United States Patent Int (54] (75) 73) ey 22] [60 (st) (52) (58) (56) pe) turrisi D-METHADONE, A NONOPIOID ANALEGESIC Inventor: Charles E. Inturrisi, Torrington, Conn, Assignee: Cornell Research Foundation, Ine. Maca, NY, Appl. No. 09/010,239 Filed: Jan, 21, 1998 Related U.S. Appl tion Data Provisional application No, 60/035,308, Jan. 22, 1997 Int. Cl AOIN 33/02; AGIK 31/135 US. Cl. S14/648; 514/812 Field of Search 5141648, 812 References Cited US. PATENT DOCUMENT 3.995.056 7/1975 Billings ct al 2603490 5321012 6/1994 Mayer et al S125 51352.683 10/1994 Mayer et a. 514289 S'502058 3/1996 Mayer et a: 514289 51556,838 9/1996 Mayer eta. s1425 S16S4.281 §/1997 Mayer et a. 51425 US006008258A_ 1) Patent Number: 6,008,258 {45] Date of Patent: Dec. 28, 1999 OTHER PUBLICATIONS Olsen et al: Clinical Effects and Pharmacokinetics of Race- mie Methdone and Its Optical Isomers, 1977, 147-57, see centre abstract Kristensen et al: Stereoselective Pharmacokinetics of Methadone in Chronic Pain Patients, 1996, 7, see cenlire abstract Choi et al: Opioids and Non-Opioid Enantiomers Selec- tively Atteniate NMDA Neurotoxicity on Cortieal Neurons, 27-85, see entire absteact Primary Examiner—Peederick Krass Attorney, Agent, or FirnNixon Peabody LLP [57] ABSTRACT The present invention relates to a method of treating pain in a subject having a NMDA teeptor which includes adminis tering d-methadone, d-methadol, d-alpha-acetylmethadol, Ealpha-acetylmethadol, d-alpha-normethadol, alpha normethadol, pharmaceutically acceptable salts thereof, or mixtures thereof, to the subject under conditions effective for the substance to bind to the NMDA receptor of the subject. The present invention further relates to 4 method! of | tweating tolerance and physical dependence in a subject and a method of binding to a NMDA receptor, 20 Claims, 5 Drawing SheetsU.S. Patent Dec. 28, 1999 Sheet 1 of 5 6,008,258 —O- DEXTROMETHORPHAN MORPHINE Od} METHADONE 0+ /-METHADONE ie d- METHADONE % OF CONTROL SPECIFIC BINDING (FOREBRAI 1 3 10 100 CONCENTRATION OF COMPETING DRUG (11M) FIG. 1A —O-— DEMTROMETHORPHAN —@ ai- METHADONE —O} | - METHADONE a d- METHADONE BINDING = ® 01 1 10 100 1000 CONCENTRATION OF COMPETING DRUG (L1M) FIG. 1BU.S. Patent Dec. 28, 1999 Sheet 2 of 5 6,008,258 PERCENT ANALGESIC @ /-METHADONE © d-METHADONE 100 e 70 50 30 10 0 O—O-O0-00 1 3 10 30 100 300 1000 DOSE (ag/RAT, IT) FIG. 2