CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 16/631,277, filed Jan. 15, 2020, which is the national stage of International (PCT) Patent Application Serial No. PCT/US2018/043094, filed Jul. 20, 2018, which claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 62/535,003, filed Jul. 20, 2017, the contents of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides methods and compositions for treatment of pain, such as joint pain, using capsaicin in a procedure that attenuates transient burning sensation experienced by patients due to capsaicin administrations, through use of controlled cooling to reduce the temperature of tissue to be exposed to capsaicin optionally in combination with use of a local anesthetic agent.

BACKGROUND

Pain can function as a protective mechanism that allows healthy human beings and animals to avoid tissue damage and/or prevent further damage to injured tissue. However, there are many instances in which pain persists beyond its usefulness. Such unnecessary suffering from pain can impair a subject's physical mobility, mental performance, and even contribute to depression.

Substantial resources have been devoted over the years to researching the causes of various types of pain and to the development of medicine to attenuate pain experienced by a patient. Exemplary classes of common pain-relief medications include opioids, non-steroidal anti-inflammatory agents, corticosteroids, and centrally acting agents such as anti-depressants, anti-epileptics, pregabalin, and gabapentin. Capsaicin has been described for use in treating pain. See, for example, U.S. Pat. Nos. 5,962,532; 8,420,600; 8,367,733; and 8,158,682. Certain commercial products containing capsaicin for pain relief formulate the capsaicin as a cream (e.g., Capzasin) or in a patch (e.g., a capsaicin-containing transdermal patch marketed under the trade name QUTENZA®) for topical application to the skin of a patient.

One challenging aspect of using capsaicin to treat pain, particularly when capsaicin is administered by injection, is that administration of capsaicin causes an initial neuronal excitation resulting in the adverse side effect of a transient burning sensation. This transient burning sensation can be substantial for some patients. Certain approaches for addressing the adverse side effect of transient burning sensation caused by capsaicin have been described in the literature, including approaches described in U.S. Pat. No. 5,962,532.

Due to the unmet need for additional treatment options to achieve relief from pain, particularly treatment options that do not suffer from the addiction problems associated with many opioid-based pain therapies, the need exists for new procedures for treating pain. The present invention addresses this need and provides other related advantages.

SUMMARY

The invention provides methods and compositions for treatment of pain, such as joint pain, using capsaicin in a procedure that attenuates transient burning sensation experienced by patients due to capsaicin administration. The methods desirably provide relief from joint pain, such as osteoarthritic knee joint pain, for an extended duration, such as at least about 3 months, 6 months, 9 months, or 1 year. Because administration of capsaicin causes initial neuronal excitation resulting in the adverse side effect of a transient burning sensation, the methods utilize a cooling article, such as a material wrap cooled via a circulating fluid, to reduce the temperature of tissue to be exposed to capsaicin for certain durations of time, optionally in combination with administering a local anesthetic agent, in order to attenuate the transient burning sensation experienced by patients, resulting in the substantial reduction or even elimination of transient burning sensation caused by capsaicin. The cooling article desirably has an exterior surface temperature in the range of from about 5° C. to about 15° C., and more desirably from about 5° C. to about 10° C., for application to the exterior surface of the patient's joint, such as a knee joint.

Because overcooling of skin tissue can cause the adverse effect of skin necrosis, while insufficient cooling can be inadequate to sufficiently reduce the transient burning sensation experienced by patients due to capsaicin administration, the methods desirably apply a cooling article having a particular temperature range (e.g., from about 5° C. to about 15° C., and more desirably from about 5° C. to about 10° C.) for particular durations of time both before and after administration of capsaicin. The therapeutic methods can be further characterized according to the temperature of tissue and/or fluid in the joint into which capsaicin is administered, and in certain embodiments, fluid in the intra-articular space of a joint, such as a knee joint, is cooled to a temperature in the range from about 26° C. to about 33° C. prior to administration of capsaicin, and then maintained at a temperature in the range from about 26° C. to about 33° C. for a duration of at least 30 minutes after administration of capsaicin.

The foregoing techniques for reducing transient burning sensation due to administration of capsaicin can be used to minimize procedure pain experienced by patients undergoing capsaicin therapy for pain due to a painful nerve, and provided herein are methods for treating pain due a painful nerve, such as an intermetatarsal neuroma. The methods utilize a cooling article, such as a material wrap cooled via a circulating fluid, to reduce the temperature of tissue to be exposed to capsaicin for certain durations of time, optionally in combination with administering a local anesthetic agent, in order to attenuate the transient burning sensation experienced by patients, resulting in the substantial reduction or even elimination of transient burning sensation caused by capsaicin.

Various aspects and embodiments of the invention are described in further detail below. Accordingly, one aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee;
  
  to thereby attenuate transient burning sensation due to injection of capsaicin.

Another aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount of ranging from about 0.1 g to about 0.5 g; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Another aspect of the invention provides a method of ameliorating joint pain in a human patient, wherein the method comprises:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby ameliorate joint pain in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, wherein the method comprises:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy;
- b. optionally administering a local anesthetic agent into said joint;
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Another aspect of the invention provides a method of ameliorating joint pain in a human patient, wherein the method comprises:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby ameliorate joint pain in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, wherein the method comprises:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy;
- b. optionally administering a local anesthetic agent into said joint;
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Another aspect of the invention provides a method of ameliorating pain due to an intermetatarsal neuroma in a human patient, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot; then
- b. administering by injection into tissue adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg;
- c. applying for a duration of about 30 minutes a cooling article to the human patient's skin in proximity to the intermetatarsal neuroma in need of pain relief therapy, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot; then
- d. administering by injection into tissue adjacent to the intermetatarsal neuroma capsaicin in an amount of from about 100 μg to 300 μg; and then
- e. applying for a duration of at least about 30 minutes a cooling article to the patient's skin in proximity to the intermetatarsal neuroma, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot;
  - to thereby ameliorate pain due to the intermetatarsal neuroma in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot; then
- b. administering by injection into tissue adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg;
- c. applying for a duration of about 30 minutes a cooling article to the human patient's skin in proximity to the intermetatarsal neuroma in need of pain relief therapy, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot; then
- d. administering by injection into tissue adjacent to the intermetatarsal neuroma capsaicin in an amount of from about 100 μg to 300 μg; and then
- e. applying for a duration of at least about 30 minutes a cooling article to the patient's skin in proximity to the intermetatarsal neuroma, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the patient's foot;
  - to thereby attenuate transient burning sensation due to injection of capsaicin into tissue adjacent to an intermetatarsal neuroma in a human patient.

Another aspect of the invention provides a method of ameliorating pain due to an intermetatarsal neuroma in a human patient, wherein the method comprises:

- a. applying a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy; then
- b. administering by injection into tissue adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg;
- c. applying a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of from about 26° C. to about 33° C. for tissue in proximity to the intermetatarsal neuroma;
- d. administering by injection into tissue adjacent to the intermetatarsal neuroma capsaicin in an amount of from about 100 μg to 300 μg; and then
- e. applying a cooling article to the human patient's skin in proximity to the intermetatarsal neuroma in need of pain relief therapy;
  - to thereby ameliorate pain due to the intermetatarsal neuroma in the human patient.

Another aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into tissue adjacent to an intermetatarsal neuroma, wherein the method comprises:

- a. applying a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy; then
- b. administering by injection into tissue adjacent to the intermetatarsal neuroma a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 1 mg to about 50 mg;
- c. applying a cooling article to a human patient's skin in proximity to an intermetatarsal neuroma in need of pain relief therapy to achieve a temperature in the range of from about 26° C. to about 33° C. for tissue in proximity to the intermetatarsal neuroma;
- d. administering by injection into tissue adjacent to the intermetatarsal neuroma capsaicin in an amount of from about 100 μg to 300 μg; and then
- e. applying a cooling article to the human patient's skin in proximity to the intermetatarsal neuroma in need of pain relief therapy;
  - to thereby attenuate transient burning sensation due to injection of capsaicin into tissue in proximity to an intermetatarsal neuroma.

The foregoing therapeutic methods may be further characterized according to various features, such as the dose of lidocaine local anesthetic agent, dose of capsaicin, duration of reduction in pain, and features of the cooling article. These and other features are more fully described in the detailed description below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a cooling article, that is a wrap-on pad, applied to a human knee.

FIG. 2 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) 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 at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 3 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) 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 at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 4 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 5 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 6 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 7 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Ice Pack, as further described in Example 8. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 8 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 9 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 10 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 11 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 9. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 12 is a graph showing mean intraarticular (IA) temperature and mean skin temperature over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 10. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 13 is a graph showing mean intraarticular (IA) temperature and mean NPRS Pain scores over time using the following cooling devices: (i) a Breg Knee WrapOn Polar Pad or (ii) Elasto-Gel All Purpose Therapy Wrap, as further described in Example 10. The “Standard Cooling Device” was a Breg Knee WrapOn Polar Pad. The “Ice-Gel Pack” was an Elasto-Gel All Purpose Therapy Wrap. The following designations apply to the graph: A is the time at which any temperature reading of the temperature probe was made prior to insertion into the intraarticular space of the patient's knee; B is the time which the temperature probe was inserted into the intraarticular space of the patient's knee; C is time at which the cooling device was applied to the patient's knee; D is the time at which the cooling device was removed from the patient's knee; E is the time at which a solution of 2% w/w lidocaine was administered to the patient's knee by intraarticular injection; F is the time at which the cooling device was reapplied to the patient's knee; G is the time at which the cooling device was removed from the patient's knee; H is the time that trans-capsaicin was administered by intraarticular injection; I is the time at which the cooling device was reapplied to the patient's knee; J is the time at which the cooling device was removed from the patient's knee; K is the time at which the temperature probe was removed from the patient's knee.

FIG. 14 is a graph showing temperature profiles recorded for Breg Knee WrapOn Polar Pad, Elasto-gel cooling device, and ice-pack, as further described in Example 11.

DETAILED DESCRIPTION

The invention provides methods and compositions for treatment of pain, such as joint pain, using capsaicin in a procedure that attenuates transient burning sensation experienced by patients due to capsaicin administration. The methods desirably provide relief from joint pain, such as osteoarthritic knee joint pain, for an extended duration, such as at least about 3 months, 6 months, 9 months, or 1 year. Because administration of capsaicin causes initial neuronal excitation resulting in the adverse side effect of a transient burning sensation, the methods utilize a cooling article, such as a material wrap cooled via a circulating fluid, to reduce the temperature of tissue to be exposed to capsaicin for certain durations of time, optionally in combination with administering a local anesthetic agent, in order to attenuate the transient burning sensation experienced by patients, resulting in the substantial reduction or even elimination of transient burning sensation caused by capsaicin. The cooling article desirably has an exterior surface temperature in the range of from about 5° C. to about 15° C., and more desirably from about 5° C. to about 10° C., for application to the exterior surface of the patient's joint, such as a knee joint.

Transient burning sensation due to capsaicin administration may manifest in patients in the form of a burning sensation, pain, and/or ache in the area in which capsaicin was administered. Techniques described herein are designed to reduce the magnitude of such transient burning sensation experienced by the patient.

The foregoing techniques for reducing transient burning sensation due to administration of capsaicin can be used to minimize procedure pain experienced by patients undergoing capsaicin therapy for pain due to painful nerve, and provided herein are methods for treating pain due a painful nerve, such as an intermetatarsal neuroma. The methods utilize a cooling article, such as a material wrap cooled via a circulating fluid, to reduce the temperature of tissue to be exposed to capsaicin for certain durations of time, optionally in combination with administering a local anesthetic agent, in order to attenuate the transient burning sensation experienced by patients, resulting in the substantial reduction or even elimination of transient burning sensation caused by capsaicin.

The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques are explained in the literature, such as in “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 herein incorporated by reference in its entirety. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

I. Definitions

To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

The phrase “Injection Pain Scale” refers to a measure of pain experienced by a patient upon administration of capsaicin by injection, where the extent of pain experienced by the patient is rated by the patient as one of the following: (i) none, (ii) mild pain, (iii) moderate pain, or (iv) intense pain.

The abbreviation “NPRS” refers to Numerical Pain Rating Scale, as further described herein.

As used herein, the terms “subject” and “patient” refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect (e.g., lessening, reducing, modulating, or eliminating) that results in the improvement of the condition, disease, disorder, and the like. The terms “ameliorate” and “ameliorating” refer to lessening, reducing, and/or eliminating the stated condition, such as pain. The terms “attenuate” and “attenuating” refer to lessening, reducing, and/or eliminating the stated condition, such as pain.

Compounds of the disclosure may contain a C—C double bond and, therefore, exist as geometric isomers. Individual geometric isomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain a single geometric isomer in high purity and/or through separating a mixture of geometric isomers using chromatographic procedures known in the art. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

The compounds may be in amorphic or crystalline form, and the invention encompasses all such amorphic and crystalline forms.

As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].

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 which, upon administration to a subject, is capable of providing a compound of this invention. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW₄⁺, wherein W is C_1-4alkyl, and the like.

Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na⁺, NH₄⁺, and NW₄⁺ (wherein W is a C_1-4alkyl group), and the like.

For therapeutic use, salts of the compounds of the present 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.

The phrase “therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable 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 benefit/risk ratio.

Unless specified otherwise, the term “about” refers to within ±10% of the stated value. The invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl, C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary 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, etc.

The term “hydroxyalkyl” refers to an alkyl group substituted by 1 or 2 hydroxyl groups. In certain embodiments, the hydroxyalkyl is an alkyl group substituted by only 1 hydroxyl group.

The term “hydroxyalkanoic acid” refers to saturated straight or branched hydrocarbon that is substituted by (i) one —CO₂H group, and (ii) one or two hydroxyl groups.

The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl, respectively. Exemplary 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.

The term “hydroxyalkenyl” refers to an alkenyl group substituted by 1 or 2 hydroxyl groups. In certain embodiments, the hydroxyalkenyl is an alkenyl group substituted by only 1 hydroxyl group.

The term “hydroxyalkenoic acid” refers to an unsaturated straight or branched hydrocarbon having one carbon-carbon double bond, wherein the hydrocarbon is substituted by (i) one —CO₂H group, and (ii) one or two hydroxyl groups.

The term “polyethylene glycolyl” refers to a radical of polyethylene glycol. The polyethylene glycolyl is a chemical fragment that is part of a larger molecule. When the polyethylene glycolyl is bonded at one location to the remainder of the molecule, then the polyethylene glycolyl is a mono-radical, such as “—(CH₂CH₂O)x-H” where x is an integer greater than 1. When the polyethylene glycolyl is used as a component within a molecule connecting two fragments of the molecule, the polyethylene glycolyl is a diradical, having a point of attachment at each terminus of the polyethylene glycolyl, which may illustrated as “—(CH₂CH₂O)x-” where x is an integer greater than 1. In certain embodiments, x is an integer in the range of about 5 to about 100, about 5 to about 50, about 5 to about 25, about 5 to about 15, about 10 to about 50, about 10 to about 30, or 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.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

II. Therapeutic Applications for Joint Pain

One aspect of the invention provides methods for treating joint pain using injectable capsaicin and procedures to attenuate transient burning sensation due to capsaicin administration. The methods desirably provide relief from joint pain for an extended duration, such as at least about 3 months, 6 months, 9 months, or 1 year. The methods utilize a cooling article, such as a material wrap cooled via a circulating fluid, to reduce the temperature of tissue to be exposed to capsaicin for certain durations of time, optionally in combination with administering a local anesthetic agent. In a preferred embodiment, the methods are used to ameliorate osteoarthritic knee joint pain in a human patient by administering capsaicin to the intra-articular space of the joint of the patient's knee via a protocol that applies a cooling article to an exterior surface of the patient's knee presenting with osteoarthritic knee joint pain before and after administration of capsaicin, such as where the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C., and more preferably from about 5° C. to about 10° C., for application to the exterior surface of the patient's knee. Various aspects and embodiments of the methods are described below.

First Method

One aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

Second Method

One aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

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

Third Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Fourth Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to an exterior surface of said knee for a duration of at least about 30 minutes, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C.;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Fifth Method

One aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

Sixth Method

One aspect of the invention provides a method of ameliorating osteoarthritic knee joint pain in a human patient, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to an exterior surface of said knee;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

In certain embodiments, the method comprises step (e), which is applying a cooling article to an exterior surface of said knee.

Seventh Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount of ranging from about 0.1 g to about 0.5 g; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Eighth Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, wherein the method comprises:

- a. applying a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof; then
- c. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 26° C. to about 33° C. for fluid in the intra-articular space of the joint of said knee; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to an exterior surface of said knee;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

In certain embodiments, the method comprises step (e), which is applying a cooling article to an exterior surface of said knee.

Exemplary Features of the First, Second, Third, and Fourth Methods

The above First, Second, Third, and Fourth Methods may be further characterized by additional features, such as a step comprising flexing the knee, characterization of the temperature of the cooling article surface for application to the exterior surface of the knee, dose of lidocaine, characterization of the pharmaceutical composition comprising a single pain-relief agent, and the like. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.

Flexing the Knee

The methods may be further characterized according to the presence or absence of a step that involves flexing the knee that received capsaicin. For example, in certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed. In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed about 5 times. In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed about 5 times over a period of about 1 minute. In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed and extended. In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed and extended about 5 times. In certain embodiments, after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed and extended about 5 times over a period of about 1 minute.

Temperature of the Cooling Article Surface for Application to Exterior Surface of the Knee

The methods may be further characterized according to temperature of the cooling article surface for application to the exterior surface of the knee. For example, in certain embodiments, the cooling article has an exterior surface temperature in the range of from about 6° C. to about 13° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 7° C. to about 13° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 7° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 8° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 6° C. to about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 7° C. for application to the exterior surface of said knee.

In certain embodiments, the cooling article has an exterior surface temperature of about 12° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 11° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 9° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 7° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 6° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 5° C. for application to the exterior surface of said knee.

Temperature of Fluid in the Intra-Articular Space of the Joint of Said Knee

The methods may be further characterized according to the temperature of fluid in the intra-articular space of the joint of the knee to receive or has received capsaicin according to the method. For example, in certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 26° C. to about 33° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 26° C. to about 33° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 26° C. to about 28° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 26° C. to about 28° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 28° C. to about 30° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 28° C. to about 30° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 30° C. to about 32° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature in the range of from 30° C. to about 32° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 26° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 26° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 27° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 27° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 28° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 28° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 29° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 29° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 30° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 30° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 31° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 31° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 32° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 32° C. for a duration of from about 30 minutes to about 90 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 33° C. for a duration of at least 30 minutes. In certain embodiments, in step (e) fluid in the intra-articular space of the joint of said knee is maintained at a temperature of about 33° C. for a duration of from about 30 minutes to about 90 minutes.

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

Dose of Lidocaine

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

Pharmaceutical Composition Comprising a Single Pain-Relief Agent

The methods may be further characterized according to features of the pharmaceutical composition comprising a single pain-relief agent. For example, in certain embodiments, the pharmaceutical composition comprising a single pain-relief agent is an aqueous mixture that contains lidocaine at a concentration of about 2% w/w. In certain embodiments, the pharmaceutical composition comprising a single pain-relief agent is an aqueous mixture that contains lidocaine at a concentration of about 1% w/w. In certain embodiments, the pharmaceutical composition comprising a single pain-relief agent further comprises sodium chloride. In certain embodiments, the pharmaceutical composition comprising a single pain-relief 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-relief agent has a volume in the range of from about 13 mL to about 17 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relief agent has a volume of about 15 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relief agent has a volume of about 15 mL. In yet other embodiments, the pharmaceutical composition comprising a single pain-relief agent has a volume in the range of 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-relief 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.

The methods may be further characterized according to the temperature of the pharmaceutical composition comprising a single pain-relief agent, which is to be administered to the patient. For example, in certain embodiments, the pharmaceutical composition comprising a single pain-relief agent has a temperature in the range of 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-relief agent has a temperature of about 23° C.

Pharmaceutical Composition Comprising Capsaicin

The methods may be further characterized according to features 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 from 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.

Duration of Cooling in Step (e)

The methods may be further characterized according to the duration of cooling in step (e). In certain embodiments, the duration in step (e) is from about 30 minutes to about 90 minutes. In certain embodiments, the duration in step (e) is from about 30 minutes to about 60 minutes. In certain embodiments, the duration in step (e) is from about 60 minutes to about 90 minutes. In certain embodiments, unless it would conflict with a minimum duration of time already specified in step (e), the duration in step (e) is from about 30 minutes to about 60 minutes, from about 60 minutes to about 90 minutes, from about 90 minutes to about 120 minutes, or from about 120 minutes to about 180 minutes.

Dose of Capsaicin

The methods may be further characterized according to the dose of capsaicin. In certain embodiments, the dose of capsaicin is 1 mg.

Exemplary Features of the Fifth, Sixth, Seventh, and Eighth Methods

The above Fifth, Sixth, Seventh, and Eighth Methods may be further characterized by additional features, such as a step comprising flexing the knee, characterization of the temperature of fluid in the intra-articular space of the joint of the knee to receive or has 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 cooling step (a), the dose of lidocaine, characterization of the pharmaceutical composition comprising a single pain-relief agent, and the like. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.

Flexing the Knee

Temperature of Fluid in the Intra-Articular Space of the Joint of Said Knee

In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature in the range of from about 26° C. to about 28° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature in the range of from about 28° C. to about 30° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature in the range of from about 30° C. to about 32° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 26° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 27° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 28° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 29° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 30° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 31° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 32° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 33° C. for fluid in the intra-articular space of the joint of said knee. In certain embodiments, in step (c) comprises applying a cooling article to an exterior surface of the knee to achieve a temperature of about 29° C. for fluid in the intra-articular space of the joint of said knee.

Temperature of the Cooling Article Surface for Application to Exterior Surface of the Knee

The methods may be further characterized according to the temperature of the cooling article surface for application to the exterior surface of the knee to receive capsaicin. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 6° C. to about 13° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 7° C. to about 13° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 7° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 8° C. to about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 6° C. to about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature in the range of from about 5° C. to about 7° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 12° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 11° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 10° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 9° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 8° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 7° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 6° C. for application to the exterior surface of said knee. In certain embodiments, the cooling article has an exterior surface temperature of about 5° C. for application to the exterior surface of said knee.

Duration in Step (a)

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

Dose of Lidocaine

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

Pharmaceutical Composition Comprising a Single Pain-Relief Agent

The methods may be further characterized according to features of the pharmaceutical composition comprising a single pain-relief agent. In certain embodiments, the pharmaceutical composition comprising a single pain-relief 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-relief agent further comprises sodium chloride. In certain embodiments, the pharmaceutical composition comprising a single pain-relief 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-relief agent has a volume in the range of from about 13 mL to about 17 mL. In certain embodiments, the pharmaceutical composition comprising a single pain-relief agent has a volume of about 15 mL. In yet other embodiments, the pharmaceutical composition comprising a single pain-relief agent has a volume in the range of 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-relief 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.

Pharmaceutical Composition Comprising Capsaicin

Duration of Cooling

The methods may be further characterized according to the duration of cooling. For example, in certain embodiments, in step (a) the cooling article is applied for a duration of from about 5 minutes to about 20 minutes to the exterior surface of said knee. In certain embodiments, in step (a) the cooling article is applied for a duration of about 10 minutes to the exterior surface of said knee. In certain embodiments, in step (c) the cooling article is applied for a duration of from about 15 minutes to about 45 minutes to the exterior surface of said knee. In certain embodiments, in step (c) the cooling article is applied for a duration of about 45 minutes to the exterior surface of said knee. In certain embodiments, in step (c) the cooling article is applied for a duration of about 30 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of at least about 10 minutes, at least about 20 minutes, or at least about 30 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of about 10 minutes, about 20 minutes, or about 30 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of from about 15 minutes to about 90 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of from about 30 minutes to about 90 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of from about 30 minutes to about 60 minutes to the exterior surface of said knee. In certain embodiments, in step (e) the cooling article is applied for a duration of from about 60 minutes to about 90 minutes to the exterior surface of said knee. In certain embodiments, in step (e), the duration in step (e) is from about 15 minutes to about 30 minutes, from about 30 minutes to about 60 minutes, from about 60 minutes to about 90 minutes, from about 90 minutes to about 120 minutes, or from about 120 minutes to about 180 minutes.

Exemplary Features of the First Through the Eighth Methods

The above First, Second, Third, Fourth, Fifth, Sixth, Seventh, and Eighth Methods may be further characterized by additional features, such as the presence or absence of additional procedures to reduce transient burning sensation caused by capsaicin, magnitude of the transient burning sensation due to capsaicin, duration of reduction in osteoarthritic knee joint pain, and the like. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features

Additional Procedure to Reduce Transient Burning Sensation and/or Treat Osteoarthritic Knee Joint Pain

The methods may be further characterized according to the presence or absence of additional procedures to reduce transient burning sensation caused by capsaicin. For example, in certain embodiments, other than the procedures set forth in steps (a), (b), (c), (d), (e), and optionally flexing said knee, the method does not contain any procedure that reduces transient burning sensation experienced by the patient due to administration of capsaicin. In certain embodiments, other than the procedures set forth in steps (a), (b), (c), (d), (e), and optionally flexing said knee, the method does not contain any procedure that reduces osteoarthritic knee joint pain. In certain embodiments, other administration of (i) the pharmaceutical composition comprising lidocaine and (ii) the pharmaceutical composition comprising capsaicin, the patient does not receive any other pain-relief medicine. In certain embodiments, other than the procedures set forth in steps (a), (b), (c), (d), (e), and optionally flexing and extending said knee, the method does not contain any procedure that reduces transient burning sensation experienced by the patient due to administration of capsaicin. In certain embodiments, other than the procedures set forth in steps (a), (b), (c), (d), (e), and optionally flexing and extending said knee, the method does not contain any procedure that reduces osteoarthritic knee joint pain.

Magnitude of Transient Burning Sensation Due to Capsaicin

The methods may be further characterized according to the magnitude of the transient burning sensation due to capsaicin. For example, in certain embodiments, the patient experiences transient burning sensation no greater than level one on a visual analog scale ranging from zero to four (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, and (4) severe), due to administering the pharmaceutical composition comprising capsaicin. In certain embodiments, the patient experiences transient burning sensation no greater than level two on a visual analog scale ranging from zero to four (i.e., (0) none, (1) mild, (2) moderate, (3) moderately severe, and (4) severe), due to administering the pharmaceutical composition comprising capsaicin. In certain embodiments, transient burning sensation is evaluated at about 10 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, transient burning sensation is evaluated at about 30 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, transient burning sensation is evaluated at about 60 minutes after administration of the pharmaceutical composition comprising capsaicin. In certain embodiments, transient burning sensation is evaluated at about 120 minutes after administration of the pharmaceutical composition comprising capsaicin.

Duration of Reduction in Osteoarthritic Knee Joint Pain

The methods may be further characterized according to the duration of reduction in osteoarthritic knee joint pain. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 3 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 4 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 5 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 6 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 7 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of at least 8 months. In certain embodiments, the method is characterized by achieving a reduction in 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 months to 6 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 6 months to 9 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 6 months to 12 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 9 months to 12 months. In certain embodiments, the method is characterized by achieving a reduction in osteoarthritic knee joint pain for a duration of 12 months to 18 months.

Characterization of the Cooling Article

The methods may be further characterized according to features of the cooling article. In certain embodiments, the cooling article is a material wrap cooled via a circulating fluid. In certain embodiments, the cooling article is a textile wrap cooled via a circulating fluid. In certain embodiments, the cooling article covers at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the external surface of said patient's knee. In certain embodiments, the cooling article covers at least 70% of the external surface of said patient's knee. In certain embodiments, the cooling article covers at least 80% of the external surface of said patient's knee. In certain embodiments, the cooling article covers at least 90% of the external surface of said patient's knee. In certain embodiments, the cooling article covers at least 95% of the external surface of said patient's knee.

In certain embodiments, the cooling article is a wrap-on cooled 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. FIG. 1 herein is an illustration of a cooling article, that is a wrap-on pad, applied to a human knee.

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

In certain embodiments, the cooling article is an Elasto-Gel All Purpose Therapy Wrap, such as one that measures 6 inches by 24 inches in size. The Elasto-Gel All Purpose Therapy Wrap may be characterized as one that is removed from a freezer (approximately 0° F.) just prior to application to a patient.

Ninth Method

One aspect of the invention provides a method of ameliorating joint pain in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby ameliorate joint pain in the human patient.

In certain embodiments, the method comprises step (e) which is applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint.

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

Tenth Method

One aspect of the invention provides a method of ameliorating joint pain in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 0° C. to about 18° C.; then
- d. administering by injection into said joint a pharmaceutical composition comprising a therapeutically effective amount of capsaicin; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 0° C. to about 18° C.;
  - to thereby ameliorate joint pain in the human patient.

Eleventh Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Twelfth Method

One aspect of the invention provides a method of ameliorating joint pain in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
- to thereby ameliorate joint pain in the human patient.

In certain embodiments, the method comprises step (e) which is applying a cooling article to the patient's skin in proximity to said joint.

Thirteenth Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

In certain embodiments, the method comprises step (e) which is applying a cooling article to the patient's skin in proximity to said joint.

Exemplary Features of the Twelfth and Thirteenth Methods

The above Twelfth Method and Thirteenth Method may be further characterized by additional features, such as the temperature of tissue or fluid in the interior of the joint to receive or which has received capsaicin according to the method, and the like. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.

Temperature of Tissue or Fluid in the Interior of the Joint

The methods may be further characterized according to the temperature of tissue or fluid in the interior of the joint to receive or which has received capsaicin according to the method. For example, in certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 20° C. to about 22° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 22° C. to about 24° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 24° C. to about 26° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 26° C. to about 28° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 28° C. to about 30° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 30° C. to about 32° C. for tissue or fluid in the interior of the joint. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 25° C. to about 31° C. for tissue or fluid in the interior of the joint.

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

Fourteenth Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 5° C. to about 30° C. for said skin; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

In certain embodiments, the method comprises step (a) which is applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy. In certain embodiments, the method comprises step (b) which is administering a local anesthetic agent into said joint. In certain embodiments, the method comprises step (e) which is applying a cooling article to the patient's skin in proximity to said joint. In certain embodiments, the method comprises (i) step (a) which is applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy, (ii) step (b) which is administering a local anesthetic agent into said joint, and step (e) which is applying a cooling article to the patient's skin in proximity to said joint.

Fifteenth Method

One aspect of the invention provides a method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 5° C. to about 30° C. for said skin; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of from about 0.01 mg to about 4 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Exemplary Features of the Fourteenth and Fifteenth Methods

The above Fourteenth Method and Fifteen Method may be further characterized by additional features, such as the temperature of the patient's skin in proximity to the joint to receive or which has received capsaicin according to the method, and the like. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.

Temperature of the Patient's Skin in Proximity to the Joint

The methods may be further characterized according to the temperature of the patient's skin in proximity to the joint to receive or which has received capsaicin according to the method. For example, in certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 5° C. to about 7° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 7° C. to about 9° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 9° C. to about 11° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 11° C. to about 13° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 13° C. to about 15° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 15° C. to about 17° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 17° C. to about 19° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 19° C. to about 21° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 21° C. to about 23° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 23° C. to about 25° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 25° C. to about 27° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 27° C. to about 29° C. for said skin. In certain embodiments, step (c) comprises applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 29° C. to about 30° C. for said skin.

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

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

In certain embodiments, said duration is from about 30 minutes to about 60 minutes. In certain embodiments, said duration is from about 30 minutes to about 90 minutes. In certain embodiments, said duration is from about 60 minutes to about 90 minutes.

Exemplary More Specific Embodiments

In another aspect, the methods pertain to the following more specific embodiments.

Embodiment No. 1

A method of ameliorating osteoarthritic knee joint pain in a human patient, comprising:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 7° C. to about 30° C. for skin in contact with the cooling article; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 7° C. to about 30° C. for skin in contact with the cooling article for a duration of at least about 30 minutes;
  - to thereby ameliorate osteoarthritic knee joint pain in the human patient.

Embodiment No. 2

A method of attenuating transient burning sensation due to injection of capsaicin into a human osteoarthritic knee joint, comprising:

- a. applying for a duration of about 15 minutes a cooling article to an exterior surface of a human patient's knee presenting with osteoarthritic knee joint pain; then
- b. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g; then
- c. applying for a duration of about 30 minutes a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 7° C. to about 30° C. for skin in contact with the cooling article; then
- d. administering by injection into the intra-articular space of the joint of said knee a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. applying a cooling article to an exterior surface of said knee to achieve a temperature in the range of from about 7° C. to about 30° C. for skin in contact with the cooling article for a duration of at least about 30 minutes;
  - to thereby attenuate transient burning sensation due to injection of capsaicin.

Embodiment No. 3

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 7° C. to about 9° C.

Embodiment No. 4

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 9° C. to about 11° C.

Embodiment No. 5

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 11° C. to about 13° C.

Embodiment No. 6

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 13° C. to about 15° C.

Embodiment No. 7

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 15° C. to about 17° C.

Embodiment No. 8

The method of embodiment 1 or 2, wherein said temperature in steps (c) and (e) is from about 17° C. to about 19° C.

Embodiment No. 9

The method of any one of embodiments 1-8, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the exterior surface of said knee.

Embodiment No. 10

The method of any one of embodiments 1-8, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 7° C. for application to the exterior surface of said knee.

Embodiment No. 11

The method of any one of embodiments 1-8, wherein the cooling article has an exterior surface temperature in the range of from about 7° C. to about 9° C. for application to the exterior surface of said knee.

Embodiment No. 12

The method of any one of embodiments 1-8, wherein the cooling article has an exterior surface temperature in the range of from about 9° C. to about 11° C. for application to the exterior surface of said knee.

Embodiment No. 13

Embodiment No. 14

The method of any one of embodiments 1-8, wherein the cooling article has an exterior surface temperature in the range of from about 13° C. to about 15° C. for application to the exterior surface of said knee.

Embodiment No. 15

The method of any one of embodiments 1-14, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed.

Embodiment No. 16

The method of any one of embodiments 1-14, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said knee is flexed about 5 times.

Embodiment No. 17

The method of any one of embodiments 1-16, wherein in step (b) the dose of lidocaine is about 0.3 g.

Embodiment No. 18

The method of any one of embodiments 1-16, wherein in step (b) the dose of lidocaine is 0.3 g.

Embodiment No. 19

The method of any one of embodiments 1-18, wherein the pharmaceutical composition comprising a single pain-relief agent is an aqueous mixture that contains lidocaine at a concentration of about 2% w/w.

Embodiment No. 20

The method of any one of embodiments 1-19, wherein the pharmaceutical composition comprising a single pain-relief agent further comprises sodium chloride.

Embodiment No. 21

The method of any one of embodiments 1-19, wherein the pharmaceutical composition comprising a single pain-relief agent further comprises sodium chloride at a concentration ranging from about 4 mg/mL to about 8 mg/mL.

Embodiment No. 22

The method of any one of embodiments 1-21, wherein the pharmaceutical composition comprising a single pain-relief agent has a volume in the range of from about 13 mL to about 17 mL.

Embodiment No. 23

The method of any one of embodiments 1-21, wherein the pharmaceutical composition comprising a single pain-relief agent has a volume of about 15 mL.

Embodiment No. 24

The method of any one of embodiments 1-23, wherein the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin.

Embodiment No. 25

The method of any one of embodiments 1-24, wherein the pharmaceutical composition comprising capsaicin has a volume of about 4 mL.

Embodiment No. 26

The method of any one of embodiments 1-24, wherein the pharmaceutical composition comprising capsaicin has a volume of about 2 mL.

Embodiment No. 27

The method of any one of embodiments 1-26, wherein the duration in step (e) is from about 30 minutes to about 90 minutes.

Embodiment No. 28

The method of any one of embodiments 1-26, wherein the duration in step (e) is from about 30 minutes to about 60 minutes.

Embodiment No. 29

The method of any one of embodiments 1-28, wherein the dose of capsaicin is 1 mg.

In another aspect, the methods pertain to the following more specific embodiments.

Embodiment No. 1

A method of ameliorating joint pain in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby ameliorate joint pain in the human patient, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint.

Embodiment No. 2

A method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy;
- b. optionally administering a local anesthetic agent into said joint;
- c. applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying for a duration of at least about 10 minutes a cooling article to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the human patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint.

Embodiment No. 3

A method of ameliorating joint pain in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy; then
- b. optionally administering a local anesthetic agent into said joint; then
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby ameliorate joint pain in the human patient, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint.

Embodiment No. 4

A method of attenuating transient burning sensation due to injection of capsaicin into a joint in a human patient, comprising:

- a. optionally applying a cooling article to a human patient's skin in proximity to a joint in need of pain relief therapy;
- b. optionally administering a local anesthetic agent into said joint;
- c. applying a cooling article to the patient's skin in proximity to said joint to achieve a temperature in the range of from about 20° C. to about 33° C. for tissue or fluid in the interior of the joint; then
- d. administering by injection into said joint a pharmaceutical composition comprising capsaicin in order to deliver a dose of capsaicin in an amount of about 1 mg; and then
- e. optionally applying a cooling article to the patient's skin in proximity to said joint;
  - to thereby attenuate transient burning sensation due to injection of capsaicin, wherein the joint pain is osteoarthritic joint pain, and the joint is a knee joint.

Embodiment No. 5

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 24° C. to about 26° C. for tissue or fluid in the interior of the joint.

Embodiment No. 6

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 26° C. to about 28° C. for tissue or fluid in the interior of the joint.

Embodiment No. 7

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 28° C. to about 30° C. for tissue or fluid in the interior of the joint.

Embodiment No. 8

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 30° C. to about 32° C. for tissue or fluid in the interior of the joint.

Embodiment No. 9

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 27° C. for tissue or fluid in the interior of the joint.

Embodiment No. 10

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 28° C. for tissue or fluid in the interior of the joint.

Embodiment No. 11

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 29° C. for tissue or fluid in the interior of the joint.

Embodiment No. 12

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 30° C. for tissue or fluid in the interior of the joint.

Embodiment No. 13

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 31° C. for tissue or fluid in the interior of the joint.

Embodiment No. 14

The method of embodiment 3 or 4, wherein step (c) comprises applying a cooling article to the patient's skin in proximity to the joint to achieve a temperature of about 32° C. for tissue or fluid in the interior of the joint.

Embodiment No. 15

The method of any one of embodiments 1-14, wherein the method comprises step (e) in which a cooling article is applied for a duration of at least about 10 minutes to the patient's skin in proximity to said joint, wherein the cooling article has an exterior surface temperature in the range of from about 1° C. to about 15° C. for application to the exterior surface of the human patient's skin in proximity to said joint.

Embodiment No. 16

The method of any one of embodiments 1-14, wherein the method comprises step (e) in which a cooling article is applied to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 24° C. to about 26° C. for tissue or fluid in the interior of the joint for a duration of at least 15 minutes.

Embodiment No. 17

The method of any one of embodiments 1-14, wherein the method comprises step (e) in which a cooling article is applied to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 26° C. to about 28° C. for tissue or fluid in the interior of the joint for a duration of at least 15 minutes.

Embodiment No. 18

The method of any one of embodiments 1-14, wherein the method comprises step (e) in which a cooling article is applied to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 28° C. to about 30° C. for tissue or fluid in the interior of the joint for a duration of at least 15 minutes.

Embodiment No. 19

The method of any one of embodiments 1-14, wherein the method comprises step (e) in which a cooling article is applied to the patient's skin in proximity to the joint to achieve a temperature in the range of from about 30° C. to about 32° C. for tissue or fluid in the interior of the joint for a duration of at least 15 minutes.

Embodiment No. 20

The method of any one of embodiments 15-19, wherein said duration in step (e) is at least 20 minutes.

Embodiment No. 21

The method of any one of embodiments 15-19, wherein said duration in step (e) is at least 30 minutes.

Embodiment No. 22

The method of any one of embodiments 15-19, wherein said duration is step (e) from about 30 minutes to about 90 minutes.

Embodiment No. 23

The method of any one of embodiments 15-19, wherein said duration is step (e) from about 30 minutes to about 60 minutes.

Embodiment No. 24

The method of any one of embodiments 1-23, wherein the method comprises step (a) in which for a duration of from about 5 minutes to about 30 minutes a cooling article is applied to a human patient's skin in proximity to a joint in need of pain relief therapy.

Embodiment No. 25

The method of any one of embodiments 1-23, wherein the method comprises step (a) in which for a duration of about 15 minutes a cooling article is applied to a human patient's skin in proximity to a joint in need of pain relief therapy.

Embodiment No. 26

The method of any one of embodiments 1-23, wherein the method does not contain step (a).

Embodiment No. 27

The method of any one of embodiments 1-26, wherein the method comprises step (b) of administering by injection into the joint a pharmaceutical composition comprising lidocaine in order to deliver a dose of lidocaine in an amount of about 0.1 g to about 0.5 g.

Embodiment No. 28

The method of any one embodiments 1-26, wherein the method comprises step (b) of administering by injection into the joint a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g.

Embodiment No. 29

The method of any one of embodiments 1-26, wherein the method comprises the following additional step that is performed between steps (c) and (d): administering into said joint a pharmaceutical composition comprising a single pain-relief agent selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof, in order to deliver a dose of lidocaine in an amount ranging from about 0.1 g to about 0.5 g.

Embodiment No. 30

The method of embodiment 29, wherein the method does not contain step (b).

Embodiment No. 31

The method of any one of embodiments 27-30, wherein the dose of lidocaine is about 0.3 g.

Embodiment No. 32

The method of any one of embodiments 27-30, wherein the dose of lidocaine is about 0.15 g.

Embodiment No. 33

The method of any one of embodiments 27-31, wherein the pharmaceutical composition comprising lidocaine is an aqueous mixture containing lidocaine at a concentration of about 2% w/w.

Embodiment No. 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 No. 35

The method of any one of embodiments 27-31, wherein the pharmaceutical composition comprising lidocaine has a volume in the range of from about 13 mL to about 17 mL.

Embodiment No. 36

The method of any one of embodiments 27-31, wherein the pharmaceutical composition comprising lidocaine has a volume of about 15 mL.

Embodiment No. 37

The method of any one of embodiments 1-36, wherein step (c) comprises applying for a duration of about 20 minutes the cooling article to an exterior surface of said knee.

Embodiment No. 38

The method of any one of embodiments 1-36, wherein step (c) comprises applying for a duration of about 30 minutes the cooling article to an exterior surface of said knee.

Embodiment No. 39

The method of any one of embodiments 1-38, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said joint is flexed.

Embodiment No. 40

The method of any one of embodiments 1-38, wherein after administration of the pharmaceutical composition comprising capsaicin in step (d) but prior to step (e) said joint is flexed about 5 times.

Embodiment No. 41

The method of any one of embodiments 1-40, wherein the pharmaceutical composition comprising capsaicin is an aqueous mixture containing capsaicin.

Embodiment No. 42

The method of any one of embodiments 1-40, wherein the pharmaceutical composition comprising capsaicin has a volume of about 2 mL.

Embodiment No. 43

The method of any one of embodiments 1-40, wherein the pharmaceutical composition comprising capsaicin has a volume of about 1 mL.

Embodiment No. 44

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 15° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 45

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 7° C. to about 13° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 46

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 8° C. to about 10° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 47

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 5° C. to about 7° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 48

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 7° C. to about 9° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 49

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 9° C. to about 11° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 50

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 11° C. to about 13° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 51

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature in the range of from about 13° C. to about 15° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 52

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature of about 8° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 53

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature of about 9° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 54

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature of about 10° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 55

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature of about 11° C. for application to the human patient's skin in proximity to said joint.

Embodiment No. 56

The method of any one of embodiments 1-40, wherein the cooling article has an exterior surface temperature of about 12° C. for application to the human patient's skin in proximity to said joint.

Additional Exemplary More Specific Embodiments