Naltrexone: (Vivitrol )

Naltrexone:

Injectable Formulation

Injectable

Formulation

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.

4

Opioid

Receptors

and

Alcohol

Dependence

1. VIVITROL [full prescribing information]. Cambridge, MA: Alkermes, Inc; May 2009. 2. Oswald LM et al. Physiol Behav. 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.

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

5

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 Vi it l® _{t t b d i i t d}

Epidermis

Dermis _{• 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 

tissue (fat)

Dermis Adipose Muscle

Vivitrol

_{Pharmacokinetics:}

Alcohol

Dependence

and

the

Liver

• Vivitrol®_{is given as an intramuscular injection}

– Reduces first‐pass hepatic metabolism compared to oral naltrexone

– Delivers ¼ the total monthly dose of oral naltrexone (380 mg vs.1500 mg)

• Naltrexone’s boxed warningg came from the use of oral naltrexone giveng  in excessive 

doses

– Patients in study received greater than 5 times the recommended dose

• Vivitrol®_{does not appear to be a hepatotoxin at the recommended dose}

– Available only in 1 dose (380 mg)

– Dispensed in single‐dose cartons

– Administered by a healthcare professional

• Patients who experience symptoms and/or signs of acute hepatitis should seek medical 

attention and discontinue use of Vivitrol® 7

Campral

®

(acamprosate)

Campral:

Patient

Selection

•

Diagnosis

of

alcohol

use

disorder

•

Anxiety/insomnia

during

periods

of

abstinence

which,

by

the

patient’s

history,

leads

to

relapse

•

Patients

who

report

relief

of

negative

emotional

states

when

they

drink

alcohol

•

Patients

who

desire

to

be

in

recovery,

are

willing

to

engage

in

treatment,

and

endorse

the

goal

of

total

Pharmacokinetics

(cont.)

• No pharmacokinetic differences in alcohol dependent subjects

• No dose adjustment necessary with mild to moderate hepatic 

Special

Populations

j y p

(liver) impairment or mild renal (kidney) disease

• Dose adjustment is necessary in moderate renal disease (i.e.,  creatinine clearance, 30‐50 mL/min)

• Contraindicated in severe renal disease (i.e., creatinine clearance, 30 mL/min)

Effects

of

Alcohol

on

Neural

Circuits

Glutamate

System

Chronic 

Alcohol Use

Acute Alcohol Effect

Inhibits NMDA receptors Effect:anxiety, sedation

Administration of Alcohol

Source: Littleton J. Alcohol Health Res World. 1998;22:13-24.

Adaptation

# and/or function of NMDA receptors on neurons Balances acute alcohol effect Effect: tolerance, dependence Withdrawal

Increased glutamatergic activity Effect:― Acute:dysphoria, 

hallucinations  ―Post‐acute:sleep/mood 

disturbances 

Removal of 

Alcohol

Alcohol Free CNS Equilibrium

NMDA = N-methyl-D-aspartate.

Pathophysiology

of

Potential

Relapse

Balancing

Pathophysiology

Campral

_(acamprosate

_calcium)

C

Glutamate

C Campral

NMDA 

Receptor

Reduction in glutamate release

Reduction in post-synaptic effects mGluR5 C C C C

Neuroadaptation:

Potential

for

Relapse

Normal Tolerance

Adaptation Alcohol

Acute Alcohol Intake

Alcohol

Excitation (Glutamate) Inhibition

(GABA)

Acute Withdrawal

Adaptation C

Post‐Acute Withdrawal and Cue‐Induced Responses

Campral®_{(acamprosate calcium) may balance glutamate} 

over‐activity, thus reducing the potential for relapse

50 60 70 80 90

Acamprosate

48

‐

and

52

‐

Week

Clinical

Trials:

%

Days

Abstinent

Placebo ACAMP of Day s e nt 67% 74% 85% P<.001* P<.001* 0 10 20 30 40 50 n=136 (1332/1998 mg/d) n=136 n=173 (1998 mg/d) n=177

48-Week Study 52-Week Study

Percentage

Abstin

e

Acamprosate

Common

Spontaneously

Reported

Adverse

Events

in

Placebo

‐

Controlled

Trials

Dosage

and

Administration

• Initiate as soon as possible after alcohol withdrawal when  patient achieves abstinence

–Maintain treatment if patient relapses

• Recommended dose: two 333 mg tablets taken 3 times a  day 

–Patients with moderate renal impairment should have a  starting dose of 1 x 333 mg 3 times daily

–Patients with severe renal impairment should not be  given Campral® _{(acamprosate)}

• Can be taken with or without meals

Monthly

Cost

of

Medications



Antabuse

_~

_$100



Oral naltrexone ~ $50 – 150

Oral

naltrexone

$50

150



Vivitrol

_~

_$750

_{– 1,500}

Anticonvulsants

Anticonvulsants

Anticonvulsants

• Topamax®_{(topiramate), Tegretol}®_{(carbamazepine), and} 

Depakote®_{(divalproex)  have increasingly been of interest, with} 

one study confirming topiramate as being beneficial.

• These medications act as GABA agonists and glutamate  antagonists (similar to acamprosate).

• Preliminary studies show superiority to placebo in reductions in  drinks/day, drinks/drinking day, drinking days, and GGTP  reduction levels.

• Topiramate shows the greatest amount of research support,  and should be initiated in a slowly increasing dosage (maximum  300 mg/day).

Topiramate:

Patient

Selection

•

Diagnosis

of

alcohol

use

disorder

•

Patents

with

co

‐

occurring

bipolar

disorder

•

Persons

with

high

‘reward’

from

alcohol

or

who

use

Topiramate:

Mechanism

of

Action

•

GABA

‐

ergic agent

(facilitates

GABA

functioning

via

action

on

a

non

‐

benzodiazepine

site

on

the

GABA

‐

A

receptor)

•

Also

inhibits

dopamine

release

in

the

limbic

system,

thus

l h l

d

d

f

l h l

attenuating

alcohol

reward

and

craving

for

alcohol

•

May

decrease

obsessional

thoughts

and

compulsions

about

drinking

Topiramate:

Dosing

Morning Dose

Evening Dose

Week 1 25 mg 25 mg

Week 2 50 mg 50 mg

Week 2 50 mg 50 mg

Week 3 75 mg 75 mg

Week 4 100 mg 100 mg

Week 5 150 mg 150 mg

Topiramate:

Adverse

Effects

•

Sedation/somnolence,

fatigue

•

Dizziness

•

Tingling

of

arms

and

legs

•

Cognitive

clouding

•

Decreased

appetite

and

weight

loss

•

Funny

tastes,

nausea

Topiramate:

Adverse

Effects

•

Acute

secondary

‐

angle

glaucoma

(acute

eye

pain

and

myopia)

•

Metabolic

acidosis

via

decreased

serum

bicarbonate

(symptoms

of

hyperventilation,

tiredness,

loss

of

appetite,

irregular

heartbeat,

decreased

alertness)

•

Kidney

stone

formation

•

Must

warn

about

pregnancy

complications

or

increase

in

suicidal

thinking

Other Agents

Other

Agents

Other

Agents

• Lioresal®_{(baclofen) – antispasmodic with GABA‐B agonist} 

activity.  However, there is evidence of misuse, overdose,  delirium sufficient to recommend more research prior to use in  alcoholism.

• SSRI a ents inconsistent findin s ith no likel benefit in

• SSRI agents – inconsistent findings with no likely benefit in  alcohol dependent patients without co‐morbid depression.

• Zofran®_{(ondansetron) – serotonin receptor (5‐HT3) antagonist} 

selectively reduced drinking among some patients with early  onset of problem drinking, but more studies are needed before  differentiating treatment by alcohol dependence subtypes.

Medication

Assisted

Therapy for Sedative

Therapy

for

Sedative

‐

Hypnotic

Addiction

Agents

for

Sedative

‐

Hypnotic

Dependence

• No medications have been approved or found to be effective  specifically for sedative‐hypnotic dependence (usually  benzodiazepines taken for anxiety or imidazopyridines  [e.g.:  Ambien] for sleep).

• Phenobarbital ( sed for ac te deto ification) ma be sed for

• Phenobarbital (used for acute detoxification) may be used for  treatment of the protracted withdrawal syndrome beyond the  initial withdrawal phase.

• Campral®_{(acamprosate) theoretically should have efficacy for} 

sedative‐hypnotic dependence due to it’s effect on the GABA and  glutamate receptor systems (similar to its effects for alcohol  dependence).

Opiate

Use

Use

Progression

of

Opioid

Abuse

and

Addiction

Dopamine

System

and

Drug

Misuse

•

Early

Phase

(Use)

–LIKE

• Pleasure circuit

•

Middle Phase (Abuse)

Middle

Phase

(Abuse)

–WANT

• Desire and urge circuit

•

Late

Phase

(Addiction)

–NEED

• Pathologic desire and 

demand circuit

Opioid

Withdrawal

•

Patients’

worst

nightmare

– a

major

barrier

to

beginning

treatment

•

“It

doesn’t

kill,

you,

just

makes

you

wish

you

were

dead…”

•

Objective,

subjective,

acute

and

protracted

Opioid

Withdrawal

Syndrome

•

Acute

and

protracted

phases

•

Can

occur

after

even

two

weeks

of

opioid

use

•

Duration

of

acute

withdrawal

is

dependent

upon

the

half

‐

life of the drug used:

half

‐

life

of

the

drug

used:

–Peak of withdrawal occurs 36 to 72 hours after last dose

–Acute symptoms subside over 3 to 10 days

–Protracted symptoms may linger for weeks or months

Opioid

Withdrawal



Acute

symptoms

(generally

last

3

– 10

days)

–

Autonomic

symptoms

(Physiologic)

•Rebound increased norepinephrine activity from the  locus coeruleus

•Increase blood pressure and heart rate, peristalsis  (intestinal cramps and diarrhea), diaphoresis (sweating),  irritability, anxiety, etc.

–

Affective

symptoms

(Subjective)

•Suppressed in the dopaminergic reward pathways

•Depression, anxiety, anhedonia, craving, anergia

Protracted

Opioid

Withdrawal



Can

persist

for

3

– 6

months

•

Anergia

•

Anhedonia

•

Sleep

p

disturbance,

, p

poor

appetite

pp

•

Emotional

lability/dysphoria

•

Stress

over

‐

sensitivity

•

Drug

cravings

and

obsessive

thoughts

of

drugs

•

Deep

muscle

aches

and

pains

Comprehensive

Treatment of Opiate

Treatment

of

Opiate