WO2010017405A1

WO2010017405A1 - Methods and compositions for the treatment of pain

Info

Publication number: WO2010017405A1
Application number: PCT/US2009/053024
Authority: WO
Inventors: Adam Heller
Original assignee: Adam Heller
Priority date: 2008-08-06
Filing date: 2009-08-06
Publication date: 2010-02-11

Abstract

The invention features methods, kits, and compositions for the treatment of pain.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF PAIN

Background of the Invention

Chronic pain is one of the most important clinical problems in all of medicine. For example, it is estimated that over 5 million people in the United States are disabled by back pain. The economic cost of chronic back pain is enormous, resulting in over 100 million lost work days annually at an estimated cost of $50-100 billion. It has been reported that approximately 8 million people in the U.S. report that they experience chronic neck or facial pain and spend an estimated $2 billion a year for treatment. The cost of managing pain for oncology patients is thought to approach $12 billion. Chronic pain disables more people than cancer or heart disease and costs the American public more than both cancer and heart disease combined. In addition to the physical consequences, chronic pain has numerous other costs including loss of employment, marital discord, depression and prescription drug addiction. It goes without saying, therefore, that reducing the morbidity and costs associated with persistent pain remains a significant challenge for the healthcare system. Intractable severe pain resulting from injury, illness, scoliosis, spinal disc degeneration, spinal cord injury, malignancy, arachnoiditis, chronic disease, pain syndromes (e.g., failed back syndrome, complex regional pain syndrome) and other causes is a debilitating and common medical problem. In many patients, the continued use of analgesics, particularly drugs like narcotics, are not a viable solution due to tolerance, loss of effectiveness, and addiction potential.

Oxidizing agents are widely used as disinfectants. Examples of oxidizing disinfectants include aqueous solutions of chlorine, where hypochlorite and hypochlorous acid co-exist near neutral pH; of iodine, often dissolved as potassium tri-iodide in potassium iodide containing solutions; of hydrogen peroxide; of N-chloro-compounds, like Chloramine-T, the sodium salt of N-chloro-p-toluenesulfonamide and its salts with other cations or like Chloramine-B, the sodium salt of N-chloro-benzenesulfonamide and its salts with other cations; and of chloramine, NH₂Cl, also known as monochloramine; and of ozone. All are bactericidal and/or fungicidal, and some also deactivate viruses. Chlorine and the product of its reaction with water hypochlorous acid, and chloramine, as well as ozone, are widely used to disinfect municipal drinking water. Oxidizing agents are also applied in sterilization, for example of surgical instruments.

Oxidizing agents are also used in treatment of wounds and disease. Bactericidal oxidizing agents are used also to disinfect wounds, to prevent and control pathogen-caused inflammation, to assist in the healing of skin and other wounds, and to treat pathogen-caused diseases. When used to disinfect wounds, they are optionally topically applied, for example by swabbing, brushing, spraying, or in a dressing. They are applied topically also in order to prevent infection before the skin is purposely pierced or cut, for example, prior to an injection, withdrawal of a blood sample, or surgery.

It is an object of the invention to provide new methods, kits, and compositions for the treatment of pain and itch.

Summary of the Invention

Applicants have discovered that oxidizing amines, such as N-chlorinated amines and N-brominated amines, are useful for the treatment of pain and itch.

In a first aspect, the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including hypochlorous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-chlorinated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N- chlorinated amine to a subject. In a related aspect, the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including hypobromous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-brominated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N- brominated amine to a subject.

In another related aspect, the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form a mixture of N-brominated amine and N-chlorinated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N-brominated amine and N-chlorinated amine to a subject. Alternatively, the device is a three chamber device for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof. The three solutions are mixed in a mixing chamber to form a mixture of N-brominated amine and N- chlorinated amine. In certain embodiments of the above aspects, the device is a syringe, a spray bottle, a spray canister, an irrigation bottle or bag. The device may be gravity-driven, pressurized, or mechanically driven.

The invention features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming an N- chlorinated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including hypochlorous acid, or a salt thereof.

The invention further features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming an N-brominated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including hypobromous acid, or a salt thereof.

The invention further features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming a mixture of N-brominated amine and N-chlorinated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof. Alternatively, the device is a three barrel syringe for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof. In a related aspect, the invention features a device for delivery of an N- chlorinated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypochlorous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port. The invention further features a device for delivery of an N-brominated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypobromous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port. The invention also features a device for delivery of a mixture of an N- chlorinated amine and an N-brominated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing (i) hypobromous acid, or a salt thereof, and (ii) hypochlorous acid, or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.

Alternatively, the device is a three reservoir device for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof.

In certain embodiments of the above aspects, the device further includes a mechanism to control the flow from the first and second reservoirs through the first and second conduits to the delivery point. The delivery port may be a catheter, a needle, or a spray nozzle. In particular embodiments, the output is a stream or a mist.

In any of the above devices, the amine is selected from ammonia, urea, methylamine, ethylamine, isobutylamine, 2-methylbutylamine, pyrrolidine, phenethylamine, agmatine, histamine, tryptamine, 3-methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha-aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2-aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threonine, cystine, methionine, glutamine, tryptophane, histidine, arginine, lysine, alpha-aminobutyric acid, gamma-aminobutyric acid, alpha, epsilon diamino pimelic acid, ornithine, hydroxylysine, anthranilic acid, p- aminobenzoic acid, sulfanilic acid, orthanilic acid, phenyl sulfamic acid, aminopropanesulfonic acid, 2-aminopropanol, diethanolamine, ethylenediamine tetraacetic acid, aminomethane-sulfonic, glycylglycine, glycylglycylglycine, metanilic acid, N-octodecanyl glycine, 2,2- dimethyltaurine, 1,1,2,2-tetramethyltaurine, 2-methyltaurine, 2,2,3,3- tetramethyl-β-alanine, 3,3-dimethylhomotaurine, 1 -methyl- 1-amino- ethanesulfonic acid, 2-methyl-2-amino-ethanesulfonic acid, aminotrimethylene phosphonic acid. 2-amino-5-phosphonopentanoic acid, aminoethylphosponic acid, 1 -amino- 1-methylethane phosphonic acid, 1 -amino-2-methylethane phosphonic acid, l-amino-2-methylpropane phosphonic acid, leucine phosphonic acid, 4-amino-4-phosphonobutyric acid, 2-amino-5- phosphonovaleric acid, 2-amino-5-phosphonovaleric acid, 2-amino-8- phosphonooctanoic acid, leucine boronic acid, β-alanine boronic acid, and salts thereof. Alternatively, the amine is any amine described herein. In particular embodiments, the amine is taurine, 2,2-dimethyltaurine, 1,1,2,2- tetramethyltaurine, or 2-methyltaurine. In another embodiment of the above devices, one or more of the solutions includes a buffer and has a pH of between 7 and 10. For example, the solution can include a buffer and have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9.

In certain embodiments of the above devices, the solution formed by mixing the components (e.g., solutions and/or solids) of the device result in a solution having a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20).

In particular embodiments of the above devices, the solution formed by mixing the components (e.g., solutions and/or solids) of the device result in a solution having a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).

The invention features a method of treating pain in a patient in need thereof, the method including (i) mixing a solid ammonia salt and a solid hypochlorite salt with water to form an N-chlorinated amine solution, and (ii) administering the solution to a patient for the treatment of pain or itch. The invention further features a method of treating pain in a patient in need thereof, the method including (i) mixing a solid amine salt and a solid hypobromite salt with water to form an N-brominated amine solution, and (ii) administering the solution to a patient for the treatment of pain or itch.

The invention further features a method of treating pain in a patient in need thereof, the method including (i) mixing (a) a solid amine salt, (b) a solid hypobromite salt, and (c) a solid hypochlorite salt with water to form a solution containing N-brominated amine and N-chlorinated amine, and (ii) administering the solution to a patient for the treatment of pain or itch.

In certain embodiments of the above methods, the patient suffers from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.

In particular embodiments of the above methods, the amine salt is salt of ammonia, urea, methylamine, ethylamine, isobutylamine, 2-methylbutylamine. pyrrolidine, phenethylamine, agmatine, histamine, tryptamine, 3- methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha-aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2-aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threonine, cystine, methionine, glutamine, tryptophane, histidine, arginine, lysine, alpha- aminobutyric acid, gamma- aminobutyric acid, alpha, epsilon diamino pimelic acid, ornithine, hydroxy lysine, anthranilic acid, p-aminobenzoic acid, sulfanilic acid, orthanilic acid, phenyl sulfamic acid, aminopropanesulfonic acid, 2-aminopropanol, diethanolamine, ethylenediamine tetraacetic acid, aminomethane- sulfonic, glycylglycine, glycylglycylglycine, metanilic acid, 2,2-dimethyltaurine, 1,1,2,2-tctramethyltaurine, 2-methyltaurine, 2,2,3,3-tetramethyl-β-alanine, 3,3- dimethylhomotaurine, 1 -methyl- 1-amino-ethanesulfonic acid, 2-methyl-2- amino-ethanesulfonic acid, aminotrimethylene phosphonic acid, 2-amino-5- phosphonopentanoic acid, aminoethylphosponic acid, 1 -amino- 1 -methy lethane phosphonic acid, l-amino-2 -methyl ethane phosphonic acid, l-amino-2- methylpropane phosphonic acid, leucine phosphonic acid, 4-amino-4- phosphonobutyric acid, 2-amino-5-phosphonovaleric acid, 2-amino-5- phosphonovaleric acid, 2-amino-8-phosphonooctanoic acid, leucine boronic acid, β-alanine boronic acid, or N-octodecanyl glycine. In a particular embodiment of the above methods, the amine salt is a salt of taurine, 2,2- dimethyltaurine, 1,1,2,2-tetramethyltaurine, or 2-methyltaurine.

In other embodiments of the above methods, the solution includes a buffer and has a pH of between 7 and 10. For example, the solution can be buffered and have a pH of between 7 and 9, 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9.

In certain embodiments of the above methods, the solution has a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20). In particular embodiments of the above methods, the solution has a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M). The invention features a kit including (i) a device of the invention for producing a solution (e.g., an N-brominated amine solution, an N-chlorinated amine solution, or a mixture thereof), and (ii) instructions for administering the solution to a patient for the treatment of pain or itch.

The invention further features a kit including (i) an amine salt, (ii) a hypochlorite salt, and (iii) instructions for contacting the amine salt, and the hypochlorite salt with water to form a solution, and (iv) instructions for administering the solution to a patient for the treatment of pain or itch.

The invention also features a kit including (i) an amine salt, (ii) a hypobromite salt, and (iii) instructions for contacting the amine salt, and the hypobromite salt with water to form a solution, and (iv) instructions for administering the solution to a patient for the treatment of pain or itch.

The invention further features a kit including (i) an amine salt, (ii) a hypobromite salt, (iii) a hypochlorite salt, and (iv) instructions for contacting the amine salt, the hypobromite salt, and the hypochlorite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch. The invention features a kit including (i) a solid including an N- chlorinated amine, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch. In certain embodiments, the N-chlorinated amine is N-chloro-taurine, N-chloro-2,2-dimethyltaurine, N-chloro- 1 , 1 ,2,2- tetramethyltaurine, N-chloro-2,2,3,3-tetramethyl-β-alanine, N-chloro-3,3- dimethylhomotaurine, N,N-dichloro- taurine, N,N-dichloro-2,2-dimethyltaurine, N,N-dichloro-l,l,2,2-tetramethyltaurine, N,N-dichloro-2,2,3,3-tetramethyl-β- alanine, N,N-dichloro-3,3-dimethylhomotaurine, or a salt thereof, or any other N-chlorinated amine described herein.

The invention also features a kit including (i) a solid including an N- brominated amine, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch. In certain embodiments, the N-brominated amine is N-bromo-taurine, N N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2- tetramethyltaurinc, N-bromo-2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3- dimethylhomotaurine, N,N-dibromo-taurine, N,N-dibromo-2,2- dimethyltaurine, N,N-dibromo-l , 1 ,2,2-tetramethyltaurine, N,N-dibromo- 2,2,3, 3 -tetramethyl-β- alanine, N,N-dibromo-3,3-dimethylhomotaurine, or a salt thereof, or any other N-brominated amine described herein.

The invention further features a kit including (i) a solid including a halogenated amine selected from N-brominated amines, N-chlorinated amines, N-bromo-N-chloroamines, and mixtures thereof, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch. In certain embodiments, the halogenated amine is selected from N-bromo-taurine, N N- bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- 2,2,3, 3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N,N- dibromo-taurine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2- tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N-dibromo- 3,3-dimethylhomotaurine, N-chloro-taurine, N-chloro-2,2-dimethyltaurine, N- chloro-l,l,2,2-tetramethyltaurine, N-chloro-2,2,3,3-tetramethyl-β-alanine, N- chloro-3,3-dimethylhomotaurine, N,N-dichloro-taurine, N,N-dichloro-2,2- dimethyltaurine, N,N-dichloro- 1 , 1 ,2,2-tetramethyltaurine, N,N-dichloro- 2,2,3,3-tetramethyl-β-alanine, N,N-dichloro-3,3-dimethylhomotaurine, N- bromo-N-chloro-taurine, N-bromo-N-chloro-2,2-dimethyltaurine, N-bromo-N- chloro- 1,1, 2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramethyl-β- alanine, and N-bromo-N-chloro-3,3-dimethylhomotaurine, or a salt thereof, or any other N-brominated amine, N-chlorinated amine, or N-bromo-N- chloroamine described herein. In certain embodiments of any of the above kits, the solution further includes a buffer in an amount sufficient to produce upon mixing a pH of between 7 and 10. For example, the solution can be buffered to produce a pH of between 7 and 9, 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9. In certain embodiments of any of the the above kits, the components are present in amounts to produce upon mixing a solution having a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20).

In particular embodiments of any of the the above kits, the components are present in amounts to produce upon mixing a solution having a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M). In certain embodiments, the kits of the invention further include instructions for administering the composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder. The invention features a method of treating pain in a patient in need thereof by topically administering to the patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain. The invention also features a method of treating pain in a patient in need thereof by topically administering to the patient an N-bromo-N-chloroamine in an amount sufficient to treat the pain. In certain embodiments, the N-bromo-N- chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro- 2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- N-chloro-2,2,3,3-tetramethyl-β-alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.

The invention further features a method of treating pain in a patient in need thereof by topically administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain.

The invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain. The invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site an N-bromo-N-chloroamine in an amount sufficient to treat the pain. In certain embodiments, the N-bromo-N- chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro- 2,2-dimethyltaurine, N-bromo-N-chloro- 1, 1 ,2,2-tetramethyltaurine, N-bromo- N-chloro-2,2,3,3-tetramethyl-β-alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.

The invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain.

The invention further features a method of treating pain in a patient in need thereof by administering to the patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain, wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

The invention further features a method of treating pain in a patient in need thereof by administering to the patient an N-bromo-N-chloroamine in an amount sufficient to treat the pain, wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease. In certain embodiments, the N- bromo-N-chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo- N-chloro-2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramethyl-β-alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.

The invention further features a method of treating pain in a patient in need thereof by administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain, and wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

In certain embodiments of the above methods the pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein. In a related aspect, the invention features a method of treating itch in a patient in need thereof by topically administering to the patient an agent selected from N-bromoamines and N,N-dibromoamines in an amount sufficient to treat the itch. In a related aspect, the invention features a method of treating itch in a patient in need thereof by topically administering to the patient an N-bromo-N- chloroamine in an amount sufficient to treat the itch. In certain embodiments, the N-bromo-N-chloroamine is selected from N-bromo-N-chloro-taurine, N- bromo-N-chloro-2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2- tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramethyl-β-alanine, and N- bromo-N-chloro-3,3-dimethylhomotaurine, or a salt thereof.

In a related aspect, the invention features a method of treating itch in a patient in need thereof by topically administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the itch.

In an embodiment of any of the above aspects, the agent is administered locally at the site of pain or itch. In another related aspect, the invention features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N,N- dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N- chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of pain. In certain embodiments, the composition is formulated for topical administration (e.g., formulated as a cream, lotion, spray, stick, iontophoresis solution, or ointment). The invention also features a kit including (i) a composition formulated for injection and including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N- chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for locally injecting the composition at a site of a patient for the treatment of pain.

The invention further features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N.N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for administering the composition to a patient for the treatment of nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease. In certain embodiments, the kit further includes instructions for administering the composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.

The invention also features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat itch when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of itch.

In a related aspect, the invention features a kit including (i) an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) instructions for contacting the inorganic oxide, the ammonium salt, and the hypobromite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch. In certain embodiments, the kit further includes a buffer. In still other embodiments, the kit includes instructions for topically administering the solution into a patient for the treatment of pain or itch or instructions for infusing the solution into a patient at a site of pain. In another related aspect, the invention features a kit including (i) an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) a hypochlorite salt, and (v) instructions for contacting the inorganic oxide, the ammonium salt, the hypobromite salt, and the hypochlorite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch. In certain embodiments, the kit further includes a buffer. In still other embodiments, the kit includes instructions for topically administering the solution into a patient for the treatment of pain or itch or instructions for infusing the solution into a patient at a site of pain. The invention features a bandage including an N-bromo-N-chloroamine in an amount sufficient to treat pain or itch when applied to the skin of a patient.

The invention also features a bandage including a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are present in an amount sufficient to treat pain or itch when applied to the skin of a patient.

The invention further features a bandage including an agent selected from N-bromoamines and N,N-dibromoamines in an amount sufficient to treat pain or itch when applied to the skin of a patient.

In a related aspect, the invention features an infusion device including: (i) a first reservoir containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second reservoir containing a second solution including hypobromous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-brominated amine; and (iv) a cannula in fluid communication with the mixer chamber for delivering the N-bromoamine to a subject.

In another related aspect, the invention features an infusion device including: (i) a first reservoir containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second reservoir containing a second solution including hypobromous acid, or a salt thereof, and hypochlorous acid, or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form solution containing N- halogenated amine; and (iv) a cannula in fluid communication with the mixer chamber for delivering the N-halogenated amine to a subject. The invention further features an infusion device including: (i) a reservoir containing a first solution including an ammonium bromide salt and/or an amine and bromide ion; (ii) a power source electrically connected to an electrode in contact with the solution and configured to produce N- bromoamine via electrolysis; and (iii) a cannula in fluid communication with the solution for delivering the N-bromoamine to a subject.

The invention features an infusion device including: (i) a reservoir containing a first solution including (a) an ammonium salt, bromide ions, and chloride ions; (ii) a power source electrically connected to an electrode in contact with the solution and configured to produce N-bromoamine, N- chloroamine, and/or N-bromo-N-chloroamine, via electrolysis; and (iii) a cannula in fluid communication with the solution for delivering the solution to a subject.

The invention also features an infusion device including: (i) a first reservoir containing a first solution including an amine or a salt thereof; (ii) a second reservoir containing a second solution including bromide ions; (iii) a power source electrically connected to an electrode in contact with the second solution and configured to produce hypobromous acid or a salt thereof via electrolysis; (iv) a mixing chamber for combining the first solution and the hypobromous acid or a salt thereof to form an N-bromoamine; and (v) a cannula in fluid communication with the mixing chamber for delivering the N- bromoamine to a subject.

The invention further features an infusion device including: (i) a first reservoir containing a first solution including an amine or a salt thereof; (ii) a second reservoir containing a second solution containing chloride and bromide ions; (iii) a power source electrically connected to an electrode in contact with the second solution and configured to produce both hypochlorous acid, or a salt thereof, and hypobromous acid, or a salt thereof, via electrolysis; (iv) a mixing chamber for combining the first solution and the second solution to form an N- halogenated amine; and (v) a cannula in fluid communication with the mixing chamber for delivering the solution containing the N-halogenated amine to a subject. Preferably, the ratio of the concentrations of the chloride ions to to the bromide ions is greater than about 1, more preferably it is greater than about 10 and most preferably it equals or exceeds about 100.

In one embodiment of any of the above methods, kits, devices, or bandages the patient experiences some pain relief or some itch relief within 5, 10, 15, 20, 30, or 45 minutes of administering the N-halogenated amine of the invention.

In another embodiment of any of the above methods, kits, devices, or bandages, the pain or itch does not result from an infection in the patient.

In yet another embodiment of any of the above methods, kits, devices, or bandages, the agent is selected from bromourea, N-bromo-methyl amine, N- bromo-ethylamine, N-bromo-isobutylamine, N-bromo-2-methylbutylamine, N- bromo-pyrrolidine, N-bromo-phenethylamine, N-bromo-agmatine, N-bromo- histamine, N-bromo-tryptamine, N-bromo-3-methylthiopropanamine, N- bromo- spermine, N-bromo-carnosine, N-bromo-carcinine, N-bromo- glutathione sulfonamide, N-bromoglycine, N-bromosulfamic acid, N- bromosarcosine, N-bromo-alpha-aminoisobutyric acid, N-bromotaurine, N- bromotaurine ethyl ester, N-bromotaurine sulfonamide, N-bromo-2- aminoethanol, N-bromo-acetylglycine, N-bromoalanine, N-bromo-beta- alanine, N-bromoserine, N-bromo-phenyl alanine, N-bromo-norvaline, N- bromoleucine, N-bromo-isoleucine, N-bromoproline, N-bromo- hydroxyproline, N-bromo-omega aminoundecanoic acid, N-bromoaspartic acid, N-bromoglutamic acid, N-bromoasparagine, N-bromovaline, N- bromothreonine, N-bromocystine, N-bromomethionine, N-bromoglutamine, N- bromotryptophane, N-bromohistidine, N-bromoarginine, N-bromolysine (alpha or omega), N-bromo-alpha-aminobutyric acid, N-bromo-gamma-aminobutyric acid, N-bromo-alpha, epsilon diamino pimelic acid, N-bromo-ornithine, N- bromo-hydroxylysine (alpha or omega), N-bromoanthranilic acid, N-bromo-p- aminobenzoic acid, N-bromosulfanilic acid, N-bromo-orthanilic acid, N- bromo-phenyl sulfamic acid, N-bromoaminopropanesulfonic acid, N-bromo-2- aminopropanol, N-bromo-diethanolamine, N-bromo-ethylenediamine tetraacetic acid, N-bromo-aminomethane-sulfonic, N-bromo-glycylglycine, N- bromo-glycylglycylglycine, N-bromo-metanilic acid, N-bromo-N-octodecanyl glycine, N-bromo-2,2-dimethyltaurine, N-bromo- 1,1,2,2-tetramethyltaurine, N- bromo-2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N- bromo ethanesulfonic acid, N-bromo-1 -methyl ethanesulfonic acid, N-bromo- 2-methyltaurine, N-bromo-2-methyl-2-amino-ethanesulfonic acid, N-bromo aminotrimethylene phosphonic acid, N-bromo-2-amino-5-phosphonopentanoic acid, N-bromo aminoethylphosponic acid, N-bromo-1 -amino- 1-methylethane phosphonic acid, N-bromo- l-amino-2-methyl ethane phosphonic acid, N- bromo-l-amino-2-methylpropane phosphonic acid, N-bromoleucine phosphonic acid, N-bromo-4-amino-4-phosphonobutyric acid, N-bromo-2- amino-5-phosphonovaleric acid, N-bromo-2-amino-5-phosphonovaleric acid, N-bromo-2-amino-8-phosphonooctanoic acid, N-bromoleucine boronic acid, N-bromo-β-alanine boronic acid, N,N-dibromo-methylamine, N,N-dibromo- ethylamine, N,N-dibromo-isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo-phenethylamine, N.N-dibromo-agmatine, N,N-dibromo- histamine, N,N-dibromo-tryptamine, N,N-dibromo-3 -methylthiopropanamine, N,N-dibromo-spermine, N,N-dibromo-carnosine, N,N-dibromo-carcinine, N₅N- dibromoglycine, N,N-dibromo-alpha-aminoisobutyric acid, N₅N- dibromotaurine, N,N-dibromotaurine ethyl ester, N,N-dibromotaurine sulfonamide, N,N-dibromo-2-aminoethanol, N,N-dibromoalanine, N,N- dibromo-beta-alanine, N,N-dibromoserine, N,N-dibromo-phenyl alanine, N₅N- dibromo-norvaline, N,N-dibromoleucine, N,N-dibromo-isoleucine, N₅N- dibromoproline, N,N-dibromo-hydroxyproline, N.N-dibromo-omega aminoundecanoic acid, N,N-dibromoaspartic acid, N,N-dibromoglutamic acid, N,N-dibromoasparagine, N,N-dibromovaline, N,N-dibromothreonine, N₅N- dibromomethionine, N,N-dibromoglutamine, N,N-dibromotryptophane, N₅N- dibromoarginine, N,N-dibromolysine (alpha or omega), N,N-dibromo-alpha- aminobutyric acid, N,N-dibromo-gamma-aminobutyric acid, N,N-dibromo- alpha, epsilon diamino pimelic acid, N,N-dibromo-ornithine, N,N-dibromo- hydroxylysine (alpha or omega), N,N-dibromo-2-aminopropanol, N₅N- dibromo-diethanolamine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1,1,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N- dibromo-3,3-dimethylhomotaurine, N,N-dibromo ethanesulfonic acid, N₅N- dibromo-1 -methyl ethanesulfonic acid, N,N-dibromo-2-methyl-2-amino- ethanesulfonic acid, N,N-dibromo aminotrimethylene phosphonic acid, N₅N- dibromo-2-amino-5-phosphonopentanoic acid, N,N-dibromo aminoethylphosponic acid diesters, such as the diethylester, N,N-dibromo-l- amino-1-methylethane phosphonic acid, N,N-dibromo-l-amino-2- methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylpropane phosphonic acid, N,N-dibromoleucine phosphonic acid, N,N-dibromo-4- amino-4-phosphonobutyric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino- 8-phosphonooctanoic acid, N,N-dibromoleucine boronic acid, N,N-dibromo-β- alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof. In still another embodiment of any of the above methods, kits, devices, or bandages, the agent is an N-bromo-N-chloroamine selected from N-bromo- N-chloro-methylamine, N-bromo-N-chloro-ethylamine, N-bromo-N-chloro- isobutylamine, N-bromo-N-chloro-2-methylbutylamine, N-bromo-N-chloro- phenethylamine, N-bromo-N-chloro-agmatine, N-bromo-N-chloro-histamine,

N-bromo-N-chloro-S-methylthiopropanamine, N-bromo-N-chloro-spermine, N-bromo-N-chloro-carnosine, N-bromo-N- chloro-carcinine, N-bromo-N-chloroglycine, N-bromo-N-chloro-alpha- aminoisobutyric acid, N-bromo-N-chlorotaurine, N-bromo-N-chlorotaurine ethyl ester, N-bromo-N-chlorotaurine sulfonamide, N-bromo-N-chloro-2- aminoethanol, N-bromo-N-chloroalanine, N-bromo-N-chloro-beta-alanine, N- bromo-N-chloroserine, N-bromo-N-chloro-phcnyl alanine, N-bromo-N-chloro- norvaline, N-bromo-N-chloroleucine, N-bromo-N-chloro-isoleucine, N-bromo- N-chloroproline, N-bromo-N-chloro-hydroxyproline, N-bromo-N-chloro- omega aminoundecanoic acid, N-bromo-N-chloro-aspartic acid, N-bromo-N- chloroglutamic acid, N-bromo-N-chloroasparagine, N-bromo-N-chlorovaline, N-bromo-N-chlorothreonine, N-bromo-N-chloro- methionine N-bromo-N- chloroglutamine, N-bromo-N-chlorotryptophane, N-bromo-N-chloroarginine, any N-bromo-N-chlorolysine (alpha or omega), N-bromo-N-chloro-alpha- aminobutyric acid, N-bromo-N-chloro-gamma-aminobutyric acid, N-bromo-N- chloro-alpha, epsilon diamino pimelic acid, N-bromo-N-chloro-ornithine, any N-bromo-N-chloro-hydroxylysine (alpha or omega), N-bromo-N-chloro-2- aminopropanol, N-bromo-N-chloro-diethanolamine, N-bromo-N-chloro-2,2- dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N- chloro-2,2,3,3-tetramethyl-β-alanine, N-bromo-N-chloro-3,3- dimethylhomotaurine, N-bromo-N-chloro-ethanesulfonic acid, N-bromo-N- chloro- 1 -methyl ethanesulfonic acid, N-bromo-N-chloro-2-methyl-2-amino- ethanesulfonic acid, N-bromo-N-chloro-aminotrimethylene phosphonic acid, N-bromo-N-chloro-2-amino-5-phosphonopentanoic acid, N-bromo-N-chloro- aminoethylphosponic acid diesters, such as the diethylester, N-bromo-N- chloro- 1 -amino- 1-methylethane phosphonic acid, N-bromo-N-chloro- 1-amino- 2-methyl ethane phosphonic acid, N-bromo-N-chloro- l-amino-2-methylpropane phosphonic acid, N-bromo-N-chloroleucine phosphonic acid, N-bromo-N- chloro-4-amino-4-phosphonobutyric acid, N-bromo-N-chloro-2-amino-5- phosphonovaleric acid, N-bromo-N-chloro-2-amino-5-phosphonovaleric acid, N-bromo-N-chloro-2-amino-8-phosphonooctanoic acid, N-bromo-N- chloroleucine boronic acid, N-bromo-N-chloro- β-alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof.

In certain embodiment of any of the above methods, kits, devices, or bandages, the agent is a brominated analgesic, brominated tricyclic antidepressant, brominated stimulant, or a polymer bearing N-bromoamine groups. Brominated analgesics which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N-bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl-N-bromo-ropivacaine, desbutyl-N- bromo-bupivacaine, desbutyl-N-bromo-levobupivacaine, desmethyl-N-bromo- mepivacaine, desethyl-N-bromo-procaine, desethyl-N-bromo-proparacaine, desethyl-N-bromo-allocain, desmethyl-N-bromo-encainide, desethyl-N-bromo- procainamide, desethyl-N-bromo-metoclopramide, desmethyl-N-bromo- stovaine, desethyl-N-bromo-propoxycaine, desethyl-N-bromo-bromoprocaine, N-bromo-flecainide, desethyl-N-bromo-tetracaine, N-bromo-procaine, N- bromo-proparacaine, N-bromo-procainamide, N-bromo-metoclopramide, N- bromo-propoxycaine, N-bromo-bromoprocaine, N-bromo-tetracaine, N-bromo- benzocaine, N-bromo-butamben, and desethyl-N-bromo-dibucaine.

Brominated tricyclic antidepressants which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N- bromo-amoxapine, desmethyl-N-bromo-trimipramine, desmethyl-N-bromo- dothiepin, desmethyl-N-bromo-doxepin, desmethyl-N-bromo-amitriptyline, N- bromo-protriptyline, N-bromo-desipramine, desmethyl-N-bromo- clomipramine, desmethyl-N-bromo-clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptyline, desmethyl-N-bromo-cyclobenzaprine, desmethyl-N- bromo- cyproheptadine, desmethyl-N-bromo-olopatadine, desmethyl-N-bromo- promethazine, desmethyl-N-bromo-trimeprazine, desmethyl-N-bromo- chlorprothixene, desmethyl-N-bromo-chlorpromazine, desmethyl-N-bromo- propiomazine, desmethyl-N-bromo-prochlorperazine, desmethyl-N-bromo- thiethylperazine, desmethyl-N-bromo-trifluoperazine, desethyl-N-bromo- ethacizine, and desmethyl-N-bromo-imipramine.

Brominated stimulants which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-bromo- amphetamine, N,N-dibromo-amphetamine, and N-bromo-methamphetamine. Polymers bearing N-bromoamine groups which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N-brominated amino-cellulose, and N-brominated poly lysine (alpha or omega).

Alternatively, any of the above methods, kits, devices, or bandages, the agent is a mixture of N-brominated agent and N-chlorinate agent, or an N- bromo-N-chloroamine. The agent can be selected from a halogenated analgesic, halogenated tricyclic antidepressant, halogenated stimulant, or a polymer bearing N-halogenated amine groups. Such agents or mixtures of agents bear both N-bromoamine groups and N-chloroamine groups.

In certain embodiment of any of the above methods, kits, devices, or bandages, the agent is selected from N-bromotaurine, N,N-dibromotaurine, N- bromo-N-chlorotaurine, N-bromo-desmethylchlorpromazine, N-bromo- lidocaine, N-bromo-amphetamine, N,N-dibromo-amρhetamine, N-bromo-N- chloroamphetamine and N-bromo-methamphetamine and from their mixtures with their N-chloro-analogs, exemplified by the mixture of N-bromotaurine with N-chlorotaurine.

When used for topical administration, the N-brominated amine of the invention desirably has a solubility at about 25 ⁰C of at least about 10^"6 M, 10^"5 M, 10^"4 M, or

10^"3 M both in water and in bromoform to allow for rapid diffusion to the nerve endings.

In certain embodiments the N-brominated amine of the invention has a long life (i.e., is highly stable) in comparison to chloramine, which has a half- life on the order of days. For example, sulfonate salts of N-bromotaurine may be desirable to use as such salts can be stored for many months without significant decomposition.

In a related aspect, the invention features a method of treating pain in a patient in need thereof by topically administering to the patient a compound of formula (I):

or a salt thereof, in an amount sufficient to treat the pain. In formula (I), X is - NHCl, -NHBr, -NCl₂, -NBr₂, or -NBrCl; Y is -COOH, -CONH₂, -SO₃H, - SO₂NH₂, -P(O)(OH)₂, or -B(OH)₂; Z is selected from -0-,-S-, -OC(O)-, - C(O)O-, -S(O)₂-, -NR³C(O)-, and -C(O)NR³- or Z is absent; each of R¹ and R² is, independently, selected from CH₃, CH₂CH₃, and CH₂CH₂CH₃, or R¹ and R² combine to form a carbocyclic ring of 3 to 8 carbon atoms; each of R³ and R⁴ is, independently, selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; R^a is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is O or an integer from 1 to 3; and m is O or an integer from 1 to 3.

The invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site a compound of formula (I) in an amount sufficient to treat the pain.

In certain embodiments of the above methods, the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease. In certain embodiments the pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.

In a related aspect, the invention features a method of treating itch in a patient in need thereof by topically administering to the patient a compound of formula (I) in an amount sufficient to treat the itch. In an embodiment of any of the above aspects, the agent is administered locally at the site of pain or itch.

In another related aspect, the invention features a kit including (i) a composition including a compound of formula (I) in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of pain. In certain embodiments, the composition is formulated for topical administration (e.g., formulated as a cream, lotion, spray, stick, iontophoresis solution, or ointment). The invention also features a kit including (i) a composition formulated for injection and including a compound of formula (I) in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for locally injecting the composition at a site of a patient for the treatment of pain.

In any of the above aspects, the compound of formula (I) is selected from N-chloro-2,2-dimethyltaurine, N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N- chloro-2,2,3,3-tetramethyl-β-alanine, N-chloro-3,3-dimethylhomotaurine, N₅N- dichloro-2,2-dimethyltaurine, N.N-dichloro- 1 , 1 ,2,2-tetramethyltaurine, N,N- dichloro-2,2,3,3-tetramethyl-β-alanine, N,N-dichloro-3,3- dimethylhomotaurine, N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2- tetramethyltaurine, N-bromo-2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3- dimethylhomotaurine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N- dibromo-3,3-dimethylhomotaurine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro-l,l,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3- tetramethyl-β-alanine, N-bromo-N-chloro-3,3-dimethylhomotaurine, and salts thereof.

The invention features a solution including a mixture of halogenated amine and unhalogcnated amine dissolved in a buffered aquous solution having a pH of between 7 and 10, wherein (i) the halogenated amine is a chlorinated amine or a brominated amine; (ii) the ratio of unhalogenated amine to halogenated amine in the solution is greater than 1.5; and (iii) the concentration of halogenated amine is between 0.0001 M and 0.25 M. In certain embodiments, the solution has a pH of between 8 and 9.5 (e.g., the solution can have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9). In particular embodiments, the solution includes a ratio of unhalogenated amine to halogenated amine of between 2 and 10 (e.g., the ration can be between 1.5 and 50, 1.5 and 10, 2 and 50, 2 and 15, 3 and 50, 3 and 20, or 5 and 25). In still other embodiments, the concentration of halogenated amine in the solution is between 0.0005 M and 0.015 M (e.g., between 0.0001 M and 0.25 M, 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M). The amine can be selected from taurine, 2,2-dimethyltaurine, 1,1,2,2-tetramethyltaurine, 2,2,3,3-tetramethyl-β-alanine, 3,3- dimethylhomotaurine, and salts thereof, or any other amine described herein. The invention also features a kit including (i) the above solution of the invention, and (ii) instructions for keeping the solution refrigerated.

The invention also features a method of treating pain in a subject by administering to the subject the above solution of the invention in an amount sufficient to treat the pain. The invention also features a method of treating itch in a subject by administering to the subject the above solution of the invention in an amount sufficient to treat the itch.

The invention further features a compound of formula (II) , or a salt thereof:

In formula (II) X is -NBrCl; Y is -COOH, -CONH₂, -SO₃H, -SO₂NH₂, - P(O)(OH)₂, or -B(OH)₂; Z is selected from -O-,-S-, -OC(O)-, -C(O)O-, -S(O)₂-, -NR²C(O)-, and -C(O)NR^a- or Z is absent; each of R¹ and R² is, independently, selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃, or R¹ and R² combine to form a carbocyclic ring of 3 to 8 carbon atoms; each of R³ and R⁴ is, independently, selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; R^a is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is 0 or an integer from 1 to 3; and m is 0 or an integer from 1 to 3. The compound of formula (II) can be selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3 ,3- tetramethyl-β-alanine, and N-bromo-N-chloro-S^-dimethylhomotaurine, or a salt thereof, or any N-bromo-N-chloroamine described herein. The compounds can be used in any of the methods and kits of the invention.

The invention features a pharmaceutical composition including (i) a brominated amine, (ii) a chlorinated amine, and (iii) a buffered aquous solution having a pH of between 7 and 10, wherein the concentration of brominated amine is between 0.0001 M and 0.25 M and the concentration of chlorinated amine is between 0.0001 M and 0.25 M. ). In particular embodiments, the concentration of brominated amine and chlorinated amine in the pharmaceutical composition is between 0.0005 M and 0.015 M (e.g., between 0.0001 M and 0.25 M, 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M). . In certain embodiments, the pharmaceutical composition has a pH of between 8 and 9.5 (e.g., the solution can have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9). The pharmaceutical composition can be formulated for topical administration, formulated for injection, or formulated in any manner described herein. In particular embodiments, the ratio of chlorinated amine to brominated amine in the pharmaceutical composition is between 100:1 and 1 :100 (e.g., between 10: 1 and 1 : 100, 100:1 and 1 :10, 50:1 and 1 :50, 20:1 and 1 :20, 1 :1 and 1 :20, or 20:1 and 1 :1). The pharmaceutical composition can be used in any of the methods and kits of the invention.

The invention features a compound selected from N-chloro-piperidine- 4-sulfonic acid, N-chloro-piperidine-3 -sulfonic acid, N-bromo-piperidine-4- sulfonic acid, and N-bromo-piperidine-3 -sulfonic acid, or a salt thereof. The compounds can be used in any of the methods and kits of the invention. In an embodiment of any of the above aspects, the pain or itch does not result from an infection in the patient. The term "pain" is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.

The term "nociceptive pain" is used to include all pain caused by noxious stimuli that threaten to or actually injure body tissues, including, without limitation, by a cut, bruise, bone fracture, crush injury, and the like. Pain receptors for tissue injury (nociceptors) are located mostly in the skin, musculoskeletal system, or internal organs. The term "nociceptive pain"

The term "somatic pain" is used to refer to pain arising from bone, joint, muscle, skin, or connective tissue. This type of pain is typically well localized.

The term "visceral pain" is used herein to refer to pain arising from visceral organs, such as the respiratory, gastrointestinal tract and pancreas, the urinary tract and reproductive organs. Visceral pain includes pain caused by tumor involvement of the organ capsule. Another type of visceral pain, which is typically caused by obstruction of hollow viscus, is characterized by intermittent cramping and poorly localized pain. Visceral pain may be associated with inflammation as in cystitis or reflux esophagitis. The term "inflammatory pain" includes pain associated with active inflammation that may be caused by trauma, surgery, infection and autoimmune diseases.

The term "neuropathic pain" is used herein to refer to pain originating from abnormal processing of sensory input by the peripheral or central nervous system consequent on a lesion to these systems.

The term "procedural pain" refers to pain arising from a medical, dental or surgical procedure wherein the procedure is usually planned or associated with acute trauma.

The term "itch" (also known as pruritus) is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent. The itch may be idiopathic, allergic, metabolic, drug-induced, due to liver, kidney disease, or cancer.

By "patient" is meant any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the invention include but are not limited to non-human primates (e.g., monkeys, gorillas, chimpaneees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

The term "pharmaceutically acceptable salt" represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the agents of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include but are not limited to acetate, adipate, alginate, aspartate, benzenesulfonate, benzoate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfatc, cthanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, mesylate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include but are not limited to sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. As used herein, the terms "ester" and "amide" refer derivatives of the N- halogenated amines and their mixtures described herein, including carboxylic acid esters and amides and sulfonic acid esters and amides. Examples of such derivatives include, without limitation the methyl, ethyl, isopropyl, propyl, butyl, and hexyl sulfonic acid esters of N-chloro-taurine and N,N-dichloro- taurine; sulfonamides of N-chloro-taurine and N,N-dichloro-taurine (e.g., formed from ammonia, secondary amines, or primary amines); methyl, ethyl, isopropyl, propyl, butyl, and hexyl carboxylic acid esters of amino acids, such as gamma aminobutyric acid; and carboxylic acid amides (e.g., formed from ammonia, secondary amines, or primary amines) of amino acids, such as gamma aminobutyric acid. Methods for making such derivatives are well known in the art.

By "treating pain" is meant preventing, reducing, or eliminating the sensation of pain in a subject. To treat pain, according to the methods of this invention, the treatment does not necessarily provide therapy for the underlying pathology that is causing the painful sensation. Treatment of pain can be purely symptomatic.

By "treating itch" is meant preventing, reducing, or eliminating the sensation of itch in a subject. To treat itch, according to the methods of this invention, the treatment does not necessarily provide therapy for the underlying pathology that is causing the itch. Treatment of itch can be purely symptomatic.

By "an amount sufficient" is meant an amount of an agent administered in a method of the invention required to prevent, reduce, or eliminate the sensation of pain (nociception) or itch. The effective amount of agent used to practice the present invention for therapeutic treatment of pain or itch varies depending upon the manner of administration, the age, and body weight, of the subject as well as the route of administration and underlying pathology that is causing the pain or itch. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as a "sufficient" amount. By "musculoskeletal disorder" is meant an immune system-related disorder of the muscles, ligaments, bones, joints, cartilage, or other connective tissue. Among the most commonly- occurring musculoskeletal disorders are various forms of arthritis, e.g., osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and gout. Other musculoskeletal disorders include acquired hyperostosis syndrome, acromegaly, ankylosing spondylitis, Behcet's disease, bone diseases, bursitis, cartilage diseases, chronic fatigue syndrome, compartment syndromes, congenital hypothyroidism, congenital myopathies, dentigerous cyst, dermatomyositis, diffuse idiopathic skeletal hyperostosis, Dupuytren's contracture, eosinophilia-myalgia syndrome, fasciitis, Felty's syndrome, fibromyalgia, hallux valgus, infectious arthritis, joint diseases, Kabuki make-up syndrome, Legg-Perthes disease, lupus, Lyme disease, Melas syndrome, metabolic bone diseases, mitochondrial myopathies, mixed connective tissue disease, muscular diseases, muscular dystrophies, musculoskeletal abnormalities, musculoskeletal diseases, myositis, myositis ossificans, necrotizing fasciitis, neurogenic arthropathy, osteitis deformans, osteochondritis, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, Paget' s disease, Pierre Robin syndrome, polymyalgia rheumatica, polymyositis, postpoliomyelitis syndrome, pseudogout, psoriatic arthritis, reactive arthritis, Reiter disease, relapsing polychondritis, renal osteodystrophy, rhabdomyolysis, rheumatic diseases, rheumatic fever, scleroderma, Sever' s disease (calceneal apophysitis), Sjogren's syndrome, spinal diseases, spinal stenosis, Still's disease, synovitis, temporomandibular joint disorders, tendinopathy, tennis elbow, tenosynovitis, Tietze's syndrome, and Wegener's granulomatosis.

The term "administration" or "administering" refers to a method of giving a dosage of agent to a patient, where the method is, e.g., topical, oral, nasal, ocular, subcutaneous, intravenous, intraperitoneal, or intramuscular. The preferred method of administration can vary depending on various factors, e.g., the components of the composition being administered, site of the pain or itch, and its severity. The term "injection" refers to bolus or infusion delivery of an agent via needle or cannula, for example, subcutaneously, intravenously, intraperitoneally, or intramuscularly.

As used herein, "topical administration" refers to application of an agent of the invention to the skin of a subject. Topical administration includes transdermal administration, such as by iontophoresis.

A used herein, "local" administration or administration "locally" refers to the delivery of an agent at, or adjacent to, the site of pain or itching, or near part of a nerve transmitting the pain or itching-signal. For example, local administration is typically within about 2 cm or less from the affected nerve ending, preferably within less than about 0.5 cm and most preferably within less than about 2 mm from the ending.

The term "halogenated amine" is a generic term refering to N- chloroamines, N,N-dichloroamines, N-bromoamines, N,N-dibromoamines, N- bromo-N-chloroamines, and/or mixtures thereof (including, e.g., Halo-NR2, HaIo-NHR, N-halogenated amine-bearing polymers, N-halo-amides, N-halo- ureas, and N-halo-sulfonamides). The term "brominated amine" is a generic term refering to N-bromoamines, N,N-dibromoamines, N-bromo-N- chloroamines, and/or mixtures thereof. The term "chlorinated amine" is a generic term refering to N-chloroamines, N,N-dichloroamines, N-bromo-N- chloroamines, and/or mixtures thereof. Throughout this disclosure N,N- dichloro means that two chlorine atoms are nitrogen-bound to the same nitrogen atom and N,N-dibromo- means that two bromine atoms are nitrogen- bound to the same nitrogen atom, except where the compound has two nitrogens for which the two halogen atoms can be bound either to the same nitrogen atom or to different nitrogen atoms. Also, nitrogens of the listed N,N- dibromoamines and N,N-dichloroamines can be bound to one chlorine atom and one bromine atom instead of two chlorine or two bromine atoms to form mixed N-bromo-N-chloroamines. Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims. Brief Description of the Drawings

Figure 1 diagrammatically illustrates a mechanically driven spray bottle of the present invention. In the embodiment shown, the separate amine and hypochlorite anion and/or hypobromite anion sources are kept in separate compartments, 51 and 52, of the spray bottle. A septum 50 divides one compartment from the other. A single screw top opening straddles the two compartments and a spray nozzle 54 is attached. The spray nozzle 54 includes a trigger 55. Actuating the trigger initially pulls and delivers a precise volume of a first reactant from compartment 51 through delivery conduit 56.

Continued actuation of the trigger pulls an equal volume of the second reactant from compartment 52 through delivery conduit 57. In this manner, a single actuation of the trigger consecutively delivers a first and then second reactant through separate delivery ports, 58 and 59, of the nozzle. The reactants combine at the target site to produce N-chlorinated amine or N-brominated amine or a mixture of the two.

Figure 2 diagrammatically illustrates the tip of a two-reservoir system of the invention that includes a mixing chamber. The catheter, shown generally as 220, is a dual-lumen type having lumens 222 and 224. An enclosed reaction chamber 226 serves as a mixing reservoir in which the reactants can react prior to delivery to a subject. A reaction chamber port 228 serves as a point from which N-chlorinated amine and/or N-brominated amine exits the device.

Figure 3 diagrammatically illustrates a two-reservoir dispenser in the form of a double barrel syringe. The double barrel syringe 507 has a first chamber 507a and a second chamber 507b. Preferably, both chambers will be of equal volume for case of determining the final mixture of the N-chlorinated amine and/or N-brominated amine, although double barrel syringes with two chambers of unequal volumes can be used as well. Likewise, multi-chamber syringes may be used for multi-component N-chlorinated amines and/or N- brominated amines. The two chambers 507a and 507b will also preferably contain osmolality-adjusting agents, viscosity-adjusting agents, and/or pH- adjusting agents for both ease and efficiency of mixing and biocompatibility. Preferably, the first chamber 507a will contain hypochlorous acid, or a salt thereof and/or hypobromous acid, or a salt thereof. The contents of the second chamber 507b will include an amine, or a salt thereof. As the plunger 507d of the two-reservoir dispenser 507 is depressed, the contents of the first chamber 507a and the second chamber 507b are forced through a mixing tip 507c where they are mixed to form an N-chlorinated amine and/or N-brominated amine. The syringe optionally includes a needle for injecting the N-chlorinated amine and/or N-brominated amine into a subject. Figure 4 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain. Prior to the carrageenan injection, one of four solutions was injected in the hind paws near the carrageenan-injected site: (1) saline, up-pointing triangles; (2) 0.1 M taurine, diamonds; (3) 0.01 M N-chlorotaurine; down- pointing triangles; and (4) 0.1 M N-chlorotaurin, solid squares. Following carrageenan injection, the rats were hypersensitive to radiant heat from a focused beam of heat. The time interval between the application of the focused heat and the hind paw withdrawal response is defined as the escape latency. The resulting escape latencies were measured every 30 minutes post carrageenan injection. As seen in Figure 4, the 0.1 M N-chlorotaurine injection made the paw insensitive to pain. For example, the escape latency at 60 min was about 12 s, similar to or longer than the about 10 sec escape latency in the paw prior to the carrageenan injection. When saline water or when 0.1 M taurine were injected, the escape latency at 60 min dropped to about 4 sec; there was a small, but still measurable, pain-desensization also when the 0.01 M N-chlorotaurine was injected, the escape latency being about 7 sec.

Figure 5 is is a graph depicting the the elimination of pain- hypersensitivity caused by thermal injury. Following thermal injury, the rats were hypersensitive to radiant heat from a focused beam of heat. The time interval between the application of the focused heat and the hind paw withdrawal response is defined as the escape latency. One of four solutions was injected in the hind paws: (1) saline, open squares; (2) 0.1 M N- chlorotaurine, closed cirlces; (3) 0.3 M N-chlorotaurine; up-pointing triangles; and (4) 1 M N-chlorotaurin, solid squares. As is seen in the top part of Figure

5, the injection of N-chlorotaurine at t=0 min increased the escape latency in an N-chlorotaurine dose-dependent manner relative to the escape latency for the water- injected paw. The bottom part of Figure 5 shows the integrated areas onder or above the 10 sec escape latency line, 10 s being the escape latency for the uninjured paw, the integrated area being the interval between the thermal injury and t=120 min. The increase in escape latency is greatest for 1 M NCT (N-chlorotaurine), followed by 0.3 M NCT, followed by 0.1 M NCT, which also increased the withdrawal latency relative to the escape latency of the water- injected paw, demonstrating that the hypersensitivity to pain following thermal injury decreased when the dose of injected N-chlorotaurine was increased. Figure 6 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain. Prior to the carrageenan injection, one of four solutions was injected in the hind paws near the carrageenan-injected site: (1) saline, up-pointing triangles; (2) 0.1 M N-chlorotaurine, diamonds; (3) 0.3 M N-chlorotaurine; down-pointing triangles; and (4) 1 M N-chlorotaurin, solid squares. The resulting escape latencies were measured every 30 minutes post carrageenan injection. Unlike the N-chlorotaurine solutions used in the experiments of Figure 4, the solution used in the experiments used in Figure 6 was not fresh and because of partial decomposition of the N-chlorotaurine, contained less N- chlorotaurine then the nominal concentrations shown at the top right of Figure

6. The bottom part of Figure 6 shows the integrated areas onder or above the 10 sec escape latency line, 10 s being the escape latency for the uninjured paw, the integrated area being the interval between the thermal injury and t=360 min. The potency of N-chlorotaurine in eliminating or decreasing the carrageenan-caused pain hypersensensitivity decreases from the nominally 1 M solution of N-chlorotaurine to the nominally 0.3 M solution of N-chlorotaurine to the nominally 0.1 M solution of N-chlorotaurine.

Figure 7 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain. Prior to the carrageenan injection, one of three solutions was injected in the hind paws near the carrageenan- injected site: (1) 0.018 M N- bromotaurine, diamonds; (2) 0.06 M N-bromotaurine, down-pointing triangles; and (3) 0.18 M N-bromotaurine; solid squares. Significantly, the 10 s escape latency for the uninjured paw is increased to about 14 s, for 0.18 M N- bromotaurine, showing that the N-bromotaurine desensitizes the carrageenan injured paw less even relative to the uninjured paw (data not shown). The bottom part of Figure 7 shows the integrated areas under or above the 10 sec escape latency line, 10 s being the escape latency for the uninjured paw, the integrated area being the interval between the carrageenan-injection and t=l 80 min. At 0.06 M concentration, the N-bromotaurine is still reduces carrageenan-injection caused sensitivity to pain and that at 0.018 M concentration N-bromotaurine still has some beneficial effect.

Figure 8 is a graph depicting the heat pain thresholds in UV-B light injured skin (Pre-Injured), and in injured skin before (Pre-NCT), and 30min (Post-NCT 30min) and 90min (Post-NCT 90min) after NCT (right column) or placebo (left column) injection as described in Example 4. Experimental UV-B caused inflammation of the skin resulted in marked heat hyperalgesia as indicated by a decrease in heat (-4.2⁰C) pain threshold. NCT but not placebo exerted robust anti-hyperalgesic effects to heat (+2.8 ⁰C) stimulation 30 minutes after injection. NCT-mediated antihyperalgesic effects were likely present but attenuated for heat stimulation (+0.8 ⁰C) 90 minutes after injection. Figure 9 is a graph depicting the mechanical pain thresholds in non- UV- B light injured skin (Pre-Injured), and in UV-B light injured skin before (Pre- NCT), and 30min (Post-NCT 30min) and 90min (Post-NCT 90min) after NCT (right column) or placebo (left column) injection as described in Example 4. Experimental inflammation of the skin resulted in marked mechanical hyperalgesia as indicated by a decrease in mechanical (-3Og) pain threshold. NCT but not placebo exerted robust anti-hyperalgesic effects to mechanical (+45g) stimulation 30 minutes after injection. NCT-mediated antihyperalgesic effects were maintained for mechanical stimulation (+45g).

Detailed Description

We have discovered that N-chlorinated amines, such as chloramine, and N-brominated amines, N-bromo-N-chloroamines, and their mixtures can be used to relieve pain and itch.

N-Chlorinated Amines

The methods, kits, and compositions of the invention can include one or more N-chloroamines. The term "N-chloroamine" is a generic term meaning N-monochloro-compounds (e.g., Cl-NR₂, Cl-NHR, N-chlorinated amine- bearing polymers, N-chloro-amides, N-chloro-ureas, and N-chloro- sulfonamides). The term "N-dichloroamine" is a generic term meaning N₅N- dichloro-compounds (e.g., Cl₂-NR). The N-chlorinated amines of this disclosure are oxidants, for example, of glutathione in vivo and are useful for the treatment of pain and itch. The invention can be carried out using chlorinated simple amines, such as ammonia, methylamine, or ethylamine, or amines which in their unchlorinated form have additional therapeutic utility, such as an analgesic (e.g., N-chloro-lidocaine, desethyl-N-chloro-lidocaine, N- chloro-prilocaine, N-chloro-tocainide, desethyl-N-chloro-etidocaine, desbutyl- N-chloro-ropivacaine, desbutyl-N-chloro-bupivacaine, desbutyl-N-chloro- levobupivacaine, desmethyl-N-chloro-mepivacaine, desethyl-N-chloro- procaine, desethyl-N-chloro-proparacaine, desethyl-N-chloro-allocain, desmethyl-N-chloro-encainide, desethyl-N-chloro-procainamide, desethyl-N- chloro-metoclopramide, desmethyl-N-chloro-stovaine, desethyl-N-chloro- propoxycaine, desethyl-N-chloro-chloroprocaine, N-chloro-flecainide, desethyl-N-chloro-tetracaine, N-chloro-procaine, N-chloro-proparacaine, N- chloro-procainamide, N-chloro-metoclopramide, N-chloro-propoxycaine, N- chloro-chloroprocaine, N-chloro-tetracaine, N-chloro-benzocaine, N-chloro- butamben, and desethyl-N-chloro-dibucaine); tricylic antidepressant (e.g., N- chloro-amoxapine, desmethyl-N-chloro-trimipramine, desmethyl-N-chloro- dothiepin, desmethyl-N-chloro-doxepin, desmethyl-N-chloro-amitriptyline, N- chloro-protriptyline, N-chloro-desipramine, desmethyl-N-chloro-clomipramine, desmethyl-N-chloro-clozapine, desmethyl-N-chloro-loxapine, N-chloro- nortriptyline, desmethyl-N-chloro-cyclobenzaprine, desmethyl-N-chloro- cyproheptadine, desmethyl-N-chloro-olopatadine, desmethyl-N-chloro- promethazine, desmethyl-N-chloro-trimeprazine, desmethyl-N-chloro- chlorprothixene. desmethyl-N-chloro-chlorpromazine, desmethyl-N-chloro- propiomazine, desmethyl-N-chloro-prochlorperazine, desmethyl-N-chloro- thiethylperazine, desmethyl-N-chloro-trifluoperazine, desethyl-N-chloro- cthacizine, or desmethyl-N-chloro-imipramine), or stimulant (e.g., N-chloro- amphetamine, N,N-dichloro-amphetamine, or N-chloro-methamphetamine). Other N-chlorinated amines that can be used in the methods, compositions, and kits of the invention are described below.

N-Monochloroamines

Exemplary N-monochloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, chloramine, chlorourea, N-chloro-methylamine, N-chloro-ethylamine, N-chloro- isobutylamine, N-chloro-2-methylbutylamine, N-chloro-pyrrolidine, N-chloro- phenethyl amine, N-chloro-agmatine, N-chloro-histamine, N-chloro-tryptamine, N-chloro-3-methylthiopropanamine, N-chloro-spermine, N-chloro-carnosine, N-chloro-carcinine, chloramine T, chloramine B, N-chloro-glutathione sulfonamide, N-chloroglycine, N-chlorosulfamic acid, N-chlorosarcosine, N- chloro-alpha-aminoisobutyric acid, N-chlorotaurine, N-chlorotaurine ethyl ester, N-chlorotaurine sulfonamide, N-chloro-2-aminoethanol, N-chloro- acetylglycine, N-chloroalanine, N-chloro-beta- alanine, N-chloroserine, N- chloro-phenyl alanine, N-chloro-norvaline, N-chloroleucine, N-chloro- isoleucine, N-chloroproline, N-chloro-hydroxyproline, N-chloro-omega aminoundccanoic acid, N-chloroaspartic acid, N-chloroglutamic acid, N- chloroasparagine, N-chlorovaline, N-chlorothreonine, N-chlorocystine, N- chloromethionine, N-chloroglutamine, N-chlorotryptophane, N-chlorohistidine, N-chloroarginine, N-chlorolysine (alpha or omega), N-chloro-alpha- aminobutyric acid, N-chloro-gamma-aminobutyric acid, N-chloro-alpha, epsilon diamino pimelic acid, N-chloro-ornithine, N-chloro-hydroxylysine (alpha or omega), N-chloroanthranilic acid, N-chloro-p-aminobenzoic acid, N- chlorosulfanilic acid, N-chloro-orthanilic acid, N-chloro-phenyl sulfamic acid, N-chloroaminopropanesulfonic acid, N-chloro-2-aminopropanol, N-chloro- diethanolamine, N-chloro-ethylenediamine tetraacetic acid, N-chloro- aminomethane-sulfonic, N-chloro-glycylglycine, N-chloro- glycylglycylglycine, N-chloro-metanilic acid, N-chloro ethanesulfonic acid, N- chloro-1 -methyl ethanesulfonic acid, N-chloro-2-methyltaurinc, N-chloro-2- methyl-2-amino-ethanesulfonic acid, N-chloro aminotrimethylene phosphonic acid, N-chloro-2-amino-5-phosphonopentanoic acid, N-chloro aminoethylphosponic acid, N-chloro- 1 -amino- 1-methylethane phosphonic acid, N-chloro- l-amino-2-methylethane phosphonic acid, N-chloro- l-amino-2- methylpropane phosphonic acid, N-chloroleucine phosphonic acid, N-chloro-4- amino-4-phosphonobutyric acid, N-chloro-2-amino-5-phosphonovaleric acid, N-chloro-2-amino-5-phosphonovaleric acid, N-chloro-2-amino-8- phosphonooctanoic acid, N-chloroleucine boronic acid, N-chloro- β-alanine boronic acid, and N-chloro-N-octodecanyl glycine.

Exemplary N-chloro-sulfonamides that can be used in the methods, kits, and compositions of the invention include, without limitation, N-chloro- glutathione sulfonamide, Chloramine-B and Chloramine-T. N-chloro- sulfonamides can be used in their un-ionized and anionic forms. When anionic, it can be the free anion, or a salt, such as a Li⁺, Na⁺, K⁺, Ca²⁺, Mg²⁺, or Zn²⁺ salt. Chlorinated Amine Polymers

The methods, kits, and compositions of the invention can include one or more N-chlorinated amine-bearing polymers. Exemplary chlorinated polymers which can be used in the methods, kits, and compositions of the invention include, without limitation, N-chlorinated chitosan, N-chlorinated deacetylated hyaluronic acid, N-chlorinated amino-cellulose, and N-chlorinated polylysine. N-chlorinated amine-bearing polymers can be prepared using methods analogous to those described in U.S. Patent No. 5,773,608, incorporated herein by reference.

N-Dichloroamines

The methods, kits, and compositions of the invention can include one or more N,N-dichloroamines. Exemplary N-chloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, dichloramine, N,N-dichloro-methylamine, N,N-dichloro-ethylamine, N₅N- dichloro-isobutylamine, N,N-dichloro-2-methylbutylamine, N,N-dichloro- phenethylamine, N,N-dichloro-agmatine, N,N-dichloro-histamine, N₅N- dichloro-tryptamine, N,N-dichloro-3-methylthiopropanamine, N,N-dichloro- spermine, N,N-dichloro-carnosine, N,N-dichloro-carcinine, N₅N- dichloroglycine, N,N-dichloro-alpha-aminoisobutyric acid, N₅N- dichlorotaurine, N,N-dichlorotaurine ethyl ester, N,N-dichlorotaurine sulfonamide, N,N-dichloro-2-aminoethanol, N,N-dichloroalanine, N₅N- dichloro-beta-alaninc, N,N-dichloroserine, N.N-dichloro-phenyl alanine, N₅N- dichloro-norvaline, N,N-dichloroleucine, N,N-dichloro-isoleucine, N₅N- dichloroproline, N,N-dichloro-hydroxyproline, N,N-dichloro-omega aminoundecanoic acid, N,N-dichloroaspartic acid, N,N-dichloroglutamic acid, N,N-dichloroasparagine, N,N-dichlorovaline, N,N-dichlorothreonine, N₅N- dichloromethionine, N₅N-dichloroglutamine, N,N-dichlorotryptophane, N₅N- dichloroarginine, N,N-dichlorolysine (alpha or omega) or N(alpha)-N- (omega)dichlorolysine, N,N-dichloro-alpha-aminobutyric acid. N,N-dichloro- gamma-aminobutyric acid, N,N-dichloro-alpha, epsilon diamino pimelic acid, N,N-dichloro-ornithine, N,N-dichloro-hydroxylysine (alpha or omega), N₅N- dichloro-2-aminopropanol, N,N-dichloro ethanesulfonic acid, N,N-dichloro-l- methyl ethanesulfonic acid, N,N-dichloro-2-methyltaurine, N,N-dichloro-2- methyl-2-amino-ethanesulfonic acid, N,N-dichloro aminotrimethylene phosphonic acid, N,N-dichloro-2-amino-5-phosphonopentanoic acid, N₅N- dichloro aminoethylphosponic acid, N,N-dichloro-l -amino- 1 -methylethane phosphonic acid, N,N-dichloro-l-amino-2-methylethane phosphonic acid, N₅N- dichloro-l-amino-2-methylpropane phosphonic acid, N,N-dichloroleucine phosphonic acid, N,N-dichloro-4-amino-4-phosphonobutyric acid. N₅N- dichloro-2-amino-5-phosphonovaleric acid, N,N-dichloro-2-amino-5- phosphonovaleric acid, N,N-dichloro-2-amino-8-phosphonooctanoic acid, N,N- dichloroleucine boronic acid, N,N-dichloro-β-alanine boronic acid, and N₅N- dichloro-diethanolamine.

N-Bromo-N-Chloroamines

The methods, kits, and compositions of the invention can include one or more N-bromo-N-chloroamines. Exemplary N-bromo-N-chloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, N-bromo-N-chloramine, N-bromo-N-chloro-methylamine, N-bromo-N-chloro-ethylamine, N-bromo-N-chloro-isobutylamine, N-bromo- N-chloro-2-methylbutylamine, N-bromo-N-chloro-phenethylamine, N-bromo- N-chloro-agmatine, N-bromo-N-chloro-histamine, N-bromo-N-chloro- tryptamine, N-bromo-N-chloro-3 -methy lthiopropanamine, N-bromo-N-chloro- spermine, N-bromo-N-chloro-carnosine, N-bromo-N-chloro-carcinine, N- bromo-N-chloroglycine, N-bromo-N-chloro-alpha-aminoisobutyric acid, N- bromo-N-chlorotaurine, N-bromo-N-chlorotaurine ethyl ester, N-bromo-N- chlorotaurine sulfonamide, N-bromo-N-chloro-2-aminoethanol, N-bromo-N- chloroalanine, N-bromo-N-chloro-beta-alanine, N-bromo-N-chloroserine, N- bromo-N-chloro-phenyl alanine, N-bromo-N-chloro-norvaline, N-bromo-N- chloroleucine, N-bromo-N-chloro-isoleucine, N-bromo-N-chloroproline, N- bromo-N-chloro-hydroxyproline, N-bromo-N-chloro-omega aminoundecanoic acid, N-bromo-N-chloroaspartic acid, N-bromo-N-chloroglutamic acid, N- bromo-N-chloroasparagine, N-bromo-N-chlorovaline, N-bromo-N- chlorothreonine, N-bromo-N-chloromethionine, N-bromo-N-chloroglutamine, N-bromo-N-chlorotryptophane, N-bromo-N-chloroarginine, N-bromo-N- chlorolysine, N-bromo-N-chloro-alpha-aminobutyric acid, N-bromo-N-chloro- gamma-aminobutyric acid, N-bromo-N-chloro-alpha, epsilon diamino pimelic acid, N-bromo-N-chloro-omithine, either N-bromo-N-chloro-hydroxylysine, N-bromo-N-chloro-2-aminopropanol, N-bromo-N-chloro ethanesulfonic acid, N-bromo-N-chloro-1 -methyl ethanesulfonic acid, N-bromo-N-chloro-2- methyltaurine, N-bromo-N-chloro-2-methyl-2-amino-ethanesulfonic acid, N- bromo-N-chloro aminotrimethylene phosphonic acid, N-bromo-N-chloro-2- amino-5-phosphonopentanoic acid, N-bromo-N-chloro aminoethylphosponic acid, N-bromo-N-chloro-1 -amino- 1-methylethane phosphonic acid, N-bromo- N-chloro- l-amino-2-methylethane phosphonic acid, N-bromo-N-chloro- 1- amino-2-methylpropane phosphonic acid, N-bromo-N-chloroleucine phosphonic acid, N-bromo-N-chloro-4-amino-4-phosphonobutyric acid, N- bromo-N-chloro-2-amino-5-phosphonovaleric acid, N-bromo-N-chloro-2- amino-5-phosphonovaleric acid, N-bromo-N-chloro-2-amino-8- phosphonooctanoic acid, N-bromo-N-chloroleucine boronic acid, N-bromo-N- chloro-β-alanine boronic acid, and N-bromo-N-chloro-diethanolamine.

Preparation of N-halogenated amines

Halogenated amines can be prepared by the reaction of the amine with a halogen source under reaction conditions which lead to the replacement of one or two hydrogen atoms at the amino nitrogen with halogen atoms. Such reactions are known to chemists skilled in the art. For example, the following halogen sources, without limitation, may be used to produce the N,N-dihalo- amines: HOCl or HOBr or their salts (for example, NaOCl, NaOBr, KOBr or KOCl), N-haloarylsulfonamide salts (i.e., N-halo-4-alkylbenzenesulfonamide); N-halo-succinimide, Cl₂, and related halogenating agents. In a typical reaction, the amine is dissolved in an aqueous buffer. To this solution an aqueous NaOCl solution is added. The production of N-halo- versus N,N-dihalo- derivatives can be controlled by the relative stoichiometry the amine and halogenating agent. N-bromo-N-chloroamines can be prepared, for example, as described in Haag, Werner R. Journal of Inorganic and Nuclear Chemistry 42:1123 ((1980).

Preparation of N-chlorinated amines

Chlorinated amines can be prepared by the reaction of the amine with a chlorine source under reaction conditions which lead to the replacement of one or two hydrogen atoms at the amino nitrogen with chlorine atoms. Such reactions are known to chemists skilled in the art. For example, the following chlorine sources, without limitation, may be used to produce the N₅N- dichloroamines: HOCl or its salts (for example, NaOCl or KOCl), N- chloroarylsulfonamide salts (i.e., N-chloro-4-alkylbenzenesulfonamide); N- chloro-succinimide, Cl₂, and related chlorinating agents. In a typical reaction, the amine is dissolved in an aqueous buffer. To this solution an aqueous NaOCl solution is added. The production of N-chloro-versus N,N-dichloro- derivatives can be controlled by the relative stoichiometry the amine and chlorinating agent. For additional experimental protocols see, for example, Marcinkiewicz et al., J. of Inflammatory Research 49:280 (2000); Chinake et al., Phys. Chem. Chem. Phys. 3:4957 (2001); Martincigh et al., J. Phys. Chem. A. 102:9838 (1998), and U.S. Patent No. 3,932,605, each of which is incorporated herein by reference. The N-brominated amines described herein can be prepared using analogous methods.

N-Brominated Amines

The methods, kits, and compositions of the invention can include one or more N-bromoamines. The term "N-bromoamine" is a generic term meaning N-monobromo-compounds (e.g., Br-NR₂, Br-NHR, N-brominated amine- bearing polymers, N-bromo-amides, N-bromo-ureas, and N-bromo- sulfonamides). The term "N-dibromoamine" is a generic term meaning N₅N- dibromo-compounds (e.g., Br₂-NR). The N-brominated amines of this disclosure are oxidants, for example, of glutathione in vivo and are useful for the treatment of pain and itch. The invention can be carried out using brominated simple amines, such as ammonia, methylamine, or ethylamine, or amines which in their unbrominated form have additional therapeutic utility, such as an analgesic (e.g., N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N- bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl- N-bromo-ropivacaine, desbutyl-N-bromo-bupivacaine, desbutyl-N-bromo- levobupivacaine, desmethyl-N-bromo-mepivacaine, desethyl-N-bromo- procaine, desethyl-N-bromo-proparacaine, desethyl-N-bromo-allocain, desmethyl-N-bromo-encainide, desethyl-N-bromo-procainamide, desethyl-N- bromo-metoclopramide, desmethyl-N-bromo-stovaine, desethyl-N-bromo- propoxycaine, desethyl-N-bromo-bromoprocaine, N-bromo-flecainide, desethyl-N-bromo-tetracaine, N-bromo-procaine, N-bromo-proparacaine, N- bromo-procainamide, N-bromo-metoclopramide, N-bromo-propoxycaine, N- bromo-bromoprocaine, N-bromo-tetracaine, N-bromo-benzocaine, N-bromo- butamben, and desethyl-N-bromo-dibucaine); tricylic antidepressant (e.g., N- bromo-amoxapine, desmethyl-N-bromo-trimipramine, desmethyl-N-bromo- dothiepin, desmethyl-N-bromo-doxepin, desmethyl-N-bromo-amitriptyline, N- bromo-protriptyline, N-bromo-desipramine, desmethyl-N-bromo- clomipramine, desmethyl-N-bromo-clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptyline, desmethyl-N-bromo-cyclobenzaprine, desmethyl-N- bromo-cyproheptadinc, dcsmethyl-N-bromo-olopatadine, desmethyl-N-bromo- promethazine, desmethyl-N-bromo-trimeprazine, desmethyl-N-bromo- chlorprothixene, desmethyl-N-bromo-chlorpromazine, desmethyl-N-bromo- propiomazine, desmethyl-N-bromo-prochlorperazine, desmethyl-N-bromo- thiethylperazine, desmethyl-N-bromo-trifluoperazine, desethyl-N-bromo- ethacizine, or desmethyl-N-bromo-imipramine), or stimulant (e.g., N-bromo- amphetamine, N,N-dibromo-amphetamine, or N-bromo-methamphetamine). Other N-brominated amines that can be used in the methods, compositions, and kits of the invention are described below. N-Monobromoamines

Exemplary N-bromoamines that can be used in the methods, kits, and compositions of the invention include, without limitation, bromamine, bromourea, N-bromo-methylamine, N-bromo-ethylamine, N-bromo- isobutylamine, N-bromo-2-methylbutylamine, N-bromo-pyrrolidine, N-bromo- phenethylamine, N-bromo-agmatine, N-bromo-histamine, N-bromo- tryptamine, N-bromo-3-methylthiopropanamine, N-bromo-spermine, N-bromo- carnosine, N-bromo-carcinine, N-bromo- glutathione sulfonamide, N- bromoglycine, N-bromosulfamic acid, N-bromosarcosine, N-bromo-alpha- aminoisobutyric acid, N-bromotaurine, N-bromotaurine ethyl ester, N- bromotaurine sulfonamide, N-bromo-2-aminoethanol, N-bromo-acetyl glycine, N-bromoalanine, N-bromo-beta-alaninc, N-bromoserine, N-bromo-phenyl alanine, N-bromo-norvaline, N-bromoleucine, N-bromo-isoleucine, N- bromoproline, N-bromo-hydroxyproline, N-bromo-omega aminoundecanoic acid, N-bromoaspartic acid, N-bromoglutamic acid, N-bromoasparagine, N- bromovaline, N-bromothreonine, N-bromocystine, N-bromomethionine, N- bromoglutamine, N-bromotryptophane, N-bromohistidine, N-bromoarginine, N-bromolysine (alpha or omega), N-bromo-alpha-aminobutyric acid, N-bromo- gamma-aminobutyric acid, N-bromo-alpha, epsilon diamino pimelic acid, N- bromo- ornithine, N-bromo-hydroxylysine (alpha or omega), N- bromoanthranilic acid, N-bromo-p-aminobenzoic acid, N-bromosulfanilic acid, N-bromo-orthanilic acid, N-bromo-phenyl sulfamic acid, N- bromoaminopropanesulfonic acid, N-bromo-2-aminopropanol, N-bromo- diethanolamine, N-bromo-ethylenediamine tetraacetic acid, N-bromo- aminomethane-sulfonic, N-bromo-glycylglycine, N-bromo- glycylglycylglycine, N-bromo-metanilic acid, N-bromo-2,2-dimethyltaurine, N-bromo- 1,1,2,2-tetramethyltaurine, N-bromo-2,2,3,3-tetramcthyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N-bromo ethanesulfonic acid, N-bromo- 1- methyl ethanesulfonic acid, N-bromo-2-methyltaurine, N-bromo-2-methyl-2- amino-ethancsulfonic acid, N-bromo aminotrimethylene phosphonic acid, N- bromo^-amino-S-phosphonopentanoic acid, N-bromo aminoethylphosponic acid, N-bromo- 1 -amino- 1-methylethane phosphonic acid, N-bromo- l-amino-2- methylethane phosphonic acid, N-bromo- l-amino-2-methylpropane phosphonic acid, N-bromoleucine phosphonic acid, N-bromo-4-amino-4- phosphonobutyric acid, N-bromo-2-amino-5-phosphonovaleric acid, N-bromo- 2-amino-5-phosphonovaleric acid, N-bromo-2-amino-8-phosphonooctanoic acid, N-bromoleucine boronic acid, N-bromo-β-alanine boronic acid, and N- bromo-N-octodecanyl glycine.

Exemplary N-bromo-sulfonamides that can be used in the methods, kits, and compositions of the invention include, without limitation, N-bromo- glutathione sulfonamide. N-bromo-sulfonamides can be used in their unionized and anionic forms. When anionic, it can be the free anion, or a salt, such as a Li⁺, Na⁺, K⁺, Ca²⁺, Mg²⁺, or Zn²⁺ salt.

Brominated Amine Polymers

The methods, kits, and compositions of the invention can include one or more N-brominated amine-bearing polymers. Exemplary brominated polymers which can be used in the methods, kits, and compositions of the invention include, without limitation, N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N-brominated amino-cellulose, and N-brominated polylysine. N-brominated amine-bearing polymers can be prepared using methods analogous to those described in U.S. Patent No. 5,773,608, incorporated herein by reference.

N-Dibromoamines

The methods, kits, and compositions of the invention can include one or more N,N-dibromoamines. Exemplary N-bromoamines that can be used in the methods, kits, and compositions of the invention include, without limitation, N,N-dibromo-methyl amine, N,N-dibromo-ethylamine, N,N-dibromo- isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo- phenethylamine, N,N-dibromo-agmatine, N,N-dibromo-histamine, N,N- dibromo-tryptamine, N,N-dibromo-3 -methylthiopropanamine, N,N-dibromo- spermine, N,N-dibromo-carnosine, N,N-dibromo-carcinine, N₅N- dibromoglycine, N,N-dibromo-alpha-aminoisobutyric acid, N₅N- dibromotaurine, N,N-dibromotaurine ethyl ester, N,N-dibromotaurine sulfonamide, N,N-dibromo-2-aminoethanol, N,N-dibromoalanine, N₅N- dibromo-beta-alanine, N,N-dibromoserine, N,N-dibromo-phenyl alanine, N₅N- dibromo-norvaline, N,N-dibromoleucine, N,N-dibromo-isoleucine, N₅N- dibromoproline, N,N-dibromo-hydroxyproline, N,N-dibromo-omega aminoundecanoic acid, N,N-dibromoaspartic acid, N,N-dibromoglutamic acid, N,N-dibromoasparagine, N,N-dibromovaline, N,N-dibromothreonine, N₅N- dibromomethionine, N,N-dibromoglutamine, N,N-dibromotryptophane, N₅N- dibromoarginine, N,N-dibromolysine (alpha or omega), N,N-dibromo-alpha- aminobutyric acid, N,N-dibromo-gamma-aminobutyric acid, N,N-dibromo- alpha, epsilon diamino pimelic acid, N,N-dibromo-ornithine, N,N-dibromo- hydroxy lysine (alpha or omega), N,N-dibromo-2-aminopropanol, N₅N- dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2-tetramethyltaurine, N₅N- dibromo-2,2,3,3-tetramethyl-β-alanine, N,N-dibromo-3,3- dimethylhomotaurine, N,N-dibromo ethanesulfonic acid, N,N-dibromo-l- methyl ethanesulfonic acid, N,N-dibromo-2-methyl-2-amino-ethanesulfonic acid, N,N-dibromo aminotrimethylene phosphonic acid, N,N-dibromo-2- amino-5-phosphonopentanoic acid, N,N-dibromo aminoethylphosponic acid diesters, such as the diethylester, N,N-dibromo-l -amino- 1-methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylpropane phosphonic acid, N,N-dibromoleucine phosphonic acid, N,N-dibromo-4-amino-4-phosphonobutyric acid, N₅N- dibromo-2- amino- 5 -phosphonoval eric acid, N,N-dibromo-2-amino-5- phosphonovaleric acid, N,N-dibromo-2-amino-8-phosphonooctanoic acid, N,N-dibromoleucine boronic acid, N,N-dibromo-β-alanine boronic acid, and N,N-dibromo-diethanolamine. Therapy and Formulation

The agents of the invention, N-chloroamines, N,N-dichloroamines, N- bromoamines, N,N-dibromoamines, N-bromo-N-chloroamines, and mixtures thereof may be administered by any appropriate route for treatment of pain or itch. The administered agents can also be the paired reactive precursors of the N-chloroamines, N,N-dichloroamines, N-bromoamines or N₅N- dibromoamines. The N-halocompounds are formed in situ, from the precursor pair consisting of the chlorine or bromine source and the amine, the precursors being generally more stable and longer-lived than the N-chloroamines, N₅N- dichloroamines, N-bromoamines or N,N-dibromoamines. The agents, or their reactive precursor pairs, may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.

Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, ear drops, or aerosols.

Methods well known in the art for making formulations are found, for example, in "Remington: The Science and Practice of Pharmacy" (20th ed., ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins). Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration. The agents may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, malic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metal complexes include zinc, iron, and the like.

Administration of compounds in controlled release formulations is useful where the compound of formula I has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD₅₀) to median effective dose (ED₅₀)); (ii) a narrow absorption window in the gastro- intestinal tract; or (iii) a short biological half- life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.

Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). In accordance with the methods, kits, and compositions of the invention, agents can be infused into a patient using an infusion pump system. For example, skin-adhered infusion delivery systems which can be used include, without limitation, the pump systems described in U.S. Patent Nos. 7,303,549; 7,303,543; 7,300,419; 7,297,138; 7,144,384; 7,070,580; 7,029,455; 7,018,360; 7,014,625; 6,960,192; 6,830,558; 6,768,425; 6,749,587; 6,740,059; 6,702,779; 6,699,218; 6,692,457; 6,669,669; 6,656, 159; 6,656,158; 6,589,229; 6,520,938; 6,485,461; 6,475,196; 6,056,718 and 5,997,501, each of which is incorporated herein by reference. Existing insulin infusion pumps can be used to deliver an agent to a patient. Insulet Corporation of Bedford, MA manufactures and sells OmniPod, a small, lightweight self-adhesive insulin pod that the user fills with insulin and wears directly on the body for up to three days and then replaces. The OmniPod delivers precise, personalized doses of insulin into the body through a small subcutaneously inserted flexible cannula. The company also sells a wireless, handheld device that programs the OmniPod with the user's personalized insulin delivery instructions, wirelessly monitors the OmniPod's operation and incorporates a calibration device. The insulin solution typically employed with these devices can be replaced with an agent of the invention to deliver pain relief at the site of infusion. The dose-rate of agent is between about 10^"9 moles per hour and about 10^"4 moles per hour, preferably between about 10^" moles per hour and about 10^" moles per hour. To relieve pain or itch a preferably aqueous solution or a gel including an agent of the invention is applied topically, for example in a dressing. The concentration of the agent in the solution or gel of the dressing is generally higher than about 0.1 mM and less than about 0.1 M. Preferably, it is higher than about 1 mM and is less than about 30 mM. Where the agent of the invention is gaseous, the dressing has a flexible shell that reduces at least tenfold, preferably one hundred fold, the out diffusion of gases other than hydrogen, for example of oxygen, chlorine, or chloramine. The shell can be adhered to the skin at its edges to form an adequately gas-tight seal slowing the leakage of the volatile agent. The shell can be made of a metallized, for example aluminized, plastic; or it can be made of a plastic through which gases permeate slowly, including, for example, polyvinylidene chloride, used in Saran™ wrap to retard evaporation of water and other volatile components of food. In certain embodiments, the agents of the invention are adsorbed onto dry carrier particles, such as particles of talcum or zinc oxide, for gradual release when applied topically. In general the weight percentage of the adsorbed agent is at least about 0.01 wt % and is less than about 10 wt %; it is preferably at least about 0.1 wt % and is less than about 2 wt %. In general the weight percentage of the chemisorbed oxidant is at least about 0.01 wt % and is less than about 10 wt %; it is preferably at least about 0.1 wt % and is less than about 2 wt %.

The agents of the invention can also be delivered topically by iontophoresis. Iontophoresis is a needle-free, non-invasive technology for delivering bioactive agents through the skin using a small electric current to apply an electromotive force that transports ions through the stratum corneum, the outermost layer of skin, and into the dermis, the inner layer of skin that is comprised of connective tissue, blood and lymph vessels, sweat glands, hair follicles and an elaborate sensory nerve network. Two-Reservoir Systems

The hypochlorous acid, or a salt thereof, and/or the hypobromous acid, or a salt thereof, can be contained in a first reservoir to be reacted with an amine, or a salt thereof, contained in a second reservoir. Release from the two reservoirs can be controlled in a variety of way s. For example, the two- reservoir system can be a two-reservoir spray bottle or a dual-barrel syringe. These can be sold as kits containing solids (e.g., an ammonium salt or hypochlorite salt) to be reconstituted just prior to use. Alternatively, the kits can include solutions (e.g., hypochlorite solution and ammonium salt solution), which can be used without reconstitution. Rapid reaction of the hypohalous acid, e.g., hypochlorous acid, or a salt thereof, with the amine produces an N- halogenated, e.g., N-chlorinated amine upon mixing.

Hypobromous acid and its salts can be conveniently prepared in-situ by reacting a bromide, such as NaBr or KBr with the hypochlorous acid, or its salt, by co-dissolving the two.

Single-Reservoir Systems

Where the agents of the invention have a short half-life, the agent can be prepared just prior to administration. For example, a dry powder including an ammonium salt and hypochlorite salt can be mixed with water to produce an N- chloroamine just prior to use. Alternatively, an ammonium salt and hypobromite salt can be mixed with water to produce an N-bromoamine just prior to use.

Indications

The methods, compositions, and kits of the invention are useful for treating pain, including clinical pain, namely inflammatory pain, functional pain, nociceptive pain, and neuropathic pain (e.g., peripheral neuropathic pain), whether acute or chronic (e.g., pain lasting for greater than one, two, three, four, or more months). Conditions that may be associated with pain include, for example, soft tissue, joint, bone inflammation and/or damage (e.g., acute trauma, osteoarthritis, or rheumatoid arthritis), myofascial pain syndromes (fibromylagia), headaches (including cluster headache, migraine and tension type headache), neurodegenerative disorders (i.e., particularly those leading to nerve demyelination), stump pain, myocardial infarction, angina, ischemic cardiovascular disease, post-stroke pain, sickle cell anemia, peripheral vascular occlusive disease, cancer, inflammatory conditions of the skin or joints, diabetic neuropathy, and acute tissue damage from surgery or traumatic injury (e.g., lacerations or fractures). The present invention is also useful for the treatment, reduction, or prevention of musculo-skeletal pain (after trauma or exercise), neuropathic pain caused by spinal cord injury, tumors, compression, inflammation, dental pain, episiotomy pain, deep and visceral pain (e.g., heart pain, bladder pain, or pelvic organ pain), muscle pain, eye pain, orofacial pain (e.g., odontalgia, trigeminal neuralgia, glossopharyngeal neuralgia), abdominal pain, gynecological pain (e.g., dysmenorrhea and labor pain), pain associated with nerve and root damage due to trauma, compression, inflammation, toxic chemicals, metabolic disorders, hereditary conditions, vasculitis and autoimmune diseases, central nervous system pain, such as pain due to spinal cord or brain stem damage, cerebrovascular accidents, tumors, infections, demyelinating diseases including multiple sclerosis, chronic lower back pain (e.g., ankylosing spondylitis, degenerative disk disease, radiculopathy, and radicular pain), sciatica, chronic neck pain, and post-operative pain (e.g., mastectomy, orthopedic and phantom limb pain). The present invention is also useful for treating pain associated with post-herpetic neuralgia, cancer, cystic fibrosis, HIV, and polymyalgia rheumatica. The methods, compositions, and kits of the invention can be used to treat pain associated with any of a number of conditions, including back and neck pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis and other rheumatological pains, orthopedic pains, post herpetic neuralgia and other neuropathic pains, sickle cell crises, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, postoperative pain, and procedural pain (i.e., pain associated with injections, draining an abcess, surgery, dental procedures, opthalmic procedures, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, and the like).

Pain and function indices

In order to measure the efficacy of any of the methods, compositions, or kits of the invention, a measurement index may be used. Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain associated with musculoskeletal, immunoinflammatory and neuropathic disorders include a visual analog scale (VAS), a Likert scale, categorical pain scales, descriptors, the Lequesne index, the WOMAC index, and the AUSCAN index, each of which is well known in the art. Such indices may be used to measure pain, itch, function, stiffness, or other variables.

A visual analog scale (VAS) provides a measure of a one-dimensional quantity. A VAS generally utilizes a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., ten 1- cm intervals. For example, a patient can be asked to rank a sensation of pain or itch by choosing the spot on the line that best corresponds to the sensation of pain or itch, where one end of the line corresponds to "no pain" (score of 0 cm) or "no itch" and the other end of the line corresponds to "unbearable pain" or "unbearable itch" (score of 10 cm). This procedure provides a simple and rapid approach to obtaining quantitative information about how the patient is experiencing pain or itch. VAS scales and their use are described, e.g., in U.S. Patent Nos. 6,709,406 and 6,432,937. A Likert scale similarly provides a measure of a one-dimensional quantity. Generally, a Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain). A patient experiencing pain is asked to choose a number between the low value and the high value to represent the degree of pain experienced. Likert scales and their use are described, e.g.. in U.S. Patent Nos. 6,623,040 and 6,766,319. The Lequesne index and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index assess pain, function, and stiffness in the knee and hip of OA patients using self-administered questionnaires. Both knee and hip are encompassed by the WOMAC, whereas there is one Lequesne questionnaire for the knee and a separate one for the hip. These questionnaires are useful because they contain more information content in comparison with VAS or Likert. Both the WOMAC index and the Lequesne index questionnaires have been extensively validated in OA, including in surgical settings (e.g., knee and hip arthroplasty). Their metric characteristics do not differ significantly.

The AUSCAN (Australian-Canadian hand arthritis) index employs a valid, reliable, and responsive patient self-reported questionnaire. In one instance, this questionnaire contains 15 questions within three dimensions (Pain, 5 questions; Stiffness, 1 question; and Physical function, 9 questions). An AUSCAN index may utilize, e.g., a Likert or a VAS scale.

Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain include the Pain Descriptor Scale (PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales (VDS), the Numeric Pain Intensity Scale (NPTS), the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the Present Pain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGiIl Pain Questionnaire (MPQ), mean pain intensity (Descriptor Differential Scale), numeric pain scale (NPS) global evaluation score (GES) the Short-Form McGiIl Pain Questionnaire, the Minnesota Multiphasic Personality Inventory, the Pain Profile and Multidimensional Pain Inventory, the Child Heath Questionnaire, and the Child Assessment Questionnaire.

Itch can be measured by subjective measures (VAS, Lickert, descriptors). Another approach is to measure scratch which is an objective correlate of itch using a vibration transducer or movement-sensitive meters. The following examples are intended to illustrate the invention, and is not intended to limit it. Example 1. Preparation of N-chlorotaurine solution.

Sodium bicarbonate (100 mL of 0.1 M NaHCOs) solution was prepared by dissolving 840 mg (0.01 mols) OfNaHCO₃, MW 84) in 100 mL de-ionized water. The solution was cooled to about 4 "C.

Taurine (612 mg, 0.005 mols; ^H₃CH₂CH₂SO₃ ^" , MW 125) was dissolved in 50 mL of the NaHCO₃ solution. The taurine concentration in the resulting solution is 0.1 M, and the NaHCO₃ concentration is about 0.1M. The solution was maintained at 4 °C. Sodium hypochlorite (about 13 % w/w Cl₂, about 1.75 M) solution was diluted with the chilled 0.1 M NaHCO₃ solution (2.5 mL of the 1.75 M NaOCl into 50 mL NaHCO₃ solution). The concentration of NaOCl in the resulting solution is about 0.1 M, and the concentration OfNaHCO₃ is about 0.1 M.

With rapid stirring the chilled NaOCl solution (50 mL, 0.005 mols) was added to the chilled taurine solution (50 mL, 0.005 mols), while the temperature was maintained between 0 ⁰C and 5 °C. The resulting solution contains about 0.043 M N-chlorotaurine in about 0.1 M NaHCO₃ (the solution is about isotonic and very slightly basic, pH about 8.3).

This refrigerated N-chlorotaurine stock solution can be used for at least 4 hours. It may be diluted immediately before use with physiological saline phosphate buffer (pH 7.3, 0.14 M NaCl, 0.02 M phosphate) and administered to a subject according to the methods of the invention.

Example 2. Stability of N-chlorotaurine and N-bromotaurine Solutions. We have found that the concentration of N-chlorotaurine and N- bromotaurine is, at a particular pH, temperature and taurine concentration, given by Equation 1.

C_t= C_o (C_okt +l) Equation (1)

In Equation 1 C₀ is the initial concentration, C_t is the concentration at time t, and k is a constant. We have observed that (i) the initial fractional loss of concentration is fast when the concentration is high, (ii) it is slow when the concentration is low, (iii) k increases with temperature, and (iv) decreases with the concentration of co-dissolved taurine. Effect of Concentration

The half-life of an N-chlorotaurine solution decreases when the N- chlorotaurine concentration is increased. The concentration of N-chlorotaurine is conveniently monitored by its absorption of 252 nm UV light, where at neutral or slightly acidic pH its molar absorbance is about 430 cm^"1. An example of the initial N-chlorotaurine concentration effect is shown in Table 1.

Table 1. Effect of the Initial Concentration of N-Chlorotaurine on the Half Life of its Solution.

Elapsed Solution time, h 252 nm abs. Est. 1/2-Life

50 mM NCT 0 0.23 > 2 weeks

0.3 M T 3.3 pH 7.2-8.3 20.5 0.22

NaHCO₃ 70 0.215

Elapsed

Solution time, h 252 nm abs. Est. 1/2-Life

0.2 M NCT 0 0.78 abt. 2 days

0.27 M T 20 0.7 pH 7.6-8 Low

NaHCO₃

In Table 1 NCT is N-chlorotaurine; T is taurine; NaHCO3 is added sodium bicarbonate. The residual concentration of N-chlorotaurine was monitored through diluting its solution one hundred fold, adjusting the pH to about neutral, and measuring the absorbance at about 252 nm. Ambient temperature of about 21 ⁰C.

Similarly, the rate of decay of the N-bromotaurine concentration decreases when its solution is diluted. 24.5 g (ca. 0.21 moles) of KBr were dissolved in 250 mL of a NaOH-stabilized 6.6 % sodium hypochlorite solution with a pH of about 12. Using concentrated HCl, the pH was lowered to about pH 9. The 250 mL volume of this solution contained 0.21 moles of NaOCl. The hypobromite concentration in the resulting solution was about 0.82 M and the hypochlorite concentration was about 0.06 M. The N-bromotaurine solution was made by adding 30 mL of the hypobromite solution to 50 mL of the taurine solution drop-wise with stirring over 20 minutes. The pH increased upon the mixing from 7.3 to about 8.1. The resulting solution was about 0.25 M NBT, about 0.02 M NCT and about 0.14 M taurine. The absorption maximum and the absorbance of the solution was pH dependent. The maximum was downshifted from about 280 nm to about 260 nm as the pH was raised from 7 to 8.5 and there was an about three-fold decrease in the absorbance. The concentration decay was tracked by measuring the decay of the absorbance at 410 nm. The rate of decay was about 0.43 % min^"1. The solution was kept at the ambient temperature of about 21 °C for about 30-40 minutes, and was then diluted with an equal volume of de-ionized water. The pH of the diluted solution was about 8.1. The rate of the decay was reduced upon the dilution from about 0.43 % min ^"* to about 0.17 % min^'1. Effect of pH It has been reported that the decay of the N-chlorotaurine concentration is pH dependent, the solutions being more stable at higher pH (see Gottardi et al., Arch Pharm (Weinheim) 335:411 (2002). We found that this is also the case for N-bromotaurine. Table 2 shows the favorable effect of higher pH, particularly a pH of >8.0, and most particularly a pH of about 8.4-8.6 on the stability of an about 0.2 M N-chlorotaurine solution. Even though there was a lesser concentration of stabilizing taurine in the higher pH solution, the stability improved. In general it is preferred to maintain the solution in the about 8-10 pH range (e.g., a pH range of between about 8 and about 9, desirably between about 8.3 and about 8.8).

Table 2. Effect of pll

Elapsed 252 nm

Solution time, h abs. Est. 1/2-Life

0.2 M NCT 0 0.78 abt. 4 days pH 7.6-8 20.5 0.7

0.27 M T 70 Low

NaHCO₃

Elapsed 252 nm

Solution time, h abs. Est. 1/2-Life

0.2 M NCT 0 0.79 abt. 2 weeks pH 8.4-8.6 2 0.77

0.03 M T 20 0.81

69 0.67

In Table 2 NCT is N-chlorotaurine; T is taurine; and NaHCO₃ is added sodium bicarbonate. The residual concentration of N-chlorotaurine was monitored through diluting its solution one hundred fold and measuring the absorbance at about 252 nm. Ambient temperature of about 21 ⁰C.

Effect of Halide

We have observed that dissolved N-chlorotaurine is more stable than dissolved N-bromotaurine. The concentration of N-bromotaurine is conveniently monitored by its absorption of 283 nm UV light, where it molar absorbance in neutral or slightly acidic solutions is about 415 cm^"1. Table 3 compares the stabilities of about 0.2M solutions of N-chlorotaurine and N- bromotaurine at about similar pH and about similar taurine excess.

Table 3: Half Lives of N-Chlorotaurine and N-Bromotaurine Solutions

Elapsed 252 nm

Solution time, h absorbance Est. Y₂ -Life

0.2 M NCT 0 0.79 abt. 2 weeks pH 8.4-8.6 2 0.77

0.03 M T 20 0.81

69 0.67

Elapsed 283 nm

Solution time, h absorbance. Est. 1/2-Life

0.2 M NBT 0 0.71 abt. 18 hrs pH 8.6-8.7 17 0.37

0.03 M T 68 0.12

In Table 3 NCT is N-chlorotaurine; NBT is N-bromotaurine; T is taurine; and the residual concentrations of N-chlorotaurine and of N-bromotaurine were monitored through diluting their solution one hundred fold and measuring their absorbances respectively at about 252 nm and 283 nm. Decay was monitored at an ambient temperature of about 21 ⁰C.

Effect of Co-Dissolved Taurine

We have observed that co-dissolved taurine (e.g., the addition of 1, 2, 3, 4, or more molar equivalents of the unhalogenated amine) has a stabilizing effect on N-chlorotaurine and N-bromotaurine. Because the solubility of taurine limits its upper concentration to about 1 M at body temperature (about 37 ⁰C), a taurine concentration of between about 0.3 M and about 1 M is utilized to improve the stability of the halogenated taurine. Table 4 shows that co-dissolved taurine stabilizes the about 0.2 M N-bromotaurine solution.

Table 4. Stabilization of an N-bromotaurine Solution by Co-dissolved Taurine

Elapsed 283 nm Est. 1/2-

Solution time, h absorbance Life

0.2 M NBT 0 0.71 abt. 18 hrs pH 8.6-8.7 17 0.37

0.03 M T 68 0.12

0.2 M NBT 0 0.73 abt. 25 hrs pH 7.9-8.7 1 0.68

0.27 M T 18 0.4

69 0.15

In Table 4 NBT is N-bromotaurine; T is taurine; and the residual concentration of N-bromotaurine was monitored through diluting their solution one hundred fold and measuring the absorbance at about 283 nm at an ambient temperature of about 21 °C.

A solution containing about 0.25 M NBT, about 0.02 M NCT and about 0.55 M taurine was prepared as described above (except the dilution was carried out with 0.825 M taurine solution instead of water). The initial pH of 7.4 was adjusted to the pH of 8.1 by adding solid sodium carbonate. The rate of the decay of the N-bromotaurine concentration decreased to less than l/3^rd of the rate observed for the water-diluted solution (0.05 % min ^~l versus 0.17 % min ^-1). Effect of Temperature

We have observed that at low concentration, and when taurine- stabilized, a refrigerated 2 mM N-bromotaurine solution kept at about 4⁰C has a half-life of at least 1 year. In 15 mL of de-ionized water 1.03g (0.01 moles) of NaBr (sodium bromide) was dissolved. A 6.2 mL volume of a nominally 11- 13 wt% NaOCl sodium hypochlorite solution (0.01 moles) was diluted to 15 mL. The NaOCl solution was added drop-wise to the NaBr solution over 5 minutes, and then the mixture was allowed to stand for 5 minutes to produce the sodium hypobromite (NaOBr) solution, which was deep yellow. Next, taurine (5 g, 0.04 moles) was dissolved in 20 mL of dcionized water and the pH of the solution was raised to 8-9 by adding solid sodium bicarbonate. The NaOBr solution was added drop-wise over 15 minutes to the taurine solution, to produce N-bromotaurine (see Reaction 1).

O₃S-CH₂ CH₂ NH₃ ⁺ + NaOBr→ O₃S-CH₂ CH₂ NHBr + Na ⁺ + H₂O Reaction

(1)

The pH of the solution was adjusted to about 8.3 +/- 0.7 by adding NaHCO₃. The solution was then kept for 1 hour at ambient temperature to allow completion of the reaction. The resulting solution contained about 0.01 moles of N-bromotaurine and about 0.03 moles of taurine; thus the N-bromotaurine concentration was about 0.2 M and the taurine concentration was about 0.6 M. The solution was next diluted with 200 mL water to produce a solution volume of 250 mL. The resulting solution had 0.04 M in N-bromotaurine and 0.12 M taurine concentrations. In a one-week stability test, this solution was unstable, losing most of its UV light absorbance at 283 nm, where the absorbance of N- bromotaurine is maximal.

The freshly made 0.04 M N-bromotaurine, 0.12 M taurine solution was then diluted twenty fold, to a nominal 0.002 M N-bromotaurine and a nominal 0.006 M taurine concentration. Measurement of the absorbance at about 283 nm, for which the molar absorbance is about 415 M^"1 cm^"1, showed that the actual N-bromotaurine concentration was about 0.0019 M. The decay of the N- bromotaurine solution at about 4 ⁰C was then monitored periodically by its about 283 nm UV absorption. In a 4.4 month period the solution lost only about 10 % of its N-bromotaurine when kept at about 4 ⁰C, as evidenced by the relatively small decline of the initial UV absorption over that time period. Example 3. Animal Model for Hyperplasia. Behavioral Tests

Following intraplantar injection of N-chlorotaurine, N-bromotaurine, or a control (taurine or saline), animals were subjected to a thermal paw withdrawal test after an inflammation- evoked thermal hyperalgesia was induced by subcutaneous injection of carrageenan (100 μL of an aqueous solution of 2 wt % carrageenan) into the plantar surface of the left hind paw. Alternatively, of pain-hypersensitivity was caused by thermal injury instead of carrageenan injection. To induce a thermal injury, under continuous 2% halothane (oxygen/air) anesthesia with a nose cone, one hind paw of the rat was placed on a 52°C ± 1°C surface for 45 s, with a 10-g sand pouch placed on the heel portion of the paw for constant pressure.

To assess the thermally evoked paw withdrawal response, a Hargreaves- type testing device was used (Dirig et al., J. Neurosci. Methods 76:183 (1991)). The device consists of a glass surface (maintained at 30 ^°C) on which the rats are placed individually in Plexiglas cubicles. The thermal nociceptive stimulus originates from a focused projection bulb positioned below the glass surface. A timer is activated by the light source, and latency was defined as the time required for the paw to show a brisk withdrawal as detected by photodiode motion sensors that stopped the timer and terminated the stimulus.

The thermal stimulator permits the focusing a beam of radiant heat on the plantar surface of the paw, usually the hind paw, through a glass surface on which the animal stands. After a period of time, the paw is heated by the beam to a pain-causing temperature. When the rat feels pain, it withdraws the paw. Usually the rat is placed in a clear plastic cage that rests on an elevated floor of clear glass. An x-y movable focused radiant heat source is located under the glass floor maintained at 3O⁰C. The current to the radiant heat source was controlled by a variable current supply, permitting increase or decrease of the intensity of the radiant heat focused on the paw. The focused radiant heat was aimed on the carrageenan- injected or thermally injured portion of the plantar surface of the hind paw. After about 30 min of acclimation of the rat in the cage, the radiant beam was adjusted so that the average escape latency in normal untreated rats, meaning the time interval between the application of the focused beam of radiant heat and the brisk paw withdrawal, was about 10 sec. The paw withdrawal was detected automatically with a photodetector. The results are shown in Figures 4-7. Intraplantar administration of N- chlorotaurine or N-bromotaurine reverses carrageenan and thermal injury evoked hyperalgesic states in a dose dependent fashion. Furthermore, the N- chlorotaurine and N-bromotaurine had no effect on "normal" (uninjured) pain- thresholds. No untoward effects were observed at the maximum doses/concentration employed.

Example 4. Anti-Hyperalgesic Activity of N-chlorotaurine in Human Subjects. General design Two subjects participated in a single study session over the course of two days. On study day one, an experimental sunburn lesion was induced in non-tanned skin on each thigh. On study day two and 22 hours after induction of the experimental sunburn lesions, subjects participated in behavioral pain experiments. Before study participation a subject's sensitivity to UVB irradiation was determined. Experimental sunburn

Experimental sunburns were induced with aid of a calibrated ultraviolet B (UBV) source (Saalman Multitester SBB LT 400, Saalmann GmbH, Herford, Germany). Accurate delivery of energy (mJ/cm²) was assured with a UV- meter (RM 12, Dr. Grobel UV-Electronic GmbH, Ettlingen, Germany). Both subjects had a skin type H-I V according to the classification of Fitzpatrick.

The minimal erythemal dose (MED; mJ/cm²), i.e.. the minimal energy of UVB causing complete reddening of skin 22 hours after irradiation was determined in each subject in non tanned skin of the upper thigh before study participation. Both subjects had an MED of lOOmJ/cm². Experimental sunburn lesions (1.5x1.5 cm) were induced using close to three times the MED (280mJ/cm ) in non tanned skin of each upper thigh 22 h before the behavioral pain testing. Pain testing

Pain thresholds to heat and mechanical stimulation were determined in experimental sunburn lesions and at non-inflamed skin control sites. Pain thresholds are defined as the minimal heat or mechanical stimulus necessary to evoke a painful sensation.

Heat pain.

The pain threshold was determined with aid of a thermal sensory analyzer (TSA II, Medoc Advanced Medical Systems, Durham, NC). In brief, a hand-held 16x16 mm thermode was brought into full contact with skin. After equilibration between skin and thermode temperature at 35⁰C, the temperature of the thermode was increased by l°C/s (cut-off 52°C). Subject were asked to push the button of a hand-held device as soon as pain was perceived, thereby triggering the recording of the temperature causing pain as well as the immediate cooling of the probe. This procedure was repeated 4 times and the average was recorded.

Mechanical pain.

Mechanical hyperalgesia was quantified with eight calibrated punctuated probes. The eight probes are made of identical cylindrical stainless steel wires (240 μm diameter) mounted on copper rods of various weights (1, 2, 4, 8, 16, 32, 64 and 81 g) moving freely within a wider hand-held tube. Punctuated stimuli were applied by positioning the steel wire tip perpendicular to the skin surface such that the weight of a rod rested solely on the wire tip. Starting with the lightest probe, consecutively heavier probes were applied until a subject reported pain for the first time. Subsequently, the next lighter probe was applied if pain had been reported for the preceding stimulus, or the next heaλder probe was applied if no pain had been reported for the preceding stimulus. The procedure was repeated until a subject had reported four times that a non- painful stimulation had changed to a painful stimulation and three times that a painful stimulation had changed to a non-painful stimulation, respectively. This way seven data points were obtained reflecting the weight of the probe that caused a change from a non-painful to a painful perception and vice versa. The mechanical pain threshold was defined as the mean of these seven data points.

Administration

N-Chlorotaurine (NCT) was administered in one experimental sunburn lesion, while an identical looking placebo formulation was administered in the other experimental sunburn lesion. Λ total of 800μl of NCT solution or placebo were injected in each lesion via a 27G needle attached to a ImL syringe. The 800μl were injected as follows: lOOμl each were injected intra- cutaneously in each quadrant of the experimental sunburn lesion, and 400μl were injected subcutaneously into the center of the lesion. Administration was performed after determining the pre-drug heat and mechanical pain threshold twice. Pain thresholds were reassessed in both lesions 30 and 90min after drug administration.

Chlorotaurine was dissolved 5-10 minutes before the injection. The active solution was formulated as follows: 2ml water was added to a vial containing 42mg of NCT-Na salt to obtain a 0.1 M solution. In addition 8.4mg NaHCO₃ were added to provide a final concentration of 0.05M. The placebo solution was formulated as follows: 2ml water was added to a vial containing 25.2mg NaHCO₃ to provide a final concentration of 0.15M. Outcome/Rational

Primary outcomes are the increase in heat and mechanical pain thresholds after the administration of chlorotaurine compared with the administration of placebo. A benchmark comparison is given by the effects of 800 mg oral ibuprofen on heat and mechanical pain thresholds in the same experimental sunburn lesion used in this protocol. Ibuprofen elevated the heat and mechanical pain threshold by about 1.5 ⁰C and 12 g, respectively. Assessment of the heat pain threshold and mechanical pain threshold allows determining the effects of NCT on C and A-delta fiber mediated pain. C and A-delta afferent fibers represent the two major nerve fiber populations transmitting nociceptive signals from the periphery to the spinal cord. Results Heat and mechanical pain thresholds in non-inflamed skin (Pre- Inflamed), and in inflamed skin before (Pre-drug), and 30min (Post-drug 30min) and 90min (Post-drug 90min) after drug (blue column) or placebo (purple column) injection are depicted in Figures 8 and 9. Experimental inflammation of the skin resulted in marked heat and mechanical hyperalgesia as indicated by a decrease in heat (-4.2⁰C) and mechanical (-3Og) pain thresholds. NCT but not placebo exerted robust anti-hyperalgesic effects to heat (+2.8 ⁰C) and mechanical (+45g) stimulation 30 minutes after injection. NCT-mediated antihyperalgesic effects were maintained for mechanical stimulation (+45g), and were likely present but attenuated for heat stimulation (+0.8 ⁰C) 90 minutes after injection.

Additional Observations

Both participants noted a throbbing pain after injection of NCT that lasted > 30 minutes. The pain was described as flu-shot like. No such pain was noted after injection of placebo. One subjected noted that no pricking sensation was elicited in the lesion injected with NCT. Preserved sensations were pressure and touch. Both subjects noted that injection of NCT but not placebo caused a swelling (no signs of inflammation) that lasted >90 minutes.

Other Embodiments

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims.

What is claimed is:

Claims

1. A device comprising:

(i) a first chamber containing a first solution comprising an ammonium salt or an amine or a salt thereof;

(ii) a second chamber containing a second solution comprising hypochlorous acid or a salt thereof;

(iii) a mixing chamber for combining said first solution and said second solution to form an N-chlorinated amine; and

(iv) a channel in fluid communication with said mixer chamber for delivering said N-chlorinated amine to a subject.

2. A device comprising:

(ii) a second chamber containing a second solution comprising hypobromous acid or a salt thereof;

(iii) a mixing chamber for combining said first solution and said second solution to form an N-brominated amine; and

(iv) a channel in fluid communication with said mixer chamber for delivering said N-brominated amine to a subject.

3. A device comprising:

(ii) a second chamber containing a second solution comprising (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof;

(iii) a mixing chamber for combining said first solution and said second solution to form a mixture of N-brominated amine and N-chlorinated amine; and

(iv) a channel in fluid communication with the mixer chamber for delivering said N-brominated amine and N-chlorinated amine to a subject.

4. The device of any of claims 1-3, wherein said device is a syringe.

5. The device of any of claims 1-3, wherein said device is a spray bottle.

6. The device of any of claims 1-3, wherein said device is a spray canister.

7. The device of any of claims 1-3, wherein said device is an irrigation bottle or bag.

8. The device of any of claims 1-3, wherein said device is gravity- driven.

9. The device of any of claims 1-3, wherein said device is pressurized.

10. The device of any of claims 1-3, wherein said device is mechanically driven.

11. A device comprising: a double barrel syringe, said double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of said first and second barrels when mixed forming an N-chlorinated amine, said first barrel of said double barrel syringe comprising an amine, or a salt thereof, said second barrel of said double barrel syringe comprising hypochlorous acid, or a salt thereof.

12. A device comprising: a double barrel syringe, said double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of said first and second barrels when mixed forming an N-brominated amine, said first barrel of said double barrel syringe comprising an amine, or a salt thereof, said second barrel of said double barrel syringe comprising hypobromous acid, or a salt thereof.

13. A device comprising: a double barrel syringe, said double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of said first and second barrels when mixed forming a mixture of N-brominated amine and N-chlorinated amine, said first barrel of said double barrel syringe comprising an amine, or a salt thereof, said second barrel of said double barrel syringe comprising (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof.

14. A device for delivery of an N-chlorinated amine comprising: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypochlorous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.

15. A device for delivery of an N-brominated amine comprising: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypobromous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.

16. A device for delivery of a mixture of an N-chlorinated amine and an N-brominated amine comprising: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing (i) hypobromous acid, or a salt thereof, and (ii) hypochlorous acid, or a salt thereof; c) a first conduit connecting said first reservoir to a delivery port; and d) a second conduit connecting said second reservoir to the delivery port.

17. The device according to any of claims 13 to 16, further comprising a mechanism to control the flow from the first and second reservoirs through the first and second conduits to the delivery point.

18. The device according to any of claims 13 to 16, wherein the delivery port is a catheter.

19. The device according to any of claims 13 to 16, wherein the delivery port is a needle.

20. The device according to any of claims 13 to 16, wherein the delivery port is a spray nozzle.

21. The device according to any of claims 13 to 16, wherein the output is a stream.

22. The device according to any of claims 13 to 16, wherein the output is a mist.

23. The device of any of claims 1-22, wherein said amine is selected from ammonia, urea, methylamine, ethylamine, isobutylamine, 2- methylbutylamine, pyrrolidine, phenethylamine, agmatine, histamine, tryptamine, 3-methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha- aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2- aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threonine, cystine, methionine, glutamine, tryptophane, histidine, arginine, lysine, alpha-aminobutyric acid, gamma-aminobutyric acid, alpha, epsilon diamino pimelic acid, ornithine, hydroxylysine, anthranilic acid, p- aminobenzoic acid, sulfanilic acid, orthanilic acid, phenyl sulfamic acid, aminopropanesulfonic acid, 2-aminopropanol, diethanolamine, ethylenediamine tetraacetic acid, aminomethane- sulfonic, glycylglycine, glycylglycylglycine, metanilic acid, N-octodecanyl glycine, 2,2- dimethyltaurine, 1 , 1 ,2,2-tetramethyltaurine, 2-methyltaurine, 2,2,3,3- tetramethyl-β-alanine, 3,3-dimethylhomotaurine, 1 -methyl- 1-amino- ethanesulfonic acid, 2-methyl-2-amino-ethanesulfonic acid, aminotrimethylene phosphonic acid, 2-amino-5-phosphonopentanoic acid, aminoethylphosponic acid, 1 -amino- 1 -methylethane phosphonic acid, 1 -amino-2-methylethane phosphonic acid, l-amino-2-methylpropane phosphonic acid, leucine phosphonic acid, 4-amino-4-phosphonobutyric acid, 2-amino-5- phosphonovaleric acid, 2-amino-5-phosphonovaleric acid, 2-amino-8- phosphonooctanoic acid, leucine boronic acid, β-alanine boronic acid, and salts thereof.

24. The device of claim 23, wherein said amine is taurine, 2,2- dimethyltaurine, 1 , 1 ,2,2-tetramethyltaurine, 2-methyltaurine, or a salt thereof.

25. A method of treating pain in a patient in need thereof, said method comprising (i) mixing a solid ammonia salt and a solid hypochlorite salt with water to form an N-chlorinated amine solution, and (ii) administering said solution to a patient for the treatment of pain or itch.

26. A method of treating pain in a patient in need thereof, said method comprising (i) mixing a solid amine salt and a solid hypobromitc salt with water to form an N-brominated amine solution, and (ii) administering said solution to a patient for the treatment of pain or itch.

27 1.. A method of treating pain in a patient in need thereof, said method comprising (i) mixing (a) a solid amine salt, (b) a solid hypobromite salt, and (c) a solid hypochlorite salt with water to form a solution containing N- brominated amine and N-chlorinated amine, and (ii) administering said solution to a patient for the treatment of pain or itch.

28. The method of any of claims 25 to 27, wherein said patient suffers from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.

29. The method of any of claims 25 to 28, wherein said amine salt is salt of ammonia, urea, methylamine, ethylamine, isobutylamine, 2- methylbutylamine, pyrrolidine, phenethylamine, agmatine, histamine, tryptamine, 3-methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha- aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2- aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threonine, cystine, methionine, glutamine, tryptophane, histidine, arginine, lysine, alpha-aminobutyric acid, gamma-aminobutyric acid, alpha, epsilon diamino pimelic acid, ornithine, hydroxylysine, anthranilic acid, p- aminobenzoic acid, sulfanilic acid, orthanilic acid, phenyl sulfamic acid, aminopropanesulfonic acid, 2-aminopropanol, diethanolamine, ethylenediamine tetraacetic acid, aminomethane-sulfonic, glycylglycine, glycylglycylglycine, metanilic acid, 2,2-dimethyltaurine, 1,1,2,2- tetramethyltaurine, 2-methyltaurine, 2,2,3, 3 -tetramethyl-β- alanine, 3,3- dimethylhomotaurine, 1 -methyl- 1-amino-ethanesulfonic acid, 2-methyl-2- amino-ethanesulfonic acid, aminotrimethylene phosphonic acid, 2-amino-5- phosphonopentanoic acid, aminoethylphosponic acid, 1 -amino- 1 -methylethane phosphonic acid, l-amino-2-methylethane phosphonic acid, l-amino-2- methylpropane phosphonic acid, leucine phosphonic acid, 4-amino-4- phosphonobutyric acid, 2-amino-5-phosphonovaleric acid, 2-amino-5- phosphonovaleric acid, 2-amino-8-phosphonooctanoic acid, leucine boronic acid, β-alanine boronic acid, or N-octodecanyl glycine.

30. The method of claim 29, wherein said amine salt is a salt of taurine, 2,2-dimethyltaurine, 1,1,2,2-tetramethyltaurinc, or 2 -methyl taurine.

31. The method of any of claims 25 to 27, wherein said solution includes a buffer and has a pH of between 7 and 10.

32. A kit comprising (i) a device of any of claims 1-24 for producing a solution, and (ii) instructions for administering said solution to a patient for the treatment of pain or itch.

33. A kit comprising (i) an amine salt, (ii) a hypochlorite salt, and (iii) instructions for contacting said amine salt, and said hypochlorite salt with water to form a solution, and (iv) instructions for administering said solution to a patient for the treatment of pain or itch.

34. A kit comprising (i) an amine salt, (ii) a hypobromite salt, and (iii) instructions for contacting said amine salt, and said hypobromite salt with water to form a solution, and (iv) instructions for administering said solution to a patient for the treatment of pain or itch.

35. A kit comprising (i) an amine salt, (ii) a hypobromite salt, (iii) a hypochlorite salt, and (iv) instructions for contacting said amine salt, said hypobromite, and said hypochlorite salt salt with water to form a solution, and (v) instructions for administering said solution to a patient for the treatment of pain or itch.

36. The kit of any of claims 33 to 35, wherein said solution further comprising a buffer.

37. A kit comprising (i) a solid comprising an N-chlorinated amine, (ii) instructions for contacting said solid with water to form a solution, and (iii) instructions for administering said solution to a patient for the treatment of pain or itch.

38. The kit of claim 37, wherein said N-chlorinated amine is N-chloro- taurine, N-chloro-2,2-dimethyltaurine, N-chloro-l,l,2,2-tctramcthyltaurine, N- chloro-2,2,3,3-tetramethyl-β-alanine, N-chloro-3,3-dimethylhomotaurine, N,N- dichloro-taurine, N,N-dichloro-2,2-dimethyltaurine, N,N-dichloro-l,l,2,2- tetramethyltaurine, N,N-dichloro-2,2,3,3-tetramethyl-β-alanine, N,N-dichloro- 3,3-dimethylhomotaurine, or a salt thereof.

39. A kit comprising (i) a solid comprising an N-brominated amine, (ii) instructions for contacting said solid with water to form a solution, and (iii) instructions for administering said solution to a patient for the treatment of pain or itch.

40. The kit of claim 39, wherein said N-brominated amine is N-bromo- taurine, N N-bromo-2,2-dimethyltaurine, N-bromo-l,l,2,2-tetramethyltaurine, N-bromo-2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N,N-dibromo-taurine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1,1,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N- dibromo-3,3-dimethylhomotaurine, or a salt thereof.

41. A kit comprising (i) a solid including a halogenated amine selected from N-brominated amines, N-chlorinated amines, N-bromo-N-chloroamines, and mixtures thereof, (ii) instructions for contacting said solid with water to form a solution, and (iii) instructions for administering said solution to a patient for the treatment of pain or itch.

42. The kit of claim 41. wherein said halogenated amine is N-bromo-N- chloro-taurine, N-bromo-N-chloro-2,2-dimethyltaurine, N-bromo-N-chloro-

1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramcthyl-β- alanine, and N-bromo-N-chloro-3,3-dimethylhomotaurine, or a salt thereof, or a salt thereof.

43. The kit of any of claims 37-42, further comprising a buffer to produce said solution having a pH of between 7 and 10.

44. The kit of any of claims 37-43, further comprising instructions for administering said composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.

45. A method of treating pain in a patient in need thereof, said method comprising topically administering to said patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat said pain.

46. A method of treating pain in a patient in need thereof, said method comprising topically administering to said patient an N-bromo-N-chloroamine in an amount sufficient to treat said pain.

47. A method of treating pain in a patient in need thereof, said method comprising topically administering to said patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein said first agent and said second agent are administered in an amount that together is sufficient to treat the pain.

48. A method of treating pain at a site in a patient in need thereof, said method comprising locally injecting at said site an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat said pain.

49. A method of treating pain at a site in a patient in need thereof, said method comprising locally injecting at said site an N-bromo-N-chloroamine in an amount sufficient to treat said pain.

50. A method of treating pain at a site in a patient in need thereof, said method comprising locally injecting at said site a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein said first agent and said second agent are administered in an amount that together is sufficient to treat the pain.

51. A method of treating pain in a patient in need thereof, said method comprising administering to said patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat said pain, wherein said pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

52. A method of treating pain in a patient in need thereof, said method comprising administering to said patient an N-bromo-N-chloroamine in an amount sufficient to treat said pain, wherein said pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

53. A method of treating pain in a patient in need thereof, said method comprising administering to said patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein said first agent and said second agent are administered in an amount that together is sufficient to treat the pain, and wherein said pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

54. The method of any of claims 51-53, wherein said pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.

55. The method of any of claims 51-54, wherein said agent is administered locally at the site of pain.

56. A method of treating itch in a patient in need thereof, said method comprising topically administering to said patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat said itch.

57. A method of treating itch in a patient in need thereof, said method comprising topically administering to said patient an N-bromo-N-chloroamine in an amount sufficient to treat said itch.

58. A method of treating itch in a patient in need thereof, said method comprising topically administering to said patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein said first agent and said second agent are administered in an amount that together is sufficient to treat the itch.

59. The method of any of claims 45, 48, 51, and 56, wherein said agent is selected from bromourea, N-bromo-methylamine, N-bromo-ethylamine, N- bromo-isobutylamine, N-bromo-2-methylbutylamine, N-bromo-pyrrolidine, N- bromo-phenethylamine, N-bromo-agmatine, N-bromo-histamine, N-bromo- tryptamine, N-bromo-3-methylthiopropanamine, N-bromo-spermine, N-bromo- carnosine, N-bromo-carcinine, N-bromo-glutathione sulfonamide, N- bromoglycine, N-bromosulfamic acid, N-bromosarcosine, N-bromo-alpha- aminoisobutyric acid, N-bromotaurine, N-bromotaurine ethyl ester, N- bromotaurine sulfonamide, N-bromo-2-aminoethanol, N-bromo-acetylglycine, N-bromoalanine, N-bromo-beta-alanine, N-bromoserine, N-bromo-phenyl alanine, N-bromo-norvaline, N-bromoleucine, N-bromo-isoleucine, N- bromoproline, N-bromo-hydroxyproline, N-bromo-omega aminoundecanoic acid, N-bromoaspartic acid, N-bromoglutamic acid, N-bromoasparagine, N- bromovaline, N-bromothreonine, N-bromocystine, N-bromomethionine, N- bromoglutamine, N-bromotryptophane, N-bromohistidine, N-bromoarginine, N-bromolysine (alpha or omega), N-bromo-alpha-aminobutyric acid, N-bromo- gamma-aminobutyric acid, N-bromo- alpha, epsilon diamino pimelic acid, N- bromo-ornithine, N-bromo-hydroxylysine (alpha or omega), N- bromoanthranilic acid, N-bromo-p-aminobenzoic acid, N-bromosulfanilic acid, N-bromo- orthanili c acid, N-bromo-phenyl sulfamic acid, N- bromoaminopropanesulfonic acid, N-bromo-2-aminopropanol, N-bromo- diethanolamine, N-bromo-ethylenediamine tetraacetic acid, N-bromo- aminomethane-sulfonic, N-bromo-glycylglycine, N-bromo- glycylglycylglycine, N-bromo-metanilic acid, N-bromo-N-octodecanyl glycine, N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- 2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N-bromo ethanesulfonic acid, N-bromo- 1 -methyl ethanesulfonic acid, N-bromo-2- methyltaurine, N-bromo-2-methyl-2-amino-ethanesulfonic acid, N-bromo aminotrimethylene phosphonic acid, N-bromo-2-amino-5-phosphonopentanoic acid, N-bromo aminoethylphosponic acid, N-bromo- 1 -amino- 1-methylethane phosphonic acid, N-bromo- 1 -amino-2-methylethane phosphonic acid, N- bromo-l-amino-2-methylpropane phosphonic acid, N-bromoleucine phosphonic acid, N-bromo-4-amino-4-phosphonobutyric acid, N-bromo-2- amino-5-phosphonovaleric acid, N-bromo-2-amino-5-phosphonovaleric acid, N-bromo-2-amino-8-phosphonooctanoic acid, N-bromoleucine boronic acid, N-bromo-β-alanine boronic acid, N,N-dibromo-methylamine, N,N-dibromo- ethylamine, N,N-dibromo-isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo-phenethylamine, N,N-dibromo-agmatine, N,N-dibromo- histamine, N,N-dibromo-tryptamine, N,N-dibromo-3-methylthiopropanamine, N,N-dibromo-spermine, N,N-dibromo-carnosine, N,N-dibromo-carcinine, N,N- dibromoglycine, N,N-dibromo-alpha-aminoisobutyric acid, N₅N- dibromotaurine, N,N-dibromotaurine ethyl ester, N,N-dibromotaurine sulfonamide, N,N-dibromo-2-aminoethanol, N,N-dibromoalanine, N,N- dibromo-beta-alanine, N,N-dibromoserine, N,N-dibromo-phenyl alanine, N,N- dibromo-norvaline, N,N-dibromoleucine, N,N-dibromo-isoleucine, N,N- dibromoproline, N,N-dibromo-hydroxyproline, N,N-dibromo-omega aminoundecanoic acid, N,N-dibromoaspartic acid, N,N-dibromoglutamic acid, N,N-dibromoasparagine, N,N-dibromovaline, N,N-dibromothreonine, N₅N- dibromomethionine, N,N-dibromoglutamine, N,N-dibromotryptophane, N₅N- dibromoarginine, N₅N- dibromoly sine (alpha or omega), N,N-dibromo-alpha- aminobutyric acid, N,N-dibromo-gamma-aminobutyric acid, N,N-dibromo- alpha, epsilon diamino pimelic acid, N,N-dibromo-omithine, N,N-dibromo- hydroxylysine (alpha or omega), N,N-dibromo-2-aminopropanol, N₅N- dibromo-diethanolamine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N- dibromo-3,3-dimethylhomotaurine, N,N-dibromo ethanesulfonic acid, N₅N- dibromo-1 -methyl ethanesulfonic acid, N,N-dibromo-2-methyl-2-amino- ethanesulfonic acid, N,N-dibromo aminotrimethylene phosphonic acid, N₅N- dibromo-2-amino-5-phosphonopentanoic acid, N,N-dibromo aminoethylphosponic acid diesters, such as the diethylester, N,N-dibromo-l- amino-1-methylethane phosphonic acid, N,N-dibromo-l-amino-2- methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylpropane phosphonic acid, N,N-dibromoleucine phosphonic acid, N,N-dibromo-4- amino-4-phosphonobutyric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino- 8-phosphonooctanoic acid, N,N-dibromoleucine boronic acid, N,N-dibromo-β- alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof.

60. The method of any of claims 45, 48, 51, and 56, wherein said agent is a brominated analgesic, brominated tricyclic antidepressant, brominated stimulant, or a polymer bearing N-bromoamine groups.

61. The method of claim 60, wherein said agent is a brominated analgesic selected from N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N- bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl- N-bromo-ropivacaine, desbutyl-N-bromo-bupivacaine, desbutyl-N-bromo- levobupivacaine, desmethyl-N-bromo-mepivacaine, desethyl-N-bromo- procaine, desethyl-N-bromo-proparacaine, desethyl-N-bromo-allocain, desmethyl-N-bromo-encainide, desethyl-N-bromo-procainamidc, desethyl-N- bromo-metoclopramide, desmethyl-N-bromo-stovaine, desethyl-N-bromo- propoxycaine, desethyl-N-bromo-bromoprocaine, N-bromo-flecainide, desethyl-N-bromo-tetracaine, N-bromo-procaine, N-bromo-proparacaine, N- bromo-procainamide, N-bromo-metoclopramide, N-bromo-propoxycaine, N- bromo-bromoprocaine, N-bromo-tetracaine, N-bromo-benzocaine, N-bromo- butamben, and desethyl-N-bromo-dibucaine.

62. The method of claim 60, wherein said agent is a brominated tricyclic antidepressant selected from N-bromo-amoxapine, desmethyl-N- bromo-trimipramine, desmethyl-N-bromo-dothiepin, desmethyl-N-bromo- doxepin, desmethyl-N-bromo-amitriptyline, N-bromo-protriptyline, N-bromo- desipramine, desmethyl-N-bromo-clomipramine, desmethyl-N-bromo- clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptylinc, dcsmethyl-N- bromo-cyclobenzaprine, desmethyl-N-bromo-cyproheptadine, desmethyl-N- bromo-olopatadine, desmethyl -N-bromo-promethazine, desmethy 1-N-bromo- trimeprazine, desmethyl-N-bromo-chlorprothixene, desmethyl-N-bromo- chlorpromazine, desmethyl-N-bromo-propiomazine, desmethyl-N-bromo- prochlorperazine, desmethyl-N-bromo-thiethylperazine, desmethyl-N-bromo- trifiuoperazine, deselhyl-N-bromo-ethacizine, and desmethyl-N-bromo- imipramine.

63. The method of claim 60, wherein said agent is a brominated stimulant selected from N-bromo-amphetamine, N,N-dibromo-amphetamine, and N-bromo-methamphetamine.

64. The method of claim 60, wherein said agent is a polymer selected from N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N- brominated amino-cellulose, and N-brominated polylysine.

65. The method of any of claims 45, 48, 51, and 56, wherein said agent is selected from N-bromotaurine, N,N-dibromo-taurine, N-bromo- desmethylchlorpromazine, N-bromo-lidocaine, N-bromo-amphetamine, N,N- dibromo-amphetamine, and N-bromo-methamphetamine.

66. The method of any of claims 46, 49, 52, and 57, wherein said agent is selected from N-bromo-N-chloro-methylamine, N-bromo-N-chloro- ethylamine, N-bromo-N-chloro-isobutylamine, N-bromo-N-chloro-2- methylbutylamine, N-bromo-N-chloro-phenethylamine, N-bromo-N-chloro- agmatine, N-bromo-N-chloro-histamine, N-bromo-N-chloro-tryptamine, N- bromo-N-chloro-3-methylthiopropanamine, N-bromo-N-chloro-spermine, N- bromo-N-chloro-camosine, N-bromo-N-chloro-carcinine, N-bromo-N- chloroglycine, N-bromo-N-chloro-alpha-aminoisobutyric acid, N-bromo-N- chlorotaurine, N-bromo-N-chlorotaurine ethyl ester, N-bromo-N-chlorotaurine sulfonamide, N-bromo-N-chloro-2-aminoethanol, N-bromo-N-chloroalanine, N-bromo-N-chloro-beta-alanine, N-bromo-N-chloroserine, N-bromo-N-chloro- phenyl alanine, N-bromo-N-chloro-norvaline, N-bromo-N-chloroleucine, N- bromo-N-chloro-isoleucine, N-bromo-N-chloroproline, N-bromo-N-chloro- hydroxyproline, N-bromo-N-chloro-omega aminoundecanoic acid, N-bromo- N-chloro-aspartic acid, N-bromo-N-chloroglutamic acid, N-bromo-N- chloroasparagine, N-bromo-N-chlorovaline, N-bromo-N-chlorothreonine, N- bromo-N-chloro- methionine N-bromo-N-chloroglutamine, N-bromo-N- chlorotryptophane, N-bromo-N-chloroarginine, any N-bromo-N-chlorolysine (alpha or omega), N-bromo-N-chloro-alpha-aminobutyric acid, N-bromo-N- chloro-gamma-aminobutyric acid, N-bromo-N-chloro-alpha, epsilon diamino pimelic acid, N-bromo-N-chloro- ornithine, any N-bromo-N-chloro- hydroxylysine (alpha or omega), N-bromo-N-chloro-2-aminopropanol, N- bromo-N-chloro-diethanolamine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3 ,3- tetramethyl-β-alanine, N-bromo-N-chloro-3,3-dimethylhomotaurine, N-bromo- N-chloro-ethanesulfonic acid, N-bromo-N-chloro- 1 -methyl ethanesulfonic acid, N-bromo-N-chloro-2-methyl-2-amino-ethanesulfonic acid, N-bromo-N- chloro-aminotrimethylene phosphonic acid, N-bromo-N-chloro-2-amino-5- phosphonopentanoic acid, N-bromo-N-chloro- aminoethylphosponic acid diesters, such as the diethylester, N-bromo-N-chloro- 1 -amino- 1 -methylethane phosphonic acid, N-bromo-N-chloro- l-amino-2-methylethane phosphonic acid, N-bromo-N-chloro- l-amino-2-methylpropane phosphonic acid, N-bromo-N- chloroleucine phosphonic acid, N-bromo-N-chloro-4-amino-4- phosphonobutyric acid, N-bromo-N-chloro-2-amino-5-phosphonovaleric acid, N-bromo-N-chloro-2-amino-5-phosphonovaleric acid, N-bromo-N-chloro-2- amino-8-phosphonooctanoic acid, N-bromo-N-chloroleucine boronic acid, N- bromo-N-chloro- β-alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof.

67. The method of any of claims 46, 49, 52, and 57, wherein said agent is a halogenated analgesic, halogenated tricyclic antidepressant, halogenated stimulant, or a halogenated polymer bearing N-bromo-N-chloroamine groups.

68. The method of any of claims 45 to 53, wherein said patient experiences some pain relief within 20 minutes of administering said agent.

69. The method of any of claims 56-58, wherein said patient experiences some relief from itch within 20 minutes of administering said agent.

70. The method of any of claims 45-69, with the proviso that said pain does not result from an infection in said patient.

71. A kit comprising ((i) a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N- chloroamine, or (c) a mixture of a N-chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for topically administering said composition to a patient for the treatment of pain.

72. The kit of claim 71, wherein said composition is formulated for topical administration.

73. The kit of claim 72, wherein said composition is formulated as a cream, lotion, spray, stick, iontophoresis solution, or ointment.

74. A kit comprising (i) a composition formulated for injection and including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for locally injecting said composition at a site of a patient for the treatment of pain.

75. A kit comprising (i) a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N- chloroamine, or (c) a mixture of a N-chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for administering said composition to a patient for the treatment of nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

76. The kit of claim 75, further comprising instructions for administering said composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.

77. A kit comprising ((i) a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N- chloroamine, or (c) a mixture of a N-chlorinated amine and N-brominated amine in an amount sufficient to treat itch when administered to a patient, and (ii) instructions for topically administering said composition to a patient for the treatment of itch.

78. The kit of any of claims 71-77, wherein said agent is selected from bromourea, N-bromo-methylamine, N-bromo-ethylamine, N-bromo- isobutylamine, N-bromo-2-mcthylbutylamine, N-bromo-pyrrolidine, N-bromo- phenethylamine, N-bromo-agmatine, N-bromo-histamine, N-bromo- tryptamine, N-bromo-3-methylthiopropanamine, N-bromo-spermine, N-bromo- carnosine, N-bromo-carcinine, N-bromo-glutathione sulfonamide, N- bromoglycine, N-bromosulfamic acid, N-bromosarcosinc, N-bromo-alpha- aminoisobutyric acid, N-bromotaurine, N-bromotaurine ethyl ester, N- bromotaurine sulfonamide, N-bromo-2-aminoethanol, N-bromo-acetylglycine, N-bromoalanine, N-bromo-beta-alanine, N-bromoserine, N-bromo-phenyl alanine, N-bromo-norvaline, N-bromoleucine, N-bromo-isoleucine, N- bromoproline, N-bromo-hydroxyproline, N-bromo-omega aminoundecanoic acid, N-bromoaspartic acid, N-bromoglutamic acid, N-bromoasparagine, N- bromovaline, N-bromothreonine, N-bromocystine, N-bromomethionine, N- bromoglutamine, N-bromotryptophane, N-bromohistidine, N-bromoarginine, N-bromolysine (alpha or omega), N-bromo-alpha-aminobutyric acid, N-bromo- gamma-aminobutyric acid, N-bromo-alpha, epsilon diamino pimelic acid, N- bromo-ornithine, N-bromo-hydroxylysine (alpha or omega), N- bromoanthranilic acid, N-bromo-p-aminobenzoic acid, N-bromosulfanilic acid, N-bromo-orthanilic acid, N-bromo-phenyl sulfamic acid, N- bromoaminopropanesulfonic acid, N-bromo-2-aminopropanol, N-bromo- diethanolamine, N-bromo-ethylenediamine tetraacetic acid, N-bromo- aminomethane-sulfonic, N-bromo-glycylglycine, N-bromo- glycylglycylglycine, N-bromo-metanilic acid, N-bromo-N-octodecanyl glycine, N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- 2,2,3, 3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N-bromo ethanesulfonic acid, N-bromo- 1 -methyl ethanesulfonic acid, N-bromo-2- methyltaurine, N-bromo-2-methyl-2-amino-ethanesulfonic acid, N-bromo aminotrimethylene phosphonic acid, N-bromo-2-amino-5-phosphonopentanoic acid, N-bromo aminoethylphosponic acid, N-bromo- 1 -amino- 1 -methylethane phosphonic acid, N-bromo- l-amino-2-methylethane phosphonic acid, N- bromo-l-amino-2-methylpropane phosphonic acid, N-bromoleucine phosphonic acid, N-bromo-4-amino-4-phosphonobutyric acid, N-bromo-2- amino-5-phosphonovaleric acid, N-bromo-2-amino-5-phosphonovaleric acid, N-bromo-2-amino-8-phosphonooctanoic acid, N-bromoleucine boronic acid, N-bromo-β-alanine boronic acid, N,N-dibromo-methylamine, N,N-dibromo- ethylamine, N,N-dibromo-isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo-phenethylamine, N,N-dibromo-agmatine, N,N-dibromo- histamine, N,N-dibromo-tryptamine, N,N-dibromo-3 -methylthiopropanamine, N,N-dibromo-spermine, N,N-dibromo-carnosine, NjN-dibromo-carcinine, N₅N- dibromoglycine, N,N-dibromo-alpha-aminoisobutyric acid, N₅N- dibromotaurine, N,N-dibromotaurine ethyl ester, N,N-dibromotaurine sulfonamide, N,N-dibromo-2-aminoethanol, N,N-dibromoalanine, N₅N- dibromo-beta-alanine, N,N-dibromoserine, N,N-dibromo-phenyl alanine, N₅N- dibromo-norvaline, N,N-dibromoleucine, N,N-dibromo-isoleucine, N₅N- dibromoproline, N,N-dibromo-hydroxyproline, N,N-dibromo-omega aminoundecanoic acid, N,N-dibromoaspartic acid, N,N-dibromoglutamic acid, N,N-dibromoasparagine, N,N-dibromovaline, N,N-dibromothreonine, N₅N- dibromomethionine, N,N-dibromoglutamine, N,N-dibromotryptophane, N₅N- dibromoarginine, N,N-dibromolysine (alpha or omega), N,N-dibromo-alpha- aminobutyric acid, N,N-dibromo-gamma-aminobutyric acid, N,N-dibromo- alpha, epsilon diamino pimelic acid, N,N-dibromo-ornithine, N,N-dibromo- hydroxylysine (alpha or omega), N,N-dibromo-2-aminopropanol, N₅N- dibromo-diethanolamine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1,1,2,2-tetramethyltaurine. N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N₅N- dibromo-3,3-dimethylhomotaurine, N,N-dibromo ethanesulfonic acid, N₅N- dibromo-1 -methyl ethanesulfonic acid, N,N-dibromo-2-methyl-2-amino- ethanesulfonic acid, N,N-dibromo aminotrimethylene phosphonic acid, N₅N- dibromo-2-amino-5-phosphonopentanoic acid, N,N-dibromo aminoethylphosponic acid diesters, such as the diethylester, N,N-dibromo- 1 - amino- 1-methylethane phosphonic acid, N,N-dibromo-l-amino-2- methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylpropane phosphonic acid, N,N-dibromoleucine phosphonic acid, N,N-dibromo-4- amino-4-phosphonobutyric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino- 8-phosphonooctanoic acid, N,N-dibromoleucine boronic acid, N,N-dibromo-β- alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof.

79. The kit of any of claims 71-77, wherein said agent is a brominated analgesic, brominated tricyclic antidepressant, brominated stimulant, or a polymer bearing N-bromoamine groups.

80. The kit of claim 79, wherein said agent is a brominated analgesic selected from N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N-bromo- prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl-N- bromo-ropivacaine, desbutyl-N-bromo-bupivacaine, desbutyl-N-bromo- levobupivacaine, desmethyl-N-bromo-mepivacaine, d esethyl-N-bromo- procaine, desethyl-N-bromo-proparacaine, desethyl-N-bromo-allocain, desmethyl-N-bromo-encainide, desethyl-N-bromo-procainamide, desethyl-N- bromo-metoclopramide, desmethyl-N-bromo-stovaine, desethyl-N-bromo- propoxycaine, desethyl-N-bromo-bromoprocaine, N-bromo-flecainide, desethyl-N-bromo-tetracaine, N-bromo-procaine, N-bromo-proparacaine, N- bromo-procainamide, N-bromo-metoclopramide, N-bromo-propoxycaine, N- bromo-bromoprocaine, N-bromo-tetracaine, N-bromo-benzocaine, N-bromo- butamben, and desethyl-N-bromo-dibucaine.

81. The kit of claim 79, wherein said agent is a brominated tricyclic antidepressant selected from N-bromo-amoxapine, desmethyl-N-bromo- trimipramine, desmethyl-N-bromo-dothiepin, desmethyl-N-bromo-doxepin, desmethyl-N-bromo-amitriptyline, N-bromo-protriptyline, N-bromo- desipramine, desmethyl-N-bromo- clomipramine, desmethyl-N-bromo- clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptyline, desmethyl-N- bromo-cyclobenzaprine, desmethyl-N-bromo-cyproheptadine, desmethyl-N- bromo-olopatadine, desmethyl-N-bromo-promethazine, desmethyl-N-bromo- trimeprazine, desmethyl-N-bromo-chlorprothixene, desmethyl-N-bromo- chloφromazine, desmethyl-N-bromo-propiomazine, desmethyl-N-bromo- prochlorperazine, desmethyl-N-bromo-thiethylperazine, desmethyl-N-bromo- trifluoperazine, desethyl-N-bromo-ethacizine, and desmethyl-N-bromo- imipramine.

82. The kit of claim 79, wherein said agent is a brominated stimulant selected from N-bromo-amphetamine, N,N-dibromo-amphetamine, and N- bromo-methamphetamine.

83. The kit of claim 79, wherein said agent is a polymer selected from N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N- brominated amino-cellulose, and N-brominated polylysine.

84. The kit of any of claims 71-77, wherein said agent is selected from N-bromo- taurine, N,N-dibromo-taurine, N-bromo-desmethylchlorpromazine, N-bromo-lidocaine, N-bromo-amphetamine, N,N-dibromo-amphetamine, and N-bromo-methamphetamine.

85. A kit comprising (i) optionally an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) instructions for contacting said inorganic oxide, said ammonium salt, and said hypobromite salt with water to form a solution, and (v) instructions for administering said solution to a patient for the treatment of pain or itch.

86. A kit comprising (i) optionally an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) a hypochlorite salt, and (v) instructions for contacting said inorganic oxide, said ammonium salt, said hypobromite salt, and said hypochlorite salt with water to form a solution, and (v) instructions for administering said solution to a patient for the treatment of pain or itch.

87. The kit of claim 85 or 86, further comprising a buffer.

88. The kit of claim 85 or 86, further comprising instructions for topically administering said solution into a patient for the treatment of pain or itch.

89. The kit of claim 85 or 86, further comprising instructions for infusing said solution into a patient at a site of pain.

90. A bandage comprising an N-bromo-N-chloroamine in an amount sufficient to treat pain or itch when applied to the skin of a patient.

91. A bandage comprising a mixture of (i) a first agent selected from N- chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein said first agent and said second agent are present in an amount sufficient to treat pain or itch when applied to the skin of a patient.

92. A bandage comprising an agent selected from N-bromoamines and N,N-dibromoamines in an amount sufficient to treat pain or itch when applied to the skin of a patient.

93. The bandage of claim 92, wherein said agent is selected from bromourea, N-bromo-methylamine, N-bromo-ethylamine, N-bromo- isobutylamine, N-bromo-2-methylbutylamine, N-bromo-pyrrolidine, N-bromo- phcnethylamine, N-bromo-agmatine, N-bromo-histamine, N-bromo- tryptamine, N-bromo-3-methylthiopropanamine, N-bromo-spermine, N-bromo- carnosine, N-bromo-carcinine, N-bromo-glutathione sulfonamide, N- bromoglycine, N-bromosulfamic acid, N-bromosarcosine, N-bromo- alpha- aminoisobutyric acid, N-bromotaurine, N-bromotaurine ethyl ester, N- bromotaurine sulfonamide, N-bromo-2-aminoethanol, N-bromo-acetylglycine, N-bromoalanine, N-bromo-beta-alanine, N-bromoserine, N-bromo-phenyl alanine, N-bromo-norvaline, N-bromoleucine, N-bromo-isoleucine, N- bromoproline, N-bromo-hydroxyproline, N-bromo-omega aminoundecanoic acid, N-bromoaspartic acid, N-bromoglutamic acid, N-bromoasparagine, N- bromovaline, N-bromothreonine, N-bromocystine, N-bromomethionine, N- bromoglutamine, N-bromotryptophane, N-bromohistidine, N-bromoarginine, N-bromolysine (alpha or omega), N-bromo-alpha-aminobutyric acid, N-bromo- gamma-aminobutyric acid, N-bromo- alpha, epsilon diamino pimelic acid, N- bromo-ornithine, N-bromo-hydroxylysine (alpha or omega), N- bromoanthranilic acid, N-bromo-p-aminobenzoic acid, N-bromosulfanilic acid, N-bromo-orthanilic acid, N-bromo-phenyl sulfamic acid, N- bromoaminopropanesulfonic acid, N-bromo-2-aminopropanol, N-bromo- diethanolamine, N-bromo-ethylenediamine tetraacetic acid, N-bromo- aminomethane-sulfonic, N-bromo-glycylglycine, N-bromo- glycylglycylglycine, N-bromo-metanilic acid, N-bromo-N-octodecanyl glycine, N-bromo-2,2-dimethyltaurine, N-bromo- 1,1, 2,2-tetramethyltaurine, N-bromo- 2,2,3,3-tetramethyl-β-alanine, N-bromo-3,3-dimethylhomotaurine, N-bromo ethanesulfonic acid, N-bromo- 1 -methyl ethanesulfonic acid, N-bromo-2- methyltaurine, N-bromo-2-methyl-2-amino-ethanesulfonic acid, N-bromo aminotrimethylene phosphonic acid, N-bromo-2-amino-5-phosphonopentanoic acid, N-bromo aminoethylphosponic acid, N-bromo- 1 -amino- 1-methylethane phosphonic acid, N-bromo- l-amino-2-methylethane phosphonic acid, N- bromo-l-amino-2-methylpropane phosphonic acid, N-bromoleucine phosphonic acid, N-bromo-4-amino-4-phosphonobutyric acid, N-bromo-2- amino-5-phosphonovaleric acid, N-bromo-2-amino-5-phosphonovaleric acid, N-bromo-2-amino-8-phosphonooctanoic acid, N-bromoleucine boronic acid, N-bromo- β- alanine boronic acid, N,N-dibromo-methylamine, N,N-dibromo- ethylamine, N,N-dibromo-isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo-phenethylamine, N,N-dibromo-agmatine, N,N-dibromo- histamine, N,N-dibromo-tryptamine, N,N-dibromo-3-methylthiopropanamine, N,N-dibromo-spermine, N,N-dibromo-carnosine, NjN-dibromo-carcininc, N₅N- dibromoglycine, N,N-dibromo-alpha-aminoisobutyric acid, N₅N- dibromotaurine, N,N-dibromotaurine ethyl ester, N,N-dibromotaurine sulfonamide, N,N-dibromo-2-aminoethanol, N,N-dibromoalanine, N₅N- dibromo-beta-alanine, N,N-dibromoserine, N,N-dibromo-phenyl alanine, N₅N- dibromo-norvaline, N.N-dibromoleucine, N,N-dibromo-isoleucine, N₅N- dibromoproline, N,N-dibromo-hydroxyproline, N,N-dibromo-omega aminoundecanoic acid, N,N-dibromoaspartic acid, N,N-dibromoglutamic acid, N,N-dibromoasparagine, N,N-dibromovaline, N,N-dibromothreonine, N₅N- dibromoraethionine, N,N-dibromoglutamine, N,N-dibromotryptophane, N₅N- dibromoarginine, N,N-dibromolysine (alpha or omega), N,N-dibromo-alpha- aminobutyric acid, N,N-dibromo-gamma-aminobutyric acid, N,N-dibromo- alpha, epsilon diamino pimelic acid, N,N-dibromo-ornithine, N,N-dibromo- hydroxylysine (alpha or omega), N,N-dibromo-2-aminopropanol, N₅N- dibromo-diethanolamine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N₅N- dibromo-3,3-dimethylhomotaurine, N,N-dibromo ethanesulfonic acid, N₅N- dibromo-1 -methyl ethanesulfonic acid, N,N-dibromo-2-methyl-2-amino- ethanesulfonic acid, N,N-dibromo aminotrimethylene phosphonic acid, N₅N- dibromo-2-amino-5-phosphonopentanoic acid, N,N-dibromo aminoethylphosponic acid diesters, such as the diethylester, N,N-dibromo-l- amino- 1 -methylethane phosphonic acid, N,N-dibromo-l-amino-2- methylethane phosphonic acid, N,N-dibromo-l-amino-2-methylpropane phosphonic acid, N,N-dibromoleucine phosphonic acid, N,N-dibromo-4- amino-4-phosphonobutyric acid, N,N-dibromo-2-amino-5-phosphonoval eric acid, N,N-dibromo-2-amino-5-phosphonovaleric acid, N,N-dibromo-2-amino- 8-phosphonooctanoic acid, N,N-dibromoleucine boronic acid, N,N-dibromo-β- alanine boronic acid, and pharmaceutically acceptable salts, esters, and amides thereof.

94. The bandage of claim 92, wherein said agent is a brominated analgesic, brominated tricyclic antidepressant, brominated stimulant, or a polymer bearing N-bromoamine groups.

95. The bandage of claim 94, wherein said agent is a brominated analgesic selected from N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N- bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl- N-bromo-ropivacaine, desbutyl-N-bromo-bupivacaine, desbutyl-N-bromo- levobupivacaine, desmethyl-N-bromo-mepivacaine, desethyl-N-bromo- procaine, desethyl-N-bromo-proparacaine, desethyl-N-bromo-allocain, desmethyl-N-bromo-encainide, desethyl-N-bromo-procainamide, desethyl-N- bromo-metoclopramide, desmethyl-N-bromo-stovaine, desethyl-N-bromo- propoxycaine, desethyl-N-bromo-bromoprocaine, N-bromo-flecainide, desethyl-N-bromo-tetracaine, N-bromo-procaine, N-bromo-proparacaine, N- bromo-procainamide, N-bromo-metoclopramide, N-bromo-propoxycaine, N- bromo-bromoprocaine, N-bromo-tetracaine, N-bromo-benzocaine, N-bromo- butamben, and desethyl-N-bromo-dibucaine.

96. The bandage of claim 94, wherein said agent is a brominated tricyclic antidepressant selected from N-bromo-amoxapine, desmethyl-N- bromo-trimipramine, desmethyl-N-bromo-dothiepin, desmethyl-N-bromo- doxepin, desmethyl-N-bromo-amitriptyline, N-bromo-protriptyline, N-bromo- desipramine, desmethyl-N-bromo-clomipramine, desmethyl-N-bromo- clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptyline, desmethyl-N- bromo-cyclobenzaprine, desmethyl-N-bromo-cyproheptadine, desmethyl-N- bromo-olopatadine, desmethyl-N-bromo-promethazine, desmethyl-N-bromo- trimeprazine, desmethyl-N-bromo-chlorprothixene, desmethyl-N-bromo- chlorpromazine, desmethyl-N-bromo-propiomazine, desmethyl-N-bromo- prochlorperazine, desmethyl-N-bromo-thiethylperazine, desmethyl-N-bromo- trifluoperazine, desethyl-N-bromo-ethacizine, and desmethyl-N-bromo- imipramine.

97. The bandage of claim 94, wherein said agent is a brominated stimulant selected from N-bromo-amphetamine, N,N-dibromo- amphetamine, and N-bromo-methamphetamine.

98. The bandage of claim 94, wherein said agent is a polymer selected from N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N- brominated amino-cellulose, and N-brominated poly Iy sine.

99. The bandage of claim 92, wherein said agent is selected from N- bromo-taurine, N,N-dibromo-taurine, N-bromo-desmethylchlorpromazine, N- bromo-lidocaine, N-bromo-amphetamine, N,N-dibromo-amphetamine, and N- bromo-methamphetamine .

100. The bandage of any of claims 90 to 92, wherein a patient experiences some relief from pain or itch within 20 minutes of applying said bandage to the skin of said patient.

101. An infusion device comprising:

(i) a first reservoir containing a first solution comprising an ammonium salt or an amine or a salt thereof;

(ii) a second reservoir containing a second solution comprising hypobromous acid or a salt thereof;

(iv) a cannula in fluid communication with said mixer chamber for delivering said N-bromoamine to a subject.

102. An infusion device comprising: (i) a first reservoir containing a first solution comprising an ammonium salt or an amine or a salt thereof;

(ii) a second reservoir containing a second solution hypobromous acid, or a salt thereof, and hypochlorous acid, or a salt thereof;

(iii) a mixing chamber for combining said first solution and said second solution to form solution containing N-halogenated amine; and

(iv) a cannula in fluid communication with said mixer chamber for delivering said N-halogenated to a subject.

103. An infusion device comprising:

(i) a reservoir containing a first solution comprising an ammonium bromide salt and/or an amine and bromide ion;

(ii) a power source electrically connected to an electrode in contact with said solution and configured to produce N-bromoamine via electrolysis; and

(iii) a cannula in fluid communication with said solution for delivering said N-bromoamine to a subject.

104. An infusion device comprising:

(i) a reservoir containing a first solution comprising an ammonium salt, bromide ions, and chloride ions;

(ii) a power source electrically connected to an electrode in contact with said solution and configured to produce produce N-bromoamine, N- chloroamine, and/or N-bromo-N-chloroamine via electrolysis; and

(iii) a cannula in fluid communication with said solution for delivering said solution to a subject.

105. An infusion device comprising:

(i) a first reservoir containing a first solution comprising an amine or a salt thereof; (ii) a second reservoir containing a second solution comprising bromide ions;

(iii) a power source electrically connected to an electrode in contact with said second solution and configured to produce hypobromous acid or a salt thereof via electrolysis;

(iv) a mixing chamber for combining said first solution and said hypobromous acid or a salt thereof to form an N-bromoamine; and

(v) a cannula in fluid communication with said mixing chamber for delivering said N-bromoamine to a subject.

106. An infusion device comprising:

(i) a first reservoir containing a first solution comprising an amine or a salt thereof;

(ii) a second reservoir containing a second solution comprising chloride and bromide ions;

(iii) a power source electrically connected to an electrode in contact with said second solution and configured to produce hypochlorous acid, or a salt thereof, and hypobromous acid, or a salt thereof, via electrolysis;

(iv) a mixing chamber for combining said first solution and said hypobromous acid or a salt thereof to form an N-halogenated amine; and

(v) a cannula in fluid communication with said mixing chamber for delivering said N-halogenated to a subject.

107. A method of treating pain in a patient in need thereof, said method comprising topically administering to said patient a compound of formula (I):

wherein

X is -NHCl, -NHBr, -NCl₂, -NBr₂, or -NBrCl; Y is -COOH, -CONH₂, -SO₃H, -SO₂NH₂, -P(O)(OH)₂, or -B(OH)₂;

Z is selected from -0-,-S-, -OC(O)-, -C(O)O-, -S(O)₂-, -NR³C(O)-, and -

C(O)NR³- or Z is absent; each of R¹ and R² is, independently, selected from CH₃, CH₂CH₃, and

CH₂CH₂CH₃, or R and R combine to form a carbocyclic ring of 3 to 8 carbon atoms; each of R³ and R⁴ is, independently, selected from H, CH₃, CH₂CH₃, and

CH₂CH₂CH₃; R^a is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is O or an integer from 1 to 3; and m is O or an integer from 1 to 3, or a salt thereof, in an amount sufficient to treat said pain.

108. A method of treating pain at a site in a patient in need thereof, said method comprising locally injecting at said site a compound of formula (I):

wherein

X is -NHCl, -NHBr, -NCl₂, -NBr₂, or -NBrCl;

Y is -COOH, -CONH₂, -SO₃H, -SO₂NH₂, -P(O)(OH)₂, or -B(OH)₂;

Z is selected from -0-,-S-, -OC(O)-, -C(O)O-, -S(O)₂-, -NR³C(O)-, and -

C(O)NR³- or Z is absent; each of R and R is, independently, selected from CH₃, CH₂CH₃, and

CH₂CH₂CH₃, or R¹ and R² combine to form a carbocyclic ring of 3 to 8 carbon atoms; each of R³ and R⁴ is, independently, selected from H, CH₃, CH₂CH₃, and

CH₂CH₂CH₃; R³ is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is O or an integer from 1 to 3; and m is O or an integer from 1 to 3, or a salt thereof, in an amount sufficient to treat said pain

109. The method of claim 107 or 108, wherein said pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.

110. The method of claim 107 or 108, wherein said pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.

111. A method of treating itch in a patient in need thereof, said method comprising topically administering to the patient a compound of formula (I):

wherein

X is -NHCl, -NHBr, -NCl₂, -NBr₂, or -NBrCl;

Y is -COOH, -CONH₂, -SO₃H, -SO₂NH₂, -P(O)(OH)₂, or -B(OH)₂;

Z is selected from -0-,-S-, -OC(O)-, -C(O)O-, -S(O)₂-, -NR³C(O)-, and -

CH₂CH₂CH₃; R^a is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is 0 or an integer from 1 to 3 ; and m is 0 or an integer from 1 to 3, or a salt thereof, in an amount sufficient to treat said itch.

112. The method of any of claims 107-111, wherein said compound of formula (I) is selected from N-chloro-2,2-dimethyltaurine, N-chloro-1,1,2,2- tetramethyltaurine, N-chloro-2,2,3,3-tetramethyl-β-alanine, N-chloro-3,3- dimethylhomotaurine, N,N-dichloro-2,2-dimethyltaurine, N,N-dichloro- 1,1 ,2,2-tetramethyltaurine, N,N-dichloro-2,2,3,3-tetramethyl-β-alanine, N,N- dichloro-3 ,3 -dimethylhomotaurine, N-bromo-2,2-dimethyltaurine, N-bromo- 1,1,2,2-tetramethyltaurine, N-bromo-2,2,3,3-tetramethyl-β-alanine, N-bromo- 3, 3 -dimethylhomotaurine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1,1,2,2-tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl-β-alanine, N,N- dibromo-3,3-dimethylhomotaurine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3 ,3- tetramethyl-β-alanine, N-bromo-N-chloro-3, 3 -dimethylhomotaurine, and salts thereof.

113. A method of treating pain in a subject, said method comprising administering to said subject N,N-dichloro-2,2-dimethyltaurine, or a salt thereof, in an amount sufficient to treat said pain.

114. A method of treating itch in a subject, said method comprising administering to said subject N,N-dichloro-2,2-dimethyltaurine, or a salt thereof, in an amount sufficient to treat said itch.

115. A method of treating pain in a subject, said method comprising administering to said subject a cmopound selected from N,N-dichloro- 1,1,2,2- tetramethyltaurine; N,N-dibromo-2,2-dimethyltaurine; N,N-dibromo- 1 , 1 ,2,2- tetramethyltaurine; N,N-dichloro-2-methyltaurine; and N,N-dichloro-3,3- dimethylhomotaurine, or a salt thereof, in an amount sufficient to treat said pain.

116. A method of treating itch in a subject, said method comprising administering to said subject a cmopound selected from N,N-dichloro-l,l,2,2- tetramethyltaurine; N,N-dibromo-2,2-dimethyltaurine; N,N-dibromo- 1 , 1 ,2,2- tetramethyltaurine; N,N-dichloro-2-methyltaurine; and N,N-dichloro-3,3- dimethylhomotaurine, or a salt thereof, in an amount sufficient to treat said itch.

117. A solution comprising a mixture of halogenated amine and unhalogenated amine dissolved in a buffered aquous solution having a pH of between 7 and 10, wherein (i) said halogenated amine is a chlorinated amine or a brominated amine; (ii) the ratio of unhalogenated amine to halogenated amine in said solution is greater than 1.5; and (iii) the concentration of halogenated amine is between 0.0001 M and 0.25 M.

118. The solution of claim 117, wherein said buffered aquous solution has a pH of between 8 and 9.5.

119. The solution of claim 117, wherein the ratio of unhalogenated amine to halogenated amine is between 2 and 10.

120. The solution of claim 117, wherein the concentration of halogenated amine is between 0.0005 M and 0.015 M.

121. The solution of claim 117, wherein said amine is selected from taurine, 2,2-dimethyltaurine, 1,1,2,2-tetramethyltaurine, 2,2,3,3-tetramethyl-β- alanine, 3,3-dimethylhomotaurine, and salts thereof.

122. A kit comprising (i) a solution of any of claims 117-121, and (ii) instructions for keeping said solution refrigerated.

123. A method of treating pain in a subject, said method comprising administering to said subject a solution of any of claims 117-121 in an amount sufficient to treat said pain.

124. A method of treating itch in a subject, said method comprising administering to said a solution of any of claims 117-121 in an amount sufficient to treat said itch.

125. A compound of formula (I):

wherein

X is -NBrCl;

Y is -COOH, -CONH₂, -SO₃H, -SO₂NH₂, -P(O)(OH)₂, or -B(OH)₂;

Z is selected from -0-,-S-, -OC(O)-, -C(O)O-, -S(O)₂-, -NR^aC(O>, and -

C(O)NR³- or Z is absent; each of R¹ and R² is, independently, selected from H, CH₃, CH₂CH₃, and

CH₂CH₂CH₃; R^a is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; n is O or an integer from 1 to 3; and m is O or an integer from 1 to 3, or a salt thereof.

126. The compound of claim 125, wherein said compound is selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro-l,l,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3- tetramethyl-β-alanine, and N-bromo-N-chloro-3,3-dimethylhomotaurine, or a salt thereof.

127. A pharmaceutical composition comprising (i) a brominated amine, (ii) a chlorinated amine, and (iii) a buffered aquous solution having a pH of between 7 and 10, wherein the concentration of brominated amine is between 0.0001 M and 0.25 M and the concentration of chlorinated amine is between 0.0001 M and 0.25 M.

128. The pharmaceutical composition of claim 127, wherein said pharmaceutical composition is formulated for topical administration.

129. The pharmaceutical composition of claim 127, wherein said pharmaceutical composition is formulated for injection.

130. The pharmaceutical composition of claim 127, wherein the ratio of chlorinated amine to brominated amine in said pharmaceutical composition is between 100:1 and 1 :100.

131. A compound selected from N-chloro-piperidine-4-sulfonic acid, N- chloro-piperidine-3 -sulfonic acid, N-bromo-piperidine-4-sulfonic acid, and N- bromo-piperidine-3 -sulfonic acid, or a salt thereof.