Varenicline (Chantix) For Alcoholism?

We
already knew that rel="tag">varenicline
could be used to help people stop smoking.  Now there is a
report that it can help reduce alcohol consumption, at least for rats.



This was reported in title="Proceedings of the National Academy of Sciences">PNAS
(Varenicline, an α4β2
nicotinic acetylcholine receptor
partial agonist, selectively decreases ethanol consumption and seeking
)on
an open-access basis, and echoed in a report in Scientific
American
( href="http://www.sciam.com/article.cfm?articleID=ACE9FF1E-E7F2-99DF-31F26EC00AA05F4A&sc=I100322">Need
a Cigarette and a Cocktail? Just Pop a Pill Instead
)...





To
review what we already knew:



i-45d1335da24ce88d0c178235d2d1206c-180px-Laburnum_anagyroides2.jpgVarenicline tartrate was the Prous
Scientific href="http://www.prous.com/molecules/default.asp?ID=145">Molecule
of the Month
for March 2006.  



It is a
synthetic drug, modeled after the alkaloid href="http://en.wikipedia.org/wiki/Cytisine" rel="tag">cytisine.
 Cytisine
is found in the plant, Laburnum, among
others.  Laburnum is a flowering shrub typically found in the
mountains of southern Europe.  Cytisine is known to interact
with nicotine receptors, and does have some effectiveness for smoking
cessation, but not as much as varenicline.

 








i-8a682560b29c02536b572758331d5dcb-200px-Cytisine.png

cytisine



i-c0389def8edc5292acadbdb81af4e8f9-varenicline.jpg

Chantix® (varenicline tartrate)



i-a983aa11479ff95635eeb08ba030f3f9-nicotine.gif



Varenicline
is a partial
agonist for a particular type of href="http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor">nicotine
receptor.  The term href="http://en.wikipedia.org/wiki/Agonist">partial
agonist

refers to a chemical that activates the receptor, but is not able
activate the receptor to its full extent.  



In the case of varenicline, it acts on a subtype of nicotine receptor
called the α4β2 (alpha4beta2)
nicotinic receptors.  Varenicline activates these receptors,
providing an effect similar to that of a low to medium amount of
nicotine.  However, because it is a partial agonist, it is not
possible to get as strong an effect as one would get with a high dose
of nicotine.  In fact, the presence of Chantix would make it
impossible for the receptors to be activated fully, even in the
presence of a high dose of nicotine.



As a result, the patient gets relief from nicotine craving, but only to
a certain extent.  Smoking a cigarette while taking
varenicline
would not result in increased activation of the receptors.  




In May 2006, it was href="http://www.fda.gov/bbs/topics/NEWS/2006/NEW01370.html">approved
by the US FDA to assist with smoking cessation.



In January 2007, a href="http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006103/frame.html">Chochrane
Review Group href="http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006103/abstract.html">reported (HT: href="http://scienceblogs.com/clock/2007/01/new_treatments.php">Coturnix)
that there was evidence that varenicline was superior to href="http://scienceblogs.com/corpuscallosum/2007/07/selection_of_antidepressants_w.php"
rel="tag">bupropion ( href="http://www.wellbutrin-xl.com/" rel="tag">Wellbutrin®/ href="http://websearch.gsk.com/search?Action=Search&output=xml_no_dtd&oe=UTF-8&ie=UTF-8&client=us_gsk_com_FE&proxystylesheet=us_gsk_com_FE&site=gsk_com&sitesearch=us.gsk.com&filter=0&q=zyban&x=0&y=0"
rel="tag">Zyban®) for
smoking cessation.



We
found five trials of varenicline compared with
placebo for smoking
cessation; three of these also included a bupropion experimental arm.
We also found one relapse prevention trial, comparing varenicline with
placebo. The six trials covered 4924 participants, 2451 of whom used
varenicline...



The pooled odds ratio (OR) for continuous abstinence at 12 months for
varenicline versus placebo was 3.22 (95% confidence interval [CI] 2.43
to 4.27). The pooled OR for varenicline versus bupropion was 1.66 (95%
CI 1.28 to 2.16). The main adverse effect of varenicline was nausea,
which was mostly at mild to moderate levels and usually subsided over
time. The two trials which tested the use of varenicline beyond the
12-week standard regimen found the drug to be well-tolerated and
effective during long-term use.



The one cytisine trial included in this review found that more
participants taking cytisine stopped smoking compared with placebo at
two-year follow up, with an OR of 1.77 (95% CI 1.30 to 2.40)...



Cytisine may also increase the chances of quitting, but the evidence at
present is inconclusive.



The Cochrane folks are pretty conservative, and relatively free of
commercial bias.  So if they are happy with varenicline, it is
a good indication that it works. (For some people, at least)



So, we have a commercially-available drug that works for one kind of
addiction.  It seems to make sense that it would work for
nicotine dependence, based upon its mechanism of action.
 However, at first glance, there seems to be little reason to
hypothesize that it could help with a different kind of addiction.
 



As is often the case with psychopharmacology, though, there is a huge
difference between what these kinds of soft hypotheses would suggest,
and what actually happens in the brain.



href="http://www.pnas.org/cgi/content/abstract/0705368104v1">Varenicline,
an α4β2 nicotinic acetylcholine receptor

partial
agonist, selectively decreases ethanol


consumption
and seeking.


Pia
Steensland, Jeffrey A. Simms, Joan Holgate, Jemma K. Richards, and
Selena E. Bartlett*

Ernest
Gallo Clinic and Research Center, University of California, San
Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608



Published online before print July 11, 2007

Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0705368104



Alcohol dependence is a disease that impacts millions of
individuals worldwide. There has been some progress with
pharmacotherapy for alcohol-dependent individuals; however, there
remains a critical need for the development of novel and additional
therapeutic approaches. Alcohol and nicotine are commonly abused
together, and there is evidence that neuronal nicotinic acetylcholine
receptors (nAChRs) play a role in both alcohol and nicotine dependence.
Varenicline, a partial agonist at the {alpha}4{beta}2 nAChRs, reduces
nicotine intake and was recently approved as a smoking cessation aid.
We have investigated the role of varenicline in the modulation of
ethanol consumption and seeking using three different animal models of
drinking. We show that acute administration of varenicline, in doses
reported to reduce nicotine reward, selectively reduced ethanol but not
sucrose seeking using an operant self-administration drinking paradigm
and also decreased voluntary ethanol but not water consumption in
animals chronically exposed to ethanol for 2 months before varenicline
treatment. Furthermore, chronic varenicline administration decreased
ethanol consumption, which did not result in a rebound increase in
ethanol intake when the varenicline was no longer administered. The
data suggest that the {alpha}4{beta}2 nAChRs may play a role in
ethanol-seeking behaviors in animals chronically exposed to ethanol.
The selectivity of varenicline in decreasing ethanol consumption
combined with its reported safety profile and mild side effects in
humans suggest that varenicline may prove to be a treatment for alcohol
dependence.



A Medline search turns up only one article on both varenicline and
ethanol.  So what is in the article is the sum total of
published knowledge on the subject. It is reported that clinical trials
in humans are href="http://pub.ucsf.edu/newsservices/releases/200707063/">planned,
although none is registered
yet. (Interestingly, there are trials of varenicline for href="http://www.schizophrenia.com/">schizophrenia,
but that is another story.)



The fact that varenicline reduces consumption of ethanol but not
sucrose suggests that it does not act merely by inducing nausea, or
some such nonspecific mechanism.



So if there is a specific mechanism, then what is it?  The
details are still being worked out, but the text of the paper does give
us some clues.  



face="Helvetica, Arial, sans-serif">Studies have shown that
the nonselective nAChR antagonist, href="http://en.wikipedia.org/wiki/Mecamylamine" rel="tag">mecamylamine,
decreases ethanol consumption in rats (20–22) and attenuates
ethanol-induced rel="tag">dopamine release in the href="http://en.wikipedia.org/wiki/Nucleus_accumbens" rel="tag">nucleus
accumbens (21, 23, 24). Furthermore, mecamylamine has been
reported to block the stimulant or euphoric subjective effects of
alcohol and decreases the self-reported desire to consume more alcohol
in healthy human volunteers (25–27). href="http://en.wikipedia.org/wiki/Acetylcholine">Acetylcholine
(Ach) levels in the href="http://en.wikipedia.org/wiki/Ventral_tegmental_area">ventral
tegmental area and dopamine levels in the nucleus accumbens
are increased in animals consuming ethanol (28). Changes in Ach levels
in the nucleus accumbens have been suggested to be involved in
modulating alcohol withdrawal (29). These results suggest that the
nAChRs may be involved in mediating the rewarding properties of
ethanol...



Even though the nicotinic receptors are not affected directly by
ethanol in any specific way, they are affected indirectly.  It
appears that varenicline interrupts the reward pathway that is involved
in alcohol addiction.  



I doubt anyone thinks this is going to be a cure.  But
alcoholism is such a huge problem that anything that can help some
people should be welcome.


  

Categories

More like this

One of the more recent offerings in the pernicious practice of direct-to-consumer (DTC) advertising from Big Pharma is a tortoise and a hare hawking a smoking cessation med: Chantix. The drug, varenicline tartrate, has a dual action in that it acts as both a partial agonist (enhancing activity but…
Looks like yet another interesting toxin was found, this time in a venomous snail. This discovery comes from the lab of an old player in the field, who apparently discovered the conotoxin that is used in Prialt. McIntosh says the OmIA toxin will be useful in designing new medicines because it fits…
Smoking cessation is tricky business - most of the time, people have used nicotine replacement therapy (the patch, the gum, etc) or CNS active drugs (like Wellbutrin/Zyban/Bupropion). None of it works that well - the manufacturers of today's molecule, Chantix, considered it news to brag about when…
T face="Helvetica, Arial, sans-serif">his is another post in a series detailing the selection of antidepressant medication.  Use the "Antidepressants" link in the "Categories" part of the sidebar to find the other posts in the series. In this post, I am sort of assuming that the reader has read…

Excellent review, Joseph. We need to be extremely careful of the conclusions drawn from Pfizer's five varenicline studies as a conversation with any new user will likely reveal that before ever quitting smoking they experienced a spooking and eerie sensation, as there was no dopamine "aaah" explosion inside their brain within 8-10 seconds of a puff of nicotine. In fact, as one user commented, puffing on a cigarette was like smoking a carrot.

It was false for Pfizer to suggest that the study's blind was maintained when almost all of the active group had powerful evidence of assignment BEFORE ever quitting. It makes the impact of record number of ongoing counseling and support contacts by Pfizer, each with their own proven effectiveness, call into question the efficacy findings you quote.

Also, I'm now pretty much convinced that in drug addiction studies, use of the placebo controlled double-blind study format is a license to steal. Cessation pharamacology has yet to prevail in any real-world quitting method survey conducted to date yet in RCTs in consistently demonstrates efficacy from 1.5 to the 3.22 pooled odds ratio you reference here. But how?

Studying drug addiction in placebo controlled RCTs is unique in actually punishing participants by placebo group assignment. We actually guarantee that each will be thrown into a state of full-blown nicotine withdrawal, and that's atop any underlying medical or health problems they already had. In studies of other medical conditions we attempt to improve an underlying condition, not create one.

You quote the Cochrane folks favorably but years ago I pointed the above out to them. Their "group think" regarding pharmacology efficacy was so deep that they shrugged it off.

It may be that out in real-world use varenicline will prove to be vastly superior to quitting without it but in that those expecting to endure full-blown withdrawal, a massive group reflecting 80-90% of all quitters (who we refer to as cold turkey quitters) have yet to be invited to go head-to-head against pharmacology in any real-world study.

My guess is that when their expectations are at last pitted against those joining clinical "medicine" studies in hopes of experiencing some degree of withdrawal syndrome reduction that the pharmaceutical industry will do its very best to keep them in ignorance and darkness, when educating and supporting them as to successful abrupt nicotine cessation would likely have made the active chemical being tested have vastly less efficacy.

Regards,

John R. Polito
Editor WhyQuit

Great, the why Quit guy. interesting that here he states that it may prove good in the real world, but one his website he quotes it as a failure.

I used Chantix to quit smoking and thought it was great.
I quit 12/25/06. I only took the drug for 30 days total.
We'll be hearing alot more good news as more people have success with it.

I took began Chantix for smoking cessation, but soon realized I was coming home from working and downing ice water instead of a martini. It wasn't a problem I was looking to address, but more a happy accident. I was a 20 year smoker, and am impressed with my lack of urge to smoke.

varenicline may reduce and even take away the need for tobacco smoking, but will that take away ADDICTION per se? the stimulant effect of varenicline is similar to nicotine. are we telling everyone that we now have a government approved form of stimulant/ addictive substance in the market for all?

please don't be confused with eagerness to quite smoking, until we forget that we are mere switching to another form of stimulant, with added cost to buy it?remember the price for varenicline is not cheap and God knows how long we need to depend on it? for life???

By Joseph Lee, MB… (not verified) on 02 Apr 2008 #permalink

I used chantix and it made me go insane, i was seeing things and hearing things and literally going crazy. The second they took me off I was fine and sadly, started smoking again.

Not sure if anyone's still reading this, but there is some precidence for this method working with other systems. Alcoholism is treated effectively about 80% of the time by taking naltrexone (endorphin antagonist) and drinking while the receptors are clogged. This is gaining popularity right now under the name of "Sinclair Method". The drinking part is necessary, though - its effectiveness is worse than placebo if you don't drink while on naltrexone. No telling if the acetylcholine pathways work the same way, though.