction care
Tobacco Use Disorder Treatment
• No contraindications for NRT (ICU, CVD, pregnancy)
• Patients may smoke while using the patch
• Gradual replacement of cigarettes may work better than fixed quit date
• Combination NRT beats varenicline (Surgeon General Report on Tobacco, 2008)
• Need to give enough of NRT (2-4 mg per cigarette)
• Many patients need long term NRT (up to 6 months or longer)
• Women metabolize nicotine faster – need higher doses
Nicotine Replacement Treatment
Nicotine Levels Obtained by Various Forms of
Replacement
Pre-Cessation NRT
• Meta-analysis (2008): Effectiveness of and abstinence rates for
smokers not willing to quit (but willing to change their smoking
patterns or reduce their smoking) after receiving NRT compared
to placebo (n = 5 studies)
• Placebo 3.6 % (OR1)
• Nicotine replacement (gum, inhaler,or patch)
• 8.4% (5.9–12.0) (OR 2.2)
• www.surgeongeneral.gov/tobacco/gdlnrefs.htm
• www.cochrane.org
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Treatment of Tobacco Dependence with
Antidepressants
�Bupropion (36 trials, N = 11,140, risk ratio [RR] 1.69; 95% confidence interval [CI] 1.53 to 1.85) and nortriptyline (six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) both significantly increased long term cessation
� From the available data bupropion and nortriptyline appear to be equally effective and of similar efficacy to nicotine replacement therapy. The mode of action of bupropion and nortriptyline is independent of their antidepressant effect.
�SSRIs not effective, MAOIs (moclobemide, selegiline) and venlafaxine (SNRI) not effective
Treatment of Tobacco Dependence with
Varenicline (Partial Nicotinic Agonist)
• RR for continuous abstinence at six months for
varenicline vs placebo was 2.33 (95% confidence
interval [CI] 1.95 to 2.80).
• The pooled RR for varenicline versus bupropion at one
year was 1.52 (95% CI 1.22 to 1.88).
• The RR for varenicline versus NRT at one year was 1.31
(95% CI 1.01 to 1.71)
Varenicline vs.Bupropion
• Comparable in efficacy (a bit higher with varenicline)
• Agonist (?) and partial agonist on nicotinic receptor
• 2008 FDA suicidal warning on both: 90% of suicides on varenicline, 7% on bupropion and 3% on NRT (Moore,Tet al,2011)
• Varenicline may exacerbate CVD (FDA, 2011) but 2012 meta-analysis does not confirm it (Prochaska,J et al, 2012)
• Varenicline is contraindicated in pilots and traffic controllers (FAA)
• Both can be safely used in combination (Ebbert,J et al, 2008)
Cannabis: Clinical Issues
• 60 cannabinoids and cannabinoid-antagonists, one of them is THC
• Associated with early onset of psychosis (Large,M et all, 2011), may be causal
• Causes neuropsych decline (Meier,M et al,2012); amotivational syndrome (1970-1980s); lower educational attainment; lower income (Gruber,A et al,2003); lower life satisfaction (Fergusson,D et al, 2008)
• Respiratory effects comparable to tobacco (Moore, B et al, 2005), more carcinogens
• Use declines with age
Cannabis: Treatment
• No FDA approved meds
• Oral THC 10 mg 5 times daily and Divalproex 1500 mg daily (Haney, M et al, 2004)
• Dronabinol (Levin,F et al,2008)
• Gabapentin 1200 mg daily (Mason,B et al, 2012)
• Mirtazapine 15-45 mg nightly (Benyamina,A 2008)
• NAC (N-Acetylcysteine) : 1200 mg twice daily for 8 weeks and contingency management – beats placebo in negative urines OR 2.4 (Gray, K et al, 2012)
Cannabis: Clinical Pearls
• Rimonabant (CB 1 blocker) off the market
• Medical marijuana
• Decriminalization vs. legalization debate
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Opiate relapse prevention medications
Relapse prevention
–Methadone
–Buprenorphine
–Naltrexone
What is goal of pharmacological treatment?
The Ideal Medication
– Stops withdrawal
– Reduces craving
– Blocks the high from abused drugs
Methadone Maintenance
• Stops withdrawal
• Reduces craving
• Blocks the high from heroin
• Saves lives
Opiate relapse prevention medications
0
100
AD
MIS
SIO
N
Pre- | 1st Year | 2nd Year | 3rd Year | 4th YearAdmission
*
*
Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991
Methadone Maintenance Treatment is Effective
Problems with Methadone
•Methadone is a full opiate agonist
•Strict federal state and local controls
•Limited to methadone clinics
•Too little availability
Buprenorphine
• Partial mu opiate agonist, kappa antagonist
• Parenteral analgesic (Buprenex®)
• Available for opiate dependence since 2002
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Opiate relapse prevention medications
Buprenorphine Is As Effective as Methadone
Johnson et al. N Engl J Med. 2000;343(18):1290-7.
The Advantage of Buprenorphine
•Not improved efficacy but increased availability
•Buprenorphine is available for office use
Opiate relapse prevention medications
• Naltrexone
– Blocks opiate receptors
– Compliance impacts effectiveness
– It does not stop withdrawal
– Its anti-craving effect is weak
– Very effective in certain populations
Opiate relapse prevention medications
• 250 patients
• 6 month trial
• Double blind placebo controlled
• 380 mg extended release naltrexone monthly
Krupitsky et al. Lancet 2011; 377: 1506-13
Extended release naltrexone in Russia
Response ProfileCumulative % of Participants at Each Rate of Weekly
Confirmed Abstinence: XR-NTX 380 mg vs. Placebo
� Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 (35.7%)
of subjects in the XR-NTX group versus 28 (22.6%) subjects in placebo group (P=0.0224).
Cocaine: Treatment
• No FDA approved meds
• Disulfiram (250 mg daily) was effective in four trials (Carroll,Ket al, 2004) , not effective in one (Olivetto,A et al, 2011)
• Modafinil (200-400 mg daily) decreased cocaine intake in one controlled clinical trial (Dackis,C et al,2005) but not in a second larger trial (Anderson,A et al, 2009)
• Anticonvulsants are effective:
– topiramate (200 mg daily) (Kampman,K 2004), tiagabine(12 mg or 24 mg daily) (Gonzales, 2007), and vigabatrin (3 g/day) (Brodie, 2009)
– Gabapentin (1800 to 3200 mg/day) not effective (Brodie,2009)
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Cocaine: Treatment
• Citalopram 10 mg daily (Moeller,F et al,2007)
• Ondansetron 4 mg twice daily (Johnson,B et al,2006)
• Agonist substitution with amphetamines (Mooney et al,2009; Shearer,J2008)
• Bupropion 300 g daily with contingency management (Poling,J 2006)
• Naltrexone 100 mg daily (Schmitz,J et al,2009; Pettinati,H et al, 2008; Schmitz,J et al, 2003, Hersh D, 1998)
• Buprenorphine/Naloxone 16-32 mg daily (Montoya,I et al,2004)
• Beta-blockers (Propranolol) reduces cravings (Leri, 2002),reinforcing
effects (Sofuoglu, 2000), withdrawal (Kampman,2001)
• Cocaine vaccine
• Acupuncture, herbal remedies – not effective