ANTI-CRAVING DRUGS

its efficacy and evidences

CRAVING & PATHWAYS Craving mainly refers to the strong desire or urge to

experience the effect of a previously experienced psychoactive substance.

There are 3 novel pathways for craving in alcoholics

1. The reward pathway suggests that craving or desire for the rewarding, stimulating and/or enhancing effects of alcohol might result from either dopaminergic/ opioidergic dysregulation or a personality style characterized by reward seeking and/or hedonism.

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CRAVING & PATHWAYS2. The relief pathway suggests that craving or desire for the reduction of tension, arousal or withdrawal might result from either GABAergic/glutamatergic dysregulation or a personality style characterized by stress reactivity, anxiety sensitivity, and/or hyperarousability.

3. The obsessive pathway can be defined as a lack of control over intrusive thoughts about drinking resulting in impaired functioning. This pathway of craving might result from serotonin deficiency or a personality style characterized by low constraint or disinhibition.

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MEDICATIONS USED TO PREVENT RELAPSE OF AN ADDICTIVE

DISORDER

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ALCOHOL DEPENDENCE

ALCOHOL DEPENDENCE Chronic relapsing disorder Results from genetic, psychosocial, and

environmental factors. Pharmacotherapy, in conjunction with behavioural

therapy, is considered as best modality to prevent relapse and enhance abstinence.

To date, three medications - disulfiram, naltrexone, and acamprosate - have been approved by the US FDA for treatment of alcohol dependence

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MEDICATIONS FOR RELAPSE PREVENTION OF ALCOHOL DEPENDENCE

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NALTREXONE Naltrexone is an mu opioid receptor antagonist and

is thought to reduce the rewarding effect of alcohol. The US FDA's approval of naltrexone for the

treatment of alcohol dependence was based mainly on two small, double-blind, placebo-controlled trials demonstrating a reduced rate of relapse to heavy drinking, reduced craving, and less frequent drinking in naltrexone-treated patients.

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NALTREXONE For the first 90 days of abstinence, when the risk of

relapse is greatest, the recommended dosage of naltrexone is a single dose of 50 mg/day but doses of 25 mg to 100 mg daily are sometimes used.

Most common ADR: nausea, headache, anxiety, sedation

• Dose-related hepatotoxicity, generally occurs at doses of 300 mg per day.

• Contraindicated in patients with hepatitis or liver failure.

ACAMPROSATE Acamprosate normalizes the dysregulation of N-

methyl-D-aspartate (NMDA)-mediated glutamatergic excitation that occurs in alcohol withdrawal and early abstinence.

Acamprosate has been used in Europe for many years and is proven to reduce cravings for alcohol.

Acamprosate protects the brain until the GABA and glutamate systems can come back into balance, and this may dramatically increase treatment retention in the critical few months of recovery

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ACAMPROSATE Mechanism: decrease in glutamate release, a

decrease in calcium ion influx through voltage-dependent calcium channels, a decrease in NMDA receptor excitability, and an increased level of taurine, an inhibitory neurotransmitter

Acamprosate is available in 333-mg enteric coated tablets. Dosing is determined by weight ( 60 kg: 1998 mg, < 60 kg: 1332 mg).

Most common ADR: headache, diarrhoea Given cautiously with renal impairment.

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COMPARISON OF THE CHARACTERISTICS OF NALTREXONE

AND ACAMPROSATE

COMBINATION PHARMACOTHERAPY: NALTREXONE +ACAMPROSATE

Since naltrexone and acamprosate have different mechanisms of action and different target neurotransmitter systems, presumably, they affect different aspects of alcohol use behaviour. (Naltrexone decreases alcohol consumption and acamprosate stabilizes abstinence.)

Pharmacokinetic and behavioural assessments of combining naltrexone and acamprosate have found the combination to be safe.

EFFICACY STUDY Kiefer et al. performed a randomized, double blind,

placebo-controlled, clinical trial of 160 alcohol- dependent patients and assessed the efficacy of naltrexone and acamprosate, as monotherapy and in combination.

Proportion of patients remaining absolutely abstinent at the end of the 12-week treatment period was around twice as high in the combination therapy group than in the monotherapy group (placebo 25%, naltrexone alone 65%, acamprosate alone 50%, combination therapy 73%).

DISULFIRUM Disulfirum was the first drug approved for the

prevention of relapse in alcoholism. It does not specifically block craving, although, if taken

regularly, it may simplify the daily struggle against urges toward alcohol.

Disulfiram blocks the enzyme alcohol dehydrogenase so that if the patient takes a drink, acetaldehyde is produced, causing a very unpleasant flushing reaction.

In large randomized, controlled trials, disulfiram has not been effective because of the lack of medication adherence

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OTHER MEDICATIONS • Topiramate : US FDA approved for seizure

disorders only. Topiramate was reported to reduce relapse in alcoholics and in cocaine addicts

• Serotonin 5-HT3 antagonist ondansetron: It has FDA approval for the treatment of nausea by the parenteral route, but a randomized, controlled trial with a special formulation for research in alcoholics found a significant reduction in drinking for early-onset alcoholics

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NICOTINE ADDICTION

• Bupropion is well known as an antidepressant, but clinician noted that it had a specific effect on nicotine craving.

• Randomized, controlled trials concluded it to be the single most effective treatment for cigarette smoking.

• In combination with the nicotine patch, the success rate for smoking cessation has improved.

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BUPROPION

VARENICLINE • Recently approved synthetic drug for cessation of smoking.• It has partial antagonist action on presynaptic Nn receptors

located at dopaminergic neurons present in ventral tegmental area covering nucleus accumbens, prefrontal cortex, amygdala and hippocampus.

• Activation of mesolimbic dopaminergic system by nicotine causes release of dopaminewhich promotes reinforcement and reward process leads to craving.

• Varenicline antagonize this and decrease dopamine release.• 0.5 mg OD then 1 mg BD from day 8 for 6 months.• ADR: nausea, headache, insomnia depression

HL Sharma textbook pg. 192

JAMA. 2015 Feb 17;313(7):68794.

Effect of varenicline on smoking cessation through smoking reduction: a

randomized clinical trial.Ebbert JO , Hughes JR , West RJ , Rennard SI , Russ C , McRae TD , Treadow J , Yu CR , Dutro MP , Park PW .

Abstract

Objective: To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction.

Design: Randomized, doubleblind, placebo controlled, multinational clinical trial with a 24week treatment period and 28week follow up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising.

Intervention: 24 weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks.

Result: The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07).

Conclusion: Among cigarette smokers not willing or able to quit within thenext month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation.

RIMONABANT Rimonabant is a specific antagonist to CB-1

receptors (Cannabinoid receptors) FDA approved medication.

Cannabinoid (CB-1) receptors are widely distributed throughout multiple brain systems and, they play a critical role in memory, motor control, pain perception, and many other functions.

Moreover, there is an indication that it will have a general usefulness in reducing appetite for food as well as the craving for a range of drugs, including nicotine, alcohol, cocaine, and heroin.

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COCAINE ADDICTION

DISULFIRUM FDA approved for alcohol abuse but not for cocaine

addiction In addition to its effects on alcohol metabolism,

disulfiram also blocks the enzymatic degradation of cocaine and dopamine and leads to extremely high cocaine and dopamine levels when cocaine is ingested.

This does not increase the cocaine-induced high, as one might expect, but rather it makes the high less pleasant by increasing the associated anxiety.

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BACLOFEN Baclofen is GABA B agonist used as a muscle

relaxant. As a GABA agonist, baclofen may reduce the

amount of dopamine released into the nucleus accumbens as a result of cocaine stimulation or cocaine craving.

In a human laboratory study, baclofen decreased the craving response provoked by exposure to conditioned reminders (cues) of prior cocaine use.

Baclofen has been shown to blunt the characteristic pattern of brain activation associated with cocaine cue induced craving.

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TIAGABINE Tiagabine is another GABAergic medication

that may be promising for the treatment of cocaine dependence.

Tiagabine is a selective blocker of the presynaptic GABA reuptake transporter type 1, and it is currently approved for the treatment of seizures.

Tiagabine was found to be well tolerated and moderately effective for improving abstinence in a pilot study. Psychiatry (Edgmont). 2005 Dec; 2(12): 44–48

MODAFINIL Modafinil, approved for the treatment of

narcolepsy, has been found to reduce the high from cocaine and to reduce cocaine craving.

The mechanism of action of modafinil is unknown, but it does increase glutamate levels in the brain, thus reversing the effect of chronic cocaine use.

In addition, modafinil was found to block the euphoric effects of cocaine in two independent human laboratory studies.

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PROPRANOLOL During cocaine withdrawal, patients are sensitive

to the effects of adrenalin and noradrenalin, and this may contribute to the anxiety and restlessness they feel.

As a beta-blocker, propranolol may be able to reduce the anxiety associated with cocaine withdrawal as well as reduce some of the more uncomfortable symptoms of cocaine craving.

Beta-blockers may also be able to reduce some of the rewarding properties of cocaine.

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OPIOID ADDICTION

SUBSTITUTION THERAPY• Shift from short acting opioid to long acting agonist-

Methadone.• By doing so, addict is spared from the undesirable effect

of withdrawal because the opioid receptors remain occupied for a longer duration.

• Thereafter, methadone can be withdrawn in tapering doses over a period of weeks.

• Levo-alfa-acetyl methadol (LAAM) with alternate day oral dosing is long acting analogue which reduced abuse potential but with a caution as it prolongs QT interval.

• Buprenorphine-partial opioid agonist (OD)HL Sharma textbook pg. 515