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Pharmacological Treatment of Addictive Disorders. Larissa Mooney, M.D. Assistant Professor of Psychiatry UCLA Integrated Substance Abuse Programs. Objectives. Introduction to medication treatment approaches for addictive disorders Pharmacological treatment options within drug classes:

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pharmacological treatment of addictive disorders

Pharmacological Treatment of Addictive Disorders

Larissa Mooney, M.D.

Assistant Professor of Psychiatry

UCLA Integrated Substance Abuse Programs

objectives
Objectives
  • Introduction to medication treatment approaches for addictive disorders
  • Pharmacological treatment options within drug classes:
    • Alcohol
    • Opioids
    • Nicotine
    • Stimulants
  • Clinical implications of co-occurring psychiatric disorders
introduction
Introduction
  • Addiction is a chronic, relapsing brain disease characterized by compulsive use despite harmful consequences
  • Pharmacotherapy as part of multimodal treatment plan
  • Treatment approaches:
    • Medications (Bio)
    • Therapy, lifestyle changes (Psycho-Social)
  • Thorough evaluation and diagnosis essential
neurobiology of addiction
Neurobiology of Addiction
  • Reward system: mesolimbic dopamine pathway
    • Natural vs. drug rewards
    • Dopamine release: pleasure and reinforcement
  • Dopaminergic projections from ventral tegmental area (VTA) to nucleus accumbens (NA), amygdala, and prefrontal cortex (PFC)
  • Process of addiction causes dysfunctional learning and memory and maladaptive behavioral patterns
  • “Hypo-frontality”: impaired decision-making, loss of control (orbitofrontal cortex, anterior cingulate)
  • Altered neurocircuitry: relapse risk even after extended periods of abstinence
pharmacotherapy in substance use disorders
Pharmacotherapy in Substance Use Disorders
  • Treatment of withdrawal (“detox”)
  • Treatment of psychiatric symptoms or co-occurring disorders
  • Reduction of cravings and urges
  • Substitution therapy
  • Prevention
medications for alcohol dependence
Medications for Alcohol Dependence
  • FDA-Approved:
    • Disulfuram (Antabuse)
    • PO naltrexone (Revia)
    • IM naltrexone (Vivitrol)
    • Acamprosate (Campral)
  • Non-FDA-approved:
    • Topiramate (Topamax)
    • Ondansetron (Zofran)
disulfuram antabuse
Disulfuram (Antabuse)
  • FDA approved 1951
  • Dosing: 250mg-500mg qd
  • Mechanism: inhibits aldehyde dehydrogenase, causing buildup of acetaldehyde with alcohol ingestion:
    • Flushing, nausea, vomiting, dizziness, dyspnea, diaphoresis, headache, palpitations
    • In severe cases: arrhythmias, seizures, coma, cardiovascular collapse
disulfuram antabuse11
Disulfuram (Antabuse)
  • Reactions may occur 1-2 weeks after last dose
  • Caution: “hidden” alcohol in perfumes, mouthwash, cough medicines, desserts, sauces, salad dressings
  • Side effects: fatigue, headache, hepatitis, psychosis (dopamine), neuritis, rash, aftertaste
  • Most likely to benefit: highly motivated and directly observed patients
  • Neiderhofer and Staffen ’03a: increased abstinence with disulfuram in adolescent alcoholics
naltrexone revia
Naltrexone (Revia)
  • FDA approved 1994
  • Dosing: 50 mg PO qd (start at 25 mg qd)
  • Mechanism: mu-opioid antagonist
    • Decreases positive reinforcing effects
    • Decreases cue- and alcohol-induced cravings
  • Side effects: nausea, dysphoria, increased LFTs
  • Results: fewer drinking days, less alcohol consumed, decreased craving
  • Deas et al., ’05: pilot study in adolescent alcoholics
im naltrexone vivitrol
IM Naltrexone (Vivitrol)
  • FDA approved 2006
  • Dose: 380 mg IM q 4 weeks
  • No need for oral lead-in
  • Stop drinking 7 days prior (ideal)
  • Mechanism: opioid antagonist
  • Results: Decreased heavy drinking days, decreased frequency of drinking
acamprosate campral
FDA Approved 2004

Dose: 666mg PO tid

Renal excretion

Structural analog of amino acid taurine and GABA

Mechanism: NMDA receptor modulation

Restores GABA-glutamate balance

Blocks “negative” reinforcement

Acamprosate (Campral)
acamprosate campral15
Start post-detox (ideal)

Side effects: diarrhea, abdominal discomfort

Results: increased time to relapse, increased total abstinence, reduced drinking days

Niederhofer and Staffen ’03: increased abstinence in adolescents with AUDs relative to placebo

Acamprosate (Campral)
treating opioid dependence aims
Treating Opioid Dependence: Aims
  • Detoxification:
    • Opioid-based agonist (methadone, buprenorphine)
    • Non-opioid based (clonidine, supportive meds)
    • Antagonist-based (naltrexone: “rapid”)
  • Relapse prevention:
    • Agonist maintenance (methadone)
    • Partial agonist maintenance (buprenorphine)
    • Antagonist maintenance (naltrexone)
  • Lifestyle and behavior change
opioid detoxification
Opioid Detoxification
  • Medications used to alleviate withdrawal symptoms:

- Opioid agnonists (methadone, buprenorphine)

- Clonidine (alpha-2 agonist)

      • Dose: 0.1 mg PO tid (increase as tolerated)
      • Caution: hypotension

- Other supportive meds

      • anti-diarrheals, anti-emetics, ibuprofen, muscle relaxants, BDZs
opioid substitution goals
Opioid Substitution Goals
  • Reduce symptoms & signs of withdrawal
  • Reduce or eliminate craving
  • Block effects of illicit opioids
  • Restore normal physiology
  • Promote psychosocial rehabilitation and non-drug lifestyle
methadone clinical properties
Methadone: Clinical Properties
  • Orally active synthetic μ agonist
  • Action: CNS depressant/ Analgesic
  • Quick absorption, slow elimination, long half-life
  • Effects last 24 hours; once-daily dosing maintains constant blood level
  • Prevents withdrawal, reduces craving and use
  • Facilitates rehabilitation
  • Clinic dispensing limits availability
buprenorphine for opioid dependence
Buprenorphine for Opioid Dependence
  • FDA approved 2002, age 16+
  • Mandatory certification from DEA (100 pt. limit)
  • Mechanism: partial mu agonist
  • Office-based, expands availability
  • Analgesic properties
  • Ceiling effect
  • Lower abuse potential
  • Safer in overdose
buprenorphine formulations
Buprenorphine Formulations
  • Sublingual administration
  • Subutex (Buprenorphine)

-2mg, 8mg

  • Suboxone (4:1 Bup:naloxone)

-2mg/0.5 mg , 8mg/2mg

  • Dose: 2mg-32mg/day
buprenorphine pharmacological characteristics
Buprenorphine: Pharmacological Characteristics

Partial Agonist (ceiling effect)

  • -less euphoria
  • -safer in overdose

High Receptor Affinity

  • -long duration of action
  • -1st dose given during withdrawal
medications for nicotine dependence
Medications for Nicotine Dependence
  • FDA approved in adults:

- Nicotine replacement therapies

      • Patch, gum, lozenge, inhaler

- Bupropion SR (Zyban)

- Varenicline (Chantix)

  • Some efficacy but not FDA approved:

- Nortriptyline

- Clonidine

nicotine patch
OTC

Dosing: 7, 14, and 21 mg

> 10 cig’s/day: 21 mg

< 10 cig’s/day: 14 mg

24 or 16 hour dosing

Stop smoking at onset

Side effects: skin reaction, insomnia

Nicotine Patch
nicotine gum
OTC

2mg if < 25 cig’s/day

4mg if > 25 cig’s/day

Use q 1-2 h

“Park” and chew method

Slow, buccal absorption

Avoid eating/drinking

Side effects: mouth/throat soreness

Nicotine Gum
nicotine lozenge
OTC

2mg if 1st cigarette > 30 min after waking

4mg if 1st cigarette < 30 min after waking

Up to 20 lozenges/day

More discrete than gum

Nicotine Lozenge
bupropion sr zyban
Bupropion SR (Zyban)
  • Dose: 150 mg PO bid

-if < 90 lbs, 150 mg qd max

  • Start 5-7 days before quit date
  • Mechanism:

-NE and dopamine reuptake inhibition

-Nicotinic receptor antagonism

  • Side effects: headache, insomnia
  • Contraindications: seizures, eating disorders
  • Muramoto et al., ’07: efficacy of 300 mg dose relative to placebo in adolescents
varenicline chantix
Varenicline (Chantix)
  • Dosing: Starter Pak, Continuing Pak (0.5 mg qd to 1 mg bid) for 12 weeks
  • Start 7 days before quit date
  • Mechanism: partial nicotinic agonist
    • Attenuates withdrawal
    • Decreases Craving
  • Side effects: nausea, headache, insomnia
  • Renal clearance (primary)
  • Caution: risk of mood disturbance, suicidality
stimulants
Stimulants

COCAINE

CRACK

METHAMPHETAMINE

methamphetamine vs cocaine
Methamphetamine

synthetic

high lasts 8-24 hours

T ½: 12 hours

mechanism: both DA reuptake and release

limited medical uses

neurotoxicity

Cocaine

plant-derived

high lasts 20-30 minutes

T ½: 1 hour

mechanism: mainly DA reuptake

used medically

not directly neurotoxic

Methamphetamine vs. Cocaine
medications considered for cocaine
Medications Considered for Cocaine

Negative Results+/Under Consideration

  • Desipramine* Modafinil
  • Amantadine* Disulfuram
  • Gabapentin Propanolol (WD)
  • Bupropion* Topiramate

Baclofen

TA-CD Vaccine

medications considered for methamphetamine
Medications considered for Methamphetamine

Negative Results +/Under Consideration

  • Imipramine Bupropion
  • Desipramine Modafinil
  • Tyrosine Topirimate
  • Ondansetron Disulfiram
  • Fluoxetine Lobeline
  • Aripiprazole Gabapentin
fda approved meds lacking
FDA-Approved Meds Lacking
  • There are no FDA-approved medications for the following addictive disorders:
    • Cocaine
    • Methamphetamine
    • Marijuana
    • Pathological Gambling
    • Sexual Addiction
    • Compulsive shopping
co occurring psychiatric d o and sud in adolescents
Co-Occurring Psychiatric D/O and SUD in Adolescents
  • “Potential problems with the diagnostic process increase almost exponentially when substance use disorders and psychiatric disorders occur together.” (Schukit, 2006)
  • Perform comprehensive psychiatric evaluation including SUD screening
  • Obtain info from multiple sources
  • Have a high index of suspicion for SUD co-morbidity when patient not responding to tx
clinical management of cods
Clinical Management of CODs
  • Individualize and integrate treatment for CODs whenever possible
  • Consider developmental needs and stages
  • Consider random drug testing
  • Consider need for higher level of care
  • Consult addiction medicine specialist if necessary
medication management in cod
Medication Management in COD
  • Ambivalence is common re: use of meds in adolescents with SUDs.
  • Q: When to initiate pharmacotherapy when diagnosis is unclear?
    • With psychosis, moderate to severe depression, or mania, treat sooner
  • Strategies include:

-Communicate frequently with caregivers

-Verbalize clear expectations (re: medication outcomes, confidentiality)

-Assume potential for misuse and drug interactions

-Schedule frequent follow-ups

medication management in cod41
Medication Management in COD
  • For patients with anxiety d/o’s and SUDs:
    • Try to avoid BDZs
    • Consider: SSRIs, buspirone, mirtazapine, trazodone, low-dose quetiapine
  • For patients with ADHD and SUD, consider:
    • Atomoxetine (Strattera)
    • Bupropion SR or XL (Wellbutrin)
    • Modafinil (Provigil)
    • If stimulant necessary:
      • Long-acting formulations (e.g., Concerta)
      • Lisdexamphetamine
      • Daytrana patch
in conclusion
In Conclusion
  • Addiction is a serious, chronic and relapsing disorder, but treatments are available
  • Medications should be considered as part of a comprehensive treatment plan, addressing both disordered physiology and disrupted lives
  • Medications should be considered for treatment of: psychiatric sx’s, addictive d/o’s, and co-occurring d/o’s
  • Emerging literature supports use of meds in youth with SUDs and psychiatric comorbidity
references
References
  • Deas D, May MP, Randall C, Johnson N, and Anton R, 2005. Naltrexone treatment of adolescents: an open-label pilot study. J Child Adol Psychopharmacol 15(5):723-8.
  • Killen JD, Robinson TN, Ammerman S, Hayward C, Rogers J, Stone C, Samuels D, Levin SK, Green S, and Schatzberg AF, 2004. Randomized clinical trial of the efficacy of bupropion combined with nicotine patch in the treatment of adolescent smokers. J Consult Clin Psychol 72(4): 729-35.
  • Marsch LA, Bickel WK, Badger GJ, Stothart ME, Quesnel KJ, Stanger C, and Brooklyn J, 2005. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry 62(10): 1165.
  • Monuteaux MC, Spencer TJ, Faraone SV, Wilson AM, and Biederman J, 2007. A randomized, placebo-controlled trial of bupropion for the prevention of smoking in children and adolescents with ADHD. J Clin Psychiatry 68(7): 1094-101.
references44
References
  • Muramoto ML, Leischow SJ, Sherrill D, Matthews E, and Strayer LJ, 2007. Randomized, double-blind, placebo-controlled trial of 2 dosages of sustained-release bupropion for adolescent smoking cessation. Arch Pediatr Adolesc Med 161(11): 1068-74.
  • Newton TF, Roache JD, De La Garza R 2nd, Fong T, Wallace CL, Li SH, Elkashef A, Chiang N, and Kahn R, 2006. Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology 31(7):1537-44.
  • Niederhofer H and Staffen W, 2003a. Acamprosate and its efficacy in treating alcohol dependent adolescents. Eur Child Adolesc Psychiatry 12(3):144-8.
  • Niederhofer H and Staffen W, 2003b. Comparison of disulfuram and placebo in treatment of alcohol dependence in adolescents. Drug and Alcohol Rev 22:295-97.
  • Kreek MJ, Schlussman SD, Bart J, LaForge KS, and Butelman ER, 2004. Evolving perspectives on neurobiological research on the addictions: celebration of the 30th anniversary of NIDA. Neuropharmacology 47 Suppl 1:324-44.
thank you
Thank you!

Larissa Mooney, M.D.

UCLA Integrated Substance Abuse Programs

lmooney@mednet.ucla.edu