PHARMACEUTICAL COMPOSITIONS

• US 20090175939A1
• Filed: 01/09/2009
• Published: 07/09/2009
• Est. Priority Date: 01/09/2008
• Status: Active Grant

• Current Assignee: LOCL Pharma, Inc. (Charleston Laboratories, Inc.)
• Original Assignee: Charleston Laboratories, Inc.
• Inventors: Takigiku, Ray, Schachtel, Bernard, Ameling, John, Bosse, Paul
• Granted Patent: US 8,124,126 B2
• Time in Patent Office: Days
• US Class Current: 424/472
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/515 Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2086 : Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 : containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/4808 : characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5084 : Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 1/08 : for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Methods and compositions are provided which comprise effective amounts of analgesic to treat a subject, including reducing or eliminating an adverse effect associated with the analgesic.

Claims

1. A composition comprising (1) an effective amount of:

(a) an opioid analgesic;

(b) a stimulant;

(c) an antiemetic; and

(2) a pharmaceutically acceptable carrier or vehicle.

2. The composition of claim 1, wherein the composition is an oral dosage form comprising an immediate-release layer and a controlled-release layer, wherein the immediate release layer comprises an antiemetic and a stimulant;

and the controlled-release layer comprises an opioid analgesic.

3. The composition of claim 1, wherein the opioid analgesic is hydrocodone, oxycodone, morphine, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine sulfate, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol, or a pharmaceutically acceptable salt thereof;

the antiemetic is aprepitant, dronabinol, perphenazine, palonosetron, trimethyobenzamide, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, prochloperazine, metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, or propofol, or a pharmaceutically acceptable salt thereof; and

the stimulant is aminophylline, caffeine, dyphlline, oxitriphylline, theophhylline, amphetamine, benzphetamine, dextroamphetamine, diethylpropion, mazindol, methamphetamine, methylphenidate, dexmethylphenidate, pemoline, sibutramine, modafinil, atomoxetine, phendimetrizine, phenteramine, adrafinil, phenylpropanolamine, psuedoephedrine, synephrine, amphetaminil, or furfenorex, or a pharmaceutically acceptable salt thereof.

4. The composition of claim 2, wherein the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

5. The composition of claim 3, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

6. The composition of claim 3, wherein the stimulant is modafinil or a pharmaceutically acceptable salt thereof.

7. The composition of claim 3, wherein the stimulant is caffeine or a pharmaceutically acceptable salt thereof.

8. The composition of claim 2, wherein the composition further comprises an oxicam, a Cox-2 inhibitor, an NSAID analgesic, an NMDA receptor antagonist, or an α

₂-adrenoreceptor agonist, or a pharmaceutically acceptable salt thereof.

9. The composition of claim 2, wherein composition further comprises acetaminophen, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, or suprofen, or a pharmaceutically acceptable salt thereof.

10. The composition of claim 2, wherein composition further comprises valdecoxib, celecoxib, or rofecoxib, or a pharmaceutically acceptable salt thereof.

11. The composition of claim 2, wherein composition further comprises lidocaine, or mexiletine, or a pharmaceutically acceptable salt thereof.

12. The composition of claim 2, wherein composition further comprises amitriptyline, carbamazepine, gabapentin, or pregabalin, or a pharmaceutically acceptable salt thereof.

13. The composition of claim 2, wherein composition further comprises orphenadrine, cyclobenzaprine, scopolamine, atropine, or gabapentin, or a pharmaceutically acceptable salt thereof.

14. The composition of claim 2, wherein composition further comprises an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof.

15. The composition of claim 14, wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof.

16. The composition of claim 2, wherein composition further comprises an α

₂-adrenoreceptor agonist or a pharmaceutically acceptable salt thereof.

17. The composition of claim 16, wherein the α

₂-adrenoreceptor agonist is clonidineor a pharmaceutically acceptable salt thereof.

18. The composition of claim 1, further comprising an opioid antagonist agent or abuse deterrent agent.

19. The composition of claim 18, wherein the opioid antagonist agent is nalmefene, naloxone, naltrexone, cyclazacine or levallorphan, or a pharmaceutically acceptable salt thereof.

20. The composition of claim 18, wherein the abuse deterrent agent is niacin or a pharmaceutically acceptable salt thereof;

zinc sulfate;

or sodium lauryl sulfate.

21. The composition of claim 18, wherein the opioid antagonist agent is naltrexone or a pharmaceutically acceptable salt thereof.

22. The composition of claim 18, wherein the abuse deterrent agent is niacin or a pharmaceutically acceptable salt thereof.

23. The composition of claim 1, wherein the effective amount of the opioid analgesic is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

24. A composition comprising (1) an effective amount (a) oxycodone or a pharmaceutically acceptable salt thereof, (b) promethazine or a pharmaceutically acceptable salt thereof, (c) modafinil or a pharmaceutically acceptable salt thereof, and (d) naltrexone or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

25. The composition of claim 24, wherein the composition is in the form of a bi-layer tablet.

26. The composition of claim 24, wherein the bi-layer tablet comprises a controlled-release layer and an immediate-release layer.

27. The composition of claim 26, wherein the controlled-release layer comprises oxycodone or a pharmaceutically acceptable salt thereof and the immediate-release layer comprises promethazine or a pharmaceutically acceptable salt thereof.

28. The composition of claim 24, wherein the effective amount of the oxycodone or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

29. A composition comprising (1) an effective amount of (a) morphine or a pharmaceutically acceptable salt thereof, (b) promethazine or a pharmaceutically acceptable salt thereof, and (c) modafinil or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

30. The composition of claim 29, wherein the composition is in the form of a bi-layer tablet.

31. The composition of claim 30, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

32. The composition of claim 31, wherein the controlled-release layer comprises the modafinil or a pharmaceutically acceptable salt thereof and the immediate-release layer comprises promethazine or a pharmaceutically acceptable salt thereof.

33. The composition of claim 32, wherein the effective amount of the morphine or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

34. The composition of claim 29, further comprising an effective amount of naltrexone or a pharmaceutically acceptable salt thereof.

35. The composition of claim 34, wherein composition is in the form of a bi-layer tablet.

36. The composition of claim 35, wherein the effective amount of the morphine or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

37. A composition comprising (1) an effective amount of:

(a) an opioid analgesic agent, (b) a non-opioid analgesic agent, and (c) a barbiturate agent; and

(2) a pharmaceutically acceptable carrier or vehicle.

38. The composition of claim 37, further comprising an effective amount of a stimulant agent or an agent that reduces or eliminates an adverse effect of the opioid or non-opioid analgesic.

39. The composition of claim 37, wherein the barbiturate agent is allobarbital, alphenal, amobarbital, aprobarbital, barbexaclone, barbital, brallobarbital, butabarbital, butalbital, butobarbital, butallylonal, crotylbarbital, cyclobarbital, cyclopal, ethallobarbital, febarbamate, heptabarbital, hexethal, hexobarbital, mephobarbital, metharbital, methohexital, methylphenobarbital, narcobarbital, nealbarbital, pentobarbital, primidone, probarbital, propallylonal, proxibarbal, proxibarbital, reposal, secbutabarbital, secobarbital, sigmodal, talbutal, thialbarbital, thiamylal, thiobarbital, thiobutabarbital, thiopental, valofane, vinbarbital, vinylbital, 1,3-dimethoxymethyl 5,5-diphenyl-barbituric acid, 1-monomethoxymethyl 5,5-diphenylbarbituric acid diphenyl-barbituric acid, or a pharmaceutically acceptable salt thereof.

40. The composition of claim 38, wherein the agent that reduces or eliminates an adverse effect is an antiemetic.

41. The composition of claim 37, further comprising an effective amount of an opioid antagonist agent or abuse deterrent agent.

42. The composition of claim 41, wherein the opioid antagonist is nalmefene, naloxone, naltrexone, cyclazacine or levallorphan, or a pharmaceutically acceptable salt thereof.

43. The composition of claim 41, wherein the abuse deterrent agent is niacin or a pharmaceutically acceptable salt thereof;

zinc sulfate;

or sodium lauryl sulfate.

44. The composition of claim 41, wherein the opioid antagonist agent is naltrexone or a pharmaceutically acceptable salt thereof.

45. The composition of claim 41, wherein the abuse deterrent agent is niacin or a pharmaceutically acceptable salt thereof.

46. A composition comprising (1) an effective amount of (a) butalbital or a pharmaceutically acceptable salt thereof, (b) acetaminophen and (c) promethazine or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

47. The composition of claim 46, wherein the composition is in the form of a bilayer tablet.

48. The composition of claim 46, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

49. The composition of claim 48, wherein the immediate-release layer comprises promethazine or a pharmaceutically acceptable salt thereof.

50. A composition comprising (1) an effective amount of (a) an opioid analgesic agent;

(b) an anti-emetic agent and (c) a beta blocker, serotonin receptor agonist, vasoconstrictor, anti-platelet agent, anti-convulsant, triptan, ergot, or calcitonin-gene-related peptide receptor antagonist; and

(2) a pharmaceutically acceptable carrier or vehicle.

51. The composition of claim 50, wherein the composition is in the form of a bilayer tablet.

52. The composition of claim 51, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

53. The composition of claim 52, wherein the controlled-release layer comprises the opioid-analgesic agent.

54. A composition comprising (1) an effective amount of (a) an opioid analgesic agent and (b) sumatriptan or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

56. The composition of claim 54, wherein the composition is in the form of a bilayer tablet.

58. The composition of claim 56, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

61. The composition of claim 58, wherein the opioid analgesic is oxycodone HCl and the oxycodone HCl is present in the controlled-release layer.

55. A composition consisting of (1) an effective amount of (a) sumatriptan or a pharmaceutically acceptable salt thereof and (b) promethazine or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

57. The composition of claim 55, wherein the composition is in the form of a bilayer tablet.

59. The composition of claim 57, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

60. The composition of claim 59, wherein the immediate-release layer comprises the promethazine or pharmaceutically acceptable salt thereof.

62. A composition comprising (1) an effective amount of (a) an opioid analgesic agent, (b) a Cox-2 inhibitor agent, an anti-depressant agent, an anti-convulsant agent, an anti-cholinergic agent, an NMDA receptor antagonist agent, an anesthetic agent or an α

₂-adrenoreceptor agonist agent, (c) an opioid antagonist agent, (d) an agent that reduces or eliminates an adverse effect of the opioid agent; and

(2) a pharmaceutically acceptable carrier or vehicle.

63. The composition of claim 62, wherein the composition is in the form of a bilayer tablet.

64. The composition of claim 63, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

65. The composition of claim 64, wherein the controlled-release layer comprises the opioid-analgesic agent.

66. The composition of claim 62, wherein the Cox-2 inhibitor agent is valdecoxib, celecoxib, or rofecoxib;

or a pharmaceutically acceptable salt thereof.

67. The composition of claim 62, wherein the anesthetic agent is lidocaine or mexiletine;

or a pharmaceutically acceptable salt thereof.

68. The composition of claim 62, wherein the anti-depressant agent is amitriptyline or cyclobenzaprine;

or a pharmaceutically acceptable salt thereof.

69. The composition of claim 62, wherein the anti-convulsant agent is carbamazepine, gabapentin, or pregabalin;

or a pharmaceutically acceptable salt thereof.

70. The composition of claim 62, wherein the anti-cholinergic agent is scopolamine, or atropine;

or a pharmaceutically acceptable salt thereof.

71. The composition of claim 62, wherein the NMDA receptor antagonist is ketamine or orphenadrine;

or a pharmaceutically acceptable salt thereof.

72. A composition comprising (1) an effective amount of (a) an opioid analgesic agent, (b) a non-opioid analgesic agent, (c) cyclazacine or levallorphan;

(d) an agent that reduces or eliminates an adverse effect of the opioid analgesic agent; and

(2) a pharmaceutically acceptable carrier.

73. The composition of claim 72, wherein the composition is in the form of a bilayer tablet.

74. The composition of claim 73, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

75. The composition of claim 74, wherein the controlled-release layer comprises the opioid-analgesic agent and the non-opioid analgesic agent.

76. A composition comprising (1) an effective amount of (a) an opioid analgesic agent, (b) a non-opioid analgesic agent, (c) an antiemetic;

(d) an abuse deterrent agent; and

(2) a pharmaceutically acceptable carrier.

77. The composition of claim 76, wherein the composition is in the form of a bilayer tablet.

78. The composition of claim 77, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

79. The composition of claim 78, wherein the controlled-release layer comprises the opioid-analgesic agent and the non-opioid analgesic agent, and the immediate-release layer comprises the antiemetic.

80. The composition of claim 76, wherein the abuse deterrent agent is niacin or a pharmaceutically acceptable salt thereof;

zinc sulfate;

or sodium lauryl sulfate.

81. A composition comprising (1) an effective amount of (a) an opioid analgesic agent, (b) a non-opioid analgesic agent, (c) an opioid antagonist agent, (d) aprepitant, perphenazine, acetylleucine monoethanolamine, azasetron, benzquinamide, bietanautine, bromopride, clebopride, diphenidol, methallatal, metopimazine, oxyperndyl, pipamazine, sulpiride, thiethylperazine, thioproperazine, or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

82. The composition of claim 81, wherein the composition is in the form of a bilayer tablet.

83. The composition of claim 82, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

84. The composition of claim 83, wherein the controlled-release layer comprises the opioid-analgesic agent and the non-opioid analgesic agent.

85. A bi-layer tablet comprising:

(1) a controlled-release layer comprising from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof; and

(2) an immediate-release layer comprising from about 11 mg to about 14 mg of promethazine or a pharmaceutically salt thereof.

86. The bilayer tablet of claim 85, wherein the controlled-release layer further comprises from about 290 to about 360 mg of acetaminophen or a pharmaceutically salt thereof.

87. The bi-layer tablet of claim 85, wherein the controlled-release layer comprises about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof;

and wherein the immediate-release layer comprises about 12 mg of promethazine or a pharmaceutically acceptable salt thereof.

88. The bilayer tablet of claim 87, wherein the controlled-release layer further comprises about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof.

89. The bi-layer tablet of claim 88, wherein the controlled-release layer further comprises one or more of:

silicified microcrystalline cellulose, hydroxy methyl propyl cellulose, magnesium stearate, and stearic acid.

90. The bi-layer tablet of claim 86, wherein the immediate-release layer further comprises one or more of:

silicified microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

91. The bi-layer tablet of claim 86, wherein the tablet has a hardness of about 9.5 kilopond and thickness from about 6.9 to about 7.0 mm.

92. The bi-layer tablet of claim 86, wherein the hydrocodone salt is hydrocodone bitartrate.

93. The bi-layer tablet of claim 86, wherein the promethazine salt is promethazine HCl.

94. A bi-layer tablet comprising (1) an effective amount of (a) an opioid analgesic and (b) an antiemetic;

and (2) a pharmaceutically acceptable carrier or vehicle.

95. The bi-layer tablet of claim 94, wherein the opioid analgesic is oxycodone or pharmaceutically acceptable salt thereof;

and the one or more antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

96. The bi-layer tablet of claim 94, wherein the effective amount is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

97. The bi-layer tablet of claim 94, wherein the bi-layer tablet comprises an immediate release layer and a controlled-release layer.

98. The bi-layer tablet of claim 94, wherein the immediate release layer comprises the promethazine or pharmaceutically acceptable salt thereof, and wherein the controlled-release layer comprises the oxycodone or a pharmaceutically acceptable salt thereof.

99. The bi-layer tablet of claim 95, wherein about 70% of the promethazine or pharmaceutically acceptable salt thereof is capable of dissolving in a dissolution fluid in about 5 minutes after contact with the solution, and wherein about 30% of the oxycodone or pharmaceutically acceptable salt is capable of dissolving in a dissolution fluid in about 10 minutes after contact with the solution.

100. The bi-layer tablet of claim 99, wherein the controlled-release layer further comprises an antiemetic agent.

101. A bi-layer tablet comprising:

(1) a controlled-release layer comprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, (b) from about 135 mg to about 170 mg of silicified microcrystalline cellulose, (c) from about 17 mg to about 23 mg of hydroxy methyl propyl cellulose, (d) from about 1 mg to about 4 mg of magnesium stearate, and (e) from about 1 mg to about 4 mg of stearic acid; and

(2) an immediate release layer comprising (a) from about 11 mg to about 14 mg of promethazine or a pharmaceutically acceptable salt thereof, (b) from about 100 mg to about 140 mg of silicified microcrystalline cellulose, (c) from about 12 mg to about 18 mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of magnesium stearate.

102. The bilayer tablet of claim 101, wherein the controlled-release layer further comprises (f) from about 290 to about 360 mg of acetaminophen or a pharmaceutically acceptable salt thereof.

103. The bi-layer tablet of claim 101, wherein the effective amount of the hydrocodone or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

104. The bi-layer tablet of claim 101, wherein the controlled-release layer comprises about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, about 152 mg of silicified microcrystalline cellulose, about 20 mg of hydroxy methyl propyl cellulose, about 2.7 mg of magnesium stearate, and about 2.7 mg of stearic acid;

and the immediate release layer comprises about 12.5 mg of promethazine or a pharmaceutically acceptable salt thereof, about 121.5 mg of silicified microcrystalline cellulose, about 15 mg of croscarmellose sodium and about 1 mg of magnesium stearate.

105. The bilayer tablet of claim 101, wherein the controlled-release layer further comprises about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof,

106. A composition comprising (1) an effective amount of (a) hydrocodone or a pharmaceutically acceptable salt thereof or oxycodone or a pharmaceutically acceptable salt thereof;

(b) acetaminophen or a pharmaceutically acceptable salt thereof, (c) promethazine or a pharmaceutically acceptable salt thereof and (d) about 0.75 mg of naltrexone or a pharmaceutically acceptable salt thereof; and

(2) a pharmaceutically acceptable carrier or vehicle.

107. The composition of claim 106, wherein the composition is in the form of a bilayer tablet.

108. The composition of claim 107, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

109. The composition of claim 108, wherein the controlled-release layer comprises the (a) hydrocodone or a pharmaceutically acceptable salt thereof or oxycodone or a pharmaceutically acceptable salt thereof and (b) acetaminophen or a pharmaceutically acceptable salt thereof, and the immediate-release layer comprises the promethazine or pharmaceutically acceptable salt thereof.

110. The composition of claim 106, wherein effective amount is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

111. A composition consisting of (1) an effective amount of (a) oxycodone or a pharmaceutically acceptable salt thereof, (b) promethazine or a pharmaceutically acceptable salt thereof and (c) naltrexone or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

112. The composition of claim 111, wherein the composition is in the form of a bilayer tablet.

113. The composition of claim 112, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

114. The composition of claim 113, wherein the controlled-release layer comprises the oxycodone or a pharmaceutically acceptable salt thereof, and the immediate-release layer comprises the promethazine or pharmaceutically acceptable salt thereof.

115. The composition of claim 111, wherein the effective amount of the oxycodone or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

116. A composition consisting of (1) an effective amount of (a) promethazine or a pharmaceutically acceptable salt thereof, (b) propoxyphene or a pharmaceutically acceptable salt thereof, (c) naproxen or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

117. The composition of claim 116, wherein the composition is in the form of a bilayer tablet.

118. The composition of claim 117, wherein the bi-layer tablet comprises a controlled-release layer and an immediate release layer.

119. The composition of claim 118, wherein the controlled-release layer comprises the propoxyphene or a pharmaceutically acceptable salt thereof, and the immediate-release layer comprises the promethazine or pharmaceutically acceptable salt thereof.

120. The composition of claim 116, wherein effective amount is an amount effective for treating or preventing pain for a period of about 12 hours immediately following administration to a subject.

121. A method for treating or preventing pain, comprising administering to a subject in need thereof an effective amount of (a) an opioid analgesic agent, (b) an antiemetic agent or an antihistamine, and (c) a stimulant agent.

122. A method for treating or preventing a migraine headache comprising administering to a subject in need thereof an effective amount of (a) an opioid analgesic agent;

(b) an antiemetic agent; and

(c) a stimulant agent.

123. A method for treating or preventing a headache comprising administering to a subject in need thereof an effective amount of (a) an opioid analgesic agent;

and (b) an antiemetic agent.

124. The method of claim 123, wherein the headache is a migraine headache, cluster headache or hemicrania continua headache.

125. The method of claim 123, wherein the headache is a chronic headache, tension headache or chronic tension headache.

126. A method for treating pain, comprising administering to a subject in need thereof an effective amount of (a) an opioid analgesic agent, (b) an antiemetic agent;

and (c) a non-opioid analgesic agent;

wherein the subject is about 65 years of age or older.

127. A method for treating or preventing photophobia comprising administering to a subject in need thereof an effective amount of (a) an opioid analgesic agent;

and (b) an antiemetic agent.

128. The method of claim 127, wherein the photophobia is associated with migraine headache.

129. A method for treating or preventing headache comprising:

administering to a subject in need thereof (1) an effective amount of (a) triptan or a pharmaceutically acceptable salt thereof and (b) promethazine or a pharmaceutically acceptable salt thereof; and

(2) a pharmaceutically acceptable carrier or vehicle.

130. The method of claim 129, wherein the triptan is sumatriptan or pharmaceutically acceptable salt thereof.

131. The method of claim 129, wherein said headache is migraine headache.

132. A method for treating or preventing pain comprising:

administering to a subject in need thereof (1) an effective amount of (a) an opioid analgesic agent, (b) a Cox-2 inhibitor agent, an anti-depressant agent, an anti-convulsant agent, an anti-cholinergic agent, an NMDA receptor antagonist agent, an anesthetic agent or an α

₂-adrenoreceptor agonist agent, (c) an opioid antagonist agent, (d) an agent that reduces or eliminates an adverse effect of the opioid agent; and

(2) a pharmaceutically acceptable carrier or vehicle.

133. A method for treating or preventing pain comprising, administering to a subject in need thereof a bi-layer tablet comprising:

(1) a controlled-release layer comprising from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof; and

from about 290 to about 360 mg of acetaminophen or a pharmaceutically salt; and

(2) an immediate-release layer comprising from about 11 mg to about 14 mg of promethazine or a pharmaceutically salt thereof.

134. A method for treating or preventing pain comprising, administering to a subject in need thereof a bi-layer tablet comprising (1) an effective amount of (a) oxycodone or a pharmaceutically acceptable salt thereof and (b) promethazine or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

135. A method for treating or preventing pain comprising, administering to a subject in need thereof a bi-layer tablet comprising:

(1) a controlled-release layer comprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, (b) from about 290 to about 360 mg of acetaminophen or a pharmaceutically acceptable salt thereof, (c) from about 135 mg to about 170 mg of silicified microcrystalline cellulose, (d) from about 17 mg to about 23 mg of hydroxy methyl propyl cellulose, (e) from about 1 mg to about 4 mg of magnesium stearate, and (f) from about 1 mg to about 4 mg of stearic acid; and

(2) an immediate release layer comprising (a) from about 11 mg to about 14 mg of promethazine or a pharmaceutically acceptable salt thereof, (b) from about 100 mg to about 140 mg of silicified microcrystalline cellulose, (c) from about 12 mg to about 18 mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of magnesium stearate.

136. A method for treating or preventing pain comprising, administering to a subject in need thereof composition consisting of (1) an effective amount of (a) promethazine or a pharmaceutically acceptable salt thereof, (b) propoxyphene or a pharmaceutically acceptable salt thereof, (c) naproxen or a pharmaceutically acceptable salt thereof;

and (2) a pharmaceutically acceptable carrier or vehicle.

137. A bilayer tablet comprising:

(1) a controlled-release layer comprising (a) about 7.5 mg of hydrocodone bitartrate, (b) about 150 mg of silicified microcrystalline cellulose, (c) about 20 mg of hydroxy methyl propyl cellulose, (d) about 3 mg of magnesium stearate, and (e) about 3 mg of stearic acid; and

(2) an immediate-release layer comprising (a) about 12.5 mg of promethazine hydrochloride, (b) about 120 mg of silicified microcrystalline cellulose, (c) about 15 mg of croscarmellose sodium and (d) about 1.0 mg of magnesium stearate.

138. The bilayer tablet of claim 137, wherein the controlled-release layer further comprises about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof.