Naltrexone
Precautions
Liver Function Tests: baseline and periodic monitoring is indicated
Mild Noncompliance and continued alcohol/drug use
elevations
(< 3 fold) Often seen in alcoholism/narcotic addition
Not a contraindication
Moderate
elevations
Persistent Naltrexone should be discontinued
elevations
Contraindicated in patients with liver failure or acute hepatitis
Used during pregnancy only when the benefit > risks 501
Naltrexone
Important studies
• In 1990s Two double-blind, placebo-controlled trials
• (Oral Naltrexone 50mg/day)
• Patients were more likely to remain abstinent (54 % vs. 31 %)
• Experience fewer days of drinking (3.1 % vs. 7.5 %)
• Lower rates of relapse to heavy drinking (25% vs. 52 %)
502
Efficacy of naltrexone may be more pronounced
in1.: Male
2. Smokers
3. Antisocial traits
4. High levels of craving
5. Positive family history of alcoholism
6. Asn40Asp polymorphism of the μ-opioid receptor (OPRM1) gene:
stronger effect of naltrexone in Asp40 carriers
7. When used to control progression to heavier drinking behavior
without a goal of abstinence
8. May be useful on the days when drinking is anticipated
503
ER formulation (380 mg and 190 mg) versus placebo
▪ Both preparations well tolerated
▪ 380-mg preparation
✔ Prolonged abstinence
✔ Reduced drinking days
✔ Reduced heavy drinking days by 25%
504
Acamprosate
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Acamprosate
Background
• The compound was approved for the treatment of alcohol
dependence in 1989 in France
• In July 2004, the FDA approved acamprosate for the
maintenance of abstinence from alcohol in detoxified patients
with alcohol use disorder
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Acamprosate
Pharmacology
• Acamprosate is the calcium salt of N-acetyl-homotaurine
(calcium acetyl-homotaurine)
• A synthetic analog of the endogenous amino acid taurine with
additional carboxyl and methyl groups in its chain
507
Acamprosate
Pharmacokinetics
• Formulated as calcium salt to assist in its GI absorption
• Peak plasma concentrations are usually reached within 3 to 8 hrs
• Steady-state levels are achieved by the 5th to 7th day of dosing
• Terminal half-life ranges from 20 to 33 hrs
• Protein binding is negligible
• Eliminated unchanged in the urine and the feces
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Acamprosate
Mechanism of Action
• Acamprosate bears structural similarities to several amino acids,
including GABA, glycine, aspartate, and glutamate
• Blockade of Glutamate NMDA receptors
• Activation of GABA-A receptors
• Acamprosate restores the imbalance in the excitatory & inhibitory
neurotransmitters, caused by alcohol.
(Littleton 1995; Rammes et al, 2001)
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Acamprosate
Dosage and Administration
Acamprosate is dosed by weight:
Patients >60 kg should receive 1,998 mg/day
Patients <60 kg should receive 1,332 mg/day
In three divided doses
Available as tablet 333mg
• No dose titration is required while starting or stopping
• Can be started early in the abstinence
• Acamprosate treatment should not be interrupted if relapses
occur and is recommended to proceed for 12 months
510
Acamprosate
Adverse Drug Effects
• More frequently ADR: Headaches, insomnia, stomach upset with
nausea, vomiting, and abdominal pain, as well as sexual
dysfunctions (e.g., decreased libido, frigidity, and impotence)
• In clinical trials the most commonly reported side effects were
diarrhea and pruritus, though these adverse effects were
usually transient
• Rare but more serious side effects include allergic reaction to
the drug, arrhythmias, and fluctuations of blood pressure
(Mason, 2003)
511
Acamprosate
Drug-drug Interactions
• Because acamprosate does not rely on hepatic metabolism, it
has relatively few drug–drug interactions
• Benzodiazepines, disulfiram, antidepressants or alcohol do not
change acamprosate’s pharmacokinetic properties
• Naltrexone increase blood levels of acamprosate but requires no
adjustment of the dosage
The absorption of several agents (tetracyclines, quinolones,
levothyroxine, atenolol, iron, alendronate, sodium fluoride, and
zinc) may be decreased by the calcium component of
acamprosate during concurrent administration
512
Cost: one month treatment
Name Strength Cost per tablet Frequency Monthly cost
INR INR
Naltrexone 50mg/ (0-0-1)
Acamprosate 333mg 75 (1-1-2) 2250
Disulfiram 250mg (1-0-0)
13 1560
3 90
(Cost are approximate and taken from 1mg.com website)
513
Choosing the Medication
• Depends on several Patient-dependent
factors, cost of medication
• If the Goal is complete Abstinence: Disulfiram
but Patient has to be highly motivated and
ready to follow up
• Reduction in drinking: Naltrexone and
Acamprosate
• Family history positive: Naltrexone better
• Very advanced Liver disease : Naltrexone not
suitable 514
Further Reading
• Indian Psychiatry Society Clinical Practice
Guidelines for SUD 2015 Synopsis (link)
• A Primer for Treating Alcohol and Tobacco Use
Disorder, Centre for Addiction Medicine
NIMHANS 2016 (Iink)
• Holt SR, Tobin DG. Pharmacotherapy for
alcohol use disorder. Medical Clinics. 2018
Jul 1;102(4):653-66.
515
Thank You!
516
Prescribing Anticraving agent II (off-label):
Nalmefene, Baclofen, Topiramate and Gabapentin
Dr. Shabina Sheth
M.D Psychiatry
Senior Resident, VKN Nimhans
517
Educational Objectives
Nalmefene ● Mechanism of action
Baclofen ● Effectiveness
Topiramate ● Prescribing methods
Gabapentin ● Current Status
518
off-label
● At this point not approved by various Country regulators
● But Scientific data justify this therapeutic use.
● Off-label use is generally legal but an appropriate
monitoring is important
● The patient has been given comprehensive information
concerning the potential benefits and risks of the
treatment. (https://en.wikipedia.org/wiki/Off-label_use)
519
Nalmefene
520
Background
● μ- and δ-opioid receptor antagonist and a κ-opioid receptor partial agonist
● United States: Complete or partial reversal of opioid drug effects
● European Union: Help reduce alcohol consumption in adults with alcohol
dependence who consume >60 g (≈4 drinks) per day (men) or >40 g (≈3
drinks/ day) (women).
521
Prescribing method
● Approved dosage for AUD (in the European Union): 18 mg/d (as needed)
● Dosage in clinical trials for AUD: 5-80 mg/d in 1 dose or 2 divided doses
● After an initial visit- record of alcohol consumption for 2 weeks; patients who continue
to have a high drinking risk level during those 2 weeks can be initiated on nalmefene
● Nalmefene is taken as needed: on each day the patient perceives a risk of drinking
alcohol, 18 mg should be taken 1–2 hours before the anticipated time of drinking.
● If the patient has already begun drinking, 18 mg should be taken as soon as possible.
522
Adverse effects Do not use
● Nausea, ● If patient is taking opioid analgesics
● dizziness, ● If patient is currently dependent on
● insomnia,
● headache, opioids or is in acute opiate withdrawal
● vomiting, ● If patient has severe renal or hepatic
● fatigue,
● somnolence impairment
● If patient has a recent history of acute
alcohol withdrawal syndrome
● If there is a proven allergy to nalmefene
523
Baclofen
524
Background
● Baclofen-1962-epilepsy in children, 1974- muscle relaxant
● GABA-B receptor agonist
● T1/2: 4 hours
● Excretion: 80% -renal unchanged, 15%- Hepatic, into inactive metabolite, 5%
Feces-unchanged
525
The key effects of baclofen on the Alcohol Addicted
patient are:
● Anti-craving
● Anxiolytic
526
Prescribing Methods
Initiating treatment:
● Start low, go slow
● Dosage in clinical trials for AUD: 30-180 mg/d in up to 4 divided doses
● Generally one starts with small daily doses of about 15mg, then one
increases to 30 mg 3-4 days later
● then increases by 10 mg every 3 to 5 days
527
Adverse effects The least frequent SEs
The most common side ● Tremors
effects ● Double vision
● Painful paraesthesia in arms and legs
● Sleepiness ● Nocturnal apnoea
● Fatigue ● Mania or hypomania mood shift:
● Dizziness ● Confusional syndrome/delirium
● Headaches ● Anorgasmia/loss of libido
● Nausea,vomiting,
gastrointestinal disorders
● Sleep disorders
Prescribing-Guide-for-Baclofen-in-the-Treatment-of-Alcoholism-Don.pdf
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Baclofen Withdrawal Syndrome (BWS)
● The typical symptoms are ● The simplest treatment for BWS is to
○ anxiety, agitation, confusion, restart the baclofen at the previous dose
delusions and hallucinations – as soon as possible.
auditory or visual.
● More severe cases have an agitated ● If the patient cannot swallow eg
delirium and can have new onset unconscious, it will be necessary to
seizures. administer the baclofen via nasogastric
tube as there is no intravenous or
intramuscular formulation.
529
Drug Interaction Contraindications:
● Antihypertensives ● Bipolar disorder, depression,
● CNS depressants psychosis, schizophrenia
● Skeletal Muscle relaxants
● stroke
(Acetaminophen; Butalbital; ● seizures
Caffeine; Codeine: ● chronic kidney disease
Amitriptyline, Clozapine) ● Allergies to Baclofen
● Caution in Diabetes-
Hyperglycemia
530
Do patient have to be completely Stop Alcohol
before starting the Anti-craving Drugs
1. Agree
2. Disagree
3. Not sure
531
Answer
Studies have not directly compared the effects of requiring abstinence before
initiation of a medication to treat AUD.
Although there is evidence that a longer period of abstinence prior to initiating
treatment with long-acting naltrexone may result in better treatment outcomes,
studies of naltrexone and topiramate that did not require abstinence before
treatment have shown the active medication’s superiority to placebo treatment
● Henry R. Kranzler,Michael Soyka. Diagnosis and Pharmacotherapy of Alcohol Use Disorder A Review, JAMA. 2018;320(8):815-824. 532
doi:10.1001/jama.2018.11406
Topiramate
533
Background
● Monotherapy and as an adjuvant in GTCS, Migraine prophylaxis, Weight loss
● there is a growing interest in the use of anticonvulsant drugs for the
management of AUDs.
● inhibits dopamine release through antagonism of glutamate activity and
facilitation of gamma-aminobutyric acid (GABA) transmitter in areas of the
brain that may be associated with reward effects of alcohol.
● t1/2: 21 hours,primarily eliminated unchanged in urine
534
Prescribing Methods
● gradual dose escalation over 4 weeks, starting with 25 mg twice a
day for 1 week,
● and advancing by 25 mg increments each week (ie, 50 mg twice a
day for 1 week, then 75 mg twice a day, etcetera) to a goal of 100
mg twice a day.
● Abrupt withdrawal should always be avoided.
● Special tests prior to induction: Renal function tests.
535
Adverse effects Serious side effects
● dizziness and somnolence ● Metabolic acidosis
● ataxia ● Kidney stones
● impaired concentration ● Secondary angle-closure glaucoma
● confusion
● fatigue ● Wait, Wait, Wait
● Paresthesias ● Take at night to reduce daytime
● speech difficulties
● diplopia sedation
● nausea ● Increase fluid intake to reduce
● Depression and cognitive
the risk of kidney stones
impairment have been reported. ● Switch to another agent.
536
● Stahl’s Essential Psychopharmacology Prescriber’s Guide- 5th edition
Drug Interactions
● Carbamazepine, phenytoin, and valproate may increase the clearance of
topiramate and vice versa.
● Topiramate may increase plasma levels of metformin; also, metformin may
reduce clearance of topiramate and increase topiramate levels.
● Topiramate may interact with carbonic anhydrase inhibitors to increase the
risk of kidney stones.
● Topiramate may reduce the effectiveness of oral contraceptives.
537
Gabapentin
538
Background
● Gabapentin is an oral anticonvulsant that was FDA-approved as an adjunctive treatment for
partial epileptic seizures in 1993, and for postherpetic neuralgia in 2004.
● A Cochrane review (2014) also found evidence supportive of gabapentin as a treatment for
diabetic neuropathy.
● Pharmacology: Calcium channel γ-aminobutyric acid modulator
● T1/2: 5-7 hours
● The renal clearance is directly proportional to creatinine clearance.
● Pregnancy Category C.
539
● Stahl’s Essential Psychopharmacology Prescriber’s Guide- 5th edition
Prescribing Methods
● Dosage in clinical trials for AUD: 75-300 mg/d in 2 divided doses
● Abrupt withdrawal should always be avoided.
● Start LOW, go SLOW dosing
Henry R. Kranzler,Michael Soyka. Diagnosis and Pharmacotherapy of Alcohol Use Disorder A Review, JAMA. 2018;320(8):815-824. doi:10.1001/jama.2018.11406 540
Stahl’s Essential Psychopharmacology Prescriber’s Guide- 5th edition
Adverse effects Drug Interaction
● Sedation, dizziness, ataxia, fatigue, ● Antacids
nystagmus, tremor ● Naproxen
● CNS depressants
● Vomiting, dyspepsia, diarrhea, dry
mouth, constipation, weight gain
● Blurred vision
● Peripheral edema
● Rare activation of suicidal ideation
and behavior (suicidality)
541
● Stahl’s Essential Psychopharmacology Prescriber’s Guide- 5th edition
What are the Evidences for these drugs
1. Nalmefene: In a meta-analysis of 5 RCTs (N = 2567), nalmefene treatment was associated with
a reduction in binge drinking of 1.65 d (95% CI, 0.89 to 2.41) more per month at 6 mo and by 1.60 d
more per month (95% CI, 0.35 to 2.85) at 1 y, and with a reduction in total alcohol consumption of
20% (95% CI, 0.10 to 0.30) at 6 mo
2. Baclofen: In a meta-analysis of 13 RCTs (N = 1492), baclofen was associated with a significantly
greater time to first lapse to drinking [SMD = 0.42 (95% CI, 0.19 to 0.64)] and a greater likelihood of
abstinence during treatment [odds ratio = 1.93 (95% CI, 1.17 to 3.17)], with no greater difference at
a higher dosage (>60 mg/d). Persons who drank very heavily at study entry had a greater
association of abstinence with baclofen.
542
Henry R. Kranzler,Michael Soyka. Diagnosis and Pharmacotherapy of Alcohol Use Disorder A Review, JAMA. 2018;320(8):815-824. doi:10.1001/jama.2018.11406
Cont...
3. Topiramate: In a meta-analysis of 7 RCTs (N = 1125), there were small-to-medium effects of
topiramate on abstinent days (Hedges g = 0.468)a and binge drinking days (Hedges’ g = 0.406)
4. Gabapentin: Of 3 peer-reviewed, placebo-controlled RCTs (total N = 231), the largest (N = 150)
showed that gabapentin resulted in a rate of abstinence of 11.1% (95% CI, 5.2 to 22.2) in the 900-mg/d
group and 17.0% (95% CI, 8.9 to 30.1) in the 1800-mg/d group, compared with 4.1% (95% CI, 1.1 to 13.7)
for placebo. The rate of no binge drinking was 22.5% (95% CI, 13.6 to 37.2) in the placebo group, 29.6%
(95% CI, 19.1 to 42.8) in the gabapentin 900 mg/d group, and 44.7% (95% CI, 31.4 to 58.8) in the 1800
mg/d group.
Henry R. Kranzler,Michael Soyka. Diagnosis and Pharmacotherapy of Alcohol Use Disorder A Review, JAMA. 2018;320(8):815-824. doi:10.1001/jama.2018.11406
543
Current status
Nalmefene Baclofen Topiramate Gabapentin
Clinical Approved Temporary Consider Consider
notes in Europe with
for treating recommendat with comorbid
AUD neuropathy;
ion in France comorbid starting
dose 300
for use in the seizure mg TID;
side effects
management disorder; include
fatigue,
of alcohol requires ataxia,
cognitive
dependence 4-wk dose impairment
at a titration;
maximum side effects
recommende include
d dosage of paresthesia
80 mg/d s, GI upset,
cognitive
impairment
Stephen R. Holt, Daniel G. Tobin. Pharmacotherapy for Alcohol Use Disorder, Med Clin N Am 102 (2018) 653–666 544
Other Non-FDA approved drugs
1. Varenicline: a 2014 systematic review of 7 RCTs to reduce rates of heavy
drinking with a moderate treatment effect size (d 5 0.3–0.5).
2. Ondansetron may be more effective in patients with particular genotypes
of the serotonin transporter gene, suggesting that this drug may be
increasingly useful in an evolving era of personalized medicine.
3. Quetiapine seemed to be a promising drug as well, but in a recent RCT
there was no significant difference between placebo and quetiapine.
4. Aripiprazole, has also yielded disappointing results in a large multisite
12-week RCT.
5. Memantine (used to treat Alzheimer’s dementia) has also been found to be
largely ineffective.
● Stephen R. Holt, Daniel G. Tobin. Pharmacotherapy for Alcohol Use Disorder, Med Clin N Am 102 (2018) 653–666 545
Take home points
Choosing the best medication- patient-dependent factors.
● Treatment goal
● Opioid dependency
● Comorbid disease
● Cost effectiveness
● Drug interaction
● Dosing regimen
A patient-centered and personalized approach is critically important when
choosing a medication to treat AUD.
● Stephen R. Holt, Daniel G. Tobin. Pharmacotherapy for Alcohol Use Disorder, Med Clin N Am 102 (2018) 653–666
546
References
● Stahl’s Essential Psychopharmacology Prescriber’s Guide- 5th edition
● The Maudsley Prescribing Guidelines in Psychiatry, Twelfth Edition. David
Taylor, Carol Paton and Shitij Kapur.
● Stephen R. Holt, Daniel G. Tobin. Pharmacotherapy for Alcohol Use Disorder,
Med Clin N Am 102 (2018) 653–666
● Henry R. Kranzler,Michael Soyka. Diagnosis and Pharmacotherapy of Alcohol
Use Disorder A Review, JAMA. 2018;320(8):815-824.
doi:10.1001/jama.2018.11406
● Ambekar, Atul & Kattimani, Shivanand. (2013). Anti-craving medications for
long-term treatment of alcohol dependence.
● Prescribing-Guide-for-Baclofen-in-the-Treatment-of-Alcoholism-Don.pdf
547
THANK YOU
548
Increasing Motivation: I
Ms. Sandeepa Kaur
Clinical Psychologist
NIMHANS Digital Academy
549
Educational Objectives
● Definition
● Brief history
● When to use
● Differentiation of MI from Conventional
model
● Spirits of MI
● Skills
550