Compositions comprising GABA analogs and caffeine

Details Compositions comprising GABA analogs and caffeine Compositions comprising GABA analogs and caffeine

2001-01-09

2001-12-04

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06326374

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions comprising analogs of glutamic acid and gamma-aminobutyric acid (GABA) in combination with a central nervous system stimulant (CNS). The present invention also relates to a method of using these compositions for treating pain.
2. Description of Related Art
GABA analogs are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity. It has also been suggested that the compounds can be used as antidepressants, anxiolytics, and antipsychotics. See WO 92/09560 (U.S. Ser. No. 618,692 filed Nov. 27, 1990) and WP 93/23383 (U.S. Ser. No. 886,080 filed May 20, 1992).
WO 97/33858 teaches that compounds related to gabapentin are useful or treating epilespy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specify what forms of pain are treated.
Additionally, GABA analogs are known for treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain, March, 1996 12:1, 56-8; Segal A Z; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, April, 1996 46:4, 1175-6; Wetzel C H; Connelly J F., Use of gabapentin in pain management. Ann Pharmacother, September, 1997 31:9, 1082-3; Zapp J J., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam Physician, June 1996 53:8, 2442, 2445; Cheville A, et al., Neuropathic pain in radiation myelopathy:a case report. Program book, American Pain Society (14th Annual Scientific Meeting). Abstract #95823, p. A-115; Sist T; Filadora V; Miner M; Lema M., Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology, May, 1997 48:5, 1467; Waldman S D, Tutorial 28: Evaluation and Treatment of Trigerninal Neuralgia. Pain Digest (1997) 7:21-24; Mellick L B; Mellick G A., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, January, 1995 13:1, 96; Mellick G A; Seng M I., The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. Am J Pain Manage 1995; 5:7-9; Mellick G A; Mellicy L B; Mellick L B., Gabapentin in the management of reflex sympathetic dystrophy [letter]. J Pain Symptom Manage, May, 1995 10:4, 265-6; Mellick G A; Mellick L B., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil, January, 1997 78:1, 98-105 and Mackin G A., Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther, April-June, 1997 10:2, 96-109.
Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, has the structural formula:
Caffeine is a central nervous system stimulant that has been used, either alone or in coinbination with other drugs, in the treatment of headaches. Compositions containing one or more of the analgesics aspirin, acetaminophen and phenacetin in combination with varying amounts of caffeine have been marketed in the past. In several cases, such non-narcotic analgesic/caffeine combination products have further included one of the narcotic analgesics codeine, propoxyphene or oxycodone. Examples of these combinations include the products known commercially as Excedrin® SK-65® Compound, Darvon® Compound, Anacin®, A.P.C., and A.P.C. with Codeine, Tabloid® Brand.
Caffeine use in the treatment of headache has a long history. The FDA Advisory Panel, in its review of caffeine [Federal Register, 1977, 42(131): 35482-35485] argued that the known biochemical effect of caffeine on small blood vessels provides a plausible explanation for its effectiveness in treating headache associated with cerebral blood vessels. Sechzer [Curr. Therapy Research, 1979, 26(4)] found that intravenous administration of caffeine sodium benzoate rapidly provided relief in the majority of patients experiencing headache resulting from dural puncture or spinal anesthesia. The author, referring to the literature on the mechanism of action of caffeine on cerebral blood flow and on cerebral vascular tone, argues from the opposite perspective of the Panel that the analgesic relief obtained implies that an intracranial vascular component is the primary factory in such headaches.
Changes in mood and over all sense of “well being” after administration of caffeine have been widely reported in the literature. Beginning in the early part of this century, Hollingsworth (Arch. Psychol., 1912, 22: 1) reported beneficial motor and mental effects from 65 to 130 mg of caffeine, and tremor, poor motor performance, and insomnia caused by 390 mg of caffeine. Many studies over the past 70 years have confirmed these findings. Review articles on the xanthines [Ritchie, J. M., “Central nervous system stimulants. 2. The xanthines,” Goodman, L. S. & Gilman, A. (Eds.) The pharmacological basis of therapeutics, 4th Ed., New York: Macmillian Co., 1970; Stephenson, P. E., “Physiologic and psychotropic effects of caffeine on man,” J. Amer. Diet. Assoc., 1977, 71(3): 240-247] report that doses of 50 to 200 mg of caffeine result in increased alertness, decreased drowsiness, and lessened fatigue. Doses in the range of 200 to 500 mg may produce headaches, tremor, nervousness and irritability.
After extensively reviewing the relevant literature, the FDA Advisory Panel in 1977 concluded that caffeine when used as an analgesic adjuvant was safe, but that there was insufficient data to demonstrate that caffeine contributes anything to the action of the analgesic [Federal Register, 1977, 42(131): 35482-35485]. The Panel stated: Unfortunately, the information and data submitted, fail to demonstrate conclusively that caffeine in combination is effective as an analgesic, antipyretic and/or anti-rheumatic ingredient. The Panel finds there is little evidence to show that this ingredient even contributes to these pharmacological effects in the clinical situation. This remains the official position on the question up to the present time. Consequently, many of the analgesic/caffeine combination products previously available are no longer on the market.
U.S. Pat. No. 4,656,177 discloses combinations of non-narcotic analgesics
onsteroidal anti-inflammatory drugs and/or narcotic analgesics and caffeine. The compositions elicit a more potent and more rapid analgesic response than if the pain reliever is given alone.
U.S. Pat. No. 5,248,678 teaches a method of increasing the arousal an alertness of comatose patients or nea-comatose patients comprising administering to the patients effective amouts of an adenosine receptor antagonist, such as caffeine, and a GABA agonist, such as gabapentin.
SUMMARY OF THE INVENTION
The present inventors have discovered that a new class of pain relievers, not chemically related to aspirin, phenacetin, ibuprofen, other NSAIDS or narcotic analgesics can provide improved efficacy when combined with caffeine or other central nervous system stimulants. This invention provides a composition for treating pain including a combination of an effective amount of a GABA analog and caffeine. The GABA analog is a cyclic amino acid compound of Formula I
wherein R
1
is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where R
1
is hydrogen and n is 4. This compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin.
In another embodiment, the invention is directed to a composition for treating pain comprising a compound of Formula II.
wherein R
2
is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R
3
is hydrogen or methyl; and R
4
is hydrogen, methyl, or carboxyl; or an individual enantiomeric isomer the

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