# Patent

## Title
Compositions for controlling food intake and uses therefor

## Abstract

The present invention is directed to a combination treatment for: individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. In particular embodiments, the combination therapy reduces the intake of fatty foods, sugar-rich foods, or foods that are both fatty and sugar-rich (e.g., fast foods).

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the U.S. national stage application of International Patent Application No. PCT/US2012/065486, filed Nov. 16, 2012, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/560,356, filed Nov. 16, 2011, the disclosures of which are hereby incorporated by reference in their entirety, including all figures, tables and nucleic acid sequences.


TECHNICAL FIELD
The present invention relates to a combination therapy for the treatment of food addiction, obesity, binge eating disorder, or binge eating behavior.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to a combination treatment of a mu-opioid receptor antagonist and a GABA B receptor agonist and, optionally, a third therapeutic agent selected from CB-1 receptor antagonists, glycine reuptake inhibitors, dopamine augmenting compounds, nicotine receptor agonists, psychostimulants, mGlu2/3 agonists, mGlu5 antagonists, glycine-site partial agonists, cystine-glutamate exchangers, cystine-glutamate activators, glutamate transporter inhibitors, mGlu5 receptor agonists or NMDA receptor co-agonists, for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. Specific combinations of these classes of compounds are provided in Table 1. Tables 2-3 provide exemplary combinations of specific compounds suitable for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25 or having a BMI between 25 and 35); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. The invention may also be used for individuals who have difficulty in controlling the amounts of fast food consumed during a given period of time.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1—Baclofen (alone) has no effect on binge eating of sugar.
FIGS. 2A-2B—Baclofen (alone) reduces intake of oil-containing palatable foods.
FIGS. 3A-3C—Naltrexone has a trend toward reducing food intake in the oil containing groups, but has no effect on sugar-binging rats.
FIGS. 4A-4C. The combination of baclofen/naltrexone at higher doses (naltrexone at 1.0 mg/kg and baclofen at 1.8 mg/kg) robustly reduces intake of sugar, fat, or both fat and sugar.
FIGS. 5A-5C. The effect of baclofen/naltrexone on suppressing palatable food intake is specific to palatable food regardless of the group tested. No effects were seen on the intake of plain chow.
FIG. 6. The Yale Food Addiction Scale (survey).



DETAILED DISCLOSURE OF THE INVENTION
The present invention is directed to a combination treatment of a mu-opioid receptor antagonist and a GABA B agonist and, optionally, a third therapeutic agent selected from CB-1 receptor antagonists, glycine reuptake inhibitors, dopamine augmenting compounds, nicotine receptor agonists, psychostimulants, mGlu2/3 agonists, mGlu5 antagonists, glycine-site partial agonists, cystine-glutamate exchangers, cystine-glutamate activators, glutamate transporter inhibitors, mGlu5 receptor agonists or NMDA receptor co-agonists, for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. Specific combinations of these classes of compounds are provided in Table 1. Tables 2-3 provide exemplary combinations of specific compounds suitable for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25 or having a BMI between 25 and 35); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. The invention may also be used for individuals who have difficulty in controlling the amounts of fast food consumed during a given period of time.
The term “combination” as in the phrase “a first compound in combination with a second compound” includes co-administration of a first therapeutically effective compound and a second therapeutically effective compound, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier. The term “concurrently administered” when referring to the various compounds disclosed herein indicates that the compounds can be administered separately at the same time or sequentially in any order at different points in time. The compounds, however, should be administered close in time so as to provide an effect suitable for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. Typically, concurrently administered compounds are administered within 60 minutes of one another.
The term “synergistic effect” as used herein refers to the combined effect of administering two (or three) therapeutic compounds where the overall response is greater than the sum of the two individual effects (e.g., the effects observed when each compound is administered alone as a monotherapy).
The dosage of the individual therapeutic compounds that are to be administered to individuals may be adjusted to provide the optimal therapeutic response. Thus, the specific dose level for any particular patient may vary depending upon a variety of factors, including, but not limited to, the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; the drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. The considerations for determining the proper dose levels are well-known in the art.
In one embodiment, naltrexone is co-administered or administered in combination with baclofen and, optionally, additional therapeutic compounds. In certain cases, naltrexone, in an amount of about 25 to 100 milligrams per day, and baclofen, in an amount ranging between about 15 and about 120 milligrams per day (preferably between about 20 milligrams and about 80 milligrams per day) can be administered in combination or co-administered. As set forth in the Tables, a combination of three therapeutic compounds can be used in the disclosed methods. For example, a combination of naltrexone, baclofen and acamprosate or bupropion (or bupropion extended release) can be co-administered or administered in combination to a subject according to the disclosed methods. In such embodiments, naltrexone, in an amount of about 25 to 100 milligrams per day, baclofen, in an amount ranging between about 15 and about 120 milligrams per day (preferably between about 20 milligrams and about 80 milligrams per day), and acamprosate, in an amount between about 300 and 2500 milligrams per day (e.g., as two 333-mg tablets taken three times a day), can be co-administered or administered in combination. Alternatively, naltrexone, in an amount of about 25 to 100 milligrams per day, baclofen, in an amount ranging between about 15 and about 120 milligrams per day (preferably between about 20 milligrams and about 80 milligrams per day), and bupropion (or bupropion extended release), in an amount of between 75 milligrams and 450 milligrams per day (preferably between about 150 and about 300 milligrams per day), can be co-administered or administered in combination within the disclosed methods. Other combinations of therapeutic compounds and compositions according to the invention are set forth in Tables 2 and 3.
The therapeutic compounds used in the disclosed combination therapies can be administered in oral forms. These include, but are not limited to, tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Rapid-release and time-controlled release (extended release) formulations of the disclosed therapeutic compounds can be used for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. The therapeutic compounds disclosed herein can, typically, be administered in “pharmaceutically acceptable carriers” such as pharmaceutical diluents, pharmaceutical excipients or pharmaceutical carriers. For instance, tablets or capsules can comprise one or more of the disclosed therapeutic compounds and lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like. Liquid formulations can comprise one or more therapeutic agents in combination with ethanol, glycerol, water and the like. Additionally, the compositions can contain binders, lubricants, disintegrating agents, coloring agents and/or flavoring agents as desired.
In the context of the present invention, the term “individual” refers to a mammal. In particular embodiments, the mammal can be a rodent, such as a mouse or rat. In other embodiments, the mammal is a human. Individuals to whom the methods disclosed herein can be applied can be identified by a variety of means, including the use of body mass index (BMI) or surveys that identify individuals exhibiting symptoms of food addiction (e.g., the Yale Food Addiction Scale (see FIG. 6)).
Thus, certain aspects of the disclosed invention provide methods for the treatment of individuals who meet the definition of food addiction; individuals who are overweight or obese (e.g., a BMI≧25); individuals who have a binge eating disorder; or individuals who engage in a binge eating behavior. These methods comprise the administration of a composition as set forth in any one of Tables 1-3 to an individual meeting the definition of food addiction, an individual who is obese or overweight, an individual who has a binge-eating disorder or an individual who engages in binge eating behavior in amounts effective to control or reduce the intake of food. In preferred embodiments of this aspect of the invention, the foods are fatty foods, sugar-rich foods, or foods that are both fatty and sugar-rich.
It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) of any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated within the scope of the invention without limitation thereto.
EXAMPLES
Example 1
Drugs (2 doses/drug)
Baclofen (at 1.0 and 1.8 mg/kg, administered i.p.)
Naltrexone (at 0.1 and 1.0 mg/kg, administered i.p.)
Baclofen+naltrexone (mixed low and mixed high)
Saline
Groups (n=10/group)
1. Binge Sugar (10% sucrose solution, w/v)
2. Binge Fat (35% oil emulsion, w/v)
3. Binge Sugar/Fat (10% sucrose, 35% oil emulsion, w/v)
Procedure
Groups of animals (rats) were maintained on their diets for 3 weeks to establish stable binge eating behavior. After this period of time, the rats were administered three days of daily i.p. injections of saline (to acclimate to the injection procedure), and sugar/chow intake was measured after the first hour of access and then hourly for the next 3 hours, as well as at the end of the 12-h access period. After this three-day period, rats were given baclofen+naloxone, and measurements taken as described above. Other dosage amounts of baclofen and naloxone were tested, as were the effects of these compounds alone (with measurements being performed as described above). Vehicle injections were performed between the various tests in order to allow for suitable clearance of compounds from the animals. Interestingly, the effect of baclofen/naltrexone on suppressing palatable food intake is specific to palatable food (fatty foods, sweet foods or food choices that were both fatty and sweet, see FIGS. 1-5); no effects were seen on the rats' intake of plain chow. Thus, the treatment appears ideally suited for food addicts, hedonic overeaters and changes food choice but not appetite.
Example 2
Materials and Methods
Male Sprague-Dawley rats, 250-300 g at the onset of the experiment, were obtained from Taconic Farms (Germantown, N.Y., USA). Rats were housed individually on a 12-h reversed light/dark cycle and given 1 wk to acclimate before diet training began.
Diets
The rats were divided into groups (n=10/group) matched for body weight and assigned to one of the following dietary conditions: (1) Binge Sugar, (2) Binge Fat or (3) Binge Sugar-Fat. All rats received palatable diets and standard rodent chow (LabDiet #5001, PMI Nutrition International, Richmond, Ind., USA; 10% fat, 20% protein, 70% carbohydrate, 3.02 kcal/g) for 12 h/day, starting 4 h after the onset of the dark cycle. Water was available ad libitum.
All palatable foods were mixed in the laboratory. The Binge Sugar group had access to a 10% (w/v) sucrose solution (Domino® Granulated Pure Cane Sugar, dissolved in tap water, 0.4 kcal/mL), the Binge Fat group had access to a 35% (w/v) fat emulsion (3.1 kcal/mL) and the Binge Sugar-Fat group had access to a 10% (w/v) sugar solution and 35% (w/v) fat emulsion (3.5 kcal/mL). Both emulsions were made with Wesson® Pure Vegetable Oil in tap water and 0.6% (w/v) Emplex, a commercially available emulsifier (American Ingredients Company, Kansas City, Mo., USA). Palatable food intakes were recorded daily. Chow intake was recorded weekly. Body weights were taken at the beginning and end of the 21-day diet period.
Injection Procedures
After 21 days on these diets, drug testing began. During testing, diet regimens were maintained. Approximately 3.5 h into the dark cycle, animals were weighed and intraperitoneal (i.p.) injections of drug were given (according to the schedule below). 30 min later (4 h into the dark cycle) palatable food and chow were made available to the rats. For the first 3 days, rats were acclimated to handling and daily vehicle injections (0.9% saline, Hospira, Lake Forest, Ill., USA, i.p. 1 mL/kg). For days 4-16 of drug testing, either vehicle or drug was alternatively administered, starting with drug on day 4. Drug injections included combinations of R-baclofen (Tocris, Ellisville, Mo., USA) and naltrexone hydrochloride (Sigma, St. Louis, Mo., USA): 0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, or 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen, or either drug was tested alone: 0.1 and 1.0 mg/kg naltrexone, or 1.0 and 1.8 mg/kg baclofen. Intake of palatable food and chow was measured hourly after injection for 4 h and again at the end of the 12-h access period.
Analysis and Statistics
Palatable food and standard chow intakes following saline injections between days 4-16 were averaged. All data were analyzed using one-way ANOVAs with post hoc Multiple Comparisons, when appropriate. In Tables 4-7, values having the same letter superscript are statistically different from one another.
Results
At the beginning of the study, the groups were weight-matched [F(2,29)≦0.001, 6 p=n.s.; 280.0±3.6 g (Binge Sugar), 280.1±3.4 g (Binge Fat), 280.0±3.6 g (Binge Sugar-Fat)]. There was still no difference in body weight among groups after 21 days on their respective diets [F(2,29)=0.39, p=n.s.; 387.2±7.2 g (Binge Sugar), 396.7±5.7 g (Binge Fat), 393.83±10.0 g (Binge Sugar-Fat)], or at the completion of injections [F(2,29)=1.68, p=n.s.; 419.9±9.3 g (Binge Sugar), 442.4±6.5 g (Binge Fat), 438.3±11.2 g (Binge Sugar-Fat)].
Effects of Naltrexone, Baclofen or the Combination on Palatable Food Intake
Table 4 shows a summary of palatable food intake in response to the drugs tested as a percent of each groups' saline injections. Naltrexone significantly decreased 1 h (F(2,29)=3.66, p<0.05, Table 5) and 12-h intake in the Binge Sugar group (F(2,29)=5.94, p<0.01), with the greatest suppression of intake seen following the higher dose (p<0.05). Similar to previous reports (Berner, 2009 #597; Corwin, 2009 #607), there was no effect of baclofen on sugar intake at 1 h (F(2, 29)=0.79, p=n.s.) or at 12 h (F(2,29)=0.13, p=n.s.). The combination of naltrexone and baclofen decreased sugar intake at 1 h (F(2,29)=4.067, p<0.05), with the strongest suppression seen at the high-dose combination (p<0.05). However, this effect was not apparent at 12 h (F(2,29)=0.28, p=n.s.).
For the Binge Fat group, there was no significant effect of naltrexone at 1 h (F(2,29)=2.55, p=n.s.) or 12 h (F(2,29)=0.96, p=n.s.). Baclofen decreased fat intake at 1 h (F(2,29)=6.85, p<0.01) and 12 h (F(2,29)=8.15, p<0.01), with the strongest suppression seen following the higher dose (p<0.01). The combination of naltrexone and baclofen also decreased fat intake at 1 h (F(2,29)=12.11, p<0.0001) and 12 h 7 (F(2,29)=8.41, p<0.01), again with the strongest suppression seen following the high-dose combination (p<0.01).
In terms of the sugar-fat combination, naltrexone had no effect on palatable food intake at 1 h (F(2,29)=1.84, p=n.s.) or 12 h (F(2,29)=1.27, p=n.s.). Baclofen significantly decreased intake at 1 h (F(2,29)=9.69, p<0.01) at both doses tested (p<0.01). At 12 h, baclofen suppressed intake (F(2,29)=4.25, p<0.05), with the strongest effect seen following the higher dose (p<0.05). Lastly, there was an effect of the naltrexone and baclofen combination on sugar-fat intake at 1 h (F(2,29)=13.29, p<0.0001), with the strongest suppression seen at the higher dose (p<0.01), but no effect was observed at 12 h (F(2,29)=0.82, p=n.s.).
Effects of Naltrexone, Baclofen or the Combination on Standard Chow Intake
There was no effect of naltrexone (F(2,29)=3.31, p=n.s.; Table 6) or baclofen (F(2,29)=1.07, p>0.05) on standard chow intake in the Sugar group at 1 h. However, at 12 h, naltrexone (F(2,29)=6.18, p<0.01) and baclofen (F(2,28)=4.56, p<0.05) both stimulated chow intake. The combination of naltrexone and baclofen had a significant effect on standard chow intake in the Sugar group at 1 h (F(2,29)=5.34, p<0.05), with the high dose reducing intake compared to the low dose (p<0.01). At 12 h (F(2,28)=9.32, p<0.01), the combination stimulated intake of standard rodent chow at both drug doses (p<0.01, for each) compared to saline.
There was no effect of naltrexone or baclofen alone on standard chow intake in the Fat group at 1 h (naltrexone: F(2,29)=2.01, p=n.s.; baclofen F(2,29)=0.44, p>0.05) or 12 h (naltrexone: F(2,29)=0.28, p=n.s.; baclofen: F(2,29)=0.27, p>0.05; Table 7). There was, however, an effect of the combination of naltrexone and baclofen 1 h (F(2,29)=10.92, p<0.0001), with less chow intake at the high dose compared to the other two groups (saline: p<0.05 and low dose: p<0.0001). This effect did not persist, as no significant effect was seen at 12 h (F(2,29)=0.47, p=n.s.).
There was no effect of naltrexone on chow intake in the Binge Sugar-Fat group at 1 h (F(2,29)=0.65, p=n.s.) or at 12 h (F(2,29)=0.85, p=n.s.). Baclofen had a significant effect at 1 h (F(2,29)=3.58, p<0.05), with less chow intake at the high dose compared to the low dose (p<0.05), but not at 12 h (F(2,28)=0.05, p=n.s.). There was no effect of the naltrexone and baclofen combination 1 h (F(2,29)=1.07, p=n.s.) or 12 h (F(2,29)=0.46, p=n.s.).
Effects of Naltrexone, Baclofen or the Combination on Total Caloric Intake
Naltrexone significantly increased total caloric intake in the Sugar group at 1 h (F(2,29)=4.53, p<0.05; low dose compared to saline p<0.05). However, at 12 h, differences were no longer evident (F(2,27)=3.15, p=n.s.). Baclofen had no effect on total caloric intake in the Sugar group at 1 h (F(2,29)=1.63, p=n.s.) or 12 h (F(2,26)=3.22, p=n.s.). The combination of naltrexone and baclofen, however, did significantly reduce total caloric intake 1 h (F(2,29)=8.11, p<0.01; high dose (P<0.01). An effect was still apparent at 12 h (F(2,26)=6.52, p<0.01), but this time, caloric intake was increased in rats given both the low (p<0.01) and high dose (p<0.05) of the drug.
In the Fat group, naltrexone had no effect on total caloric intake at 1 h (F(2,29)=3.25, p=n.s.) or 12 h (F(2, 29)=1.13, p=n.s.). Baclofen, however, significantly reduced total caloric intake at 1 h (F(2,29)=6.73, p<0.01) and 12 h (F(2,29)=4.96, p<0.05), at the high dose, at each time point (p<0.05). Likewise, the combination of naltrexone and baclofen reduced total caloric intake at 1 h (F(2,29)=22.07, p<0.0001) and 12 h (F(2,29)=8.02, p<0.01), at the high dose at each time point (p<0.05).
In the Sugar-Fat group, naltrexone had no effect on total caloric intake at 1 h (F(2,29)=2.17, p=n.s.) or 12 h (F(2,27)=1.16, p=n.s.). Conversely, baclofen reduced total caloric intake in the Sugar-Fat group at 1 h (F(2,29)=15.02, p<0.0001), at the high dose (p<0.01), but this effect was not apparent at 12 h (F(2,27)=2.435, p=n.s.). Likewise, the combination of naltrexone and baclofen reduced total caloric intake at 1 h (F(2,29)=13.46, p<0.0001), with less intake at the high dose (p<0.01), but this effect was not seen at 12 h (F(2,27)=0.76, p=n.s.).







TABLE 1





Triple Combination Compound Classes



















GABA-B agonists and Mu antagonists and




CB-1 antagonists




GABA-B agonists and Mu antagonists and




Glycine reuptake inhibitors




GABA-B agonists and Mu antagonists and




Dopamine augmenting compounds




GABA-B agonists and Mu antagonists and




Nicotine receptor agonists




GABA-B agonists and Mu antagonists and




Psychostimulants




GABA-B agonists and Mu antagonists and




mGlu2⁄3 agonists




GABA-B agonists and Mu antagonists and




mGlu5 antagonists




GABA-B agonists and Mu antagonists and




Glycine-site partial agonists




GABA-B agonists and Mu antagonists and




Cystine-glutamate exchangers




GABA-B agonists and Mu antagonists and




Cystine-glutamate activators




GABA-B agonists and Mu antagonists and




Glutamate transporter inhibitors




GABA-B agonists and Mu antagonists and




mGlu5 receptor agonists




GABA-B agonists and Mu antagonists and




NMDA receptor co-agonists

















TABLE 2





Two Compound Combinations



















baclofen and naltrexone




baclofen and naloxone




baclofen and nalorphine 




baclofen and levallorphan




baclofen and buprenorphine




baclofen and extended release naltrexone




baclofen and 2-methyl-4aalpha-(3-




hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-




octahydro-quinolino(2,3-g)isoquinoline




(TAN-67)




baclofen and (+)-4-[(αR)-α-((2S,5R)-4-Allyl-




2,5-dimethyl-1-piperazinyl)-3-




methoxybenzyl]-N,N-diethylbenzamide




(SNC80)




lesogaberan and naltrexone




lesogaberan and naloxone




lesogaberan and nalorphine




lesogaberan and levallorphan




lesogaberan and buprenorphine




lesogaberan and extended release naltrexone




lesogaberan and TAN-67




lesogaberan and SNC80




gabapentin and naltrexone




gabapentin and naloxone




gabapentin and nalorphine




gabapentin and levallorphan




gabapentin and buprenorphine




gabapentin and extended release naltrexone




gabapentin and TAN-67




gabapentin and SNC80




pregabalin and naltrexone




pregabalin and naloxone




pregabalin and nalorphine




pregabalin and levallorphan




pregabalin and buprenorphine




pregabalin and extended release naltrexone




pregabalin and TAN-67




pregabalin and SNC80

















TABLE 3





Three Compound Combinations

















baclofen and naltrexone and rimonabant



baclofen and naloxone and N-(Piperidin-1-yl)-5-(4-



iodophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-



pyrazole-3-carboxamide (AM-251)



baclofen and nalorphine and 2-[methyl-[(3R)-3-



phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]



amino]acetic acid (org24598)



baclofen and naltrexone and acamprosate



baclofen and naltrexone and buproprion



baclofen and naltrexone and buproprion



(extended release)



baclofen and naltrexone and nicotine



baclofen and naltrexone and varenicline



baclofen and naloxone and rimonabant



baclofen and naloxone and am-251



baclofen and naloxone and org24598



baclofen and naloxone and acamprosate



baclofen and naloxone and buproprion



baclofen and naloxone and buproprion



(extended release)



baclofen and naloxone and nicotine



baclofen and naloxone and varenicline



baclofen and nalorphine and rimonabant



baclofen and nalorphine and am-251



baclofen and nalorphine and org24598



baclofen and nalorphine and acamprosate



baclofen and nalorphine and buproprion



baclofen and nalorphine and buproprion



(extended release)



baclofen and nalorphine and nicotine



baclofen and nalorphine and varenicline



baclofen and levallorphan and rimonabant



baclofen and levallorphan and am-251



baclofen and levallorphan and org24598



baclofen and levallorphan and acamprosate



baclofen and levallorphan and buproprion



baclofen and levallorphan and buproprion



(extended release)



baclofen and levallorphan and nicotine



baclofen and levallorphan and varenicline



baclofen and buprenorphine and rimonabant



baclofen and buprenorphine and am-251



baclofen and buprenorphine and org24598



baclofen and buprenorphine and acamprosate



baclofen and buprenorphine and buproprion



baclofen and buprenorphine and buproprion



(extended release)



baclofen and buprenorphine and nicotine



baclofen and buprenorphine and varenicline



baclofen and extended release naltrexone and rimonabant



baclofen and extended release naltrexone and am-251



baclofen and extended release naltrexone and org24598



baclofen and extended release naltrexone and acamprosate



baclofen and extended release naltrexone and buproprion



baclofen and extended release naltrexone and buproprion



(extended release)



baclofen and extended release naltrexone and nicotine



baclofen and extended release naltrexone and varenicline



baclofen and tan-67 and rimonabant



baclofen and tan-67 and am-251



baclofen and tan-67 and org24598



baclofen and tan-67 and acamprosate



baclofen and tan-67 and buproprion



baclofen and tan-67 and buproprion



(extended release)



baclofen and tan-67 and nicotine



baclofen and tan-67 and varenicline



baclofen and snc80 and rimonabant



baclofen and snc80 and am-251



baclofen and snc80 and org24598



baclofen and snc80 and acamprosate



baclofen and snc80 and buproprion



baclofen and snc80 and buproprion



(extended release)



baclofen and snc80 and nicotine



baclofen and snc80 and varenicline



lesogaberan and naltrexone and rimonabant



lesogaberan and naltrexone and am-251



lesogaberan and naltrexone and org24598



lesogaberan and naltrexone and acamprosate



lesogaberan and naltrexone and buproprion



lesogaberan and naltrexone and buproprion



(extended release)



lesogaberan and naltrexone and nicotine



lesogaberan and naltrexone and varenicline



lesogaberan and naloxone and rimonabant



lesogaberan and naloxone and am-251



lesogaberan and naloxone and org24598



lesogaberan and naloxone and acamprosate



lesogaberan and naloxone and buproprion



lesogaberan and naloxone and buproprion



(extended release)



lesogaberan and naloxone and nicotine



lesogaberan and naloxone and varenicline



lesogaberan and nalorphine and rimonabant



lesogaberan and nalorphine and am-251



lesogaberan and nalorphine and org24598



lesogaberan and nalorphine and acamprosate



lesogaberan and nalorphine and buproprion



lesogaberan and nalorphine and buproprion



(extended release)



lesogaberan and nalorphine and nicotine



lesogaberan and nalorphine and varenicline



lesogaberan and levallorphan and rimonabant



lesogaberan and levallorphan and am-251



lesogaberan and levallorphan and org24598



lesogaberan and levallorphan and acamprosate



lesogaberan and levallorphan and buproprion



lesogaberan and levallorphan and buproprion



(extended release)



lesogaberan and levallorphan and nicotine



lesogaberan and levallorphan and varenicline



lesogaberan and buprenorphine and rimonabant



lesogaberan and buprenorphine and am-251



lesogaberan and buprenorphine and org24598



lesogaberan and buprenorphine and acamprosate



lesogaberan and buprenorphine and buproprion



lesogaberan and buprenorphine and buproprion



(extended release)



lesogaberan and buprenorphine and nicotine



lesogaberan and buprenorphine and varenicline



lesogaberan and extended release naltrexone and rimonabant



lesogaberan and extended release naltrexone and am-251



lesogaberan and extended release naltrexone and org24598



lesogaberan and extended release naltrexone and acamprosate



lesogaberan and extended release naltrexone and buproprion



lesogaberan and extended release naltrexone and buproprion



(extended release)



lesogaberan and extended release naltrexone and nicotine



lesogaberan and extended release naltrexone and varenicline



lesogaberan and tan-67 and rimonabant



lesogaberan and tan-67 and am-251



lesogaberan and tan-67 and org24598



lesogaberan and tan-67 and acamprosate



lesogaberan and tan-67 and buproprion



lesogaberan and tan-67 and buproprion



(extended release)



lesogaberan and tan-67 and nicotine



lesogaberan and tan-67 and varenicline



lesogaberan and snc80 and rimonabant



lesogaberan and snc80 and am-251



lesogaberan and snc80 and org24598



lesogaberan and snc80 and acamprosate



lesogaberan and snc80 and buproprion



lesogaberan and snc80 and buproprion



(extended release)



lesogaberan and snc80 and nicotine



lesogaberan and snc80 and varenicline



gabapentin and naltrexone and rimonabant



gabapentin and naltrexone and am-251



gabapentin and naltrexone and org24598



gabapentin and naltrexone and acamprosate



gabapentin and naltrexone and buproprion



gabapentin and naltrexone and buproprion



(extended release)



gabapentin and naltrexone and nicotine



gabapentin and naltrexone and varenicline



gabapentin and naloxone and rimonabant



gabapentin and naloxone and am-251



gabapentin and naloxone and org24598



gabapentin and naloxone and acamprosate



gabapentin and naloxone and buproprion



gabapentin and naloxone and buproprion



(extended release)



gabapentin and naloxone and nicotine



gabapentin and naloxone and varenicline



gabapentin and nalorphine and rimonabant



gabapentin and nalorphine and am-251



gabapentin and nalorphine and org24598



gabapentin and nalorphine and acamprosate



gabapentin and nalorphine and buproprion



gabapentin and nalorphine and buproprion



(extended release)



gabapentin and nalorphine and nicotine



gabapentin and nalorphine and varenicline



gabapentin and levallorphan and rimonabant



gabapentin and levallorphan and am-251



gabapentin and levallorphan and org24598



gabapentin and levallorphan and acamprosate



gabapentin and levallorphan and buproprion



gabapentin and levallorphan and buproprion



(extended release)



gabapentin and levallorphan and nicotine



gabapentin and levallorphan and varenicline



gabapentin and buprenorphine and rimonabant



gabapentin and buprenorphine and am-251



gabapentin and buprenorphine and org24598



gabapentin and buprenorphine and acamprosate



gabapentin and buprenorphine and buproprion



gabapentin and buprenorphine and buproprion



(extended release)



gabapentin and buprenorphine and nicotine



gabapentin and buprenorphine and varenicline



gabapentin and extended release naltrexone and rimonabant



gabapentin and extended release naltrexone and am-251



gabapentin and extended release naltrexone and org24598



gabapentin and extended release naltrexone and acamprosate



gabapentin and extended release naltrexone and buproprion



gabapentin and extended release naltrexone and buproprion



(extended release)



gabapentin and extended release naltrexone and nicotine



gabapentin and extended release naltrexone and varenicline



gabapentin and tan-67 and rimonabant



gabapentin and tan-67 and am-251



gabapentin and tan-67 and org24598



gabapentin and tan-67 and acamprosate



gabapentin and tan-67 and buproprion



gabapentin and tan-67 and buproprion



(extended release)



gabapentin and tan-67 and nicotine



gabapentin and tan-67 and varenicline



gabapentin and snc80 and rimonabant



gabapentin and snc80 and am-251



gabapentin and snc80 and org24598



gabapentin and snc80 and acamprosate



gabapentin and snc80 and buproprion



gabapentin and snc80 and buproprion



(extended release)



gabapentin and snc80 and nicotine



gabapentin and snc80 and varenicline



pregabalin and naltrexone and rimonabant



pregabalin and naltrexone and am-251



pregabalin and naltrexone and org24598



pregabalin and naltrexone and acamprosate



pregabalin and naltrexone and buproprion



pregabalin and naltrexone and buproprion



(extended release)



ppregabalin and naltrexone and nicotine



pregabalin and naltrexone and varenicline



pregabalin and naloxone and rimonabant



pregabalin and naloxone and am-251



pregabalin and naloxone and org24598



pregabalin and naloxone and acamprosate



pregabalin and naloxone and buproprion



pregabalin and naloxone and buproprion



(extended release)



pregabalin and naloxone and nicotine



pregabalin and naloxone and varenicline



pregabalin and nalorphine and rimonabant



pregabalin and nalorphine and am-251



pregabalin and nalorphine and org24598



pregabalin and nalorphine and acamprosate



pregabalin and nalorphine and buproprion



pregabalin and nalorphine and buproprion



(extended release)



pregabalin and nalorphine and nicotine



pregabalin and nalorphine and varenicline



pregabalin and levallorphan and rimonabant



pregabalin and levallorphan and am-251



pregabalin and levallorphan and org24598



pregabalin and levallorphan and acamprosate



pregabalin and levallorphan and buproprion



pregabalin and levallorphan and buproprion



(extended release)



pregabalin and levallorphan and nicotine



pregabalin and levallorphan and varenicline



pregabalin and buprenorphine and rimonabant



pregabalin and buprenorphine and am-251



pregabalin and buprenorphine and org24598



pregabalin and buprenorphine and acamprosate



pregabalin and buprenorphine and buproprion



pregabalin and buprenorphine and buproprion



(extended release)



pregabalin and buprenorphine and nicotine



pregabalin and buprenorphine and varenicline



pregabalin and extended release naltrexone and rimonabant



pregabalin and extended release naltrexone and am-251



pregabalin and extended release naltrexone and org24598



pregabalin and extended release naltrexone and acamprosate



pregabalin and extended release naltrexone and buproprion



pregabalin and extended release naltrexone and buproprion



(extended release)



pregabalin and extended release naltrexone and nicotine



pregabalin and extended release naltrexone and varenicline



pregabalin and tan-67 and rimonabant



pregabalin and tan-67 and am-251



pregabalin and tan-67 and org24598



pregabalin and tan-67 and acamprosate



pregabalin and tan-67 and buproprion



pregabalin and tan-67 and buproprion



(extended release)



pregabalin and tan-67 and nicotine



pregabalin and tan-67 and varenicline



pregabalin and snc80 and rimonabant



pregabalin and snc80 and am-251



pregabalin and snc80 and org24598



pregabalin and snc80 and acamprosate



pregabalin and snc80 and buproprion



pregabalin and snc80 and buproprion



(extended release)



pregabalin and snc80 and nicotine



pregabalin and snc80 and varenicline



baclofen and naltrexone and phentermine



baclofen and naltrexone and dexmethylphenidate



baclofen and naltrexone and dextroamphetamine



baclofen and naltrexone and dexedrine



baclofen and naltrexone and Adderall



baclofen and naltrexone and methylphenidate



baclofen and naltrexone and modafanil



baclofen and naltrexone and lisdexamfetamine



baclofen and naloxone and phentermine



baclofen and naloxone and dexmethylphenidate



baclofen and naloxone and dextroamphetamine



baclofen and naloxone and dexedrine



baclofen and naloxone and Adderall



baclofen and naloxone and methylphenidate



baclofen and naloxone and modafanil



baclofen and naloxone and lisdexamfetamine



baclofen and nalorphine and phentermine



baclofen and nalorphine and dexmethylphenidate



baclofen and nalorphine and dextroamphetamine



baclofen and nalorphine and dexedrine



baclofen and nalorphine and Adderall



baclofen and nalorphine and methylphenidate



baclofen and nalorphine and modafanil



baclofen and nalorphine and lisdexamfetamine



baclofen and levallorphan and phentermine



baclofen and levallorphan and dexmethylphenidate



baclofen and levallorphan and dextroamphetamine



baclofen and levallorphan and dexedrine



baclofen and levallorphan and Adderall



baclofen and levallorphan and methylphenidate



baclofen and levallorphan and modafanil



baclofen and levallorphan and lisdexamfetamine



baclofen and buprenorphine and phentermine



baclofen and buprenorphine and dexmethylphenidate



baclofen and buprenorphine and dextroamphetamine



baclofen and buprenorphine and dexedrine



baclofen and buprenorphine and Adderall



baclofen and buprenorphine and methylphenidate



baclofen and buprenorphine and modafanil



baclofen and buprenorphine and lisdexamfetamine



baclofen and extended release naltrexone and phentermine



baclofen and extended release naltrexone and dexmethylphenidate



baclofen and extended release naltrexone and dextroamphetamine



baclofen and extended release naltrexone and dexedrine



baclofen and extended release naltrexone and Adderall



baclofen and extended release naltrexone and methylphenidate



baclofen and extended release naltrexone and modafanil



baclofen and extended release naltrexone and lisdexamfetamine



baclofen and tan-67 and phentermine



baclofen and tan-67 and dexmethylphenidate



baclofen and tan-67 and dextroamphetamine



baclofen and tan-67 and dexedrine



baclofen and tan-67 and Adderall



baclofen and tan-67 and methylphenidate



baclofen and tan-67 and modafanil



baclofen and tan-67 and lisdexamfetamine



baclofen and snc80 and phentermine



baclofen and snc80 and dexmethylphenidate



baclofen and snc80 and dextroamphetamine



baclofen and snc80 and dexedrine



baclofen and snc80 and Adderall



baclofen and snc80 and methylphenidate



baclofen and snc80 and modafanil



baclofen and snc80 and lisdexamfetamine



lesogaberan and naltrexone and phentermine



lesogaberan and naltrexone and dexmethylphenidate



lesogaberan and naltrexone and dextroamphetamine



lesogaberan and naltrexone and dexedrine



lesogaberan and naltrexone and Adderall



lesogaberan and naltrexone and methylphenidate



lesogaberan and naltrexone and modafanil



lesogaberan and naltrexone and lisdexamfetamine



lesogaberan and naloxone and phentermine



lesogaberan and naloxone and dexmethylphenidate



lesogaberan and naloxone and dextroamphetamine



lesogaberan and naloxone and dexedrine



lesogaberan and naloxone and Adderall



lesogaberan and naloxone and methylphenidate



lesogaberan and naloxone and modafanil



lesogaberan and naloxone and lisdexamfetamine



lesogaberan and nalorphine and phentermine



lesogaberan and nalorphine and dexmethylphenidate



lesogaberan and nalorphine and dextroamphetamine



lesogaberan and nalorphine and dexedrine



lesogaberan and nalorphine and Adderall



lesogaberan and nalorphine and methylphenidate



lesogaberan and nalorphine and modafanil



lesogaberan and nalorphine and lisdexamfetamine



lesogaberan and levallorphan and phentermine



lesogaberan and levallorphan and dexmethylphenidate



lesogaberan and levallorphan and dextroamphetamine



lesogaberan and levallorphan and dexedrine



lesogaberan and levallorphan and Adderall



lesogaberan and levallorphan and methylphenidate



lesogaberan and levallorphan and modafanil



lesogaberan and levallorphan and lisdexamfetamine



lesogaberan and buprenorphine and phentermine



lesogaberan and buprenorphine and dexmethylphenidate



lesogaberan and buprenorphine and dextroamphetamine



lesogaberan and buprenorphine and dexedrine



lesogaberan and buprenorphine and Adderall



lesogaberan and buprenorphine and methylphenidate



lesogaberan and buprenorphine and modafanil



lesogaberan and buprenorphine and lisdexamfetamine



lesogaberan and extended release naltrexone and phentermine



lesogaberan and extended release naltrexone and dexmethylphenidate



lesogaberan and extended release naltrexone and dextroamphetamine



lesogaberan and extended release naltrexone and dexedrine



lesogaberan and extended release naltrexone and Adderall



lesogaberan and extended release naltrexone and methylphenidate



lesogaberan and extended release naltrexone and modafanil



lesogaberan and extended release naltrexone and lisdexamfetamine



lesogaberan and tan-67 and phentermine



lesogaberan and tan-67 and dexmethylphenidate



lesogaberan and tan-67 and dextroamphetamine



lesogaberan and tan-67 and dexedrine



lesogaberan and tan-67 and Adderall



lesogaberan and tan-67 and methylphenidate



lesogaberan and tan-67 and modafanil



lesogaberan and tan-67 and lisdexamfetamine



lesogaberan and snc80 and phentermine



lesogaberan and snc80 and dexmethylphenidate



lesogaberan and snc80 and dextroamphetamine



lesogaberan and snc80 and dexedrine



lesogaberan and snc80 and Adderall



lesogaberan and snc80 and methylphenidate



lesogaberan and snc80 and modafanil



lesogaberan and snc80 and lisdexamfetamine



gabapentin and naltrexone and phentermine



gabapentin and naltrexone and dexmethylphenidate



gabapentin and naltrexone and dextroamphetamine



gabapentin and naltrexone and dexedrine



gabapentin and naltrexone and Adderall



gabapentin and naltrexone and methylphenidate



gabapentin and naltrexone and modafanil



gabapentin and naltrexone and lisdexamfetamine



gabapentin and naloxone and phentermine



gabapentin and naloxone and dexmethylphenidate



gabapentin and naloxone and dextroamphetamine



gabapentin and naloxone and dexedrine



gabapentin and naloxone and Adderall



gabapentin and naloxone and methylphenidate



gabapentin and naloxone and modafanil



gabapentin and naloxone and lisdexamfetamine



gabapentin and nalorphine and phentermine



gabapentin and nalorphine and dexmethylphenidate



gabapentin and nalorphine and dextroamphetamine



gabapentin and nalorphine and dexedrine



gabapentin and nalorphine and Adderall



gabapentin and nalorphine and methylphenidate



gabapentin and nalorphine and modafanil



gabapentin and nalorphine and lisdexamfetamine



gabapentin and levallorphan and phentermine



gabapentin and levallorphan and dexmethylphenidate



gabapentin and levallorphan and dextroamphetamine



gabapentin and levallorphan and dexedrine



gabapentin and levallorphan and Adderall



gabapentin and levallorphan and methylphenidate



gabapentin and levallorphan and modafanil



gabapentin and levallorphan and lisdexamfetamine



gabapentin and buprenorphine and phentermine



gabapentin and buprenorphine and dexmethylphenidate



gabapentin and buprenorphine and dextroamphetamine



gabapentin and buprenorphine and dexedrine



gabapentin and buprenorphine and Adderall



gabapentin and buprenorphine and methylphenidate



gabapentin and buprenorphine and modafanil



gabapentin and buprenorphine and lisdexamfetamine



gabapentin and extended release naltrexone and phentermine



gabapentin and extended release naltrexone and dexmethylphenidate



gabapentin and extended release naltrexone and dextroamphetamine



gabapentin and extended release naltrexone and dexedrine



gabapentin and extended release naltrexone and Adderall



gabapentin and extended release naltrexone and methylphenidate



gabapentin and extended release naltrexone and modafanil



gabapentin and extended release naltrexone and lisdexamfetamine



gabapentin and tan-67 and phentermine



gabapentin and tan-67 and dexmethylphenidate



gabapentin and tan-67 and dextroamphetamine



gabapentin and tan-67 and dexedrine



gabapentin and tan-67 and Adderall



gabapentin and tan-67 and methylphenidate



gabapentin and tan-67 and modafanil



gabapentin and tan-67 and lisdexamfetamine



gabapentin and snc80 and phentermine



gabapentin and snc80 and dexmethylphenidate



gabapentin and snc80 and dextroamphetamine



gabapentin and snc80 and dexedrine



gabapentin and snc80 and Adderall



gabapentin and snc80 and methylphenidate



gabapentin and snc80 and modafanil



gabapentin and snc80 and lisdexamfetamine



pregabalin and naltrexone and phentermine



pregabalin and naltrexone and dexmethylphenidate



pregabalin and naltrexone and dextroamphetamine



pregabalin and naltrexone and dexedrine



pregabalin and naltrexone and Adderall



pregabalin and naltrexone and methylphenidate



pregabalin and naltrexone and modafanil



pregabalin and naltrexone and lisdexamfetamine



pregabalin and naloxone and phentermine



pregabalin and naloxone and dexmethylphenidate



pregabalin and naloxone and dextroamphetamine



pregabalin and naloxone and dexedrine



pregabalin and naloxone and Adderall



pregabalin and naloxone and methylphenidate



pregabalin and naloxone and modafanil



pregabalin and naloxone and lisdexamfetamine



pregabalin and nalorphine and phentermine



pregabalin and nalorphine and dexmethylphenidate



pregabalin and nalorphine and dextroamphetamine



pregabalin and nalorphine and dexedrine



pregabalin and nalorphine and Adderall



pregabalin and nalorphine and methylphenidate



pregabalin and nalorphine and modafanil



pregabalin and nalorphine and lisdexamfetamine



pregabalin and levallorphan and phentermine



pregabalin and levallorphan and dexmethylphenidate



pregabalin and levallorphan and dextroamphetamine



pregabalin and levallorphan and dexedrine



pregabalin and levallorphan and Adderall



pregabalin and levallorphan and methylphenidate



pregabalin and levallorphan and modafanil



pregabalin and levallorphan and lisdexamfetamine



pregabalin and buprenorphine and phentermine



pregabalin and buprenorphine and dexmethylphenidate



pregabalin and buprenorphine and dextroamphetamine



pregabalin and buprenorphine and dexedrine



pregabalin and buprenorphine and Adderall



pregabalin and buprenorphine and methylphenidate



pregabalin and buprenorphine and modafanil



pregabalin and buprenorphine and lisdexamfetamine



pregabalin and extended release naltrexone and phentermine



pregabalin and extended release naltrexone and dexmethylphenidate



pregabalin and extended release naltrexone and dextroamphetamine



pregabalin and extended release naltrexone and dexedrine



pregabalin and extended release naltrexone and Adderall



pregabalin and extended release naltrexone and methylphenidate



pregabalin and extended release naltrexone and modafanil



pregabalin and extended release naltrexone and lisdexamfetamine



pregabalin and tan-67 and phentermine



pregabalin and tan-67 and dexmethylphenidate



pregabalin and tan-67 and dextroamphetamine



pregabalin and tan-67 and dexedrine



pregabalin and tan-67 and Adderall



pregabalin and tan-67 and methylphenidate



pregabalin and tan-67 and modafanil



pregabalin and tan-67 and lisdexamfetamine



pregabalin and snc80 and phentermine



pregabalin and snc80 and dexmethylphenidate



pregabalin and snc80 and dextroamphetamine



pregabalin and snc80 and dexedrine



pregabalin and snc80 and Adderall



pregabalin and snc80 and methylphenidate



pregabalin and snc80 and modafanil



pregabalin and snc80 and lisdexamfetamine



baclofen and naltrexone and n-acetylcysteine



baclofen and naltrexone and d-cycloserine



baclofen and naltrexone and ceftriaxone



baclofen and naloxone and n-acetylcysteine



baclofen and naloxone and d-cycloserine



baclofen and naloxone and ceftriaxone



baclofen and nalorphine and n-acetylcysteine



baclofen and nalorphine and d-cycloserine



baclofen and nalorphine and ceftriaxone



baclofen and levallorphan and n-acetylcysteine



baclofen and levallorphan and d-cycloserine



baclofen and levallorphan and ceftriaxone



baclofen and buprenorphine and n-acetylcysteine



baclofen and buprenorphine and d-cycloserine



baclofen and buprenorphine and ceftriaxone



baclofen and extended release naltrexone and n-acetylcysteine



baclofen and extended release naltrexone and d-cycloserine



baclofen and extended release naltrexone and ceftriaxone



baclofen and tan-67 and n-acetylcysteine



baclofen and tan-67 and d-cycloserine



baclofen and tan-67 and ceftriaxone



baclofen and snc80 and n-acetylcysteine



baclofen and snc80 and d-cycloserine



baclofen and snc80 and ceftriaxone



lesogaberan and naltrexone and n-acetylcysteine



lesogaberan and naltrexone and d-cycloserine



lesogaberan and naltrexone and ceftriaxone



lesogaberan and naloxone and n-acetylcysteine



lesogaberan and naloxone and d-cycloserine



lesogaberan and naloxone and ceftriaxone



lesogaberan and nalorphine and n-acetylcysteine



lesogaberan and nalorphine and d-cycloserine



lesogaberan and nalorphine and ceftriaxone



lesogaberan and levallorphan and n-acetylcysteine



lesogaberan and levallorphan and d-cycloserine



lesogaberan and levallorphan and ceftriaxone



lesogaberan and buprenorphine and n-acetylcysteine



lesogaberan and buprenorphine and d-cycloserine



lesogaberan and buprenorphine and ceftriaxone



lesogaberan and extended release naltrexone and n-acetylcysteine



lesogaberan and extended release naltrexone and d-cycloserine



lesogaberan and extended release naltrexone and ceftriaxone



lesogaberan and tan-67 and n-acetylcysteine



lesogaberan and tan-67 and d-cycloserine



lesogaberan and tan-67 and ceftriaxone



lesogaberan and snc80 and n-acetylcysteine



lesogaberan and snc80 and d-cycloserine



lesogaberan and snc80 and ceftriaxone



gabapentin and naltrexone and n-acetylcysteine



gabapentin and naltrexone and d-cycloserine



gabapentin and naltrexone and ceftriaxone



gabapentin and naloxone and n-acetylcysteine



gabapentin and naloxone and d-cycloserine



gabapentin and naloxone and ceftriaxone



gabapentin and nalorphine and n-acetylcysteine



gabapentin and nalorphine and d-cycloserine



gabapentin and nalorphine and ceftriaxone



gabapentin and levallorphan and n-acetylcysteine



gabapentin and levallorphan and d-cycloserine



gabapentin and levallorphan and ceftriaxone



gabapentin and buprenorphine and n-acetylcysteine



gabapentin and buprenorphine and d-cycloserine



gabapentin and buprenorphine and ceftriaxone



gabapentin and extended release naltrexone and n-acetylcysteine



gabapentin and extended release naltrexone and d-cycloserine



gabapentin and extended release naltrexone and ceftriaxone



gabapentin and tan-67 and n-acetylcysteine



gabapentin and tan-67 and d-cycloserine



gabapentin and tan-67 and ceftriaxone



gabapentin and snc80 and n-acetylcysteine



gabapentin and snc80 and d-cycloserine



gabapentin and snc80 and ceftriaxone



pregabalin and naltrexone and n-acetylcysteine



pregabalin and naltrexone and d-cycloserine



pregabalin and naltrexone and ceftriaxone



pregabalin and naloxone and n-acetylcysteine



pregabalin and naloxone and d-cycloserine



pregabalin and naloxone and ceftriaxone



pregabalin and nalorphine and n-acetylcysteine



pregabalin and nalorphine and d-cycloserine



pregabalin and nalorphine and ceftriaxone



pregabalin and levallorphan and n-acetylcysteine



pregabalin and levallorphan and d-cycloserine



pregabalin and levallorphan and ceftriaxone



pregabalin and buprenorphine and n-acetylcysteine



pregabalin and buprenorphine and d-cycloserine



pregabalin and buprenorphine and ceftriaxone



pregabalin and extended release naltrexone and n-acetylcysteine



pregabalin and extended release naltrexone and d-cycloserine



pregabalin and extended release naltrexone and ceftriaxone



pregabalin and tan-67 and n-acetylcysteine



pregabalin and tan-67 and d-cycloserine



pregabalin and tan-67 and ceftriaxone



pregabalin and snc80 and n-acetylcysteine



pregabalin and snc80 and d-cycloserine



pregabalin and snc80 and ceftriaxone
















TABLE 4







Palatable food intake following drug injections


as a percent of intake after saline injections













Naltrexone-



Naltrexone
Baclofen
Baclofen














low
high
low
high
low
high


Group
dose
dose
dose
dose
dose
dose










1-H Intake (%)













Binge Sugar
158
92
131
96
115
51


Binge Fat
70
59
106
38
110
26


Binge Sugar-Fat
74
75
100
37
106
44







12-H Intake (%)













Binge Sugar
92
85
88
90
85
82


Binge Fat
85
91
93
56
83
59


Binge Sugar-Fat
92
109
85
75
94
89
















TABLE 5







Palatable food intake following drug injections (Kcals)











Naltrexone
Baclofen
Naltrexone-Baclofen














Group
Saline
low dose
high dose
low dose
high dose
low dose
high dose










1-H Palatable Food Intake (Kcal)














Binge Sugar
2.8 ± 0.5 
 4.4 ± 0.7a
 2.6 ± 0.4a
 3.6 ± 0.8
2.7 ± 0.5 
  3.2 ± 0.6b
  1.4 ± 0.4b


Binge Fat
 16.8 ± 3.0c,h,i
11.7 ± 1.9
 9.9 ± 2.0
 17.9 ± 2.4d
  6.5 ± 2.0c,d
 18.5 ± 2.3g
   4.3 ± 1.4g,h


Binge Sugar-Fat
 23.5 ± 2.7k,m
17.3 ± 1.7
17.6 ± 3.5
 23.5 ± 3.9j
 8.6 ± 1.6j,k
 24.9 ± 1.9n
  10.4 ± 2.5m,n







12-H Palatable Food Intake (Kcal)














Binge Sugar
12.8 ± 2.3  
 18.7 ± 2.4r
 10.8 ± 1.8r
11.3 ± 2.5
11.4 ± 2.4 
10.8 ± 2.3
10.4 ± 2.8


Binge Fat
58.6 ± 6.3e,i
49.9 ± 3.6
53.3 ± 4.5
 54.5 ± 4.5f
32.6 ± 4.9e,f
48.7 ± 3.8
 34.8 ± 3.1i


Binge Sugar-Fat
76.4 ± 5.8p 
70.6 ± 3.4
83.3 ± 8.1
64.9 ± 6.6
57.4 ± 4.1p 
71.8 ± 6.5
67.9 ± 4.5
















TABLE 6







Chow intake following drug injections (Kcals)











Naltrexone
Baclofen
Naltrexone-Baclofen














Group
Saline
low dose
high dose
low dose
high dose
low dose
high dose










1-H Chow Intake (Kcal)














Binge Sugar
18.2 ± 1.7
25.5 ± 3.2
20.1 ± 1.3
23.0 ± 1.5
19.3 ± 3.4
 23.0 ± 1.8d
 15.7 ± 1.7d


Binge Fat
 11.3 ± 1.3g
 8.5 ± 1.1
10.1 ± 1.2
12.2 ± 1.7
10.6 ± 1.0
 13.1 ± 0.8h
   8.1 ± 0.7g,h


Binge Sugar-Fat
 8.2 ± 1.4
 6.6 ± 1.0
 7.1 ± 0.9
 11.3 ± 1.7i
  6.3 ± 1.0i
10.1 ± 1.1
 7.5 ± 1.6







12-H Chow Intake (Kcal)














Binge Sugar
   58.5 ± 2.7a,b,c,e,f
 73.7 ± 5.1a
 78.6 ± 4.7b
 73.5 ± 4.5c
62.5 ± 3.8
 77.0 ± 3.2e
 75.4 ± 4.5f


Binge Fat
38.0 ± 3.4
34.1 ± 4.3
37.0 ± 3.4
34.1 ± 3.3
35.0 ± 5.0
35.1 ± 3.8
33.3 ± 3.3


Binge Sugar-Fat
23.6 ± 2.5
26.4 ± 1.9
27.4 ± 2.6
24.6 ± 2.2
24.1 ± 3.1
26.3 ± 2.2
24.8 ± 1.9
















TABLE 7







Total caloric intake following drug injections (Kcals)











Naltrexone
Baclofen
Naltrexone-Baclofen














Group
Saline
low dose
high dose
low dose
high dose
low dose
high dose










1-H Total Caloric Intake (Kcal)














Binge Sugar
20.9 ± 2.2a 
 29.9 ± 3.9a
22.6 ± 1.7
26.7 ± 2.3
21.9 ± 4.4
26.2 ± 2.4b
17.1 ± 2.1b


Binge Fat
28.2 ± 3.4e,h
20.2 ± 3.0
19.9 ± 3.2
 30.1 ± 4.1f
 17.0 ± 3.0e,f
31.6 ± 3.1i 
 12.4 ± 2.1h,i


Binge Sugar-Fat
31.7 ± 4.1k,n
23.9 ± 2.7
24.8 ± 4.4
 34.8 ± 5.6m
  15.0 ± 2.6k,m
35.0 ± 3.0o
 17.9 ± 4.0n,o







12-H Total Caloric Intake (Kcal)














Binge Sugar
71.3 ± 5.0c,d
85.4 ± 7.5
89.4 ± 6.4
84.8 ± 7.0
74.0 ± 6.3
87.9 ± 5.5c
85.9 ± 7.3d


Binge Fat
 96.6 ± 9.6 g,j
84.0 ± 7.9
90.3 ± 8.3
88.6 ± 7.8
 67.7 ± 9.9g
83.7 ± 7.5 
68.1 ± 6.4j 


Binge Sugar-Fat
100.0 ± 8.3  
97.0 ± 5.7
110.7 ± 10.7
89.5 ± 8.8
81.4 ± 7.3
98.1 ± 8.7 
92.7 ± 6.3

## Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of baclofen or a pharmaceutically acceptable salt thereof; and naltrexone or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof is an amount of about 25 to 100 milligrams and baclofen or a pharmaceutically acceptable salt thereof is an amount between about 15 and about 120 milligrams.

2. The composition of claim 1, wherein said composition further comprises a therapeutically effective amount of extended release bupropion or bupropion or a pharmaceutically acceptable salt thereof.

3. The composition according to claim 2, wherein the composition comprises:
naltrexone, or a pharmaceutically acceptable salt thereof, in an amount of about 25 to 100 milligrams, baclofen, or a pharmaceutically acceptable salt thereof, in an amount between about 15 and about 120 milligrams and bupropion or bupropion extended release, or pharmaceutically acceptable salts thereof in an amount of between 75 milligrams and 450 milligrams.

4. A method for reducing the intake of fatty foods, sugar rich foods, or foods that are both fatty and sugar-rich comprising the administration of a composition according to claim 1 to an individual whose diet includes fatty foods, sugar rich foods, or foods that are both fatty and sugar-rich.

5. The method according to claim 4, wherein said individual is an individual meeting the definition of food addiction, an individual who is obese or overweight, has a binge-eating disorder or an individual that engages in binge eating behavior.

6. The pharmaceutical composition of claim 1, wherein the composition comprises synergistic amounts of baclofen and naltrexone.

7. The pharmaceutical composition of claim 6, wherein the composition further comprises extended release bupropion or bupropion or a pharmaceutically acceptable salt thereof.