Methods and compositions for treating pain using capsaicin

Abstract

To provide a pharmaceutical composition for use in the amelioration of osteoarthritic knee joint pain in human patients.SOLUTION: There is provided a pharmaceutical composition the use of which ameliorates osteoarthritic knee joint pain in human patients and which involves: a. applying a cooling article having an external surface temperature of 5-15°C for 15 minutes to the external surface of a knee of a human patient presenting with osteoarthritic knee joint pain; b. injecting a pharmaceutical composition comprising 0.1-0.5 g of lidocaine as the sole pain relief agent into the intra-articular space of the knee joint; c. applying a cooling article having an external surface temperature of 5-15°C for 30 minutes to the external surface of the knee; d. injecting a pharmaceutical composition containing 1 mg of capsaicin into the intra-articular space of the knee joint; and e. applying a cooling article having an external surface temperature of 5-15°C for at least 30 minutes to the external surface of the knee.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 535,003, filed July 20, 2017, the contents of which are incorporated herein by reference.

[0002] The present invention provides methods and compositions for the treatment of pain, such as arthritis pain, using capsaicin in a procedure that attenuates the transient burning sensation experienced by a patient upon capsaicin administration through the use of controlled cooling to reduce the temperature of tissue exposed to capsaicin, optionally in combination with the use of a local anesthetic. [Background technology]

[0003] Pain can function as a protective mechanism that allows healthy humans and animals to avoid tissue damage and / or prevent further damage to injured tissue.However, there are many cases where pain persists beyond its usefulness.Such unnecessary suffering caused by pain can impair the subject's physical mobility, mental behavior, and therefore contribute to depression.

[0004] Over the years, substantial resources have been devoted to studying the causes of various types of pain and developing drugs to reduce the pain experienced by patients. Representative classes of common pain-relieving drugs include opioids, nonsteroidal anti-inflammatory drugs, corticosteroids, and centrally acting drugs such as antidepressants, antiepileptic drugs, pregabalin, and gabapentin. Capsaicin has been described for use in pain treatment. See, for example, U.S. Pat. Nos. 5,962,532; 8,420,600; 8,367,733; and 8,158,682. In certain commercial products containing capsaicin for pain relief, capsaicin is formulated as a cream (e.g., Capzasin) or a patch (e.g., a capsaicin-containing transdermal patch marketed under the trade name QUTENZA®) for topical application to a patient's skin.

[0005] One challenging aspect of using capsaicin to treat pain, especially when capsaicin is administered by injection, is that the administration of capsaicin causes initial nerve excitation, resulting in a transient burning side effect.This transient burning sensation can be significant for some patients.Specific approaches to address the harmful side effect of the transient burning sensation caused by capsaicin have been described in the literature, including the approach described in U.S. Patent No. 5,962,532. Summary of the Invention [Problem to be solved by the invention]

[0006] Because there is an unmet need for additional treatment options for achieving pain relief, particularly treatment options that do not have the addiction problems associated with many opioid-based pain therapies, there is a need for new procedures for treating pain. The present invention addresses this need and provides other related advantages. [Means for solving the problem]

[0007] The present invention provides methods and compositions for treating pain, such as joint pain, using capsaicin in a procedure that reduces the transient burning sensation experienced by a patient due to capsaicin administration. This method desirably provides relief from joint pain, such as osteoarthritic knee pain, over an extended period of time, such as at least about three months, six months, nine months, or one year. Because capsaicin administration causes initial nerve excitation and results in the side effect of a transient burning sensation, this method utilizes a cooling device, such as a material wrap cooled via circulating fluid, to reduce the temperature of tissue exposed to capsaicin over a specified period of time, optionally in combination with the administration of a local anesthetic, to reduce the transient burning sensation experienced by the patient and significantly reduce or even eliminate the transient burning sensation caused by capsaicin. The cooling device, which is intended for application to the exterior surface of a patient's joint, such as the knee, desirably has an exterior surface temperature ranging from about 5°C to about 15°C, more desirably from about 5°C to about 10°C.

[0008] While insufficient cooling may be sufficient to sufficiently reduce the transient burning sensation experienced by a patient due to capsaicin administration, as excessive cooling of skin tissue may cause the adverse effect of skin necrosis, this method desirably involves applying a cooling device having a specific temperature range (e.g., about 5°C to about 15°C, more desirably about 5°C to about 10°C) for a specific period of time before and after administration of capsaicin. Treatment methods can be further characterized according to the temperature of the tissue and / or fluid within the joint into which capsaicin is administered. In certain embodiments, fluid within the intra-articular space of a joint, such as a knee joint, is cooled to a temperature in the range of about 26°C to about 33°C prior to administration of capsaicin, and then maintained at a temperature in the range of about 26°C to about 33°C for a duration of at least 30 minutes after administration of capsaicin.

[0009] The techniques described above for reducing the transient burning sensation caused by administration of capsaicin can be used to minimize procedural pain experienced by patients undergoing capsaicin therapy for painful nerve-related pain, and provided herein are methods for treating painful nerve-related pain, such as intermetatarsal neuroma, that utilize cooling devices, such as material wraps cooled via circulating fluid, to reduce the temperature of tissue exposed to capsaicin over a specified period of time, optionally in combination with administration of a local anesthetic, to attenuate the transient burning sensation experienced by the patient and result in a significant reduction or even elimination of the transient burning sensation caused by capsaicin.

[0010] Various aspects and embodiments of the invention are described in further detail below. Accordingly, one aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0011] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0012] Another aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling agent to the exterior surface of said knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0013] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling agent to the exterior surface of said knee. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0014] Another aspect of the invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby ameliorating joint pain in a human patient.

[0015] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; b. optionally, administering a local anesthetic into said joint; c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0016] Another aspect of the invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby ameliorating joint pain in a human patient.

[0017] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; b. optionally, administering a local anesthetic into said joint; c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0018] Another aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 15 minutes, the cooling device having an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma requiring pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. applying a cooling device to the patient's skin adjacent to the intermetatarsal neuroma for a duration of at least about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0019] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 15 minutes, the cooling device having an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma requiring pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. applying a cooling device to the patient's skin adjacent to the intermetatarsal neuroma for a duration of at least about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot. thereby attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient.

[0020] Another aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient proximal to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 26°C to about 33°C for tissue proximal to the intermetatarsal neuroma; d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. Applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0021] Another aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma, comprising: a. applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient proximal to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 26°C to about 33°C for tissue proximal to the intermetatarsal neuroma; d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. Applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy. thereby reducing the transient burning sensation caused by injection of capsaicin into tissues near an intermetatarsal neuroma.

[0022] The aforementioned treatment methods may be further characterized according to various characteristics, such as the dose of lidocaine local anesthetic, the dose of capsaicin, the duration of pain relief, and the characteristics of the cooling product, etc. These and other characteristics are described in more detail in the detailed description below. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 is a diagram of a cooling article that is a wrap-on pad applied to a person's knee. [Figure 2]

[0023] Figure 1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) an ice pack, as further described in Example 7. The "standard cooling device" was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken prior to insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 3]

[0023] Figure 1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad; or (ii) an ice pack, as further described in Example 7. The "standard cooling device" was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken prior to insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 4]1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 5]1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 6]1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 7]1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 8]FIG. 1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 9]FIG. 1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 10]1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 11]1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 12]FIG. 1 is a graph showing mean intra-articular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 10. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 13]1 is a graph showing mean intra-articular (IA) temperature and mean NPRS pain scores over time using the following cooling devices: (i) Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 10. The "standard cooling device" was the Breg Knee WrapOn Polar Pad. The "ice gel pack" was the Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time any temperature reading of the temperature probe was taken before insertion into the intra-articular space of the patient's knee; B is the time the temperature probe was inserted into the intra-articular space of the patient's knee; C is the time the cooling device was applied to the patient's knee; D is the time the cooling device was removed from the patient's knee; E is the time a solution of 2% w / w lidocaine was administered to the patient's knee by intra-articular injection; F is the time the cooling device was reapplied to the patient's knee; G is the time the cooling device was removed from the patient's knee; H is the time trans-capsaicin was administered by intra-articular injection; I is the time the cooling device was reapplied to the patient's knee; J is the time the cooling device was removed from the patient's knee; and K is the time the temperature probe was removed from the patient's knee. [Figure 14] 1 is a graph showing the temperature profiles recorded for a Breg Knee WrapOn Polar Pad, an Elasto-gel cooling device, and an ice pack, as further described in Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention provides methods and compositions for treating pain, such as joint pain, using capsaicin in a procedure that reduces the transient burning sensation experienced by a patient due to capsaicin administration. The method desirably provides relief from joint pain, such as osteoarthritic knee pain, over an extended period of time, such as at least about three months, six months, nine months, or one year. Because capsaicin administration causes initial nerve excitation, resulting in the harmful side effect of a transient burning sensation, the method utilizes a cooling device, such as a material wrap cooled via circulating fluid, to reduce the temperature of tissue exposed to capsaicin for a specified duration, optionally in combination with the administration of a local anesthetic, to reduce the transient burning sensation experienced by the patient and substantially reduce or even eliminate the transient burning sensation caused by capsaicin. The cooling device desirably has an outer surface temperature ranging from about 5°C to about 15°C, more desirably from about 5°C to about 10°C, for application to the outer surface of a patient's joint, such as the knee.

[0025] Because excessive cooling of skin tissue can cause the adverse effect of skin necrosis, while insufficient cooling to sufficiently reduce the transient burning sensation experienced by a patient due to capsaicin administration can be inadequate, this method desirably involves applying a cooling device having a specific temperature range (e.g., about 5°C to about 15°C, more desirably about 5°C to about 10°C) for a specific duration both before and after administration of capsaicin. Treatment methods can be further characterized according to the temperature of the tissue and / or fluid within the joint into which capsaicin is administered; in certain embodiments, fluid within the intra-articular space of a joint, such as a knee joint, is cooled to a temperature in the range of about 26°C to about 33°C before administration of capsaicin, and then maintained at a temperature in the range of about 26°C to about 33°C for a duration of at least 30 minutes after administration of capsaicin.

[0026] The transient burning sensation caused by capsaicin administration may manifest in the patient as a burning sensation, pain, and / or soreness in the area where the capsaicin was administered. The techniques described herein are designed to reduce the magnitude of such transient burning sensation experienced by the patient.

[0027] The aforementioned techniques for reducing the transient burning sensation caused by administration of capsaicin can be used to minimize procedural pain experienced by patients undergoing capsaicin therapy for painful nerve-related pain, and provided herein are methods for treating painful nerve-related pain, such as intermetatarsal neuroma. The methods utilize cooling devices, such as material wraps cooled via circulating fluid, to reduce the temperature of tissue exposed to capsaicin for a specified duration, optionally in combination with administration of a local anesthetic, to attenuate the transient burning sensation experienced by the patient and result in a substantial reduction or even elimination of the transient burning sensation caused by capsaicin.

[0028] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques are described in such references as "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992), "Current Protocols in Molecular Biology" (F.M. Ausubel et al., eds., 1987, and periodic updates), and "Current Protocols in Immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety. Various aspects of the present invention are presented in the sections below, although aspects of the invention described in a particular section should not be limited to any particular section.

[0029] I. Definition To facilitate understanding of the present invention, several terms and phrases are defined below.

[0030] The terms "a" and "an" as used herein mean "one or more" and include plurals unless the context requires otherwise.

[0031] The phrase "injection pain scale" refers to a measure of pain experienced by a patient upon administration of capsaicin by injection, where the degree of pain experienced by the patient is rated by the patient as either: (i) none, (ii) mild pain, (iii) moderate pain, or (iv) severe pain.

[0032] As further explained herein, the abbreviation "NPRS" refers to the Numeric Pain Rating Scale.

[0033] As used herein, the terms "subject" and "patient" refer to an organism treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), and more preferably humans.

[0034] As used herein, the term "effective amount" refers to an amount of a compound (e.g., a compound of the present invention) sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more administrations, applications, or doses, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treat" includes any effect that results in the improvement of a condition, disease, disorder, or the like (e.g., reduction, lowering, modulating, or elimination). The terms "ameliorate" and "ameliorating" refer to the reduction, lowering, and / or elimination of a given condition, such as pain. The terms "attenuate" and "attenuating" refer to the reduction, lowering, and / or elimination of a given condition, such as pain.

[0035] The compounds of the present disclosure may contain a C-C double bond and therefore may exist as geometric isomers. Individual geometric isomers of the compounds of the present invention can be synthetically prepared from commercially available starting materials containing a single geometric isomer in high purity and / or by separating a mixture of geometric isomers using chromatographic procedures well known in the art. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Substituents around a carbon-carbon double bond can alternatively be designated as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond.

[0036] The compounds may be in amorphous or crystalline form, and the present invention encompasses all such amorphous and crystalline forms.

[0037] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo therapeutic use.

[0038] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to a subject, is capable of providing a compound of the present invention. As is known to those skilled in the art, "salts" of compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, are not themselves pharmaceutically acceptable but may be used in the preparation of salts useful as intermediates in obtaining compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0040] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxide, alkaline earth metal (e.g., magnesium) hydroxide, ammonia, and bases of formula NW4 + (Wherein W is C 1-4 Examples include compounds in which the aryl group is alkyl.

[0041] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. + , NH4 + and NW4 +(Wherein W is C 1-4 and the anion of a compound of the present invention combined with a suitable cation such as an alkyl group.

[0042] For therapeutic uses, salts of the compounds of the invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0043] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or composition, including a compound of the invention, effective to produce some desired therapeutic effect in at least a subpopulation of cells of an animal, at a reasonable risk-benefit ratio applicable to any drug treatment.

[0044] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk-benefit ratio.

[0045] Unless otherwise specified, the term "about" means within ±10% of the stated value. The invention includes embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0046] The term "alkyl," as used herein, refers to a straight-chain or branched saturated hydrocarbon, e.g., a straight-chain or branched group of 1 to 12, 1 to 10, or 1 to 6 carbon atoms (referred to herein as C1 to C6, respectively). 12 Alkyl, C1-C 10alkyl and C1-C6 alkyl). Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0047] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or two hydroxyl groups. In certain embodiments, a hydroxyalkyl is an alkyl group that is substituted with only one hydroxyl group.

[0048] The term "hydroxyalkanoic acid" refers to a linear or branched saturated hydrocarbon substituted with (i) one -COH group, and (ii) one or two hydroxyl groups.

[0049] The term "alkenyl," as used herein, refers to a straight-chain or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, e.g., a straight-chain or branched group of 2 to 12, 2 to 10, or 2 to 6 carbon atoms (referred to herein as C2 to C6, respectively). 12 Alkenyl, C2-C 10 alkenyl and C2-C6 alkenyl). Typical alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

[0050] The term "hydroxyalkenyl" refers to an alkenyl group substituted with one or two hydroxyl groups. In certain embodiments, the hydroxyalkenyl is an alkenyl group substituted with only one hydroxyl group.

[0051] The term "hydroxyalkenoic acid" refers to a straight-chain or branched unsaturated hydrocarbon having one carbon-carbon double bond, where the hydrocarbon is substituted with (i) one -COH group, and (ii) one or two hydroxyl groups.

[0052] The term "polyethylene glycolyl" refers to a radical of polyethylene glycol. Polyethylene glycolyl is a chemical fragment of a portion of a larger molecule. When polyethylene glycolyl is attached to the rest of the molecule at a certain position, the polyethylene glycolyl forms a monoradical, e.g., "-(CH2CHO) x -H" where x is an integer greater than 1. When polyethylene glycolyl is used as an internal moiety connecting two fragments of a molecule, the polyethylene glycolyl is "-(CH2CH2O) x - (where x is an integer greater than 1), is a diradical with an attachment point at each end of polyethylene glycolyl. In certain embodiments, x is an integer ranging from about 5 to about 100, from about 5 to about 50, from about 5 to about 25, from about 5 to about 15, from about 10 to about 50, from about 10 to about 30, or from about 10 to about 20. In certain embodiments, x is about 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19. In certain preferred embodiments, x is about 15.

[0053] Throughout the description, where compositions are described as having, including, or comprising specific ingredients, or processes and methods are described as having, including, or comprising specific steps, it is considered that in addition there are compositions of the invention that consist essentially of, or consist of, the recited ingredients, and there are processes and methods according to the invention that consist essentially of, or consist of, the recited processing steps.

[0054] As a general matter, percentages specifying compositions are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, the variable's preceding definition controls.

[0055] II. Therapeutic Use for Joint Pain One aspect of the present invention provides a method for treating joint pain using injectable capsaicin and a procedure for attenuating the transient burning sensation associated with capsaicin administration. The method desirably provides joint pain relief for an extended period of time, such as at least about three months, six months, nine months, or one year. The method utilizes a cooling device, such as a material wrap cooled via circulating fluid, optionally in combination with the administration of a local anesthetic, to reduce the temperature of tissue exposed to capsaicin over a specified period of time. In a preferred embodiment, the method is used to ameliorate osteoarthritic knee joint pain in a human patient by administering capsaicin to the intra-articular space of the patient's knee joint via a protocol in which a cooling device is applied to the outer surface of the patient's knee before and after administration of capsaicin, e.g., the cooling device has an outer surface temperature in the range of about 5°C to about 15°C, more preferably about 5°C to about 10°C, for application to the outer surface of the patient's knee. Various aspects and embodiments of the method are described below.

[0056] First Method One aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0057] Second Method One aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C; and b. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0058] In certain embodiments, the method includes step (e) applying a cooling article to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of about 5°C to about 15°C.

[0059] Third Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0060] Fourth Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C; and b. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 5°C to about 15°C. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0061] In certain embodiments, the method includes step (e) applying a cooling article to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of about 5°C to about 15°C.

[0062] Fifth Method One aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling agent to the exterior surface of said knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0063] Method 6 One aspect of the invention is a method for ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling material to the exterior surface of said knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0064] In certain embodiments, the method includes the step (e) of applying a cooling article to the exterior surface of the knee.

[0065] 7th Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling agent to the exterior surface of said knee. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0066] Method 8 One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling article to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain; then b. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising a single pain-reducing agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof; and c. applying a cooling product to the exterior surface of the knee to achieve a temperature in the range of about 26°C to about 33°C for fluid within the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling material to the exterior surface of said knee. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0067] In certain embodiments, the method includes the step (e) of applying a cooling article to the exterior surface of the knee.

[0068] Exemplary Characteristics of the First, Second, Third, and Fourth Methods The first, second, third, and fourth methods described above may be further characterized by additional features, such as a step involving knee flexion, characterization of the temperature of the cooling article surface for application to the outer surface of the knee, the dose of lidocaine, and characterization of the pharmaceutical composition including a single pain-relieving agent. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0069] knee flexion The method may be further characterized depending on the presence or absence of a step including flexion of the knee to which capsaicin has been administered. For example, in certain embodiments, the knee is flexed after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed about 5 times over about 1 minute after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed and straightened after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed and straightened about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the knee is flexed and extended about 5 times over a period of about 1 minute.

[0070] Coolant surface temperature for application to the exterior of the knee The method may be further characterized according to the temperature of the surface of the cooling device for application to the outer surface of the knee. For example, in certain embodiments, the cooling device has an outer surface temperature in the range of about 6°C to about 13°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 7°C to about 13°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 7°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 5°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 8°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 6°C to about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 5°C to about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of about 5°C to about 7°C for application to the exterior surface of the knee.

[0071] In certain embodiments, the cooling product has an outer surface temperature of about 12°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 11°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 9°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 7°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 6°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 5°C for application to the outer surface of the knee.

[0072] the temperature of the fluid within the intra-articular space of the knee joint The method may be further characterized according to the temperature of the fluid within the intra-articular space of the knee joint that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 33°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 33°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 28°C to about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 28°C to about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 30°C to about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 30°C to about 32°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 26°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature of about 26° C. for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature of about 27° C. for a duration of at least 30 minutes.In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 27°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 29°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 29°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 31°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 31°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 32° C. for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 33° C. for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 33° C. for a duration of about 30 minutes to about 90 minutes.

[0073] In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature in the range of about 26°C to about 28°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature in the range of about 28°C to about 30°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature in the range of about 30°C to about 32°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 26°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 27°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 28°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 29°C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 30° C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 31° C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 32° C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 33° C. In certain embodiments, step (c) comprises cooling the fluid in the intra-articular space of the knee joint to a temperature of about 29° C.

[0074] Lidocaine dosage The method may be further characterized according to the dose of lidocaine administered to the patient. For example, in certain embodiments, the dose of lidocaine in step (b) is about 0.3 g. In certain embodiments, the dose of lidocaine in step (b) is 0.3 g. In yet other embodiments, the dose of lidocaine in step (b) is about 0.1 g, about 0.2 g, about 0.4 g, or about 0.5 g. In yet other embodiments, the dose of lidocaine in step (b) is about 0.15 g.

[0075] Pharmaceutical compositions containing a single pain-relieving agent The method can be further characterized according to the characteristics of the pharmaceutical composition comprising a single pain-relieving agent. For example, in certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent is an aqueous mixture containing lidocaine at a concentration of about 2% w / w. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent is an aqueous mixture containing lidocaine at a concentration of about 1% w / w. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride at a concentration ranging from about 4 mg / mL to about 8 mg / mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume ranging from about 13 mL to about 17 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume of about 15 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume of about 15 mL. In yet other embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume ranging from about 1 mL to about 3 mL, about 3 mL to about 5 mL, about 5 mL to about 7 mL, about 7 mL to about 9 mL, about 9 mL to about 11 mL, about 11 mL to about 13 mL, about 13 mL to about 15 mL, or about 17 mL to about 19 mL. In yet other embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mL.

[0076] The method may be further characterized according to the temperature of the pharmaceutical composition comprising a single pain-relieving agent administered to the patient. For example, in certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a temperature ranging from about 1°C to about 5°C, about 5°C to about 10°C, about 10°C to about 15°C, about 15°C to about 20°C, about 20°C to about 25°C, or about 22°C to about 24°C. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a temperature of about 23°C.

[0077] Pharmaceutical compositions containing capsaicin The method can be further characterized according to the characteristics of the pharmaceutical composition comprising capsaicin. For example, in certain embodiments, the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 4 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 2 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 0.05 mL, 0.1 mL, 0.125 mL, 0.2 mL, 0.5 mL, 0.75 mL, 1.0 mL, 1.25 mL, 1.5 mL, 1.75 mL, 2.0 mL, 2.25 mL, 2.5 mL, 2.75 mL, 3.0 mL, 3.25 mL, 3.5 mL, 3.75 mL, or 4.0 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume in the range of about 0.01 mL to about 0.1 mL, about 0.1 mL to about 0.2 mL, about 0.2 mL to about 0.5 mL, about 0.5 mL to about 0.75 mL, about 0.75 mL to about 1.0 mL, about 1.0 mL to about 1.5 mL, about 1.5 mL to about 2.0 mL, about 2.0 mL to about 2.5 mL, about 2.5 mL to about 3.0 mL, about 3.0 mL to about 3.5 mL, about 3.5 mL to about 4.0 mL, about 4.0 mL to about 5.0 mL, about 5.0 mL to about 6.0 mL, about 6.0 mL to about 9 mL, or about 9 mL to about 12 mL.

[0078] Duration of cooling in step (e) The method may be further characterized according to the duration of cooling in step (e). In certain embodiments, the duration of step (e) is about 30 minutes to about 90 minutes. In certain embodiments, the duration of step (e) is about 30 minutes to about 60 minutes. In certain embodiments, the duration of step (e) is about 60 minutes to about 90 minutes. In certain embodiments, the duration of step (e) is about 30 minutes to about 60 minutes, about 60 minutes to about 90 minutes, about 90 minutes to about 120 minutes, or about 120 minutes to about 180 minutes, provided that it is not inconsistent with the minimum duration already specified in step (e).

[0079] Capsaicin dosage The method may be further characterized according to the dose of capsaicin. In certain embodiments, the dose of capsaicin is 1 mg.

[0080] Exemplary characteristics of the fifth, sixth, seventh and eighth methods The fifth, sixth, seventh, and eighth methods above may be further characterized by additional features, such as steps including knee flexion, characterization of the temperature of the fluid within the intra-articular space of the knee joint receiving or having received capsaicin according to the method, characterization of the temperature of the cooling article surface for application to the exterior surface of the knee, the duration of the cooling step (a), the dose of lidocaine, and characterization of the pharmaceutical composition comprising a single pain-relieving agent. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0081] knee flexion The method may be further characterized depending on the presence or absence of a step including flexion of the knee subjected to capsaicin. For example, in certain embodiments, the knee is flexed after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed about 5 times over about 1 minute after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed and straightened after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed and straightened about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the knee is flexed and extended about 5 times for about 1 minute.

[0082] the temperature of the fluid within the intra-articular space of the knee joint The method may be further characterized according to the temperature of the fluid within the intra-articular space of the knee joint that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 33°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 33°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature in the range of 26°C to about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 28°C to about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 28°C to about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 30°C to about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature in the range of 30°C to about 32°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 26°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature of about 26° C. for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid within the intra-articular space of the knee joint is maintained at a temperature of about 27° C. for a duration of at least 30 minutes.In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 27°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 29°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 29°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 31°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 31°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 32° C. for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 33° C. for a duration of at least 30 minutes. In certain embodiments, in step (e), the fluid in the intra-articular space of the knee joint is maintained at a temperature of about 33° C. for a duration of about 30 minutes to about 90 minutes.

[0083] In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature in the range of about 26°C to about 28°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature in the range of about 28°C to about 30°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature in the range of about 30°C to about 32°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of about 26°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of about 27°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of about 28°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 29°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 30°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 31°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 32°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 33°C for fluid in the intra-articular space of the knee joint. In certain embodiments, step (c) comprises applying a cooling product to the outer surface of the knee to achieve a temperature of approximately 29°C for fluid in the intra-articular space of the knee joint.

[0084] Coolant surface temperature for application to the exterior of the knee The method may be further characterized according to the temperature of the cooling device surface for application to the outer surface of the knee to receive the capsaicin. In certain embodiments, the cooling device has an outer surface temperature in the range of about 6°C to about 13°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 7°C to about 13°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 7°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 5°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 8°C to about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 6°C to about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling device has an outer surface temperature in the range of about 5°C to about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature in the range of about 5°C to about 7°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 12°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 11°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 10°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 9°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 8°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 7°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 6°C for application to the outer surface of the knee. In certain embodiments, the cooling product has an outer surface temperature of about 5°C for application to the outer surface of the knee.

[0085] Duration of step (a) The method may be further characterized according to the duration of the cooling step (a). For example, in certain embodiments, in step (a), the cooling article is applied to the lateral surface of the knee of a patient with osteoarthritic knee pain for a duration of about 5 minutes to about 30 minutes. In certain embodiments, in step (a), the cooling article is applied to the lateral surface of the knee of a patient with osteoarthritic knee pain for a duration of about 5 minutes to about 15 minutes. In certain embodiments, in step (a), the cooling article is applied to the lateral surface of the knee of a patient with osteoarthritic knee pain for a duration of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes. In certain embodiments, in step (a), the cooling article is applied to the lateral surface of the knee of a patient with osteoarthritic knee pain for a duration of about 15 minutes.

[0086] Lidocaine dosage The method may be further characterized according to the dose of lidocaine administered to the patient. For example, in certain embodiments, the dose of lidocaine in step (b) is about 0.3 g. In certain embodiments, the dose of lidocaine in step (b) is 0.3 g. In still other embodiments, the dose of lidocaine in step (b) is about 0.1 g, about 0.2 g, about 0.4 g, or about 0.5 g. In still other embodiments, the dose of lidocaine in step (b) is about 0.15 g. In still other embodiments, the dose of lidocaine in step (b) is less than about 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1.0 g.

[0087] Pharmaceutical compositions containing a single pain-relieving agent The method can be further characterized according to the characteristics of the pharmaceutical composition comprising a single pain-relieving agent. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent is an aqueous mixture containing lidocaine at a concentration of about 2% w / w. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride at a concentration ranging from about 4 mg / mL to about 8 mg / mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume ranging from about 13 mL to about 17 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume ranging from about 1 mL to about 3 mL, about 3 mL to about 5 mL, about 5 mL to about 7 mL, about 7 mL to about 9 mL, about 9 mL to about 11 mL, about 11 mL to about 13 mL, about 13 mL to about 15 mL, or about 17 mL to about 19 mL. In still other embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a volume of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mL.

[0088] The method may be further characterized according to the temperature of the pharmaceutical composition comprising a single pain-relieving agent administered to the patient. For example, in certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a temperature ranging from about 1°C to about 5°C, about 5°C to about 10°C, about 10°C to about 15°C, about 15°C to about 20°C, about 20°C to about 25°C, or about 22°C to about 24°C. In certain embodiments, the pharmaceutical composition comprising a single pain-relieving agent has a temperature of about 23°C.

[0089] Pharmaceutical compositions containing capsaicin The method can be further characterized according to the characteristics of the pharmaceutical composition comprising capsaicin. For example, in certain embodiments, the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 4 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 2 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 0.05 mL, 0.1 mL, 0.125 mL, 0.2 mL, 0.5 mL, 0.75 mL, 1.0 mL, 1.25 mL, 1.5 mL, 1.75 mL, 2.0 mL, 2.25 mL, 2.5 mL, 2.75 mL, 3.0 mL, 3.25 mL, 3.5 mL, 3.75 mL, or 4.0 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume in the range of about 0.01 mL to about 0.1 mL, about 0.1 mL to about 0.2 mL, about 0.2 mL to about 0.5 mL, about 0.5 mL to about 0.75 mL, about 0.75 mL to about 1.0 mL, about 1.0 mL to about 1.5 mL, about 1.5 mL to about 2.0 mL, about 2.0 mL to about 2.5 mL, about 2.5 mL to about 3.0 mL, about 3.0 mL to about 3.5 mL, about 3.5 mL to about 4.0 mL, about 4.0 mL to about 5.0 mL, about 5.0 mL to about 6.0 mL, about 6.0 mL to about 9 mL, or about 9 mL to about 12 mL.

[0090] Cooling duration The method may be further characterized according to the duration of cooling. For example, in certain embodiments, in step (a), the cooling product is applied to the outer surface of the knee for a duration of about 5 minutes to about 20 minutes. In certain embodiments, in step (a), the cooling product is applied to the outer surface of the knee for a duration of about 10 minutes. In certain embodiments, in step (c), the cooling product is applied to the outer surface of the knee for a duration of about 15 minutes to about 45 minutes. In certain embodiments, in step (c), the cooling product is applied to the outer surface of the knee for a duration of about 45 minutes. In certain embodiments, in step (c), the cooling product is applied to the outer surface of the knee for a duration of about 30 minutes. In certain embodiments, in step (e), the cooling product is applied to the outer surface of the knee for a duration of at least about 10 minutes, at least about 20 minutes, or at least about 30 minutes. In certain embodiments, in step (e), the cooling product is applied to the outer surface of the knee for a duration of about 10 minutes, about 20 minutes, or about 30 minutes. In certain embodiments, in step (e), the cooling device is applied to the outer surface of the knee for a duration of about 15 minutes to about 90 minutes. In certain embodiments, in step (e), the cooling device is applied to the outer surface of the knee for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the cooling device is applied to the outer surface of the knee for a duration of about 30 minutes to about 60 minutes. In certain embodiments, in step (e), the cooling device is applied to the outer surface of the knee for a duration of about 60 minutes to about 90 minutes. In certain embodiments, in step (e), the duration is about 15 minutes to about 30 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 90 minutes, about 90 minutes to about 120 minutes, or about 120 minutes to about 180 minutes.

[0091] Exemplary characteristics of the first to eighth methods The first, second, third, fourth, fifth, sixth, seventh, and eighth methods described above may be further characterized by additional features, such as the presence or absence of additional procedures to reduce the transient burning sensation caused by capsaicin, the magnitude of the transient burning sensation caused by capsaicin, and the duration of the relief of osteoarthritic knee pain. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0092] Further procedures for reducing transient burning sensations and / or treating osteoarthritic knee pain The method may be further characterized depending on the presence or absence of additional procedures for alleviating the transient burning sensation caused by capsaicin. For example, in certain embodiments, the method does not include any procedures for alleviating the transient burning sensation experienced by the patient due to the administration of capsaicin other than the procedures described in steps (a), (b), (c), (d), and (e) and optionally flexing the knee. In certain embodiments, the method does not include any procedures for alleviating osteoarthritic knee joint pain other than the procedures described in steps (a), (b), (c), (d), and (e) and optionally flexing the knee. In certain embodiments, the patient does not receive any other pain-relieving medication other than the administration of (i) a pharmaceutical composition containing lidocaine and (ii) a pharmaceutical composition containing capsaicin. In certain embodiments, the method does not include any steps other than steps (a), (b), (c), (d), and (e) and optionally flexing and straightening the knee to reduce the transient burning sensation experienced by the patient due to administration of capsaicin. In certain embodiments, the method does not include any steps other than steps (a), (b), (c), (d), and (e) and optionally flexing and straightening the knee to reduce osteoarthritic knee joint pain.

[0093] The magnitude of the transient burning sensation caused by capsaicin The method may be further characterized by the magnitude of the transient burning sensation caused by capsaicin. For example, in certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 1 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 2 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the transient burning sensation is assessed about 10 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is assessed about 30 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 60 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 120 minutes after administration of the pharmaceutical composition comprising capsaicin.

[0094] Duration of osteoarthritic knee pain relief The method can be further characterized according to the duration of the relief of osteoarthritic knee joint pain. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 3 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 4 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 5 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 6 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 7 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 8 months. In certain embodiments, the method is characterized by achieving relief of osteoarthritic knee joint pain for a duration of at least 9 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 10 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 11 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 12 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 4 to 6 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 6 to 9 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 6 to 12 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 9 to 12 months. In certain embodiments, the method is characterized by achieving relief from osteoarthritic knee pain for a duration of 12 to 18 months.

[0095] Cooling Device Characterization The method may be further characterized according to the characteristics of the cooling device. In certain embodiments, the cooling device is a material wrap that is cooled via circulating fluid. In certain embodiments, the cooling device is a fabric wrap that is cooled via circulating fluid. In certain embodiments, the cooling device covers at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the exterior surface of the patient's knee. In certain embodiments, the cooling device covers at least 70% of the exterior surface of the patient's knee. In certain embodiments, the cooling device covers at least 80% of the exterior surface of the patient's knee. In certain embodiments, the cooling device covers at least 90% of the exterior surface of the patient's knee. In certain embodiments, the cooling device covers at least 95% of the exterior surface of the patient's knee.

[0096] In certain embodiments, the cooling article is a wrap-on cooling pad sold by Breg, Inc. Exemplary wrap-on pads sold by Breg, Inc. use circulating ice water to achieve cooling and include the Breg Knee WrapOn Polar Pad. Figure 1 herein is an illustration of a cooling article that is a wrap-on pad applied to a human knee.

[0097] In certain embodiments, the cooling article is an at least partially frozen gel pack.

[0098] In a particular embodiment, the cooling article is an Elasto-Gel All Purpose Therapy Wrap, such as one measuring 6 inches by 24 inches. The Elasto-Gel All Purpose Therapy Wrap may be characterized as having been removed from the freezer (approximately 0°F) immediately prior to application to the patient.

[0099] 9th Method One aspect of the invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby ameliorating joint pain in a human patient.

[0100] In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint.

[0101] In certain embodiments, step (c) comprises applying a cooling article to the patient's skin adjacent said joint for a duration of at least about 45 minutes.

[0102] 10th Method One aspect of the invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin adjacent the joint, the cooling device having an outer surface temperature in the range of about 0°C to about 18°C; and d. administering by injection into said joint a pharmaceutical composition comprising a therapeutically effective amount of capsaicin; and e. Optionally, applying a cooling device to the patient's skin adjacent to the joint for a duration of about 10 minutes, wherein the cooling device has an outer surface temperature in the range of about 0°C to about 18°C. thereby ameliorating joint pain in a human patient.

[0103] In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint for a duration of about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 0°C to about 18°C.

[0104] 11th Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0105] In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint.

[0106] 12th Method One aspect of the invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby ameliorating joint pain in a human patient.

[0107] In certain embodiments, the method includes the step (e) of applying a cooling article to the patient's skin adjacent said joint.

[0108] 13th Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0109] In certain embodiments, the method includes the step (e) of applying a cooling article to the patient's skin adjacent said joint.

[0110] Exemplary characteristics of the twelfth and thirteenth methods The twelfth and thirteenth methods above may be further characterized by additional characteristics, such as the temperature of the tissue or fluid within the joint that is or has been subjected to capsaicin according to the method. A more detailed description of such characteristics is provided below. The present invention encompasses all permutations and combinations of these characteristics.

[0111] Temperature of tissues or fluids inside the joint The method may be further characterized according to the temperature of the tissue or fluid within the joint that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature in the range of about 20°C to about 22°C for the tissue or fluid within the joint. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature in the range of about 22°C to about 24°C for the tissue or fluid within the joint. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature in the range of about 24°C to about 26°C for the tissue or fluid within the joint. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature in the range of about 26°C to about 28°C for the tissue or fluid within the joint. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the tissues or fluids within the joint in a range of about 28° C. to about 30° C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the tissues or fluids within the joint in a range of about 30° C. to about 32° C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the tissues or fluids within the joint in a range of about 25° C. to about 31° C.

[0112] In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 20° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 21° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 22° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 23° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 24° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 25° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 26° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 27° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 28° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 29° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 30° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 31° C. for the tissues or fluids within the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature of about 32°C for the tissue or fluids within the joint.In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature of about 33°C for the tissue or fluids within the joint.

[0113] 14th Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling article to the patient's skin adjacent to said joint to achieve a temperature for said skin in the range of about 5°C to about 30°C; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0114] In certain embodiments, the method includes the step (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy. In certain embodiments, the method includes the step (b) of administering a local anesthetic into the joint. In certain embodiments, the method includes the step (e) of applying a cooling article to the skin of the patient near the joint. In certain embodiments, the method includes the steps (i) (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy, (ii) (b) of administering a local anesthetic into the joint, and (e) of applying a cooling article to the skin of the patient near the joint.

[0115] 15th Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling article to the patient's skin adjacent to said joint to achieve a temperature for said skin in the range of about 5°C to about 30°C; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby reducing the transient burning sensation caused by injection of capsaicin.

[0116] In certain embodiments, the method includes the step (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy. In certain embodiments, the method includes the step (b) of administering a local anesthetic into the joint. In certain embodiments, the method includes the step (e) of applying a cooling article to the skin of the patient near the joint. In certain embodiments, the method includes the steps (i) (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy, (ii) (b) of administering a local anesthetic into the joint, and (e) of applying a cooling article to the skin of the patient near the joint.

[0117] Exemplary characteristics of the fourteenth and fifteenth methods The fourteenth and fifteenth methods above may be further characterized by additional characteristics, such as the temperature of the patient's skin near the joint receiving or having received capsaicin according to the method. A more detailed description of such characteristics is provided below. The present invention encompasses all permutations and combinations of these characteristics.

[0118] The temperature of the patient's skin near the joint The method may be further characterized according to the temperature of the patient's skin near the joint that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 5°C to about 7°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 7°C to about 9°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 9°C to about 11°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 11°C to about 13°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 13°C to about 15°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 15°C to about 17°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 17°C to about 19°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 19°C to about 21°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 21°C to about 23°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 23°C to about 25°C. In certain embodiments, step (c) comprises applying a cooling product to the patient's skin near the joint to achieve a temperature for the skin in the range of about 25°C to about 27°C. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin adjacent to said joint to achieve a temperature for said skin in the range of about 27°C to about 29°C.In certain embodiments, step (c) comprises applying a cooling article to the patient's skin adjacent to said joint to achieve a temperature for said skin in the range of about 29°C to about 30°C.

[0119] In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 7°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 8°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 9°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 10°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 11°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 12°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 13°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 14°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 15°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 16°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 17°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 18°C ​​for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 19°C for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 20°C for the skin.In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 21° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 22° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 23° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 24° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 25° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 25° C. for the skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 26° C. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin of about 28° C. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin of about 29° C. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin of about 30° C.

[0120] Furthermore, in certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 5°C to about 30°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 5°C to about 7°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 7°C to about 9°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 9°C to about 11°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 11°C to about 13°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 13°C to about 15°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 15°C to about 17°C for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 17°C to about 19°C for a duration of at least 30 minutes. In certain embodiments, the method includes a step (e) in which a cooling article is applied to the patient's skin near said joint for a duration of at least 30 minutes to achieve a temperature for said skin in the range of about 19°C to about 21°C.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 21° C. to about 23° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 23° C. to about 25° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 25° C. to about 27° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for the skin in the range of about 27° C. to about 29° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 5° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 6° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 7° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 8° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 9° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes a step (e) in which a cooling article is applied to the patient's skin near said joint for a duration of at least 30 minutes to achieve a temperature for said skin of about 10°C.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 11° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 12° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 13° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 14° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 15° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint to achieve a temperature of about 16° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint to achieve a temperature of about 17° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint to achieve a temperature of about 18° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint to achieve a temperature of about 19° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near the joint to achieve a temperature of about 20° C. for the skin for a duration of at least 30 minutes.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 21° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 22° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 23° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 24° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 25° C. for the skin for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 26° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 27° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 28° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature of about 29° C. for the skin for a duration of at least 30 minutes.

[0121] In certain embodiments, the duration is about 30 minutes to about 60 minutes. In certain embodiments, the duration is about 30 minutes to about 90 minutes. In certain embodiments, the duration is about 60 minutes to about 90 minutes.

[0122] Exemplary More Specific Embodiments In another aspect, the method relates to the following more specific embodiments. Embodiment 1. A method of ameliorating osteoarthritic knee joint pain in a human patient, comprising: a. applying a cooling device to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain for a duration of about 15 minutes; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of said knee for a duration of about 30 minutes to achieve a temperature in the range of about 7°C to about 30°C for the skin in contact with the cooling device; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of said knee to achieve a temperature in the range of about 7°C to about 30°C for the skin in contact with the cooling device for a duration of at least about 30 minutes. thereby ameliorating osteoarthritic knee joint pain in a human patient. Embodiment 2. A method of attenuating the transient burning sensation caused by injection of capsaicin into a human osteoarthritic knee joint, comprising: a. applying a cooling device to the outer surface of the knee of a human patient exhibiting osteoarthritic knee joint pain for a duration of about 15 minutes; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of said knee for a duration of about 30 minutes to achieve a temperature in the range of about 7°C to about 30°C for the skin in contact with the cooling device; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of said knee to achieve a temperature in the range of about 7°C to about 30°C for the skin in contact with the cooling device for a duration of at least about 30 minutes. thereby reducing the transient burning sensation caused by injection of capsaicin. Embodiment 3. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is from about 7°C to about 9°C. Embodiment 4. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is from about 9°C to about 11°C. Embodiment 5. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is from about 11°C to about 13°C. Embodiment 6. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is about 13°C to about 15°C. Embodiment 7. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is from about 15°C to about 17°C. Embodiment 8. The method of embodiment 1 or 2, wherein the temperature in steps (c) and (e) is about 17°C to about 19°C. Embodiment 9. The method of any one of embodiments 1 to 8, wherein the cooling article has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. Embodiment 10. The method of any one of embodiments 1 to 8, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 7°C for application to the outer surface of the knee. Embodiment 11. The method of any one of embodiments 1 to 8, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 9°C for application to the outer surface of the knee. Embodiment 12. The method of any one of embodiments 1 to 8, wherein the cooling article has an outer surface temperature in the range of about 9°C to about 11°C for application to the outer surface of the knee. Embodiment 13. The method of any one of embodiments 1 to 8, wherein the cooling article has an outer surface temperature in the range of about 9°C to about 11°C for application to the outer surface of the knee. Embodiment 14. The method of any one of embodiments 1 to 8, wherein the cooling article has an outer surface temperature in the range of about 13°C to about 15°C for application to the outer surface of the knee. Embodiment 15. The method of any one of embodiments 1 to 14, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the knee is flexed. Embodiment 16. The method of any one of embodiments 1 to 14, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the knee is flexed about 5 times. Embodiment 17. The method of any one of embodiments 1 to 16, wherein in step (b), the dose of lidocaine is about 0.3 g. Embodiment 18. The method of any one of embodiments 1 to 16, wherein in step (b), the dose of lidocaine is 0.3 g. Embodiment 19. The method of any one of embodiments 1 to 18, wherein the pharmaceutical composition comprising a single pain-relieving agent is an aqueous mixture containing lidocaine at a concentration of about 2% w / w. Embodiment 20. The method of any one of embodiments 1-19, wherein the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride. Embodiment 21. The method of any one of embodiments 1 to 19, wherein the pharmaceutical composition comprising a single pain-relieving agent further comprises sodium chloride at a concentration ranging from about 4 mg / mL to about 8 mg / mL. Embodiment 22. The method of any one of embodiments 1 to 21, wherein the pharmaceutical composition comprising a single pain-relieving agent has a volume ranging from about 13 mL to about 17 mL. Embodiment 23. The method of any one of embodiments 1 to 21, wherein the pharmaceutical composition comprising a single pain-relieving agent has a volume of about 15 mL. Embodiment 24. The method of any one of embodiments 1 to 23, wherein the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin. Embodiment 25. The method of any one of embodiments 1 to 24, wherein the pharmaceutical composition comprising capsaicin has a volume of about 4 mL. Embodiment 26 The method of any one of embodiments 1 to 24, wherein the pharmaceutical composition comprising capsaicin has a volume of about 2 mL. Embodiment 27. The method of any one of embodiments 1 to 26, wherein the duration in step (e) is from about 30 minutes to about 90 minutes. Embodiment 28. The method of any one of embodiments 1 to 26, wherein the duration in step (e) is from about 30 minutes to about 60 minutes. Embodiment 29. The method of any one of embodiments 1 to 28, wherein the dose of capsaicin is 1 mg.

[0123] In another aspect, the method relates to the following more specific embodiments. Embodiment 1. A method of ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby ameliorating joint pain in a human patient, wherein the joint pain is osteoarthritic joint pain and the joint is a knee joint. Embodiment 2. A method of attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; b. optionally, administering a local anesthetic into said joint; c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby attenuating the transient burning sensation caused by injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint. Embodiment 3. A method of ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby ameliorating joint pain in a human patient, wherein the joint pain is osteoarthritic joint pain and the joint is a knee joint. Embodiment 4. A method of attenuating the transient burning sensation caused by injection of capsaicin into a joint in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; b. optionally, administering a local anesthetic into said joint; c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby attenuating the transient burning sensation caused by injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint. Embodiment 5. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 24°C to about 26°C for the tissue or fluid within the joint. Embodiment 6. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 26°C to about 28°C for the tissue or fluid within the joint. Embodiment 7. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 28°C to about 30°C for the tissue or fluid within the joint. Embodiment 8. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 30°C to about 32°C for the tissue or fluid within the joint. Embodiment 9. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 27°C for the tissues or fluids inside the joint. Embodiment 10. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 28°C for the tissues or fluids inside the joint. Embodiment 11. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 29°C for the tissue or fluids inside the joint. Embodiment 12. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of about 30°C for the tissue or fluids inside the joint. Embodiment 13. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of approximately 31°C for the tissue or fluids inside the joint. Embodiment 14. The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin near the joint to achieve a temperature of approximately 32°C for the tissue or fluids inside the joint. Embodiment 15. The method of any one of embodiments 1-14, comprising step (e) applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the outer surface of the human patient's skin near the joint. Embodiment 16. The method of any one of embodiments 1 to 14, comprising step (e) of applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 24°C to about 26°C for tissue or fluid within the joint for a duration of at least 15 minutes. Embodiment 17. The method of any one of embodiments 1 to 14, comprising step (e) of applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 26°C to about 28°C for tissue or fluid within the joint for a duration of at least 15 minutes. Embodiment 18. The method of any one of embodiments 1 to 14, comprising step (e) of applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 28°C to about 30°C for tissue or fluid within the joint for a duration of at least 15 minutes. Embodiment 19. The method of any one of embodiments 1 to 14, comprising step (e) of applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 30°C to about 32°C for tissue or fluid within the joint for a duration of at least 15 minutes. Embodiment 20. The method of any one of embodiments 15 to 19, wherein the duration in step (e) is at least 20 minutes. Embodiment 21. The method of any one of embodiments 15 to 19, wherein the duration in step (e) is at least 30 minutes. Embodiment 22. The method of any one of embodiments 15 to 19, wherein the duration of step (e) is from about 30 minutes to about 90 minutes. Embodiment 23. The method of any one of embodiments 15 to 19, wherein the duration of step (e) is from about 30 minutes to about 60 minutes. Embodiment 24. The method of any one of embodiments 1 to 23, comprising step (a) applying the cooling article to the skin of the human patient near the joint in need of pain relief therapy for a duration of about 5 minutes to about 30 minutes. Embodiment 25. The method of any one of embodiments 1-23, comprising step (a) applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy for a duration of about 15 minutes. Embodiment 26. The method of any one of embodiments 1 to 23, which does not include step (a). Embodiment 27. The method of any one of embodiments 1 to 26, comprising step (b) administering by injection into the joint a pharmaceutical composition comprising lidocaine to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g. Embodiment 28. The method of any one of embodiments 1 to 26, comprising step (b) administering by injection into the joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g. Embodiment 29. The method of any one of embodiments 1 to 26, comprising the following additional step performed between steps (c) and (d): administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g. Embodiment 30. The method of embodiment 29, which does not include step (b). Embodiment 31. The method of any one of embodiments 27-30, wherein the dose of lidocaine is about 0.3 g. Embodiment 32. The method of any one of embodiments 27-30, wherein the dose of lidocaine is about 0.15 g. Embodiment 33. The method of any one of embodiments 27 to 31, wherein the pharmaceutical composition comprising lidocaine is an aqueous mixture containing lidocaine at a concentration of about 2% w / w. Embodiment 34. The method of any one of embodiments 27-30 or 32, wherein the pharmaceutical composition comprising lidocaine is an aqueous mixture containing lidocaine at a concentration of about 1% w / w. Embodiment 35. The method of any one of embodiments 27 to 31, wherein the pharmaceutical composition comprising lidocaine has a volume ranging from about 13 mL to about 17 mL. Embodiment 36. The method of any one of embodiments 27 to 31, wherein the pharmaceutical composition comprising lidocaine has a volume of about 15 mL. Embodiment 37. The method of any one of embodiments 1 to 36, wherein step (c) comprises applying a cooling article to the outer surface of the knee for a duration of about 20 minutes. Embodiment 38. The method of any one of embodiments 1 to 36, wherein step (c) comprises applying a cooling article to the outer surface of the knee for a duration of about 30 minutes. Embodiment 39. The method of any one of embodiments 1 to 38, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the joint is flexed. Embodiment 40. The method of any one of embodiments 1 to 38, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the joint is flexed about 5 times. Embodiment 41 The method of any one of embodiments 1 to 40, wherein the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin. Embodiment 42. The method of any one of embodiments 1 to 40, wherein the pharmaceutical composition comprising capsaicin has a volume of about 2 mL. Embodiment 43 The method of any one of embodiments 1 to 40, wherein the pharmaceutical composition comprising capsaicin has a volume of about 1 mL. Embodiment 44. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 15°C for application to the skin of a human patient near the joint. Embodiment 45. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 13°C for application to the skin of a human patient near the joint. Embodiment 46. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 8°C to about 10°C for application to the skin of a human patient near the joint. Embodiment 47. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 7°C for application to the skin of a human patient near the joint. Embodiment 48. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 9°C for application to the skin of a human patient near the joint. Embodiment 49. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 9°C to about 11°C for application to the skin of a human patient near the joint. Embodiment 50. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 11°C to about 13°C for application to the skin of a human patient near the joint. Embodiment 51. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature in the range of about 13°C to about 15°C for application to the skin of a human patient near the joint. Embodiment 52. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature of about 8°C for application to the skin of a human patient near the joint. Embodiment 53. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature of about 9°C for application to the skin of a human patient near the joint. Embodiment 54. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature of about 10°C for application to the skin of a human patient near the joint. Embodiment 55. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature of about 11°C for application to the skin of a human patient near the joint. Embodiment 56. The method of any one of embodiments 1 to 40, wherein the cooling article has an outer surface temperature of about 12°C for application to the skin of a human patient near the joint.

[0124] Further exemplary, more specific embodiments In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0125] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 30 to 45 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0126] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and b. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0127] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee for a duration of about 30 minutes, the cooling device having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling device to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0128] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling device to the exterior surface of the knee for a duration of about 20 minutes, the cooling device having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and d. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling device to the exterior surface of the knee for a duration of at least about 20 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0129] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling device to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 20-30 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling device to the exterior surface of the knee for a duration of at least about 20 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0130] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and b. applying a cooling device to the exterior surface of the knee for a duration of about 20 minutes, the cooling device having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling device to the exterior surface of the knee for a duration of at least about 20 minutes, wherein the cooling device has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby providing a method for ameliorating osteoarthritic knee joint pain in a human patient.

[0131] In another aspect, the present invention provides a method for ameliorating osteoarthritic knee pain in a human patient, comprising: a. applying a cooling article to the exterior surface of the knee for a duration of about 20 minutes, the cooling article having an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee; then b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and d. applying a cooling article to the exterior surface of the knee for a duration of at least about 20 minutes, wherein the cooling article has an exterior surface temperature in the range of about 7°C to about 13°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in a human patient.

[0132] Exemplary characteristics of the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth and fifteenth methods The ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth methods above may be further characterized by additional features, such as the temperature and duration of cooling in step (e), the characteristics of step (a), and the presence and characteristics of administration of a local anesthetic. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0133] Temperature and duration of cooling in step (e) The method may be further characterized according to the temperature and duration of cooling in step (e). For example, in certain embodiments, the method comprises step (e) of applying a cooling article to a patient's skin near the joint for a duration of at least about 10 minutes, the cooling article having an external surface temperature in the range of about 1°C to about 15°C for application to the external surface of the human patient's skin near the joint. In certain embodiments, the method comprises step (e) of applying a cooling article to a patient's skin near the joint to achieve a temperature in the range of about 20°C to about 22°C for tissues or fluids within the joint for a duration of at least 15 minutes. In certain embodiments, the method comprises step (e) of applying a cooling article to a patient's skin near the joint to achieve a temperature in the range of about 22°C to about 24°C for tissues or fluids within the joint for a duration of at least 15 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 24°C to about 26°C for a duration of at least 15 minutes for the tissues or fluids within the joint. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 26°C to about 28°C for the tissues or fluids within the joint for a duration of at least 15 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 28°C to about 30°C for the tissues or fluids within the joint for a duration of at least 15 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 30°C to about 32°C for the tissues or fluids within the joint for a duration of at least 15 minutes. In certain embodiments, the method includes a step (e) in which a cooling article is applied to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 25°C to about 31°C for tissue or fluid within the joint for a duration of at least 15 minutes.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 24°C to about 26°C for a duration of at least 10 minutes for the tissues or fluids within the joint. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 26°C to about 28°C for the tissues or fluids within the joint for a duration of at least 10 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 28°C to about 30°C for the tissues or fluids within the joint for a duration of at least 10 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature in the range of about 30°C to about 32°C for the tissues or fluids within the joint for a duration of at least 10 minutes.

[0134] In certain embodiments, the duration is at least about 30 minutes. In certain embodiments, the duration is about 30 minutes to about 90 minutes. In certain embodiments, the duration is about 30 minutes to about 60 minutes. In certain embodiments, the duration is about 60 minutes to about 90 minutes.

[0135] The term adjacent is understood from the perspective of a physician skilled in the art and can be, for example, tissue within 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 1cm, 1.5cm or 2cm of the joint.

[0136] In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for tissues or fluids within the joint in the range of about 25° C. to about 31° C. for a duration of at least 30 minutes. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint to achieve a temperature for tissues or fluids within the joint in the range of about 25° C. to about 31° C. for a duration of about 30 minutes to about 90 minutes.

[0137] Characterization of step (a) The method may be further characterized according to the characteristics of step (a). For example, in certain embodiments, the method includes step (a) in which a cooling article is applied to the skin of a human patient near a joint in need of pain relief therapy.

[0138] In certain embodiments, the method includes step (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy for a duration of about 5 minutes to about 30 minutes. In certain embodiments, the method includes step (a) of applying a cooling article to the lateral surface of the knee of a patient experiencing osteoarthritic knee pain for a duration of about 5 minutes to about 30 minutes. In certain embodiments, the method includes step (a) of applying a cooling article to the lateral surface of the knee of a patient experiencing osteoarthritic knee pain for a duration of about 5 minutes to about 15 minutes. In certain embodiments, the method includes step (a) of applying a cooling article to the lateral surface of the knee of a patient experiencing osteoarthritic knee pain for a duration of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes. In certain embodiments, the method includes step (a) of applying a cooling article to the lateral surface of the knee of a patient experiencing osteoarthritic knee pain for a duration of about 15 minutes.

[0139] Administration of local anesthetic The method may be further characterized according to the presence or absence of administration of a local anesthetic and its characteristics. For example, in certain embodiments, the method includes step (b) of administering a local anesthetic into the joint. In certain embodiments, the local anesthetic is a caine analgesic. In certain embodiments, the local anesthetic is lidocaine, dibucaine, bupivacaine, ropivacaine, etidocaine, tetracaine, procaine, chlorocaine, prilocaine, mepivacaine, xylocaine, 2-chloroprocaine, a pharmaceutically acceptable salt thereof, or a combination of one or more of the foregoing. In certain embodiments, the local anesthetic is lidocaine or a pharmaceutically acceptable salt thereof. In certain embodiments, the local anesthetic is lidocaine hydrochloride. In certain embodiments, the method includes step (b) of administering a pharmaceutical composition comprising lidocaine by injection into the joint to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g. In certain embodiments, the dose of lidocaine is about 0.3 g. In certain embodiments, the dose of lidocaine is about 0.15 g. In certain embodiments, the dose of lidocaine is about 0.1 g, 0.2 g, 0.3 g, 0.4 g, or 0.5 g. In certain embodiments, the pharmaceutical composition comprising lidocaine is an aqueous mixture containing lidocaine at a concentration of about 2% w / w. In certain embodiments, the pharmaceutical composition comprising lidocaine is an aqueous mixture containing lidocaine at a concentration of about 1% w / w.

[0140] The local anesthetic may be administered as part of a pharmaceutical composition. The method may be further characterized depending on the temperature of the pharmaceutical composition containing the local anesthetic administered to the patient. For example, in certain embodiments, the pharmaceutical composition containing the local anesthetic has a temperature ranging from about 1°C to about 5°C, about 5°C to about 10°C, about 10°C to about 15°C, about 15°C to about 20°C, about 20°C to about 25°C, or about 22°C to about 24°C. In certain embodiments, the pharmaceutical composition containing the local anesthetic has a temperature of about 23°C.

[0141] Joint flexion The method may be further characterized depending on the presence or absence of a step including flexion of the joint to which capsaicin has been administered. For example, in certain embodiments, the joint is flexed after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the joint is flexed about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the knee is flexed about 5 times over a period of about 1 minute after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the joint is flexed and extended after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, the joint is flexed and extended about 5 times after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e). In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but before step (e), the knee is flexed and extended about 5 times over a period of about 1 minute.

[0142] Pharmaceutical compositions containing capsaicin The method can be further characterized according to the characteristics of the pharmaceutical composition comprising capsaicin. For example, in certain embodiments, the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 4 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 2 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 1 mL. In certain embodiments, the pharmaceutical composition comprising capsaicin has a volume of about 0.5 mL.

[0143] Types of joints and joint pain The method may be further characterized according to the identity and type of joint. For example, in certain embodiments, the joint is a knee, hip, shoulder, elbow, ankle, wrist, ankle, or metatarsal joint. In certain embodiments, the joint is a knee joint. In certain embodiments, the joint is a big toe joint. In certain embodiments, the joint is a hip joint. The joint may be further characterized according to whether or not the joint has a synovial membrane. In certain embodiments, the joint has an intra-articular space surrounded by a synovial membrane. In embodiments where the joint has an intra-articular space surrounded by a synovial membrane, a pharmaceutical composition comprising a local anesthetic and capsaicin is administered by injection into the intra-articular space.

[0144] In certain embodiments, the joint pain is arthritic joint pain. In certain embodiments, the joint pain is osteoarthritic joint pain. In certain embodiments, the joint pain is rheumatoid arthritis joint pain. In still other embodiments, the joint pain is due to trauma to the joint. In still other embodiments, the joint pain is due to aging of the patient. In still other embodiments, the joint pain is due to an inflammatory disease affecting the joint. In still other embodiments, the joint pain is due to a non-inflammatory disease affecting the joint. In still other embodiments, the joint pain is due to psoriatic arthritis. In still other embodiments, the joint pain is due to ankylosing spondylitis.

[0145] In certain embodiments, the joint is a painful knee joint. In certain embodiments, the joint is an osteoarthritic knee joint. In certain embodiments, the joint is a rheumatoid arthritis-affected knee joint.

[0146] In certain embodiments, the joint is a knee joint affected by one or more of rheumatoid arthritis, joint trauma, inflammatory disease, or non-inflammatory disease. In yet other embodiments, the joint is a knee joint and the joint pain is due to aging of the patient.

[0147] Cooling equipment surface temperature The method may be further characterized depending on the temperature of the cooling device surface. For example, in certain embodiments, the cooling device has an outer surface temperature in the range of about 1°C to about 3°C ​​for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 3°C ​​to about 5°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 5°C to about 7°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 7°C to about 9°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 9°C to about 11°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 11°C to about 13°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling device has an outer surface temperature in the range of about 13°C to about 15°C for application to the skin of a human patient near the joint.

[0148] In certain embodiments, the cooling article has an outer surface temperature of about 1°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 2°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 3°C ​​for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 4°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 5°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 6°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 7°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 8°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 9°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 10°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 11°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 12°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 13°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 14°C for application to the skin of a human patient near the joint. In certain embodiments, the cooling article has an outer surface temperature of about 15°C for application to the skin of a human patient near the joint.

[0149] Capsaicin dosage The method may be further characterized according to the dose of capsaicin administered. For example, in certain embodiments, the dose of capsaicin is about 0.01 mg to about 0.1 mg. In certain embodiments, the dose of capsaicin is about 0.1 mg to about 0.5 mg. In certain embodiments, the dose of capsaicin is about 0.5 mg to about 1.0 mg. In certain embodiments, the dose of capsaicin is about 1 mg to about 1.5 mg. In certain embodiments, the dose of capsaicin is about 1.5 mg to about 2.0 mg. In certain embodiments, the dose of capsaicin is about 2.0 mg to about 4.0 mg. In certain embodiments, the dose of capsaicin is about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 6 mg, or 7 mg. In certain embodiments, the dose of capsaicin is about 1 mg. In certain embodiments, the dose of capsaicin is 1 mg.

[0150] Further steps to relieve temporary burning sensation The method may be further characterized depending on the presence or absence of additional steps to reduce the transient burning sensation caused by capsaicin. For example, in certain embodiments, the method does not include any steps to reduce the transient burning sensation experienced by the patient due to administration of capsaicin, other than the steps described in steps (a), (b), (c), (d), and (e) and, optionally, flexing the joint. In certain embodiments, the method does not include any steps to reduce joint pain, other than the steps described in steps (a), (b), (c), (d), and (e) and, optionally, flexing the joint. In certain embodiments, the patient does not receive any other pain-relieving medication other than the administration of (i) a local anesthetic and (ii) a pharmaceutical composition containing capsaicin. In certain embodiments, the method does not include any steps to reduce the transient burning sensation experienced by the patient due to administration of capsaicin, other than the steps described in steps (a), (b), (c), (d), and (e) and, optionally, flexing the joint. In certain embodiments, the method does not include any procedures to reduce joint pain other than those described in steps (a), (b), (c), (d), (e) and optionally flexing and extending the joint.

[0151] The magnitude of the transient burning sensation caused by capsaicin The method may be further characterized by the magnitude of the transient burning sensation caused by capsaicin. For example, in certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 1 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 2 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the transient burning sensation is assessed about 10 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is assessed about 30 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 60 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 120 minutes after administration of the pharmaceutical composition comprising capsaicin.

[0152] Duration of joint pain relief The method may be further characterized according to the duration of joint pain relief. For example, in certain embodiments, the method is characterized by achieving joint pain relief for at least three months. In certain embodiments, the method is characterized by achieving joint pain relief for at least four months. In certain embodiments, the method is characterized by achieving joint pain relief for at least five months. In certain embodiments, the method is characterized by achieving joint pain relief for at least six months. In certain embodiments, the method is characterized by achieving joint pain relief for at least seven months. In certain embodiments, the method is characterized by achieving joint pain relief for at least eight months. In certain embodiments, the method is characterized by achieving joint pain relief for at least nine months. In certain embodiments, the method is characterized by achieving joint pain relief for at least ten months. In certain embodiments, the method is characterized by achieving joint pain relief for at least eleven months. In certain embodiments, the method is characterized by achieving joint pain relief for at least 12 months of duration. In certain embodiments, the method is characterized by achieving joint pain relief for 4 to 6 months of duration. In certain embodiments, the method is characterized by achieving joint pain relief for 6 to 9 months of duration. In certain embodiments, the method is characterized by achieving joint pain relief for 6 to 12 months of duration. In certain embodiments, the method is characterized by achieving joint pain relief for 9 to 12 months of duration. In certain embodiments, the method is characterized by achieving joint pain relief for 12 to 18 months of duration.

[0153] Characterization of cooling products The method may be further characterized according to the characteristics of the cooling device. For example, in certain embodiments, the cooling device is a material wrap that is cooled via circulating fluid. In certain embodiments, the cooling device is a fabric wrap that is cooled via circulating fluid. In certain embodiments, the cooling device is an at least partially frozen gel pack. In certain embodiments, the cooling device covers at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the outer surface of the joint. In certain embodiments, the cooling device covers at least 70% of the outer surface of the joint. In certain embodiments, the cooling device covers at least 80% of the outer surface of the joint. In certain embodiments, the cooling device covers at least 90% of the outer surface of the joint. In certain embodiments, the cooling device covers at least 95% of the outer surface of the joint.

[0154] Exemplary characteristics of methods 1 to 15 The first through fifteenth methods described above may be further characterized by additional properties, such as isomeric purity of capsaicin, chemical purity of capsaicin, avoidance of heat to the area exposed to capsaicin, etc. A more detailed description of such properties is provided below. The present invention encompasses all permutations and combinations of these properties.

[0155] Capsaicin Isomeric Purity The method can be further characterized according to the isomeric purity of the capsaicin. For example, in certain embodiments, the capsaicin is a mixture of cis-capsaicin and trans-capsaicin containing at least 98% by weight of trans-capsaicin. In certain embodiments, the capsaicin is a mixture of cis-capsaicin and trans-capsaicin containing at least 99% by weight of trans-capsaicin.

[0156] Chemical Purity of Capsaicin The method can be further characterized according to the chemical purity of the capsaicin. For example, in certain embodiments, the capsaicin has a chemical purity of at least 98% by weight (meaning that the presence of components other than capsaicin is 2% by weight or less). In certain embodiments, the capsaicin has a chemical purity of at least 99% by weight (meaning that the presence of components other than capsaicin is 1% by weight or less). In certain embodiments, the capsaicin has a chemical purity of at least 99.5% by weight (meaning that the presence of components other than capsaicin is 0.5% by weight or less). In certain embodiments, the capsaicin has a chemical purity of at least 99.8% by weight (meaning that the presence of components other than capsaicin is 0.2% by weight or less).

[0157] Avoiding heat The method can be further characterized according to whether or not there is a step of avoiding heat for a certain duration after administering capsaicin.For example, in certain embodiments, the patient does not expose the area that has received capsaicin to heat for a duration of at least 12 hours after administering capsaicin.In certain embodiments, the patient does not expose the area that has received capsaicin to heat for a duration of at least 24 hours after administering capsaicin.

[0158] Procedures for assessing pain relief The pain relief experienced by the patient can be assessed using procedures described in the literature, such as the Patient Global Impression of Change (PGIC; change from baseline in the painful knee on a 7-point scale: 1 = much improved, 7 = much worse, with a score of 1 or 2 indicating significant improvement), the Patient Specific Functional Scale (PSFS; rating of 3 or fewer important activities that are difficult to perform due to pain in the painful knee on a 0-10 scale: 0 = able to do, 10 = unable to do), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) B stiffness subscale and WOMAC C function subscale.

[0159] The period between steps The method may be further characterized according to the period of time that elapses between the performance of individual steps of the method, such as the period from the completion of step (a) to the initiation of step (b). In certain embodiments, the method is characterized by one or more of: (i) the period between the completion of step (a) and the initiation of step (b); (ii) the period between the completion of step (b) and the initiation of step (c); (iii) the period between the completion of step (c) and the initiation of step (d); and (iv) the period between the completion of step (d) and the initiation of step (e). In certain embodiments, the period between successive steps is as fast as reasonably achievable in accordance with standard medical procedures. In certain embodiments, the period between successive steps is less than 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes, or 1 minute. In preferred embodiments, the period between successive steps is less than 20 minutes.

[0160] The method may be further characterized according to the time period between the completion of step (b) and the initiation of step (d). In certain embodiments, the time period between the completion of step (b) and the initiation of step (d) is about 30 minutes to about 60 minutes. In certain embodiments, the time period between the completion of step (b) and the initiation of step (d) is about 40 minutes to about 60 minutes. In certain embodiments, the time period between the completion of step (b) and the initiation of step (d) is about 50 minutes to about 60 minutes. In certain embodiments, the time period between the completion of step (b) and the initiation of step (d) is about 30 minutes to about 50 minutes. In certain embodiments, the time period between the completion of step (b) and the initiation of step (d) is about 30 minutes to about 45 minutes.

[0161] Decreased fluid volume in effusion-affected joints In patients where the joint receiving capsaicin is a joint with effusion, in certain embodiments, the volume of intra-articular fluid within the joint representing the joint effusion is reduced prior to administration of a local anesthetic (e.g., a pharmaceutical composition comprising a single pain-reducing agent) and / or capsaicin. In certain embodiments, the volume of intra-articular fluid within the joint representing the joint effusion is reduced prior to administration of a local anesthetic. In certain embodiments, the volume of intra-articular fluid within the joint representing the joint effusion is reduced to achieve an intra-articular fluid volume within about 5%, 10%, or 20% of that of a healthy patient of similar height, weight, and age.

[0162] The temperature of the patient's skin near the joint The method may be further characterized according to the temperature of the patient's skin near the joint that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, applying a cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 5°C to about 7°C. In certain embodiments, applying a cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 7°C to about 9°C. In certain embodiments, applying a cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 9°C to about 11°C. In certain embodiments, applying a cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 11°C to about 13°C. In certain embodiments, applying a cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 13°C to about 15°C. In certain embodiments, applying the cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 15°C to about 17°C. In certain embodiments, applying the cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 17°C to about 19°C. In certain embodiments, applying the cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 19°C to about 21°C. In certain embodiments, applying the cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 21°C to about 23°C. In certain embodiments, applying the cooling product to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 23°C to about 25°C. In certain embodiments, in step (c), a temperature in the range of about 25°C to about 27°C is achieved for the skin by applying a cooling article to the patient's skin adjacent to the joint.In certain embodiments, applying the cooling device to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 27° C. to about 29° C. In certain embodiments, applying the cooling device to the patient's skin near the joint in step (c) achieves a temperature for the skin in the range of about 29° C. to about 30° C.

[0163] In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 7°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 8°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 9°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 10°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 11°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 12°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 13°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 14°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 15°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 16°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 17°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 18°C ​​for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 19°C for the skin.In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 20°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 21°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 22°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 23°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 24°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 25°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 25°C for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 26° C. for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 28° C. for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 29° C. for the skin. In certain embodiments, applying the cooling article to the patient's skin near the joint in step (c) achieves a temperature of about 30° C. for the skin.

[0164] Furthermore, in certain embodiments, the method includes step (e) of applying a cooling product to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 5°C to about 30°C. In certain embodiments, the method includes step (e) of applying a cooling product to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 5°C to about 7°C. In certain embodiments, the method includes step (e) of applying a cooling product to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 7°C to about 9°C. In certain embodiments, the method includes step (e) of applying a cooling product to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 9°C to about 11°C. In certain embodiments, the method includes step (e) of applying a cooling product to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 11°C to about 13°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 13°C to about 15°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 15°C to about 17°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 17°C to about 19°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 19°C to about 21°C. In certain embodiments, the method includes a step (e) in which a cooling article is applied to the patient's skin near said joint for a duration of at least 30 minutes to achieve a temperature for said skin in the range of about 21°C to about 23°C.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 23°C to about 25°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 25°C to about 27°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin in the range of about 27°C to about 29°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 5°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 6°C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 7° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 8° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 9° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 10° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 11° C. for the skin.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 12° C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 13° C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 14° C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 15° C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 16° C. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 17° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 18° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 19° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 20° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 21° C. for the skin. In certain embodiments, the method includes a step (e) in which a cooling article is applied to the patient's skin near said joint for a duration of at least 30 minutes to achieve a temperature of about 22°C for said skin.In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 23° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 24° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 25° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 26° C. for the skin. In certain embodiments, the method includes step (e) of applying a cooling article to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature of about 27° C. In certain embodiments, the method includes step (e) wherein a cooling article is applied to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 28° C. In certain embodiments, the method includes step (e) wherein a cooling article is applied to the patient's skin near the joint for a duration of at least 30 minutes to achieve a temperature for the skin of about 29° C.

[0165] In certain embodiments, the duration is about 30 minutes to about 60 minutes. In certain embodiments, the duration is about 30 minutes to about 90 minutes. In certain embodiments, the duration is about 60 minutes to about 90 minutes.

[0166] 16th Method The above-described methods involving administration of capsaicin can also be used to administer a vanilloid receptor agonist compound to a patient. Vanilloid receptor agonists, such as capsaicin, often cause a transient burning sensation upon administration. Therefore, cooling techniques and the optional administration of a local anesthetic (such as lidocaine) provide advantages when administering a vanilloid receptor agonist to a patient. Accordingly, the present invention includes variations of the above-described methods 1 through 15, in which capsaicin is replaced with a vanilloid receptor agonist. Furthermore, for variations of the above-described methods 1 through 15, in which capsaicin is replaced with a vanilloid receptor agonist, further characterization of each of the above-described methods 1 through 15 is repeated here.

[0167] As discussed above, one aspect of the present invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling device having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint; and d. administering by injection into said joint a therapeutically effective amount of a pharmaceutical composition comprising a vanilloid receptor agonist; and e. optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin near the joint. thereby ameliorating joint pain in a human patient.

[0168] In certain embodiments, the method includes step (a) applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy. In certain embodiments, the method includes step (b) administering a local anesthetic into said joint. In certain embodiments, the method includes step (e) applying a cooling article to the patient's skin near said joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1° C. to about 15° C. for application to the human patient's skin near said joint.

[0169] Further to the foregoing, one aspect of the present invention is a method for ameliorating joint pain in a human patient, comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling device to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 20°C to about 33°C for the tissue or fluid within the joint; and d. administering by injection into said joint a therapeutically effective amount of a pharmaceutical composition comprising a vanilloid receptor agonist; and e. Optionally, applying a cooling article to the patient's skin adjacent to said joint. thereby ameliorating joint pain in a human patient.

[0170] In certain embodiments, the method includes the step (a) of applying a cooling article to the skin of a human patient near a joint in need of pain relief therapy. In certain embodiments, the method includes the step (b) of administering a local anesthetic into said joint. In certain embodiments, the method includes the step (e) of applying a cooling article to the skin of the patient near said joint.

[0171] Exemplary vanilloid receptor agonists include, for example, capsaicin, resiniferatoxin, N-vanillylnonanamide, N-vanillylsulfonamide, N-vanillylurea, N-vanillylcarbamate, N-[(substituted phenyl)methyl]alkylamides, methylene-substituted N-[(substituted phenyl)methyl]alkanamides, N-[(substituted phenyl)methyl]-cis-monosaturated alkenamides, N-[(substituted phenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide, hydroxyphenylacetamide, pseudocapsaicin, dihydrocapsaicin, nordihydrocapsaicin anandamide, piperine, zingerone, warburganal, polygodial, aframodial, cinnamodial, cinnamosmolide, cinnamolide, isovelleral, scalarradial, ancystrodial, β-acaridial, merlidial, and scutigeral. In certain preferred embodiments, the vanilloid receptor agonist is resiniferatoxin.

[0172] III. Therapeutic Use for Pain Caused by Painful Nerves One aspect of the present invention provides a method for treating pain from painful nerves, such as intermetatarsal neuromas, using injectable capsaicin and a procedure for attenuating the transient burning sensation associated with capsaicin administration. The method desirably provides relief from pain from painful nerves for an extended period of time, such as at least about three months, six months, nine months, or one year. The method utilizes a cooling device, such as a material wrap cooled via circulating fluid, optionally in combination with the administration of a local anesthetic, to reduce the temperature of tissue exposed to capsaicin over a specified period of time. In a preferred embodiment, the method is used to ameliorate pain from intermetatarsal neuroma in a human patient by administering capsaicin to tissue adjacent to the intermetatarsal neuroma via a protocol in which a cooling device is applied to the lateral surface of the patient's foot before and after administration of capsaicin, e.g., the cooling device has an lateral surface temperature in the range of about 5°C to about 15°C, more preferably about 5°C to about 10°C, for application to the lateral surface of the patient's foot. Various aspects and embodiments of the method are described below.

[0173] First Method One aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 15 minutes, the cooling device having an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. applying a cooling device to the patient's skin adjacent to the intermetatarsal neuroma for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0174] Second Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 15 minutes, the cooling device having an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. applying a cooling device to the patient's skin adjacent to the intermetatarsal neuroma for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot. thereby attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient.

[0175] Third Method One aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient proximal to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 26°C to about 33°C for tissue proximal to the intermetatarsal neuroma; d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. Applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0176] Fourth Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma, comprising: a. applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg; c. applying a cooling device to the skin of a human patient proximal to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 26°C to about 33°C for tissue proximal to the intermetatarsal neuroma; d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. Applying a cooling product to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy. thereby attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma.

[0177] Fifth Method One aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of at least about 10 minutes, wherein the cooling device has an outer surface temperature in the range of about 1°C to about 15°C; then b. administering a therapeutically effective amount of capsaicin by injection into the intermetatarsal neuroma or tissues adjacent to the intermetatarsal neuroma; and c. Optionally, applying a cooling device to the patient's skin adjacent the intermetatarsal neuroma for a duration of about 10 minutes, wherein the cooling device has an outer surface temperature in the range of about 1°C to about 15°C. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0178] Method 6 One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of at least about 10 minutes, wherein the cooling device has an outer surface temperature in the range of about 1°C to about 15°C; then b. administering a therapeutically effective amount of capsaicin by injection into tissue adjacent to the intermetatarsal neuroma; and c. Optionally, applying a cooling device to the patient's skin adjacent the intermetatarsal neuroma for a duration of about 10 minutes, wherein the cooling device has an outer surface temperature in the range of about 1°C to about 15°C. thereby reducing the transient burning sensation caused by injection of capsaicin into tissues near an intermetatarsal neuroma.

[0179] 7th Method One aspect of the invention is a method for ameliorating pain from intermetatarsal neuroma in a human patient, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 20°C to about 33°C for tissue adjacent to the intermetatarsal neuroma; and b. administering a therapeutically effective amount of capsaicin by injection into tissue adjacent to the intermetatarsal neuroma; and c. Optionally, applying a cooling agent to the patient's skin adjacent to the intermetatarsal neuroma. thereby ameliorating pain from intermetatarsal neuroma in a human patient.

[0180] Method 8 One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of about 20°C to about 33°C for tissue adjacent to the intermetatarsal neuroma; and b. administering a therapeutically effective amount of capsaicin by injection into tissue adjacent to the intermetatarsal neuroma; and c. Optionally, applying a cooling agent to the patient's skin adjacent to the intermetatarsal neuroma. thereby reducing the transient burning sensation caused by injection of capsaicin into tissues near an intermetatarsal neuroma.

[0181] Exemplary Characteristics of Methods 1-8 Involving the Use of Capsaicin in Relation to the Treatment of Intermetatarsal Neuroma The above-described first through eighth methods involving the use of capsaicin in connection with the treatment of intermetatarsal neuroma may be further characterized by additional properties, such as the dosage of capsaicin, the temperature characterization of the cooling article surface, the dosage of lidocaine, and the characterization of the pharmaceutical composition containing a single pain-relieving agent. A more detailed description of such properties is provided below. The present invention encompasses all permutations and combinations of these properties.

[0182] Capsaicin dosage The method may be further characterized according to the dose of capsaicin administered to the patient. For example, in certain embodiments, the dose of capsaicin is in an amount ranging from about 100 μg to about 300 μg. In certain embodiments, the dose of capsaicin is in an amount ranging from about 150 μg to about 250 μg. In certain embodiments, the first dose of capsaicin is about 200 μg.

[0183] Total dose of capsaicin Method can be further characterized according to the total number of capsaicin doses administered to patient.For example, in certain embodiments, over a period of one year, patient receives capsaicin doses of four or less by injection into the intermetatarsal space of the patient with intermetatarsal neuroma.In certain embodiments, over a period of one year, patient receives capsaicin doses of three or less by injection into the intermetatarsal space of the patient with intermetatarsal neuroma.In certain embodiments, over a period of one year, patient receives capsaicin doses of two or less by injection into the intermetatarsal space of the patient with intermetatarsal neuroma.

[0184] The methods may also be characterized according to the total number of additional doses of capsaicin administered to the patient following the second dose of capsaicin. For example, in certain embodiments, the patient receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, or 30 additional doses of capsaicin beyond the second dose of capsaicin. In certain embodiments, the patient receives 1 to 3, 1 to 5, 1 to 10, 5 to 10, 5 to 15, 10 to 15, 10 to 20, 15 to 20, or 15 to 25 additional doses of capsaicin following the second dose of capsaicin. In certain preferred embodiments, the patient receives at least two additional doses of capsaicin following the second dose of capsaicin. In yet other embodiments, the patient receives at least four additional doses of capsaicin following the second dose of capsaicin. In yet other embodiments, the patient receives the second dose of capsaicin followed by at least six additional doses of capsaicin.

[0185] Patients may continue to receive capsaicin by injection to relieve pain from intermetatarsal neuroma for months or even years, as long as medical precautions are followed, including pain relief that is well tolerated and provides adequate pain relief.

[0186] Duration of pain relief The method can be further characterized according to the duration of remission of pain caused by intermetatarsal neuroma. For example, in certain embodiments, the pain is remitted for a duration of at least 4 months. In certain embodiments, the pain is remitted for a duration of at least 5 months. In certain embodiments, the pain is remitted for a duration of at least 6 months. In certain embodiments, the pain is remitted for a duration of at least 7 months. In certain embodiments, the pain is remitted for a duration of at least 8 months. In certain embodiments, the pain is remitted for a duration of at least 9 months. In certain embodiments, the pain is remitted for a duration of at least 10 months. In certain embodiments, the pain is remitted for a duration of at least 11 months. In certain embodiments, the pain is remitted for a duration of at least 12 months. In still other embodiments, the pain is relieved for a duration of about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 24 months, about 6 months to about 12 months, about 6 months to about 24 months, or about 12 months to about 24 months.

[0187] Surface temperature of cooling article for application to patient's feet The method may be further characterized according to the temperature of the cooling article surface for application to a patient's foot. For example, in certain embodiments, the cooling article has an outer surface temperature in the range of about 6°C to about 13°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 7°C to about 13°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 7°C to about 10°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 5°C to about 10°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 8°C to about 10°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 6°C to about 8°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 5°C to about 8°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature in the range of about 5°C to about 7°C for application to a patient's foot.

[0188] In certain embodiments, the cooling article has an outer surface temperature of about 12°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 11°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 10°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 9°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 8°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 7°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 6°C for application to a patient's foot. In certain embodiments, the cooling article has an outer surface temperature of about 5°C for application to a patient's foot.

[0189] Temperature of tissues adjacent to intermetatarsal neuroma The method may be further characterized according to the temperature of the tissue in the vicinity of the intermetatarsal neuroma that is or has been subjected to capsaicin in accordance with the method. For example, in certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 26°C to about 33°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 26°C to about 33°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 26°C to about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 26°C to about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 28°C to about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 28°C to about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 30°C to about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of 30°C to about 32°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 26°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 26° C. for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 27° C. for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 27° C. for a duration of about 30 minutes to about 90 minutes.In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 28°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 28°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 29°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 29°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 30°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 30°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 31°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 31°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 32°C for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 32°C for a duration of about 30 minutes to about 90 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature of about 33° C. for a duration of at least 30 minutes. In certain embodiments, in step (e), the tissue in the vicinity of the intermetatarsal neuroma is maintained at a temperature in the range of about 33° C. for a duration of about 30 minutes to about 90 minutes. The term "in the vicinity" is understood from the perspective of a physician skilled in the art, and can be, for example, tissue within 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, or 7 mm of the intermetatarsal neuroma.

[0190] In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature in the range of about 26°C to about 28°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature in the range of about 28°C to about 30°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature in the range of about 30°C to about 32°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 26°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 27°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 28°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 29°C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 30° C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 31° C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 32° C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 33° C. In certain embodiments, step (c) comprises cooling the tissue adjacent to the intermetatarsal neuroma to a temperature of about 29° C.

[0191] Duration of cooling in step (e) The method may be further characterized according to the duration of cooling in step (e). For example, in certain embodiments, the duration of step (e) is about 30 minutes to about 60 minutes. In certain embodiments, the duration of step (e) is about 60 minutes to about 90 minutes. In certain embodiments, the duration of step (e) is about 30 minutes to about 60 minutes, about 60 minutes to about 90 minutes, about 90 minutes to about 120 minutes, or about 120 minutes to about 180 minutes.

[0192] Further steps to relieve temporary burning sensation The method may be further characterized depending on the presence or absence of additional procedures for reducing the transient burning sensation caused by capsaicin. For example, in certain embodiments, the method does not include any procedures for reducing the transient burning sensation experienced by the patient due to the administration of capsaicin other than those described in steps (a), (b), (c), (d), and (e). In certain embodiments, the method does not include any procedures for reducing pain caused by intermetatarsal neuroma other than those described in steps (a), (b), (c), (d), and (e). In certain embodiments, the patient does not receive any other pain-relieving medication other than the administration of (i) a local anesthetic and (ii) a pharmaceutical composition containing capsaicin.

[0193] The magnitude of the transient burning sensation caused by capsaicin The method may be further characterized by the magnitude of the transient burning sensation caused by capsaicin. For example, in certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 1 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 2 or less on a visual analog scale ranging from 0 to 4 (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, (4) severe). In certain embodiments, the transient burning sensation is assessed about 10 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is assessed about 30 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 60 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, the transient burning sensation is evaluated about 120 minutes after administration of the pharmaceutical composition comprising capsaicin.

[0194] Characterization of cooling products The method may be further characterized according to the characteristics of the cooling device. For example, in certain embodiments, the cooling device is a material wrap that is cooled via circulating fluid. In certain embodiments, the cooling device is a fabric wrap that is cooled via circulating fluid. In certain embodiments, the cooling device is an at least partially frozen gel pack. In certain embodiments, the cooling device covers at least 10% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 20% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 30% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 50% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 70% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 80% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 90% of the outer surface of the patient's foot. In certain embodiments, the cooling device covers at least 95% of the outer surface of the patient's foot.

[0195] Capsaicin Capsaicin has the chemical name N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide and, due to the presence of a C-C double bond, can exist as a mixture of cis and trans isomers. The method can be further characterized according to the isomeric purity of the capsaicin administered to the patient. For example, in certain embodiments, the capsaicin is a mixture of cis-capsaicin and trans-capsaicin containing at least 95% trans-capsaicin by weight. In certain embodiments, the capsaicin is a mixture of cis-capsaicin and trans-capsaicin containing at least 98% trans-capsaicin by weight. In certain embodiments, the capsaicin is a mixture of cis-capsaicin and trans-capsaicin containing at least 99% trans-capsaicin by weight.

[0196] Injectable preparations The methods can be further characterized according to the formulation used to administer capsaicin to the patient. For example, in certain embodiments, capsaicin is administered in the form of a liquid, injectable pharmaceutical formulation comprising a pharmaceutically acceptable carrier for injection into the patient. In certain embodiments, the liquid, injectable pharmaceutical formulation comprises water, capsaicin, and poly(ethylene glycol). In certain other embodiments, the liquid, injectable pharmaceutical formulation consists essentially of water, capsaicin, and poly(ethylene glycol).

[0197] The formulation may be further characterized according to the poly(ethylene glycol) in the formulation, such as the poly(ethylene glycol) having a number average molecular weight of about 250 g / mole to about 350 g / mole. In certain embodiments, the poly(ethylene glycol) has a number average molecular weight of about 300 g / mole.

[0198] The formulations may be further characterized according to the amount of poly(ethylene glycol) in the formulation, such as poly(ethylene glycol) being present in an amount ranging from about 25% to about 35% by weight of the pharmaceutical formulation. In certain embodiments, poly(ethylene glycol) is present in an amount ranging from about 30% by weight of the pharmaceutical formulation.

[0199] Amount of unit dose of liquid formulation administered to patient The method may be further characterized according to the amount of formulation administered to the patient per injection. For example, in certain embodiments, the first dose of capsaicin, the second dose of capsaicin, and any additional doses of capsaicin are liquid injectable pharmaceutical formulations, each having a volume ranging from about 1 to 3 mL. In other embodiments, the first dose of capsaicin, the second dose of capsaicin, and any additional doses of capsaicin are liquid injectable pharmaceutical formulations, each having a volume of about 2 mL.

[0200] In certain other embodiments, the administered volume can be smaller, such as when administered to a pediatric patient. In certain embodiments, the first dose of capsaicin, the second dose of capsaicin, and any additional doses of capsaicin are liquid injectable pharmaceutical formulations, each having a volume ranging from about 0.25 to 2 mL, 0.25 to 1 mL, 0.5 to 1 mL, or 0.5 to 1.5 mL.

[0201] Injection procedure The method can be further characterized according to the identity of the tissue into which capsaicin is injected. For example, in certain embodiments, any dose of capsaicin is injected into the tissue adjacent to the intermetatarsal neuroma, so that the medical device performing the injection does not penetrate into the intermetatarsal neuroma. It is understood that the injected capsaicin can diffuse through the tissue adjacent to the intermetatarsal neuroma to reach the intermetatarsal neuroma. The medical personnel performing the injection can use ultrasound imaging to help guide the medical device (e.g., syringe) used to administer the formulation containing capsaicin. This procedure helps the medical device performing the injection not penetrate into the intermetatarsal neuroma, but delivers capsaicin to the tissue adjacent to the intermetatarsal neuroma, so that the capsaicin can diffuse through the tissue adjacent to the intermetatarsal neuroma and contact the intermetatarsal neuroma.

[0202] Avoiding heat The method can be further characterized according to the activity that the patient should avoid after receiving the capsaicin. For example, in certain embodiments, the patient does not expose the area receiving the capsaicin to heat for a duration of at least 24 hours after receiving the capsaicin dose.

[0203] Identity of local anesthetic If the method recites the administration of a local anesthetic, the method may be further characterized according to the identity of the local anesthetic. If the method is silent regarding the administration of a local anesthetic, further embodiments of the invention relate to embodiments in which a local anesthetic is administered to a patient immediately prior to injecting capsaicin to ameliorate the pain experienced by the patient from the administration of capsaicin.

[0204] The local anesthetic may be, for example, a caine analgesic. Exemplary caine analgesics include, for example, lidocaine, dibucaine, bupivacaine, ropivacaine, etidocaine, tetracaine, procaine, chlorocaine, prilocaine, mepivacaine, xylocaine, 2-chloroprocaine, and pharmaceutically acceptable salts thereof. In certain embodiments, the local anesthetic is lidocaine or a pharmaceutically acceptable salt thereof.

[0205] The dose of local anesthetic will depend on the site to which the local anesthetic is administered along with the anesthetic being administered. For example, in embodiments where the local anesthetic is administered via a regional block (e.g., an ankle block), the dose of anesthetic may range from about 1 mL to about 30 mL of a 1% solution of anesthetic (e.g., lidocaine). In other embodiments, a dose of up to 5 mg / kg of a solution containing 0.25% to 5% anesthetic (e.g., lidocaine) may be administered as a nerve block, for example, by administration to the site of pain or an area adjacent to the site of pain. In still other embodiments, the dose of local anesthetic may range from about 0.5 mL to about 60 mL of a 0.25% to 5% solution of anesthetic.

[0206] The method can be further characterized according to the location where the local anesthetic is administered. In certain embodiments, the local anesthetic is administered to tissue adjacent to the intermetatarsal neuroma. In certain embodiments, the local anesthetic is administered to the ankle attached to the foot of a patient with an intermetatarsal neuroma.

[0207] Location of intermetatarsal neuroma The method can be further characterized according to the location of the intermetatarsal neuroma. In certain embodiments, the patient has an intermetatarsal neuroma in the third intermetatarsal space. In certain embodiments, the patient has an intermetatarsal neuroma in the second intermetatarsal space.

[0208] Characteristics of intermetatarsal neuroma The method may be further characterized according to characteristics of the intermetatarsal neuroma, such as numbness in the toes of the foot having the intermetatarsal neuroma, paresthesia in the toes of the foot having the intermetatarsal neuroma, the amount of pain experienced by the patient due to the intermetatarsal neuroma, and / or the size of the intermetatarsal neuroma.

[0209] Thus, in certain embodiments, the method is further characterized by the property that the patient experiences toe numbness or toe paresthesia, respectively, due to an intermetatarsal neuroma.

[0210] In certain embodiments, the method may be characterized by the level of pain experienced by the patient due to intermetatarsal neuroma. In certain embodiments, the patient experiences pain due to intermetatarsal neuroma of at least level 4 at some point in the 24 hours prior to administering the first dose of capsaicin. In certain embodiments, the patient experiences pain due to intermetatarsal neuroma of at least level 5 at some point in the 24 hours prior to administering the first dose of capsaicin. In certain embodiments, the patient experiences pain due to intermetatarsal neuroma of at least level 4 at some point in the 24 hours prior to administering capsaicin. In certain embodiments, the patient experiences pain due to intermetatarsal neuroma of at least level 5 at some point in the 24 hours prior to administering capsaicin.

[0211] Characteristics of the pain-reducing effect of capsaicin treatment The method can be further characterized according to the pain reduction provided by capsaicin treatment. For example, in certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma for a certain duration. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 3 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 4 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 5 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 6 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 7 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 8 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 9 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 10 months.In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 11 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months, wherein the patient is characterized by a condition in which nerve growth is delayed in the region of the intermetatarsal neuroma, such as diabetes mellitus.

[0212] In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma by at least 2 on the Numeric Pain Rating Scale (NPRS) for a particular duration. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma by at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 3 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma by at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 4 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma by at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 5 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma by at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 6 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 7 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 8 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 9 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 10 months.In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 11 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months. In certain embodiments, the method is characterized by achieving a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months, wherein the patient is characterized by a condition in which nerve growth is delayed in the region of the intermetatarsal neuroma, such as diabetes mellitus.

[0213] The method may be further characterized according to the maximum amount of pain experienced by the patient due to intermetatarsal neuroma after administration of capsaicin. For example, in certain embodiments, the method is characterized by reducing the average walking foot pain of patients with intermetatarsal neuroma such that the average walking foot pain of patients with intermetatarsal neuroma is 1 or less on the Numerical Pain Rating Scale (NPRS) for a particular duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. Thus, in certain embodiments, the method is characterized by reducing the average walking foot pain of patients with intermetatarsal neuroma such that the average walking foot pain of patients with intermetatarsal neuroma is 1 or less on the Numerical Pain Rating Scale (NPRS) for a duration of at least 3 months. In certain embodiments, the method is characterized by reducing the average walking foot pain of patients with intermetatarsal neuroma such that the average walking foot pain of patients with intermetatarsal neuroma is 1 or less on the Numerical Pain Rating Scale (NPRS) for a duration of at least 4 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 5 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 6 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 7 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 8 months.In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 9 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 10 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 11 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months. In certain embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the patient's mean walking foot pain is 1 or less on a Numerical Pain Rating Scale (NPRS) for a duration of at least 12 months, and wherein the patient is characterized by a condition that retards nerve growth in the region of the intermetatarsal neuroma, such as diabetes mellitus. In yet other embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the patient's mean walking foot pain is 2 or less on a Numerical Pain Rating Scale (NPRS) for a specified duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In yet other embodiments, the method is characterized by reducing the patient's mean walking foot pain due to intermetatarsal neuroma such that the patient's mean walking foot pain due to intermetatarsal neuroma is 3 or less on the Numerical Pain Rating Scale (NPRS) for a specified duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.In yet other embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 4 or less on a Numerical Pain Rating Scale (NPRS) for a specified duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In yet other embodiments, the method is characterized by reducing mean walking foot pain in patients with intermetatarsal neuroma such that the mean walking foot pain in patients with intermetatarsal neuroma is 5 or less on a Numerical Pain Rating Scale (NPRS) for a specified duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0214] The method can be further characterized according to the reduction in pain experienced by the patient due to intermetatarsal neuroma after administering the first dose of capsaicin.Therefore, in certain embodiments, the method is characterized by the following characteristic: when administering the first dose of capsaicin, the patient experiences a reduction in the average walking foot pain caused by intermetatarsal neuroma of at least 1 on the Numerical Pain Rating Scale (NPRS) within 2 weeks after administering the first dose of capsaicin, and the reduction lasts for at least 2 months.In certain embodiments, when administering the first dose of capsaicin, the patient experiences a reduction in the average walking foot pain caused by intermetatarsal neuroma of at least 2 on the Numerical Pain Rating Scale (NPRS) within 2 weeks after administering the first dose of capsaicin, and the reduction lasts for at least 2 months. In certain embodiments, upon administration of the first dose of capsaicin, the patient experiences a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 1 on the Numeric Pain Rating Scale (NPRS) that lasts for at least three months of duration within two weeks after administration of the first dose of capsaicin. In certain embodiments, upon administration of the first dose of capsaicin, the patient experiences a reduction in mean walking foot pain due to intermetatarsal neuroma of at least 2 on the Numeric Pain Rating Scale (NPRS) that lasts for at least three months of duration within two weeks after administration of the first dose of capsaicin.

[0215] The method may be further characterized according to its ability to reduce a patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale for a specified duration, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In certain embodiments, the method is characterized by reducing a patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 3 months. In certain embodiments, the method is characterized by reducing a patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 4 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 5 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 6 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 7 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 8 months.In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 9 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 10 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 11 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months. In certain embodiments, the method is characterized by reducing the patient's worst neuroma foot pain due to intermetatarsal neuroma such that the patient's worst neuroma foot pain due to intermetatarsal neuroma is 1 or less on a Numeric Pain Rating Scale (NPRS) for a duration of at least 12 months, wherein the patient is characterized by a condition in which nerve growth is delayed in the region of the intermetatarsal neuroma, such as diabetes mellitus.

[0216] The method may be further characterized according to its ability to reduce a patient's worst intermetatarsal neuroma foot pain such that the patient's worst intermetatarsal neuroma neuroma pain is at or below a particular threshold (e.g., 1 or 2) on a numeric pain rating scale for a particular duration after administration of the first dose of capsaicin, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In certain embodiments, upon administration of the first dose of capsaicin, the patient experiences a reduction in worst intermetatarsal neuroma foot pain of at least 1 on a numeric pain rating scale (NPRS) within two weeks after administration of the first dose of capsaicin, lasting for a duration of at least two months. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences a reduction in worst intermetatarsal neuroma foot pain of at least 2 on the Numeric Pain Rating Scale (NPRS) that lasts for at least two months within two weeks after administration of the first dose of capsaicin. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences a reduction in worst intermetatarsal neuroma foot pain of at least 1 on the Numeric Pain Rating Scale (NPRS) that lasts for at least three months within two weeks after administration of the first dose of capsaicin. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences a reduction in worst intermetatarsal neuroma foot pain of at least 2 on the Numeric Pain Rating Scale (NPRS) that lasts for at least three months within two weeks after administration of the first dose of capsaicin.

[0217] The method can be further characterized according to its ability to achieve an improvement in the patient's Revised Foot Function Index (FFI-R) score. Thus, in certain embodiments, upon administration of a first dose of capsaicin, the patient experiences an improvement in the Revised Foot Function Index (FFI-R) score of at least 1 within two weeks after administration of the dose of capsaicin, which continues for a duration of at least two months. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences an improvement in the Revised Foot Function Index (FFI-R) score of at least 2 within two weeks after administration of the dose of capsaicin, which continues for a duration of at least two months. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences an improvement in the Revised Foot Function Index (FFI-R) score of at least 1 within two weeks after administration of the dose of capsaicin, which continues for a duration of at least three months. In certain embodiments, upon administration of said dose of capsaicin, the patient experiences an improvement in the Revised Foot Function Index (FFI-R) score of at least 2 within two weeks of administration of the dose of capsaicin, sustained for a duration of at least two months. In certain embodiments, the method is characterized in that the patient experiences an improvement in the Revised Foot Function Index (FFI-R) score of at least 1 (or at least 2 or 3) for a duration of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0218] The method may be further characterized according to its ability to achieve an improvement in the patient's Personal Activity Rating Scale (PARS) score. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences an improvement of at least 1 Personal Activity Rating Scale (PARS) score within two weeks after administration of the dose of capsaicin, which continues for at least one month. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences an improvement of at least 2 Personal Activity Rating Scale (PARS) score within two weeks after administration of the dose of capsaicin, which continues for at least one month. In certain embodiments, upon administration of the dose of capsaicin, the patient experiences an improvement of at least 1 Personal Activity Rating Scale (PARS) score within two weeks after administration of the dose of capsaicin, which continues for at least two months. In certain embodiments, upon administration of said dose of capsaicin, the patient experiences an improvement in the Personal Activity Rating Scale (PARS) score of at least 2 within two weeks of administration of the dose of capsaicin, sustained for a duration of at least two months. In certain embodiments, the method is characterized in that the patient experiences an improvement in the Personal Activity Rating Scale (PARS) score of at least 1 (or at least 2 or 3) for a duration of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0219] The method can be further characterized according to the improvement in the patient's quality of life after administering capsaicin to alleviate pain caused by intermetatarsal neuroma. For example, in certain embodiments, the method is characterized by an improvement in the patient's quality of life score, such as an improvement in the EuroQol-5 Dimension (EQ-5D-5L) scale.

[0220] Patient population for treatment The method can be further characterized according to the characteristics of the patient to be treated.For example, in certain embodiments, in the 24-hour period before the administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) mean walking foot pain due to intermetatarsal neuroma, of at least 4 on the Numerical Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma, of at least 4 on the Numerical Pain Rating Scale (NPRS); or (c) a Revised Foot Function Index (FFI-R) score indicating that the patient experiences at least two of the following: (i) moderate pain due to intermetatarsal neuroma, (ii) moderate stiffness due to intermetatarsal neuroma, and (iii) moderate difficulty in physical activity due to intermetatarsal neuroma. In certain other embodiments, during the 24-hour period prior to administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) average walking foot pain due to intermetatarsal neuroma of at least 6 on the Numeric Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma of at least 6 on the Numeric Pain Rating Scale (NPRS); or (c) a Revised Foot Function Index (FFI-R) score indicating the patient is experiencing at least two of the following: (i) severe pain due to intermetatarsal neuroma, (ii) severe stiffness due to intermetatarsal neuroma, and (iii) severe difficulty with physical activity due to intermetatarsal neuroma. In certain other embodiments, during the 24-hour period prior to administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) average walking foot pain due to intermetatarsal neuroma of at least 8 on the Numerical Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma of at least 8 on the Numerical Pain Rating Scale (NPRS); or (c) a Revised Foot Function Index (FFI-R) score indicating the patient is experiencing all of the following: (i) severe pain due to intermetatarsal neuroma, (ii) severe stiffness due to intermetatarsal neuroma, and (iii) severe difficulty with physical activity due to intermetatarsal neuroma.

[0221] In certain embodiments, patients are characterized according to one or more of average walking foot pain due to intermetatarsal neuroma, worst neuroma foot pain due to intermetatarsal neuroma, Foot Function Index-Revised (FFI-R) score, and Personal Activity Rating Scale (PARS). Thus, in certain embodiments, during the 24-hour period prior to administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) average walking foot pain due to intermetatarsal neuroma of at least 4 on the Numeric Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma of at least 4 on the Numeric Pain Rating Scale (NPRS); (c) a Revised Foot Function Index (FFI-R) score indicating that the patient is experiencing at least two of the following: (i) moderate pain due to intermetatarsal neuroma, (ii) moderate stiffness due to intermetatarsal neuroma, and (iii) moderate difficulty with physical activity due to intermetatarsal neuroma; or (d) a Personal Activities Rating Scale (PARS) score of at least 4 for at least one physical activity. In certain embodiments, during the 24-hour period prior to administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) average walking foot pain due to intermetatarsal neuroma of at least 6 on the Numeric Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma of at least 6 on the Numeric Pain Rating Scale (NPRS); (c) a Revised Foot Function Index (FFI-R) score indicating the patient is experiencing at least two of the following: (i) severe pain due to intermetatarsal neuroma, (ii) severe stiffness due to intermetatarsal neuroma, and (iii) severe difficulty with physical activity due to intermetatarsal neuroma; or (d) a Personal Activities Rating Scale (PARS) score of at least 6 for at least one physical activity.In certain embodiments, during the 24-hour period prior to administration of the first dose of capsaicin, the patient exhibits one or more of the following: (a) average walking foot pain due to intermetatarsal neuroma of at least 8 on the Numeric Pain Rating Scale (NPRS); (b) worst neuroma foot pain due to intermetatarsal neuroma of at least 8 on the Numeric Pain Rating Scale (NPRS); (c) a Revised Foot Function Index (FFI-R) score indicating the patient is experiencing all of the following: (i) severe pain due to intermetatarsal neuroma, (ii) severe stiffness due to intermetatarsal neuroma, and (iii) severe difficulty with physical activity due to intermetatarsal neuroma; or (d) a Personal Activities Rating Scale (PARS) score of at least 8 for at least one physical activity.

[0222] The method may be further characterized according to whether the patient has a poor quality of life score, such as a poor score on the EuroQol-5 Dimensions (EQ-5D-5L) scale, due to pain or other symptoms from the intermetatarsal neuroma.

[0223] The method may be further characterized according to whether the patient has previously been able to achieve temporary relief of pain from intermetatarsal neuroma using other therapies, such as injectable steroids, oral analgesics, or sclerosing agents. Thus, in certain embodiments, the method is further characterized by the property that the patient has not achieved relief of pain from intermetatarsal neuroma for a sustained period of more than two months following treatment with the administration of injectable steroids, oral analgesics, or sclerosing agents to relieve pain from intermetatarsal neuroma.

[0224] The methods may be further characterized according to the age of the patient. In certain embodiments, the patient has an age ranging from about 20 to about 30 years, from about 30 to about 40 years, from about 40 to about 50 years, from about 50 to about 60 years, or from about 60 to about 70 years, or is over 70 years old.

[0225] The methods may be further characterized according to the gender of the patient, such as a male or female patient. In certain embodiments, the patient is an adult male or female. In certain embodiments, the patient is a transgender human.

[0226] In certain embodiments, the patient is a human child.

[0227] Exemplary More Specific Embodiments Exemplary more specific embodiments include, for example: Embodiment 1: A method of attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to an intermetatarsal neuroma, comprising: a. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 15 minutes, the cooling device having an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and b. administering by injection into tissues adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 30 mg to about 50 mg; c. applying a cooling device to the skin of a human patient adjacent to an intermetatarsal neuroma in need of pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot; and d. administering capsaicin in an amount of about 100 μg to 300 μg by injection into tissue adjacent to the intermetatarsal neuroma; and e. applying a cooling device to the patient's skin adjacent to the intermetatarsal neuroma for a duration of at least about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to the patient's foot. thereby ameliorating neuralgia in a human patient.

[0228] Embodiment 2: The method of embodiment 1, wherein the dose of lidocaine is about 40 mg.

[0229] Embodiment 3: The method of embodiment 1 or 2, wherein the cooling article covers at least 20% of the exterior surface of the patient's foot.

[0230] Embodiment 4: The method of embodiment 1 or 2, wherein the cooling article covers at least 30% of the exterior surface of the patient's foot.

[0231] Embodiment 5: The method of embodiment 1 or 2, wherein the cooling article covers at least 40% of the exterior surface of the patient's foot.

[0232] Embodiment 6: The method of embodiment 1 or 2, wherein the cooling article covers at least 50% of the exterior surface of the patient's foot.

[0233] Embodiment 7: The method of embodiment 1 or 2, wherein the cooling article covers at least 70% of the exterior surface of the patient's foot.

[0234] Embodiment 8: The method of embodiment 1 or 2, wherein the cooling article covers at least 80% of the exterior surface of the patient's foot.

[0235] Embodiment 9: The method of embodiment 1 or 2, wherein the cooling article covers at least 90% of the exterior surface of the patient's foot.

[0236] Embodiment 10: The method of any one of embodiments 1 to 9, wherein step (c) comprises administering capsaicin in an amount of about 200 μg by injection into tissue adjacent to the intermetatarsal neuroma.

[0237] Embodiment 11: The method of any one of embodiments 1 to 9, wherein step (c) comprises administering capsaicin in an amount of about 250 μg by injection into tissue adjacent to the intermetatarsal neuroma.

[0238] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 6°C to about 13°C for application to the patient's foot.

[0239] Embodiment 13: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 13°C for application to the patient's foot.

[0240] Embodiment 14: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 10°C for application to the patient's foot.

[0241] Embodiment 15: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 10°C for application to the patient's foot.

[0242] Embodiment 16: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 8°C to about 10°C for application to the patient's foot.

[0243] Embodiment 17: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 6°C to about 8°C for application to the patient's foot.

[0244] Embodiment 18: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 8°C for application to the patient's foot.

[0245] Embodiment 19: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature in the range of about 5°C to about 7°C for application to the patient's foot.

[0246] Embodiment 20: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 12°C for application to the patient's foot.

[0247] Embodiment 21: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 11° C. for application to the patient's foot.

[0248] Embodiment 22: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 10°C for application to the patient's foot.

[0249] Embodiment 23: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 9°C for application to the patient's foot.

[0250] Embodiment 24: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 8°C for application to the patient's foot.

[0251] Embodiment 25: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 7°C for application to the patient's foot.

[0252] Embodiment 26. The method of any one of embodiments 1-11, wherein the cooling article has an outer surface temperature of about 6°C for application to the patient's foot.

[0253] Embodiment 27: The method of any one of embodiments 1 to 11, wherein the cooling article has an outer surface temperature of about 5°C for application to the patient's foot.

[0254] Embodiment 28: The method of any one of embodiments 1 to 27, which does not include any steps other than those described in steps (a), (b), (c), (d), and (e) to reduce the transient burning sensation experienced by the patient due to administration of capsaicin.

[0255] Embodiment 29: The method of any one of embodiments 1 to 28, which does not include any other procedures for alleviating pain from intermetatarsal neuroma other than those described in steps (a), (b), (c), (d), and (e).

[0256] Embodiment 30: The method of any one of embodiments 1 to 29, wherein the patient does not receive any other pain-relieving medication other than the administration of (i) lidocaine and (ii) capsaicin.

[0257] Embodiment 31: The method of any one of embodiments 1 to 30, wherein the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 1 or less on a visual analog scale ranging from 0 to 4.

[0258] Embodiment 32: The method of any one of embodiments 1 to 30, wherein the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 2 or less on a visual analog scale ranging from 0 to 4.

[0259] Further Exemplary Embodiments for Treating Painful Nerves The procedures described above for treating intermetatarsal neuromas can be used to treat painful nerves more generally. Exemplary embodiments for treating painful nerves include, for example:

[0260] First Method One aspect of the invention is a method for ameliorating neuralgia in a human patient, comprising: a. applying a cooling device to the skin of a human patient near a painful nerve in need of pain relief therapy for a duration of about 15 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin; and b. administering by injection into tissue adjacent to the painful nerve a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver an effective amount of lidocaine (e.g., an amount of lidocaine ranging from about 1 mg to about 50 mg); c. applying a cooling device to the skin of a human patient near a painful nerve in need of pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin; and d. administering an effective amount (e.g., about 100 μg to 300 μg) of capsaicin by injection into tissue adjacent to the painful nerve; and then e. applying a cooling device to the patient's skin near the painful nerve for a duration of at least about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin. thereby ameliorating neuralgia in a human patient.

[0261] Second Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to a painful nerve in a human patient, comprising: a. applying a cooling device to the skin of a human patient near a painful nerve in need of pain relief therapy for a duration of about 15 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin; and b. administering by injection into tissue adjacent to the painful nerve a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver an effective amount of lidocaine (e.g., an amount of lidocaine ranging from about 1 mg to about 50 mg); c. applying a cooling device to the skin of a human patient near a painful nerve in need of pain relief therapy for a duration of about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin; and d. administering an effective amount (e.g., about 100 μg to 300 μg) of capsaicin by injection into tissue adjacent to the painful nerve; and then e. applying a cooling device to the patient's skin near the painful nerve for a duration of at least about 30 minutes, wherein the cooling device has an outer surface temperature in the range of about 5°C to about 15°C for application to said skin. thereby attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to a painful nerve in a human patient.

[0262] Third Method One aspect of the invention is a method for ameliorating neuralgia in a human patient, comprising: a. applying a cooling article to the skin of a human patient near a painful nerve in need of pain relief therapy; then b. administering by injection into tissue adjacent to the painful nerve a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver an effective amount of lidocaine (e.g., an amount of lidocaine ranging from about 1 mg to about 50 mg); c. applying a cooling article to the skin of a human patient in proximity to a painful nerve in need of pain relief therapy to achieve a temperature in the range of about 26°C to about 33°C for the tissue in proximity to the painful nerve; d. administering an effective amount (e.g., about 100 μg to 300 μg) of capsaicin by injection into tissue adjacent to the painful nerve; and then e. applying a cooling article to the skin of a human patient near a painful nerve in need of pain relief therapy. thereby ameliorating neuralgia in a human patient.

[0263] Fourth Method One aspect of the present invention is a method for attenuating the transient burning sensation caused by injection of capsaicin into tissue adjacent to a painful nerve, comprising: a. applying a ...

Claims

1. A pharmaceutical composition for use in ameliorating osteoarthritic knee joint pain in a human patient, said use comprising: a. applying a cooling article to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain for a duration of about 15 minutes, said cooling article having an exterior surface temperature in the range of about 5°C to about 15°C for application to said exterior surface of said knee; and b. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; and c. applying a cooling article to the exterior surface of the knee for a duration of about 30 minutes, the cooling article having an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee to achieve a temperature in the range of 26°C to 28°C or in the range of 28°C to 30°C for fluid in the intra-articular space of the knee joint; and d. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling article to the exterior surface of the knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of about 5°C to about 15°C for application to the exterior surface of the knee. thereby ameliorating osteoarthritic knee joint pain in said human patient; the patient does not receive any other pain-relieving medication other than administration of (i) the pharmaceutical composition comprising lidocaine, and (ii) the pharmaceutical composition comprising capsaicin; Pharmaceutical compositions.

2. 10. The pharmaceutical composition for use according to claim 1, wherein said cooling article has an exterior surface temperature in the range of about 7°C to about 13°C for application to said exterior surface of said knee.

3. A pharmaceutical composition for use in ameliorating osteoarthritic knee joint pain in a human patient, said use comprising: a. applying a cooling article to the exterior surface of the knee of a human patient experiencing osteoarthritic knee joint pain; and b. administering by injection into the intra-articular space of said knee joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g; and c. applying a cooling product to an outer surface of the knee to achieve a temperature in the range of 26°C to 28°C for fluid within the intra-articular space of the joint of the knee; and d. administering by injection into the intra-articular space of the knee joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. applying a cooling product to the exterior surface of the knee thereby ameliorating osteoarthritic knee joint pain in said human patient; the patient does not receive any other pain-relieving medication other than administration of (i) the pharmaceutical composition comprising lidocaine, and (ii) the pharmaceutical composition comprising capsaicin; Pharmaceutical compositions.

4. A pharmaceutical composition for use in the alleviation of joint pain in a human patient, said use comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling article to the patient's skin adjacent to the joint for a duration of at least about 10 minutes, the cooling article having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin adjacent to the joint to achieve a temperature in the range of 26°C to 28°C or in the range of 28°C to 30°C for fluid in the intra-articular space of the knee joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling article having an outer surface temperature in the range of about 1° C. to about 15° C. for application to the human patient's skin near the joint. thereby alleviating joint pain in said human patient, wherein said joint pain is osteoarthritic joint pain and said joint is a knee joint; the patient does not receive any other pain-relieving medication other than administration of (i) the local anesthetic, and (ii) the pharmaceutical composition comprising capsaicin; said use comprising the step (b) of (i) administering by injection into said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; or (ii) the further step of administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; Pharmaceutical compositions.

5. A pharmaceutical composition for use in reducing the transient burning sensation caused by injection of capsaicin into a joint in a human patient, said use comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint in need of pain relief therapy; b. Optionally, administering a local anesthetic into the joint; c. applying a cooling article to the patient's skin adjacent to the joint for a duration of at least about 10 minutes, the cooling article having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin adjacent to the joint to achieve a temperature in the range of 26°C to 28°C or in the range of 28°C to 30°C for fluid in the intra-articular space of the knee joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling article to the patient's skin near the joint for a duration of at least about 10 minutes, the cooling article having an outer surface temperature in the range of about 1° C. to about 15° C. for application to the human patient's skin near the joint. thereby reducing the transient burning sensation caused by injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint; the patient does not receive any other pain-relieving medication other than administration of (i) the local anesthetic, and (ii) the pharmaceutical composition comprising capsaicin; said use comprising the step (b) of (i) administering by injection into said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; or (ii) the further step of administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; Pharmaceutical compositions.

6. 6. The pharmaceutical composition of claim 4 or 5, wherein step (c) comprises applying the cooling article to the exterior surface of the knee for a duration of about 15 minutes to about 45 minutes.

7. 7. The pharmaceutical composition according to any one of claims 4 to 6, wherein in step (c), the temperature range is in the range of 28°C to 30°C for the fluid of the intra-articular space of the joint.

8. 8. The pharmaceutical composition of any one of claims 4 to 7, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 13°C for application to the skin of the human patient in the vicinity of the joint.

9. 8. The pharmaceutical composition of any one of claims 4 to 7, wherein the cooling article has an outer surface temperature in the range of about 8°C to about 10°C for application to the skin of the human patient in the vicinity of the joint.

10. A pharmaceutical composition for use in the alleviation of joint pain in a human patient, said use comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling article to the patient's skin adjacent to the joint to achieve a temperature in the range of 26°C to 28°C for tissue or fluids within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling product to the patient's skin adjacent to the joint. thereby alleviating joint pain in said human patient, wherein said joint pain is osteoarthritic joint pain and said joint is a knee joint; the patient does not receive any other pain-relieving medication other than administration of (i) the local anesthetic, and (ii) the pharmaceutical composition comprising capsaicin; said use comprising the step (b) of (i) administering by injection into said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; or (ii) the further step of administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; Pharmaceutical compositions.

11. A pharmaceutical composition for use in reducing the transient burning sensation caused by injection of capsaicin into a joint in a human patient, said use comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint in need of pain relief therapy; b. Optionally, administering a local anesthetic into the joint; c. applying a cooling article to the patient's skin adjacent to the joint to achieve a temperature in the range of 26°C to 28°C for tissue or fluids within the joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling product to the patient's skin adjacent to the joint. thereby reducing the transient burning sensation caused by injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint; the patient does not receive any other pain-relieving medication other than administration of (i) the local anesthetic, and (ii) the pharmaceutical composition comprising capsaicin; said use comprising the step (b) of (i) administering by injection into said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; or (ii) the further step performed between steps (c) and (d): administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g.

12. 12. The pharmaceutical composition of claim 10 or 11, wherein step (c) comprises applying a cooling product to the patient's skin in the vicinity of the joint to achieve a temperature of 26°C for fluid within the joint.

13. 12. The pharmaceutical composition of claim 10 or 11, wherein step (c) comprises applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature of 27°C for fluid within the joint.

14. 14. The pharmaceutical composition of any one of claims 10-13, wherein use comprises step (e) of applying a cooling article to the patient's skin in the vicinity of the joint to achieve a temperature in the range of about 28°C to about 30°C for tissue or fluids within the joint for a duration of at least 15 minutes.

15. A pharmaceutical composition for use in the alleviation of joint pain in a human patient, said use comprising: a. optionally applying a cooling article to the skin of a human patient adjacent to a joint requiring pain relief therapy; and b. optionally, administering a local anesthetic into said joint; and c. applying a cooling article to the patient's skin adjacent to the joint for a duration of at least about 30 minutes, the cooling article having an outer surface temperature in the range of about 1°C to about 15°C for application to the human patient's skin adjacent to the joint to achieve a temperature in the range of 26°C to 28°C or in the range of 28°C to 30°C for fluid in the intra-articular space of the knee joint; and d. administering by injection into said joint a pharmaceutical composition comprising capsaicin to deliver a dose of capsaicin in an amount of about 1 mg; and e. Optionally, applying a cooling article to the patient's skin proximate the joint for a duration of at least about 10 minutes, wherein the cooling article has an outer surface temperature in the range of about 1° C. to about 15° C. for application to the human patient's skin proximate the joint. thereby alleviating joint pain in said human patient, wherein said joint pain is osteoarthritic joint pain and said joint is a knee joint; the patient does not receive any other pain-relieving medication other than administration of (i) the local anesthetic, and (ii) the pharmaceutical composition comprising capsaicin; said use comprising the step (b) of (i) administering by injection into said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; or (ii) the further step performed between steps (c) and (d): administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g.

16. 16. The pharmaceutical composition of any one of claims 10 to 15, wherein the use comprises step (a) of applying the cooling article to the skin of a human patient in the vicinity of a joint in need of pain relief therapy for a duration of about 15 minutes.

17. The pharmaceutical composition according to any one of claims 10 to 15, wherein the use does not include step (a).

18. 18. The pharmaceutical composition of any one of claims 10-17, wherein the use comprises the following further step carried out between steps (c) and (d): administering to said joint a pharmaceutical composition comprising a single pain-relieving agent selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g.

19. 19. The pharmaceutical composition for use according to claim 18, wherein the use does not include step (b).

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the pharmaceutical composition comprising lidocaine has a volume of about 15 mL.

21. 16. The pharmaceutical composition of claim 15, wherein step (c) comprises applying the cooling article to the exterior surface of the knee for a duration of about 30 minutes.

22. 22. The pharmaceutical composition of any one of claims 10 to 21, wherein the pharmaceutical composition comprising capsaicin has a volume of about 2 mL.

23. 23. The pharmaceutical composition of any one of claims 10 to 22, wherein the cooling article has an outer surface temperature in the range of about 7°C to about 13°C for application to the skin of the human patient near the joint.

24. 23. The pharmaceutical composition of any one of claims 10 to 22, wherein the cooling article has an outer surface temperature in the range of about 8°C to about 10°C for application to the skin of the human patient near the joint.

25. 23. The pharmaceutical composition of any one of claims 10 to 22, wherein the cooling article has an outer surface temperature of about 9°C for application to the skin of the human patient near the joint.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the patient experiences a transient burning sensation upon administration of the pharmaceutical composition comprising capsaicin of level 2 or less on a visual analogue scale ranging from 0 to 4.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the cooling article is a material wrap that is cooled via circulating fluid or an at least partially frozen gel pack.

28. 28. The pharmaceutical composition of any one of claims 1 to 27, wherein the cooling article covers at least 80% of the exterior surface of the joint.

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