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Review Article

THE ROLE OF NEWER AND EMERGING DRUGS IN THE MANAGEMENT OF ALCOHOL DEPENDENCE

 Sagar Karia1  Avinash De Sousa,2.Nilesh Shah,3Sushma Sonavane4

1Resident Doctor,2 Research Associate  3Professor And Head, 4addl. Professor

Department Of Psychiatry, Lomenta Tilak Municipal Medical College And General Hospital, Sion, Mumbai – 22

 

Abstract

Alcohol dependence is a major health problem worldwide. Various pharmacological agents have been used in the management of alcohol dependence. This present review looks at the role of newer off label drugs like topiramate, tiapride, pregabalin, gabapentin, baclofen and levetiracetam along with their proposed mechanism in alcohol dependence. The data available for each drug is reviewed along with its side effect profile and potential for long term use in the management of alcohol dependence. Future research and clinical needs are discussed as well.

Keywords: Alcohol dependence, tiapride, baclofen, topiramate, pregabalin, gabapentin, levetiracetam.

Introduction

Alcohol dependence constitutes the most serious alcohol use disorder (AUD) and is the single most preventable cause of mortality and morbidity across the world.1 In addition to alcohol dependence, unhealthy alcohol consumption includes other AUDs such as alcohol abuse and heavy drinking.2 Treatment of alcohol dependence involves detoxification and rehabilitation phases. Detoxification manages the signs and symptoms of withdrawal, and rehabilitation is intended to help the patient avoid future problems with alcohol and prevention of relapse.3Alcohol withdrawal syndrome (AWS) occurs when alcohol dependant patients decrease or discontinue their consumption too suddenly and it is characterized by increase in blood pressure and pulse rate, tremors, hyperreflexia, irritability, anxiety and depression in mild to moderate forms and may progress to more complicated forms characterized by delirium tremens, seizures and coma.4 Study of neurobiology of  alcohol withdrawal syndrome suggests role of  neurotransmitters and neuromodulaters like glutamate, dopamine, noradrenaline, serotonin (5-HT), corticotropin-releasing factor (CRF) and adenosine acetylcholine.5

Long-term exposure to alcohol causes adaptive changes in several neurotransmitter systems, including gamma-aminobutyric acid (GABA) receptors, glutamate receptors and central noradrenaline and dopamine activity.6 Glutamate represents the most common excitatory neurotransmitter in the human brain, acting on several types of receptors in the central nervous system. The one most affected by alcohol is the N-methyl-D-aspartate (NMDA) receptor. GABA is the major inhibitory neurotransmitter, and binds to a fast-acting receptor complex denoted as GABA-A, which hyperpolarizes the cell membrane and thereby inhibits neural activity.7 GABA plays a key role in mechanisms on the basis of intoxication, tolerance and withdrawal the neurochemical mechanisms on the basis of intoxication, tolerance and withdrawal.8 Thus there is need for drugs which act on these neurotransmitters and pathways in brain involving them. A number of newer drugs are now being used and have been found to be potentially useful in the long term management of alcohol dependence.

Topiramate

It is a sulfamate substituted analog of fructose 1-6-disphosphate and is an oxygen rich molecule and structurally similar to acetazolamide.9 It is used as antiepileptic, prevention of migraine10 and to counteract weight gain by psychotropic medications.11 It facilitates inhibitory action of gamma amino butyric (GABA) through non-benzodiazepine receptor and reduces excitatory effect of glutamate in the alpha-amino-3 hydroxy-5 metylisoxazole-4 propionic (AMPA) receptor and the kainate receptors. In this way it reduces mesolimbic cortical activity of dopamine and this seems the principal mechanism to decrease rewarding effects of alcohol consumption.12 Topiramate is an efficacious and potent anticonvulsant drug13-14 with proven neuro-protective effects.15-16 Topiramate has six important mechanisms of action viz. the potentiation of inhibitory gamma amino butyric acid – A (GABA-A) mediated currents at non-benzodiazepine sites on GABA-A receptors17-18 inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and kainate glutamate receptors19-20, inhibition of L-type calcium channels and limitation of calcium-dependent second messenger systems21, limits activity-dependent depolarization and excitation of voltage-dependent sodium channels22, activation of potassium conductance and weak inhibition of carbonic anhydrase isoenzymes II and IV in neurons and peripheral tissues.18

Researchers have concluded that topiramate was more effective than placebo after assessing clinical parameters like number of days to relapse, severity of craving and laboratory markers. Also effect was significant when topiramte was used at daily dose of 200-300mg.12 A 12 week clinical trial showed that topiramate improved odds of overall well being, reported abstinence and overall life satisfaction. Also there was significant shift from higher to lower drinking quartiles on percentage of heavy drinking days.23 Other studies have found topiramate helpful in reducing liver function test values, plasma gamma glutamyl transferases, plasma cholesterol, plasma bicarbonate levels, systolic and diastolic blood pressure and body mass index.24 Trials comparing efficacy of topiramate to disulfiram25and naltrexone26 have found favourable results for topiramate. Topiramate has been found effective as an add-on drug in non responders to naltrexone and acamprosate.27 Side effect profile includes paresthesias, memory problems, cognitive impairment in word finding, psychomotor slowing, fatigue and confusion.28 Renal acidosis and kidney stones may arise so adequate hydration is recommended for all patients.29

Tiapride

Tiapride, a substituted benzamide, has a selective D2- and D3- dopamine receptor antagonist activity in limbic brain areas or the locus coerulus.30 It has been used for AWS treatment since the late 1970 s, especially in France.31 Main indications of tiapride are extrapyramidal symptoms or other dyskinesias, hyperkinesias, Huntington’s Chorea32 and also geriatric agitation and restlessness.33 The common side effects with tiapride are drowsiness, extrapyramidal symptoms, dizziness, and orthostatic hypotension.34 Tiapride has no antihistaminic action and is known to control psychomotor restlessness without causing considerable benzodiazepine-like sedation.35 It also does not have a possibility of dependence and abuse.

In alcohol withdrawal, dopamine and N-methyl-D-aspartate (NMDA) levels are increased and GABA is decreased.36 There is positive correlation between withdrawal symptoms and  peripheral dopamine levels on day 1 of a detoxification treatment37; the D2 antagonist tiapride reduces this possible dopamine hyperactivity. It does not have an antiepileptic action[34] so it is preferable to combine tiapride with carbamazepine. The open label study comparing efficacy of  carbamazepine (upto 1200mg/day) and tiapride (upto 1800 mg/day) with clomethiazole (upto 3840mg/day) and diazepam (upto 80mg/day) which had 127 patients who were analyzed after 9 days of treatment, found that tiapride had favourable results upon mood variables and similar results in relation to safety (delirium and seizure) as compared to standard medications i.e. diazepam and clomethiazole.38 A clinical open study  involving 50 patients found good improvement in CIWA-A scores at lower doses of carbamazepine (600mg) and tiparide (800mg) after 5 days of treatment and no cases of seizures or delirium were recorded.39

Baclofen

Baclofen, a gamma-aminobutyric acid (GABA)-B receptor agonist, is a muscle relaxant introduced in the 1960s for the treatment of muscle spasticity due to spinal cord injury, multiple sclerosis and cerebral injuries resulting in spasticity.40-41 It is rapidly absorbed after oral administration and has a half-life of approximately 3.5 hours. It is partially metabolized by the liver but largely excreted by the kidneys, unchanged.[42] Baclofen has been found effective in treating patients with alcohol dependence in multiple randomized controlled trials (RCT’s).43-45Experimental evidence suggests that mesolimbic dopamine neurons are involved in the mediation of alcohol intake and reinforcement.46 GABA-B receptors are located both on the cell body of dopamine neurons and on the terminals of glutamatergic afferent neurons in the ventral tegmental area. Their activation by GABA-B receptor agonists may exert an inhibitory action on the dopamine neurons47 - the possible mechanism through which baclofen suppresses alcohol stimulated dopamine release and, in turn, dopamine mediated, alcohol reinforced and motivated behaviours. It has been hypothesized that baclofen-induced activation of GABA-B receptors might counterbalance AWS-associated, enhanced function of NMDA-mediated glutamate excitatory neurotransmission and thus reducing symptoms of alcohol withdrawal.48

A two year observational study of 100 patients found baclofen was helpful in effortless reduction in alcohol craving when used in dose range of 20-330mg/day.49 The incidence of adverse effects with oral baclofen has been reported as 10–75% and that too at doses greater than 60mg/day.40 The most common side effects are sedation or somnolence, weakness, vertigo, nausea, dry mouth and psychological disturbances which can be minimized by initiating treatment with low doses and gradually titrating the dose upwards. It may cause impairments of cognitive function, particularly confusion, memory and attention.50 Rapid dose reduction or abrupt cessation of baclofen leads to majority of  neuropsychiatric effects. A review51 found that such psychiatric symptoms were consistent with delirium, and included hallucinations (auditory, visual, tactile),delusional beliefs, confusion, disorientation, fluctuating level of consciousness, anxiety, agitation and formal thought disorder. These symptoms were associated with autonomic changes, seizures, spasticity and sometimes dyskinesia.

Pregabalin

Pregabalin (PRE), a structural analogue of GABA, is a novel compound with broad-spectrum efficacy in the treatment of diabetic neuropathy52, post-herpetic neuralgia53 and partial epilepsy54. Different double-blind, placebo-controlled studies suggest that PRE may also be efficacious in the treatment of general anxiety disorder.55-57 PRE acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of excitatory neurotransmitters, including glutamate58, substance P, calcitonin gene-related peptide and monoaminergic neurotransmitters.59,60 It is inactive at GABA or benzodiazepines receptors. It neither binds to serotonin receptors nor does it inhibit reuptake of serotonin or norepinephrine.61It binds selectively to the α²-δ subunit protein of voltage gated calcium channels, and rapidly reduces the influx of calcium, subsequently reducing the exocytosis of synaptic vescicles in the synaptic cleft. It has relatively little effect on neuronal function under conditions of normal activity and its effect appears to be correlated strongly with the degree of hyperexcitation of  the presynaptic neuron.62

Alcohol withdrawal is typically thought to encompass the first 2–5 days after alcohol cessation but a more protracted phase may last for weeks to months after the acute symptoms of withdrawal have subsided.63During this protracted phase, patients experience sleep dysregulation, irritability, and mood instability.64-65 PRE is useful as anxiolytic both in acute as well as protracted phase of alcohol withdrawal. Being a novel sleep modulator and ability to induce restorative sleep it may aid with the sleep dysfunction experienced during and after acute alcohol withdrawal.66 Various double blind controlled studies have found PRE used in dose range of 150-600mg/day  efficacious in management of alcohol withdrawal and also in relapse prevention of alcohol-dependent subjects.67-69 Side effects include dizziness and drowsiness,blurred vision, ataxia, memory impairment, hypoaesthesia and hypotension.70

Gabapentin

Gabapentin is structurally analogous to GABA but, unlike GABA, crosses the blood-brain barrier when administered systemically. The mechanism of action may be an increase in GABA-mediated inhibition and inactivation of voltage-dependent sodium channels.[71] Gabapentin may also exert neuronal stabilization effects by binding to the L-amino acid transporter on the plasma membrane or the subunit of voltage-gated calcium channels.[72] The above observations suggest that gabapentin may be a promising candidate for the treatment of alcohol withdrawal symptoms. Open label reports as well as case studies have shown the utility of gabapentin in managing alcohol withdrawal symptoms and tonic clonic seizures that may occur upon alcohol withdrawal. [73-75] Although studies have shown a very modest effect of gabapentin in managing long-term alcohol dependence, large-scale double-blind randomized controlled studies are needed to strengthen these findings and look at relapse prevention.76

Levetiracetam

Levetiracetam is a newer anti-epileptic drug with a multi-site mechanism of action, and is effective against a variety of seizure types. It is currently being used especially in the management of especially juvenile myoclonic seizures, Lennox Gastaut syndrome and refractory seizures in children and adults. There is preclinical evidence that it may have potential benefit also in anxiety disorders, stress, and mood disorders.77 To date, there has been only one study with a negative outcome when levetiracetam was used in the management of alcohol dependence with co-morbid anxiety.78 In an open label trial, levetiracetam was effective in the management of alcohol withdrawal symptoms and prevention of seizures during the withdrawal phase.79

Conclusions

Several recent reviews have supported the role of topiramate in the management of various phases of alcohol dependence, from the alcohol withdrawal syndrome to long-term management and relapse prevention. In clinical practice I have often found that in the management of alcohol withdrawal syndrome, particularly in patients who suffer from both alcohol dependence and a comorbid antisocial personality disorder, anticonvulsants act as mood stabilizers during withdrawal, thereby reducing mood swings and irritability along with their anti-epileptic potential. The role of topiramate in managing this specific subset of alcohol dependence has not been investigated, and this research is warranted. Alcohol dependence pharmacotherapy is at an interesting crossroads. Increases in co-morbidity in alcohol dependence, in the form of mood disorders as well as personality disorders, requires the use of poly-pharmacy when it comes to the long-term management of alcohol dependence. It is well-known that depression and bipolar disorder may exist at sub-threshold or subclinical levels in these patients. It is here that a combination of drugs like disulfiram, naltrexone, or acamprosate with anticonvulsant drugs may help in sustaining abstinence and promoting the long-term management of alcohol dependence. Further studies of various combinations of traditional drugs with newer ones or newer ones alone in various populations across cultures is required in order to judge the efficacy of these agents, as well as to reach clear guidelines for their usage in alcohol dependence.

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