I was trying to find a particular study and all I could find were abstracts of it and websites that were trying to charge me money for it. My best friend is in a PhD program at Johns Hopkins University in Baltimore, so I called him up and he gave me his login and pass for JHU's intranet and resources.

I've now got access to TONS of medical journals and I'm seeing so many studies that just plain aren't available on the regular internet.

Here's one I just pulled up, I haven't even read it yet but the title is interesting:

Effect of the combination of naltrexone and baclofen, on acquisition of alcohol drinking behavior in alcohol-preferring rats

Giancarlo Colomboa, Corresponding Author Contact Information, E-mail The Corresponding Author, Salvatore Serrab, Giovanni Vaccab, Mauro A.M. Caraib and Gian Luigi Gessaa, b

aC.N.R. Institute of Neuroscience, Section of Cagliari, Viale Diaz 182, 1-09126 Cagliari, Italy

bBernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz, 182, I-09126 Cagliari (CA), Italy

Received 5 March 2004;
revised 20 July 2004;
accepted 20 July 2004.
Available online 11 September 2004.

Abstract

Recent surveys suggest that positive outcomes in the pharmacotherapy of alcoholism may be obtained through drug combinations. The present study evaluated the effect of the combination of the opioid receptor antagonist, naltrexone, with the GABAB receptor agonist, baclofen, on the acquisition of alcohol drinking behavior in Sardinian alcohol-preferring (sP) rats. Rats were treated with either saline, 0.5 mg/kg naltrexone, 1 mg/kg baclofen, or 0.5 mg/kg naltrexone plus 1 mg/kg baclofen once a day for 10 days. alcohol was offered immediately after the first drug injection under the 2-bottle regimen. alcohol intake in saline-treated rats rose to 5–6 g/kg/day within a few days, indicative of a rapid acquisition of alcohol drinking behavior. Neither naltrexone nor baclofen, when given alone, affected alcohol drinking behavior. In contrast, the drug combination resulted in a significant reduction in daily alcohol intake and retardation in the acquisition of alcohol drinking behavior. These results suggest that combination of naltrexone plus baclofen may result in a synergistic reduction in alcohol intake in sP rats. These results are discussed in terms of naltrexone and baclofen exerting a concomitant and reciprocally potentiating inhibitory action on alcohol-induced activation of mesolimbic dopamine transmission.

Keywords: naltrexone; Baclofen; Drug combination; Acquisition of alcohol drinking behavior; Sardinian alcohol-preferring (sP) rats
Article Outline

1. Introduction
2. Methods

2.1. Animals
2.2. Experimental procedures

3. Results
4. Discussion
Acknowledgements
References

1. Introduction

The results of recent clinical surveys suggest that, in the alcohol dependence field, positive therapeutic outcomes may be achieved by drug combinations. Specifically, it has been reported that the combination of the opioid receptor antagonist naltrexone with either the putative glutamate receptor antagonist acamprosate (Kiefer et al., 2003) or the serotonin 5-HT3 receptor antagonist ondansetron (Ait-Daoud et al., 2001) may be more beneficial, in terms of reaching and maintaining alcohol abstinence, than a monotherapy with each of the above drugs. Beside a better outcome in terms of alcohol abstinence, the drug combination is expected to possess a better therapeutic index than each single drug, because of the possible use of lower drug dosages and, in turn, fewer or less pronounced side effects.

On the basis on a number of findings from animal models, indicating the ability of opioid receptor antagonists to decrease alcohol intake and different alcohol-motivated behaviors, naltrexone has been repeatedly tested and found to be effective as a treatment for alcoholism. Specifically, naltrexone has been reported to reduce alcohol consumption and prevent alcohol relapses in human alcoholics (see Modesto-Lowe and Van Kirk, 2002 and Anton and Swift, 2003).

Recent work has suggested that also the GABAB receptor agonist baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients. Indeed, a single administration of a non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology in alcohol-dependent patients (Addolorato et al., 2002b). Further, a double-blind survey demonstrated that the repeated daily treatment with baclofen was associated, in comparison to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of craving for alcohol (Addolorato et al., 2002a).

The present study was designed to investigate the effect of the combination of naltrexone and baclofen on alcohol consumption. Specifically, we tested the hypothesis that the combination of naltrexone and baclofen would result in a potentiation of the reducing effect of each single drug on alcohol intake in rats. The working hypothesis has been tested using a) the acquisition of alcohol drinking behavior as experimental procedure, since it has been found to be particularly sensitive to the suppressing effect of both naltrexone (Davidson and Amit, 1997) and baclofen (Colombo et al., 2002), and b) the selectively bred Sardinian alcohol-preferring (sP) rats as animal model of excessive alcohol consumption. Notably, these rats appear to constitute a proper animal model for the proposed investigation, in that they achieve a consumption of pharmacologically relevant amounts of alcohol rather rapidly and without the need of any induction procedure (e.g.: Colombo et al., 2002).
2. Methods
2.1. Animals

Male sP rats, from the 56th generation and approximately 75-days-old at the start of the study, were used. Rats derived from a population of sP rats which underwent caesarian derivation at Charles River (Lyon, France) for production of Specific Pathogen Free individuals. Rats were individually housed in standard plastic cages with wood chip bedding. The animal facility was under an inverted 12:12 h light-dark cycle (lights on at 11:00 p.m.), at a constant temperature of 22 ± 2 °C and relative humidity of approximately 60%. Food pellets (MIL Morini, San Polo d’Enza, RE, Italy) were always available. Rats were extensively habituated to handling and i.p. injection. Rat body weight was monitored every two days.
2.2. Experimental procedures

Throughout the duration of the experiment, alcohol was offered under the standard, homecage 2-bottle free choice regimen between alcohol (10% in tap water, v/v) and tap water, with unlimited access for 24 h/day. Bottles were refilled every day with fresh solution and their left-right positions interchanged at random to avoid development of position preference.

Rats were divided into 4 groups (n = 8), matched for body weight. alcohol presentation was initiated at the start of the dark phase of Day 1. Rats received their first treatment (specifically: saline, 0.5 mg/kg naltrexone, 1 mg/kg baclofen, or 0.5 mg/kg naltrexone plus 1 mg/kg baclofen) 30 min before alcohol presentation. Both naltrexone (Sigma Chemical Co., St. Louis, MO, U.S.A.) and baclofen (Sigma Chemical Co., St. Louis, MO, U.S.A.) were dissolved in saline; when combined, naltrexone and baclofen were dissolved in the same solution. Drug doses were chosen on the basis of the results of preliminary experiments designed to identify, for each drug, the highest ineffective dose when given alone. Drugs were injected intraperitoneally (injection volume: 2 ml/kg). Drug administration was repeated once a day (30 min before lights off) for 10 consecutive days. alcohol, water and food intake was monitored by weighing the bottles and food pellets (0.1-g accuracy) once daily immediately before the onset of the dark phase. Recording of daily alcohol, water and food intake was performed throughout the 10 days of treatment as well as for an additional 5 days after termination of treatment.

Data concerning daily alcohol, water, total fluid (i.e., the sum of alcohol solution and water consumed) and food intake during the 10-day treatment period and the 5-day post-treatment period were expressed in g/kg, ml/kg, ml/kg and g/kg, respectively, and evaluated separately by two-way (drug; day) ANOVAs with repeated measures on the day factor, followed by the Newman–Keuls test for multiple comparisons. Data on the number of rats fulfilling the selection criterion to qualify an sP rat [i.e., a daily intake of alcohol equal to or greater than 4 g/kg (Colombo, 1997)] were evaluated by comparison of the survival curves by the Logrank test.

The experimental procedures employed in the present study were in accordance with the Italian law on the “Protection of animals used for experimental and other scientific reasons” and approved by the Ethical Committee of the University of Cagliari.
3. Results

ANOVA revealed significant effects of drug treatment [Fdrug(3;252) = 11.83, P < 0.00005], treatment period [Fday(9;252)=14.60, P<0.000001] and interaction of the two factors [Finteraction(27;252) = 1.66, P < 0.05] on alcohol intake. As expected, saline-treated rats rapidly acquired alcohol drinking behavior. Indeed, mean daily alcohol intake in saline-treated rats was already higher than 3 g/kg on Day 1 and rose to 5–6 g/kg (i.e., the amount of alcohol usually consumed daily by sP rats) within a very few days (Fig. 1A). Post hoc analysis showed that daily alcohol intake in the rat group receiving baclofen alone was significantly lower than control rats on Days 1 and 2. In contrast, naltrexone alone did not significantly alter daily alcohol intake on any day of treatment. Administration of the combination of naltrexone plus baclofen resulted in a marked and significant reduction in daily alcohol intake, which persisted throughout the 10-day treatment period (Fig. 1A). Daily alcohol intake in the combination group was virtually suppressed over the first 7 days of treatment and rose to 2–3 g/kg over Days 8–10. Post hoc analysis revealed that, since Day 3, alcohol intake in the combination group was steadily lower than that recorded in baclofen and naltrexone groups.


Full-size image (32K) - Opens new window Full-size image (32K)

Fig. 1. Effect of the repeated administration of the opioid receptor antagonist naltrexone the GABAB receptor agonist baclofen or their combination on the acquisition of alcohol drinking behavior in Sardinian alcohol-preferring (sP) rats. The dashed line indicates the completion of the 10-day treatment period and the start of the 5-day post-treatment period. Each point is the mean ± S.E.M. for n = 8 rats. * : P < 0.05 with respect to saline-treated rats (Newman–Keuls test); +: P < 0.05 with respect to rats treated with both baclofen and naltrexone (Newman–Keuls test).

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When the effect of drug treatment on alcohol intake was analyzed in terms of rats fulfilling the selection criterion [a daily intake of alcohol equal to or greater than 4 g/kg (Colombo, 1997)], the comparison of the survival curves showed significant differences among rat groups (P < 0.0001; Logrank test). Specifically, all rats in the saline-treated group fulfilled the criterion within Day 2. At the end of treatment period, 7/8 rats in the naltrexone-treated group and 8/8 rats in the baclofen-treated group reached the criterion. In contrast, in the combination group only 4/8 rats met the criterion during the treatment period.

Reduction in daily alcohol intake in the naltrexone plus baclofen group was associated with a compensatory increase in water intake, so that daily total fluid intake remained unchanged; daily food intake was not significantly altered by drug treatment (Fig. 1) [water intake: Fdrug(3;252) = 9.01, P < 0.0005; Fday(9;252) = 11.05, P < 0.000001; Finteraction(27;252) = 2.39, P < 0.0005; total fluid intake: Fdrug(3;252) = 2.46, P > 0.05; Fday(9;252) = 10.22, P < 0.000001; Finteraction(27;252) = 1.10, P > 0.05; food intake: [Fdrug(3;252) = 2.24, P > 0.05; Fday(9;252) = 7.20, P < 0.000001; Finteraction(27;252) = 1.12, P > 0.05]. alcohol preference (defined as the ratio between alcohol solution and total fluid intake consumed daily) closely paralleled alcohol intake (data not shown).

After treatment completion, daily alcohol intake in the combination group immediately reached control values; neither water, total fluid nor food intake differed among rat groups during the post-treatment period (Fig. 1) [alcohol intake: Fdrug(3;112) = 1.62, P > 0.05; Fday(4;112) = 23.15, P < 0.000001; Finteraction(12;112) = 1.55, P > 0.05; water intake: Fdrug(3;112) = 2.09, P > 0.05; Fday(4;112) = 3.25, P < 0.05; Finteraction(12;112) = 1.07, P > 0.05; total fluid intake: Fdrug(3;112) = 0.31, P > 0.05; Fday(4;112) = 29.56, P < 0.000001; Finteraction(12;112) = 1.55, P > 0.05; food intake: Fdrug(3;112) = 2.89, P > 0.05; Fday(4;112) = 21.30, P < 0.000001; Finteraction(12;112) = 1.32, P > 0.05].
4. Discussion

The results of the present study demonstrate that the combination of the opioid receptor antagonist naltrexone with the GABAB receptor agonist baclofen resulted in a potentiation of the reducing effect of each drug on alcohol intake in alcohol-preferring sP rats. Specifically, doses of naltrexone or baclofen which were ineffective when given alone markedly delayed the acquisition of alcohol drinking behavior, as if the naltrexone plus baclofen combination prevented the disclosure and experience of the central effects of alcohol which sustain alcohol drinking behavior in sP rats. Importantly, the drug combination exerted a specific effect on alcohol intake, since food intake was not altered by drug treatment. The lower intake of alcohol solution recorded in the rat group treated with the drug combination was totally compensated by a proportionally higher intake of water, so that daily fluid intake remained normal. In close agreement with the results of the present study, Stromberg (2003) has recently reported that the combination of naltrexone (1 mg/kg) and baclofen (2.5–7.5 mg/kg) reduced alcohol intake to a higher extent than each single drug in alcohol-experienced Wistar rats consuming alcohol under a limited access paradigm.

The results of the present study, together with those by Stromberg (2003), extend to baclofen the ability of some drugs, including acamprosate, ondansetron, the serotonin reuptake inhibitor fluoxetine, the thyrotropin-releasing hormone analogue TA-0910, the calcium channel blocker isradipine, and the cannabinoid CB1 receptor antagonist SR 141716, to potentiate the reducing effect of naltrexone on alcohol intake or alcohol's motivational properties in rats and mice (Lê and Sellers, 1994, Gardell et al., 1997, Rezvani et al., 2000, Gallate et al., 2004 and Kim et al., 2004).

Acquisition of alcohol drinking behavior, as well as other reward processes associated to alcohol consumption, has been proposed to be secondary to activation of the mesolimbic dopamine system. Ikemoto et al. (1997) found that reduction of dopamine innervation to the nucleus accumbens by bilateral microinjection of 6-hydroxydopamine disrupted the acquisition of alcohol drinking behavior in selectively bred Indiana alcohol-preferring P rats. The results of the study by Ikemoto and colleagues (1997) are consistent with different lines of experimental evidence which suggest a role for mesolimbic dopamine in the acquisition of conditioned responses (see Di Chiara, 2002).

In keeping with this hypothesis, naltrexone and baclofen might suppress acquisition of alcohol drinking behavior (Davidson and Amit, 1997 and Colombo et al., 2002) interfering with the dopamine-mediated processes associated with this behavioral response. Consistently, both naltrexone and baclofen have been found to antagonize different effects of alcohol on dopamine transmission, including (a) stimulation of dopamine release, induced by self-administered alcohol, in the nucleus accumbens of alcohol-preferring rats (Gonzales and Weiss, 1998 and Colombo et al., 2004), and (b) alcohol-induced stimulation of locomotor activity in rats and mice (Prunell et al., 1987 and Chester and Cunningham, 1999).

Thus, the results of the present study may be interpreted suggesting that naltrexone and baclofen exerted a concomitant and reciprocally potentiating inhibitory action on alcohol-induced activation of mesolimbic dopamine transmission, resulting in an apparently synergistic suppression of acquisition of alcohol drinking behavior. If this hypothesis were correct, the data of the present study would also provide further support to the notion that accessing dopamine transmission indirectly (i.e., via receptor systems modulating dopamine function, such as the opioid and GABAB receptor systems), rather than directly [i.e., via direct agonists and antagonists of dopamine receptors, which have been found to produce controversial effects on alcohol intake (e.g.: Dyr et al., 1993, Linseman, 1990, Ng and George, 1994, Pfeffer and Samson, 1988 and Wolffgramm et al., 2000)], would constitute a more effective approach to control dopamine-related alcohol-motivated behaviors, including alcohol drinking behavior.

Other studies are needed to investigate whether the suppressing effect of the naltrexone plus baclofen combination on alcohol intake observed in the present study and in the work by Stromberg, 2003 Stromberg, M.F., 2003. Effect of baclofen alone and in combination with naltrexone on alcohol consumption. alcohol. Clin. Exp. Res. 27, 61A.Stromberg (2003) extends to other experimental models of excessive alcohol drinking. Their possible, subsequent generalization to human alcoholics might suggest a new therapeutic strategy.
Acknowledgements

The authors are grateful to Mrs. Anne Farmer for language editing of the manuscript. The present study was supported by a grant from the Italian Ministry for Education and Research (M.l.U.R.) to the “Center of Excellence on Neurobiology of Dependence”, Department of Neuroscience, University of Cagliari.

WTF do they mean by previous?

Would someone be so kind as to translate this into layman terms for me. I do use both and have a lot of confusion about the combination.
I am not having very good success and my drinking level remains constant. I am extremely frustrated and alone in my world. I feel like this is a failure for me. I am getting depressed and unambitious about my continued intake. This is not serving me well.
So if you can please simplify the study. Thanks so much.

My computer inserted the word previous before alcohol EVERY SINGLE TIME the word alcohol was used in the document. It happened when I cut and pasted it, I know why it did it but it's hard to explain. It did the same for naltrexone (previous naltrexone )

Read it again. It should be much easier to understand this time.

Thanks waiting, I always do know your are there and as a matter of fact, you are a pillar of strength for me, and for that I sincerely thank you.

When you study it a bit, hopefully it will help me understand, goodnight for now.

OK, here is a brief translation to the plain English:

Some Italian study published in a respectable but far from top notch journal used one genetic line of rats that are known to like alcohol better than normal lab rats (there are three different lines of rats like this; they differ in genetic background and in various details of their "alcoholic behaviour").

The study used small statistical sample: four experimental groups with just 8 rats in each. It followed consumption of ethanol and water (meaning two bottle with free access in the cage all the time) for non-treated control groups and three experimental (baclofen only, naltrexone only and both drugs in combination). The study lasted ten days of treatment followed by five days of observation when no treatment was administered. See attached figure from the experiment. Bottom line is that only combination of the two drugs very significantly lowered alcohol consumption but even that group tended to progress closer to the untreated group once medications were withdrawn.

Implication to humans are limited - humans are not rats. But it we were rats, the conclusion would be that 1) if you are genetically predisposed to like alcohol, then 2) when you are put in the environment where you can freely decide to consume ethanol or not, 3) in order to keep you from consuming alcohol in excess of water, you have to keep taking combination of baclofen and naltrexon simultaneously
(and even conclusion is limited to the particular dosages used in the study; by the way, common pharmacological practice of linearly extrapolating drug dosage per kg of body weight from rats to humans is deeply wrong - in other words, even if we had 100% rat responses, the dosages used in the study may have little to do with what should be used on humans).

I'd like to see a study with the same design but at much higher dosages for both drugs.

All of the studies I've seen on rats with Naltrexone their Nal dosage was 4 times higher than .5mg/kg. And they all had dramatically different results than this one.

I'd like to see a higher dose of bac too and a combination with higher dosages.

ART---I'm sorry, these studies mean NOTHING to us right now. I apologize if I may have made you think it was significant. I just thought it was interesting when I happened across it, in fact I still haven't even read the whole thing. ortho is right, these are rats, not humans. All of the relevant knowledge you could possibly have for your situation (Nal+bac in a human) you probably already have.

And I'll summarize that:
Naltrexone + Drinking = Cure
Naltrexone + Drinking + Baclofen = I want to try it too but who knows..??

Adding further to the meaninglessness of this study is that we better hope it has no applicability to humans because if it did, TSM would not work as we are doing it. Not without Baclofen anyway.

But I do like seeing the studies Evan. Aren't there studies going on right now with naltrexone at UPenn? Also, we should limit the posted studies to the ones that only involve humans to have any value whatsoever. Also, I personally would love to see more studies directly testing TSM, as in studies where the protocol is "take naltrexone one hour before drinking." Of the 102 studies cited in Eskapa's book, I'm not sure if there is more than one with this protocol. The vast majority of the studies cited in the book involved taking naltrexone with abstinence and the TSM effect occurred by accident, with patients who drank in spite of instructions not to do so. Even the Combine study included naltrexone with instructions of abstinence, which is not the TSM protocol.

Evan, can you help me with this? Which studies directly test TSM as a theory, as in, which studies involve subjects who were specifically told, "take naltrexone one hour before you drink and then drink as you normally would"? If I had a handful of cases to lay at the feet of my doctor that most convincingly show that TSM is legitimate, what would they be?

It's incredibly disappointing. I read one study (I'll cite it when I can find it), where they took over 600 Vietnam vets, who've already been through hell and back, gave them Naltrexone and told them not to drink.

Average rate of relapse (time to first drink) was 72 days (no significant difference between placebo and nal groups). [DUH]

Then at 12 weeks they switched the Nal group to Placebo (because 12 weeks is one of the normal protocols for treatment with Nal)

They continued to monitor these poor souls for 52 weeks to conclude that Naltrexone therapy was of no benefit.

72 DAYS-average time to first relapse (possible extinction session among Nal groups)
12 WEEKS=84 DAYS (the point at which they switched everyone to placebo)

UGHH