Device and method for nerve block by local cooling

Abstract

Provided herein are methods of nerve blockade, for example for treatment of obesity, heart failure, cardiovascular disease, muscle spasms, surgical pain, acute pain, chronic pain, or urinary retention in a patient. The method includes treating a nerve for a duration that leads to reversible nerve blockade as opposed to nerve damage, and also by cooling the nerve below physiological temperature to a temperature in which reversible nerve blockade is achieved, for example from 15ºC to 30ºC.

Description

DEVICE AND METHOD FOR NERVE BLOCK BY LOCAL COOLINGCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 554,31 1 , filed February 16, 2024, the disclosure of which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERAL FUNDING

[0002] This invention was made with government support under Grant No. 20261 12, awarded by the National Science Foundation, and Grant No. NS1 15460, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION

[0003] Mammalian myelinated nerves can be blocked by locally cooling the nerves below 5QC. However, these extremely low temperatures require significant amount of energy to produce, and can also cause nerve tissue damage for a long duration application (Jia et al. (1999)). “Cold nerve injury is enhanced by intermittent cooling.” Muscle & Nerve 22, 1644-1652; Vujaskovic et al., (1994). “Effects of intraoperative hyperthermia on peripheral nerves: neurological and electrophysiological studies.” (Int J Hyperthermia 10, 41 -49). Therefore, clinical application of cold block to treat chronic diseases currently remains elusive. If a thermal block of nerve conduction is practically achievable, it will have a wide range of clinical applications to treat many chronic diseases, for example, blocking peripheral nerves to treat pain, blocking the abdominal vagus nerve to treat obesity, blocking sensory axons in the dorsal roots to treat chronic pain of peripheral origin, blocking sympathetic nerves to treat heart failure, and blocking the pudendal nerve to induce efficient voiding after spinal cord injury or other neurological disfunction.SUMMARY OF THE INVENTION

[0004] Provided herein is a method of reversibly blocking a nerve, including steps of treating the nerve and cooling the nerve to a temperature below 37QC and above a temperature at which an irreversible nerve block is produced to produce a reversible nerve block. In non-limiting embodiments, the nerve is cooled to a temperature ranging from 15QC to 30QC.

[0005] In non-limiting embodiments, the method further includes a step of, prior to treating the nerve, implanting a temperature controller and / or treatment deliverydevice at the nerve to cool the nerve and / or deliver treatment, the temperature controller including a cooling element and a temperature sensor, and the temperature controller optionally being wirelessly connected to a controller for controlling cooling of the cooling element, and monitoring temperature at the nerve by the temperature sensor. In non-limiting embodiments, the cooling element is a coolant tube / pad, vapor compression cooler, cold fluid, a reservoir with cold fluid, and / or a Peltier cooler, and / or the temperature sensor is a thermocouple or a thermistor.

[0006] In non-limiting embodiments, the nerve may be cooled by use of liquid or slurry solutions, such as the treatment composition, a mixture of ice and water or a similar solution containing salt or other additive(s) to adjust solution temperatures, or by use of any other means of cooling including by use of an implanted or noninvasive temperature controller.

[0007] Also provided herein is a method of treating a condition in a patient by blocking a nerve of the patient by the method described above.

[0008] Further non-limiting embodiments are set forth in the following numbered clauses:

[0009] 1 . A method of blocking a nerve in a patient, comprising : first treating the nerve with a composition for a time period sufficient to increase the threshold temperature for producing a cold conduction block within the nerve; and cooling the nerve to a temperature ranging from 15 °C to 30 °C to produce a nerve block at a higher temperature than would be required without the treatment with the composition.

[0010] 2. The method of clause 1 , wherein the treating comprises sensitizing the nerve with the composition.

[0011] 3. The method of clause 1 or clause 2, wherein the composition comprises one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, acids, calcium ions, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof.

[0012] 4. The method of any of clauses 1 -3, wherein the composition comprises ethanol.

[0013] 5. The method of any of clauses 1 -4, wherein the composition comprises 50-70% ethanol.

[0014] 6. The method of any of clauses 1 -5, wherein a concentration of the composition in proximity to the nerve comprises 0.3% to 50% ethanol.

[0015] 7. The method of any of clauses 1 -6, wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, acids, calcium ions, terpenes, terpenoids, piperine, and / or one or more vanilloids.

[0016] 8. The method of any of clauses 1 -7, wherein the treatment comprises transdermal administration of the composition, optionally with a chemical permeation enhancer, abrasion, iontophoresis, electroporation, microneedles, ultrasound, magnetophoresis, and / or photomechanical waves.

[0017] 9. The method of any of clauses 1 -8, wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

[0018] 10. The method of any of clauses 1 -9, wherein the treatment comprises oral administration of the composition.

[0019] 1 1. The method of any of clauses 1 -10, wherein the treatment comprises parenteral administration of the composition.

[0020] 12. The method of any of clauses 1 -1 1 , further comprising, prior to treating the nerve, placing a temperature controller with optional ability to deliver treatment in proximity to the nerve to cool and / or treat the nerve with the composition, the temperature controller comprising a cooling element and optionally a temperature sensor, and the temperature controller optionally being wirelessly connected to a controller for controlling cooling of the cooling element, delivering the composition to the nerve, and / or and monitoring temperature at the nerve by the temperature sensor.

[0021] 13. The method of any of clauses 1 -12, wherein the cooling element is ice, a cooled fluid, a cooled treatment composition a cooled slurry or slush solution, a fluidic tube / pad, a vapor compression cooler, a Peltier cooler, and / or reservoir with cold fluid, and the temperature sensor is a thermocouple or a thermistor.

[0022] 14. The method of any of clauses 1 -13, wherein the patient has a condition selected from is experiencing pain or and a motor neuron dysfunction, and wherein blocking the nerve treats and / or diagnoses the patient’s condition or diagnoses the condition.

[0023] 15. The method of any of clauses 1 -14, wherein the pain is chronic pain.

[0024] 16. The method of any of clauses 1 -15, wherein the pain is peripheral pain.

[0025] 17. The method of any of clauses 1 -16, wherein the motor dysfunction is caused by a stroke.

[0026] 18. The method of any of clauses 1 -17, wherein the motor dysfunction is caused by a ventricular arrythmia.

[0027] 19. The method of any of clauses 1 -18, wherein the nerve is pretreated with the composition for about 90 minutes or less prior to cooling.

[0028] 20. The method of any of clauses 1 -19, wherein the nerve is a sensory nerve.

[0029] 21 . The method of any of clauses 1 -20, wherein the nerve is a motor nerve

[0030] 22. The method of any of clauses 1 -21 , wherein multiple nerves are targeted.

[0031] 23. The method of any of clauses 1 -22, wherein multiple mixed sensory and motor nerves are targeted.

[0032] 24. The method of any of clauses 1 -23, wherein the nerve is reversibly blocked.

[0033] 25. The method of any of clauses 1 -24, wherein the nerve is repeatedly reversibly blocked.

[0034] 26. The method of any of clauses 1 -25, wherein the nerve is irreversibly blocked.

[0035] 27. Use of a composition for sensitizing a nerve for blocking the nerve by cooling with a device, the device comprising: a temperature controller comprising a processor; a thermoelectric device in communication with the temperature controller and configured to be placed in proximity to a nerve; a temperature sensor in communication with the temperature controller and configured to be placed in proximity to the nerve; and a power source to provide power to the temperature controller and the thermoelectric device, the use comprising treating the nerve with the composition with or without the device and cooling the nerve to a temperature between about 15 °C and about 30 °C with the device.

[0036] 28. The use of clause 27, wherein the composition comprises one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and / or combinations thereof.

[0037] 29. The use of clause 27 or clause 28, wherein the composition comprises ethanol.

[0038] 30. The use of any of clauses 27-29, wherein the composition comprises 50-70% ethanol.

[0039] 31. The use of any of clauses 27-30, wherein the concentration in proximity to the nerve comprises 0.3% to 50% ethanol.

[0040] 32. The use of any of clauses 27-31 , wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, terpenes, terpenoids, piperine, and / or one or more vanilloids.

[0041] 33. The use of any of clauses 27-32, wherein the treatment comprises transdermal administration of the composition.

[0042] 34. The use of any of clauses 27-33, wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

[0043] 35. The use of any of clauses 27-34, wherein the treatment comprises oral administration of the composition.

[0044] 36. The use of any of clauses 27-35, wherein the treatment comprises parenteral administration of the composition.

[0045] 37. The use of any of clauses 27-36, wherein the sensory nerve is pre-treated with the composition for 90 minutes or less prior to cooling.

[0046] 38. Use of a composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof for blocking a nerve.

[0047] 39. Use of a cooled composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof for blocking a nerve.

[0048] 40. Use of one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids piperine, dimethyl sulfoxide (DMSO), and combinations thereof in combination with ice, a cooled fluid, a cooled slurry, cooled treatment composition, and / or a cooled slushy solution for blocking a nerve.

[0049] 41. A method of blocking and / or ablating a nerve in a patient, comprising: treating the nerve with a composition for a time period sufficient toincrease the threshold temperature for producing a cold conduction block within the nerve; and cooling the nerve to produce a nerve block and / or ablation at a higher temperature than would be required without the treatment with the composition.

[0050] 42. The method of clause 41 , wherein the treatment and cooling are performed substantially simultaneously, and comprise applying a cooled composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, acids, calcium ions, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof to the nerve.

[0051] 43. The method of clause 41 or clause 42, wherein the composition comprises ethanol.

[0052] 44. The method of any of clauses 41 -43, wherein the composition comprises 50-70% ethanol.

[0053] 45. The method of any of clauses 41 -44, wherein a concentration of the composition in proximity to the nerve comprises 0.3% to 50% ethanol.

[0054] 46. The method of any of clauses 41 -45, wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, terpenes, terpenoids, piperine, and / or one or more vanilloids.

[0055] 47. The method of any of clauses 41 -46, wherein the treatment comprises transdermal administration of the composition.

[0056] 48. The method of any of clauses 41 -47, wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

[0057] 49. The method of any of clauses 41 -48, wherein the treatment comprises oral administration of the composition.

[0058] 50. The method of any of clauses 41 -49, wherein the treatment comprises parenteral administration of the composition.

[0059] 51. The method of any of clauses 41 -50, wherein the nerve is reversibly blocked.

[0060] 52. The method of any of clauses 41 -51 , wherein the nerve is irreversibly blocked.

[0061] 53. The method of any of clauses 41 -52, wherein the patient is experiencing obesity, pain from needle stick(s), pain from bunions, neuromas, pain from arthritis, heart disease, ventricular arrythmia, ventricular tachycardia, or longCOVID, and wherein blocking the nerve treats the patient’s condition or diagnoses the condition.BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 shows a block diagram of a device for providing local cooling to a nerve according to non-limiting embodiments described herein;

[0063] Figure 2 shows locations of testing for pain and light touch testing;

[0064] Figure 3 shows a block diagram of a device for manually providing local treatment and cooling to a nerve according to non-limiting embodiments described herein;

[0065] Figure 4 shows a block diagram of a device for manually and automatically providing treatment to a nerve according to non-limiting embodiments described herein;

[0066] Figure 5 shows a block diagram of a device for providing local treatment and cooling to a nerve according to non-limiting embodiments described herein;

[0067] Figure 6 shows a block diagram of a device for providing direct local cooling to a nerve according to non-limiting embodiments described herein;

[0068] Figure 7 shows a block diagram of a device for providing direct local cooling to a nerve according to non-limiting embodiments described herein;

[0069] Figure 8 shows a block diagram of a device for providing treatment and local cooling to a nerve according to non-limiting embodiments described herein;

[0070] Figure 9 shows a block diagram of a device for providing treatment and local cooling to a nerve according to non-liming embodiments described herein;

[0071] Figure 10 shows a block diagram of a device for providing cooling to one or more nerves of one or more patients according to non-limiting embodiments described herein; and

[0072] Figure 1 1 shows a block diagram of a device for providing treatment and cooling to the ulnar nerve, median nerve, and radial nerve branches at the wrist according to non-limiting embodiments described herein.DETAILED DESCRIPTION

[0073] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word "about". In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within theranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For definitions provided herein, those definitions refer to word forms, cognates and grammatical variants of those words or phrases.

[0074] The figures accompanying this application are representative in nature, and should not be construed as implying any particular scale or directionality, unless otherwise indicated. For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal” and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0075] As used herein, the term “comprising” and like terms are open-ended. The term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The term “consisting of” excludes any element, step, or ingredient not specified in the claim.

[0076] As used herein, the terms “a” and “an” refer to one or more.

[0077] As used herein, the term “patient” is any mammal, including humans, and a “human patient” is any human.

[0078] As used herein, the terms “communication” and “communicate” refer to the receipt, transmission, or transfer of one or more signals, messages, commands, or other type of data. For one unit or device to be in communication with another unit or device means that the one unit or device is able to receive data from and / or transmit data to the other unit or device. A communication can use a direct or indirect connection, and can be wired and / or wireless in nature. Additionally, two units or devices can be in communication with each other even though the data transmitted can be modified, processed, routed, etc., between the first and second unit or device. For example, a first unit can be in communication with a second unit even though the first unit passively receives data and does not actively transmit data to the second unit. As another example, a first unit can be in communication with a second unit if an intermediary unit processes data from one unit and transmits processed data to the second unit. It will be appreciated that numerous other arrangements are possible.Any known electronic communication protocols and / or algorithms can be used such as, for example, TCP / IP (including HTTP and other protocols), WLAN (including 802.1 1 a / b / g / n and other radio frequency-based protocols and methods), analog transmissions, Global System for Mobile Communications (GSM), 3G / 4G / 5G / LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, and the like known to those of skill in the art.

[0079] As used herein, “treatment” may refer to delivery of a composition, for example to sensitize the nerve or neuron, deliver cooling, and / or both, for example in an ordered combination (e.g., delivery of a composition prior to delivery of cooling), and may refer to invasive, insertable, percutaneous, and non-invasive methods and devices.

[0080] Provided herein is a method of blocking a nerve to treat a condition in a patient, such as a human patient, treatable by such a nerve block, including, without limitation: obesity, heart failure, long COVID-19, muscle spasms, urinary retention, arthritis, cardiovascular disease, surgical pain, acute pain, chronic pain, phantom pain, and neuromas is provided. Without limitation, irritable bowl syndrome, obesity, ventricular arrhythmia or ventricular tachycardia, or obesity could be treated invasively by blocking a nerve near the heart or the vagus nerve near the stomach. Without limitation, noninvasive treatment could treat pain from osteoarthritis or other knee pain in place of or as an adjuvant to total or partial knee arthroplasty, particularly but without limitation for patients who are not good candidates for surgery or administered as part of a multi-modal anesthesia or pain management regimen. As used herein, “acute pain” means pain lasting for less than about three months and “chronic pain” means pain lasting for about three months. Pain as described herein may be any type of pain, with any etiology, including, without limitation, post-surgical pain, bone breaks, tearing and / or spraining of muscle, tendon, joints, and / or ligaments, puncture wounds, headache, stomachache, ulcers, fibromyalgia, and the like. “Nerve block” refers to rendering a nerve incapable of, or substantially incapable of, firing an action potential, propagating a nerve signal, and / or releasing a neurotransmitter. By “irreversible,” in the context of a nerve block, it is meant that the nerve blockade is retained well beyond the blocking treatment (e.g., nerve damage), for example for at least one week past the treatment, and by “reversible,” it is meant that the nerve fully or substantially recovers from blockade either immediately or after a short period beyond the blockingperiod, for example within one second, minute, hour, or days, and increments there between.

[0081] In non-limiting embodiments, the method includes treating an area at or adjacent to a nerve or neuron to be blocked with a pre-treatment, and then cooling the nerve to a temperature below physiological temperature (that is, below 37QC in a human), and above a temperature at which irreversible nerve block is achieved, e.g., above 15QC, all values and subranges therebetween inclusive. In non-limiting embodiments, the pre-treatment excludes heating the area at or adjacent the nerve or neuron to be blocked. In non-limiting embodiments, the nerve is cooled to a lower temperature, for example to ablate the nerve, but to a higher temperature than would normally be required for nerve ablation (e.g., above -60 ’C) and / or for a shorter period of time that would normally be required for nerve ablation. The terms “nerve” and “neuron” are used interchangeably herein. The combination of pre-treating and cooling of the nerve causes reversible or irreversible nerve block of the nerve, depending on the treatment composition cooling temperature(s) and time(s) used, and thus relief of one or more symptoms of a condition treatable by blockade of the nerve. In non-limiting embodiments, the pre-treatment and treatment are performed at substantially the same time. For example, the pre-treatment as described herein may be delivered simultaneously with, or may concomitantly be, the cooling treatment as well. In non-limiting embodiments, the blockade is not reversible, and instead is permanent. Without wishing to be bound by the theory, it is believed that alcohol may aid in improving block outcomes, for example as described in Valderrabano et al. “Effect of Catheter Ablation With Vein of Marshall Ethanol Infusion vs Catheter Ablation Alone on Persistent Atrial Fibrillation: The VENUS Randomized Clinical Trial.” (JAMA, (2020)), and Joo et al. “Comparison of alcohol ablation with repeated thermal radiofrequency ablation in medial branch neurotomy for the treatment of recurrent thoracolumbar facet joint pain.” (J Anesthesia (2012), 27: 390-395).

[0082] The composition used to treat the nerve or neuron may be, for example and without limitation, a compound that sensitizes the nerve and / or neuron to the cooling treatment. Without wishing to be bound by the theory, it is believed that sensitizing the nerve and / or neuron with a composition allows for the cooling step to be delivered at a higher temperature and / or a shorter duration, which may be more comfortable for the patient, while still achieving the same level of block. Thus, in nonlimiting embodiments, the nerve or neuron is pre-treated prior to cooling.

[0083] In non-limiting embodiments, a composition useful for treating a nerve and / or neuron may include one or more alcohols, such as ethanol, propylene glycol, isopropyl alcohol, 1 -butanol, and the like. In non-limiting embodiments, a composition may include between about 1 % and about 100%, about 10% and about 90%, about 20% and about 80%, about 30% and about 70%, about 40% and about 60%, and / or about 50% alcohol, all values and subranges therebetween inclusive. In non-limiting embodiments, a composition may include any suitable molar concentration of alcohol, for example 0.1 to 0.5 mM, in non-limiting embodiments about 0.2mM, all values and subranges therebetween inclusive. In non-limiting embodiments, alcohols such as ethanol or glycols may be used for their solvent properties, skin permeation properties, and / or their heat shock protein activation properties. Concentrations of an alcohol, or any composition described herein, may refer to the concentration of the composition in a fluid that is used to deliver treatment (e.g., pre-treat and / or cool a nerve), or the concentration of the composition at the site of the nerve.

[0084] In non-limiting embodiments, the composition may include dimethyl sulfoxide (DMSO), hexane, chemical surfactants, N-methyl-2-pyrrolidone, citric acid and / or calcium citrate, ascorbic acid, terpenes, Transcutol® P, azone, and / or oleic acid. In non-limiting embodiments, the foregoing, including, alcohol, DMSO, and / or hexane may be included for their heat shock protein (HSP) activation and / or for its solvent properties, and the composition may additionally include one or more additional agents, such as one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more HSP activators, piperine, and combinations thereof. As used herein, the term “vanilloid” means any composition including a vanillin group (e.g., an aromatic ring including a substitution with both a hydroxyl and an ether, for example as shown in gray text below (R may be any substituent, as it is the aromatic ring with the noted substitutions that renders the structure a vanillin group):

[0085] Suitable examples of vanilloids may include, without limitation, vanillyl alcohol, vanillin, ethyl vanillin, Capsazepine, vanillic acid, vanillate, acetovanillon,vanillylamine, and capsaicin. In non-limiting embodiments, the treatment excludes capsaicin.

[0086] TRPV agonists are known to those of skill in the art may include endogenous (including agonists derived from polyunsaturated fatty acids) as well as exogenous compounds, may include vanilloids, such as capsaicin or resiniferatoxin (RTX), and may include cannabinoid ligands such as cannabidiol, and may include terpene or terpenoid compounds such as myrcene, and may also include:,y y , oxytocin, and lysophosphatidic acid.

[0088] HSP activators are known to those of skill in the art and may include ethanol, other alcohols, acids, DMSO, mechanical stress such as pressure, Methylprednisolone, pyrrolidine dithiocarbamate, glucocorticoids, peroxides or other reactive oxygen species, ischemia, arsenic, calcium and trace metals, with or without application of heat. Calcium concentration, for example 1 mM concentration, or other HSP activators may be adjusted to improve heat resistance in addition to their HSP activation properties, for example for applications where ischemia or heat stress is a potential risk or cause of concern to the patient, for example during surgery or to treat heat hyperalgesia or heat allodynia. Accordingly, in non-limiting embodiments, the pretreatment includes treatment with an alcohol, such as ethanol.

[0089] Compositions useful for treating the nerve and / or neuron may be delivered to the patient in any known manner. In non-limiting embodiments, the compositions are delivered to and / or through the skin, for example through contact (e.g., transdermally), or by introduction through the skin, for example subcutaneously, intramuscularly, and / or intradermally. In non-limiting embodiments, the compositions are delivered parenterally or orally. In non-limiting embodiments the composition may be delivered with an ampule, pump, sponge, pad, or other medium which provides slow delivery through skin contact.

[0090] In non-limiting embodiments, treatments (e.g., compositions for treating the nerve and / or neuron) may be aided by increasing skin permeation. In non-limiting embodiments, the skin is treated, before, during, and / or after treatment with the composition as described herein, with a chemical permeation enhancer, iontophoresis, abrasion, electroporation, microneedles, ultrasound, magnetophoresis, photomechanical waves, and / or other methods known to those skilled in the art to increase skin permeation.

[0091] Treatment with a composition prior to and / or during cooling may proceed with any suitable duration. In non-limiting embodiments, the treatment may occur for hours (e.g., overnight), minutes, and / or seconds (e.g., in situations where a composition is administered directly to the nerve and / or neuron such as pre- operatively). As noted throughout this disclosure, treatments may be delivered prior to, during, or following cooling.

[0092] Prior to, during, or following treatment, in non-limiting embodiments, the nerve is cooled. In non-limiting embodiments, in the cooling step the nerve and / or neuron is cooled to a temperature ranging from 15QC to 30QC, all values and subranges therebetween inclusive, for example, for a time ranging from 5 minutes to about 720 minutes, in non-limiting embodiments from 5 to 90 minutes, in non-limiting embodiments from 1 to 40 minutes, in non-limiting embodiments from 10 minutes to 40 minutes, all values and subranges therebetween inclusive. In non-limiting embodiments, the nerve can be cooled for up to 12 hours or more for surgical anesthesia followed by continued usage post-surgery for as little as 1 minute or for multiple days with repeated application of the treatment and / or cooling. In non-limiting embodiments, the nerve can be noninvasively cooled for up to 90 minutes or as little as 5 minutes or for multiple days with repeated application of the treatment and or cooling. In non-limiting embodiments, the nerve can be cooled for up to about 12 hours with an implanted temperature controller or as little as 1 minute to 40 minutes or for multiple days with repeated application of the treatment and or cooling with the temperature controller. The time for the block can be extended by treating and cooling the nerve for longer or shorter periods of time, more than once, and / or repeatedly. In yet another aspect, the method further comprises, prior to the treatment step, implanting a device at the nerve to cool the nerve, the device may optionally include a temperature controller, a thermoelectric device including a cooling element, and / or a temperature sensor. As described herein, methods of cooling, in addition to use ofdevices (such as those exemplified herein and in the attached drawings), may include ice, cooled fluids, for example fluids containing one or more of the treatments described herein, cooled to any desirable temperature for a cooling step as described herein, and may be delivered prior to, during, and / or following treatment with any composition described herein.

[0093] With reference to Figure 1 , devices and systems useful in the present methods may include a temperature controller (10) in communication, a device (20), such as a thermoelectric device, for delivering cooling to the nerve, and a temperature sensor (30). Temperature controller (10) may be in communication with one or both of device (20) and / or temperature sensor (30). In non-limiting embodiments, device (20) may also be configured to hold and / or supply a treatment composition as described herein to the region of interest, for example a nerve and / or an anatomical region surrounding a nerve. The device (20) and system may receive power from an implantable power supply (40) and receive instructions from an external controller (50). It is to be appreciated that non-invasive devices are included in the scope of this disclosure, and that any element shown in Figure 1 may be arranged external to a patient. Moreover, minimally-invasive devices (e.g., devices that may be inserted into a body cavity of a patient without surgical intervention) are also within the scope of the present disclosure. For example, any device described herein, including at least those depicted in Figures 1 and 3-8, may be configured for insertion into, without limitation, the oral cavity, nasal cavity, external auditory canal, vagina, and / or anus to provide treatment and / or cooling as described herein.

[0094] The temperature controller (10) may be in wireless communication with external controller (50). Temperature controller and / or external controller (50) may include a processor, memory, a display, such as an LCD, LED or OLED display, and an input device, such as a microphone, keypad, mouse, touchscreen, touchpad or trackpad, and the like, for entering data into the temperature controller (10) and / or external controller (50). External controller (50) is depicted as sending and receiving wireless transmissions to temperature controller (10), to permit monitoring of one or more parameters of the temperature controller (10), device (20), temperature sensor (30), and / or power supply (40), including, without limitation, output signal characteristics (e.g., voltage, frequency, amplitude, etc., from the power supply to the temperature controller and to the thermoelectric device; temperature to whichthermoelectric device is to be cooled, temperature as measured by the temperature sensor, and / or functioning / status of any of the implanted components).

[0095] Activity of temperature controller (10) and external controller (50) is processor controlled and software / firmware installed onto the temperature controller (10) and external controller (50) hardware may be used to implement the described methods, and to provide, for example and without limitation, a GUI (graphical user interface) for the optional display associated with the external controller (50), which facilitates use of the device and system. A person of skill in the electronic arts will be able to implement such a system using readily-available electronics parts and ordinary programming skills. Proprietary chips, chipsets, etc. may be designed and manufactured to implement the devices described herein.

[0096] In one aspect, external controller (50) is a proprietary device that is specifically designed for the task, or, in another example, external controller (50) is a non-proprietary device, such as a smart phone, smart watch, tablet, portable / laptop computer, or desktop computer. As described above, communication between external controller (50) and temperature controller (10) is achieved wirelessly. Such communication can be via any suitable wireless protocol, such as near-field communication, TCP / IP (including HTTP and other protocols), WLAN (including 802.1 1 a / b / g / n and other radio frequency-based protocols and methods), analog transmissions, Global System for Mobile Communications (GSM), 3G / 4G / 5G / LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, and the like known to those of skill in the art.

[0097] One potential difficulty with use of wireless devices is one of identity. In non-limiting embodiments, an external controller (50) may only control one temperature controller (10) to prevent accidental stimulation of unintended subjects, or even intentional stimulation. In non-limiting embodiments, the transmission range of the devices can also be limited to prevent transmission over distances more than a few feet, thereby limiting the chances of unintended stimulation (crosstalk). In nonlimiting embodiments, the transmission range may be larger, based on ability of devices to communicate using wireless protocols as described herein and as known to those of skill in the art. Also, any number of identity-verification mechanisms may be utilized to prevent crosstalk. In one aspect, different transmission wavelengths are used for different devices, thus lowering the likelihood of crosstalk. In another aspect, the temperature controller (10) is programmed to only respond to a transmissioncontaining a pre-defined signal, such that the temperature controller (10) and external controller (50) must first, and / or periodically “handshake” in order to communicate. In another aspect, the temperature controller (10) and / or external controller (50) transmit encrypted signals which only can be decrypted by a key stored in the other of the temperature controller (10) and / or external controller (50). In yet another aspect, RFID tagging technology is used to ensure that the temperature controller and external controller match. Any combination of these proximity and / or identity verification measures may be used to prevent cross-talk. Other useful technologies for ensuring security and identity in communication are or may be available and are equally applicable.

[0098] While a temperature controller (10) is exemplified in the attached Figure 1 , the device and system may include an ampule of an ionic compound or molecule with an endothermic heat of solution which cools liquid when the ampule is broken. Non-limiting embodiments of other arrangements and modes for delivering compositions and / or cooling are shown in Figures 3-8. Suitable endothermic ionic compounds or molecules include, without limitation, potassium chlorate, potassium bromate, or imidazole. The device may use the solution to cool the nerve or the treatment directly or indirectly. Moreover, as described herein, cooling may be achieved by ice, a cooled liquid (e.g., in a reservoir), a cooling tube, a thermoelectric cooler, or the like. Thus, in non-limiting embodiments, the temperature controller (10) may be any device or implement for cooling.

[0099] With further reference to Figure 1 , temperature controller (10) and / or external controller (50) can include memory having stored thereon programming instructions that, when executed by a processor (either included with temperature controller (10), external controller (50), or both) cause the thermoelectric device to cool the nerve of interest according to the methods described herein. Such programming instructions can take into account feedback from the temperature sensor, which relays the temperature to which the nerve is cooled, and, based on said feedback, to modulate output of the temperature controller (10) to the thermoelectric device. In one aspect, the programming instructions are transferred from the external controller (50) and stored on a memory of the temperature controller (10), so that a patient need not remain near the external controller (50), for example in aspects where the external controller (50) is a desktop or laptop computer, in order for the device and system to perform the methods described herein.

[0100] Again with reference to Figure 1 , the device and system may include a device (20) for generating cooling to block the nerve of interest and / or holding and / or supplying a treatment composition as described herein to the region of interest, for example a nerve and / or an anatomical region surrounding a nerve. In non-limiting embodiments, device (20) is a thermoelectric device. Suitable thermoelectric devices include, without limitation, resistors, thin film semiconductors, Peltier coolers, coolant tubes, and cooling pads. Such devices are available commercially (e.g., Micropelt thermogeneratures and Peltier coolers commercially available from Micropelt GmbH, Freiburg Germany), and improved devices are currently under development. In aspects of the present invention, the device (20) is one or more Peltier devices. Such devices are described in, for example, Imoto et al. (“Use of a Peltier chip with a newly devised local brain-cooling system for neocortical seizures in the rat.” J Neurosurg 104: 150-156, 2006) and Long and Fee (“Using temperature to analyse temporal dynamics in the songbird motor pathway.” Nature 456: 189-194, 2008). These devices convert electric voltage to a temperature difference. Thus, by applying differing voltages to the device (20), cooling can be generated, and the nerve of interest is affected accordingly. The device (20) may be in communication with the temperature controller (10), and may receive power from the implantable power source (40) to generate the temperature difference and cool the nerve of interest.

[0101] Again with reference to Figure 1 , the device and system may include a temperature sensor (30) for detecting temperature of the nerve of interest and / or of tissue in the vicinity of the nerve of interest. Suitable temperature sensors include thermocouples and thermistors. A thermocouple is a pair of conductors that form electrical connections at differing temperatures, thus producing a temperaturedependent voltage and a measure of temperature. A thermistor is a resistor, the resistance of which changes based on temperature, thus providing a measurement of temperature. The temperature sensor (30) useful in the present device and system can be a negative temperature coefficient (NTC) thermistor, in which resistance decreases as the temperature increases. Such thermistors are available commercially from, for example, Vishay Intertechnology, Inc. (Shelton, CT) or TE Technology, Inc. (Traverse City, Ml). The temperature sensor (30) may be in communication with the temperature controller (10) and may provide feedback to modulate the amount of energy applied to the device (20).

[0102] With further reference to Figure 1 , also included with the device and system may be an implantable power supply (40). Implantable power supply (40) may provide energy for temperature controller (10) and / or device (20) to generate cooling of the nerve of interest. Implantable power supply (40) may be a battery, for example as are used in the pacemaker arts, for example a lithium or zinc-based battery. Implantable power supply (40) may be wirelessly rechargeable, for example and without limitation, by an external wireless charging device (60). An external wireless charging device may charge implantable power supply (40) by, for example and without limitation, inductive charging. Implantable power supply (40) may also be rechargeable through a photovoltaic array.

[0103] Turning to Figure 3, shown is a non-limiting embodiment in which the treatment is delivered non-invasively, with cooling delivered through a transcutaneous treatment, for example a pad or compress. As used here, “treatment” may refer to delivery of a composition, for example to sensitive the nerve or neuron, delivery of cooling, and / or both, for example in an ordered combination (e.g., delivery of a composition prior to delivery of cooling), and may refer to both invasive and non- invasive methods and devices. In non-limiting embodiments, the cooling includes ice or chemical cooling methods, as described herein and as known in the art.

[0104] With reference to Figure 4, shown is another non-limiting embodiment in which the treatment is delivered non-invasively. In the illustrated non-limiting embodiment, the device and system may include an ampule of an ionic compound or molecule with an endothermic heat of solution which cools liquid when the ampule is broken. Suitable endothermic ionic compounds or molecules include, without limitation, potassium chlorate, potassium bromate, or imidazole. The device may use the solution to cool the nerve or the treatment directly or indirectly without limitation. In addition, or as an alternative, cooling may be delivered through a transcutaneous treatment, for example a pad or compress. In non-limiting embodiments, the cooling includes ice or chemical cooling methods, as described herein and as known in the art. An active pump may be included to provide a constant level of cooling, for example by delivering cooled fluid, and / or chemical cooling, as is known in the art. In nonlimiting embodiments, the ampule is used to soak the pad or compress.

[0105] With further respect to Figure 4, in non-limiting embodiments, a treatment reservoir may be refilled by a trained technician at a facility. With furtherrespect to Figure 4, in non-limiting embodiments, the treatment may be provided in single dose ampules or containers for replacement at home.

[0106] With reference to Figure 5, shown is another non-limiting embodiment in which the treatment is delivered non-invasively. In the illustrated non-limiting embodiment, the system includes a temperature controller, which may be controlled by an application running, for example, on a smartphone, smart watch, tablet, laptop computer, desktop computer, or any computing device as described herein and known in the art. Without limitation, a large reservoir capable of holding multiple treatments may deliver treatment to multiple patients at a physical therapists’ office. As shown in Figure 5, the system may include a temperature controller, temperature sensor, one or more reservoirs (for cooling and / or treatment), one or more pumps connected to those reservoir(s), a cooling pad, and / or a compress. The system may be powered, for example with alternating current (AC), direct current (DC), and / or a battery as described herein. In non-limiting embodiments, the reservoir may be refilled using a syringe, replacement of the reservoir, or by pouring. In non-limiting embodiments, a reservoir may contain a single dose of treatment to facilitate ease of use.

[0107] With reference to Figure 6, shown is a non-limiting embodiment in which the treatment is delivered invasively. In the illustrated non-limiting embodiment, treatment is delivered beneath the skin, for example subcutaneously and / or intradermally, for example with a hypodermic needle and / or hollow acupuncture needle, and or through an insertable and / or implantable device such as described herein. The treatment may be delivered before, during, or after cooling (which may occur non-invasively), as described herein. However, in non-limiting embodiments, the treatment is delivered before cooling, and, in non-limiting embodiments, the method excludes any step of heating the region of interest.

[0108] With reference to Figure 7, shown is a non-limiting embodiment that is similar to that shown in Figure 1 , including treatment delivered beneath the skin, for example subcutaneously and / or intradermally, for example with a hypodermic needle and / or hollow acupuncture needle.

[0109] With reference to Figure 8, shown is a non-limiting embodiment that is similar to that shown in Figures 1 and 7, but which includes a refillable treatment reservoir, which may be implanted, to deliver treatment to a nerve of interest.

[0110] With reference to Figure 9, shown is a non-liming embodiment that is similar to Figure 6, but which includes microneedles to deliver treatment and / or coldtemperatures deeper than may be practical noninvasively. The figure also consists of a treatment reservoir or delivery system that can optionally be cooled with an ice cube or other cold source.

[0111] With reference to Figure 10, shown is a non-liming embodiment that is similar to Figure 4, but with treatment that can be optionally administered to one or more patients and to one or more nerves, for example from a large treatment reservoir that could be offered to multiple patients at once prior to physical therapy.

[0112] With reference to Figure 1 1 , shown is a non-limiting embodiment that is similar to Figures 3, 4, 5, and 9, but demonstrates treatment delivery at the wrist or ankle to treat pain or motor dysfunctions at the hand or foot. Thos of skill in the art will appreciate that the exemplification of a hand, wrist, ankle, and / or foot is merely for illustrative purposes, and that the methods, systems, and devices described herein are not limited to such uses.

[0113] In non-limiting embodiments conditions such as those disclosed herein, including, without limitation, neurogenic scars, allodynia, hyperalgesia, physical therapy, neuromas, migraine, occipital neuralgia, pain, including, without limitation, joint pain (e.g. from arthritis), cardiovascular disease, long COVID, surgeries, organ control, and acute and chronic pain conditions and situations, may be treated by noninvasive, inserted, percutaneous, or invasive treatment (e.g., delivery of a composition) and noninvasive, inserted, percutaneous, or invasive cooling, for example in order, where one or both of the steps may be repeated.

[0114] In non-limiting embodiments, also provided is a method of treating obesity in a patient, by blocking an abdominal vagus nerve of the patient by a nerve block method, for example as described above.

[0115] In non-limiting embodiments, a method is provided of treating pain, such as acute or chronic pain, in a patient, comprising blocking a nerve of the patient by a nerve block method, for example as described above.

[0116] In non-limiting embodiments, a method is provided of treating heart failure in a patient, by blocking a sympathetic nerve of the patient, e.g., one or more of the greater splanchnic nerve, the lesser splanchnic nerve, or the sympathetic trunks, by a nerve block method, for example as described above.

[0117] In non-limiting embodiments, a method is provided of treating cardiovascular disease in a patient, by blocking a vagus nerve of the patient by a nerve block method, for example as described above.

[0118] In non-limiting embodiments, a method is provided of treating pain from physical therapy in a patient, for example a human patient, by enhancing the effectiveness of cooling used during physical therapy procedures, to block or partially block superficial nerves near the joint being exercised, for example as described above.

[0119] In non-limiting embodiments, a method is provided of treating pain from physical therapy in multiple patients, for example human patients, by enhancing the effectiveness of cooling used during physical therapy procedures, to block or partially block superficial nerves near the joint being exercised, for example as described above.

[0120] In non-limiting embodiments, a method is provided of treating ventricular arrhythmias in a patient, for example a human patient, by blocking a nerve near the patient’s heart by a nerve block method, for example as described above.

[0121] In non-limiting embodiments, a method is provided of treating long COVID-19 in a patient, for example a human patient, by blocking a nerve near the stellate ganglion by a nerve block method, for example as described above.

[0122] In non-limiting embodiments, a method is provided of treating arthritis or joint pain, such as knee pain in a patient, for example a human patient, in place of or as an adjuvant to arthroplasty in a patient with or without physical therapy, by, in a non-limiting embodiment noninvasively or invasively blocking the genicular nerves, for example as described above. Those of skill will appreciate that arthritis or joint pain in a different joint may be treated by a nerve block method, as described herein, being applied to a different nerve.

[0123] In non-limiting embodiments, a method is provided as an adjuvant to setting and casting fractured bones in a patient, for example a human patient, by blocking motor and sensory neurons innervating the body near the broken bone, for example by blocking the ulnar and median nerves at the wrist or near the proximal phalange to help cast a finger, for example as described above.

[0124] In non-limiting embodiments, a method is provided to treat genital arousal disorder by providing genital desensitization, by partially and / or completely blocking the pudendal nerve, for example as described above.

[0125] In non-limiting embodiments, a method is provided to treat chronic itch in a patient by blocking a nerve near the itch, for example the blocking the tibial nerve to treat Eczema on the bottom of the foot, for example as described above.

[0126] In non-limiting embodiments, a method is provided to treat Morton’s Neuroma in a patient by blocking the sciatic nerve or the tibial nerve, for example as described above.

[0127] In non-limiting embodiments, a method is provided of providing anesthesia in dental surgery or reduction of trigeminal nerve distribution pain by blocking the trigeminal nerve, for example as described above.

[0128] In non-limiting embodiments, a method is provided of treating trigeminal neuralgia in a patient, for example a human patient, by blocking the trigeminal nerve, for example as described above.

[0129] In non-limiting embodiments, a method is provided of diagnosing the relevant nerve distribution of trigeminal neuralgia in a patient, for example a human patient, by blocking the trigeminal nerve, for example as described above, where blocking the pain provides a diagnosis of the source of the neuralgia.

[0130] In non-limiting embodiments, a method is provided of providing anesthesia during ear piercings, for example while a human’s ears are being pierced by blocking a nerve by applying treatment prior to the piercing (e.g., up to 12 hours prior to) and / or using ice or a cold source to noninvasively cool the ear lobe and nerves therein following the procedure to institute and / or reinstitute a block, for example as described above.

[0131] In non-limiting embodiments, a method is provided of treating mechanical, vibrational, static, or dynamic allodynia in a patient, by blocking a nerve innervating the allodynic skin or the skin itself, for example as described above.

[0132] In non-limiting embodiments, a method is provided of treating thermal allodynia in a patient, by blocking a nerve innervating the allodynic skin or the skin itself, for example as described above.

[0133] In non-limiting embodiments, a method is provided of treating heat hyperalgesia in a patient, for example a human patient, by blocking a nerve innervating the body area with the hyperalgesia or treating the body area with hyperalgesia, for example as described above.

[0134] In non-limiting embodiments, a method is provided of treating mechanical hyperalgesia, by blocking a nerve innervating the area with hyperalgesia, for example as described above.

[0135] In non-limiting embodiments, a method is provided of diagnosing and treating occipital neuralgia in a patient, for example a human patient, by blocking oneor more of the occipital nerves, for example as described above, where blocking the pain provides a diagnosis of the source of the neuralgia.

[0136] In non-limiting embodiments, a method is provided of treating migraines in a patient, for example a human patient, by blocking the occipital and / or trigeminal nerves, for example as described above.

[0137] In non-limiting embodiments, a method is provided of treating focal dystonia in a patient, for example cervical dystonia or musician’s dystonia, in a human patient, by a nerve block method reversibly blocking a nerve causing involuntary muscle contractions, for example in the neck caused by cervical dystonia, for example as described above.

[0138] In non-limiting embodiments, a method is provided of diagnosing and managing focal pain conditions, for example diagnosing carpal tunnel syndrome and distinguishing it from other median nerve compressions as well as managing pain in place of or while scheduling corrective surgery, by a nerve block method of blocking the median nerve, for example as described above, where blocking the pain provides a diagnosis of the source of the pain.

[0139] In non-limiting embodiments, a method is provided of diagnosing and treating sacroiliac joint in a patient, for example a human patient, by a method of injecting cold treatment into the sacroiliac joint with optional external cooling for example with ice or a gel pack, or alternatively an implantable device that repeatedly reversibly or irreversibly blocks the nerves of the sacroiliac joint, for example as described above, where blocking the pain provides a diagnosis of the source of the pain.

[0140] In non-limiting embodiments, a method is provided of diagnosing and treating Meralgia paresthetica in a patient, by a nerve block method blocking the lateral femoral cutaneous nerve invasively, for example as described above, where blocking the pain provides a diagnosis of the source of the paresthetica.

[0141] In non-limiting embodiments, a method is provided for diagnosing and treating facet joint syndrome in a patient, for example a human patient, by a reversible or irreversible nerve block method of blocking the median branches of the posterior ramus of the spinal cord with an implanted device or percutaneous treatment, for example as described above, where blocking the pain provides a diagnosis of the source of the joint syndrome.

[0142] In non-limiting embodiments, a method is provided of treating phantom limb pain in a patient, for example a human patient, by a nerve block method blocking specific nerves suspected to be pain generators, for example the sciatic nerve, for example with an injection or implanted device in the residual limb, or noninvasively near the remaining portion of the limb, for example as described above.

[0143] In non-limiting embodiments, a method is provided of treating urinary retention in a patient, by blocking a sacral nerve and / or a pudendal nerve of the patient by a nerve block method, for example as described above.

[0144] In non-limiting embodiments, a method is provided of treating muscle spasms such as hand clench following stroke in a patient, by blocking a nerve innervating the muscle of the patient by a nerve block method, for example as described above.

[0145] In non-limiting embodiments, a method is provided of diagnosing and / or treating neurogenic scars in a patient, for example a human patient, by blocking nerves in the scar, for example as described above.

[0146] In non-limiting embodiments, a method is provided of treating hand clench following stroke in a patient, by blocking a nerve innervating the hand by a nerve block method, for example as described above.

[0147] In non-limiting embodiments, a method is provided for administering anesthesia during surgery or piercing in a patient, by blocking one or more nerves innervating the area of the surgery, for example as described above.

[0148] In non-limiting embodiments, a method is provided for administering anesthesia in a situation with limited medical resources such as combat, a natural disaster, an emergency amputation, or other large-scale incident, by blocking one or more nerves innervating the area of pain which can be reapplied with repeated applications of cool temperatures by a person with less skill or training, for example as described above.

[0149] In non-limiting embodiments, the devices, systems, and methods described herein may be used to attenuate and / or block pain from minor surgeries, major surgeries including amputation, post-surgical recovery requiring pain relief but not motor function block such as thoracotomy, relief of pain caused by mixed pain and motor nerves, headaches, bunions, ingrown nails, debridement procedures, and to treat conditions where overactive motor neurons are the cause of the condition (e.g. muscle spasms following spinal cord injury or stroke).

[0150] In non-limiting embodiments, a method is provided of treating post- surgical pain, by blocking one or more nerves innervating the area of the surgery by a nerve block method, for example as described above.

[0151] In non-limiting embodiments, a method is provided of treating pain from diabetes lancets in a patient, for example a human patient, by blocking the ulnar and / or median nerves, for example as described above.

[0152] For the aforementioned methods, cooling may be delivered to the site of interest (e.g., to the nerve and / or neuron of interest, and / or to skin about the nerve and / or neuron of interest), for any suitable length of time, including days, hours, minutes, and / or seconds. Cooling may be delivered at one time or repeated multiple times without limitation.Example 1

[0153] In this study it was shown that the temperature for producing cold block of mammalian myelinated nerves, including motor nerves, can be reversibly shifted from 5-15QC to room temperature (15-30QC) after a treatment.Materials and Methods

[0154] A 67% ethanol solution with a small amount of oleic acid (4%) was made by diluting 75% ethanol with tap water and mixing 20 mL of olive oil. 50-70% ethanol is known to penetrate the skin more rapidly than pure ethanol and 1 -5% oleic acid is known to increase ethanol flux by a factor of 4. See, e.g., Berner etal. “Ethanol: Water mutually enhanced transdermal therapeutic system II: Skin permeation of ethanol and nitroglycerin.” (J. Pharm. Sci. 78, 402-407 (1989)). Alcohols are known to activate HSP and improve percutaneous absorption and retention of small molecules such as ibuprofen, and may also improve the absorption of capsaicin and other van illoids. See, e.g., Ossowicz et al. “The effect of alcohols as vehicles on the percutaneous absorption and skin retention of ibuprofen modified with l-valine alkyl esters.” (RSC Adv. 10, 41727-41740 (2020)). The following equipment was utilized:Table 1

[0155] Pain was rated on the numerical rating scale (NRS), sharpness was rated on a 0 to 3 scale (0 = not sharp, 1 = mildly sharp, 2 = moderately sharp, 3 = very sharp). Light touch was assessed with a Boolean scale and finger strength was rated on a 0 to 3 scale based on the difficulty in extending all fingers under 6.6 lbs of resistance (0 = very easy, 1 = mildly easy, 2 = mild difficult, 3 = very difficult). Having described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof.Results

[0156] Pinprick pain, pinprick sharpness, light touch, and motor strength were assessed on the left hand according to Figure 2. Results are shown in Table 2, below.Table 2

[0157] Initial protocol observations and results are reproduced below, in Table 3, below:Table 3

[0158] Additional testing was completed beyond the above time points, as set forth below:

[0159] 9:24 PM: Re-administered cold to the left elbow by placing elbow on the same bag of water and ice (24 minutes post-ethanol soak). Feeling of cold is similar to previous test - more intense than expected.

[0160] 9:26 PM: motor weakness beginning. Mild difficulty flexing and extending4th and 5th digits.

[0161] 9:29 PM: tested pinprick on palmar side of 5th digit. Pain 1 / 10, no sharpness. Removed elbow from ice after.

[0162] 1 1 :30 PM: reapplied cold to left elbow

[0163] 1 1 :36 PM: motor weakness, pinprick sharpness 0 / 3, pinprick pain 1 / 10 at site #1 . Removed elbow from cold.

[0164] 12:30 AM (next day) - reapplied cold to left elbow.

[0165] 12:34 AM: motor weakness without resistance, pinprick pain 2 / 10, pinprick sharpness 0 / 3 at site #1 .

[0166] 8:22 AM: reapplied cold to elbow with new bag of ice water. Pinprick pain6 / 10, pinprick sharpness 3 / 3 prior to cold exposure.

[0167] 8:27 AM: Pinprick sharpness 0 / 3, pinprick pain 2 / 10

[0168] 8:28 AM: Pinprick sharpness 0 / 3, pinprick pain 1 / 10, minor motor weakness without resistance. Difficult to accurately move 5th digit of left hand. Did not test motor with resistance. Removed elbow from cold.

[0169] 8:35 AM: applied cold to both elbows. 5th digit of left hand (ethanol side) beginning to feel puffy within 1 minute.

[0170] 8:57 AM: extremely stark difference between sensations of 5th digit on left (ethanol) and right (control) side. Left side very puffy, tingling. Left (site 1 ): Pinprick pain 2 / 10, pinprick sharpness 0 / 3. Right (mirror of site 1 ): Pinprick pain 5 / 10; pinprick sharpness 2 / 3. Removed cold from elbows after testing pinprick. Motor weakness similar on both sides (very minor deficit)

[0171] 9:22 AM: applied to cold to both elbows while lying on mattress to avoid pressure. Pinprick pain 6 / 10, pinprick sharpness 3 / 3 for 5th digit of both hands.

[0172] 9:24 AM: 5th digit of both hands beginning to feel puffy with the left hand(ethanol side) experiencing more intense sensation. Very stark difference between intensity of tingling between ethanol vs control side.

[0173] 9:27 AM: 5th digit of right hand experiencing pinprick sharpness 2 / 3, pinprick pain 4 / 10. Left hand (site 1 ) pinprick sharpness 0 / 3, pinprick pain 2 / 10

[0174] 12:35 PM: Beginning to cool both elbows. 5th digit of left hand beginning to feel numb and tingling by 12:36 PM with no noticeable change to right hand.

[0175] 12:39 PM: 5th digit of left hand feels puffy and tingly with no corresponding change to right hand.

[0176] 12:42 PM: light touch sensation lost on 5th digit of left hand. 4th digit feels numb on outer (5th digit) side but normal on inner (3rd digit) side. No corresponding change to right hand.

[0177] 4:46 PM: began applying cold to left elbow. Fingers feel mostly normal prior to application.

[0178] 4:51 PM: pinprick pain 3 / 10, pinprick sharpness 1 / 3 at site 1. Did not test motor function. Significantly less tingling and puffy sensation. Removed elbow from cold. Motor function feels mostly normal. It seems that titrating the ethanol dose may potentially result in a partial block with pain preferentially blocked over motor function.

[0179] Further testing and observations from two days following treatment with ethanol are described below:

[0180] 8:01 AM: left hand feels mostly normal. Began cooling left elbow.

[0181] 8:10 AM: left hand feels mostly normal upon cooling. Pinprick pain 4 / 10, pinprick sharpness 2 / 3 at site #1 . Did not push lancet into site #1 as far as other tests because pain response felt normal. Removed elbow from cold.

[0182] 4:00 PM: left hand feels normal. Began cooling both elbows.

[0183] 4:05 PM: both hands feel very similar. Completely different from first experience of cooling both elbows simultaneously. Minor puffiness and tingling in 5th digit of both hands. Pinprick sharpness 3 / 3 at site #1 on left hand and right hand. Did not test pinprick pain response. Removed elbows from cold.

[0184] 8:00 PM: Both hands feel identical. Began cooling both elbows.

[0185] 8:15 PM: both hands feel identical. Slight tingling in both pinkies from cold. Pinprick pain 6 / 10 at site #1 on both hands. Motor function 0 (very easy) in both hands with 6.6 lbs of resistance.

[0186] Further testing and observations from three days following treatment with ethanol are described below:

[0187] 9:00 AM: both hands feel normal. Began cooling both elbows. Both feel the same. With no change from previous evening.

[0188] 9:04 AM: Both hands feel the same. Did not repeat pinprick. Removed elbows from cold.Example 2

[0189] In this second study it was shown that the temperature for producing cold block of mammalian myelinated nerves can be shifted from 5-15QC to room temperature (15-30QC) after a treatment using a vanilloid compound.Materials and Methods

[0190] A 50% ethanol solution with a small amount of oleic acid (4%) and vanillin was made by diluting 75% ethanol (Everclear) with 15 mL of artificial vanilla flavor (vanillin), tap water, and mixing 20 mL of olive oil.

[0191] In addition to the equipment used for the first study, a BACtrack breathalyzer was used to measure blood alcohol content (BAG).Results

[0192] Pinprick pain, pinprick sharpness, light touch, motor strength, and BAG were assessed on the left hand according to Figure 2. Results are shown in Table 4, below:Table 4

[0193] Pain was rated on the numerical rating scale (NRS), sharpness was rated on a 0 to 3 scale (0 = not sharp, 1 = mildly sharp, 2 = moderately sharp, 3 = very sharp). Light touch was assessed with a Boolean scale and finger strength was rated on a 0 to 3 scale based on the difficulty in extending all fingers under 6.6 lbs of resistance (0 = very easy, 1 = mildly easy, 2 = mild difficult, 3 = very difficult). Having described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof.

[0194] Initial protocol observations and results are reproduced in Table 5, below:Table 5

[0195] Additional testing was completed beyond the above time points, as set forth below.

[0196] Day 2, 6:00 AM: Began to apply cold to both elbows. BAG was 0.00%

[0197] Day 2, 6:10 AM: Left hand has motor weakness without resistance. Site#1 pinprick pain of 1 / 10, pinprick sharpness 0 / 3. Right hand feels the same as baseline - pinprick pain 6 / 10, pinprick sharpness 3 / 3

[0198] Day 3: Began to apply cold to both elbows. BAG was 0.00%

[0199] Day 3, 10:10 AM: Site #1 pinprick pain 6 / 10, pinprick sharpness 3 / 3. The pain and sharpness returned to baseline. Motor weakness was no longer observed.

[0200] This second example shows that the use of vanillin is at least as effective and may be more effective than ethanol and oleic acid alone.Example 3

[0201] In this study it was shown that the temperature for producing cold block of mammalian myelinated nerves can be reversibly shifted from 5-15QC to room temperature (15-30QC) after an automated treatment.Materials and Methods

[0202] A 71 % ethanol solution with -0.4% oleic acid (OA) was prepared by dissolving 2 g of olive oil in 500 mL of 75.5% ethanol and then diluting the mixture with38 mL of water. A lower concentration of OA was used than in Example 1 to attempt to limit the flux of ethanol. OA concentrations of >1% in 70% EtOH have been shown to substantially enhance ethanol flux through the skin compared to OA concentrations < 1%. The equipment utilized is shown in Table 6, below, and the assessments performed are shown in Table 7, below:Table 6Table 7

[0203] Pain was induced using a lancet and rated on the Defense and Veterans Pain rating scale (DVPRS), a 0 to 10 scale. Sharpness of the pinprick was rated on a 0 to 3 scale, difficulty of spreading fingers under resistance was assessed on a 0 to 3 scale, and the feeling of sharpness, light touch, and ability to spread the fingers were rated on a Boolean scale.Results

[0204] Day 1 , 3:00 PM: Before applying treatment to the left elbow, the following assessments were conducted on the left hand:Table 8

[0205] To automate dispensing the treatment, the solution was held in an IV drip bag. A cloth napkin was held against the left elbow above the ulnar nerve by an elbow brace and the tip of the drip bag was held in contact with the napkin by securing the tubing to a shirt while the tip was held by the brace.

[0206] Day 1 , 3:19 PM: Begin dripping alcohol solution onto the cloth napkin at a rate of 1 drop per 30 seconds (2 drops per second) before lowering rate to about 1 drop every 2 seconds (0.5 drop per second).

[0207] Day 1 , 3:49 pm: Remove cloth napkin, allow elbow to under light cooling to simulate exposure to cool outdoor air without cooling the nerve.

[0208] Day 1 , 4:00 pm: Administer assessments as shown in Table 9, below: Table 9

[0209] Day 1 , 4:08 PM: Begin administering alcohol drip using the napkin held over the ulnar nerve

[0210] Day 1 , 4:40 PM: Remove ethanol drip, begin cooling nerve using ice water bag

[0211] Day 1 , 4:50 PM: Reassess while cold water continues to be held over the nerve:Table 10

[0212] Day 2 4:00 PM: Place ice water bag over ulnar nerve without readministering treatment beforehand

[0213] Day 24:1 1 PM: Reassess while cold water continues to be held over the nerve:Table 1 1Example 4

[0214] In this study it was shown that the temperature for producing cold block of mammalian myelinated nerves can be reversibly shifted from 5-15QC to room temperature (15-30QC) after an automated treatment that has a pleasant odor. Materials and Methods

[0215] A 70% ethanol solution with 0.8% limonene and 0.7% vanillin and 0.4% OA was created by dissolving 5.8g of limonene, 5.0 g vanillin, and 2.0 g olive oil in 450 mL of 75.5% EtOH and then diluting the mixture with 30.6 mL of water.

[0216] Vanillin was chosen due to its potential interaction with the TRPV1 receptors and limonene was used as an additional penetration enhancer. Both alcohols and natural terpenes are thought to enhance drug permeation by disrupting the highly ordered lipid structure of the stratum corneum. Limonene and vanillin are also used for their pleasant aromas, potential anti-inflammatory properties, as well as their anti-oxidant properties.

[0217] For this example, pinprick assessments with the Neurotip were not repeated if sharpness was already detectable. This decision was based on the confirmation that detectable sharpness correlated with pain sensation from the pinprick and aimed to minimize unnecessary discomfort for the participant. Assessments were performed as defined in Example 3 but on the right hand.Results

[0218] Day 1 1 :50 PM: Pre-treatment assessment of the right hand:Table 12

[0219] Day 1 , 1 :56 PM: Begin exposing right elbow to treatment using a drip bag to wet a cloth held against the right elbow using an elbow brace.

[0220] Day 1 , 2:25 PM: Repeat assessments of the right hand before beginning to cool:Table 13

[0221] Day 1 , 2:26 PM: Remove ethanol drop (30 minutes total) and begin cooling right elbow using a bag of ice water

[0222] Day 1 , 2:35 PM: Reassess while holding ice water bag on the right elbow over the ulnar nerve:Table 14

[0223] Day 1 , 2:36 PM: Stop cooling

[0224] Day 1 , 3:01 PM: Elbow feels slightly cold still

[0225] Day 1 , 3:15 PM: Elbow feels normal

[0226] Day 1 , 10:01 PM: Begin cooling elbow with ice water

[0227] Day 1 , 10:11 PM: Reassess sharpness, light touch, finger spread, BAG(no pain stimulus):Table 15

[0228] Day 2, 8:00 AM: Begin cooling elbow with ice water

[0229] Day 2, 8:10 AM: Reassess sharpness, light touch, finger spread, BAG(no pain stimulus):Table 16

[0230] Key takeaways from Examples 3 and 4 are provided below, in Table 16:Table 17

[0231] Additional key takeaways for each example are presented in Table 18 with “Successfully shown” marking that the takeaway was demonstrated in the example and a “Not Assessed” that the takeaway was not assessed in the Example

[0232] Combined with Examples 1 and 2, Examples 3 and 4 demonstrate that the invention can be used to block only pain or could be used to block both pain and motor function noninvasively, indicating it could be used without limitation for minor surgeries, major surgeries including amputation, post-surgical recovery requiring pain relief but not motor function block such as thoracotomy, relief of pain caused by mixed pain and motor nerves, headaches, bunions, ingrown nails, debridement procedures, and to treat conditions where overactive motor neurons are the cause of the condition (e.g. muscle spasms following spinal cord injury or stroke).

[0233] While the present invention is described with reference to several distinct aspects or embodiments, those skilled in the art may make modifications and alterations without departing from the scope and spirit. Accordingly, the above detailed description is intended to be illustrative rather than restrictive.

Claims

What is claimed is:1 . A method of blocking a nerve in a patient, comprising: treating the nerve with a composition for a time period sufficient to increase the threshold temperature for producing a cold conduction block within the nerve; and cooling the nerve to a temperature ranging from 15 °C to 30 °C to produce a nerve block at a higher temperature than would be required without the treatment with the composition.

2. The method of claim 1 , wherein the treating comprises sensitizing the nerve with the composition.

3. The method of claim 2, wherein the composition comprises one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, acids, calcium ions, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof.

4. The method of claim 3, wherein the composition comprises ethanol.

5. The method of claim 3, wherein the composition comprises 50- 70% ethanol.

6. The method of claim 5, wherein a concentration of the composition in proximity to the nerve comprises 0.3% to 50% ethanol.

7. The method of claim 3, wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, acids, calcium ions, terpenes, terpenoids, piperine, and / or one or more vanilloids.

8. The method of claim 3, wherein the treatment comprises transdermal administration of the composition, optionally with a chemical permeationenhancer, abrasion, iontophoresis, electroporation, microneedles, ultrasound, magnetophoresis, and / or photomechanical waves.

9. The method of claim 3, wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

10. The method of claim 3, wherein the treatment comprises oral administration of the composition.1 1 . The method of claim 3, wherein the treatment comprises parenteral administration of the composition.

12. The method of claim 1 , further comprising, prior to treating the nerve, placing a temperature controller in proximity to the nerve to cool and / or treat the nerve with the composition, the temperature controller comprising a cooling element and optionally a temperature sensor, and the temperature controller optionally being wirelessly connected to a controller for controlling cooling of the cooling element, delivering the composition to the nerve, and / or monitoring temperature at the nerve by the temperature sensor.

13. The method of claim 12, wherein the cooling element is ice, a cooled fluid, a cooled treatment composition a cooled slurry or slush solution, a fluidic tube / pad, a vapor compression cooler, a Peltier cooler, and / or reservoir with cold fluid, and the temperature sensor is a thermocouple or a thermistor.

14. The method of claim 1 , wherein the patient has a condition selected from experiencing pain and a motor neuron dysfunction, and wherein blocking the nerve treats and / or diagnoses the patient’s condition.

15. The method of claim 14, wherein the pain is chronic pain.

16. The method of claim 14, wherein the pain is peripheral pain.

17. The method of claim 14, wherein the motor dysfunction is caused by a stroke.

18. The method of claim 14, wherein the motor dysfunction is caused by a ventricular arrythmia.

19. The method of claim 1 , wherein the nerve is pre-treated with the composition for about 90 minutes or less prior to cooling.

20. The method of claim 1 , wherein the nerve is a sensory nerve.21 . The method of claim 1 , wherein the nerve is a motor nerve.

22. The method of claim 1 , wherein multiple nerves are targeted.

23. The method of claim 1 , wherein multiple mixed sensory and motor nerves are targeted.

24. The method of claim 1 , wherein the nerve is reversibly blocked.

25. The method of claim 1 , wherein the nerve is repeatedly reversibly blocked.

26. The method of claim 1 , wherein the nerve is irreversibly blocked.

27. Use of a composition for sensitizing a nerve for blocking the nerve by cooling with a device, the device comprising: a temperature controller comprising a processor; a thermoelectric device in communication with the temperature controller and configured to be placed in proximity to a nerve; a temperature sensor in communication with the temperature controller and configured to be placed in proximity to the nerve; and a power source to provide power to the temperature controller and the thermoelectric device,the use comprising treating the nerve with the composition with or without the device and cooling the nerve to a temperature between about 15 °C and about 30 °C with the device.

28. The use of claim 27, wherein the composition comprises one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and / or combinations thereof.

29. The use of claim 27, wherein the composition comprises ethanol.

30. The use of claim 29, wherein the composition comprises 50-70% ethanol.31 . The use of claim 29, wherein the concentration in proximity to the nerve comprises 0.3% to 50% ethanol.

32. The use of claim 27, wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, terpenes, terpenoids, piperine, and / or one or more vanilloids.

33. The use of claim 27, wherein the treatment comprises transdermal administration of the composition.

34. The use of claim 27, wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

35. The use of claim 27, wherein the treatment comprises oral administration of the composition.

36. The use of claim 27, wherein the treatment comprises parenteral administration of the composition.

37. The use of claim 27, wherein the sensory nerve is pre-treated with the composition for 90 minutes or less prior to cooling.

38. Use of a composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof for blocking a nerve.

39. Use of a cooled composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof for blocking a nerve.

40. Use of one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, terpenes, terpenoids piperine, dimethyl sulfoxide (DMSO), and combinations thereof in combination with ice, a cooled fluid, a cooled slurry, cooled treatment composition, and / or a cooled slushy solution for blocking a nerve.

41. A method of blocking and / or ablating a nerve in a patient, comprising: treating the nerve with a composition for a time period sufficient to increase the threshold temperature for producing a cold conduction block within the nerve; and cooling the nerve to produce a nerve block and / or ablation at a higher temperature than would be required without the treatment with the composition.

42. The method of claim 41 , wherein the treatment and cooling are performed substantially simultaneously, and comprise applying a cooled composition comprising one or more alcohols, one or more vanilloids, one or more transient receptor potential vanilloid (TRPV) agonists, one or more heat shock protein (HSP) activators, acids, calcium ions, terpenes, terpenoids, piperine, dimethyl sulfoxide (DMSO), and combinations thereof to the nerve.

43. The method of claim 41 , wherein the composition comprises ethanol.

44. The method of claim 43, wherein the composition comprises 50-70% ethanol.

45. The method of claim 43, wherein a concentration of the composition in proximity to the nerve comprises 0.3% to 50% ethanol.

46. The method of claim 41 , wherein the composition comprises: an alcohol and / or DMSO; and one or more TRPV agonists, one or more HSP activators, terpenes, terpenoids, piperine, and / or one or more vanilloids.

47. The method of claim 41 , wherein the treatment comprises transdermal administration of the composition.

48. The method of claim 41 , wherein the treatment comprises subcutaneous, intramuscular, and / or intradermal administration of the composition.

49. The method of claim 41 , wherein the treatment comprises oral administration of the composition.

50. The method of claim 41 , wherein the treatment comprises parenteral administration of the composition.51 . The method of claim 41 , wherein the nerve is reversibly blocked.

52. The method of claim 41 , wherein the nerve is irreversibly blocked.

53. The method of claim 41 , wherein the patient is experiencing obesity, pain from needle stick(s), pain from bunions, neuromas, pain from arthritis, heart disease, ventricular arrythmia, ventricular tachycardia, or long COVID, and wherein blocking the nerve treats the patient’s condition or diagnoses the condition.