Do subtypes of alcoholism matter when selecting anti craving medications? Eur Neu psy phar. 2014 Feb.

17.03.2014

10% of population suffer from alcohol use disorders. Psychosocial interventions/Self help groups and medications attempt to promote abstinence, reduce alcohol intake, and prevent relapse. Fabio Caputo et al review the medication options in this article. They also provide a survey of the literature on sub typing alcoholism/ craving with a view to  see whether subtypes respond to different treatment options differently.

Subtypes/ stages

Jellinek: Alpha, beta, gamma and delta, epsilon (Jellinek, 1960) stages based on severity.

Cloninger type I and type II : Type 1- anxiety/ social factors play more role in origin and is associated with dopaminergic defects : Type 2- impulsivity, persistent antisocial behaviors and a high familial risk for alcoholism and associated with serotonergic defects.

Babor type A and type B:  Type A:   later onset, fewer childhood risk factors, less severe dependence and less psychopathological dysfunction. Type B: childhood risk factors, familial alcoholism, early onset , greater severity,  polydrug use & greater psychopathological dysfunction.

Lesch’s typologies : Type I (or “model of allergy”) individuals suffer from severe alcohol withdrawal syndrome, and tend to use alcohol to prevent or weaken their withdrawal symptoms; Type II subtype (or “model of anxiety or conflict”) identify subjects who drink alcohol as a means of self-medication and exhibit extensive behavioral changes under the influence of alcohol. Type III (or “model of depression”) is characterized by the use of alcohol as an anti-depressant, a positive family history for alcoholism and affective disorders. Type IV  (or “model of adaptation”) is characterized by pre-morbid cerebral defects, behavioral disorders, and seizure disorders unrelated to alcohol withdrawal.

Craving subtypes:  Reward craving is characterized by a dopaminergic/opioidergic dysregulation (deficit of opioids/ endorphins, hypersensitivity to the reinforcing effects of alcohol) ,an early development of alcoholism and a positive family history of alcoholism. Relief craving (desire to decrease tension) is associated with dysregulation of glutamate with neuronal overexcitability, hypersensitivity to the sedative effects of alcohol or a personality trait manifesting itself through reactivity to stress or a combination of both factors. Obsessive craving (a loss of control over intrusive thoughts about the intake of alcohol) is characterized by serotonin deficit or a personality trait consisting of disinhibition or a combination of both factors

Medication update:

Only three drugs disulfiram (DF), naltrexone (NTX), and acamprosate (ACM)] have been approved by the FDA.Sodium oxybate (SO) is  approved in Italy and Austria. Nalmefene is licensed in UK.

Disulfuram: Irreversibly inhibits the action of the aldehyde- dehydrogenase enzyme causing accumulation of acetaldehyde during ethanol intake  leading to the “acet- aldehyde syndrome” which acts as a deterrent.Not indicated in the presence of severe liver disease, peripheral neuropathy, optic neuritis and psychosis.

Naltrexone:  m and κ-opioid receptor antagonist. Prominent anti-reward craving potential hence better results in those with high levels of craving and a positive family history of alcoholism. IM monthly  injection is available.

Nalmefene:  μ and δ-opioid antagonist and κ-opioid partial-agonist. Useful in those without physical withdrawal effects who do not require immediate detoxification.

Acamprosate:   NMDA  glutamate receptor antagonism , cause reduction of the excessive flow of intracellular calcium ions leading to neuro protective effect. It improve the dysphoria often found in chronic alcoholics, this mechanism indirectly causes a reduction in alcohol craving with the consequent reduction of its consumption (relief craving).Better effect in Lesch types I and II.

Sodium Oxybate: short-chain fatty acid, structurally similar to the GABA,  exert ethanol-mimicking effect on GABA B receptors.addiction to SO is possible.

Baclofen:  GABA B receptor agonist.Progressive dose escalation might be required.

Other medications  with some evidence:  topiramate , pregabalin  oxcarbamazepin Gabapentin,  Valproic acid and ondansetron

Combination therapy– no consistent  and robust evidence to support combinations of above agents.

Medications are  effective in reducing relapses and the number of drinks per drinking day and, consequently, the organ damage caused by alcohol consumption. However , they are not much effective in abstinence in the long run.

Pharmacogenetics: emerging ideas suggest that genetic information may help in choosing the most effective agent. Eg: Presence of polymorphic OPMR1 of the u-opioid receptor gene may induce a better response to Naltrexone. Single nucleotide polymorphism of GATA binding protein 4 (GATA4) gene is associated with very few relapses in patients treated with Acamprosate.

DBS: There is some interest in application of Deep Brain Stimulation in the Nuclues Acumbens area. Early reports suggest benefits.

Summary of the article:

Pharmacological management of alcohol dependence: from mono-therapy to pharmacogenetics and beyond.

Caputo F, Vignoli T, Grignaschi A, Cibin M, Addolorato G, Bernardi M. Eur Neuropsychopharmacol. 2014 Feb;24(2):181-91

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