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治疗上瘾问题的药物有望出现

更新时间:2014-1-15 20:25:32 来源:华尔街日报中文网 作者:佚名

A Pill to Cure Addiction?
治疗上瘾问题的药物有望出现

New research is identifying the molecular reasons why alcohol and drug habits are so difficult to break, which could point the way to new medicines to help addicts go cold turkey.

Scientists have known for years how heavy use of alcohol and drugs works on reward centers in the brain to drive dependence. The new research, including a study published in November in JAMA Internal Medicine and early-stage drug testing at the National Institute on Alcohol Abuse and Alcoholism, is revealing another, darker side to how such substances impact the brain. By transforming its chemical architecture, drinking and drug use trigger feelings of anxiety and tension that can only be eased by more consumption.

'There's been a huge amount of progress understanding what drives alcoholism and makes it difficult to stop,' says Barbara Mason, co-director of the Pearson Center for Alcoholism and Addiction Research at the Scripps Research Institute in La Jolla, Calif.

While this dark side has been documented in laboratory animals and in some human testing, its validity in people was significantly bolstered by the recent JAMA-published study, led by Dr. Mason, indicating that a drug that targets dependency's stressful effects helped quitters. Its findings: About 45% of the 150 alcoholics who took the highest dose of the drug, known generically as gabapentin, either stopped drinking altogether or did so only occasionally.

In 2011, more than 21 million Americans needed treatment for a problem related to alcohol or drugs, according to the federal government's most recent National Survey on Drug Use and Health. Many try to quit, but studies show 60% or more of alcoholics and drug addicts relapse within a year of trying to kick their habit, addiction specialists say.

Support groups like Alcoholics Anonymous and Narcotics Anonymous only work in a fraction of alcoholics and addicts, according to Michael Fingerhood, who heads Johns Hopkins University School of Medicine's division of chemical dependency. The few pharmaceuticals taking aim at alcoholism often don't work or are dropped by addicts before they achieve recovery. And while chemical-replacement therapies like methadone have proved effective at reducing pleasure and blocking cravings for certain opiates, there is no known effective prescription medicine available for treating cocaine addiction, he says.

Until now, most research has focused on the pleasure provided by drinking or drug use, studying how neurotransmitters like dopamine help give rise to rewarding feelings -- a buzz or high -- that encourage further consumption. But heavy substance abuse can compromise this reward system, researchers say, requiring the production of ever-increasing amounts of dopamine to realize the same high. Addiction can follow.

More recent research is showing that the brain's stress response also contributes to dependence. Years of heavy drinking or drug use remodels the circuitry in and around a part of the brain known as the amygdala where these feelings of anxiety are triggered, says George Koob, who pioneered study of this dark side of addiction. The brain's stress system is sent into overdrive.

The result: constant feelings of tension that alcohol or drugs temporarily lighten, but which worsen over the longer term. 'You're kind of digging a hole every time you fix the hole,' says Dr. Koob, a Scripps scientist who is the incoming director of the National Institute on Alcohol Abuse and Alcoholism.

One chemical found to play a role in the brain's stress response is known by the initials CRF (corticotropin-releasing factor). It springs into action when there is a bang in the night or a tight deadline approaching. It is also triggered by alcohol or drug use because it helps the brain return to a normal state after the heightened sensation of pleasure. But years of heavy drinking or drug taking makes the brain more sensitive to CRF.

In effect, the brain remembers that the substances relieve stress, says Paul Kenny, who studies the molecular underpinnings of addiction at the Icahn School of Medicine at Mount Sinai. The brain's stress response gets stuck in high gear.

CRF is sometimes referred to as a 'misery neurotransmitter' because it is thought to cause the anxiousness felt by addicts until they receive temporary relief by drinking again or taking drugs. The chemical is also thought to be a driver behind the difficulties that alcoholics or addicts have trying to quit, especially during stressful episodes that add to the feelings of tension.

The NIAAA, a part of the National Institutes of Health, is conducting early-stage testing in alcoholics of two experimental drugs that aim to stop CRF from revving up the brain's stress centers, says Markus Heilig, the agency's clinical director. NIAAA is also testing in alcoholics and heroin addicts a third drug that stymies another neurotransmitter involved in stress response, called neurokinin 1.

Kathy Selman says she failed several times to wean herself from alcohol because struggles to stay afloat amid the recent economic downturn propelled her to drink again.

Ms. Selman, a 57-year-old sales and marketing professional from San Diego, says she slipped into alcoholism around 2007, after her husband lost his job and the couple lost three parents, their savings and then their rental properties and home.

Afraid her two sons would only know her as an alcoholic, she enrolled in the Pearson Center's trial testing gabapentin in 2011. The drug, which is also sold under the brand name Neurontin, is approved for the treatment of epileptic seizures. It also calms the brain's stress system, addiction researchers say.

Ms. Selman doesn't know for certain whether she received gabapentin or a placebo as part of the study. She believes she got the medicine because her mood lightened during the 12 weeks she was taking the capsules and she felt depressed for a period afterward. And quickly, she quit drinking entirely, Ms. Selman says

She says she remains sober, but admits that as she tries to launch new ventures in business networking and addiction coaching, the daily stresses can be trying. As part of the study, Ms. Selman also received counseling, and through it, she says she learned how stress triggered her desire to drink and ways to cope with the related wave of anxiety. One of her strategies: She carries index cards that remind her how she felt while drinking and how she feels since going sober.

Nora Volkow, director of the National Institute on Drug Abuse, says successfully treating addiction will probably require a combination of behavioral and cognitive counseling with the prescription of multiple medicines tailored to the phase of recovery and targeting both the light and dark sides of dependence.

'These two systems interact very, very clearly with one another,' Dr. Volkow says.

新研究开始鉴定在分子层面酒瘾与毒瘾为何如此难以戒除的原因,这也许能给帮助上瘾者快速戒除酒瘾或毒瘾的新药物指明方向。

科学家们多年前就已了解大量饮酒及吸毒是如何对大脑的奖赏中心发生作用并因此促成依赖性的。目前的新调研包括一项于11月发表在《美国医学会杂志·内科学》(JAMA Internal Medicine)的研究,以及美国国家酒精滥用及酗酒问题研究所(National Institute on Alcohol Abuse and Alcoholism,简称“NIAAA”)进行的药物初期试验,它们揭示了酒精与毒品对大脑产生影响的更隐秘的一面。饮酒与吸毒会改变大脑的化学结构,从而触发焦虑感和紧张感,这些感觉只有通过加大饮酒与吸毒量才能缓解。

加州拉荷亚(La Jolla)斯克里普斯研究院(Scripps Research Institute)皮尔逊酗酒及毒瘾问题研究中心(Pearson Center for Alcoholism and Addiction Research)的联席主任芭芭拉·梅森(Barbara Mason)说:“在了解是什么引发酗酒并让它难以停止方面,研究已经取得了巨大进步。”尽管此隐秘的一面在实验室动物实验及某些人类试验中已有记录,但为其可信性提供重要支持的是由梅森博士带头、近期发表于JAMA的研究,该研究表明有一种针对依赖性所引发的紧张感的药物可帮助到戒瘾者。研究发现,在服用了该药物(通常被人称为加巴喷丁)最高剂量的150名酗酒者中,约有45%的人要么完全不再饮酒,要么只是偶尔饮酒。

美国联邦政府近期展开的“全国吸毒与健康调查”显示,2011年美国有2,100多万人需要接受与酗酒或吸毒有关的治疗。成瘾问题专家称,有许多人尝试戒瘾,但研究表明有60%或更多的酒精和毒品上瘾者在试图戒瘾的第一年中就重犯酒瘾或毒瘾。

约翰霍普金斯大学(Johns Hopkins University)医学院化学药品依赖治疗科主任迈克尔·芬格胡德(Michael Fingerhood)认为,像戒酒互助会和戒毒互助会这样的互助群体只在一小部分酗酒者和吸毒者中起作用。那几种针对酗酒问题的药品往往不起作用或是被上瘾者在康复之前就弃用了。他指出,尽管事实证明像服用美沙酮这样的化学药品替代疗法在减轻愉悦感和抑制对某些鸦片制品的渴求方面比较有效,但已知的能有效治疗可卡因上瘾问题的处方药目前还没有。

至今为止,大多数研究都集中于饮酒或吸毒带来的愉悦感,主要研究多巴胺等神经传递素如何引发让人满意的感觉,比如兴奋感或快感,并促动更多地饮酒或吸毒。研究人员指出,大量饮酒或吸毒会损害这个奖赏系统,达到同样程度的快感需要不断产生更多的多巴胺,因此上瘾行为会随之出现。

较新的研究表明,大脑的应激反应也会促发依赖性。最早对上瘾问题这一隐秘面展开研究的乔治·科布(George Koob)指出,这些焦虑感在脑部一个名为扁桃核的区域被激发出来,常年大量饮酒或吸毒会改变该区域内部及其周围的神经回路。大脑的应激系统会变得负担过重。

其结果是:酒精或毒品可暂时缓解不断出现的紧张感,但长期下去紧张感会加剧。说:“那有点儿像每次在补坑的同时又挖了一个坑。”科布是斯克里普斯研究院的一名科学家,即将就任NIAAA的主任。

有一种化学物质被发现在大脑的应激反应中发挥著作用,它被人称为促肾上腺皮质激素释放因子(首字母缩写为“CRF”)。当人们在夜晚听到一声巨响或是紧迫的最终期限逼近时,它就会产生作用。它也会被酒精或毒品激发出来,因为其有助于大脑在愉悦感增强后恢复至正常状态。不过,经年累月的酗酒或吸毒会让大脑对CRF更加敏感。

西奈山伊坎医学院(Icahn School of Medicine)研究成瘾问题分子基础的保罗·肯尼(Paul Kenny)指出,事实上,大脑会记住何种物质能缓解压力。大脑的应激反应在长期高速运转后会陷入停滞。

CRF有时又被称为 “痛苦神经传递素”,因为它被认为是上瘾者所感受到的焦虑感的诱因,这些感觉直到上瘾者再次饮酒或吸毒时才会暂时缓解。该化学物质也被认为是酗酒者或吸毒成瘾者在尝试戒酒戒毒时所面临困境背后的原因,尤其是在会令紧张感加剧的压力时期更明显。

NIAAA为美国国家卫生研究院(National Institutes of Health)的分支。该机构的医疗主任马库斯·海利希(Markus Heilig)称,他们正在就两种旨在阻止CRF刺激大脑压力中心的实验药品展开初期试验。NIAAA还在酗酒者和海洛因上瘾者中试验第三种药物,它旨在阻止另一种参与应激反应的名为神经激?1的神经传递素。

凯茜·塞尔曼(Kathy Selman)今年57岁,是加州 地亚哥的一名销售及营销人员。她说她有几次戒酒都失败了,因为这期间她还要在近些年经济衰退的环境下苦苦维持生活,所以她又再次酗酒了。

塞尔曼说她是在2007年左右开始酗酒的,在那之前她丈夫丢掉了工作,他们还失去了双方父母中的三位和他们自己的积蓄,后来又失去了他们租的房子以及他们的家。

她害怕自己只会给两个儿子留下酒鬼的印象,于是她在2011年报名参加了皮尔逊研究中心的加巴喷丁试验项目。该药物还以“Neurontin”的名称销售,被批准用于癫痫发作的治疗。研究人员称,它还可镇定大脑的应激系统。

塞尔曼不确定她服用的是加巴喷丁还是安慰剂,这是研究的一部分内容。她认为自己服用的是加巴喷丁,因为她在服用胶囊的12周里心情变轻松了,但在随后的一段时期她又感觉到抑郁。她说,她很快就完全戒掉了酒瘾。

她说现在她依然不会酗酒,但她也承认由于自己开始尝试商业网络和上瘾问题指导领域的新事业,每天的压力会让人备受考验。作为研究的一部分内容,她还接受了咨询,她说她通过咨询了解到压力是如何激发她的饮酒欲望的,并了解了应对相关焦虑情绪的方法。她的应对策略之一是:随身携带索引卡,它们提醒她在饮酒期间感受以及自戒酒以来她的感受。

美国毒瘾问题研究院(National Institute on Drug Abuse)主任诺拉·沃尔科(Nora Volkow)称,若要成功治疗上瘾问题,可能需要将行为及认知咨询与专门为康复阶段定制、针对依赖性的光明面与隐秘面这两个方面的多种药物结合在一起。

沃尔科说:“这两个系统能相互产生作用,这非常非常明显。”

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