long term pharmacotherapy for alcohol dependence: anti...
TRANSCRIPT
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Long term pharmacotherapy for Alcohol Dependence: Anti Craving agents
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Myth or Reality ?
Complete Recovery means a medication-free state
True or False?
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Treatment of AlcoholismAssessment
Motivation Alcohol Dependence Other diseases
Detoxification
Long-term
Deterrence Anti-Craving
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Treatment of AlcoholismAssessment
Motivation Alcohol Dependence Other diseases
Detoxification
Long-term
Deterrence Anti-Craving
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Treatment of AlcoholismAssessment
Motivation Alcohol Dependence Other diseases
Detoxification
Long-term
Deterrence Anti-Craving
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Treatment of AlcoholismAssessment
Motivation Alcohol Dependence Other diseases
Detoxification
Long-term
Deterrence Anti-Craving
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What is craving?
Craving: Strong urge or desire
Alcohol use Developing dependence
Treatment and abstinence Craving
Lapse to alcohol use
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Reinforcement: Neurochemical systems
EnkephalinInhibitoryNeuron
REWARD
Glutamate Excitatory InputEnkephalin or
DynorphinInhibitory Neuron
GABAInhibitory
Neuron
GABA Inhibitory Feedback
Dopamine Neuron GABANeuron
Ventral Tegmental Area(VTA)
Nucleus Accumbens(NAc)
Dopamine Receptors
GABA-A Receptors
PresynapticOpioid
Receptors(µ, δ?)
µ OpioidReceptors
κ OpioidReceptors
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin
Naltrexone
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Naltrexone
Opioid antagonistOral 50 mg tablets Role in Alcohol Dependence:Decreases alcohol craving, rate of relapse, and
length of drinking episodesStudies combined medication with psychosocial
supports
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Naltrexone: Basic scienceAlcohol affects the production, release, and activity of opioid
peptides
Opioid peptides mediate some of alcohol’s rewarding effects
Opioid antagonists suppress alcohol-induced reward
Embellished from Gianoulakis 1998
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Naltrexone: Mechanism of Action
Reduces craving thereby reinforcementThus prevents relapse
Lapse to alcohol use
Pleasure of drinking
Continued drinking
Naltrexone
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Naltrexone: Clinical scienceNaltrexone 50 mg/day: Identification of the
alcoholic subgroup (those with biological risk) most responsive to naltrexone is an important scientific goalGenetic high-risk / FH+
individuals are more responsive to naltrexone treatment
From Volpicelli et al. 1992
0 1 2 3 4 5 6 7 8 9 10 11 120.00.10.20.30.40.50.60.70.80.91.0
Placebo Naltrexone
No. of Weeks Receiving Medication
Cum
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ive
Pro
port
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wit
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ore
laps
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Naltrexone: Side-Effects
Nausea
Headache
Anxiety
Sedation
Insensitive to opioid analgesia
Hepatotoxicity (LFT should be monitored)
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin
Acamprosate
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Acamprosate: Advantages
Excreted by the kidneys
Mild side effect profile
Good documented efficacy
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Acamprosate: Basic science
Excitatory neurotransmitter NMDA contributes to alcohol’s many effects
NMDA antagonist, acamprosate, reduces the intensity of post-cessation alcohol craving on exposure to high-risk drinking situations
Embellished from Spanagel & Zieglgansberger, 1997
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Poorly absorbed with a bioavailability of approx. 10%
Excreted unmetabolized; therefore no risk of hepatotoxicity
Should be used with caution in individuals with renal impairment
Few adverse events; diarrhea is the most frequent
Dose: 666 mg thrice a dayCan be used with other alcoholism medications
such as Naltrexone or Disulfiram
Acamprosate: Clinical science
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin
Baclofen
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Baclofen: Clinical science
Baclofen (p-chlorophenyl-GABA): orally active GABA-mimetic agent
Selective GABAB receptor agonist Pharmacokinetics: Completely absorbed-oral administration low levels of liver metabolism (about 15%), Excreted unchanged in urine Plasma half-life- 3–4 hours
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Baclofen: Clinical science
Dosage: Start at 5 mg tds for 3days, then 10 mg tds increasing as tolerated to 80-100 mg daily (maximum
used- 270mg) Sustained release also available
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Baclofen- Side effects
Drowsiness Weakness Dizziness HeadacheNausea Constipation Hypotension Confusion Insomnia
Urinary frequency Seizures Allergic reaction
Withdrawal symptoms Hallucination Agitation Anxiety Confusion Delirium
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Baclofen: role in reducing alcohol withdrawals? Some studies have shown that Baclofen may be
useful in reducing alcohol withdrawal symptoms as well
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Baclofen in reducing craving for alcohol Preclinical study: Animal models Baclofen, suppresses the acquisition and maintenance of the
alcohol drinking behavior in rats Acute injection of baclofen blocked the temporary increase
in voluntary alcohol intake occurring after a period of abstinence
Clinical study: Baclofen (30 mg/day) in alcohol dependent patient Reduced alcohol craving & anxiety Significant reduction in the number of drinks per drinking
day& number of heavy drinking days
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Baclofen- Advantage
Minimal side effect Showed an excellent hepatic safe profile with the
lack of liver-related side effects in alcohol-dependent subjects both with and without liver cirrhosis
Patients who continued to drink alcohol while being treated with baclofen showed no signs of any complications
No addictive potential
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin Ondansetron
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Ondansetron: Clinical science An anti-nausea agent Ondansetron, reduces the positive
subjective effects associated with abuse liability of alcohol
Ondansetron also reduces preference for high alcohol doses
Dose: 4 mcg / kg/ BDSide effects: Malaise, fatigue, dizziness
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Neurotransmitters and Alcohol Dependence
OpioidsGlutamate GABASerotonin SSRIs (Fluoxetine)
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SSRIs: Clinical science
Weak evidence of efficacyMay be tried in patients with comorbid
psychiatric illness where SSRIs are indicated
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Other agent: Topiramate
An anticonvulsant Mechanism of action poorly knownCaution with impaired renal or hepatic functionSide Effects
psychomotor slowing, memory problems, fatigue, confusion, and somnolence.
Paresthesias Weight loss Kidney stone and Glaucoma – rare but serious
Decreases alcohol cravingDose: initially 12.5 -25 mg once or twice a day and the total daily
dose is increased by 12.5 - 25 mg every week up to 150 mg BD
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Pharmacotherapy: Issues
All pharmacotherapy should be combined with psychosocial interventionsPatient education about mech. of action, side
effects, precautions, likely duration etc.Relapse prevention
Supervised therapy as far as possible Careful monitoring and follow-upDuration: 6 months to one year
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Pharmacotherapy: Issues
Disulfiram or Anticraving drugs: how to choose?•Complete abstinence?•Normal LFT?•Supervision possible?•Compliance assured?
Disulfiram
•Controlled drinking•Normal LFT
Naltrexone
•Controlled drinking•Deranged LFT
Acamprosate / Baclofen
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Role of combinations
Many patients, though motivated, to stop completely, complain of craving
Craving:Can be a cause for relapse Can be a distressing symptom
Thus most patients on Disulfiram can also be put concurrently on anti-craving agents
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Alcohol dependence
Motivated ?Supervision possible?
Disulfiram
Significant craving?
Disulfiram + anti-craving
Motivation doubtful?
Risk of DER?
Only anti-craving
Assessment
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Thank You