Methods for Treating Dependence

Abstract

Provided are methods of treating patients suffering from or susceptible to at least one symptom of abuse of, dependence on, or withdrawal from at least one substance with Compound A. Also provided are methods of treating at least one phase of substance dependence on at least one substance in patients and certain methods of treating at least one phase of cocaine dependence in patients.

1 . A method of treating a patient suffering from or susceptible to at least one symptom of abuse of, dependence on, or withdrawal from at least one substance, the method comprising administering to the patient a therapeutically effective amount of Compound A. 
     
     
         2 . The method of  claim 1 , wherein the at least one substance is selected from a drug of abuse and a medication. 
     
     
         3 . The method of  claim 2 , wherein the drug of abuse is selected from a psychostimulant agent, an opioid, a hallucinogen, an inhalant, a sedative, a tranquilizer, a hypnotic, an anxiolytic, and an illicit substance. 
     
     
         4 . The method of  claim 3 , wherein the psychostimulant agent is a beta-phenylisopropylamine derivative. 
     
     
         5 . The method of  claim 4 , wherein the beta-phenylisopropylamine derivative is selected from amphetamine, dextroamphetamine, and methamphetamine. 
     
     
         6 . The method of  claim 3 , wherein the psychostimulant agent is selected from ecstasy, phenmetrazine, methylphenidate, diethylpropion, pemoline, mazindol, (−) cathione, and fenfluramine. 
     
     
         7 . The method of  claim 3 , wherein the opioid is selected from Lortab, Tramadol, heroin, methadone, hydrocodone, and oxycodone. 
     
     
         8 . The method of  claim 3 , wherein the hallucinogen is selected from psilocybin, a hallucinogenic mushroom, lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine. 
     
     
         9 . The method of  claim 3 , wherein the inhalant is selected from benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, fluorobenzene, o-difluorobenzene, 1,3,5-triflurobenzene, 1,2,4-trifluorobenzene, pentafluorotoluene, pentafluorobenzene, and perfluorobenzene. 
     
     
         10 . The method of  claim 2 , wherein the medication is selected from an anesthetic, an analgesic, an anticholinergic agent, an antihistamine, a muscle relaxant, a nonsteroidal anti-inflammatory medication, an over the counter medication, and an antidepressant medication. 
     
     
         11 . The method of  claim 2 , wherein the drug of abuse is cocaine, alcohol, caffeine, opium, cannabinoid, cannabis, benzodiazapine carisprodol, tobacco, nicotine, Vicodin, Lorcet, Percocet, Percodan, and Tylox. 
     
     
         12 . The method of  claim 11 , wherein the drug of abuse is cocaine and the Compound A reduces at least one symptom of cocaine abuse and dependence in the patient selected from attention deficit hyperactivity disorder; euphoria; increased energy, excitement and sociability; less hunger and fatigue; a marked feeling of physical and mental strength; decreased sensation of pain; bronchitis; shortness of breath; chest pain; heart palpitations; arrhythmia; cardiomyopathy; heart attack; dilated pupils; nausea; vomiting; headache; vertigo; dizziness; anxiety; pychosis; confusion; nasal irritation; nasal crusting; recurrent nosebleeds; nasal stuffiness; facial pain; dysphoria; and craving for cocaine. 
     
     
         13 . The method of  claim 11 , wherein the drug of abuse is cocaine and the Compound A increases at least one negative subjective symptom of cocaine abuse and dependence. 
     
     
         14 . The method of  claim 11 , wherein the drug of abuse is cocaine and the Compound A reduces at least one symptom of cocaine withdrawal selected from fatigue, lack of pleasure, depression, irritability, sleep disorders, increased appetite, pyschomotor retardation, agitation, extreme suspicion, and craving for cocaine. 
     
     
         15 . The method of  claim 1 , wherein the method further comprises co-administering a therapeutically effective amount of least one other agent selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor (NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamine β-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosine A2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), a monoamine oxidase B inhibitor, a sodium channel blocker, a calcium channel blocker, a central and peripheral alpha adrenergic receptor antagonist, a central alpha adrenergic agonist, a central or peripheral beta adrenergic receptor antagonist, a NK-1 receptor antagonist, a corticotropin releasing factor (CRF) antagonist, an atypical antidepressant/antipsychotic, a tricyclic, an anticonvulsant, a glutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABA metabolism enzyme inhibitor, a GABA synthesis activator, a partial dopamine D2 agonist, a dopamine metabolism enzyme inhibitor, a catechol-O-methyl-transferase inhibitor, an opioid receptor antagonist, a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1 agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylase inhibitor, a partial opioid agonist, a partial nicotinic agonist, and an inhalant. 
     
     
         16 . The method of  claim 1 , wherein the method further comprises co-administering a therapeutically effective amount of least one other agent selected from benzodiazepine, levodopa, carisprodol, modafenil, acamprosate, gamma-butyrolactone, gamma-hydroxybutyrate, opium, psilopcybin, hallucinogenic mushroom, tobacco, and nicotine. 
     
     
         17 . The method of  claim 1 , wherein the Compound A is administered to the patient after a 
     
     
         18 . A method of treating at least one phase of substance dependence on at least one substance in a patient, wherein the at least one phase of substance dependence is selected from acquisition, maintenance, extinction, and relapse, comprising administering to the patient a therapeutically effective amount of Compound A. 
     
     
         19 . The method of  claim 18 , wherein the Compound A inhibits the development of the acquisition phase in the patient. 
     
     
         20 . The method of  claim 18 , wherein the Compound A promotes the development of the extinction phase in the patient. 
     
     
         21 . The method of  claim 18 , wherein the Compound A reduces the frequency of relapse in the patient. 
     
     
         22 . The method of  claim 18 , wherein the at least one substance is selected from a drug of abuse and a medication. 
     
     
         23 . The method of  claim 22 , wherein the drug of abuse is selected from a psychostimulant agent, an opioid, a hallucinogen, an inhalant, a sedative, a tranquilizer, a hypnotic, an anxiolytic, and an illicit substance. 
     
     
         24 . The method of  claim 23 , wherein the psychostimulant agent is a beta-phenylisopropylamine derivative. 
     
     
         25 . The method of  claim 24 , wherein the beta-phenylisopropylamine derivative is selected from amphetamine, dextroamphetamine, and methamphetamine. 
     
     
         26 . The method of  claim 23 , wherein the psychostimulant agent is selected from ecstasy, phenmetrazine, methylphenidate, diethylpropion, pemoline, mazindol, (−) cathione, and fenfluramine. 
     
     
         27 . The method of  claim 23 , wherein the opioid is selected from Lortab, Tramadol, heroin, methadone, hydrocodone, and oxycodone. 
     
     
         28 . The method of  claim 23 , wherein the hallucinogen is selected from psilocybin, a hallucinogenic mushroom, lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine. 
     
     
         29 . The method of  claim 23 , wherein the inhalant is selected from benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, fluorobenzene, o-difluorobenzene, 1,3,5-triflurobenzene, 1,2,4-trifluorobenzene, pentafluorotoluene, pentafluorobenzene, and perfluorobenzene. 
     
     
         30 . The method of  claim 22 , wherein the medication is selected from an anesthetic, an analgesic, an anticholinergic agent, an antihistamine, a muscle relaxant, a nonsteroidal anti-inflammatory medication, an over the counter medication, and an antidepressant medication. 
     
     
         31 . The method of  claim 22 , wherein the drug of abuse is alcohol, caffeine, opium, cannabinoid, cannabis, benzodiazapine, carisprodol, tobacco, nicotine, Vicodin, Lorcet, Percocet, Percodan, and Tylox. 
     
     
         32 . The method of  claim 18 , wherein the method further comprises co-administering a therapeutically effective amount of least one other agent selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor (NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamine β-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosine A2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), a monoamine oxidase B inhibitor, a sodium channel blocker, a calcium channel blocker, a central and peripheral alpha adrenergic receptor antagonist, a central alpha adrenergic agonist, a central or peripheral beta adrenergic receptor antagonist, a NK-1 receptor antagonist, a corticotropin releasing factor (CRF) antagonist, an atypical antidepressant/antipsychotic, a tricyclic, an anticonvulsant, a glutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABA metabolism enzyme inhibitor, a GABA synthesis activator, a partial dopamine D2 agonist, a dopamine metabolism enzyme inhibitor, a catechol-O-methyl-transferase inhibitor, an opioid receptor antagonist, a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1 agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylase inhibitor, a partial opioid agonist, a partial nicotinic agonist, and an inhalant. 
     
     
         33 . A method of treating at least one phase of cocaine dependence in a patient, wherein the at least one phase is selected from acquisition, maintenance, extinction, and relapse, comprising administering to the patient a therapeutically effective amount of Compound A. 
     
     
         34 . The method of  claim 33 , wherein the Compound A inhibits the development of the acquisition phase in the patient. 
     
     
         35 . The method of  claim 33 , wherein the Compound A promotes development of the extinction phase in the patient. 
     
     
         36 . The method of  claim 33 , wherein the Compound A reduces the frequency of relapse in the patient. 
     
     
         37 . The method of  claim 33 , wherein the Compound A reduces in the patient at least one symptom of abuse of, dependence on, or withdrawal from cocaine. 
     
     
         38 . The method of  claim 37 , wherein the Compound A reduces at least one symptom of cocaine abuse in the patient selected from recurrent cocaine use resulting in a failure to fulfill major role obligations at work, school, or home; recurrent cocaine use in situations in which it is physically hazardous; recurrent cocaine-related legal problems; and continued cocaine use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the cocaine. 
     
     
         39 . The method of  claim 37 , wherein the Compound A reduces at least one symptom of cocaine dependence in the patient selected from tolerance; withdrawal; the cocaine is often taken in larger amounts or over a longer period then was intended; there is a persistent desire or unsuccessful efforts to cut down or control cocaine use; a great deal of time is spent in activities to obtain the cocaine, use the cocaine, or recover from its effects; important social, occupational or recreational activities are given up or reduced because of cocaine use; and the cocaine use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the cocaine. 
     
     
         40 . The method of  claim 37 , wherein the Compound A reduces at least one symptom of cocaine abuse and dependence selected from attention deficit hyperactivity disorder; euphoria; increased energy, excitement and sociability; less hunger and fatigue; a marked feeling of physical and mental strength; decreased sensation of pain; bronchitis; shortness of breath; chest pain; heart palpitations; arrhythmia; cardiomyopathy; heart attack; dilated pupils; nausea; vomiting; headache; vertigo; dizziness; anxiety; pychosis; confusion; nasal irritation; nasal crusting; recurrent nosebleeds; nasal stuffiness; facial pain; dysphoria; and craving for cocaine. 
     
     
         41 . The method of  claim 37 , wherein the Compound A increases at least one negative subjective symptom of cocaine abuse and dependence. 
     
     
         42 . The method of  claim 37 , wherein the Compound A reduces at least one symptom of cocaine withdrawal selected from fatigue, lack of pleasure, depression, irritability, sleep disorders, increased appetite, pyschomotor retardation, agitation, extreme suspicion, and craving for cocaine. 
     
     
         43 . The method of  claim 33 , wherein the Compound A improves a score of the patient on at least one of ADHD-IV, HAM-D, HAM-A, BDI, apathy scale from Neuropsychiatric Inventory, and a cognitive function rating scale. 
     
     
         44 . The method of  claim 43 , wherein the cognitive function rating scale is selected from WAIS-R, WMS-R, RAVLT, Trials I-VII, RCFT, and TMT, Parts A and B. 
     
     
         45 . The method of  claim 33 , wherein the Compound A reduces at least one of the amount and frequency of cocaine use by the patient. 
     
     
         46 . The method of  claim 33 , wherein the Compound A promotes remission in the patient. 
     
     
         47 . The method of  claim 46 , wherein the remission is characterized by at least one of early full remission, early partial remission, sustained full remission, and sustained partial remission. 
     
     
         48 . The method of  claim 33 , wherein the Compound A prolongs a period of remission in the patient. 
     
     
         49 . The method of  claim 33 , wherein the method further comprises treatment with at least one of contingency management and cognitive behavioral therapy. 
     
     
         50 . The method of  claim 33 , wherein the method further comprises co-administering a therapeutically effective amount of least one other agent selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor (NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamine β-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosine A2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), a monoamine oxidase B inhibitor, a sodium channel blocker, a calcium channel blocker, a central and peripheral alpha adrenergic receptor antagonist, a central alpha adrenergic agonist, a central or peripheral beta adrenergic receptor antagonist, a NK-1 receptor antagonist, a corticotropin releasing factor (CRF) antagonist, an atypical antidepressant/antipsychotic, a tricyclic, an anticonvulsant, a glutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABA metabolism enzyme inhibitor, a GABA synthesis activator, a partial dopamine D2 agonist, a dopamine metabolism enzyme inhibitor, a catechol-O-methyl-transferase inhibitor, an opioid receptor antagonist, a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1 agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylase inhibitor, a partial opioid agonist, a partial nicotinic agonist, and an inhalant.