Section 33: Addiction Medications

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Section 33Addiction Medications

• Richard A. Rawson, Ph.D., Professor
• Semel Institute for Neuroscience and Human
  Behavior
• David Geffen School of Medicine
• University of California at Los Angeles

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Alcohol and Benzodiazepines
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Alcohol

• Still the most popular drug
• In some societies over 80 of population drinks
• 8 drink daily, peak in males 60 yrs (23). 40
  drink weekly
• At-risk drinking now defined as
• risks of harm in the long term (chronic harm)
• risks of harm in the short term (acute harm)

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Risky Drinking Levels
(for chronic harm)
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Predisposing Factors for High Risk Drinking

• Family history of alcohol problems
• Childhood problem behaviours related to impulse
  control
• Poor coping responses in the face of stressful
  life events
• Depression, divorce or separation
• Drinking partner
• Working in a male dominated environment

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Alcohol Effects on Brain

• No single receptor - interacts with and alters
  function of many different cellular components
• Primary targets are GABA, NMDA glutamate,
  serotonin and ATP receptors
• Stimulates dopamine and opioid systems
• Effects of chronic consumption are opposite to
  acute because of homeostatic compensation.

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Pharmacokinetics
2 excreted unchanged in sweat, breath urine

• Rapidly absorbed into blood by stomach (20)
  and small intestine (80)

• Distributed in body fluids (not fat)

• 1 standard drink per hour raises BAC by approx.
  0.010.03 g.

Alcohol
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Effects of Alcohol Intoxication
.01-.02 Clearing of head
.02-.05 Mild throbbing rear of head, slightly dizzy, talkative, euphoria, confidence, clumsy, flippant remarks
.06-1.0 ? inhibitions, ? talkativeness, ? motor co-ord, ? pulse, stagger, loud singing!
0.2-0.3 Poor judgement, nausea, vomiting
0.3-0.4 Blackout, memory loss, emotionally labile
0.4 Stupor, breathing reflex threatened, deep anaesthesia, death
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Binge Drinking

• Binge drinking can lead to
• increased risk taking
• poor judgment/decision making
• misadventure/accidents
• increased risky sexual behaviour
• increased violence
• suicide

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Harms Associated with High-risk Alcohol Use

• Hypertension, CVA
• Cardiomyopathy
• Peripheral neuropathy
• Impotence
• Cirrhosis and hepatic or bowel carcinomas
• Cancer of lips, mouth, throat and esophagus
• Cancer of breast
• Fetal alcohol syndrome

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Alcohol-related Brain Injury

• Cognitive impairment may result from consumption
  levels of gt70 grams per day
• Thiamine deficiency leads to
• Wernickes encephalopathy
• Korsakoffs psychosis
• Frontal lobe syndrome
• Cerebellar degeneration
• Trauma

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Interventions and Treatment for Alcohol-related
Problems

• Screening and Assessment ? individualised
  interventions
• Brief intervention and Harm Reduction strategies
• Withdrawal management
• Relapse prevention / goal setting strategies
• Controlled drinking programs
• Residential programs
• Self-help groups

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Brief Intervention

• Consider the patients
• perspective on drinking
• attitudes to drinking goals
• significant others
• short-term objectives.
• Provide
• information on standard drinks, risks, and risk
  levels
• encouragement to identify positive alternatives
  to drinking
• self-help manuals
• follow-up session

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Two Steps Towards Alcohol Brief Intervention (BI)

• 1. Screening
• E.g. the alcohol AUDIT, a 10-item questionnaire
• 2. Intervention
• Information
• Brief counselling
• Advice
• Referral (if required)

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Harm Minimizing Strategies

• Benefits of cutting down or cutting out
• save money
• be less depressed
• lose weight
• less hassles for family
• have more energy
• sleep better
• better physical shape

• Reduce the risk of
• liver disease
• cancer
• brain damage
• high blood pressure
• accidents
• injury
• legal problems

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Withdrawal

• Usually occurs 624 hours after last drink
• tremor
• anxiety and agitation
• sweating
• nausea and vomiting
• headache
• sensory disturbances - hallucinations.

• Severity depends on
• pattern, quantity and duration of use
• previous withdrawal history
• patient expectations
• physical and psychological wellbeing of the
  patient (illness or injury)
• other drug use/dependence
• the setting in which withdrawal takes place.

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deCrespigny Cusack (2003) Adapted from NSW
Health Detoxification Clinical Practice
Guidelines (20002003)
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Home-based Withdrawal

• Medications for Symptomatic Treatment

• Diazepam
• Thiamine ?100 mg daily multivitamins
• Antiemetic
• Analgesia (e.g. paracetamol)
• Antidiarrhoeal.

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Post-withdrawal Management

• Treatment options
• retain in treatment, ongoing management
• seek referral
• Considerations
• patients wants (abstinence or reduced
  consumption, remaining your patient)
• severity of problems
• Pharmacotherapies
• acamprosate
• naltrexone
• disulfiram (not PBS listed)

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Naltrexone and Acamprosate

• Effective
• Work well with variety of supportive treatments
  e.g. brief intervention, CBT, supportive group
  therapy
• Start following alcohol withdrawal proven
  efficacy where goal is abstinence, uncertain with
  goal of moderation
• No contraindication while person is still
  drinking, although efficacy uncertain
• Generally safe and well tolerated

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Clinical Guidelines

• Naltrexone 50 mg daily
• indicated especially where strong craving for
  alcohol after a priming dose
• ? likelihood of lapse progressing to relapse
• LFTs lt x3 above normal
• side effects nausea headache.

• Acamprosate 600 mg (2 tabs) tds
• indicated especially where susceptible to
  drinking cues or drinking triggered by withdrawal
  symptoms
• low potential for drug interactions
• need normal renal function
• side effects diarrhoea, headache, nausea, itch.

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Disulfiram

• Acetaldehyde dehydrogenase inhibitor 200 mg
  daily
• ? unpleasant reaction with alcohol ingestion
• Indications alcohol dependence goal of
  abstinence need for external aid to abstinence
• Controlled trials ? abstinence rate in first 36
  months
• Best results with supervised ingestion
  contingency management strategies

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VIVITROL

• A Brief Clinical Overview

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Comprehensive Alcohol Dependence Treatment

• Cortex
• Role
• Decision making
• Thinking
• Reasoning
• Rationalizing

• Psychosocial treatments
• 12-step fellowships
• Faith-based support

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Oral Naltrexone Discontinuation Rates
US Department of Health and Human
Services/SAMHSA study (2004)1
Kranzler et al., Addiction 20084

• Pharmacy claims for NTX-PO 1,4
• Guidelines recommend treatment from 3-6 months to
  2 years1
• The vast majority did not persist in refills for
  a reasonable course of treatment 1,4
• Both analyses show that approximately 50 failed
  to refill even beyond 30 days1,4
• Two additional independent studies obtained
  similar discontinuation rates2,3

• 1. Harris KM, et al. Psychiatr Serv. 200455221.
• 2. Hermos JA, et al. Alcohol Clin Exp Res.
  2004281229-1235.
• 3. Un H, Addiction Health Services Research
  Conference, Boston 2008
• 4. Kranzler HR, et al. Addiction.
  2008103(11)1801-1808.

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Medications for Alcohol Dependence
1. Antabuse full Prescribing Information.
Odyssey Pharmaceuticals, Inc. 2. ReVia full
Prescribing Information. Duramed Pharmaceuticals,
Inc. 3.Campral full Prescribing Information.
Merck Santé s.a.s. 4.VIVITROLFull Prescribing
Information. Alkermes, Inc.
Based on a month with 30 days.
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What is VIVITROL?

• VIVITROL is NOT1
• Addictive
• Aversive (e.g. disulfiram)
• Euphorigenic (i.e. pleasure producing)
• VIVITROL is1
• An opioid blocker (i.e. antagonist)
• Extended-release (30 days)
• Compatible with psychosocial treatments,
  antidepressants and Alcoholics Anonymous2
• Administered by a healthcare professional
  
• (use can be monitored)

• VIVITROL Full Prescribing Information. Alkermes,
  Inc.
• Gromov, I., et al. AMERSA, Washington, DC,
  November 8, 2007.

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VIVITROL Indication

• VIVITROL is indicated for the treatment of
  alcohol dependence in patients who are able to
  abstain from alcohol in an outpatient setting
  prior to initiation of treatment with VIVITROL.
• Patients should not be actively drinking at the
  time of initial VIVITROL administration.
• Treatment with VIVITROL should be part of a
  comprehensive management program that includes
  psychosocial support.

VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
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Opioid Receptors and Alcohol Dependence

• 1.Gianoulakis C. Alcohol Health Res World.
  199822202-210.
• 2. Woodward JJ. Principles of Addiction Medicine.
  3rd ed. 2003101-118.

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VIVITROL A Targeted Approach
The mechanism by which VIVITROL exerts its
effects in alcohol-dependent patients is not
entirely understood.

• 1. VIVITROL full Prescribing Information.
  Alkermes, Inc.
• 2. Oswald LM, et al. PhysiolBehav.
  200481339-358.
• 3.Kenna GA, et al. Am J Health Syst Pharm.
  2004612272-2279.
• 4.Gianoulakis C. Alcohol Health Res World.
  199822202-210.

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VIVITROL Eliminates DailyAdherence Decisions1

• VIVITROL utilizes a delivery system that
• Provides a month of medication in a single dose
• Adherence to any treatment program is essential
  for successful outcomes
• Administration by a healthcare provider
  ensuresthat the patient receives the medication
  as directed

addressing patient adherence systematically
will maximize the effectiveness of these
medications.2 Updated NIAAA Clinicians Guide
1. Dean RL. Front Biosci. 200510643-655. 2.
NIAAA. 2007. NIH publication 07-3769.
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VIVITROL Provided Rapid Results
When VIVITROL was added to counseling Reductions
were rapid1

• Post hoc analysis of a randomized, double-blind,
  placebo-controlled study. Patients had 2 heavy
  drinking episodes/week during the month prior to
  screening. Inclusion did not require
  detoxification, abstinence or intent to abstain
  from alcohol1
• VIVITROL is indicated for the treatment of
  alcohol dependence in patients who are able to
  abstain from alcohol in an outpatient setting
  prior to initiation of
  treatment with VIVITROL. Patients should not be
  actively drinking at the
  time of initial VIVITROL administration2
• Approval of VIVITROL was based on a subset of
  patients who were able to abstain for 7 days
  prior to treatment initiation1

Counseling with PLACEBO (n209)
Counseling with VIVITROL (n205)
The counseling used with all subjects was
BRENDA, a low-intensity intervention designed to
facilitate direct feedback of alcohol-related
consequences. BRENDA consists of biopsychosocial
assessment, reporting the assessment to the
patient, an empathetic approach, identified and
stated patient needs, direct advice regarding
drinking behavior, and assessment of treatment
adherence.

1. Ciraulo D et al. J Clin Psychiatry.
   200869(2)190-195.
2. VIVITROL Full Prescribing Information.
   Cambridge, MA. Alkermes, Inc. 2008.

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VIVITROL Significantly Reduces Drinking
Days1,2
Reductions were substantial1
Counseling with VIVITROL (n28)
Counseling with PLACEBO (n28)
Baseline (n56)

• According to the SAMHSA/CSAT, 4 days is the US
  norm (median duration) for detoxification2
• Approval of VIVITROL was based on a subset of
  patients who were able to abstain for 7 days
  prior to treatment initiation1
• These results are from a post hoc subgroup
  analysis of a 6-month, multicenter, double-blind,
  placebo-controlled clinical trial of alcohol
  dependent patients. This subset analysis
  evaluated patients who were abstinent for 4 or
  more days prior to treatment initiation1

• OMalley SS et al. J ClinPsychopharmacol.
  200727(5)507-512.
• Drug and Alcohol Services Information System. The
  DASIS report discharges from detoxification
  2000. http//oas.samhsa.gov/2K4/detoxDischarges/de
  toxDischarges.pdf. Published July 9, 2004.
  Accessed January 23, 2008.

.
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VIVITROL Sustained Abstinence1
VIVITROL prolonged initial abstinence

• Results are from a post hoc subgroup analysis
  of a 6-month multicenter, double-blind,
• placebo controlled clinical trial of alcohol
  dependents who were abstinent for 4 or more days
• prior to treatment initiation.
• The approval of VIVITROL was based on a subset
  of patients who were able to
  
• abstain for 7 days prior to treatment
  initiation.

1. OMalley SS, et al. J ClinPsychopharm.
200727507-512.
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VIVITROL Sustained Reduction in Heavy Drinking
Among patients receiving VIVITROL or placebo in
the 6-month trial
Data on file. Alkermes, Inc.
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Summary of Efficacy Results1,2
In clients who were abstinent during the week
before treatment initiation, VIVITROL and
counseling, as compared to placebo and
counseling, provided

• Rapid results
• Substantial reduction in drinking days
• Prolonged initial abstinence
• Sustained continuous abstinence through the
  6-month study
• Sustained reduction in heavy drinking days
  through 18 months
• Substantial reduction in holiday drinking

1. OMalley SS, et al. J ClinPsychopharmacol.
200727507-512. 2. VIVITROL Full Prescribing
Information. Alkermes, Inc.
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Safety Profile

• During clinical trials
• Treatment with extended-release naltrexone was
  generally well tolerated
• Safety profile is based on more than 900 patients
  
• Adverse events in the majority of patients were
  mild or moderate
• Discontinuation rates due to adverse events
• 9 in patients treated with VIVITROL
• 7 in patients treated with placebo
• The safety profile of patients treated with
  VIVITROL concomitantly with antidepressants was
  similar to that of patients taking VIVITROL
  without antidepressants1
• No significant increase in mean AST or ALT
  levels2

• VIVITROL Full Prescribing Information. Alkermes,
  Inc.
• Garbutt JC, et al. JAMA. 20052931617-1625.

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Most Common Adverse Events
Occurring in gt10 of patients
VIVITROL Placebo
Injection site reaction 69 50
Nausea 33 11
Headache 25 18
Asthenic conditions 23 12
Anorexia, appetite decreased NOS, appetite disorder NOS 14 3
Vomiting 14 6
Insomnia, sleep disorder 14 12
Dizziness 13 4
Diarrhea 13 10
Anxiety 12 8
Abdominal pain 11 8
Pharyngitis 11 11
Injection site reaction (ISR) included
tenderness, induration, pain, and pruritus.
The dropout rate due to ISR was 3.
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VIVITROL Full Prescribing Information. Alkermes,
Inc.
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Dosage and Administration

• VIVITROL is given as an intramuscular (IM)
  gluteal injection every 4 weeks or once a month
• VIVITROL should not be given subcutaneously or in
  the adipose layer
• VIVITROL must not be administered intravenously
• VIVITROL should be administeredby a healthcare
  professional, into alternating buttocks each
  month
• VIVITROL should be injected into the upper outer
  quadrant of the buttock, deep into the muscle-not
  the adipose.

VIVITROL Full Prescribing Information.
Alkermes, Inc.
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Questions? Comments?
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Benzodiazepines

• Benzodiazepinesthe opium of the masses
• Malcolm Lader, Neuroscience, 1978

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Medical Indications for Use

• Anxiolytic chronic / phobic anxiety panic
  attacks
• Sedative and hypnotic sleep disturbance
  anaesthesia / premed
• Anticonvulsant status epilepticus, myoclonic
  photic epilepsy
• Muscle relaxant muscle spasm / spasticity
• Alcohol withdrawal

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Patterns of Use

• BZDs are one of the most prescribed drugs
• 4 of all prescriptions from General
  Practitioners are for benzodiazepines (BZDs)
• Predictors for BZD prescription include
• being female
• being elderly
• being an established patient
• attending a busy doctor, or a doctor in inner
  urban area
• Over 40 of prescriptions given to people gt70
  years
• Night time use tends to increase with age
• 58 of current users report daily use for gt6
  months.

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Benzos and Long-term Use

• Long-term use is common and associated with
• altered use patterns (from night time to daytime
  use)
• excessive sedation
• cognitive impairment
• increased risk of accidents
• adverse sleep effects
• dependence and withdrawal (even at therapeutic
  doses)
• BZDs have an additive effect with alcohol / other
  CNS depressants, increasing the risk of harm
• BZDs have limited long-term efficacy.

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Pharmacodynamics

• Rapidly absorbed orally (slower rate of
  absorption IM)
• Lipid soluble - differences determine rate of
  passage through blood brain barrier i.e.
• ? lipophilic ? ? speed of onset
• Duration of action variable
• ? lipophilic ? ? duration of action due to
  distribution in adipose tissue.

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Metabolism

• Metabolised in the liver mostly oxidative
  transformation prior to conjugation with
  glucuronic acid for urinary excretion
• Elimination half life (drug active metabolites)
  ranges from 8 gt60 hours, if short half life
  no active metabolites rapidly attains steady
  state with minimal accumulation.

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Neurotransmission

• Potentiate neurotransmission mediated by GABA
  (main inhibitory neurotransmitter), therefore
  neurons are more difficult to excite
• Specific neuronal membrane receptors for BZD
  closely associated with synaptic GABA receptors
• Receptors distributed through CNS, concentrated
  in reticular formation limbic systems, also
  peripheral binding sites
• Further understanding of the effects of BZDs on
  receptor subgroups may lead to the development of
  non-sedating anxiolytic BZDs.

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Effects Low Dose

• Other effects
• Drowsiness, lethargy, fatigue
• Impaired concentration, coordination, memory
• Reduced ability to think and learn
• Emotional anaesthesia
• Clumsiness, ataxia
• Depression
• Mood swings
• Blurred vision and/or vertigo
• Light-headedness
• Nausea, constipation, dry mouth, loss of appetite.

• Short term
• Sedation
• Anxiety relief
• Anticonvulsant properties
• Can usually attend daily business (though should
  not drive in first 2 weeks of treatment).

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Drug Alcohol Interactions

• CNS depressants
• e.g. Benzodiazepines
• Antipsychotics, antidepressants
• Opioid analgesics, antihistamines (some)
• Hypoglycaemics (chlorpropamide), metronidazole,
  cephalosporins (some)

Confusion, depressed respiration Decreased
metabolism, toxicity CNS depression CNS
depression Facial flushing, headache
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Overdose

• Benzodiazepines are the most commonly implicated
  drug in overdose cases
• On their own, unlikely to cause death despite
  causing respiratory depression
• Serious / potentially fatal implications when
  used in combination with other CNS depressants.

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Overdose Response

• Overdose depresses the conscious state and
  respiratory system
• Flumazenil
• a BZD antagonist which reverses BZD overdose,
  though contraindicated outside the Emergency
  Department
• precipitates seizures in
• chronic BZD users
• pre-existing epilepsy
• tricyclic antidepressant users
• concurrent amphetamine or cocaine users.

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Assessment

• Review BZD medication
• initial reasons for use
• type of BZD, response to, and patterns of use
• side-effects reported or observed
• current / past withdrawal history and symptoms
• Obtain physical history (concurrent medical
  problems)
• Mental health history (e.g. depression)
• Other drug (and alcohol / prescription drug) use
• Discuss options
• risks of continued and prolonged use
• withdrawal potential / risks, management options.

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Dependence

• Two groups of patients are especially likely to
  develop dependence
• 1. Low dose dependence occurs among women and
  elderly prescribed low doses over long time
  periods (up to 40 experience withdrawal
  symptoms)
• 2. High dose dependence occurs among polydrug
  users.

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Withdrawal

• 40 of people on long-term therapeutic BZD doses,
  will experience withdrawal if abruptly ceased
• Symptoms occur within 2 short-acting to 7 days
  long- acting forms
• BZD withdrawal
• is not life-threatening usually protracted
• initial symptoms/problems re-emerge on cessation
• issues usually more complicated on cessation
• Seizures uncommon (unless high dose use or abrupt
  withdrawal, alcohol use)
• Two main groups of dedicated users
• prescribed (older women)
• high level, erratic polydrug use.

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Withdrawal Severity

• Severity of withdrawal is dependent on
• pattern and extent of use (duration, quantity,
  type (half-life))
• withdrawal experience (prior symptoms, success,
  complications)
• coexisting physical / mental health problems.

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3 Areas of BZD Withdrawal

• Anxiety and anxiety-related symptoms
• anxiety, panic attacks, hyperventilation, tremor
• sleep disturbance, muscle spasms, anorexia,
  weight loss
• visual disturbance, sweating
• dysphoria.
• Perceptual distortions
• hypersensitivity to stimuli
• abnormal body sensations
• depersonalisation/derealisation.
• Major events
• seizures (grand mal type)
• precipitation of psychosis.

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Withdrawal Management

• Obtain an accurate consumption history
• Calculate diazepam equivalent and substitute.
  Reduce gradually over 68 weeks (or longer e.g.
  34 months)
• Reduce dose by a fixed rate at weekly intervals,
  (usually 1020 initially, then 510/week, or
  slower when dose at 15 mg or less)
• Dose at regular times
• Regularly review and titrate dose to match
  symptoms
• If symptoms re-emerge, dose may be plateaued for
  12 weeks, or increased before reduction resumed
  
• Provide support, not pharmacological alternatives
  for conditions such as insomnia and anxiety.

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Inpatient Withdrawal

• Inpatient withdrawal management is necessary if
  the patient
• is using gt 50 mg diazepam equivalent for gt14 days
• has a history of alcohol or other drug use or
  dependence
• has concurrent medical or psychiatric problem
• has a history of withdrawal seizures
• if significant symptoms are predicted
• is in an unstable social situation
• has previous poor compliance / doubtful
  motivation
• is in concurrent methadone stabilisation.

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Drug Interactions

• BZDs either potentiate / increase effects or
  interfere with metabolism or absorption of
• alcohol
• antidepressants and antihistamines
• disulfiram, cimetidine, erythromycin
• anticonvulsants
• anticoagulants, oral diabetic agents
• cisapride.

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Questions? Comments?