ANTI CRAVING AGENTS

OVERVIEW
• INTRODUCTION

• CRAVING

• ANTICRAVING AGENTS

• CONCLUSION
 Introduction
• Epidemiological study- 28.77% of prevalence
in India
• Even after adequate treatment-high rate of
relapse
• Relapse causes- stress, cues, priming dosing
• Current conceptualizations of addiction
recognize craving as a central driving force for
ongoing drug use, as well as for relapse
following abstinence
• Craving- an intense or powerful desire for
some particular thing
Subjective experience of desiring , needling or
longing for euphoric or sedative properties of
drugs.
Assessment & Measurement-
• Single-item questionnaires
• Obsessive Compulsive Drinking Scale
• Alcohol Urge Questionnaire
• Physiological changes thought to accompany
craving, such as changes in heart rate, blood
pressure , salivation, and sweat gland activity.
• Craving can be assessed by directly observing
a subject’s substance intake behavior –
Behavioral measurements may include number
of drinks consumed, time elapsed between
cue exposure and initiation of drinking (i.e.,
latency), and time elapsed between
commencement and completion of drinking.
Neurobiology of craving
Integration of behavioral control

Frontal cortex

Nucleus accumbens
Stress, antistress system
VTA

Hippocampus and amygdala

Altered neural integration in addiction
 Neuropharmacology
Experience Transmitter/Receptor

euphoria/pleasure Dopamine, Opioids

anxiolysis/ataxia  GABA
sedation/amnesia  GABA +  NMDA
nausea 5HT3
neuroadaptation NMDA, 5HT
stress CRF
 Agents against Alcohol craving
• 1951
Disulfiram- Aldehyde dehydrogenase inhibitor

• 1994
Naltrexone - Opioid antagonist

• 2004
Acamprosate- Glutamate receptor modulator

• 2006
Long-acting Injectable Naltrexone - Opioid
antagonist
Disulfirum
• Inhibits aldehyde dehydrogenase-leading to
acetaldehyde accumulation after drinking
alcohol - The Disulfiram-Ethanol Reaction (DER)
• The patient must be fully informed of DER
• Second-line option – NICE
• Dose –
• After 24 hr without alcohol – starting single
dose 800 mg - reducing to 100–200 mg daily
over 5 days – reviewed every 6 months.
 Naltrexone
• Opioid antagonist
• Role in Alcohol Dependence:
– Opiate antagonists appear to block alcohol-induced
dopamine release in the nucleus accumbens,
presumably resulting in decreased pleasure and a
decrease in alcohol intake

– Decreases alcohol craving, rate of relapse, and

length of drinking episodes
 Naltrexone: Basic science
Alcohol affects the production,
release, and activity of opioid
peptides

Opioid peptides mediate some of

alcohol’s rewarding effects

Embellished from Gianoulakis 1998

Opioid antagonists suppress
alcohol-induced reward
Naltrexone
• Dosage: 25 mg on day 1, and then 50 mg/day
for 3 to 6 months

• Identification of the alcoholic subgroup (those

with biological risk) most responsive to
naltrexone is an important scientific goal
– Genetic high-risk / FH+ individuals are more responsive
to naltrexone treatment
Naltrexone: Side-Effects
• Nausea (10%)

• Headache (7%)

• Anxiety (2%)

• Sedation (2%)

• Insensitive to opioid analgesia

• Hepatotoxicity (LFT should be monitored)

Contraindication –

Acute hepatitis / Liver failure

Long-acting Injectable Naltrexone
• Encapsulated naltrexone 380 mg, in
biodegradable polymer microspheres that
slowly release naltrexone for 1 month after a
single injection – brand name Vivitrol
• Approved by the US FDA in April 2006
• Pharmacokinetic analysis showed that
therapeutic plasma levels of naltrexone were
sustained for a month, with no significant drug
accumulation during that time
 Better than oral NTX
• Reduced first-pass elimination, allowing for
less hepatic naltrexone exposure, hence less
potential hepatic toxicity compared with oral
naltrexone
• Intramuscular naltrexone also had reduced
fluctuations in plasma concentrations
compared with oral naltrexone.
 Evidence of Clinical Efficacy
• IM NTX 380 and 190 mg- 48% reduction in heavy drinking
days, with benefits observed in both actively drinking
and abstinent patients
• Adverse events occurring in at least 10% -nausea,
headache, fatigue, decreased appetite, dizziness, and
injection site pain (Garbutt et al., 2005)
• Significantly increased the time to the first drink,
decreased the number of drinking days during
treatment, and supported a significantly greater
abstinence rate (18% vs. 10%) compared with placebo
injection (Kranzler et al., 2004)
Acamprosate
• Approved by the US FDA in July 2004 for the
maintenance of abstinence from alcohol in
alcohol-dependent patients who were
abstinent at treatment initiation

• Calcium acetyl homotaurinate- Acamprosate is a

structural analogue of the amino acid, taurine

• Modulates the glutamatergic hyperactivity

associated with chronic alcohol-induced
changes
How does it work?
• Alcohol intake disrupts the normal balance between
neuronal excitation and inhibition regulated through
GABA, NMDA- exaggeration of the inhibitory process.
• During chronic alcohol consumption,
neuroadaptation occurs via up-regulation of
excitatory NMDA receptors. The increased excitation
counteracts the inhibitory action of alcohol to restore
normal neuronal balance.
• Abrupt removal of alcohol leaves the up-regulated
glutamate/NMDA receptor system unopposed- state
of hyperexcitability
• Acamprosate may act at regulatory sites on both
inotropic and metabotropic NMDA receptors in this
domain to normalize NMDA glutamatergic hyper
Dose
• For adults of 18–65 years weighing 60 kg and
over- dose is 1998 mg daily (666 mg three times
daily).
• For adults weighing less than 60 kg, the dose
should be reduced to 1332 mg daily: 666 mg
(morning), 333 mg (midday) and 333 mg (night).
• Start soon after detoxification and continue for 1
year.
• Should be continued during relapse (up to 4-6
weeks).
Side-effects –
• diarrhoea,
• abdominal pain, nausea and vomiting
• pruritus.

Contraindications –
• Severe renal or hepatic impairment(baseline
liver and kidney function tests should be
performed before commencing treatment.
• should be avoided in individuals who are
pregnant or breast feeding.
 Pharmacotherapy: Issues
How to choose?

• Complete abstinence? • Controlled drinking • Controlled drinking

• Normal LFT? • Normal LFT • Deranged LFT
• Supervision possible?
• Compliance assured?

Disulfiram Naltrexone Acamprosate /

Baclofen
 NEWER APPROACHES
• Serotenergic system: • Dopaminergic:
– Ondansetron – Aripiprazole
– Conventional neuroleptics
• GABA:
– Baclofen • Others:
– Cannabinoid receptor
• Glutamate & GABA: antagonists
– Topiramate – CRF antagonists
– Vigabatrine – Neuropeptide Y, Adenosine
A2, antagonists
– Tiagabine
– Nicotinic receptor
– Gabapentin antagonists
– Memantine (glutamate
antagonist only)
Ondansetron
• 5-HT3 antagonist
• Approved as antiemetic for chemotherapy induced
nausea
• Efficacy in young onset alcoholics with serotonergic
deficiency.
• Combination of naltrexone + ondansetron - Safe and
efficacious
• Given at low doses 4µg/kg twice daily which is
approximately 2mg twice daily
• Adverse effects –
– headache,
– GIT disturbances,
– Fatigue
– drowsiness
Baclofen
• GABA(B) receptor agonist approved as an anti-spastic
medication
• Rapidly suppresses alcohol withdrawal symptoms;
effective in reducing voluntary alcohol intake in
alcohol-preferring rats, and alcohol craving and intake
in alcoholics
• Dose- 40-60 mg in 2-3 divided doses
• Contraindications - kidney disease or epilepsy
• Side effects: an allergic reaction; seizures; or irregular
heartbeat; may cause dizziness or drowsiness,
weakness, or unusual fatigue; headache;
constipation; stuffy nose; blurred vision; rash; or
frequent urination
 Topiramate
• An anticonvulsant
• Sulfamate substituted fructopyranose derivative
• Mechanism of action poorly known
• Mech. of action
-Antagonistic at AMPA & Kainate
-Facilitates GABA at non BZD site
-Inhibits calcium, sodium & activate
potassium channels
-CA inhibitor
 TOPIRAMATE cont..

• Topiramate has actions both in the GABAergic and

glutaminergic systems.
• Decreases DA level both in the VTA & Nac, modulates DA
release in the reward pathway.
• Decreases drinks/day, no. of heavy drinking days,
percentage of days abstinent.

(Johnson et al,2003)
 Topiramate cont..

• Caution with impaired renal or hepatic function

• Side Effects
– psychomotor slowing, memory problems, fatigue, confusion, and
somnolence.
– Paresthesias
– Weight loss
– Kidney stone and Glaucoma – rare but serious

• Dose: 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
Topiramate-efficacy

• Good for combination with other Rx that

demonstrate effect in a subset of patients.
• Topiramate+Ondansetron/Naltrexone in early
onset alcoholics.
• Topiramate+SSRI for later onset Type A
alcoholics.
• Topiramate+mood stabilizers for pts with co
morbid affective disorders.
 ANTIPSYCHOTICS

• Chronic alcoholism associated with D2 receptor

depletion state

• Antipsychotics block D2 leading to its up regulation.

Olanzapine & clozapine in co morbid ADS with
schizophrenia reduce alcohol dependence.

• Aripiprazole – partial D2 agonist. Effective in animal

models.
 OTHERS
• Rimonabant – approved in UK as antiobesity drug
• CB1 receptor antagonist
• Off label use for smoking cessation
• Rat models with KO CB1 receptor show decreased
alcohol intake with rimonabant
 OTHERS
• Gabapentin ,Vigabatrin & Tiagabine :
• Newer anticonvulsants
• Efficacy being studied in alcohol withdrawal
• Ongoing trials for long term effects on alcohol and
cocaine dependence

• Memantine: glutamate NMDA receptor antagonist

• Reduced voluntary alcohol intake in animal models also
reduced craving in moderate drinkers
 OTHERS
• CRF antagonist: CRF involved in stress
response mediated by HPA axis. Reduces
stress induced relapse in animal models

• Neuropeptide Y & Adenosine A2 antagonist

• Nicotinic & Muscarinic receptors regulate

mesolimbic dopamine.
• Nicotinic receptor antagonist –
mecamylamine.
Drug Brand name Dose Cost
(mg /day
/day) (Rs)
Ondansetron Emset,, onset 4 9.70
(4mg tablets)

Baclofen Liofen, 30-60 24

Lioresal (10,
25 mg tab)

Topiramate Topamac, 200-300 35

Topirol (25,
50, 100 tab)
Naltrexone Nodict, 50-100 40
Naltima

Acamprosate Acamprol 1332 – 24

1998
Anti craving agents against Nicotine
– Nicotine replacement therapy
– Bupropion
– Varenicline
Nicotine replacement therapy (NRT):
• 5 medications approved by the FDA
• Deliver nicotine in a form that does not involve the
risks of smoking.
• Used for a short period of time and should be
tapered down to a low dose before stopping.
• Increased the chances of stopping smoking by 50-
70% compared to placebo or to no treatment
[Link] nicotine patches deliver doses of the addictive chemical
nicotine, thus reducing the unpleasant effects of nicotine
withdrawal. These patches can give smaller and smaller doses of
nicotine, slowly reducing dependence upon nicotine and thus
tobacco. A Cochrane review found further increased chance of
success in a combination of the nicotine patch and a faster acting
form. Also, this method becomes most effective when combined
with other medication and psychological support.
2. Gum
3. Lozenges
4. Sprays
5. Inhalers.

A study found that 93 percent of over-the-counter NRT users relapse

and return to smoking within six months.
Bupropion
• Atypical antidepressant, with dopaminergic
and noradrenergic actions
• A systematic review of 19 RCTs revealed a
doubling of smoking cessation as compared to
the placebo control
Dose
• Start 1–2 weeks before the planned ‘quit date’
at 150 mg daily for 6 days
• 150 mg twice daily for a maximum of 7–9
weeks.
Side-effects
• Insomnia
• dry mouth
• headache (common ∼30%),
• Seizure ( 1 in 1000 users)
• hypersensitivity reaction or rash(rare ∼0.1%).
Contraindications
• History of seizures, eating disorders, a central
nervous system (CNS) tumour, bipolar disorder,
• Pregnancy, breast feeding
• Acute benzodiazepine or alcohol withdrawal.
Varenicline
• Partial agonist binding
with high affinity to the
α4β2 nicotinic
acetylcholine receptor

• Available in India since

2008 under the brand
name Champix

• Cost- around 10,000 for

full course
Dosage-
• Days 1–3: 0.5 mg once daily,
• Days 4–7: 0.5 mg twice daily, and
• Day 8 to end of week 12: 1 mg twice daily.

Side-effect-
• Nausea (30%)
• Depression and suicidality

Contraindicated in-
• Pregnant or breast-feeding women
• End-stage renal disease
Non-FDA approved drugs
• Moclobemide - mimicking the MAO-A
inhibiting effects of tobacco smoke

• Clonidine - reduce withdrawal symptoms

• Nortriptyline - antidepressant, has similar

success rates to bupropion

Only FDA approved combination – nicotine

patch + buproprion
 Anti craving for Cannabis dependence
• Bupropion – double blind study shows utility

• Lithium carbonate – under preliminary

examination in rodent
 Agents against Opiate craving
• Methadone Vs Buprenorphine
• Withdrawal syndrome
• Side-effect profiles
• Chronic pain
• Effectiveness
• Drug interactions
• Pregnancy
Lofexidine –
• Alfa 2-adrenergic agonist
• can counteract the adrenergic hyperactivity
associated with opioid withdrawal
Naltrexone
• Cost-effective treatment strategy – NICE
• Close monitoring - higher risk of fatal overdose
from illicit opioids & severe withdrawal
reaction due to insufficient ‘wash-out’ period
(< 7 days)
Dose-
• initial dose of 25 mg – look for withdrawal
• maintenance dose can be increased to 50 mg
daily
 Anti craving agents for Cocaine
• Only 16% of those who try cocaine develop
addiction
• No FDA approved medications
• Agents used –
o Disulfiram- known to increase plasma
concentrations of cocaine 3 to 6 fold and to
inhibit dopamine beta hydroxylase , thus
increasing the effects of cocaine and possibly
making cocaine use aversive.
o Modafinil - increases glutamate levels in the
brain , thus reversing the effect of chronic
cocaine use.
No abuse potential
o Propranolol

o GABA-enhancing medications –
Topiramate , Vigabatrin , Baclofen
 CONCLUSION
• Addiction is a chronic disorder that requires long-
term treatment
• In recent years, medications have been developed
that add to the benefits of psychosocial
interventions for the prevention of relapse
• Despite clinical trials that show benefit, anti craving
medications are not well known and are underused
by clinicians
• Recent developments in pharmacogenetics may
result in improved selection of medications based
on genotype.
 References
• New Oxford Textbook of Psychiatry,2nd edition
• Lishman’s Organic Psychiatry,4th edition
• Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical
Psychiatry, 10th Edition
• The Maudsley prescribing guidelines in psychiatry / David Taylor, Carol
Paton, Shitij Kapur. – 11th ed
• NICE clinical guideline 51 & 52
• Copeland;Development in the treatment of cannabis use disorder
• Medications and Alcohol Craving,Robert M. Swift, M.D., Ph.D.
• Anticraving Medications for Relapse Prevention:A Possible New Class of
Psychoactive Medications ,Charles P. O’Brien, M.D., Ph.D., Am J Psychiatry
2005; 162:1423–1431
• Craving: what can be done to bring the insights of neuroscience ,
behavioral science and clinical science into synchrony,ROGER E. MEYER,
Addiction (2000) 95 (Supplement 2), S219–S227
• Website:
• [Link]
• [Link]
THANK YOU