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VKN NIMHANS ECHO, NIMHANS Digital Academy and Centre for Addiction Medicine

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Published by NIMHANS Digital Academy, 2019-12-14 08:12:13

Foundation of Addiction Medicine 2019

VKN NIMHANS ECHO, NIMHANS Digital Academy and Centre for Addiction Medicine

Keywords: Addiction,Digital training

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

505

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

506

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

508

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)

509

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

528

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


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