1. Översiktlig projektbeskrivning

Engelsk titel

Can a smoking cessation medication be used to treat alcohol dependence?

Sammanfattning av projektet

SYFTE:
Mottagare för nikotin (nikotinreceptorer) i hjärnans belöningssystem hos råtta påverkas av både alkohol och nikotin. Detta resulterar i att belöningssystemet aktiveras vilket driver oss att konsumera belöningar och så småningom utvecklas ett beroende. Rökavvänjningsläkemedlet Champix® sänker alkoholkonsumtionen hos råtta och hos friska frivilliga rökare. Följande projekt undersöker om Champix® kan sänka alkoholkonsumtionen hos alkoholberoende personer och om läkemedlet påverkar subjektiva belönande egenskaperna av alkohol. Syftet är att A) direkt sänka den höga alkoholkonsumtion som finns hos så många individer för att förebygga alkoholskador, B) att finna bättre läkemedel för behandling av alkoholism och C) att öka kunskapen om både de psykologiska och de biologiska mekanismerna bakom alkoholberoende. Projektet är prövarinitierat och icke-kommersiellt, vilket innebär att det genomförs utan inblandning från läkemedelsindustrin.
GENOMFÖRANDE:
Studien har pågått på Beroendekliniken på Sahlgrenska Universitetssjukhuset, Göteborg, Karolinska Institutet, Stockholm och Universitetssjukhuset MAS, Malmö under 2009-2010. 162 personer har genomgått behandlingen varav hälften har fått läkemedel och hälften sockerpiller (dubbelblindat). Vi arbetar nu med dataanalys och beräknar avblinda data i början av 2011.
METOD:
162 frivilliga alkoholberoende män och kvinnor (30-70 år) får delta i en randomiserad placebokontrollerad dubbelblind studie där de dagligen under 14 veckor intar Champix® eller placebo i tablettform i sin hemmiljö. De får samtidigt föra dagbok över konsumtionen av alkohol och nikotin och kommer vid 8 olika besökstillfällen att besöka kliniken för att svara på formulär (frågor om fysisk och psykisk hälsa, alkohol- och nikotinkonsumtion) samt lämna blodprov. Efter studiens slut analyseras data för att undersöka om Champix® kan sänka alkoholkonsumtionen. Blodprov från studiedeltagarna sparas för analys av gener som kan vara inblandade vid alkoholsjukdom och för att studera genetiska skillnader mellan personer som har olika effekt av ett läkemedel på alkoholkonsumtionen och som tar olika stor skada av hög alkoholkonsumtion.
BETYDELSE:
Utöver det lidande som drabbar den beroende individen och anhöriga, uppskattas alkoholrelaterade konsekvenser enbart i Sverige kosta över 150 miljarder kronor/år. Idag finns tre läkemedel för behandling av alkoholism, men hos många patienter har dessa läkemedel dålig eller ingen effekt och behovet av nya läkemedel och ny kunskap om bakgrunden till alkoholsjukdomar är därför stort. Att effektivt sänka alkoholkonsumtionen och de belönande upplevelserna av alkoholen hos alkoholberoende individer skulle kunna sänka alkoholskadorna i samhället markant.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva ämnesområdet

Inlagda MeSH-termer

Alcoholism

A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. (Morse & Flavin for the Joint Commission of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism: in JAMA 1992;268:1012-4)

Tobacco Use Disorder

Tobacco used to the detriment of a person's health or social functioning. Tobacco dependence is included.

Placebos

Any dummy medication or treatment. Although placebos originally were medicinal preparations having no specific pharmacological activity against a targeted condition, the concept has been extended to include treatments or procedures, especially those administered to control groups in clinical trials in order to provide baseline measurements for the experimental protocol.

Projektets delaktighet i utbildning

Avhandling
D-uppsats / Magisterexamen
C-uppsats / Kandidatexamen
ST-läkarutbildning
Annan utbildning
Ej del i utbildning

3. Processen och projektets redovisning

Pågående aktiviteter

Planering och förberedelse före datainsamling
Datainsamling pågår
Analys av insamlade data pågår
Författande av skriftlig redovisning / publikation pågår
En eller flera publikationer från projektet är publicerade
Slutfört och inget mer görs inom ramen för detta projekt

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2007-08-01

Datum för påbörjande av datainsamling

2009-03-16

Datum då projektet är slutrapporterat

2013-07-31

4. Detaljerad projektbeskrivning

Bakgrundsbeskrivning

In 2006, I defended my PhD-thesis that investigated the mechanisms behind, and proposed new explanations for, the common co-abuse of nicotine and alcohol [1]. The main findings suggest that specific subtypes of nicotinic acetylcholine receptors (nAChRs) are crucially involved in several aspects of alcohol addiction in the experimental rat [2-3]. The thesis proposed particular nAChRs as potential targets for novel selective pharmacological interventions aimed at reducing craving and relapse in alcoholism. A compound with such property is Champix® (varenicline), a recently approved medication for smoking cessation. It acts as a partial agonist for several nAChRs [4], slightly increasing the activity of the mesolimbic dopamine system, while blocking the addictive dopamine-stimulatory properties of nicotine. We and others have demonstrated that varenicline reduces rewarding properties of alcohol and alcohol consumption in laboratory animals [5-6]. These data are supported by a recent paper demonstrating a reduction in alcohol self-administration in human heavy-drinking smokers [7]. Together these results suggest a tentative user for Champix® in treating alcohol dependence.

Syfte

The present post doc project is a multi(3)centre clinical trial. It aims at investigating whether 14 weeks of daily treatment with Champix® affects alcohol consumption in 162 alcohol dependent men and women in Sweden.

Teoretisk referensram

Alcoholism is estimated to be over 10 times more common among smokers than non-smokers, and nicotine dependent subjects suffer from a greater severity of alcohol dependence [8]. Extensive research demonstrates that the association between smoking and drinking cannot exclusively be explained by environmental or psychosocial factors. For instance, nAChRs are the common point of action for nicotine and alcohol in the mesolimbic dopamine system (the “brain reward system”) [9-11]. Indeed, the non-selective nAChR antagonist mecamylamine reduces the self-reported rewarding effects of alcohol in healthy volunteers [12-14] but is, however, associated with substantial side effects, emphasizing the need for new, more selective nAChR modulators for treatment of alcoholism.
Champix® (varenicline) is a newly registered medication for smoking cessation [15, 16]. It acts as a partial agonist for several nAChRs, slightly increasing the activity of the mesolimbic dopamine system, while blocking the addictive dopamine-stimulatory properties of nicotine [4, 17]. Research with laboratory animals points to a use for varenicline in treating alcohol dependence. Our pre-clinical data demonstrate an interaction between alcohol and varenicline on the activity of the mesolimbic dopamine system in the rat [5]. Moreover, varenicline significantly reduced alcohol seeking and consumption in alcohol high-preferring animals [6], an effect that was not observed in alcohol non-dependent rats (unpublished data from our laboratory). These data are supported by a recent paper demonstrating a reduction in alcohol self-administration in heavy-drinking smokers [7].

Metod: Gruppindelning

randomiserad dubbelblind

Resultat

PRELIMINARY RESULTS
We (the Gothenburg site) started the trial in March 2009, the clinic in Malmö started in August 2009 and the Stockholm site started in December 2009. More than 700 persons have called our clinics for an initial pre-screening. 162 trials subjects have finished treatment according to Intention To Treat. We are currently working on data analysis and expect to unblind the data in early 2011. Since the trial is double blinded we cannot speculate on a possible effect of treatment at this stage. It is clear however, that the trial compliance is excellent so far with no drop-outs and good diary and medication compliance. Many trial subjects have reduced their alcohol consumption substantially, suggesting our trial as a good prevention for alcohol-related disorders.

Diskussion

ETHICAL AND REGULATORY CONSIDERATIONS
The clinical trial is authorized by the regional ethics committee in Gothenburg (Dnr: 440-08) and by the Swedish Medical Products Agency (Läkemedelsverket; Dnr: 151:2008/52328).

OVERALL SIGNIFICANCE
Alcoholism is a world-wide problem causing considerable suffering to the individual and enormous costs to society. In Sweden alone, the annual cost for alcohol abuse is estimated to 150 billion SEK [18]. Alcoholism not only has direct medical, psychological and social consequences for the afflicted, but is often a cause of work-related accidents, traffic accidents, violent crime and foetal alcohol syndrome, etc. Three pharmacological compounds are available for the treatment of alcohol dependence (acamprosate, naltrexone, disulfiram). However, in many patients these drugs have low or no efficiency and there is a world-wide increasing need for better compounds for this indication.
The proposed project is significant on several levels. It will advance our understanding of the registered smoking cessation medication Champix® (varenicline) and evaluate its efficacy for smoking cessation also in alcohol dependent smokers as well as investigate its potential as a new treatment of alcohol dependence. If varenicline reduces both nicotine and alcohol consumption in alcohol dependent individuals, it will provide great medical value for dependent individuals as well as financial profits to society in general.
Champix® is a patented, registered medication and available on the Swedish as well as the international market. If we can demonstrate a good clinical effect of this compound on alcohol consumption in alcohol dependent individuals, there will be a short runway to introduce this indication and the compound should soon be available and useful for the dependent patients.
If genes that are important for treatment outcome can be identified, it may be possible to predict which anti-alcohol dependence compound that may be the most helpful to a specific patient and it may allow the design of better, more individual treatment programs than what is possible today.

Referenser

1.Löf, E., Conditional and non-conditional reward-related responses to alcohol - nicotinic mechanisms, in Pharmacology. 2006, Göteborg University: Gothenburg. p. 108.
2.Löf, E., et al., Ethanol-induced dopamine release in the rat - modulatory effects by subchronic treatment with nicotinic drugs. Eur J Pharmacol, 2006.
3.Löf, E., et al., Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berl). 2007 Aug 17; [Epub ahead of print] 2007.
4.Rollema, H., et al., Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology, 2007. 52(3): p. 985-94.
5.Ericson, M., et al., The smoking cessation medication varenicline attenuates alcohol and nicotine interactions in the rat mesolimbic dopamine system. J Pharmacol Exp Ther, 2009: p. jpet.108.147058.
6.Steensland, P., et al., Varenicline, an {alpha}4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. PNAS, 2007. 104(30): p. 12518-12523.
7.McKee, S.A., et al., Varenicline Reduces Alcohol Self-Administration in Heavy-Drinking Smokers. Biol Psychiatry, 2009.
8.Daeppen, J.B., et al., Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. Alcohol Alcohol, 2000. 35(2): p. 171-5.
9.Blomqvist, O., et al., The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine. Eur J Pharmacol, 1993. 249(2): p. 207-13.
10.Soderpalm, B., et al., Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res, 2000. 113(1-2): p. 85-96.
11.Larsson, A. and J.A. Engel, Neurochemical and behavioral studies on ethanol and nicotine interactions. Neurosci Biobehav Rev, 2004. 27(8): p. 713-20.
12.Blomqvist, O., et al., Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res, 2002. 26(3): p. 326-31.
13.Chi, H. and H. de Wit, Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcohol Clin Exp Res, 2003. 27(5): p. 780-6.
14.Young, E.M., et al., Mecamylamine and ethanol preference in healthy volunteers. Alcohol Clin Exp Res, 2005. 29(1): p. 58-65.
15.Jorenby, D.E., et al., Efficacy of Varenicline, an {alpha}4beta2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Placebo or Sustained-Release Bupropion for Smoking Cessation: A Randomized Controlled Trial. JAMA, 2006. 296(1): p. 56-63.
16.Gonzales, D., et al., Varenicline, an {alpha}4beta2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation: A Randomized Controlled Trial. JAMA, 2006. 296(1): p. 47-55.
17.Coe, J.W., et al., Varenicline: An alpha4beta2 Nicotinic Receptor Partial Agonist for Smoking Cessation. J. Med. Chem., 2005. 48(10): p. 3474-3477.
18.Johnson, A., Hur mycket kostar supen? Vol. Update 2003; 150 miljarder kostar supen. 2000: Sober.