Pharmacological Treatment of Addictive Disorders

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Pharmacological Treatment of Addictive Disorders

• Larissa Mooney, M.D.
• Assistant Professor of Psychiatry
• UCLA Integrated Substance Abuse Programs

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Objectives

• Introduction to medication treatment approaches
  for addictive disorders
• Pharmacological treatment options within drug
  classes
• Alcohol
• Opioids
• Stimulants
• Nicotine
• Clinical implications of co-occurring disorders

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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

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Addiction Risk Factors
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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

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Reward pathway -- mesolimbic dopamine system
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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

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Medications for Alcohol Dependence

• FDA-Approved
• Disulfuram (Antabuse)
• PO naltrexone (Revia)
• IM naltrexone (Vivitrol)
• Acamprosate (Campral)
• Non-FDA-approved
• Topiramate (Topamax)
• Ondansetron (Zofran)
• Baclofen

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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

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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

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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

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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

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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

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Acamprosate (Campral)

• Start post-detox (ideal)
• Side effects diarrhea, abdominal discomfort
• Results increased time to relapse, increased
  total abstinence, reduced drinking days

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Clinical Case 1

• 42 y.o. female who lives with her mother and 12
  y.o. son
• Reports daily use of alcohol and occasional use
  of other substances
• Mother has found hidden bottles of vodka
• Reports feeling tired, depressed, anxious, and
  difficulty motivating to do anything
• Reports nightmares and difficulty sleeping at
  night related to trauma (h/o sexual abuse)
• Admits to drinking or taking a pill to help her
  sleep

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Evaluation and Management

• What further evaluation and workup would you
  recommend?
• What is the differential diagnosis?
• What medications would you consider?

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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

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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

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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

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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

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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

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Buprenorphine Formulations

• Sublingual administration
• Subutex (Buprenorphine)
• -2mg, 8mg
• Suboxone (41 Bupnaloxone)
• -2mg/0.5 mg , 8mg/2mg
• Dose 2mg-32mg/day

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Buprenorphine Pharmacological Characteristics

• Partial Agonist (ceiling effect)
• -less euphoria
• -safer in overdose
• High Receptor Affinity
• -long duration of action
• -1st dose given during withdrawal

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Clinical Case 2

• 34 y/o female with 3-year history of Vicodin use
• Using 10-12 pills/day for back pain suffered in
  an automobile accident
• No history of heroin or other opioid use
• Sometimes takes more than prescribed by her
  physician, but would like to stop taking all
  medications
• Employed, lives with her husband and two
  children, and has private insurance

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Evaluation and Management

• What further evaluation would you recommend?
• What treatment options would you consider?

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Clinical Case 3

• 18 y/o unemployed male with a two year history of
  intravenous heroin use
• Criminal convictions for shoplifting
• Has attempted outpatient detox on two previous
  occasions most recent period of sobriety lasted
  4 months
• Lives with his parents who are unaware of his
  dependence
• Reports that he has done well on methadone though
  has difficulty obtaining the funds to remain in
  treatment

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Stimulants
CRACK
COCAINE
METHAMPHETAMINE
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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

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Medications Considered for Cocaine

• Negative Results /Under Consideration
• Desipramine Modafinil
• Amantadine Disulfuram
• Gabapentin Propanolol (WD)
• Bupropion Topiramate
• Aripiprazole Baclofen
• TA-CD Vaccine
• DHEA

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Medications considered for Methamphetamine

• Negative Results /Under Consideration
• Imipramine Bupropion
• Desipramine Modafinil
• Tyrosine Topirimate
• Ondansetron Disulfiram
• Fluoxetine Lobeline
• Aripiprazole Gabapentin
• Sertraline

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Clinical Case 4

• 21 y/o marginally-housed male with a history of
  bipolar D/O and methamphetamine dependence
• History of prior psychiatric admissions, suicide
  attempt three years ago, and prior treatment with
  lamictal and depakote currently off medications
  
• Previously employed in entertainment industry
• Attending a mandated 3-day/wk outpatient drug
  treatment program after receiving a citation for
  solicitation of sex and arrest for DWI.
• After 2 weeks of nonattendance, currently reports
  insomnia, racing thoughts, and intermittent AH
• Has visible excoriations on face described
  episodes of picking due to sensations of
  pebbles under his skin

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Evaluation and Management

• What further evaluation and workup would you
  recommend?
• What is the differential diagnosis?
• What treatment options would you consider?

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FDA-Approved Meds Lacking

• There are no FDA-approved medications for the
  following addictive disorders
• Cocaine
• Methamphetamine
• Marijuana
• Pathological Gambling
• Sexual Addiction
• Compulsive shopping

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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

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Clinical Management of CODs

• Individualize and integrate treatment for CODs
  whenever possible
• Consider random drug testing
• Consider need for higher level of care
• Consult addiction medicine specialist if
  necessary

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Medication Management in COD

• Ambivalence is common re use of meds in patients
  with SUDs.
• Q When to initiate pharmacotherapy when
  diagnosis is unclear?
• With psychosis, moderate to severe depression, or
  mania, treat sooner
• Strategies include
• -Verbalize clear expectations re medication
  outcomes
• -Assume potential for misuse and drug
  interactions
• -Schedule frequent follow-ups

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Medication Management in COD

• For patients with anxiety d/os 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

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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 sxs, addictive d/os, and
  co-occurring d/os
• Emerging literature supports use of meds in
  patients with SUDs and psychiatric comorbidity

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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

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Nicotine Patch

• OTC
• Dosing 7, 14, and 21 mg
• gt 10 cigs/day 21 mg
• lt 10 cigs/day 14 mg
• 24 or 16 hour dosing
• Stop smoking at onset
• Side effects skin reaction, insomnia

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Nicotine Gum

• OTC
• 2mg if lt 25 cigs/day
• 4mg if gt 25 cigs/day
• Use q 1-2 h
• Park and chew method
• Slow, buccal absorption
• Avoid eating/drinking
• Side effects mouth/throat soreness

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Nicotine Lozenge

• OTC
• 2mg if 1st cigarette gt 30 min after waking
• 4mg if 1st cigarette lt 30 min after waking
• Up to 20 lozenges/day
• More discrete than gum

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Bupropion SR (Zyban)

• Dose 150 mg PO bid
• -if lt 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

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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

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References

• Anton RF, OMalley SS, Ciraulo DA, Cisoler RA,
  Couper D, Donovan DM, et al., 2006. Combined
  pharmacotherapies and behavioral interventions
  for alcohol dependence the COMBINE study. JAMA
  295(17)2003-17.
• Dackis CA, Kampman KM, Lynch KG, Pettinati HM,
  OBrien, CP, 2005. A double-blind,
  placebo-controlled trial of modafinil for cocaine
  dependence. Neuropsychopharmacol 30205-11.
• Elkashef A, Vocci F, Hanson G, White J, Wickes W,
  Tiihonen J, 2008. Pharmacotherapy of
  methamphetamine addiction an update. Subst Abus
  29(3)31-49.
• Garbutt JC, 2009. The state of pharmacotherapy
  for the treatment of alcohol dependence. J Subst
  Abuse Treat 36(1) S15-23.

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References

• Garbutt JC, Kranzler HR, OMalley SS, Gastfriend
  DR, Pettinati HM, Loewy JW, et al., 2005.
  Efficacy and tolerability of long-acting
  injectable naltrexone for alcohol dependence a
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  Neuropharmacol 47 Suppl 1324-44.
• Newton TF, Roache JD, De La Garza R 2nd, Fong T,
  Wallace CL, Li SH, et al., 2006. Bupropion
  reduces methamphetamine-induced subjective
  effects and cue-induced craving.
  Neuropsychopharmacol 31(7)1537-44.
• Vigezzi P, Guglielmino L, Marzorati P, Silenzio
  R, DeChiara M, Corrado F, et al., 2006.
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• Vocci FJ, Acri J, and Elkashef A, 2005.
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  1432-40.

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Thank you!

• Larissa Mooney, M.D.
• UCLA Integrated Substance Abuse Programs
• lmooney_at_mednet.ucla.edu