Treating pain using selective antagonists of persistent sodium current Number:7,125,908 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides methods of treating chronic pain in a mammal by administering to the mammal an effective amount of a selective persistent sodium channel antagonist that has at least 20-fold selectivity for persistent sodium current relative to transient sodium current.<H antagonists, persistent, Treating, pain, u, 7125908.html, Patent, pto, 7125908

Title: Treating pain using selective antagonists of persistent sodium current

Abstract: The present invention provides methods of treating chronic pain in a mammal by administering to the mammal an effective amount of a selective persistent sodium channel antagonist that has at least 20-fold selectivity for persistent sodium current relative to transient sodium current.

Patent Number: 7,125,908 Issued on 10/24/2006 to Ehring, et al.

Inventors: Ehring; George R. (Huntington Beach, CA), Adorante; Joseph S. (Irvine, CA), Donello; John E. (Dana Point, CA), Wheeler; Larry A. (Irvine, CA), Malone; Thomas (Irvine, CA)
Assignee: Allergan, Inc. (Irvine, CA)

Appl. No.: 10/928,964

Filed: August 27, 2004

Current U.S. Class: 514/438 ; 514/443; 514/448

Current International Class: A01N 43/06 (20060101); A61K 31/38 (20060101)

Field of Search: 514/438,443,448

References Cited [Referenced By]

U.S. Patent Documents


5661035	August 1997	Tsien et al.
5688830	November 1997	Berger et al.
5922746	July 1999	Adorante
6342379	January 2002	Tsien et al.
6479498	November 2002	Marquess et al.
6646012	November 2003	Choi et al.
6686193	February 2004	Maher et al.
6699493	March 2004	Wong
6726918	April 2004	Wong et al.
6756400	June 2004	Chinn et al.
2002/0077097	June 2002	Adorante et al.
2004/0054374	March 2004	Weber et al.
2004/0137059	July 2004	Nivaggioli et al.

Foreign Patent Documents


1 182 193	Feb., 2002	EP

Other References

Nielsen et al, "Solution Structure of .mu.-Conotoxin PIIIA, a Preferential Inhibitor of Persistent Tetrodotoxin-sensitive Sodium Channels", The Journal of Biological Chemistry, vol. 277, No. 30, Jul. 26, 2002, pp. 27247-27255. cited by other .
Database Chemcats, XP002315431. cited by other .
Cervero, Fernando & Jennifer M. A. Laird, Role of Ion Channels in Mechanisms Controlling Gastrointestinal Pain Pathways, 3(6) Curr. Opin. Pharmacol. 608-612 (2003). cited by other .
Black, Joel A. et al., Changes in the Expression of Tetrodotoxin-Sensitive Sodium Channels Within Dorsal Root Ganglia Neurons in Inflammatory Pain, 108(3) PAIN 237-247 (2004). cited by other .
Li, Yunru et al., Role of Persistent Sodium and Calcium Currents in Motoneuron Firing and Spasticity in Chronic Spinal Rats, 91(2) J. Neurophysiol. 767-783 (2004). cited by other .
Catterall, William A., From Ionic Currents to Molecular Mechanism: The Structure and Function of Voltage-gated Sodium Channels, 26(1) NEURON 13-25 (2000). cited by other .
Novakovic, Sanja D. et al., Regulation of Na.sup.+ Channel Distribution in the Nervous System, 24(8) Trends Neurosci. 473-478 (2001). cited by other .
Taddese, Abraha & Bruce P. Bean, Subthreshold Sodium Current from Rapidly Inactivating Sodium Channels Drives Spontaneous Firing of Tubermammillary Neurons, 33(4) NEURON 587-600 (2002). cited by other .
Do, Michael Tri H. & Bruce P. Bean, Subthreshold Sodium Currents and Pacemaking of Subthalamic Neurons: Modulation by Slow Inactivation, 39(1) NEURON 109-120 (2003). cited by other .
Magistretti, Jacopo & Angel Alonso, Biophysical Properties and Slow-voltage Dependent Inactivation of a Sustained Sodium Current in Entorhinal Cortex Layer-II Principal Neurons: A Whole-Cell and Single-Channel Study 114(4) J. Gen. Physiol. 491-509 (1999). cited by oth- er .
Stys, Peter K., Anoxic and Ischemic Injury of Myelinated Axons in CNS White Matter: From Mechanistic Concepts to Therapeutics, 18(1) J. Cereb. Blood Flow Metab. 2-25 (1998). cited by other .
Crill, Wayne E., Persistent Sodium Current in Mammalian Central Neurons 58 Annu. Rev. Physiol. 349-362 (1996). cited by other .
Ragsdale, David S. & Avoli, Massimo, Sodium Channels as Molecular Targets for Antiepileptic Drugs, 26(1) Brain Res. Brain Res. Rev. 16-28 (1998). cited by other .
Lossin, Christoph et al., Molecular Basis of an Inherited Epilepsy 34(6) NEURON 877-84 (2002). cited by other .
Stys, Peter K. et al., Ionic Mechanisms of Anoxic Injury in Mammalian CNS White Matter: Role of Na.sup.+ Channels and Na.sup.(+)-Ca2.sup.+ Exchanger, 12(2) J. Neurosci. 430-439 (1992). cited by other .
Stys, Peter K. et al., Noninactivating, Tetrodotoxin-Sensitive Na.sup.+ Conductance in Rat Optic Nerve Axons, 90(15) Proc. Natl. Acad. Sci. USA, 6976-6980 (1993). cited by other .
Garthwaite, Gita et al., Mechanisms of Ischaemic Damage to Central White Matter Axons: A Quantitative Histological Analysis Using Rat Optic Nerve, 94(4) Neuroscience 1219-1230 (1999). cited by other .
Baker, Mark D. & John N. Wood, Involvement of Na.sup.+ Channels in Pain Pathways, 22(1) Trends Pharmacol. Sci. 27-31 (2001). cited by other .
Wood, John N. et al., Sodium Channels in Primary Sensory Neurons: Relationship to Pain States, 241 Novartis Found. Symp. 159-168 (2002). cited by other .
Lai, Josephine et al., The Role of Voltage-gated Sodium Channels in Neuropathic Pain, 13(3) Curr. Opin. Neurobiol. 291-297 (2003). cited by other .
LoGrasso, Philip & Jeffrey McKelvy, Advances in Pain Therapeutics, 7(4) Curr. Opin. Chem. Biol. 452-456 (2003). cited by other .
Birch, Phillip J. et al., Strategies to Identify Ion Channel Modulators: Current and Novel Approaches to Target Neuropathic Pain, 9(9) Drug Discov. Today 410-418 (2004). cited by other .
Lai, Josephine et al., Voltage-gated sodium channels and hyperalgesia, 44 Annu. Rev. Pharmacol. Toxicol. 371-397 (2004). cited by other .
Hains, Bryan C. et al., Upregulation of Sodium Channel Na.sub.v 1.3 and Functional Involvement in Neuronal Hyperexcitability Associated With Central Neuropathic Pain After Spinal Cord Injury, 23(26) J. Neurosci. 8881-8892 (2003). cited by other .
Hains, Bryan C. et al., Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury, 24(20) J. Neurosci. 4832-4839 (2004). cited by other .
Jayasena, Sumedha D., Aptamers: An Emerging Class of Molecules That Rival Antibodies in Diagnostics, 45(9) Clin. Chem. 1628-1650 (1999). cited by other .
Elbashir, Sayda M. et al., Duplexes of 21-nucleotide RNAs Mediate RNA Interference in Cultured Mammalian Cells, 411(6836) NATURE 494-498 (2001). cited by other .
Bass, B. L., RNA Interference. The Short Answer, 411(6836) NATURE 428-429 (2001). cited by other .
Zamore, Phillip D., RNA Interference: Listening to the Sound of Silence, 8(9) Nat. Struct. Biol. 746-750 (2001). cited by other .
Karabinos, Anton et al., Essential Roles for Four Cytoplasmic Intermediate Filament Proteins in Caenorhabditis elegans Development, 98(14) Proc. Natl. Acad. Sci. USA 7863-7868 (2001). cited by other .
Sakmann, Bert & Erwin Neher, Single Channel Recording (Plenum Press, 2.sup.nd ed. 1995). cited by other .
Shih, Tsung-Ming et al., High-level Expression and Detection of Ion Channels in Xenopus Oocytes, 529-556 (Methods in Enzymology: Ion Channels Part B, vol. 293, P. Michael Conn ed., Academic Press 1998). cited by oth- er .
Johnson, Iain D., Fluorescent Probes for Living Cells 30(3) Histochem. J. 123-140 (1998). cited by other .
Imaging Neurons: A Laboratory Manual (Rafael Yuste, et al., eds., Cold Spring Harbor Laboratory Press, 2000). cited by other .
Gonzalez, Jesus E. & Roger Y. Tsien, Improved Indicators of Cell Membrane Potential That Use Fluorescence Resonance Energy Transfer 4(4) Chem. Biol. 269-277 (1997). cited by other .
Gonzalez, Jesus E. & Michael P. Maher, Cellular Fluorescent Indicators and Voltage/Ion Probe Reader (VIPR) Tools for Ion Channel and Receptor Drug Discovery, 8(5-6) Receptors Channels 283-295, (2002) cited by other .
Molecular Cloning a Laboratory Manual (Joseph Sambrook & David W. Russell eds., Cold Spring Harbor Laboratory Press, 3.sup.rd ed. 2001). cited by other .
Current Protocols in Molecular Biology (Frederick M. Ausubel et al., eds., John Wiley & Sons, 2004). cited by other .
Goldin, Alan L., Diversity of Mammalian Voltage-gated Sodium Channels, 868 Ann. N.Y. Acad. Sci. 38-50 (1999). cited by other .
Wood, John N. & Mark D. Baker, Voltage-gated Sodium Channels, 1(1) Curr. Opin. Pharmacol. 17-21 (2001). cited by other .
Yu, Frank H. & William A. Catterall, Overview of the Voltage-Gated Sodium Channel Family, 4(3) Genome Biol. 207 (2003). cited by other .
GenBank database (National Institutes of Health, National Library of Medicine, http://www.ncbi.nlm.nih.gov/). cited by other .
Koster, R. et al., Acetic Acid for Analgesic Screening, 18 FED. Proc. 412-416 (1959). cited by other .
Dewey, William L. et al., The Effect of Narcotics and Narcotic Antagonists on the Tail-Flick Response in Spinal Mice, 21(8) J. Pharm. Pharmacol. 548-550 (1969). cited by other .
Kim, Sun H. & Jin M. Chung, An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat, 50(3) PAIN 355-363 (1992). cited by other .
Bennett, Gary J. and Yi-Kuan Xie, A Peripheral Mononeuropathy in Rat That Produces Disorders of Pain Sensation Like Those Seen in Man, 33(1) PAIN 87-107 (1988). cited by other .
Lee, Youn-Woo et al., Systemic and Supraspinal, but not Spinal, Opiates Suppress Allodynia in a Rat Neuropathic Pain Model, 199(2) Neurosci. Lett. 186:111-114 (1995). cited by other .
Malmberg, Annika B. & Tony L. Yaksh, Antinociceptive Actions of Spinal Nonsteroidal Anti-Inflammatory Agents on the Formalin Test in the Rat, 263(1) J. Pharmacol. Exp. Ther. 136-146 (1992). cited by other .
Kirk, Roger E., Experimental Design: Procedures for the Behavioral Sciences, (Wadsworth Publishing, 3.sup.rd ed. 1994). cited by other .
Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7.sup.th ed. 1999). cited by other .
Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20.sup.th ed. 2000). cited by other .
Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10.sup.th ed. 2001). cite- d by other .
Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4.sup.th edition 2003). cited by other .
Broadbent, H. Smith et al., Quinoxalines. I. Preparation and Stereochemistry of Decahydroquinoxalines, 82(1) J. Amer. Chem. Soc. 189-193 (1960). cited by other .
Heller, Biodegradable Polymers in Controlled Drug Delivery (CRC Critical Reviews in Therapeutic Drug Carrier Systems, vol. 1. CRC Press, 1987). cited by other.

Primary Examiner: Wang; Shengjun
Assistant Examiner: Chong; Yong S.
Attorney, Agent or Firm: Voet; Martin A. Baran; Robert J. Stathakis; Dean G.

Parent Case Text

CROSS REFERENCES TO RELATED APPLICATIONS

This patent application claims priority pursuant to 35 U.S.C. .sctn.119(e) to provisional application Ser. No. 60/498,900 filed Aug. 29, 2003, which is hereby incorporated by reference in its entirety.

Claims

What is claimed:

1. A method of treating neuropathic pain in a mammal, comprising administering to said mammal an effective amount of a selective persistent sodium channel antagonist, wherein said antagonist has at least 20-fold selectivity for a persistent sodium current relative to a transient sodium current, and wherein said antagonist is a compound included in formula 1, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof: ##STR00019## wherein, Ar.sup.1 is thienyl or a substituted thienyl; Ar.sup.2 is phenyl or a substituted phenyl; Y is absentor ##STR00020## R.sup.1 is selected from the group consisting of hydrogen and a C.sub.1 to C.sub.8 alkyl; R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, hydroxy, fluoro, and a C.sub.1 to C.sub.8 alkyl; and n is 1, 2, 3, 4, 5, or 6.

2. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.1 persistent current.

3. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.2 persistent current.

4. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.3 persistent current.

5. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.5 persistent current.

6. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.6 persistent current.

7. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.7 persistent current.

8. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.8 persistent current.

9. The method of claim 1, wherein said persistent sodium current is Na.sub.v1.9 persistent current.

10. The method of claim 1, wherein said mammal is a human.

11. The method of claim 1, wherein said antagonist has at least 50-fold selectivity for said persistent sodium current relative to said transient sodium current.

12. The method of claim 1, wherein said antagonist has at least 200-fold selectivity for said persistent sodium current relative to said transient sodium current.

13. The method of claim 1, wherein said antagonist has at least 400-fold selectivity for said persistent sodium current relative to said transient sodium current.

14. The method of claim 1, wherein said antagonist has at least 600-fold selectivity for said persistent sodium current relative to said transient sodium current.

15. The method of claim 1, wherein said antagonist has at least 1000-fold selectivity for said persistent sodium current relative to said transient sodium current.

16. The method of claim 1, wherein said antagonist is administered peripherally.

17. The method of claim 1, wherein said antagonist is administered systemically.

18. The method of claim 1, wherein said antagonist is administered orally.

19. The method of claim 1, wherein said antagonist is administered in a sustained release formula.

20. The method of claim 1, wherein said antagonist is administered in an bioerodible delivery system.

21. The method of claim 1, wherein said antagonist is administered in a non-bioerodible delivery system.

22. The method of claim 1, wherein said Ar.sup.1 is a substituted thienyl.

23. The method of claim 22, wherein said substituted thienyl is substituted with one or more of halogen, C.sub.1 C.sub.8 alkyl, NO.sub.2, CE.sub.3, OCF.sub.3, OCF.sub.2H, CN or (CR.sup.5R.sup.6).sub.cN(R.sup.7).sub.2, wherein c is 0, 1, 2, 3, 4, or 5; wherein R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, hydroxy, fluoro, and C.sub.1 to C.sub.8 alkyl; and R.sup.7 is selected from the group consisting of hydrogen, and C.sub.1 to C.sub.8 alkyl.

24. The method of claim 1, wherein said Ar.sup.2 is a substituted phenyl.

25. The method of claim 24, wherein said substituted phenyl is substituted with one or more of halogen, C.sub.1 C.sub.8 alkyl, arylalkyl, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, CN or (CR.sup.5R.sup.8).sub.cN(R.sup.7).sub.2, wherein c is 0, 1, 2, 3, 4, or 5: wherein R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, hydroxy, fluoro. and C.sub.1 to C.sub.8 alkyl; and R7 is selected from the group consisting of hydrogen, and C.sub.1 to C.sub.8 alkyl.

26. The method of claim 1, wherein said Ar.sup.1 is thienyl.

27. The method of claim 1, wherein said Ar.sup.2 is phenyl.

28. The method of claim 1, wherein said R.sup.1 is hydrogen, methyl, ethyl, propyl, or isopropyl.

29. The method of claim 1, wherein said R.sup.2 is hydrogen, methyl, ethyl, propyl, or isopropyl.

30. The method of claim 1, wherein said R.sup.3 is hydrogen, methyl, ethyl, propyl, or isopropyl.

31. The method of claim 1, wherein said n is 3, 4 or 5.

32. The method of claim 31, wherein said n is 4.

33. The method of claim 26, wherein said antagonist is thiophene-2-carboxylic acid (4-phenyl-butyl)-amide.

34. The method of claim 27, wherein said antagonist is ##STR00021##

35. The method of claim 1, wherein said neuropathic pain is a neuralgia.

36. The method of claim 35, wherein said neuralgia is selected from the group consisting of a trigeminal neuralgia, a post-herpetic neuralgia, a glossopharyngeal neuralgia, a sciatica and an atypical facial pain.

37. The method of claim 1, wherein said neuropathic pain is a deafferentation pain syndrome.

38. The method of claim 37, wherein said deafferentation pain syndrome is selected from the group consisting of an injury to the brain or spinal cord, a post-stroke pain, a phantom pain, a paraplegia, a peripheral nerve injury, a brachial plexus avulsion injury and a lumbar radiculopathy.

39. The method of claim 1, wherein said neuropathic pain is a complex regional pain syndrome (CRPS).

40. The method of claim 39, wherein said complex regional pain syndrome is selected from the group consisting of a reflex sympathetic dystrophy (CRPS Type I) and a causalgia (CRPS Type II).

41. The method of claim 1, wherein said neuropathic pain is a polyneuropathic pain.

42. The method of claim 41, wherein said complex regional pain syndrome is selected from the group consisting of a diabetic neuropathy, a chemotherapy-induced pain, a treatment-induced pain, and a posimastectomy syndrome.

43. The method of claim 1, wherein said neuropathic pain is a centrally-generated neuropathic pain.

44. The method of claim 43, wherein said centrally-generated neuropathic pain is selected from the group consisting of a dorsal root ganglion compression, an inflammation of the spinal cord, a contusion, a tumor of the spinal cord, a hemisection of the spinal cord, a tumor of the brainstem, a tumor of the thalamus, a tumor of the cortex, a trauma of the brainstem, a trauma of the thalamus and a trauma of the cortex.

45. The method of claim 1, wherein said neuropathic pain is a peripherially-generated neuropathic pain.

46. The method of claim 45, wherein said peripherially-generated neuropathic pain is selected from the group consisting of a neuroma, a nerve compression, a nerve crush, a nerve stretch, a nerve entrapment and an incomplete nerve transsection.

47. The method of claim 1, wherein said neuropathic pain is an allodynia, a hyperalgesia amd a hyperpathia.

48. The method of claim 1, wherein said effective amount reduces the symptoms of neuropathic pain by at least 30%.

49. The method of claim 1, wherein said effective amount reduces the symptoms of neuropathic pain by at least 50%.

50. The method of claim 1, wherein said effective amount reduces the symptoms of neuropathic pain by at least 70%.

51. The method of claim 1, wherein said effective amount reduces the symptoms of neuropathic pain by at least 90%.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the fields of neurobiology, physiology, biochemistry and medicine and can be directed toward the treatment of pain and, in particular, to the therapeutic use of compounds that selectively reduce persistent sodium currents to treat chronic pain.

2. Background Information

The lipid bilayer membrane of all cells forms a barrier that is largely impermeable to the flux of ions and water. Residing within the membrane are a superfamily of proteins called ion channels, which provide selective pathways for ion flux. Precisely regulated conductances produced by ion channels are required for intercellular signaling and neuronal excitability. In particular, a group of ion channels that open upon depolarization of excitable cells are classified as voltage-gated and are responsible for electrical activity in nerve, muscle and cardiac tissue. In neurons, ion currents flowing through voltage-gated sodium channels are responsible for rapid spike-like action potentials. During action potentials the majority of sodium channels open very briefly. These brief openings result in transient sodium currents. However, a subset of voltage-gated sodium channels does not close rapidly, but remain open for relatively long intervals. These channels therefore generate sustained or persistent sodium currents. The balance between transient and persistent sodium current is crucial for maintaining normal physiological function and electrical signaling throughout the entire nervous system.

Clinical pain encompasses nociceptive and neuropathic pain. Each type of pain is characterized by hypersensitivity at the site of damage and in adjacent normal tissue. While nociceptive pain usually is limited in duration and responds well to available opioid therapy, neuropathic pain can persist long after the initiating event has healed, as is evident, for example, in phantom pain that often follows amputation. Chronic pain syndromes such as neuropathic pain can be triggered by a variety of causes, including, without limitation, a traumatic insult, such as, e.g., a compression injury, a spinal cord injury, a limb amputation, an inflammation or a surgical procedure; an ischemic event, such as, e.g., a stroke; an infectious agent; a toxin exposure, such as, e.g., a drug or alcohol; or a disease such as, e.g., an inflammatory disorder, a neoplastic tumor, acquired immune deficiency syndrome (AIDS) or a metabolic disease.

Unfortunately, chronic pain such as chronic neuropathic pain is generally resistant to available opioid and nonsteroidal antiinflammatory drug therapies. Available drug treatments for chronic neuropathic pain, such as tricyclic antidepressants; anti-convulsants/anti-epileptic, such as, e.g., carbamazepine, phenyloin and lamotrigine; and local anesthetics/antiarrythmics, such as, e.g., lidocaine, mexiletine, tocainide and flecainide, only temporarily alleviate symptoms and to varying degrees. In addition, current therapies have serious side effects that can include cognitive changes, sedation, nausea, emesis, dizziness, ataxia, tinnitus and, in the case of narcotic drugs, addiction. Further, many patients suffering from neuropathic and other chronic pain are elderly or have medical conditions that limit their tolerance to the side effects associated with available analgesic therapy, such as, e.g., cardiotoxicity, hepatic dysfunction and leukopenia. The inadequacy of current therapy in relieving chronic pain without producing intolerable side effects is reflected in the high rate of depression and suicide in chronic pain sufferers.

Recent evidence suggests that increased persistent sodium current may be an underlying basis for chronic pain, such as, e.g., inflammatory and neuropathic pain, see e.g., Fernando Cervero & Jennifer M. A. Laird, Role of Ion Channels in Mechanisms Controlling Gastrointestinal Pain Pathways, 3(6) CURR. OPIN. PHARMACOL. 608 612 (2003); Joel A. Black et al., Changes in the Expression of Tetrodotoxin-Sensitive Sodium Channels Within Dorsal Root Ganglia Neurons in Inflammatory Pain, 108(3) PAIN 237 247 (2004) and Li Yunru et al., Role of Persistent Sodium and Calcium Currents in Motoneuron Firing and Spasticity in Chronic Spinal Rats, 91(2) J. NEUROPHYSIOL. 767 783 (2004), which are hereby incorporated by reference in their entirety. However, at present, treatments for chronic pain characterized by aberrant levels of sodium channel current, such as, e.g., Berger et al., Treatment of Neuropathic Pain, U.S. Pat. No. 5,688,830 (Nov. 18, 1997); Marquess et al., Sodium Channel Drugs and Uses, U.S. Pat. No. 6,479,498 (Nov. 12, 2002); Choi et al., Sodium Channel Modulators, U.S. Pat. No. 6,646,012 (Nov. 11, 2003); and Chinn et al., Sodium Channel Modulators, U.S. Pat. No. 6,756,400 (Jun. 29, 2004), encompass general sodium channel modulators that effect transient currents. As such, the usefulness of available sodium channel blocking drugs is severely limited by potentially adverse side effects, such as, e.g., paralysis and cardiac arrest. Thus, there is a need for novel methods of treating chronic pain that directly modulate persistent sodium current. The present invention satisfies this need and provides related advantages as well.

SUMMARY OF THE INVENTION

The present invention provides methods of treating chronic pain in a mammal, including a human. In one embodiment, the method involves administering to the mammal an effective amount of a selective persistent sodium current antagonist that has at least 20-fold selectivity for a persistent sodium current relative to transient sodium current. In further embodiments, the antagonist has at least 50-fold selectivity for a persistent sodium current, at least 200-fold selectivity for a persistent sodium current, at least 400-fold selectivity for a persistent sodium current, at least 600-fold selectively for a persistent sodium current, or at least 1000-fold selectively for a persistent sodium current, relative to a transient sodium current. A variety of mammals can be treated by the methods of the invention including, without limitation, humans.

The present invention provides methods of treating a variety of types of chronic pain. In certain embodiments, the methods are directed to treating neuropathic pain, inflammatory pain such as arthritic pain, visceral pain, post-operative pain, pain resulting from cancer or cancer treatment, headache pain, irritable bowel syndrome pain, fibromyalgia pain, and pain resulting from diabetic neuropathy.

A variety of selective persistent sodium current antagonists can be useful in the methods of the invention. In one embodiment, a method of the invention is practiced by administering an effective amount of a selective Na.sub.v1.3 antagonist that has at least 20-fold selectivity for Na.sub.v1.3 persistent sodium current relative to transient sodium current. In further embodiments, the antagonist has at least 50-fold selectivity for the Na.sub.v1.3 persistent sodium current; at least 200-fold selectivity for the Na.sub.v1.3 persistent sodium current; at least 400-fold selectivity for the Na.sub.v1.3 persistent sodium current; at least 600-fold selectively for the Na.sub.v1.3 persistent sodium current; or at least 1000-fold selectively for the Na.sub.v1.3 persistent sodium current, relative to transient sodium current.

In further embodiments, the methods of the invention involve administering an effective amount of a selective persistent sodium current antagonist belonging to one of the disclosed structural classes of selective persistent sodium current antagonists. Such a selective persistent sodium channel antagonist can be, without limitation, a compound represented by a formula selected from Formula 1:

##STR00001##

wherein,

Ar.sup.1 is an aryl group;

Ar.sup.2 is an aryl group;

Y is absent or is selected from:

##STR00002##

R.sup.1 is selected from hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl;

R.sup.2 and R.sup.3 are independently selected from hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl, hydroxy, fluoro, C.sub.1 C.sub.8 carbocyclic ring, or C.sub.1 C.sub.8 heterocyclic ring;

R.sup.4 is selected from hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl;

R.sup.5 and R.sup.5 are selected from hydrogen, fluoro, C.sub.1 to C.sub.8 alkyl, hydroxy;

R.sup.7 is selected from hydrogen, C.sub.1 to C.sub.8 alkyl, aryl, arylalkyl; and

n is an integer of from 1 to 6;

##STR00003##

wherein,

Ar.sup.3 is an aryl group;

Ar.sup.4 is an aryl group;

X.sup.1 and Y.sup.1 are independently selected from

##STR00004##

R.sup.5 and R.sup.6 are independently selected from hydrogen, fluoro, C.sub.1 to C.sub.8 alkyl, hydroxy;

R.sup.7 is selected from hydrogen, C.sub.1 to C.sub.8 alkyl, aryl, arylalkyl;

R.sup.8 and R.sup.9 are selected from hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl, COR.sup.12, COCF.sub.3;

R.sup.10 and R.sup.11 are selected from hydrogen, halogen, hydroxyl, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl, and

R.sup.12 is selected from hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl;

##STR00005##

wherein,

Ar.sup.5 is an aryl group;

Ar.sup.6 is an aryl group;

X.sup.2 is O, S, or NR.sup.14;

Y.sup.2 is N or CR.sup.15;

Z.sup.2 is N or CR.sup.16;

R.sup.5 and R.sup.6 are selected from hydrogen, fluoro, C.sub.1 to C.sub.8 alkyl, hydroxy;

R.sup.7 is selected from hydrogen, C.sub.1 to C.sub.8 alkyl, aryl, arylalkyl;

R.sup.13 is selected from halogen, C.sub.1 C.sub.8 alkyl, arylalkyl, and (CR.sup.5R.sup.6).sub.cN(R.sup.7).sub.2;

R.sup.14 is selected from hydrogen, halogen, C.sub.1 to C.sub.8 alkyl, CF.sub.3, OCH.sub.3, NO.sub.2, (CR.sup.5R.sup.6).sub.cN(R.sup.7).sub.2;

R.sup.15 is selected from hydrogen, halogen, C.sub.1 to C.sub.8 alkyl, CF.sub.3, OCH.sub.3, NO.sub.2, (CR.sup.5R.sup.6).sub.cN(R.sup.7).sub.2;

R.sup.16 is selected from hydrogen, halogen, C.sub.1 to C.sub.8 alkyl, CF.sub.3, OCH.sub.3, NO.sub.2, (CR.sup.5R.sup.6).sub.cN(R.sup.7).sub.2; and

c is 0 or an integer from 1 to 5; and

##STR00006##

wherein,

Ar.sup.7 is an aryl group;

R is selected from halogen, C.sub.1 C.sub.8 alkyl, NR.sup.22R.sup.23, OR.sup.22;

R.sup.5 and R.sup.6 are selected from hydrogen, fluoro, C.sub.1 to C.sub.8 alkyl, hydroxy;

R.sup.7 is selected from hydrogen, C.sub.1 to C.sub.8 alkyl, aryl, arylalkyl;

R.sup.17 and R.sup.18 are independently selected hydrogen, C.sub.1 C.sub.8 alkyl, aryl, arylalkyl, hydroxy;

R.sup.19 and R.sup.20 are independently selected from hydrogen, halogen, C.sub.1 C.sub.8 alkyl, hydroxy, amino, CF.sub.3;

R.sup.21, R.sup.22, and R.sup.23 are independently selected from hydrogen, aryl or C.sub.1 C.sub.8 alkyl;

a is 0 or an integer from 1 to 5; and

m is 0 or and integer from 1 to 3.

A compound corresponding to any of the above formulas also can be a pharmaceutically acceptable salt, ester, amide, or geometric, steroisomer, or racemic mixture.

Any of the variety of routes of administration can be useful for treating chemical pain according to a method of the invention. In particular embodiments, administration is performed peripherally, systemically or orally.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows four compounds that are selective persistent sodium current antagonists.

FIG. 2 shows inhibition of persistent current-dependent depolarization by sodium channel blockers. In the this assay, cells are resting in wells containing 80 .lamda.l of TEA-MeSO.sub.3 (sodium-free box) to which is added 240 .mu.l of NaMeSO.sub.3 buffer containing 13 mM KMeSO.sub.3 for a final K.sup.+ concentration of 10 mM and a final Na.sup.+ concentration of 110 mM (sodium/potassium-addition). This elicits a robust depolarizing response. Following the resolution of the sodium-dependent depolarization, a second aliquot of KMeSO.sub.3 is added to the well bringing the final K.sup.+ concentration to 80 mM (High potassium-addition). This addition results in a second depolarizing response. Compounds that reduce the sodium-dependent, but not the potassium-dependent depolarizations are selected as persistent sodium channel blockers. Circles indicate the control response with 0.1% DMSO added, triangles show the effects of the sodium channel inhibitor tetracaine (10 .mu.M) and the diamonds show the response during the application of a non-specific channel blocker.

FIG. 3 shows data from assays in which the screening window for the persistent current assay is determined. To evaluate the size of the "screening window," data was examined from assays in which responses to sodium-dependent depolarization were measured in the presence of 10 .mu.M Tetracaine to completely block the sodium-dependent depolarization or in the presence of a 0.1% DMSO control to obtain a maximum depolarization. Data were binned into histograms and a screening window (Z) was calculated from the mean and standard deviation for the maximal and minimum values according to the equation: Z=1-(3.times.STD.sub.Max+3.times.STD.sub.Min)/(Mean.sub.Max-Mean.sub.Min)- . Histograms A, B and C represent data obtained from three different assay plates. The screening window for a run was considered adequate 1.0.gtoreq.Z.gtoreq.0.5.

FIG. 4 shows sodium current traces before and after the addition of 3 .mu.M Compound 1 or 500 nM TTX. HEK cells expressing Na.sub.v1.3 channels were patch clamped in the perforated-patch mode. Currents were elicited by 200 msec test pulses to 0 mV from a holding potential of -90 mV.

FIG. 5 shows a dose-response curve for Compound 1. The peak amplitudes of transient Na.sup.+ current (I.sub.t) and the steady state amplitude of the persistent current (I.sub.p) were measured at various Compound 1 concentrations, normalized to amplitude of the control currents. The percent block was then plotted against drug concentration. Solid lines represent fits to the data with the Hill equation. The calculated EC.sub.50 values and Hill coefficients are as follows: Hillslope, I.sub.t is 0.354 and I.sub.p is 0.733; EC.sub.50, I.sub.t is 0.167 M and I.sub.p is 3.71.times.10.sup.-6 M.

FIG. 6 shows the effects of intraperitoneally administered Compound 1 on paw withdrawal threshold (mean.+-.SEM) in a test of mechanical allodynia in the spinal nerve ligation model of neuropathic pain. Paw withdrawal threshold (gram force) was determined using von Frey filament stimulation and the Dixon's up-down method. Allodynic response was measured at baseline (0 min) and at 15, 30, 60 and 120 min after of 10 mg/kg IP injection of Compound 1 or vehicle control. Percent reversal of allodynia compared with non-injected rats was calculated. Six rats were used at each dose. Data were analyzed by analysis of variance and Dunnett's test reversal of allodynia was considered significant if P<0.05

DETAILED DESCRIPTION OF THE INVENTION

I. Voltage-gated Sodium Channels

In the normal functioning of the nervous system, neurons are capable of receiving a stimulus, and in response, propagating an electrical signal away from their neuron cell bodies (soma) along processes (axons). From the axon, the signal is delivered to the synaptic terminal, where it is transferred to an adjacent neuron or other cell. Voltage-sensitive sodium channels have an important role in nervous system function because they mediate propagation of electrical signals along axons.

Voltage-gated sodium channels are members of a large mammalian gene family encoding at least 9 alpha- and 3 beta-subunits. While all members of this family conduct Na.sup.+ ions through the cell membrane, they differ in tissue localization, regulation and, at least in part, in kinetics of activation and inactivation, see, e.g., William A. Catterall, From Ionic Currents to Molecular Mechanism: The Structure and Function of Voltage-gated Sodium Channels, 26(1) NEURON 13 25 (2000); and Sanja D. Novakovic et al., Regulation of Na.sup.+ Channel Distribution in the Nervous System, 24(8) TRENDS NEUROSCI. 473 478 (2001), which are hereby incorporated by reference in their entirety.

Generally, under resting conditions, sodium channels are closed until a stimulus depolarizes the cell to a threshold level. At this threshold, sodium channels begin to open and then rapidly generate the upstroke of the action potential. Normally during an action potential, sodium channels open briefly (one millisecond) and then close (inactivate) until the excitable cell returns to its resting potential and the sodium channels re-enter the resting state.

Without wishing to be bound by the following, this behavior of voltage-gated sodium channels can be understood as follows. Sodium channels can reside in three major conformations or states. The resting or "closed" state predominates at negative membrane potentials (.ltoreq.-60 mV). Upon depolarization, channels open and allow current to flow. Transition from the resting state to the open state occurs within a millisecond after depolarization to positive membrane potentials. Finally, during sustained depolarization (>1 2 ms), channels enter a second closed or inactive state. Subsequent re-opening of channels requires recycling of channels from an inactive state to a resting state, which occurs when the membrane potential returns to a negative value (repolarization). Therefore, membrane depolarization not only causes sodium channels to open, but also causes them to close, during sustained depolarization.

A small fraction of the sodium channels can fail to inactivate even with sustained depolarization. This non-inactivating sodium current is called a "persistent" sodium current. Four sodium channels, Nav1.3, Nav1.5, Nav1.6 and Nav1.9, have historically been known to generate a persistent current. Recent evidence, however, suggests that all voltage-gated sodium channels are capable of producing a persistent current, see, e.g., Abraha Taddese & Bruce P. Bean, Subthreshold Sodium Current from Rapidly Inactivating Sodium Channels Drives Spontaneous Firing of Tubermammillary Neurons, 33(4) NEURON 587 600 (2002); Michael Tri H. Do & Bruce P. Bean, Subthreshold Sodium Currents and Pacemaking of Subthalamic Neurons: Modulation by Slow Inactivation, 39(1) NEURON 109 120 (2003), which are hereby incorporated by reference in their entirety. The mechanism that produces a persistent current is poorly understood. Two hypothesis are (1) that different sodium channels produce transient and persistent currents, and (2) that a sodium channel capable of producing transient sodium current enters a different gating mode to produce a persistent current. Persistent sodium channels can open at more negative membrane potentials relative to normal sodium channels and inactivate at more positive potentials, see, e.g., Jacopo Magistretti & Angel Alonso, Biophysical Properties and Slow-voltage Dependent Inactivation of a Sustained Sodium Current in Entorhinal Cortex Layer-II Principal Neurons: A Whole-Cell and Single-Channel Study 114(4) J. GEN. PHYSIOL. 491 509 (1999). Persistent sodium current have been observed at membrane potentials as negative as -80 mV, see, e.g., Peter K. Stys, Anoxic and Ischemic Injury of Myelinated Axons in CNS White Matter: From Mechanistic Concepts to Therapeutics, 18(1) J. CEREB. BLOOD FLOW METAB. 2 25 (1998) and have been shown to persist for seconds following depolarization at potentials as positive as 0 mV, see, e.g., Magistretti & Alonso, supra, (1999). Thus, persistent sodium current is distinct from, and can be readily distinguished from, transient sodium current.

Although the physiological role of persistent sodium current is not fully understood, such current can function in generating rhythmic oscillations; integrating synaptic input; modulating the firing pattern of neurons; and regulating neuronal excitability and firing frequency, see, e.g., Wayne E. Crill, Persistent Sodium Current in Mammalian Central Neurons 58 ANNU. REV. PHYSIOL. 349 362 (1996); and David S. Ragsdale & Massimo Avoli, Sodium Channels as Molecular Targets for Antiepileptic Drugs, 26(1) BRAIN RES. BRAIN RES. REV. 16 28 (1998). Persistent sodium current also can induce deleterious phenomena, including cardiac arrhythmia, epileptic seizure, and neuronal cell death under ischemic and anoxic conditions, see, e.g., Christoph Lossin et al., Molecular Basis of an Inherited Epilepsy 34(6) NEURON 877 84 (2002); Peter K. Stys et al., Ionic Mechanisms of Anoxic Injury in Mammalian CNS White Matter: Role of Na.sup.+ Channels and Na(+)-Ca2+ Exchanger, 12(2) J. NEUROSCI. 430 439 (1992); Peter K. Stys et al., Noninactivating, Tetrodotoxin-Sensitive Na.sup.+ Conductance in Rat Optic Nerve Axons, 90(15) PROC. NATL. ACAD. SCI. USA, 6976 6980 (1993); and Giti Garthwaite et al., Mechanisms of Ischaemic Damage to Central White Matter Axons: A Quantitative Histological Analysis Using Rat Optic Nerve, 94(4) NEUROSCIENCE 1219 1230 (1999). Thus, aberrant persistent sodium current can contribute to development or progression of pathological conditions by collapsing the normal cell transmembrane gradient for sodium, leading to reverse operation of the sodium-calcium exchanger, and resulting in an influx of intracellular calcium, which injures the axon, see, e.g., Stys et al., supra, (1992).

While abnormal activity of a persistent current can underlie a wide array of chronic pain conditions, the underlying mechanisms appears to be similar. It is generally understood that abnormally increased persistent sodium current can depolarize the resting membrane potential or reduce the rate of repolarization during an action potential. Either effect may produce a state of hyper-excitability in which aberrant neuronal behavior is manifested. This aberrant neuronal behavior can result in a neuron with increased firing rates, enhanced sensitivity to synaptic input or abnormal repetitive or rhythmic firing patterns. It is also generally understood that abnormally high levels of persistent current generate sustained membrane depolarization and a concomitant increase of Na.sup.+ within the cell. This high Na.sup.+ influx, in turn, drives the sodium/calcium exchanger, which in turn, results in detrimental levels of Ca.sup.2+ to accumulate inside affected cells. Abnormally high levels of Ca.sup.2+ result in neuronal cell dysfunction and neuronal cell death. Thus, by collapsing the normal cell transmembrane gradient for sodium, a persistent current can reverse the operation of the sodium-calcium exchanger, and the resulting an influx of intracellular calcium would cause injures or death to a nerve. As disclosed herein, conditions associated with aberrant persistent sodium current can be treated by selectively inhibiting or reducing persistent sodium current without compromising normal transient sodium current function, thereby allowing normal neuronal function (excitability). As disclosed herein, pain conditions associated with aberrant persistent sodium current can be treated by selectively inhibiting or reducing persistent sodium current without compromising normal transient sodium current function.

II. Chronic Pain and Persistent Sodium Current

There is strong evidence that altered voltage-gated sodium channel activity plays a critical role in chronic pain, such as, e.g., inflammatory and neuropathic pain, see, e.g., Mark D. Baker & John N. Wood, Involvement of Na.sup.+ Channels in Pain Pathways, 22(1) TRENDS PHARMACOL. SCI. 27 31 (2001); John N. Wood et al., Sodium Channels in Primary Sensory Neurons: Relationship to Pain States, 241 NOVARTIS FOUND. SYMP. 159 168 (2002); Josephine Lai et al., The Role of Voltage-gated Sodium Channels in Neuropathic Pain, 13(3) CURR. OPIN. NEUROBIOL. 291 297 (2003); Philip LoGrasso & Jeffrey McKelvy, Advances in Pain Therapeutics, 7(4) Curr. Opin. Chem. Biol. 452 456 (2003); Phillip J. Birch et al., Strategies to Identify Ion Channel Modulators: Current and Novel Approaches to Target Neuropathic Pain, 9(9) DRUG DISCOV. TODAY 410 418 (2004); and Josephine Lai et al., Voltage-gated sodium channels and hyperalgesia, 44 ANNU. REV. PHARMACOL. TOXICOL. 371 397 (2004), which are hereby incorporated by reference in their entirety. Alterations in sodium channel expression and/or function has a profound effect on the firing pattern of neurons in both the peripheral and central nervous systems. For example, injury to sensory primary afferent neurons often results in rapid redistribution of voltage-gated sodium channels along the axon and dendrites and in abnormal, repetitive discharges or exaggerated responses to subsequent sensory stimuli. Such an exaggerated response is considered to be crucial for the incidence of spontaneous pain in the absence of external stimuli that is characteristic of chronic pain. In addition, inflammatory pain is associated with lowered thresholds of activation of nociceptors in the periphery and altered sodium channel function is thought to underlie aspects of this phenomenon. Likewise, neuropathic pain states resulting from peripheral nerve damage is associated with altered sodium channel activity and ectopic action potential propagation.

Importantly, sodium channel inhibitors are clinically effective in the treatment of many types of chronic pain. For example, local anesthetics (such as, e.g., lidocaine, mexiletine, tocainide and flecainide) have been reported to provide effective relief in painful diabetic neuropathy, neuralgic pain, lumbar radiculopathies, complex regional pain syndrome Type I and Type II and traumatic peripheral injuries. Anticonvulsants (such as, e.g., carbamazepine and phenyloin) used as analgesics to treat chronic pain associated with neuralgic pain, trigeminal neuralgia, diabetic neuropathy. Anti-epileptic agents (such as, e.g., lamotrigine) are used with trigeminal neuralgia, diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome Type II and phantom pain. However, the usefulness of available sodium channel blocking drugs is severely limited by their failure to discriminate adequately between sodium channel a subunits. Highly systemic concentration would be associated with devastating side-effects, such as, e.g., periodic paralyses in muscle, cardiac arrest due to ventricular fibrillation and delayed cardiac repolarization in the heart, and epilepsy in the central nervous system, see, e.g., Baker & Wood, supra, (2001); and Lai et al., supra, (2004).

Recent evidence has revealed that increased activity from a persistent sodium current may be responsible for the underlying basis of chronic pain, see e.g., Cervero & Laird, supra, (2003); Black et al., supra, (2004); and Yunru et al., supra, (2004), which are hereby incorporated by reference in their entirety. An example of a sodium channel capable of mediating persistent current is the type III sodium channel Na.sub.v1.3. Under pathological pain circumstances, Na.sub.v1.3 expression can become upregulated while other sodium channels are concomitantly downregulated. For example, in adult rodents, damage to sensory neurons results in upregulation of Na.sub.v1.3 and downregulation of Na.sub.v1.8 and Na.sub.v1.9, see, e.g., Birch et al., supra, (2004), which is hereby incorporated by reference in its entirety. Furthermore, this Na.sub.v1.3 upregulation after nerve injury is associated with increased membrane potential oscillations that appear to underlie spontaneous activity, see, e.g., Bryan C. Hains et al., Upregulation of Sodium Channel Na.sub.v1.3 and Functional Involvement in Neuronal Hyperexcitability Associated With Central Neuropathic Pain After Spinal Cord Injury, 23(26) J. NEUROSCI. 8881 8892 (2003); and Bryan C. Hains et al., Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury, 24(20) J. NEUROSCI. 4832 4839 (2004), which are hereby incorporated by reference in their entirety. Selective reduction in the expression or activity of sodium channels capable of mediating persistent current relative to any reduction in normal voltage-gated (transient) sodium current can be useful for treating conditions associated with increased persistent sodium current.

Therefore, chronic pain is an example of a condition associated with increased persistent sodium current. As described herein, a compound that decreases persistent sodium current without a similar decrease in normal transient sodium current can effectively treat chronic pain without harmful side effects that generally accompany non-selective sodium channel blockers. As disclosed in Example 4, a selective persistent sodium current antagonist can effectively reverse allodynia in an animal model of neuropathic pain. Therefore, based on the identification of selective persistent sodium channel antagonists that have at least 20-fold selectivity for persistent sodium channel relative to transient sodium current, and the demonstration of the effectiveness of treating pain by selectively antagonizing persistent sodium current, the present invention provides a method of treating chronic pain in a mammal by selectively antagonizing persistent sodium current. The method involves administering to the mammal an effective amount of a selective persistent sodium channel antagonist that has at least 20-fold selectivity for persistent sodium current relative to transient sodium current.

The methods of the invention are useful for treating any of a variety of types of chronic pain, and, as non-limiting examples, pain that is neuropathic, visceral or inflammatory in origin. In particular embodiments, the methods of the invention are used to treat neuropathic pain; visceral pain; post-operative pain; pain resulting from cancer or cancer treatment; fibromyalgia pain, and inflammatory pain.

As used herein, the term "pain" encompasses both acute and chronic pain. As used herein, the term "acute pain" means immediate, generally high threshold, pain brought about by injury such as a cut, crush, burn, or by chemical stimulation such as that experienced upon exposure to capsaicin, the active ingredient in chili peppers. The term "chronic pain," as used herein, means pain other than acute pain and includes, without limitation, neuropathic pain, visceral pain, inflammatory pain, headache pain, muscle pain and referred pain. It is understood that chronic pain often is of relatively long duration, for example, months or years and can be continuous or intermittent.

In one embodiment, the methods of the invention are used to treat "neuropathic pain," which, as used herein, means abnormal sensory input by either the peripheral nervous system, central nervous systems, or both resulting in discomfort. Neuropathic pain typically is long-lasting or chronic and can develop days or months following an initial acute tissue injury. Symptoms of neuropathic pain can involve persistent, spontaneous pain, as well as allodynia, which is a painful response to a stimulus that normally is not painful, hyperalgesia, an accentuated response to a painful stimulus that usually a mild discomfort, such as a pin prick, or hyperpathia, a short discomfort becomes a prolonged severe pain. Neuropathic pain generally is resistant to opioid therapy. Neuropathic pain can be distinguished from nociceptive pain, which is pain caused by the normal processing of stimuli resulting from acute tissue injury. In contrast to neuropathic pain, nociceptive pain usually is limited in duration to the period of tissue repair and usually can be alleviated by available opioid and non-opioid analgesics.

The methods of the invention are useful for treating both centrally-generated and peripherially-generated neuropathic pain resulting from, without limitation, a trauma or disease of peripheral nerve, dorsal root ganglia, spinal cord, brainstem, thalamus or cortex. Examples of neuropathic pain that can be treated by the methods of the invention include neuralgia, such as, e.g., trigeminal neuralgia, post-herpetic neuralgia, glossopharyngeal neuralgia, sciatica and atypical facial pain; deafferentation pain syndromes, such as, e.g., injury to the brain or spinal cord, post-stroke pain, phantom pain, paraplegia, peripheral nerve injuries, brachial plexus avulsion injuries, lumbar radiculopathies and postherpetic neuralgia; complex regional pain syndromes (CRPSs) such as, e.g., reflex sympathetic dystrophy (CRPS Type I) and causalgia (CRPS Type II); and polyneuropathic pain, such as, e.g., diabetic neuropathy, chemotherapy-induced pain, treatment-induced pain, and postmastectomy syndrome. It is understood that the methods of the invention are useful in treating neuropathic pain regardless of the etiology of the pain. As non-limiting examples, the methods of the invention can be used to treat neuropathic pain resulting from a peripheral nerve disorder such as neuroma; from nerve compression; from nerve crush or stretch, nerve entrapment or incomplete nerve transsection; or from a mononeuropathy or a polyneuropathy. As further non-limiting examples, the methods of the invention are useful in treating neuropathic pain resulting from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; and tumors or trauma of the brainstem, thalamus or cortex.

As indicated above, the methods of the invention can be useful for treating neuropathic pain resulting from a mononeuropathy, polyneuropathy, complex regional pain syndromes or deafferentation. A neuropathy is a functional disturbance or pathological change in the peripheral nervous system and is characterized clinically by sensory or motor neuron abnormalities. The term mononeuropathy indicates that a single peripheral nerve is affected, while the term polyneuropathy indicates that several peripheral nerves are affected. Deafferentation indicates a loss of the sensory input from a portion of the body, and can be caused by interruption of either peripheral sensory fibres or nerves from the central nervous system. The etiology of a neuropathy can be known or unknown. Known etiologies include complications of a disease or toxic state such as diabetes, which is the most common metabolic disorder causing neuropathy, or irradiation, ischemia or vasculitis. Polyneuropathies that can be treated by a method of the invention can result, without limitation, from post-polio syndrome, diabetic neuropathy, alcohol neuropathy, amyloid, toxins, AIDS, hypothyroidism, uremia, vitamin deficiencies, chemotherapy, 2',3'-didexoycytidine (ddC) treatment, Guillain-Barre syndrome or Fabry's disease. It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology.

The methods of the invention also can used for treating chronic pain resulting from excessive muscle or nerve tension, such as certain types of back pain, such as that resulting from a herniated disc; a bone spur, sciatica, sprains, strains and joint pain. The methods of the invention can further be used for treating chronic pain resulting from activity, such as, as non-limiting examples, long hours of work at a computer, work with heavy objects or heavy machinery, or spending long hours on one's feet, and repetitive motion disorders (RMDs). RMDs are a variety of muscular conditions that can cause chronic pain. RMDs can be caused by overexertion, incorrect posture, muscle fatigue, compression of nerves or tissue, too many uninterrupted repetitions of an activity or motion, or friction caused by an unnatural or awkward motion such as twisting the arm or wrist. Common RMDs occur in the hands, wrists, elbows, shoulders, neck, back, hips, knees, feet, legs, and ankles, however, the hands and arms are most often affected. The methods of the invention can be used to treat chronic pain arising from any type of RMD. The methods of the invention further can be used to treat chronic muscle pain, chronic pain associated with substance abuse or withdrawal, and other types of chronic pain of known or unknown etiology.

Similarly, the methods of the invention can be used to treat chronic pain resulting from an inflammatory disorder, for example, from arthritis/connective tissue disorders such as, e.g., osteoarthritis, rheumatoid arthritis, juvenile arthritis, gouty arthritis; spondyloarthritis, scleroderma and fibromyalgia; autoimmune diseases such as, e.g., Guillain-Barre syndrome, myasthenia gravis and lupus erythematosus; inflammation caused by injury, such as a crush, puncture, stretch of a tissue or joint; inflammation caused by infection, such as tuberculosis; or neurogenic inflammation.

The methods of the invention can also be used to treat visceral pain, such as, e.g., functional visceral pain including chronic gastrointestinal inflammations like Crohn's disease, ulcerative colitis, gastritis, irritable bowel syndrome; orangic visceral pain including pain resulting from a traumatic, inflammatory or degenerative lesion of the gut or produced by a tumor impinging on sensory innervation; and treatment-induced visceral pain, for example, attendant to chemotherapy or radiation therapy.

The methods of the invention can be used for treating chronic pain resulting from headache, including, without limitation, tension-type headache, migraine headache, cluster headache, hormone headache, rebound headache, sinus headache, and organic headache. The methods of the invention can be used for treating chronic pain resulting infections, such as, e.g., Lymes disease, HIV/AIDS and leprosy.

III. Selective Persistent Sodium Current Blockers

The methods of the invention involve administering a compound that selectively reduces persistent sodium current relative to transient sodium current. As used herein, the term "selective," when used herein in reference to a compound, such as an antagonist, means a compound that, at least one particular dose reduces persistent sodium current at least 20-fold more than transient sodium current is reduced. Therefore, a compound that selectively reduces persistent sodium current has at least 20-fold selectively for persistent sodium current relative to transient sodium current, and can have, for example, at least 50-fold selectively for persistent sodium current relative to transient sodium current, at least 100-fold, at least 200-fold, at least 400-fold, at least 600-fold, or at least 1000-fold selectively for persistent sodium current relative to transient sodium current.

As used herein, the term "persistent sodium current" means a sodium channel mediated current that is non-transient; that can remain active during prolonged depolarization or that activates at voltage more negative than -60 mV and thus can contribute to hyperexcitability of the neural membrane. Prolonged depolarization refers to depolarization that occurs over a time period greater than the time period during which a transient current typically inactivates. As a non-limiting example, prolonged depolarization can occur within a time period greater than the time period during which the transient current of a sodium channel, such as Na.sub.v1.2, typically inactivates. Therefore, prolonged depolarization refers to depolarization that persists for at least 0.002 second, such as at least 0.01 s