An effective treatment for alcohol addiction should include methods to alleviate the physiological effects of alcohol related disorders as well as prevent the occurrence of a relapse to maladaptive/abusive behavior. Common strategies for the treatment of alcohol use disorders (AUDs) include the use of pharmacotherapy to treat the physiological symptoms and neurochemical imbalances caused by prolonged exposure to ethanol; as well as a combination of pharmacotherapy & psychotherapy (group talk therapy such as Alcoholics Anonymous) to prevent relapse in recovering patients. Alcohol dependents suffer from a variety of inter-related disturbances in their physiological and mental homeostasis including, thiamine deficiency, hyperexcitability of neurons (during the initial withdrawal phase), anxiety, mood disorders, depression, anhedonia & insomnia amongst others. Currently, the most widely used medications for the treatment of alcohol related disorders include Benzodiazepines, Naltrexone, Acamprosate and Disulfiram. In addition, patients often require thiamine (Vitamin B1) supplements to compensate for its dietary deficiency, insufficient absorption and enhanced excretion during alcohol dependency; which can lead to the development of conditions such as Wernicke’s Encephalopathy. [1]











**
  • Detoxification

**The treatment/rehabilitation process is commenced at this stage; which involves the cessation of alcohol consumption and complete abstinence. Individuals are most likely to develop Alcohol Withdrawal Syndrome (AWS) [1] during this initial stage of recovery which has the possibility of exhibiting itself in the form of seizures, Delirium Tremens (DT) and fatigue. It can also be accompanied by hallucinations and heart failure in more severe cases [2] . Sedative hypnotics such as benzodiazepines are often administered during the detoxification process to alleviate such symptoms and stabilize the neurochemical imbalances that have occurred in the brain as a result of prolonged exposure to ethanol.
    • Benzodiazepines

This class of pharmaceutics is the first line of treatment for the prevention/alleviation of the most severe symptoms associated with a withdrawal stage, such as Seizures [3] and Delirium Tremens [3] . Some of the commonly used benzodiazepines include Chlordiazepoxide and Diazepam (marketed as Valium ® in most parts of the world and as Antenex ®in Australia). These drugs perform as substitutes for ethanol in the brain as they also bind to GABAA receptors, thereby preventing hyperexcitatory activity which manifests itself in the form of Seizures. A hyperactive neurological state in the brain upon cessation of alcohol consumption is due to the excitatory effects of glutamate; consequential to the upregulation of NMDA receptors upon chronic exposure to alcohol, as well as the removal of direct excitatory effects of ethanol on the GABAA receptor which produces an inhibitory effect on the Central Nervous System (CNS) [3] . Thus, Benzodiazepines produce a sedative/inhibitory effect similar to an ethanol induced depression of the CNS and also ease other aversive symptoms of the withdrawal stage such as Insomnia, Anxiety and Anhedonia. However, the dosage of benzodiazepine administered should be very carefully monitored since an overdose could lead to excessive sedation or death. It is noteworthy that benzodiazepines would be more effective in the alleviation of withdrawal symptoms resulting from repeated alcohol consumption, while ineffective or rather detrimental for the treatment of symptoms resulting from short-term binge drinking; this is because acute exposure to ethanol would lead to direct inhibition of the CNS through its excitatory activity on the GABAA receptor and direct inhibitory activity on the NMDA receptor [1] [3] . Short term exposure to ethanol does not lead to the upregulation of NMDA receptors and hence the brain is unable to counterbalance the inhibitory effect of ethanol; hence, combined exposure to a sedative such as benzodiazepine and ethanol could lead to excessive depression of the CNS. It has been suggested that drugs of this class which exhibit their activity over longer duration have higher efficacy for the treatment of withdrawal related symptoms whereas short-acting benzodiazepines have lower hepatotoxicity [4] . Some of the adverse effects of benzodiazepines include anterograde amnesia as well as the development of secondary addictions to the drug itself since they produce similar effects as alcohol; which could result in a co-morbid disorder.

=

  • Pharmacotherapy

=

    • Naltrexone (NTX)

Currently one of the forerunners in medications prescribed for alcohol abuse disorders, NTX can be administered orally or through an intramuscular injection (Extended release NTX or XR-NTX marketed as Vivitriol®) in varying doses depending on the severity of the disorder and the physiological state of individual patients [5] [6] [7] . Initially used to treat opiate dependence [6], the most pronounced effect of naltrexone is on opioid receptors and the downstream mesolimbic pathway which is heavily influenced by the activity of mu-opioid receptors (MOR). The therapeutic action of NTX is primarily a result of its competitive antagonism to endogenous opioids (β– endorphins) [8] released upon ingestion of ethanol; which remove the tonic inhibition by GABA interneurons (disinhibition) on the dopaminergic neurons in the Ventral Tegmental Area (VTA) which terminate in the Nucleus Accumbens (N. Acc) [8] .
nrn3110-f1_(1).jpg
The reward pathway dominant in the neurobiology of addicition


Since the mesolimbic pathway is most intricately involved with the perception of a ‘reward’, NTX effectively reduces the positive reinforcement associated with alcohol consumption by preventing/reducing dopamine release in the N. Acc [9] and hence reduces cravings for alcohol as well as the likelihood of a relapse to abusive drinking upon culmination of the treatment process [10] [11] . In addition, to µ - opioid receptors, naltrexone is also known to bind to δ– opioid receptors, inducing similar effects on the mesolimbic pathway as the µ - opioid receptors [9]. Evidence for the reduction of reinforcement and cravings for alcohol consumption upon administration of NTX is shown by µ - receptor null mutant mice that do not self-administer alcohol [12] . Drugs such as NTX and Nalmefene (another opioid receptor antagonist) have also been known to activate the HPA axis resulting in higher levels of Cortisol & ACTH in circulation [12]; which increases the possibility of reduced craving, relapse and the positive reinforcement associated with repeated alcohol consumption due to concurrent stress responses induced upon administration of naltrexone. The efficacy of naltrexone as a pharmacotherapeutic agent has been previously related to family histories of alcoholism. The varied susceptibility to beneficial effects of naltrexone has been suggested to be caused by single nucleotide polymorphisms in the OPRM1 gene which encodes for the µ - opioid receptor; with OPRM1 - 118G polymorphism carriers showing a better response to NTX over non-carriers. [13] [14]

    • Acamprosate

marketed as Campral ®in the U.S. and France, acamprosate is used to treat symtpoms associated with alcohol withdrawal such as seizures and delirium tremens caused by NMDA hyperactivity [15] . It works by tempering the dysregulation of NMDA regulated glutamatergic activity in the brain, known to occur as a consequence of chronic exposure to alcohol and during withdrawal.


acamprosate.jpg


It is structurally similar to GABA and the amino acid neuromodulator Taurine [19]. The mechanism of action of acamprosate in the brain occurs in a complex manner as acamprosate binds to a spermidine sensitive site on the NMDA receptor, [16] [17] acting as a ‘partial co-agonist’ instead of solely behaving as an agonist or antagonist. The agonistic/antagonistic activity of acamprosate on NMDA receptors is mediated by levels of endogenous activity in the brain i.e. it acts as an antagonist when glutamate levels are high [since there is upregulation of NMDA upon chronic alcohol exposure [18] and as an agonist when glutamate levels are low (during acute exposure to alcohol). Thus acamprosate proves to be a better modulator of glutamate activity in the brain than a pure agonist/antagonist; it lowers the risk of relapse by alleviating sleep and mood disturbances which often occur during withdrawal and post-abstinence periods of therapy [15]. The release of Taurine, an essential neuromodulator which inhibits NMDA activity, is also known to be enhanced by acamprosate, resulting in the prevention of hyperexcitability caused by a surge in glutamate during withdrawal from alcohol consumption.[19]
    • Disulfiram

Marketed as Antabuse®, it was the most commonly used pharmaceutical treatment for alcohol abuse and dependence prior to the advent of Naltrexone and Acamprosate. Disulfiram is used to create an aversion to alcohol consumption by hypersensitizing the patient to the adverse effects of alcohol consumption a.k.a the “Hangover”. Under normal conditions, ethanol is converted to acetaldehyde (responsible for a “hangover”) by the enzyme alcohol dehydrogenase which is then converted to relatively benign acetic acid by acetaldehyde dehydrogenase in a subsequent process[20] . Disulfiram inhibits the latter enzyme, halting the removal of ethanol at the acetaldehyde stage which causes high blood acetaldehyde concentrations [BACC] [20] (in comparison to a BACC in the absence of disulfiram), for a prolonged period resulting in a more severe and extensive “hangover”.

disulfiram_mode_of_action.png
The mechanism of action of Disulfiram


Individuals being treated with disulfiram experience a severe physiological reaction ethanol exhibiting symptoms such as flushing of the skin, nausea, fatigue, severe headaches, vomiting and confusion [20]; immediately and up to two weeks after consumption of the drug. In addition, this drug also prevents the conversion of dopamine to noradrenaline by blocking dopamine-β-hydroxylase an enzyme that performs the conversion.


References
  1. ^ McKeon, A., Frye, M. A. & Delanty, N. The Alcohol Withdrawal Syndrome. J Neurol Neurosurg Psychiatry 79, 854 – 862 (2008).
  2. ^ Dart, R. C. //Medical Toxicology// 3rd edn. (Lippincott Williams & Wilkins, U.S.A, 2003) pp. 139–140.
  3. ^ Hyman, S. E. Current Treatment for Alcohol Withdrawal. J Gen Intern Med 9, 523 – 524 (1995)
  4. ^ Ntais, C., Pakos, E., Kyzas, P. et al. Benzodiazepines for Alcohol Withdrawal. Cochrane Database Sys Rev 3, CD005063 (2005).
  5. ^ Carmen, B., Angeles, M., Ana, M. & Maria, A. J. Efficacy and Safety of Naltrexone and Acamprosate in the Treatment of Alcohol Dependence: A Systematic Review. Addiction 99, 811 – 828 (2004)
  6. ^ Heilig, M., Egli, M. Pharmacological Treatment of Alcohol Dependance: Target Symptoms and Target Mechanisms. Pharmacology & Therapeutics 111, 855 – 876 (2006).
  7. ^ Kranzler, H. R., Tennen, H., Armeli, S., Chan, G., Covault, J., Arias, A., Oncken, C. Targeted Naltrexone for Problem Drinkers. J. clin. Psychopharmacology 29(4), 350 – 357 (2009).
  8. ^ Heilig, M., Goldman, D., Berretini, W., O’Brien, C. P. Pharmacogenetic Approaches to the Treatment of Alcohol Addiction. Nature Reviews Neuroscience 12, 670 – 684 (2011).
  9. ^ Hillemacher, T., Heberlein, A., Muschler, M, AN., Bleich, S., Frieling, H. Opioid Modulators for Alcohol Dependence. Expert Opin. Investig. Drugs 20(8), 1073 – 1086 (2011)
  10. ^ Oslin, D. W., Berretini, W. H.,O’Brien, C. P. targeting treatments for alcohol dependence: the pharmacogenetics of naltrexone. Addiction biology 11, 397 – 403 (2006)
  11. ^ O’Malley, S. S., Krishnan-Sarin, S., Farren, C., Sinha, R. & Kreek, M. J. Naltrexone Decreases Craving and Alcohol Self-Administration in Alcohol-Dependant Subjects and activates the Hypothalamo-pituitary-adrenocortical Axis. Psychopharmacology 160, 19 – 29 (2002).

  12. ^ Roberts, A. J.,McDonald, J. S., Heyser, C. J., Keiffer, B. L.,Matthes, H. W., Koob, G. F. et al. mu-opioid receptor knockout mice do not self-administer alcohol. J Parmacol Exp Ther 293(3), 1002 – 1008 (2000).
  13. ^ Oslin, D. W. //et al//. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. //Neuropsychopharmacology// **28**, 1546 – 1552 (2003).
  14. ^ Anton, R. F. //et al//. An evaluation of μ-opioid receptor (//OPRM1//) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. //Arch. Gen. Psychiatry// **65**, 135–144 (2008).
  15. ^ Mason, B. J., Heyser, C. J. The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence. //Expert Opin. Drug Saf//. **9**(1), 177 – 188 (2010).

  16. ^ Littleton, J. M. Acamprosate in alcohol dependence: implications of a unique mechanism of action. //J Addict Med// **1**, 115 – 125 (2007).

  17. ^ Naassila, M., Hammoumi, S., Legrand, E. //et al//. Mechanism of action of acamprosate Part I. characterization of spermidine-sensitive acamprosate binding site in rat brain. //Alcohol Clin Exp Res// **22**, 802 – 809 (1998)

  18. ^ Hoffman, P. L., Tabakoff, B. The role of the NMDA receptor in ethanol withdrawal. //EXS// **71**, 61 -70 (1994).
  19. ^ Dahchour, A., De Witte, P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. //Prog Neurobiol// **60**, 343 – 362 (2000).
  20. ^ Spanagel, R., Vengeliene, V. New pharmacological treatment strategies for relapse prevention. (Curr Topics Behav Neurosci, 2012) pp 1 – 27