Update Substance Abuse Treatment

Treatment of Substance Dependence William R. Yates, M.D. Professor of Research, OU-Tulsa Research Psychiatrist, Laureate

Disclosure 

Research Funding • Takeda Pharmaceuticals • Forest Laboratories

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Consultant • Forest Laboratories

Psychopharmacology Options 

Alcohol Dependence • • •

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Acamprosate Naltrexone Topiramate

Opiate Dependence • Buprenorphine

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Benzodiazepines Dependence • Gabapentin and slow tapers

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Nicotine Dependence • Nicotine replacement • Bupropion • Varenicline

Acamprosate 

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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 

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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   

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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 

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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 Plac/MM/CBI

68 66 64 62 60

Abstinence rates

Medical Management 

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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 

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Asn40 & asp40 genotypes Naltrexone response limited to those with asnp40 gentotype Anton et al, Arch Gen Psych 65:135, 2008

90 80 70 60 50

asn40 asp40

40 30 20 10 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 Topiramate

40 30 20 10 0 2 wks

4 wks

8 wks

14 wks

Adverse Events 50 45 40 35 30 Placebo Topiramate

25 20 15 10 5 0

Paresthes

Taste

Anorexia

Cog diff

Drug Addiction Treatment Act  

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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 

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Addiction subspecialty certification from ABPN, ASIM or other body Or complete 8 hour course • www.buprenorphinecme.com • 8 hour web-based course/$175

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Ability to appropriately refer for psychosocial addiction treatment Limited to 30 patients Requires approval letter from SAMHSA

Suboxone 

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First opioid approved for outpatient treatment opioid dependence Contains: • Buprenorpine-partial opioid agonist • Naloxone-opioid antagonist

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Buprenorphine binds tightly to opioid receptor with partial agonist effectreduce 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      

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Symptom Abdom. cramps Diarrhea Insomnia Muscle aches Hypertension

Treatment Bentyl Lomotil Trazodone NSAID Clonidine

Source: Donaher, AFP, 73:1573, 2006

Quetiapine & Opioid Withdrawal 

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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.

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Local Internists: • William Yarborough, M.D. OU Internal Medicine

Alprazolam Dependence 

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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 

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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 

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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 Nicotine Nicotine Nicotine

gum patches inhaler-prescription nasal spray-prescription

• Rapid blood levels • May be more effective for severely dependent smoker

Bupropion  

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Zyban 300 mg per day Contraindicated in seizure disorder or eating disorders Used in conjunction with behavioral program www.cancer.org

40 35 30 25 Placebo 150 mg 300 mg

20 15 10 5 0

7 weeks

12 weeks

Varenicline (Chantix)   

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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 Placebo

15 10 5 0 Gonzales

Jorenby

Genotype & Bupropion Response 35 30 25 20

Bupropion Placebo

15 10 5 0

A2/A2

Other

Cost Issues/Barriers Drug Acamprosate Naltrexone

Monthly Cost $135 $250

Topiramate

$215

Gabapentin

$90 (#90 600 mg caps)

Suboxone

$250

Bupropion SR Varenicline

$200 (generic $70) $125