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US 20130289061A1 (19) United States (12) Patent Application Publication (10) . No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013

(54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ...... 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa ; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central stimulant and an opioid receptor ’ antagonist. Examples of (60) Provisional application No. 61/233,686; ?led on Aug. (such as ) and opioid receptor antagonists 13, 2009. (such as ) are provided. Patent Application Publication Oct. 31, 2013 Sheet 1 0f 12 US 2013/0289061 A1

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METHODS AND COMPOSITIONS TO administration. In one embodiment of the various pharma PREVENT ADDICTION ceutical compositions described herein, the pharmaceutical composition is formulated as a tablet or . In one CROSS-REFERENCE TO RELATED embodiment of the various pharmaceutical compositions APPLICATIONS described herein, the opioid is formulated such that When ingested, the opioid receptor antagonist [0001] This application is a continuation application of co remains intact. The various pharmaceutical compositions pending US. patent application Ser. No. 13/389,959 ?led on described herein are suitable for use in the methods described Apr. 27, 2012, Which is a 35 U.S.C. §371 National Phase Entry Application of International Application No. PCT/ herein. US2010/045486 ?led onAug. 13, 2010, Which designated the [0006] Another aspect of the invention relates to a method United States, and Which claims the bene?t under 35 U.S.C. of reducing or preventing the development of aversion to a §119(e) of US. Provisional Application No. 61/233,686, CNS stimulant in a subject comprising, administering a thera ?led Aug. 13, 2009, the contents of each of Which are incor peutic amount of the neurological stimulant and administer porated herein by reference in their entireties. ing an antagonist of the kappa opioid receptor, to thereby prevent the development of aversion to the CNS stimulant in GOVERNMENTAL SUPPORT the subject. In one embodiment of the methods described herein, the method further comprises selecting a subject at [0002] This invention Was made With Government support risk for the development of aversion to the CNS stimulant, under research grant R0 1 DA020796 aWarded by the National prior to the administering. In one embodiment of the methods Institutes of Health. The Government has certain rights in the described herein, the subject is diagnosed With de? invention. cit hyperactivity disorder (ADHD), , chronic syndrome, or . FIELD OF THE INVENTION [0007] Another aspect of the invention relates to a method [0003] The present invention relates to the ?eld of to decrease the associated With the use of therapeu therapies and the prevention of addiction to such as doses of a CNS stimulant comprising administering a those that activate the receptor. therapeutic amount of the CNS stimulant and administering a kappa opioid receptor antagonist, to thereby decrease the BACKGROUND OF THE INVENTION dysphoria. In one embodiment of the methods described herein, the method further comprises selecting a subject at [0004] Methylphenidate (MPH) is the most commonly pre risk for the development of dysphoria, prior to administering. scribed stimulant compound for treatment of attention de?cit hyperactivity disorder (ADHD)1’2. Although its therapeutic [0008] Another aspect of the invention relates to a method e?icacy and safety is Well documented in pediatric and adult to decrease the associated With the use of therapeu patients3 , serious concerns persist about its potential tic doses of a CNS stimulant comprising administering a upon long-term usage4'9. Moreover, recreational or street-use therapeutic amount of the CNS stimulant and administering a of stimulants and is on the rise further adding to the mu opioid receptor antagonist, to thereby decrease the eupho concerns about stimulant ’lo’l 1. In fact, non-human ria. In one embodiment of the methods described herein, the primates can self-administer MPHl2’l3ia hallmark of addic method further comprises selecting a subject at risk for the tion. Prevailing notions of molecular mechanisms mediating development of euphoria, prior to administering. MPH addiction rely on the central actions of MPH on dopam [0009] Another aspect of the invention relates to a method ine and noradrenaline signaling mechanismsl4'l7. HoWever, of reducing or preventing the development of addiction to a these mechanisms alone are inadequate for CNS stimulant in a subject, comprising, administering the fully explaining MPH addiction. CNS stimulant and administering a mu opioid receptor antagonist to thereby reduce or prevent the development of SUMMARY OF THE INVENTION addiction to the CNS stimulant in the subject. In one embodi ment of the methods described herein, the method further [0005] One aspect of the invention is a pharmaceutical comprises selecting a subject at risk for the development of composition comprising a central nervous system (CNS) addiction to the CNS stimulant, prior to the administering. stimulant and an opioid receptor antagonist. In one embodi ment of the pharmaceutical compositions described herein, [0010] Another aspect of the invention relates to a method the opioid receptor antagonist is selected from the group of treating a subject for ADHD, comprising administering a consisting of naltrexone, , , etorphine, therapeutically effective amount of methylphenidate and , and combinations thereof. In one embodi administering an opioid receptor antagonist to thereby treat ment of the various pharmaceutical compositions described the subject for ADHD. In one embodiment of the methods herein, the CNS stimulant is selected from the group consist described herein, the method further comprises selecting a ing of methylphenidate, , moda?nil, and com subject at risk for the development of aversion or addiction to binations thereof. In one embodiment of the various pharma methylphenidate, prior to the administering. ceutical compositions described herein, the CNS stimulant is [0011] In one embodiment of the various methods present in a therapeutic amount and the opioid receptor described above, the CNS stimulant is selected from the antagonist is present in an amount for preferred inhibition of group consisting of methylphenidate, amphetamine, moda? the mu opioid receptor. In one embodiment of the various nil, and combinations thereof. In one embodiment of the pharmaceutical compositions described herein, the composi various methods described above, the CNS stimulant results tion is formulated for enteral administration. In one embodi in activation of a . In one embodiment, the ment of the various pharmaceutical compositions described dopamine receptor is selected from the group consisting of herein, the pharmaceutical composition is formulated for oral D1, D2, D3, D4, D5, and combinations thereof. US 2013/0289061 A1 Oct. 31,2013

[0012] In one embodiment of the various methods dose (7.5 mg/kg) MPH and (10 mg/kg; positive con described above, the opioid receptor antagonist is selected trol) Was analyZed. In FIG. 1A, time spent in the drug-paired from the group consisting of naltrexone, naloxone, diprenor chamber during the pre-conditioning (PC) and test (Test) phine, etorphine, dihydroetorphine, and combinations sessions Was calculated and the difference betWeen the tWo thereof. In one embodiment of the various methods described Was compared for each drug treatment group. Mice exposed above, the administering is oral. In one embodiment of the to cocaine or high-dose MPH and cocaine spent signi?cantly various methods described above, the CNS stimulant and the longer period of time in the drug-paired chamber during the opioid receptor antagonist are administered in the same phar test sessions compared to the PC sessions (t-test; p<0.05). maceutical composition. In one embodiment of the various There Was no statistically signi?cant difference in this mea methods described above, the CNS stimulant and the opioid sure for the saline and loW dose MPH groups (t-test; p>0.05). receptor antagonist are administered sequentially. In one In FIG. 1B, one-Way ANOVA shoWed signi?cant (F:6.7; embodiment of the various methods described above, the p<0.01) effects of drug treatment on the CPP score (FIG. 1B). opioid receptor antagonist is administered in the dosage of Multiple comparisons test shoWed that the CPP scores Were from about 50 to about 100 mg. signi?cantly higher (p<0.05) in the cocaine and high dose MPH groups compared to the saline and loW dose MPH DEFINITIONS groups (FIG. 1B). There Was no signi?cant difference betWeen the cocaine and high dose MPH groups. [0013] As the term is used herein, reduce or reducing, as used in connection With reducing dysphoria or reducing [0019] FIG. 2A-2B are graphical representations of experi euphoria, refers to a reduction or decrease in the dysphoric or mental results that indicate high supratherapeutic doses of euphoric effects experienced by the subject With administra MPH upregulate p. opioid receptor (MOPR) activity in the tion of the drug. A reduction is determined as a statistically caudate-putamen and . -stimu signi?cant, detectable, reproducible, decrease, as measured lated MOPR activity Was analyZed using the [35S]GTPyS by one or more accepted methods of detection. Dysphoric binding assay in membrane preparations of the caudate-puta effects can include, Without limitation, an abnormal mood men and nucleus accumbens from the four groups of mice state of feeling unWell, unhappy, uncomfortable, irritable, used in the CPP assay (C). In FIG. 2A, [35S]GTPyS binding disliking and anxious. Euphoria effects can include, Without using increasing concentrations of the MOPR agonist limitation, an abnormal mood state of feeling elation, abnor DAMGO Was examined in the presence of 200 mM GDP, 5 mal happiness, severe excitement, abnormal joy not con mM Mg++ and 100 mM Na+ (A). [35S]GTPyS binding Was nected to objective circumstances. increased by DAMGO in a concentration-dependent manner [0014] Reduce or reducing, as used With respect to reducing With an EC50 of ~1 and 0.1 uM. The maximal binding, Which drug aversion, or reducing drug addiction, refers to a decrease represented 1.75-fold of the basal level Was reached at 10 [1M or lessening of the aversion or addiction. Such a decrease can concentration (FIG. 2A). This concentration of DAMGO Was be evidenced, for example, by preventing or delaying the used in the bindings assays from the 4 groups of mice shoWn onset of the development of symptoms of drug aversion or in FIG. 2B. ANOVA revealed signi?cant effects of the drug addiction. treatment (Caudate putamen: F:5.89; p<0.05; nucleus accumbens: 13:33, p<0.05) on DAMGO stimulated [35 S] [0015] As the term is used herein, aversion, refers to avoid GTPyS binding and multiple comparisons analysis shoWed ance of or failure to adhere to a prescribed regimen of a therapeutic composition, due to the negative effects (dyspho that the cocaine and high dose MPH groups shoWed signi? cantly higher MOPR activity compared to the saline or loW ria) experienced therefrom. dose MPH groups (p<0.05) in both the brain regions. There [0016] As used herein, the term effective amount, refers to Was no signi?cant difference betWeen the cocaine and high an amount of a drug or agent that produced the desired result dose MPH groups. (e.g, partial or complete inhibition of one or more opioid receptors (mu or kappa). In one embodiment, an effective [0020] FIG. 3A-3C are graphical representations of experi amount is an amount that preferentially inhibits one opioid mental results that indicate naltrexone (5 or 10 mg/kg) admin receptor Without substantially inhibiting another opioid istration prior to high dose (7.5 mg/kg) methylphenidate receptor. For example, preferentially inhibiting the MOPR (MPH) blocks MPH-induced conditioned place preference Without substantially inhibiting the KOPR, or vice versa. (CPP) and MPH-induced activation of the p. opioid receptor [0017] As used herein the terms subject and patient are used (MOPR). CPP using saline (negative control), naltrexone (1, interchangeably, and refer to a recipient in need of the therapy or 10 mg/kg) or MPH (7.5 mg/kg) alone and a combination of described herein. In one embodiment, the subject is a human. MPH and naltrexone (1, 5 or 10 mg/kg) Were analyZed. In In one embodiment the human is mature (e. g., at least 18 years FIG. 3A, When the difference in time spent in the drug-paired of age). In one embodiment, the human is immature (e.g., less chamber during the pre-conditioning (PC) and test (Test) than 18 years of age), also referred to herein as a child. sessions Was analyZed, high dose of MPH alone produced Subject further refers to mammals such as rats, mice, rabbits, signi?cant increase (t-test; p<0.05) in this measure. Neither sheep, cats, dogs, coWs, pigs, horses and non-human pri saline alone nor naltrexone (1 or 10 mg/kg) alone produced mates. signi?cant changes in this measurement (i.e. did not induce CPP). When naltrexone (1, 5 or 10 mg/kg) Was administered BRIEF DESCRIPTION OF THE DRAWINGS prior to MPH, in each case there Was a signi?cant difference betWeen PC and Test sessions (p<0.05) indicating that each [0018] FIG. 1A-1B are graphical representations of experi drug treatment had induced CPP. In FIG. 3B, When the CPP mental results that indicate supratherapeutic doses of meth scores Were compared among the experimental groups, a ylphenidate (MPH) induce conditioned place preference signi?cant effect of drug treatment Was found (ANOVA; 13:9. (CPP). CPP induced by intraperitoneal administration of 78, p<0.001). Comparisons betWeen the different groups saline (negative control), loW dose (0.75 mg/kg) MPH, high shoWed that prior treatment With 1, 5 or 10 mg/kg naltrexone US 2013/0289061 A1 Oct. 31,2013

signi?cantly decreased the CPP score compared to the CPP to the drug by the subject, and to therefore promote adhere score produced When MPH Was administered alone. The ance by the subject to a prescribed therapeutic regimen. As decrease in the CPP score Was naltrexone dose-dependent. In such, another aspect of the invention relates to a method of fact, the CPP score for the group that had received the highest reducing or preventing the development of aversion to a drug dose of naltrexone (10 mg/kg) prior to MPH Was not signi? in a subject. The method comprises administering a therapeu cantly different from that for the saline group. In FIG. 3C, tic amount of the drug and administering an effective amount agonist-stimulated MOPR activity Was analyzed using the of an agent that inhibits the kappa opioid receptor, to thereby [35S]GTPyS binding in membrane preparations of the cau reduce or prevent the development of aversion to the drug in date-putamen and nucleus accumbens from the saline alone, the subject. MPH (7.5 mg/kg) alone and MPH+naltrexone (10 mg/kg) [0025] In one embodiment, a subject is ?rst identi?ed or groups of mice that had been used in the CPP assay. ANOVA selected as a subject at risk for the development of dysphoria revealed signi?cant effects of the drug treatment (caudate or aversion to the drug, prior to the administration of the drug putamen; 13:66.17; p<0.000l; nucleus accumbens; 13:45.88, and the agent. p<0.000l) and multiple comparisons analysis shoWed that the [0026] Aspects of the present invention relate to methods MOPR activity in the MPH+naltrexone (10 mg/kg) group for reducing or preventing euphoria in a subject associated Was signi?cantly loWer compared to that in the saline or MPH With administration of a therapeutic amount of a drug to the alone groups (p<0.0l). subject, by administering an effective amount of an agent that [0021] FIG. 4A-4B are graphical representations of experi inhibits the mu opioid receptor to the subject, to thereby mental results that indicate dopamine Dl-receptor antagonist reduce or prevent euphoria in the subject. The reduction of Schering 233 90 but not the D2 -receptor antagonist euphoria is expected to reduce the development of addiction can block high dose (7.5 mg/kg) methylphenidate (MPH) to the drug by the subject. As such, another aspect of the induced conditioned place preference (CPP). CPP assay invention relates to a method of reducing or preventing the using saline, Schering 23390 (dose), raclopride (dose) or development of addiction to a drug in a subject. The method MPH (7.5 mg/kg) or using a combination of MPH+Schering comprises administering a therapeutic or supratherapeutic 23390 and MPH+ raclopride Was performed. In the drug amount of the drug and administering an effective amount of combination group, MPH Was administered 10 min after the an agent that inhibits the mu opioid receptor, to thereby receptor antagonist. In FIG. 4A, When the difference in time reduce or prevent the development of addiction to the drug in spent in the drug-paired chamber during the pre-conditioning the subject. (PC) and test (Test) sessions Was analyZed, high dose MPH [0027] In one embodiment of the method, the subject is ?rst alone and MPH+ reclopride and no other drug treatment identi?ed or selected as a subject at risk for the development produced signi?cant increase (t-test; p<0.05) in this measure. of euphoria or addiction to the drug, prior to the administra In FIG. 4B, When differences in CPP score Were compared tion of the drug and the agent. among the different groups, signi?cant effect of the drug [0028] Another aspect of the present invention is a method treatment Was observed (ANOVA; F:9.3; p<0.000l). Mul of treating a subject for a disease or disorder typically treated tiple comparisons test shoWed that the MPH+Schering 23390 With a drug discussed herein. The method involves adminis group had signi?cantly loWer CPP score (p<0.0l) compared tering the drug to the subject and administering an agent that to the MPH only group and that there Was no statistically inhibits an opioid receptor (mu and/or kappa), to the subject, signi?cant difference betWeen saline and MPH+Schering to thereby treat the subject for the disease or disorder. The 23390 groups. The MPH only and MPH+raclorpide groups agent is administered in an amount effective to inhibit the mu did not shoW signi?cant differences. and/or kappa opioid receptor. In one embodiment, the subject [0022] FIG. 5 is a graph of experimental results Which is diagnosed With the disease or disorder prior to treatment. In indicate the effects of saline, naltrexone (l, 5 or 10 mg/kg) another embodiment, the subject is identi?ed as at risk for the alone, MPH (7.5 mg/kg) alone or each dose of naltrexone+ development of euphoria/ addiction or dysphoria/aversion, MPH on locomotor activity. MPH (7.5 mg/kg) increased prior to the administering of a mu or kappa opioid receptor locomotor activity signi?cantly. The increase Was not inhibitor, respectively. In one embodiment, the disease or affected by co-administration With naltrexone at any of the disorder is attention de?cit hyperactivity disorder, narco doses examined. Naltrexone alone did not affect locomotor lepsy, chronic fatigue syndrome, or depression, and the drug activity. Data Were analyZed by ANOVA. n:l l. is methylphenidate. In one embodiment, the agent is naltrex [0023] FIG. 6A-6B are bar graphs of experimental results one, naloxone, diprenorphine, etorphine, dihydroetorphine or Which indicate DAMGO-stimulated [35S]GTPyS binding in combinations thereof. In one embodiment the disease or dis corpus (FIG. 6A) and nucleus accumbens (FIG. 6B) order is age-related memory decline, attention de?cit disor membrane preparations folloWing intraperitoneal MPH (0.75 der, depression, fatigue caused by high-pressure jobs requir or 7.5 mg/kg) or cocaine (10 mg/kg) administration. (t-test; ing long hours, fatigue caused by chemotherapy treatment for MeanzSEM, **P<0.0l, *P<0.05 vs. saline; ++P<0.0l, +P<0. cancer patients, fatigue experienced by persons suffering 05 vs. MPH (0.75). from diseases such as , fatigue experienced by people Who need to be aWake and alert for extended DETAILED DESCRIPTION OF THE INVENTION amounts of times such as soldiers, truckers or students cram [0024] Aspects of the present invention relate to methods ming for ?nals, jet lag, memory problems associated With for reducing or preventing dysphoria in a subject associated AlZheimer’s disease, post- grogginess, sleepiness With administration of a therapeutic amount of a drug to the caused by other prescription , or treatment for subject, by administering an effective amount of an agent that cocaine addiction, and the drug is moda?nil. inhibits the kappa opioid receptor to the subject, to thereby [0029] Subjects Who are at risk for the development of reduce or prevent dysphoria in the subject. The reduction of aversion or addiction can be identi?ed by a variety of means dysphoria is expected to reduce the development of aversion knoWn in the art. Subjective drug experience, especially US 2013/0289061 A1 Oct. 31,2013

euphoria, is thought to be an indicator of risk of abuse (Jas composition of the present invention is formulated for enteral inski and Henning?eld, 1989; Jasinski, 2000; Kollins et al., or . In one embodiment, the pharmaceuti 2001) and dysphoria is thought to be a major determinant of cal composition is formulated as a tablet or capsule. tolerability and adherence With treatment regimen in clinical [0034] In one embodiment, the drug is a CNS stimulant, a practice. Subjective responses to oral MPH Were reported in drug Which actives one or more dopamine receptors, an ana 18 (72%) of 25 studies that evaluated detection/likeability leptic, or combinations thereof. In one embodiment, the drug (Kollins et al., 2001). Likewise the large extent of clinical is methylphenidate, amphetamine, or moda?nil. trials literature documents the frequent occurrence of dyspho [0035] In one embodiment, the agent for inhibition of ric effects in clinical populations that adversely impact toler opioid receptor is naltrexone, naloxone, diprenorphine, etor ability and eventually compliance With stimulant treatment. phine, dihydroetorphine, or combinations thereof. [0030] Subjects Who are at risk for the development of [0036] In one embodiment, the drug (e.g., CNS stimulant) aversion or addiction can be identi?ed, for example, by is present in a therapeutic amount and the opioid receptor assessment of the subjects dysphoric or euphoric response, antagonist is present in an amount for preferred inhibition of respectively, to the drug by established methods. Assessment a speci?c opioid receptor (e.g., MOPR). For example, a loW of euphoria and dysphoria can be assessed in a subject, for dose, as described herein can be included in the pharmaceu example, by assessing the subjective response of euphoria tical composition With the drug (e.g, methylphenidate). The (liking) and dysphoria (disliking) of acute oral therapeutic exact amount of the opioid receptor inhibitor can be deter doses of the drug using the Drug Rating Questionnaire mined from the amount of the drug in the composition, since (DQRS), (Jasinski and Henning?eld, 1989; Jasinski, 2000; the amount of the drug Will determine the amount and fre Kollins et al., 2001). Constituent elements of the DQRS scale quency of therapeutic administration of the pharmaceutical have been standardized by comparison to responses to knoWn composition. drugs of abuse and validated against observer ratings and [0037] A drug formulated in combination With the mu physiologic changes (Jasinski and Henning?eld, 1989). Sub opioid receptor inhibitor has the advantage that it Will be jects Who experience dysphoria or euphoria in connection “less-abusable” or “non-abusable”. That is to say, the With a speci?c drug, are likely to have the same or even an euphoric effects experience are substantially reduced or enhanced experience, upon repeated exposure to the drug. As eliminated. As such, the formulations described herein Would such, the assessment is also useful in identifying a subject at be less attractive for illegal, non-therapeutic administration, risk for ongoing dysphoria or euphoria associated With the and also far less likely to cause addition in a subject Who Was drug. In some circumstances, assessment of euphoria and self-administering for non-therapeutic purposes. Such effec dysphoria to a drug similar (e.g., in mode of action) to the tive formulations could theoretically avoid the requirement intended therapeutic prescribed drug Will also yield useful for classi?cation as a Schedule II drug. This Wouldmake them information regarding a subject’s likelihood of developing more readily available and more easily obtained for therapeu dysphoria and/or aversion, or euphoria and/or addiction. tic purposes. Another method of identifying a subject at risk for aversion/ [0038] In one embodiment, the pharmaceutical composi dysphoria or addiction/euphoria is by analysis of the subject’ s tion comprises the drug (e.g., methylphenidate) and the history With other drugs. In one embodiment, a subject With a opioid receptor inhibitor (e. g., naltrexone), formulated to pre history or drug aversion/dysphoria, or drug addiction/eupho vent MPH abuse potential Without affecting the development ria, to other drugs, is identi?ed as at risk. of dysphoria/aversion in a subject. A recent technology is [0031] Drugs for Which the herein described methods are used in Which an oral preparation (capsule or tablet) is pre appropriate include, Without limitation, CNS stimulants, pared With naltrexone embedded in the core surrounded by drugs Which activate one or more dopamine receptors, and MPH. When the capsules/tablets are ingested only MPH is analeptics. In one embodiment, the drug is methylphenidate, released and the naltrexone core passes through the gut intact. amphetamine, or moda?nil. This technology is available commercially (AVERSION©, [0032] Agents that inhibit the respective opioid receptors Acura Pharmaceuticals; Embeda®, King Pharmaceuticals). described herein include, Without limitation, agents that Work In such preparations, MPH exerts its actions Without naltrex directly (e.g., antagonists of the receptors) and also agents one interference. HoWever, if the preparation is crushed for that Work indirectly (e.g., agents that inhibit signaling from intra-nasal administration or other abuse purposes, naltrex the receptor or agents that inhibit expression of the receptors). one is released blocking MPH addiction. This approach Will Examples of such agents are described herein. In one embodi not help prevent MPH aversion, but can prevent abuse and ment, the agent is naltrexone, naloxone, diprenorphine, etor phine, dihydroetorphine or combinations thereof. addiction. [0033] Another aspect of the present invention relates to Central Nervous System (CNS) Stimulants pharmaceutical compositions comprising both the drug and the agent for inhibition of opioid receptor, described in the [0039] CNS stimulants (also called psychostimulants) are methods herein. A pharmaceutical composition includes one psychoactive drugs Which induce temporary improvements in or more active agents, formulated appropriately for the either mental or physical function or both. In one embodi desired , and a pharmaceutically ment, CNS stimulants include, but not limited to, , acceptable carrier(s) and/or (s) suitable for the , cocaine, amphetamine, . L-am desired route of administration. As used herein, “pharmaceu phetamine, , methylenedioxymetham tically acceptable carrier” includes any and all , dis phetamine (MDMA), inhibitors persion media, coatings, antibacterial and anti fungal agents, (N RIs) norepinephrine-dopamine reuptake inhibitors isotonic and absorption delaying agents, and the like that are (NDRIs), Moda?nil, , , , physiologically compatible. For example, the carrier can be phenmetratZine, methylphenidate, diethylpropion, , suitable for intravenous injection or for oral administration. , (—) cathione, fen?uramine (and other amphet include pharmaceutically acceptable stabilizers derivatives having substitutions in aromatic ring). Fur and disintegants. In one embodiment, the pharmaceutical ther exemplary CNS stimulants are shoWn in Table 1: US 2013/0289061A1 Oct. 31, 2013

TABLE 1

Examples of types of CNS stimulants

Adamantanes Adaphenoxate ' Adapromine ' ' ' Chlodantane ' Gludantane ' ' Midantane ' Dieticyclidine ' ' ' ' ' Phencyclamine ' Phencyclidine ' ' ' 6-Br-APB ' SKIS-77434 ' SKF-81297 ' SKF-82958 A-84543 ' A-366,833 ' ABT-202 ' ABT-418 ' AR-R17779 ' ' ' ' ' ' ' ' ' GTS-21 ' ' Nicotine ' PHA 543,613 ' PNU—120,596 ' PNU—282,987 ' ' ' SazetidineA ' SIB-1553A ' SSR-180,711 ' TC-1698 ' TC-1827 ' TC 2216 ' TC-5619 ' ' UB-165 ' ' WAY-317,538 AnatoXin-a ' ' DMCM ' ' ' Pentetrazol ' ' ' Adra?nil ' Armoda?nil ' CRL-40941 ' Moda?nil 4-Methylaminorex ' ' ' ' ' ' Pemoline ' 1-(4-Methylphenyl)—2—aminobutane ' Z-Fluoroamphetamine ' 2 Fluoromethamphetamine ' 2-OH-PEA ' 2-Phenyl-3-aminobutane ' 2 Phenyl-3-methylaminobutane ' 2,3-MDA ' 3-Fluoroamphetamine ' 3 Fluoroethamphetamine ' 3-Fluoromethcathinone ' 3 Methoxyamphetamine ' 3-Methylamphetamine ' 4-BMC ' 4 Ethylamphetamine ' 4-FA ' 4-FMA ' 4-MA ' 4-MMA ' 4-MTA ' 6 FNE ' ' (1-Ethylphenethylamine ' ' ' ' ' Amphetamine (Dextroamphetamine, ) ' Amphetaminil ' ' (Tomoxetine) ' [5-Methylphenethylamine ' [5-Phenylmethamphetamine ' Ben?uorex ' ' BDB (J) ' BOH (HydroXy-J) ' BPAP ' ' (Amfebutamone) ' ' ' ' ' ' ' ' Cloitermine ' D-Deprenyl ' ' ' ' Dimethylcathinone (Dimethylpropion, ) ' ' DOPA (Dextrodopa, Levodopa) ' Dopamine ' ' ' EBDB (Ethyl-J) ' ' Epinephrine () ' Epinine () ' ' (Ethylpropion) ' Ethylamphetamine () ' Ethylnorepinephrine (Butanefrine) ' ' ' ' ' ' Fencamfamine ' ' Fen?uramine () ' ' ' ' ' ' HMMA ' ' ' IMP ' Indanylamphetamine ' ' (Isoproterenol) ' L-Deprenyl () ' ' ' Lophophine (Homomyristicylamine) ' Manifaxine ' MBDB (Methyl-J; “Eden”) ' MDA (Tenamfetamine) ' MDBU ' MDEA (“Eve”) ' MDMA (“Ecstasy”, “Adam”) ' MDMPEA (Homarylamine) ' MDOH ' MDPR ' MDPEA (Homopiperonylamine) ' ' ' Mephenteimine ' ' ' Methamphetamine (Desoxyephedrine, Methedrine; Dextromethamphetamine, ) ' ' ' MMA ' (Methylpropion) ' ' Methoxyphenamine ' ' MMDA ' MMDMA ' MMMA ' ' Naphthylamphetamine ' ' Norepinephrine (Noradrenaline) ' ' ' Noimetanephrine ' ' ' OItetamine ' ' Paredrine (Norpholedrine, OXamphetamine, Mycadrine) ' PBA ' PCA ' PHA ' ' (Phenpentermine) ' ' ' ' ' ' ' (Neosynephrine) ' ' ' PIA ' PMA ' PMEA ' PMMA ' PPAP ' ' ' ' ' ' (Albuterol; ) ' ' (Oxedrine) ' ' Ti?orex (Flutiorex) ' ' ' ' ' Xylopropamine ' Zylo?rramine ZC-B-BZP ' BZP ' CM156 ' DBL-583 ' GBR-12783 ' GBR-12935 ' GBR-13069 ' GBR-13098 ' GBR-13119 ' MeOPP ' MBZP ' 1—Benzyl—4—(2-(diphenylmethoxy)ethyl) ' 2 Benzylpiperidine ' 3,4-Dichloromethylphenidate ' 4-Benzylpiperidine ' 4-Methylmethylphenidate ' ' Difemetorex ' ' ' Methylnaphthidate ' Methylphenidate () ' Nocaine ' Phacetoperane ' ' SCH-5472 US 2013/0289061 A1 Oct. 31,2013

TABLE l-continued

Examples of types of CNS stimulants MPHP ' MPPP ' MOPPP ' ' PEP ' ' Trop anes 3-CPMT ' 3-Pseudotropyl-4-fluorobenzoate ' 4'—Fluorococaine ' AHN-IOSS ' (IACFT) ' ' CFT (WIN 35,428) ' [3-CIT (RTI-SS) ' ' Cocaine ' (RTI-III) ' Difluoropine - FE-[?-CPPIT - FP-[?-CPPIT - (1231) - ' PIT ' PTT ' RTI-31 ' RTI-32 ' RTI-51 ' RTI-105 ' RTI 112 ' RTI-113 ' RTI-117 ' RTI-121(IPCIT)° RTI-126 ' RTI-150 ' RTI-154 ' RTI-171 ' RTI-177 ' RTI-183 ' RTI-194 ' RTI-202 ' RTI 229 ' RTI-241 ' RTI-336 ' RTI-354 ' RTI-371 ' RTI-386 ' Salicylmethylecgonine ' ' Troparil ([3-CPT, WIN 35,065 2) ' Tropoxane ' WF-23 ' WF-33 ' WF-6O ' Caffeine ' ' ' ' Others 1—(Thiophen-2-yl)—2—aminopropane ' 2-Amino-1,2-dihydronaphthalene ' 2-Aminoindane ' 2-Aminotetralin ' 2—Diphenylmethylpyrrolidine ' 2 MDP ' 3,3-Diphenylcyclobutanamine ' 5—(2—Aminopropyl)indole ' 5 Iodo-2-aminoindane ' AL-1095 ' Amfonelic ' ' ' ' ' ' BTQ ' BTS 74,398 ' Carphedon ' ' ' ' Cropropamide ' Crotetamide ' ' ' ' ' ' EXP-561 ' ' ' Gamfexine ' Gilutensin ' GYKI-52895 ' ' ' ' ' JNJ-7925476 ' JZ-IV-IO ' ' Leptacline ' Levopropylhexedrine ' LR-5182 ' MaZindol ' ' ' ' ' ' ' ' 0-2172 ' ' ' PNU—99,194 ' ' PRC2OO-SS ' ' ' ' SetaZindol ' ' ' ' UH-232 ' Yohimbine

[0040] In one embodiment, the CNS stimulants is an anti rine reuptake inhibitors (SNRIs). In another embodiment, . drugs include the monoamine CNS stimulants include psychostimulants, agents for treat oxidase inhibitors (MAOIs), ment of ADHD, or (cognitive enhancers). (TCAs), antidepressants (TeCAs), selective sero Examples of these types of CNS stimulants are shoWn in tonin reuptake inhibitors (SSRIs), and -norepineph Table 2. TABLE 2

Examples of psychostimulants, drugs for treatment of ADHD and nootropics

Centrally acting Amphetamine ' Amphetaminil ' Atomoxetine ' Dextroamphetamine ' sympathomimetics Dextromethamphetamine ' Fencamfamine ' Fenethylline ' Lisdexamfetamine ' Methylphenidate ' Mesocarb ' Pemoline ' Pipradrol ' Prolintane derivatives Caffeine ' Fenethylline ' Ne? ' Noopept ' ' ' ' Ampakines CX-516 ' CX-546 ' CX-614 ' CX-691 ' CX-717 ' IDRA-21 ' LY-404,187 ' LY-503,430 ' PEPA ' S 18986 ' Suni?ram ' Uni?ram Eugeroics/ Adra?nil ' Armoda?nil ' Moda?nil Benzhydryl compounds H3 A-349,821 ' ABT-239 ' Ciproxifan ' GSK-189,254 receptor antagonists GABAA 0L5 inverse (15IA ' L-655,708 ' PWZ-029 ' ' TB-21007 ' ZK-93426 Dopamine D1 A-77636 ' ' Dinapsoline ' Doxanthrine ' SKIS-81297 ' receptor agonists 6-Br-APB 0L7 nicotinic agonists/ AR-RI7779 ' PNU—282,987 ' SSR—180,711 PAMs Prolyl endopeptidase S-17092 inhibitors US 2013/0289061 A1 Oct. 31,2013

TABLE 2-continued

Examples ofpsychostimulants, drugs for treatment of ADHD and nootropics

Other Acetylcamitine ' ' ' Carbenoxolone ' psychostimulants and ' ' ' Idebenone ' Ispronicline ' nootropics Deanol ' Dimebon ' ' Leteprinim ' ' Meclofenoxate ' Nizofenone ' ' ' ' Rubidium ' Sulbutialnine ' Taltirelin ' Tricyanoalninopropene ' Vinpocetine

Analeptics tor antagonist) can be at the same time (co-administration), or at different times (e.g., sequentially). Co-administration can [0041] The methods and compositions described herein, as be in the same therapeutic formulation, or in different formu they relate to CNS stimulants, can also be used to reduce the dysphoria and euphoria associated with administration of lations, by the same or different routes. In one embodiment, the drug is administered at different times, and at different analeptics. As such, another aspect of the invention relates to rates of frequency than the opioid receptor inhibiting agent. the use of opioid receptor antagonists to reduce the dysphoria and euphoria associated with therapeutic and supra [0047] Suitable formulations for the compositions therapeutic administration. described herein are those appropriate for the desired route of administration. [0042] Analeptics are drugs that principally act as or are used as a central nervous system stimulant. Some examples [0048] Orally administered compositions may take the are, but not limited to, moda?nil and d-amphetamine. In one form of, for example, liquids, beverages, tablets, capsules, embodiment, the analeptic activates one or more dopamine lozenges, aqueous or oily suspensions, dispersible powders receptors. Analeptics may also be respiratory analeptics (e.g., or granules, emulsions, syrups, or elixirs. Compositions respiratory stimulants) such as picrotoxin, , intended for oral use may be prepared according to any caffeine, theophylline, strychnine, ethamivan and . method known in the art, and such compositions may contain which activates other receptors, (e.g., chemoreceptors, one or more agents such as sweetening agents, ?avoring GABAA receptor or receptors in central nervous agents, coloring agents, and preserving agents. They may also system). contain one or more additional ingredients such as vitamins and minerals, etc. Tablets may be manufactured to contain Administration and Formulations one or more active ingredients described herein, in admixture with non-toxic, pharrnaceutically acceptable excipients that [0043] The compositions described herein are adminis are suitable for the manufacture of tablets. These excipients tered in a manner compatible with the dosage formulation, may be, for example, inert diluents, granulating and disinte and in a therapeutically effective amount. The quantity to be grating agents, binding agents, and lubricating agents. The administered and timing depends on the subject to be treated, tablets may be uncoated or they may be coated by known capacity of the subject’s system to utilize the active ingredi techniques to delay disintegration and absorption in the gas ent, and degree of therapeutic effect desired. Precise amounts trointestinal tract and thereby provide sustained action over a of active ingredient required to be administered depend on the longer period. For example, a time delay material such as judgment of the practitioner and are peculiar to each indi glyceryl monostearate or glyceryl distearate may be used. vidual. [0049] Methylphenidate is available commercially in a [0044] The pharmaceutical compositions of the present variety of forms. Each version of methylphenidate is envi invention may be administered in a number of ways depend sioned for use in the present invention. Methylphenidate ing upon whether local or systemic treatment is desired. comes as an immediate-release tablet, a chewable tablet, a Administration may be topical (including ophthalmic, vagi solution (liquid), an intermediate-acting (extended-release) nal, rectal, intranasal, epidermal, and transdermal), enteral tablet, a long-acting (extended-release) capsule, and a long (e.g., oral) or parenteral. Parenteral administration includes acting (extended-release) tablet. The long-acting tablet and intravenous drip, subcutaneous, intraperitoneal or intramus capsules supply some immediately and release cular injection, pulmonary administration, e.g., by inhalation the remaining amount as a steady dose of medication over a or insuf?ation, or intracranial, e.g., intrathecal or intraven long time. All of these forms of methylphenidate are typically tricular, administration. administered orally for therapeutic purposes. [0045] Administration may be by transmucosal or transder mal means. For transmucosal or transdermal administration, Dosage penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in [0050] Therapeutic dosage and dose regimen of the drugs the art, and include, for example, for transmucosal adminis described herein are known in the art, and can be determined tration bile salts and fusidic acid derivatives. In addition, by the skilled practitioner for each individual subject. detergents may be used to facilitate permeation. Transmu [0051] For methylphenidate, the dose regimen usually var cosal administration may be through nasal sprays, for ies with commercially-packaged forms of methylphenidate. example, or using . For oral administration, the The regular tablets, chewable tablets (Methylin), and solution compositions of the invention are formulated into conven (Methylin) are usually taken two to three times a day by adults tional oral administration forms such as capsules, tablets and and twice a day by children, preferably 35 to 40 minutes tonics. before meals. Adults who are taking three doses should take [0046] Administration of the drug (e.g., methylphenidate) the last dose should be taken before 6:00 pm, so that the and the agent that inhibits opioid receptor (e.g., opioid recep medication will not cause dif?culty in falling asleep or stay