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AlcoholAlcohol dependence is a major cause of morbidity and mortality in the United States and throughout the world. Acute withdrawal from alcohol is a serious medical condition which can precipitate adrenergic activation,seizures,or delirium tremens,the last condition leading to 15% mortality when untreated. Many medications have been evaluated for the treatment of alcohol dependence in recent years,including those that interact with dopaminergic,serotonergic,opioid,glutamate,and γ-aminobutyric acid (GABA) systems.
# Acute withdrawal
Benzodiazepine use is the standard approach to treating withdrawal symptoms such as irritability,autonomic hyperactivity,and seizures associated with alcohol detoxification. Benzodiazepines act at GABA-A receptors to stimulate GABA release and gradually detoxify the patient from alcohol,thus avoiding associated withdrawal symptoms. The current standard approach to alcohol detoxification uses tapering dosages of benzodiazepines such as chlodiazepoxide,clonazepam,diazepam,oxazepam,or lorazepam.,Anticonvulsants,including carbamazepine and valproate,have also been studied for their efficacy in alcohol withdrawal treatment. Carbamazepine has been widely used in alcohol withdrawal. Carbamazepine has demonstrated its superiority to placebo in the speed of onset to relieve alcohol withdrawal symptoms such as tremor,sweating,palpitations,sleep disturbances,depression,anxiety,and anorexia. Furthermore,studies have also demonstrated that higher success rates and reduction in withdrawal symptoms in patients treated with carbamazepine than with benzodiazepines. -
# Relapse prevention ami maintenance
Disulfiram,acamprosate,oral naltrexone,and extended-release injectable naltrexone have FDA approval for the treatment of alcohol dependence.
Disulfiram is the first agent to be approved for treatment of alcohol dependence and has been used for over 40 years. It acts as an alcohol-sensitizing agent,creating an aversion to alcohol. Disulfiram is an irreversible inhibitor of the enzymatic conversion of acetalaldehyde to acetic acid. Accumulation of acetalaldehyde results in the disulfiram-alcohol reaction: hypotension,flushing,nausea,and vomiting.,Patients must be motivated to remain abstinent and comply with prescribed dosing; usual dosage is 250 mg/day. However,some patients may receive optimal benefit from 125 to 500 mg/day. Additional unpleasant symptoms such as chest pain,seizures,hepatotoxicity,renal failure,and even death have been reported in severe cases.,Controlled trials of disulfiram versus placebo have not demonstrated significant improvement over placebo,and metaanalyses have only shown slight improvement in drinking. A large Veterans Cooperative Study with over 600 subjects found,however,that disulfiram may be effective in patients with no major comorbid psychiatric disorder and who were motivated for abstinence. More recently,an evaluation of subjects with current depression on disulfiram reported lower craving over time than subjects with depression on naltrexone. The utility of combining disulfiram with other therapeutic interventions has also been examined. In a trial of disulfiram and acamprosate,the number of abstinent days was greater when utilizing a combination of disulfiram and acamprosate than using either medication alone.
Naltrexone acts as an antagonist at the opioid receptors,which are known to mediate the rewarding effects of alcohol and thus thought to reduce desire or craving of alcohol. Studies have found that naltrexone is more effective than placebo in promoting abstinence,reducing heavy drinking days and decreasing relapse rates,- particularly when it is combined with cognitive behavioral therapy - Naltrexone has also shown greater efficacy when compared with acamprosate. In a randomized controlled trial comparing the efficacy of acamprosate and naltrexone in the treatment of alcohol dependence,significant increases in time to first relapse was seen in those receiving naltrexone in subjects with no depression and low dependency. Furthermore,combined pharmacotherapy studies have also demonstrated that naltrexone administered with behavioral therapy can significantly reduce the risk of heavy drinking. Naltrexone is prescribed as 50 mg oral administration,most commonly for 12 weeks,and can also be given as a long-acting depot formulation every 4 weeks. Acamprosate attenuates alcohol desire or craving by normalizing the dysregulation of N-methyl-D-aspartate (NMDA)-mediated glutaminergic excitation that occurs in alcohol withdrawal and early abstinence. Acamprosate,when given at 2 g administered three times daily,has increased abstinence by 50% in over 3000 patients across a dozen clinical trials. - Side effects such as diarrhea are generally well tolerated. A placebo-controlled trial enrolled 272 patients and treated patients for 48 weeks. Compared with placebo,acamprosate-treated alcoholdependent patients had twice the rate of sustained abstinence at 48 weeks (43% vs 21%),and this difference from placebo was sustained at 96 weeks after starting the medication (37% vs 17 %). Thus,this appears to be a very effective approach to treating patients in order to maintain alcohol abstinence after detoxification.
Topiramate,an anticonvulsant medication,has been shown to improve the drinking outcomes of alcoholdependent individuals vs placebo,but only in a single study thus far,by Johnson et al. In this topiramate study the patients were actively drinking when started on medication,rather than being first detoxified from alcohol and being abstinent. The outcome was remarkable,with an increase from no days abstinent at baseline to 44% of days abstinent by week 12,compared with 18% of days abstinent for the placebo group. In cases of dual dependency on opiates and alcohol,topiramate may be useful at a low dose in buprenorphine or methadone maintained,alcohol-abusing patients who do not need medical detoxification for alcohol.
Serotonergic agents,including buspirone (a serotonin [5HT]-1A agonist),selective serotonin uptake inhibitors (SSRIs),and the 5-HT3 antagonist ondansetron have been studied more extensively as treatments for alcohol dependence. Fluoxetine or citalopram,two SSRIs,have been effective in reducing alcohol consumption in some studies,though results have been inconsistent. - Results may be inconsistent due to heterogeneity in study populations. For example,Kranzler et al suggested that SSRIs may be more effective in heavy drinkers or those with a family history of alcoholism,as well as those with a comorbid major depressive disorder.","department":"
