Transcript Section 33_Addiction Medications 1_61 slides

Section 33:
Addiction 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
Alcohol and
Benzodiazepines
3
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)

4
Risky Drinking Levels
(for chronic harm)
5
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
6
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.
7
Pharmacokinetics
5 minutes
to affect
brain
2% excreted
unchanged in
sweat, breath &
urine
• Rapidly absorbed into blood by
stomach (20%) and small intestine (80%)
• Metabolised by liver (95–99%)
alcohol
acetaldehyde
acid & H2O
CO2
acetic
• Distributed in body fluids (not fat)
• 1 standard drink per hour raises
by approx. 0.01–0.03 g%.
BAC
8
Alcohol
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 >70 grams per day
 Thiamine deficiency leads to:
 Wernicke’s encephalopathy
 Korsakoff’s psychosis
 Frontal lobe syndrome
 Cerebellar degeneration
 Trauma
12
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 patient’s:
•
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 Reduce the risk of:
or cutting out:
• liver disease
•
•
•
•
•
•
•
save money
be less depressed
lose weight
less hassles for family
have more energy
sleep better
better physical shape
•
•
•
•
•
•
cancer
brain damage
high blood pressure
accidents
injury
legal problems
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Withdrawal
Usually occurs 6–24
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 (2000–2003)
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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:


patient’s 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 < 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 3–6
months
Best results with supervised ingestion &
contingency management strategies
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VIVITROL
A Brief Clinical Overview
Comprehensive Alcohol Dependence Treatment
Psychosocial Treatment and Medication
Cortex
Role:
• Decision making
• Thinking
• Reasoning
• Rationalizing
– Psychosocial treatments
– 12-step fellowships
– Faith-based support
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Limbic Region
Role:
• Drive generation
– VIVITROL
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Oral Naltrexone Discontinuation Rates
US Department of
Kranzler et al., Addiction 20084
Health and Human Services/SAMHSA study (2004)1

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
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1. Harris KM, et al. Psychiatr Serv. 2004;55:221.
2. Hermos JA, et al. Alcohol Clin Exp Res. 2004;28:1229-1235.
3. Un H, Addiction Health Services Research Conference, Boston 2008
4. Kranzler HR, et al. Addiction. 2008:103(11):1801-1808.
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Medications for Alcohol Dependence
Antabuse®
ReVia®
Campral®
VIVITROL®
(disulfiram)1
(naltrexone)2
(acamprosate)3
(naltrexone for
extended-release
injectable suspension)4
30 tabs/month*
(1 tab/day)
30 tabs/month*
(1 tab/day)
180 tabs/month*
(2 tabs, 3x/day)
1/month
1951
1994
2004
2006
*Based on a month with 30 days.
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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.
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What is 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




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1. VIVITROL Full Prescribing Information. Alkermes, Inc.
2. 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.
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VIVITROL[full prescribing information]. Cambridge, MA: Alkermes, Inc; May 2009.
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Opioid Receptors
and Alcohol Dependence
1.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210.
2. Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003:101-118.
30
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VIVITROL: A Targeted Approach
The mechanism by which VIVITROL exerts its
effects in alcohol-dependent patients is not
entirely understood.
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1. VIVITROL full Prescribing Information. Alkermes, Inc.
2. Oswald LM, et al. PhysiolBehav. 2004;81:339-358.
3.Kenna GA, et al. Am J Health Syst Pharm. 2004;61:2272-2279.
4.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210.
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VIVITROL Eliminates Daily
Adherence 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 ensures
that the patient receives the medication as directed

“…addressing patient adherence systematically will
2
maximize the effectiveness of these medications.”
–Updated NIAAA Clinician’s Guide
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1. Dean RL. Front Biosci. 2005;10:643-655.
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 (n=209)
Counseling* with VIVITROL (n=205)
*The counseling used with all subjects was BRENDA, a low-intensity intervention designed to facilitate direct feedback of alcoholrelated 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.
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1. Ciraulo D et al. J Clin Psychiatry. 2008;69(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†
Baseline
(n=56)
Counseling with
PLACEBO
(n=28)
Counseling with
VIVITROL (n=28)
• 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
.
34
1.
O’Malley SS et al. J ClinPsychopharmacol. 2007;27(5):507-512.
2.
Drug and Alcohol Services Information System. The DASIS report: discharges from detoxification: 2000.
http://oas.samhsa.gov/2K4/detoxDischarges/detoxDischarges.pdf. Published July 9, 2004. Accessed
January 23, 2008.
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VIVITROL Sustained Abstinence1
VIVITROL prolonged initial abstinence
VIVITROL maintained 6-month abstinence
32%
11%
Nearly three
times as
many
patients
remained
abstinent
• 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.
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1. O’Malley SS, et al. J ClinPsychopharm. 2007;27:507-512.
35
VIVITROL Sustained
Reduction in Heavy Drinking
Among patients receiving VIVITROL or placebo in the 6-month trial
Data on file. Alkermes, Inc.
36
36
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 6month study
 Sustained reduction in heavy drinking days through
18 months
 Substantial reduction in holiday drinking
1. O’Malley SS, et al. J ClinPsychopharmacol. 2007;27:507-512.
2. VIVITROL Full Prescribing Information. Alkermes, Inc.
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Safety Profile
38

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
1.
2.
VIVITROL Full Prescribing Information. Alkermes, Inc.
Garbutt JC, et al. JAMA. 2005;293:1617-1625.
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Most Common Adverse Events
Occurring in >10% 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
*Injection site reaction (ISR) included tenderness, induration, pain,
Abdominal
pain The dropout rate due to ISR11was 3%.
8
and pruritus.
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Pharyngitis
VIVITROL Full Prescribing Information. Alkermes, Inc.
11
11
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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
administered
by 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.
40
Epidermis
Dermis
Adipose
Muscle
VIVITROL Full Prescribing Information. Alkermes, Inc.
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Questions?
Comments?
41
Benzodiazepines
“Benzodiazepines:
the opium of the masses”
Malcolm Lader, Neuroscience, 1978
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 >70 years
 Night time use tends to increase with age
 58% of current users report daily use for >6 months.
44
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.
45
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.
46
Metabolism
in the liver – mostly oxidative
transformation prior to conjugation with
glucuronic acid for urinary excretion
 Metabolised
 Elimination
half life (drug & active
metabolites) ranges from 8 – >60 hours, if
short half life & no active metabolites
rapidly attains steady state with minimal
accumulation.
47
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
Short term:

Sedation

Anxiety relief

Anticonvulsant properties

Can usually attend daily
business
(though should not drive in first
2 weeks of treatment).
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.
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Drug + Alcohol Interactions

CNS depressants
e.g. Benzodiazepines
Confusion, depressed
respiration

Antipsychotics,
antidepressants
Decreased metabolism,
toxicity & CNS depression

Opioid analgesics,
antihistamines (some)
CNS depression

Hypoglycaemics
(chlorpropamide),
metronidazole,
cephalosporins (some)
Facial flushing, headache
50
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.
51
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.
52
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.
53
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.
54
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.
55
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.
56
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.
57
Withdrawal Management

Obtain an accurate consumption history

Calculate diazepam equivalent and substitute. Reduce gradually
over 6–8 weeks
(or longer e.g. 3–4 months)

Reduce dose by a fixed rate at weekly intervals, (usually 10–20%
initially, then 5–10%/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
1–2 weeks, or increased before reduction resumed

Provide support, not pharmacological alternatives for conditions
such as insomnia and anxiety.
58
Inpatient Withdrawal
Inpatient withdrawal management is necessary if
the patient:

is using > 50 mg diazepam equivalent for >14 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?
61