Combination therapy using low-dose doxepin for the improvement of sleep

Abstract

A composition comprising doxepin, or a pharmaceutically acceptable salt, or prodrug thereof, and a compound that enhances sleep onset, sleep maintenance or reduces early morning awakenings. These compositions are useful for treating multiple manifestations of insomnia.

1 . A composition comprising doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and one or more of a compound that promotes sleep onset. 
     
     
         2 . The composition of  claim 1 , wherein the compound that promotes sleep onset is selected from the group consisting of a GABA modulator, an H3 agonist, an orexin receptor antagonist, a melatonin agonist and a galanin agonist. 
     
     
         3 . The composition of any of  claims 1 - 2 , wherein said composition comprises doxepin in an amount of about 0.001 to about 10 mg. 
     
     
         4 . The composition of any of  claims 1 - 3 , wherein the one or more of a compound that promotes sleep onset in a dosage that is the same as the approved prescription dosage for that compound, the same as the clinical trial dosage for the compound, the same as a literature reported dosage for treating a sleep disorder, or the same as the dosage for the compound when used to treat a sleep disorder as a monotherapy. 
     
     
         5 . The composition of any of  claims 1 - 3 , wherein the one or more of a compound that promotes sleep onset in a dosage that is less than the approved prescription dosage for that compound to treat a sleep disorder, less than the clinical trial dosage for the compound for treating a sleep disorder, less than a literature reported dosage for treating a sleep disorder, less than the dosage for the compound when used to treat a sleep disorder as a monotherapy, or less than the monotherapy dosage of the compound required to achieve substantially the same sleep therapy benefit as the compound used in combination with doxepin. 
     
     
         6 . The composition of any of  claims 1 - 5 , wherein said compound that promotes sleep onset comprises a GABA modulator. 
     
     
         7 . The composition of any of  claims 1 - 5 , wherein said compound that promotes sleep onset comprises an H3 agonist. 
     
     
         8 . The composition of any of  claims 1 - 5 , wherein said compound that promotes sleep onset comprises an orexin receptor antagonist. 
     
     
         9 . The composition of any of  claims 1 - 5 , wherein said compound that promotes sleep onset comprises a melatonin agonist. 
     
     
         10 . The composition of any of  claims 1 - 5 , wherein said compound that promotes sleep onset comprises a galanin agonist. 
     
     
         11 . A method of reducing a side effect of a sleep medication, comprising:
 identifying a patient suffering from a side effect caused by a non-doxepin sleep medication;   providing the patient with doxepin in an amount of about 0.0001 to about 10 mg of doxepin, a pharmaceutically acceptable salt of doxepin, or a prodrug of doxepin; and   providing the patient with the non-doxepin sleep medication in a dosage less than the dosage which causes the side effect when the medication is used as sleep therapy alone.   
     
     
         12 . A method of treating a sleep disorder while minimizing side effects of at least one combination drug, comprising
 providing at least one non-doxepin sleep drug and a doxepin compound, wherein the combination of the at least one non-doxepin sleep drug and the doxepin compound promote a sleep effect that is at least equivalent to the sleep effect of a greater amount of the at least one non-doxepin sleep drug when used without doxepin or when used as a monotherapy for the sleep disorder; and   where the doxepin compound is doxepin, a pharmaceutically acceptable salt of doxepin, or a prodrug of doxepin, in an amount of about 0.0001 mg to about 20 mg.   
     
     
         13 . The method of  claim 11 , wherein said side effect includes one or more of decreased inhibition, hallucinations, complex behaviors such as sleep driving, amnesia, anxiety, suicidal thinking; withdrawal symptoms; CNS depressant effects; impaired motor or cognitive performance; bad taste; headaches; parasomnias such as sleep walking; anaphylactic and anaphylactoid reactions; weight gain; and rebound insomnia or tolerance. 
     
     
         14 . A method of treating a sleep disorder, comprising:
 identifying a patient, wherein said patient is or has been administered a non-doxepin sleep medication at a first dosage; and   providing to said patient the non-doxepin sleep medication at a second dosage and doxepin, a pharmaceutically acceptable salt of doxepin or a prodrug of doxepin,   wherein said second dosage of the non-doxepin sleep medication is less than said first dosage.   
     
     
         15 . The method of  claim 14 , wherein said sleep medication is selected from the group consisting of a GABA modulator, an H3 agonist, an orexin receptor antagonist, a melatonin agonist and a galanin agonist. 
     
     
         16 . A composition comprising doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and one or more of a compound that enhances gamma-aminobutyric acid (GABA) activity, a 5HT2a antagonist, a melatonin agonist, an ion channel blocker, a serotonin-2 antagonist/reuptake inhibitor (SARIs), a 5HT1a agonist, a GABA-B agonist and an orexin receptor antagonist. 
     
     
         17 . The composition of  claim 16 , wherein said compound that enhances GABA activity is selected from the group consisting of alprozolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine and estazolam. 
     
     
         18 . The composition of  claim 16 , wherein the 5HT2a antagonist is selected from the group consisting of ketanserin, risperidone, eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488. 
     
     
         19 . The composition of  claim 16 , wherein the melatonin agonist is selected from the group consisting of melatonin, ramelteon and agomelatine. 
     
     
         20 . The composition of  claim 16 , wherein the ion channel blocker is selected from the group consisting of lamotrigine, gabapentin and pregabalin. 
     
     
         21 . The composition of  claim 16 , wherein the serotonin-2 antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin, nefazodone, serzone or trazodone. 
     
     
         22 . The composition of  claim 16 , wherein the 5HT1a agonist is repinotan, sarizotan, eptapirone, buspirone or MN-305. 
     
     
         23 . The composition of  claim 16 , wherein the orexin receptor antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or a benzamide derivative. 
     
     
         24 . The composition of any of  claims 16 - 23 , wherein said composition comprises doxepin, pharmaceutically acceptable salt or prodrug thereof, in a dosage of 0.01-49 mg. 
     
     
         25 . The composition of  claim 16  or  claim 17 , wherein the dosage is between about 0.5 mg and about 6 mg. 
     
     
         26 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof, and a compound that enhances gamma-aminobutyric acid (GABA) activity. 
     
     
         27 . The composition of  claim 26 , wherein said compound that enhances GABA activity is selected from the group consisting of alprozolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine and estazolam. 
     
     
         28 . The composition of  claim 26  or  claim 27 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         29 . The composition of  claim 26  or  claim 27 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         30 . The composition of  claim 26  or  claim 27 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         31 . The composition of  claim 26  or  claim 27 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         32 . A pharmaceutical formulation comprising the composition of any of  claims 26 - 31  and a pharmaceutically acceptable excipient or diluent. 
     
     
         33 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 16 - 31  to said individual. 
     
     
         34 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 32  to said individual. 
     
     
         35 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 16 - 31 .   
     
     
         36 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a compound that enhances gamma-aminobutyric acid (GABA) activity; and   informing the patient to take the doxepin and said one or more compounds without food or without fatty food.   
     
     
         37 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 16 - 31 .   
     
     
         38 . The method of  claim 37 , in which the compound that enhances GABA activity is selected from the group consisting of alprozolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine and estazolam. 
     
     
         39 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof, and a 5HT2a antagonist. 
     
     
         40 . The composition of  claim 39 , wherein the 5HT2a antagonist is selected from the group consisting of ketanserin, risperidone, eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488. 
     
     
         41 . The composition of  claim 39  or  claim 40 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         42 . The composition of  claim 39  or  claim 40 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         43 . The composition of  claim 39  or  claim 40 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         44 . The composition of  claim 39  or  claim 40 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         45 . A pharmaceutical formulation comprising the composition of any of  claims 39 - 44  and a pharmaceutically acceptable excipient or diluent. 
     
     
         46 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 39 - 44  to said individual. 
     
     
         47 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 45  to said individual. 
     
     
         48 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 39 - 44 .   
     
     
         49 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 39 - 44 .   
     
     
         50 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a 5HT2a antagonist; and   informing the patient to take the doxepin and said 5HT2a antagonist without food or without fatty food.   
     
     
         51 . The method of  claim 50 , in which the 5HT2a antagonist is selected from the group consisting of ketanserin, risperidone, eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488. 
     
     
         52 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and a melatonin agonist. 
     
     
         53 . The composition of  claim 52 , wherein the melatonin agonist is selected from the group consisting of melatonin, ramelteon and agomelatine. 
     
     
         54 . The composition of  claim 52  or  claim 53 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         55 . The composition of  claim 52  or  claim 53 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         56 . The composition of  claim 52  or  claim 53 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         57 . The composition of  claim 52  or  claim 53 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         58 . A pharmaceutical formulation comprising the composition of any of  claims 52 - 57  and a pharmaceutically acceptable excipient or diluent. 
     
     
         59 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 52 - 57  to said individual. 
     
     
         60 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 58  to said individual. 
     
     
         61 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 52 - 57 .   
     
     
         62 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 52 - 57 .   
     
     
         63 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a melatonin antagonist; and   informing the patient to take the doxepin and said melatonin antagonist without food or without fatty food.   
     
     
         64 . The method of  claim 63 , in which the melatonin agonist is selected from the group consisting of melatonin, ramelteon and agomelatine. 
     
     
         65 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and an ion channel blocker. 
     
     
         66 . The composition of  claim 65 , wherein the ion channel blocker is selected from the group consisting of lamotrigine, gabapentin and pregabalin. 
     
     
         67 . The composition of  claim 65  or  claim 66 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         68 . The composition of  claim 65  or  claim 66 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         69 . The composition of  claim 65  or  claim 66 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         70 . The composition of  claim 65  or  claim 66 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         71 . A pharmaceutical formulation comprising the composition of any of  claims 65 - 70  and a pharmaceutically acceptable excipient or diluent. 
     
     
         72 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 65 - 70  to said individual. 
     
     
         73 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 71  to said individual. 
     
     
         74 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 65 - 70 .   
     
     
         75 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 65 - 70 .   
     
     
         76 . The method of  claim 75 , in which the ion channel blocker is selected from the group consisting of lamotrigine, gabapentin and pregabalin. 
     
     
         77 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and an ion channel blocker; and   informing the patient to take the doxepin and said ion channel blocker without food or without fatty food.   
     
     
         78 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and a serotonin-2 antagonist/reuptake inhibitor (SARIs). 
     
     
         79 . The composition of  claim 78 , wherein the serotonin-2 antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin, nefazodone, serzone or trazodone. 
     
     
         80 . The composition of  claim 78  or  claim 79 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         81 . The composition of  claim 78  or  claim 79 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         82 . The composition of  claim 78  or  claim 79 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         83 . The composition of  claim 78  or  claim 79 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         84 . A pharmaceutical formulation comprising the composition of any of  claims 78 - 83  and a pharmaceutically acceptable excipient or diluent. 
     
     
         85 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 78 - 83  to said individual. 
     
     
         86 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 84  to said individual. 
     
     
         87 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 78 - 83 .   
     
     
         88 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 78 - 83 .   
     
     
         89 . The method of  claim 88 , in which the serotonin-2 antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin, nefazodone, serzone or trazodone. 
     
     
         90 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a serotonin-2 antagonist/reuptake inhibitor (SARIs); and   informing the patient to take the doxepin and said serotonin-2 antagonist/reuptake inhibitor (SARIs) without food or without fatty food.   
     
     
         91 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and a 5HT1a agonist. 
     
     
         92 . The composition of  claim 91 , wherein the 5HT1a agonist is repinotan, sarizotan, eptapirone, buspirone or MN-305. 
     
     
         93 . The composition of  claim 91  or  claim 92 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         94 . The composition of  claim 91  or  claim 92 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         95 . The composition of  claim 91  or  claim 92 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         96 . The composition of  claim 91  or  claim 92 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         97 . A pharmaceutical formulation comprising the composition of any of  claims 91 - 96  and a pharmaceutically acceptable excipient or diluent. 
     
     
         98 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 91 - 96  to said individual. 
     
     
         99 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 97  to said individual. 
     
     
         100 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 91 - 96 .   
     
     
         101 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 91 - 96 .   
     
     
         102 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a 5HT1a agonist; and   informing the patient to take the doxepin and said 5HT1a agonist without food or without fatty food.   
     
     
         103 . The method of  claim 102 , in which the 5HT1a agonist is repinotan, sarizotan, eptapirone, buspirone or MN-305. 
     
     
         104 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and an orexin receptor antagonist. 
     
     
         105 . The composition of  claim 104 , wherein the orexin receptor antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or a benzamide derivative. 
     
     
         106 . The composition of  claim 104  or  claim 105 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         107 . The composition of  claim 104  or  claim 105 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         108 . The composition of  claim 104  or  claim 105 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         109 . The composition of  claim 104  or  claim 105 , wherein the dosage is between about 1 mg and about 6 mg. 
     
     
         110 . A pharmaceutical formulation comprising the composition of any of  claims 104 - 109  and a pharmaceutically acceptable excipient or diluent. 
     
     
         111 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 104 - 109  to said individual. 
     
     
         112 . The method of  claim 111 , wherein said doxepin, said pharmaceutically acceptable salt or prodrug thereof, is administered at a dosage between about 0.01 mg and about 49 mg. 
     
     
         113 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 111  to said individual. 
     
     
         114 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 104 - 109 .   
     
     
         115 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 104 - 109 .   
     
     
         116 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a orexin receptor; and   informing the patient to take the doxepin and said orexin receptor without food or without fatty food.   
     
     
         117 . The method of  claim 116 , in which the orexin receptor antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or a benzamide derivative. 
     
     
         118 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and a GABA-B agonist. 
     
     
         119 . The composition of  claim 118 , wherein said composition comprises doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, in a dosage between about 0.01 mg and about 49 mg. 
     
     
         120 . The composition of  claim 118 , wherein the dosage is between about 0.1 mg and about 20 mg. 
     
     
         121 . The composition of  claim 118 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         122 . The composition of  claim 118 , wherein the dosage is between about 0.5 mg and about 10 mg. 
     
     
         123 . A pharmaceutical formulation comprising the composition of any of  claims 118 - 122  and a pharmaceutically acceptable excipient or diluent. 
     
     
         124 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 118 - 122  to said individual. 
     
     
         125 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 124  to said individual. 
     
     
         126 . The method of  claim 124 , wherein said doxepin, said pharmaceutically acceptable doxepin salt or doxepin prodrug, is administered at a dosage between about 0.01 mg and about 49 mg. 
     
     
         127 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 118 - 122 .   
     
     
         128 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a GABA-B agonist; and   informing the patient to take the doxepin and said GABA-B agonist without food or without fatty food.   
     
     
         129 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 118 - 122 .   
     
     
         130 . A pharmaceutical formulation comprising the composition of any of  claims 118 - 122  and a pharmaceutically acceptable excipient or diluent. 
     
     
         131 . A composition comprising doxepin or a pharmaceutically acceptable salt or prodrug thereof and a compound selected from an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen and an estrogen agonist. 
     
     
         132 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the composition of any of any of  claims 118 - 122  to said individual. 
     
     
         133 . A method of treating insomnia, comprising identifying an individual in need of such treatment, and administering the pharmaceutical formulation of  claim 132  to said individual. 
     
     
         134 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of any of  claims 118 - 122 .   
     
     
         135 . A method for reducing a risk of drug abuse, comprising:
 identifying a patient in need of sleep drug therapy and in need of avoidance of drugs with potential for abuse; and   administering to the patient a composition of any of  claims 118 - 122 .   
     
     
         136 . A method for treating insomnia, comprising:
 coadministering to an insomnia patient effective amounts of doxepin, a pharmaceutically acceptable doxepin salt or a doxepin prodrug, and a compound selected from an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen and an estrogen agonist; and   informing the patient to take the doxepin and said compound without food or without fatty food.