Compositions and methods for treating pain

Abstract

The present disclosure describes methods of treating conditions such as trigeminal neuralgia and pain associated therewith. The methods of the present disclosure may include administering a therapeutically effective amount of trimipramine to a patient in need thereof, thereby treating the patient. The methods may include reducing pain in the patient as determined by patient-reported or clinician-provided outcome assessments.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 337,367, filed May 2, 2022, which is hereby incorporated by reference in its entirety.

[0002] Background Trigeminal neuralgia (TN), also known as tic douloureux, is a chronic pain disorder that affects the trigeminal nerve, or the fifth cranial nerve, which is one of the most widely distributed nerves in the head. TN is a type of neuropathic pain (pain associated with nerve damage or neuropathy). In the typical "classical" form (referred to as "type 1" or TN1), extreme, sporadic, sudden burning or shock - like facial pain occurs, lasting from a few seconds to about two minutes per episode. These attacks occur continuously and can last up to two hours. The "atypical" form of this disease (referred to as "type 2" or TN2) is characterized by a somewhat less intense, constantly painful, burning, stabbing pain compared to type 1. Both types of pain can occur in the same person, sometimes simultaneously. The intensity of the pain can be physically and mentally debilitating.

[0003] The trigeminal nerve is the fifth cranial nerve (cranial nerve V) and is one of the 12 pairs of nerves attached to the brain. This nerve has three branches that originate from the "Gasserian ganglion" (semilunar ganglion), which transmits sensations from the upper, middle, and lower parts of the face, as well as from the oral cavity, to the brain. The branch of the ophthalmic ganglion (upper) (V1) supplies sensation to the scalp, forehead, and most of the frontal region. The branch of the maxillary ganglion (middle) (V2) stimulates the cheek, maxilla, upper lip, teeth and gums, and the side of the nose. The mandibular ganglion (V3) supplies nerves to the mandible, teeth and gums, and lower lip. In cases where multiple nerve branches are affected by this disorder, or more rarely, both sides of the face may be affected simultaneously (referred to as bilateral TN).

[0004] The pain varies depending on the type of TN, ranging from sudden, intense, stabbing pain to more constant pain or a burning sensation. Pain like a strong flash of light (exacerbation) may be induced by vibration or contact on the cheek (such as when shaving, washing the face, applying makeup), brushing teeth, eating or drinking, talking, or being exposed to the wind. The pain may occur in a narrow area of the face or spread. It is rare for pain attacks to occur at night or during sleep. TN is characterized by episodes that stop for a certain period and then recur, although the symptoms may progress. The attacks often worsen over time, with fewer and shorter pain-free periods before recurrence. Eventually, there are no pain-free periods, and the effectiveness of pain-suppressing medications decreases. An effective treatment regimen for managing TN is still needed.

Summary of the Invention

[0005] In some embodiments, a method for treating trigeminal neuralgia is provided, the method comprising administering a therapeutically effective amount of trimipramine to a patient in need thereof, thereby treating the trigeminal neuralgia of the patient.

[0006] In one embodiment, the therapeutically effective amount of trimipramine is administered once a day.

[0007] In one embodiment, the therapeutically effective amount of trimipramine is administered twice a day.

[0008] In some embodiments, the therapeutically effective amount of trimipramine is administered by oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, cutaneous administration, transdermal administration, nasal administration, or a combination thereof.

[0009] In some embodiments, the therapeutically effective amount of trimipramine is administered by oral administration.

[0010] In some embodiments, the therapeutically effective amount of trimipramine is administered by sublingual administration.

[0011] In some embodiments, a therapeutically effective amount of trimipramine is from about 0.5 mg to about 20 mg.

[0012] In some embodiments, a therapeutically effective amount of trimipramine is about 5 mg.

[0013] In some embodiments, a therapeutically effective amount of trimipramine is from about 0.05 mg / kg to about 20 mg / kg.

[0014] In some embodiments, a therapeutically effective amount of trimipramine is from about 0.1 mg / kg to about 10 mg / kg.

[0015] In one embodiment, treating trigeminal neuralgia includes reducing the patient's pain.

[0016] In some embodiments, reducing the patient's pain includes improving the patient's pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

[0017] In some embodiments, reducing the patient's pain includes preventing an increase in the patient's pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

[0018] In some embodiments, treating trigeminal neuralgia includes improving the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, WPAI score, or a combination thereof.

[0019] In some embodiments, treating trigeminal neuralgia includes preventing an increase in the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, or WPAI score, preventing a decrease in the PGIC score, or a combination thereof.

[0020] In some embodiments, a method for reducing pain in a patient with trigeminal neuralgia is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of trimipramine, whereby the pain of the patient is reduced.

[0021] In some embodiments, reducing pain in a patient includes an improvement in the patient's pain as measured by the Penn-FPS score as compared to the patient's Penn-FPS score prior to treatment.

[0022] In some embodiments, reducing pain in a patient includes preventing an increase in the patient's pain as measured by the Penn-FPS score as compared to the patient's Penn-FPS score prior to treatment.

[0023] In some embodiments, reducing pain in a patient includes an improvement in the patient's pain as measured by the Penn-FPS-R score as compared to the patient's Penn-FPS-R score prior to treatment.

[0024] In some embodiments, reducing pain in a patient includes preventing an increase in the patient's pain as measured by the Penn-FPS-R score as compared to the patient's Penn-FPS-R score prior to treatment.

[0025] In one embodiment, reducing pain in a patient includes an improvement in the patient's PGIC score at the end of the treatment period.

[0026] In one embodiment, reducing pain in a patient includes preventing a decrease in the PGIC score at the end of the treatment period.

[0027] In some embodiments, the therapeutically effective amount of trimipramine is from about 0.5 mg to about 20 mg.

[0028] In some embodiments, the therapeutically effective amount of trimipramine is from about 0.05 mg / kg to about 20 mg / kg.

[0029] In some embodiments, a therapeutically effective amount of trimipramine is from about 0.1 mg / kg to about 10 mg / kg.

[0030] In some embodiments, a therapeutically effective amount of trimipramine is administered by oral administration.

[0031] In some embodiments, a therapeutically effective amount of trimipramine is administered by sublingual administration.

DETAILED DESCRIPTION

[0032] Detailed Description The following describes various embodiments in more complete detail. However, such embodiments can be exemplified in many different forms and should not be construed as limited to the examples described herein. Rather, these examples are provided so that this disclosure will be thorough and complete and will fully convey the scope to those skilled in the art.

[0033] When a range of values is indicated, each value intervening between the upper and lower limits of that range, as well as other explicitly stated values or intervening values within that range, is intended to be encompassed by the present disclosure. For example, when a range of 1 mg to 8 mg is recited, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg are also intended to be explicitly disclosed, as are ranges of values greater than or equal to 1 mg and less than or equal to 8 mg.

[0034] All percentages, parts, and ratios are based on the total weight of the topical composition, and all measurements were made at about 25°C unless otherwise noted.

[0035] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes not only a single polymer but also two or more of the same or different polymers, and reference to "an excipient" includes not only a single excipient but also two or more of the same or different excipients, etc.

[0036] The term "about" when preceding a numerical value means a range of plus or minus 10% of that numerical value. For example, "about 50" means from 45 to 55, "about 25,000" means from 22,500 to 27,500, etc., unless the context of the present disclosure indicates otherwise or such an interpretation is inconsistent. For example, in a list of numerical values such as "about 49, about 50, about 55", "about 50" means a range that extends less than half of the interval between the preceding value and the succeeding value, e.g., greater than 49.5 and less than 52.5. Further, the expressions "about less than" a value or "about greater than" a value should be understood in view of the definition of the term "about" provided herein.

[0037] As used herein, the terms "administer", "administering", or "administration" refer to the direct administration of a compound (also referred to as the substance of interest) or a pharmaceutically acceptable salt or composition of the compound (substance of interest) to a subject.

[0038] As used herein, the term "carrier" includes carriers, excipients, and diluents, which are materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in transporting or delivering a medicament, cosmetic, or other agent across tissue layers such as the stratum corneum or stratum spinosum.

[0039] As used herein, the term "disorder" means, unless otherwise specified, the terms disease, condition, or illness and is used interchangeably therewith.

[0040] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in the present disclosure and refer to the amount of a compound that, when administered to a subject, can reduce the symptoms of a disorder in the subject and / or enhance the texture, appearance, color, sensation, and / or hydration of the intended tissue treatment area. The actual amount that constitutes an "effective amount" or "therapeutically effective amount" varies depending on many conditions including, but not limited to, the severity of the disorder, the physical build and health of the patient, the route of administration, and combinations thereof. A skilled medical practitioner can readily determine an "effective amount" or "therapeutically effective amount" using methods known in the medical arts.

[0041] The phrase "pharmaceutically acceptable" as used herein refers to agents / compounds, salts, compositions, dosage forms, etc. of interest that are suitable for use in contact with the tissues of humans and / or other mammals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio. In some embodiments, "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in mammals (e.g., animals), more particularly in humans.

[0042] As used herein, the term "salt" includes pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and addition salts of free bases. The nature of the salt is not critical as long as it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts such as hydrates and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids are aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl-containing carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, 3-hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0043] As used herein, the terms "patient" and "subject" are interchangeable and can be interpreted to mean any living organism that can be treated with the compounds of the present disclosure. Thus, the terms "patient" and "subject" can include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, the "patient" or "subject" is a mammal, and exemplary mammals include mice, rats, rodents other than mice and rats, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, or humans. In some embodiments, the patient or subject is an adult, pediatric, or infant. In some embodiments, the patient or subject is human.

[0044] As used herein, the term "treating" is used, for example, with respect to methods of treating a disorder or a general condition, and generally refers to reducing the frequency of symptoms of a medical condition, or delaying the onset thereof, and / or administering a compound or composition that enhances the texture, appearance, color, sensation, and / or hydration of an intended tissue treatment area on the tissue surface in a subject as compared to a subject not administered the compound or composition. This can include reversing, reducing, or preventing the symptoms, clinical signs, and underlying pathology of a disease state in a manner that improves or stabilizes the condition of the subject.

[0045] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including but not limited to non-toxic solvents, phosphate buffered saline, water, emulsions (such as oil / water or water / oil emulsions, etc.), various wetting agents, any solvent, dispersion medium, coating agent, sodium lauryl sulfate, isotonic and absorption delaying agents, oil / water or water / oil emulsions, etc.), and various types of wetting agents, any solvent, dispersion medium, coating, sodium lauryl sulfate, tonicity agents and absorption delaying agents, peptizing agents (such as potato starch or sodium starch glycolate), etc. Compositions can also include stabilizers and / or preservatives.

[0046] By reserving herein the right to exclude or condition individual members of such groups, including sub-ranges or combinations of sub-ranges within a group that can be claimed according to a range or in a similar manner, for any reason, a range less than the full scope of the present disclosure can be claimed. Further, by reserving herein the right to exclude or condition any individual substituent, analog, compound, ligand, structure, or group thereof, or any member of a claimed group, for any reason, a range less than the full scope of the present disclosure can be claimed.

[0047] For the sake of convenience, the specific terms used in this specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0048] Various aspects of the present disclosure are directed to compositions comprising phenothiazines for treating pain, as well as methods of using such compositions for treating, preventing, and / or ameliorating pain. Such compositions may further comprise various excipients that facilitate oral, topical, or both oral and topical administration. The compositions and methods described herein may reduce pain and other symptoms associated with chronic conditions.

[0049] Examples of phenothiazines include chlorpromazine, diethazine, etopropazine, fluphenazine, methdilazine, perphenazine, prochlorperazine, promazine, promethazine, mesoridazine, thietylperazine, thioridazine, trifluoperazine, triflupromazine, trimipramine, and various derivatives and salts thereof, as well as combinations thereof. In certain embodiments, the phenothiazine may be one or more of diethazine, etopropazine, methdilazine, promethazine, thietylperazine, or trimipramine, and in certain embodiments, the phenothiazine may be trimipramine.

[0050] One of ordinary skill in the art would understand and recognize the dosage and the timing thereof to be administered to a patient in need thereof. The dosage and duration of treatment can vary and can be based on an assessment by one of ordinary skill in the art based on monitoring of the underlying malignant disease and measurement of improvement. This assessment can be made based on outward physical signs of improvement such as reduction of pain. The dosage can also depend on the condition or disease being treated, the extent of the condition or disease being treated, and further on the age and weight of the patient. In some embodiments, the amount of phenothiazine administered using the exemplified method embodiments can vary and can be, for example, from about 0.05 mg / kg / day to about 20 mg / kg / day. In some embodiments, the amount of phenothiazine delivered can be from about 0.05 mg / kg / day to about 20 mg / kg / day, from about 0.1 mg / kg / day to about 10 mg / kg / day, from about 0.5 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 8 mg / kg / day, from about 1.5 mg / kg / day to about 5 mg / kg / day, from about 0.1 mg / kg / day to about 3 mg / kg / day, or any range or individual value encompassed by these exemplified ranges. The composition to be administered can generally contain from about 0.5 mg to about 20 mg of phenothiazine, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, or any range or individual dosage encompassed by these exemplified ranges. In some embodiments, the composition can be administered 1, 2, 3, 4, or more times per day to provide from about 0.5 mg to about 40 mg per day, from about 1 mg to about 30 mg per day, from about 1 mg to about 20 mg per day, or any individual amount or range encompassed by these exemplified ranges.

[0051] The specific method of administration varies depending on the indication. The selection of a particular route of administration and dosage can be adjusted or titrated by the clinician according to known methods to obtain an optimal clinical response. The amount of the compound to be administered can be a therapeutically effective amount. The dosage can depend on the characteristics of the subject being treated, such as the particular animal or human subject being treated, age, weight, health status, the type of co-treatment if any, and the frequency of treatment, and can be readily determined by one of ordinary skill in the art (e.g., a clinician).

[0052] The exemplary pharmaceutical compositions described herein can be prepared for administration by a variety of different routes. Generally, the type of carrier is selected based on the mode of administration. Compositions in various embodiments can be formulated for systemic delivery or local delivery to the diseased tissue. For example, in some embodiments, the composition can be formulated for systemic delivery by oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, dermal administration, transdermal administration, nasal administration, etc. and combinations thereof. In other embodiments, the compositions described herein can be delivered locally, for example using topical administration.

[0053] In the case of oral administration, the compounds can be easily formulated by combining these compounds with pharmaceutically acceptable carriers well-known in the art. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid, liquid filler, diluent, encapsulating material, any type of formulation adjuvant, or simply a sterile aqueous medium such as physiological saline. Examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic compatible substances used in pharmaceutical formulations, and combinations thereof. Such carriers can enable the compounds described herein to be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. for oral ingestion by the patient to be treated. Oral pharmaceutical formulations can be obtained by adding solid excipients, optionally grinding the resulting mixture, adding suitable adjuvants if desired, and then treating the mixture of granules to obtain cores of tablets or dragees.Suitable excipients include, but are not limited to, sugars such as lactose, sucrose, mannitol, and sorbitol, starches such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and cellulose preparations such as polyvinylpyrrolidone (PVP), and fillers including, but not limited to, combinations thereof. Optionally, disintegrants such as crosslinked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate, and combinations thereof can be added, but are not limited thereto.

[0054] The sugar-coated tablet core can be provided with a suitable coating. For this purpose, concentrated sugar solutions can be used and can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures, and combinations thereof. For identification or to characterize different combinations of the active compound dosage, dyes or pigments can be added to the tablets or the sugar-coated tablet coating.

[0055] Pharmaceutical preparations suitable for oral administration include, but are not limited to, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient, for example, mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer as required. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol, and combinations thereof. Additionally, stabilizers can be added. All preparations for oral administration must be in a dosage suitable for such administration.

[0056] Oral preparations can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0057] Syrups and elixirs can incorporate sweeteners such as, for example, glycerol, propylene glycol, sorbitol, sucrose and combinations thereof. Such preparations may also contain demulcents, preservatives, flavoring agents, coloring agents and combinations thereof.

[0058] For buccal or sublingual administration, the composition can take the form of tablets, flash melt agents or lozenges formulated by any conventional method.

[0059] In addition to the preparations described above, the compounds described herein can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.

[0060] Depot injections can be administered at intervals of about 1 to about 6 months or longer. Thus, for example, the compound can be formulated with a suitable polymer or hydrophobic substance (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or, for example, as a sparingly soluble salt or a sparingly soluble derivative.

[0061] For transdermal administration, the compounds described herein can be applied, for example, to a plaster or by a transdermal therapeutic system that results in delivery to the body.

[0062] In some embodiments, an exemplary pharmaceutical composition may be associated with a fiber. For example, in some embodiments, a fiber-containing composition may include an electrospun polymer having a phenothiazine associated with the electrospun polymer. In some embodiments, the phenothiazine may be dispersed within the electrospun polymer and may exclude pharmaceuticals on the outer surface of the fibers formed from the electrospun polymer. The pharmaceutical dispersed within the electrospun polymer may provide the additional advantage of being resistant to accidental and / or unanticipated removal of phenothiazine from the fiber. In other embodiments, the phenothiazine can be associated with the outer surface of the fiber additionally or alternatively, for example, by dipping, spraying, or otherwise treating the outer surface of the fiber with the pharmaceutical.

[0063] Electrospun polymers of some embodiments may include one or more polymers. In some embodiments, the polymer may be a water-soluble polymer or a combination of water-soluble polymers. In certain embodiments, the one or more polymers can include any combination and / or composition ratio of a synthetic polymer and a naturally occurring polymer.

[0064] In some embodiments, the phenothiazine associated with the polymer can be dispersed or dissolved in an oil, such as an oil selected from cannabis oil, cannabidiol (CBD) oil, olive oil, sesame oil, canola oil, palm oil, vegetable oil, derivatives thereof, or combinations thereof. In some embodiments, the pharmaceutical can have a crystalline form. In further embodiments, the phenothiazine can be a crystal dispersed or dissolved in an oil or solution.

[0065] The pharmaceutical and therapeutic compositions of the compounds can also include a suitable solid-phase or gel-phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, polymers such as polyethylene glycol, and combinations thereof.

[0066] In various embodiments, the composition can further include a pharmaceutically and / or cosmetically acceptable carrier, excipient, diluent, filler, disintegrant, desiccant, binder, lubricant, surfactant, hydrophobic vehicle, water-soluble vehicle, emulsifier, buffer, wetting agent, solubilizer, preservative, colorant, plasticizer, carrier, or combinations thereof. One of ordinary skill in the art can refer to various pharmacological references such as, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) and Goodman & Gilman’s The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co, New York (1980) to obtain guidance in determining the amounts of such components in the compositions and formulations of the embodiments. Any of the aforementioned carriers, excipients, diluents, fillers, disintegrants, desiccants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, humectants, solubilizers, preservatives, colorants, plasticizers, carriers, and combinations thereof can be incorporated into such compositions.

[0067] In some embodiments, exemplary topical compositions can include solvents such as water, isopropyl alcohol, dipropylene glycol methyl ether, butylated hydroxytoluene dipropylene glycol monomethyl ether, 1-methoxy 2-propanol (Grisolve PM / Isinol PM), ethylene glycol monobutyl ether, butyl digrisolve 1, transcutol, propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride, diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, combinations of natural oils, ethylene glycol, propylene glycol, dimethylpolysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous), liposome compositions, aloe vera derivatives or suitable vegetable oils such as sesame oil and / or its derivatives, ethosomes, azone, castor oil derivatives such as castor oil derivatives, ethoxylated castor oil, jojoba oil derivatives, corn oil derivatives, emu oil derivatives, and combinations thereof. The solvents can be present at any suitable concentration. For example, in some embodiments, the solvents can be present at about 5 wt% to about 99.9 wt%, about 10 wt% to about 95 wt%, about 25 wt% to about 90 wt%, about 20 wt% to about 80 wt% of the total composition, or any range or individual concentration of solvents encompassed by these exemplary ranges.

[0068] In some embodiments, the topical composition may include a polar water-miscible solvent such as alcohol and / or glycol. The polar water-miscible solvent can improve the skin penetration and solvation of the active agent. Examples of the polar water-miscible solvent include, for example, C1-C4 alcohols, polyethylene glycol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, glycerol, diethylene glycol monoethyl ether, propylene carbonate, and the like, and combinations and mixtures thereof. The total amount of the polar water-miscible solvent may be less than about 10 wt% based on the total weight of the composition, about 0.5 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 0.5 wt% to about 5 wt%, or any range or individual concentration of the solvents included in these exemplary ranges.

[0069] In some embodiments, the composition can include a surfactant. The surfactant can be incorporated into the oil phase, the water phase, or both. Suitable surfactants include, for example, alkyl polyglycol ethers, alkyl polyglycol esters, ethoxylated alcohols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, ionic or non-ionic surfactants, hydrogenated castor oil / polyoxyethylene glycol adducts, castor oil / polyoxyethylene glycol adducts, sorbitan fatty acid esters (such as Span20 or Span80), block copolymers of ethylene oxide and propylene oxide (such as Pluronic L121 or Pluronic F68), polymeric surfactants having cross-linked copolymers of acrylic acid such as Pemulen Tr-1 and Pemulen Tr-2, and combinations and mixtures thereof. The composition can include a surfactant in an amount of about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 3 wt%, about 0.7 wt% to about 2 wt%, or any range or individual concentration of the solvents included in these exemplary ranges.

[0070] In some embodiments, the composition can include an antioxidant. Such antioxidants can be, for example, butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-1,2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, tocopherol, etc., and pharmaceutically acceptable salts or esters thereof, or combinations thereof. The antioxidant can be present at a concentration of about 0.01 wt% to about 1 wt% of the total composition, or at any individual concentration encompassed within this exemplary range.

[0071] In some embodiments, the composition can include an emulsifier, for example, various monoglycerides, diglycerides, triglycerides, and mixtures thereof, at a concentration of about 3 wt% to about 10 wt% of the total composition.

[0072] In some embodiments, the composition can further include analgesics, for example, methyl salicylate, codeine, morphine, methadone, pethidine, buprenorphine, hydromorphone, levorphanol, oxycodone, fentanyl, non-steroidal anti-inflammatory drugs (NSAIDs), etc., and combinations thereof. The amount of analgesic in such a composition is about 0.01 wt% to about 5 wt% of the total composition.

[0073] In some embodiments, the composition can further include a humectant. Examples of humectants used in exemplary compositions include propylene glycol, glycerin, etc., and combinations thereof. The amount of humectant in such a composition can be about 0.01 wt% to about 10 wt% of the total composition.

[0074] In some embodiments, the composition may further comprise a pharmaceutically acceptable buffer sufficient to adjust and maintain the pH of the compositions described herein in the range of about 7.0 to about 14.0, or about 8.5 to about 12.0. Typically, suitable buffers include citrate, phosphate, glycine, etc., and combinations thereof. The amount of buffer in such compositions is from about 0.01 wt% to about 10 wt% of the total composition.

[0075] In some embodiments, exemplary compositions can further comprise a mineral, a mineral salt, or a combination thereof. Exemplary minerals that can be used include, but are not limited to, selenium, sulfur, zinc, iron, chlorine, cobalt, copper, manganese, molybdenum, and iodine. The amount of mineral or mineral salt in an exemplary topical formulation includes any therapeutically effective amount. For example, the mineral or mineral salt can have a concentration of about 0.01 wt% to about 5 wt% relative to the total amount of the composition, a concentration of about 0.1 wt% to about 1 wt% relative to the total amount of the composition, or any range or individual concentration included within these exemplary ranges.

[0076] In some embodiments, the composition can further comprise a vitamin or combination of vitamins. Vitamins are organic molecules that are essential nutrients required for organisms to maintain proper biological functions and metabolism. Examples of use include, but are not limited to, vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B4, vitamin B5, vitamin B6, vitamin B7, vitamin B8, vitamin B9, vitamin Bio, vitamin B11, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K. The amount of vitamin in a topical formulation may be any therapeutically effective amount. For example, the concentration of the vitamin can be about 0.01 wt% to about 5 wt% relative to the total amount of the composition, about 0.1 wt% to about 1 wt% relative to the total amount of the composition, or any range or individual concentration included within these exemplary ranges.

[0077] In some embodiments, the exemplary composition further comprises hyaluronic acid, curcumin, glutathione, methotrexate, tofacitinib, 6-mercaptopurine, azathioprine sulfasalazine, mesalazine, olsalazine chloroquine / hydroxychloroquine, penicillamine, aurothiomalic acid (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhaled, and topical injection), β2 adrenergic receptor agonists (salbutamol, terbutaline, salmeterol), xanthine (theophylline, aminophylline), cromoglycic acid, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs (such as ibuprofen), corticosteroids (such as prednisolone), phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agonists, agents that inhibit signaling by inflammatory cytokines such as TNF or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors, etc.), IL-1 converting enzyme inhibitors, T cell signaling inhibitors (such as kinase inhibitors), metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurine, angiotensin converting enzyme inhibitors, soluble cytokine receptors (soluble p55 or p75 TNF receptor, derivative p75TNFRigG (etanercept) and p55TNFRigG (renesept), siL-1RI, siL-1RII, siL-6R), anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, TGF, etc.), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, sodium aurothiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / apap, folic acid, nabumetone, diclofenac, piroxicam, etodolac, sodium diclofenac, oxaprozin, oxycodone HC1, hydrocodone bitartrate / apap, sodium diclofenac / misoprostol,Fentanyl, Anakinra, Tramadol HCl, Salsalate, Sulindac, Cyanocobalamin / FA / Pyridoxine, Acetaminophen, Sodium Alendronate, Prednisolone, Cortisone, Betamethasone, Morphine Sulfate, Lidocaine Hydrochloride, Indomethacin, Glucosamine Sulfate / Chondroitin, Amitriptyline HCl, Sulfadiazine, Oxycodone HCV Acetaminophen, Olopatadine HCl Misoprostol, Naproxen Sodium, Omeprazole, Cyclophosphamide, Rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, Anti-IL-12, Anti-IL1S, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1PI Agonist (such as FTY720), PKC Family Inhibitor (for example, Ruboxistaurin or AEB-071) or Mesopram, Budesonide, Epidermal Growth Factor, Corticosteroid, Cyclosporine, Sulfasalazine, Aminosalicylate, 6-Mercaptopurine, Azathioprine, Metronidazole, Lipoxygenase Inhibitor, Mesalamine, Olsalazine, Balsalazide, Antioxidant, Thromboxane Inhibitor, IL-1 Receptor Antagonist, Anti-IL-1 Monoclonal Antibody, Anti-IL-6 Monoclonal Antibody, Growth Factor, Elastase Inhibitor, Pyridinylimidazole Compound, Antibody or Antagonist against Other Human Cytokines or Growth Factors (such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF), Cell Surface Molecules (such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or their ligands), Methotrexate, Cyclosporine, FK506, Rapamycin, Mycophenolate Mofetil, Leflunomide, NSAID (such as Ibuprofen), Corticosteroid (such as Prednisolone), Phosphodiesterase Inhibitor, Adenosine Agonist, Antithrombotic Agent, Complement Inhibitor, Adrenergic Agonist, Agent that Inhibits Signal Transduction by Inflammatory Cytokines such as TNF5 or IL-1 (such as NIK, IKK,or MAP kinase inhibitors), IL-1 converting enzyme inhibitors, TNF converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurine, angiotensin converting enzyme inhibitors, soluble cytokine receptors (e.g., soluble p55 or p75 TNF receptor, siL-1RI, siL-1RII, siL-6R), anti-inflammatory cytokines (e.g., genes encoding cytokine-induced SH2-containing protein (CISH), antibody BGB-A317, nivolumab, or pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, etc., and therapeutic agents targeting endogenous checkpoint blockade such as combinations thereof (IL-4, IL-10, IL-11, IL-13 or TGF, etc.) may be included. The amount of the anti-inflammatory agent includes any therapeutically effective amount. For example, in some embodiments, the amount of the anti-inflammatory agent is about 0.01 wt% to about 5 wt% based on the total amount of the composition, about 0.1 wt% to about 1 wt% based on the total amount of the formulation, or any range or individual concentration included in these exemplary ranges.,

[0078] Depending on the condition being treated, exemplary compositions can include steroids, antihistamines, sympathomimetics, beta blockers, parasympathomimetics, parasympathetic blockers, prostaglandins, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, antifungals, local anesthetics, and combinations thereof.

[0079] Further aspects of the disclosure include methods of treating pain by administering a therapeutically effective amount of any of the compositions described or contemplated herein. The administering step can be carried out by any method including, but not limited to, oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, cutaneous administration, transdermal administration, etc., and combinations thereof. In some aspects, the administering step can be carried out once or twice per hour, once, twice or three times per day, once, twice, three times, four times or more per week, etc., depending on the exposure period or the severity of the symptoms.

[0080] In some aspects, the method can include administering any of the exemplary compositions described herein and co-administering one or more of the additional active agents or anti-inflammatory agents, etc. and combinations thereof as described above. Such additional active agents and anti-inflammatory agents, etc., and combinations thereof can be administered in separate dosages by any route of administration. For example, the compositions described herein can be administered topically, and the additional active agents, anti-inflammatory agents, and combinations thereof can be administered separately topically, orally, and / or by injection.

[0081] The compositions and methods of various aspects can be used, for example, to treat patients suffering from various types of pain including, but not limited to, acute pain, chronic pain, neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and / or related pain. As used herein, the term "pain" generally means any unpleasant sensory experience associated with a physical disorder. The physical disorder may or may not be apparent to the clinician. There are two types of pain: chronic pain and acute pain. Acute pain is a pain that suddenly occurs and has a short duration. Chronic pain is pain other than acute pain. Chronic pain includes neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, related pain, etc.

[0082] In some embodiments, the compositions of the present disclosure can be used to treat pain caused by or otherwise associated with a neuropathic pain condition. Neuropathic pain refers to abnormal sensory input that results in discomfort from the peripheral nervous system, the central nervous system, or both. Symptoms of neuropathic pain include persistent spontaneous pain, allodynia (a reaction of feeling pain to a stimulus that normally does not cause pain), hyperalgesia (a heightened reaction to a pain stimulus that normally causes only a mild discomfort, such as being pricked by a pin), and / or hyperpathia (a brief discomfort that becomes an intense pain that lasts for a long time). Neuropathic pain can be caused by, for example, traumatic injuries such as nerve compression injuries (e.g., nerve crush, nerve stretch, nerve entrapment, incomplete nerve transection), spinal cord injuries (e.g., hemisection of the spinal cord), amputation, contusions, inflammation (e.g., spinal cord inflammation), surgical treatments, ischemic events including stroke and / or heart attack, exposure to toxic substances such as drugs, alcohol, heavy metals (e.g., lead, arsenic, mercury), inflammatory diseases, neoplastic tumors, acquired immunodeficiency syndrome (AIDS), Lyme disease, leprosy, metabolic diseases, peripheral neuropathies such as neuropathy, mononeuropathy, and / or polyneuropathy.

[0083] Embodiments include various types of neuropathic pain, including, for example, neuralgia (pain that typically radiates along the course of one or more specific nerves without demonstrable pathological changes in the nerve structure). Types of neuralgia include trigeminal neuralgia, postherpetic neuralgia, glossopharyngeal neuralgia, sciatica, atypical facial pain, etc. Various types of neuralgia generally cause short episodes of excruciating pain that are described in various expressions such as "stabbing," "sharp," "like lightning," "burning," "itching," etc. Neuralgia can occur after infectious diseases such as varicella-zoster virus infection, syphilis, Lyme disease, depression, diabetes, chronic renal failure, porphyria, drug use, and combinations thereof.

[0084] In some embodiments, the exemplary composition can be used for the treatment of denervation. Denervation is the loss of sensory input from a part of the body and can be caused by the interruption of either peripheral sensory fibers or nerves from the central nervous system. Denervation pain syndromes include, for example, pain associated with brain or spinal cord injury, pain after stroke, phantom limb pain, paralysis, brachial plexus avulsion injury, lumbar radiculopathy, etc., and combinations thereof.

[0085] In some embodiments, the exemplary composition can be used for the treatment of complex regional pain syndrome (CRPS). CRPS is a chronic pain syndrome caused by pain maintained by the sympathetic nervous system and may present in two forms. CRPS 1 is a chronic neuropathy that most frequently occurs in the arm or leg after a mild or severe injury. CRPS 1 is accompanied by severe pain, nail, bone, skin changes, and tactile hypersensitivity of the affected limb. CRPS 2 is due to a specific injury to the nerve.

[0086] In some embodiments, the exemplary composition can be used for the treatment of neuropathy. Neuropathy is a functional or pathological change in the nerve and is clinically characterized by abnormalities in sensory or motor neurons. Central neuropathy is a functional or pathological change in the central nervous system. Peripheral neuropathy is a functional or pathological change in one or more peripheral nerves that transmit information from the central nervous system (brain and spinal cord) to muscles and other organs, and from the skin, joints, and other organs to the brain. Risk factors for neuropathy include diabetes, excessive alcohol intake, genetic predisposition, exposure to certain chemicals and drugs, prolonged compression of the nerve, etc. Neuropathy can affect any one of the sensory, motor, or autonomic nerves, or a combination thereof. Also, its symptoms can vary depending on whether they affect the whole body or only one nerve (as if due to an injury). For example, the methods of the present disclosure can be directed to the treatment of diabetic neuropathic pain (DNP), chemotherapy-induced neuropathic pain (CINP), etc., or combinations thereof.

[0087] Peripheral neuropathy can occur, for example, as a result of genetic diseases, Charcot-Marie-Tooth disease, Friedreich's ataxia, systemic or metabolic diseases, diabetes (diabetic neuropathy), dietary deficiencies (especially vitamin B-12), excessive alcohol use (alcoholic neuropathy), uremia (renal failure), cancer, infectious or inflammatory diseases, HIV / AIDS, hepatitis, Colorado tick fever, diphtheria, Guillain-Barré syndrome, leprosy, Lyme disease, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, syphilis, systemic lupus erythematosus, amyloid, exposure to toxic compounds, heavy metals (lead, arsenic, mercury, etc.), ischemia (decrease in oxygen / decrease in blood flow), long-term exposure to low temperatures, etc., and combinations thereof.

[0088] Polyneuritis is a peripheral neuropathy in which movement and sensation in a certain area are lost, caused by damage or destruction of multiple peripheral nerves. Polyneuropathic pain occurs, for example, in post-polio syndrome, post-mastectomy syndrome, diabetic neuropathy, alcoholic neuropathy, amyloid, toxins, AIDS, hypothyroidism, uremia, vitamin deficiency, chemotherapy-induced pain, 2’,3’-dideoxyinosine (ddC) treatment, Guillain-Barré syndrome, or Fabry disease.

[0089] Mononeuritis is a peripheral neuropathy accompanied by loss of movement or sensation in a certain area, caused by damage or destruction of a single peripheral nerve or nerve group. Mononeuropathy often results from local damage due to injury or trauma, but isolated nerve damage can also occur due to systemic diseases (in the case of multiple mononeuritis). Possible causes include trauma, prolonged compression of the nerve, nerve compression due to swelling or damage to nearby body structures, and damage that causes destruction of part of the nerve's myelin sheath or nerve cells. Examples of mononeuropathic pain include sciatic nerve dysfunction, peroneal nerve dysfunction, radial nerve dysfunction, ulnar nerve dysfunction, cranial mononeuropathy VI, cranial mononeuropathy V, cranial mononeuropathy VII, cranial mononeuropathy III (compression type), cranial mononeuropathy III (diabetic type), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, Bell's palsy, thoracic outlet syndrome, sixth (abducent) nerve palsy, etc., and combinations thereof.

[0090] Generalized peripheral neuropathy is symmetrical and usually results from various systemic diseases or disease processes that affect the peripheral nervous system. Generalized peripheral neuropathy includes distal axonopathy. Distal axonopathy results from metabolic or toxic abnormalities of nerve cells and is caused by, for example, diabetes, renal insufficiency, deficiency syndromes such as malnutrition and alcoholism, or the effects of toxins and drugs, acute inflammatory demyelinating polyradiculoneuropathy (AIDP, also known as Guillain - Barré syndrome), chronic inflammatory demyelinating syndrome (CIDP), genetic metabolic disorders (e.g., leukodystrophy), or spinal cord disorders caused by acute impulse conduction failure resulting from an attack on myelin due to toxins, motor neuron diseases, sensory neuropathies (such as herpes zoster), toxins, neurotoxins, autonomic dysfunction, infections, and neuropathies caused by destruction of peripheral nervous system (PNS) neurons caused by local obstructive neuropathies such as carpal tunnel syndrome.

[0091] In some embodiments, the exemplary composition can be used to treat inflammatory pain. For example, the exemplary composition can be used to treat arthritic diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), gouty arthritis, scleroderma, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter's syndrome (reactive arthritis), adult Still's disease, arthritis due to viral infection, arthritis due to bacterial infection such as gonococcal arthritis and nongonococcal bacterial arthritis (septic arthritis), tertiary Lyme disease, tuberculous arthritis, arthritis due to fungal infection such as blastomycosis, and combinations thereof. In some embodiments, the exemplary composition can be used to treat autoimmune diseases such as Guillain-Barré syndrome, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type I diabetes, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, Morgellons disease, and combinations thereof. In some embodiments, the exemplary composition can be used to treat connective tissue disorders such as spondyloarthritis, dermatomyositis, fibromyalgia, and combinations thereof. In some embodiments, the exemplary composition can be used to treat injuries and inflammation caused by injuries such as crushing, puncturing, stretching, etc. of joints or tissues associated with joints. In some embodiments, the exemplary composition can be used to treat neuritis, i.e., an inflammatory process affecting a nerve or group of nerves with symptoms including pain, paresthesia, paralysis, or hypoesthesia (numbness). Examples of neuritis include brachial neuritis, posterior root neuropathy, optic neuropathy, vestibular neuritis, and combinations thereof.

[0092] In some embodiments, exemplary compositions can be used for the treatment of headaches, including, for example, muscular / muscular - origin headaches, tension - type headaches, episodic tension - type headaches, chronic tension - type headaches, vascular headaches, migraine without aura (common migraine), migraine with aura (classical migraine), menstrual migraine, migraine equivalent (acephalgic migraine), complex migraine, abdominal migraine, and mixed - tension - type headaches, cluster headaches, hypertensive headaches, traction and inflammatory headaches, hormonal headaches, rebound headaches, chronic rhinosinusitis headaches caused by, for example, bacterial, fungal, viral infections, allergies, or autoimmune diseases of the sinuses, organic headaches, episodic headaches, etc., and combinations thereof.

[0093] In some embodiments, exemplary compounds can be used for the treatment of pain caused by, for example, overuse of the hands, wrists, elbows, shoulders, neck, back, waist, knees, feet, legs, ankles, muscle disorders, myalgias caused by, for example, polymyositis, dermatomyositis, lupus, fibromyalgia, polymyalgia rheumatica, rhabdomyolysis, infections including, for example, muscle abscesses, trichinosis, influenza, Lyme disease, malaria, Rocky Mountain spotted fever, avian influenza, colds, community - acquired pneumonia, meningitis, monkeypox, severe acute respiratory syndrome, toxic shock syndrome, trichinosis, typhoid fever, upper respiratory tract infections, etc., drugs such as, for example, cocaine, statins (atorvastatin, simvastatin, lovastatin, etc.) that lower cholesterol, ACE inhibitors (enalapril, captopril, etc.) that lower blood pressure, and combinations thereof.

[0094] In some embodiments, the exemplary composition can be used for the treatment of visceral pain originating from the body's viscera or organs, including, for example, pain associated with irritable bowel syndrome, chronic functional abdominal pain (CFAP), functional constipation, functional dyspepsia, non - cardiac chest pain (NCCP), and chronic abdominal pain, gastritis, Crohn's disease, ulcerative colitis, microscopic colitis, diverticulitis, gastroenteritis, chronic gastroenteritis such as interstitial cystitis, intestinal ischemia, cholecystitis, appendicitis, gastroesophageal reflux disease, ulcers, nephrolithiasis, urinary tract infections, pancreatitis, hernias, etc., autoimmune visceral pain such as sarcoidosis and vasculitis, organic visceral pain such as pain caused by traumatic, inflammatory, or degenerative bowel lesions, pain caused by tumors affecting sensory nerves, treatment - induced visceral pain such as pain associated with chemotherapy and radiotherapy, and combinations thereof.

[0095] In some embodiments, the exemplary composition can be used to treat related pain conditions, such as pain associated with herniated discs, for example, compression of nerves in the thigh, knee, or foot, myocardial ischemia, etc., and combinations thereof, or other related pain.

[0096] In any of the embodiments described herein, the disclosed compositions and methods relate to treating trigeminal neuralgia and reducing and / or managing pain associated therewith. In some embodiments, a method of treating trigeminal neuralgia is provided, which includes administering a therapeutically effective amount of trimipramine to a patient in need thereof, thereby treating the patient's trigeminal neuralgia.

[0097] In some embodiments, a therapeutically effective amount of trimipramine is administered once daily. In some embodiments, a therapeutically effective amount of trimipramine is administered twice daily. A therapeutically effective amount of trimipramine can be administered by any method described herein, such as oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, topical administration, transdermal administration, or combinations thereof. In some embodiments, a therapeutically effective amount of trimipramine is administered orally. In some embodiments, a therapeutically effective amount of trimipramine is administered sublingually.

[0098] In some embodiments, the therapeutically effective amount of trimipramine is from about 0.5 mg to about 20 mg, such as, for example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, or any range or value included therein. In some embodiments, the therapeutically effective amount of trimipramine is from about 0.05 mg / kg to about 20 mg / kg, such as, for example, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 14.5 mg / kg, about 15 mg / kg, about 15.5 mg / kg, about 16 mg / kg, about 16.5 mg / kg, about 17 mg / kg, about 17.5 mg / kg, about 18 mg / kg, about 18.5 mg / kg, about 19 mg / kg, about 19.5 mg / kg, about 20 mg / kg, or any range or value included therein.

[0099] Trigeminal neuralgia is of type 1 or type 2, or a combination thereof. Type 1 trigeminal neuralgia may present as severe, brief, sudden, and / or burning facial pain that lasts from seconds to minutes. Type 2 trigeminal neuralgia is characterized by persistent stabbing, aching, or burning pain that is relatively less intense than type 1. Patients may experience both type 1 TN and type 2 TN simultaneously or periodically. Further classification of TN includes primary, which is caused by vascular compression of the nerve; secondary, which is often caused by neurological diseases such as multiple sclerosis or tumors or cysts near the trigeminal nerve; and idiopathic, where the cause is not identified.

[0100] In some embodiments, treating trigeminal neuralgia includes reducing the patient's pain. Pain reduction can be evaluated by any method known to those skilled in the art, and pain assessment scales include OPQRST, QISS TAPED, SOCRATES, Pain Risk Factors Assessment Form, Numerical Rating Scale, Visual Analogue Scale, Penn Facial Pain Scale (Penn-FPS), Penn Facial Pain Scale Revised (Penn-FPS-R), Brief Pain Inventory-Short Form (BPI-SF), Brief Pain Inventory-Interference Index (BPI-PII), Patient Global Impression of Change (PGIC), Facial Pain Scale-Revised (FPS-R), Burchiel Questionnaire, McGill Pain Questionnaire, and other patient-reported outcomes (PROs) and clinician-provided assessments well known to those skilled in the art. Additionally, other assessments such as EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L), Work Productivity and Activity Impairment (WPAI) can be employed to evaluate the impact of pain and the patient's ability to perform daily activities. Treating the patient's trigeminal neuralgia may include improving and / or preventing an increase in any one or more of the evaluations as described herein.

[0101] In some embodiments, reducing a patient's pain includes improving the patient's pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof. In some embodiments, reducing a patient's pain includes preventing an increase in the patient's pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

[0102] In some embodiments, treating trigeminal neuralgia includes improving the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, WPAI score, or a combination thereof. In some embodiments, treating trigeminal neuralgia includes preventing an increase in the patient's Penn-FPS-R score, PGIC score, Penn-FPS score, EQ-5D-5L score, or WPAI score, preventing a decrease in the PGIC score, or a combination thereof.

[0103] On the Penn-FPS-R scale, the patient is asked to circle the number that best represents how much pain affects items such as eating, touching the face (including moving a hair, hugging, kissing, feeling itchy), brushing teeth or using dental floss, smiling or laughing, talking, opening the mouth wide, chewing or masticating, self-care (including washing the face or hair, shaving, applying makeup), activities with temperature changes (including moving outdoors or between air-conditioned rooms), daily activities (including work, exercise, housework), mood (how the patient feels), and human relationships (relationships with friends, family, partners, etc.). Endpoints of TN treatment include a decrease in the overall severity and duration of facial pain, a decrease in the frequency and severity of attacks (such as sharp pain flares related to TN), and a decrease in the amount of existing standard treatment analgesics used for TN (including discontinuation of the use of existing standard treatment analgesics for TN).

[0104] A method for reducing pain in a patient with trigeminal neuralgia is provided, which includes administering a therapeutically effective amount of trimipramine to a patient in need thereof, whereby the pain of the patient is reduced. The method for reducing pain in a patient with trigeminal neuralgia can use any of the compositions, formulations, or dosing regimens of any of the embodiments described herein.

[0105] In some embodiments, reducing the pain of the patient includes an improvement in the pain of the patient as measured by the Penn-FPS score as compared to the pain of the patient as measured by the pre-treatment Penn-FPS score. In some embodiments, reducing the pain of the patient includes preventing an increase in the pain of the patient as measured by the Penn-FPS score as compared to the pain of the patient as measured by the pre-treatment Penn-FPS score.

[0106] In some embodiments, reducing the pain of the patient includes an improvement in the pain of the patient as measured by the Penn-FPS-R score as compared to the pain of the patient as measured by the pre-treatment Penn-FPS-R score. In some embodiments, reducing the pain of the patient includes preventing an increase in the pain of the patient as measured by the Penn-FPS-R score as compared to the pain of the patient as measured by the pre-treatment Penn-FPS-R score.

[0107] In some embodiments, reducing the pain of the patient includes an improvement in the patient's PGIC score at the end of the treatment period. In some embodiments, reducing the pain of the patient includes preventing a decrease in the PGIC score at the end of the treatment period.

[0108] The change in the Patient Global Impression of Change (PGIC), a self-reported overall impression of the patient, reflects the patient's belief regarding the treatment effect. The PGIC represents the patient's assessment of overall improvement on a 7-point scale. The patient evaluates their change as either "much improved", "moderately improved", "slightly improved", "no change", "slightly worse", "moderately worse", or "much worse". As used herein, a low PGIC score is considered to be a score of "slightly worse", "moderately worse", or "much worse" at the end of the treatment period. Accordingly, the method of the present invention for treating trigeminal neuralgia and reducing the pain associated therewith includes preventing a score of "slightly worse", "moderately worse", or "much worse" at the end of the treatment period. Improvement in the patient's PGIC score at the end of the treatment period includes a score of "much improved", "moderately improved", or "slightly improved" at the end of the treatment period.

[0109] There is provided a method of treating a patient's pain, comprising administering to the patient a therapeutically effective amount of trimipramine, thereby treating the patient's pain. In some embodiments, the therapeutically effective amount of trimipramine is from about 0.5 mg to about 20 mg, such as, for example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, or any range or value included therein.

[0110] In some embodiments, pain can be caused by any acute, chronic, neuropathic, or other pain source as disclosed herein. For example, in some embodiments, pain is trigeminal neuralgia, postherpetic neuralgia, postherpetic neuralgia, neuritis, brachial neuritis, retrobulbar neuropathy, optic neuropathy, vestibular neuritis, glossopharyngeal neuralgia, sciatica, atypical facial pain, a deafferentation pain syndrome, complex regional pain syndrome (CRPS), central neuropathy, peripheral neuropathy, diabetic neuropathic pain (DNP), chemotherapy-induced neuropathic pain (CINP), polyneuritis, mononeuritis, generalized peripheral neuropathy, or a combination thereof.

[0111] In some embodiments, pain can be caused by an arthritis disorder such as rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), gouty arthritis, scleroderma, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter's syndrome (reactive arthritis), adult Still's disease, arthritis due to viral infection, arthritis due to bacterial infection such as gonococcal arthritis and nongonococcal bacterial arthritis (septic arthritis), tertiary Lyme disease, tuberculous arthritis, arthritis due to fungal infection such as blastomycosis, or a combination thereof.

[0112] In some embodiments, pain can be caused by an autoimmune disease such as Guillain-Barré syndrome, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type I diabetes, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, Morgellons disease, or a combination thereof.

[0113] In some embodiments, pain can be caused by an injury and inflammation caused by an injury such as a connective tissue disorder such as spondyloarthritis, dermatomyositis, fibromyalgia, for example, compression, puncture, stretching of a joint or tissue associated with a joint, or a combination thereof.

[0114] In some embodiments, the pain may be caused by headaches, including myogenic / muscular headaches, tension-type headaches, episodic tension-type headaches, chronic tension-type headaches, vascular headaches, migraine without aura (common migraine), migraine with aura (classical migraine), menstrual migraine, migraine equivalent (acephalgic migraine), complex migraine, abdominal migraine, and mixed tension-type headache, cluster headache, hypertensive headache, traction and inflammatory headache, hormonal headache, rebound headache, chronic rhinosinusitis headache, such as abdominal migraine, and mixed tension-type headache, cluster headache, hypertensive headache, traction and inflammatory headache, hormonal headache, rebound headache, chronic rhinosinusitis headache caused by, for example, bacterial infection, fungal infection, viral infection, allergy, or autoimmune disease of the sinuses, or a combination thereof.

[0115] In some embodiments, the pain may be caused by somatic pain conditions such as excessive muscle tension, sprains, muscle contusions, repetitive motion disorders, etc., resulting from, for example, excessive use of the hands, wrists, elbows, shoulders, neck, back, waist, knees, feet, legs, or ankles, or a combination thereof.

[0116] In some embodiments, the pain may be caused by muscle disorders resulting from, for example, polymyositis, dermatomyositis, lupus, fibromyalgia, polymyalgia rheumatica, rhabdomyolysis, muscle pain, such as infections including muscle abscesses, trichinosis, COVID-19, Lyme disease, malaria, Rocky Mountain spotted fever, avian influenza, colds, community-acquired pneumonia, meningitis, monkeypox, severe acute respiratory syndrome, toxic shock syndrome, trichinosis, typhoid fever, upper respiratory tract infections, or a combination thereof.

[0117] In some embodiments, the pain can be caused by visceral pain originating from the body's internal organs or organs, including, for example, pain associated with irritable bowel syndrome, chronic functional abdominal pain (CFAP), functional constipation, functional dyspepsia, non-cardiac chest pain (NCCP), and functional visceral pain including chronic abdominal pain, gastritis, Crohn's disease, ulcerative colitis, microscopic colitis, diverticulitis, gastroenteritis, interstitial cystitis, intestinal ischemia, cholecystitis, appendicitis, gastroesophageal reflux, ulcers, nephrolithiasis, urinary tract infections, pancreatitis, hernias, etc., and combinations thereof, including chronic gastroenteritis.

[0118] In some embodiments, the pain can be caused by organic visceral pain, such as autoimmune pain such as sarcoidosis and vasculitis, pain due to traumatic, inflammatory, or degenerative lesions of the intestine, or pain caused by tumors that affect sensory innervation, treatment-induced visceral pain such as pain associated with chemotherapy or radiation therapy, and combinations thereof.

[0119] In some embodiments, the pain can be caused by related pain conditions, such as, for example, pain associated with a herniated disc, compression of nerves in the thigh, knee, or foot, myocardial ischemia, etc., and combinations thereof.

[0120] In any of these embodiments, reducing the patient's pain can include reducing and / or preventing an increase in the patient's pain as evaluated by a patient-reported outcome (PRO) or an evaluation provided by a clinician well-known to those skilled in the art. The evaluations used to assess pain are not particularly limited and can be any evaluations known to those skilled in the art, including, but not limited to, any of the evaluations disclosed herein or evaluations related to the pain states and causes disclosed herein.

[0121] As described herein, the methods of the present disclosure can replace existing standard treatments for trigeminal neuralgia, or any acute pain, chronic pain, neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and / or related pain as disclosed herein, or can be used in addition to such treatments to provide further alleviation of symptoms as described herein. Without wishing to be bound by theory, examples of existing standard treatments are provided herein.

[0122] The causes of pain in any condition as described herein can be treated with various drugs. For example, drugs for the conditions and related pain as described herein include anticonvulsants such as gabapentin and pregabalin, tricyclic antidepressants such as amitriptyline and nortriptyline, serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine and desvenlafaxine, opioid-like drugs such as tramadol and tapentadol ER, opioids such as oxycodone, hydrocodone, tramadol, codeine and morphine, topical drugs such as lidocaine patch, capsaicin cream and patch, isosorbide dinitrate spray, baclofen, amitriptyline, composite gel containing ketamine, selective serotonin reuptake inhibitors (SSRI) such as citalopram, paroxetine, escitalopram, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, ibuprofen, naproxen sodium, N-methyl-D-aspartic acid (NMDA) receptor agonists such as ketamine, dextromethorphan, memantine, amantadine, opioids that are also NMDA receptor antagonists such as methadone, dextropropoxyphene, ketobemidone, acetaminophen, nerve stimulation including local or spinal nerve stimulation, psychological support such as cognitive behavioral therapy, steroid injection containing betamethasone, and local anesthetics such as lidocaine and bupivacaine hydrochloride may be included. Other drugs for the conditions disclosed herein can also be used as is well known to those skilled in the art. The methods and compositions of the present invention can be used in place of, or in combination with, other drugs disclosed herein.

[0123] Additional examples of other drugs and exemplary dosing regimens that can be used to treat the conditions disclosed herein are also described. Without wishing to be bound by theory, the drugs disclosed herein can be used to treat various pain conditions (such as those disclosed herein), and can be replaced by, or used in combination with, the compositions and methods of the present disclosure to effectively treat various causes of pain.

[0124] Carbamazepine can be administered at an initial dose of about 200 mg, for example, 2 to 4 times a day. The dosage range is from about 200 mg to about 1200 mg, and it is gradually increased by about 200 mg every about 3 days. The gradual decrease is by 200 mg every 7 days. Possible side effects include dizziness, drowsiness, fatigue, ataxia, diplopia, nausea, cognitive decline, hyponatremia, leukopenia, thrombocytopenia, skin reactions, abnormal liver function test values, etc. Carbamazepine may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia. Carbamazepine is approved in the EU for the indications of trigeminal neuralgia and painful diabetic peripheral neuropathy, and in the US for the indication of trigeminal neuralgia. Carbamazepine stabilizes the membranes of voltage-dependent sodium channels in sensitized nociceptive neurons in the PNS and CNS and suppresses the spontaneous activity of these neurons.

[0125] Oxcarbazepine can be administered at an initial dose of about 300 mg, for example, 4 times a day. The dosage range is from about 300 mg to about 1800 mg, and it is gradually increased by 300 mg every 3 days. The gradual decrease is by 300 mg every 7 days. Possible side effects include dizziness, drowsiness, fatigue, nausea, ataxia, hyponatremia, skin reactions, etc. Oxcarbazepine may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia.

[0126] The initial dose of lamotrigine is about 25 mg, and it is administered, for example, 2 times a day. The dosage range is from about 25 mg to about 400 mg, and the gradual increase is by 25 mg for 2 weeks, 50 mg for 1 week, and then by about 50 mg every week thereafter. The gradual decrease is by 50 mg every 7 days. Possible side effects include dizziness, drowsiness, fatigue, headache, gastrointestinal symptoms, hypersensitivity, sleep disorders, tremors, cognitive decline, rash, etc. Lamotrigine may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia.

[0127] Gabapentin can be administered, for example, at an initial dose of about 300 mg three times a day. The dosage range is from about 300 mg to about 3600 mg, with an increase of about 300 mg every three days. Tapering is done by 300 mg every seven days. Possible side effects include dizziness, confusion, fatigue, ataxia, somnolence, suicidal behavior, frequency of pre-withdrawal seizures, multi-organ hypersensitivity, peripheral edema, ataxia or gait disturbance, diarrhea, increased risk of infection, gastrointestinal symptoms, and weight gain. Co-administration with opioids should be done with caution. Gabapentin is an anti-epileptic / anti-convulsant drug and is approved by the FDA as a treatment for PHN in adults and is also used in the treatment of diseases including but not limited to trigeminal neuralgia and DNP. Gabapentin is approved in the EU as a treatment for peripheral neuropathic pain. It is structurally related to the GABA neurotransmitter and suppresses the release of excitatory neurotransmitters by binding to the α2-δ site of voltage-dependent calcium channels.

[0128] Pregabalin is administered at an initial dose of about 150 mg twice a day. The dosage range is from about 150 mg to about 600 mg, with an increase of about 150 mg every three days. Tapering is done by 100 mg every seven days. Possible side effects include dizziness, confusion, ataxia, increased risk of infection, gastrointestinal symptoms, and weight gain. Pregabalin is approved by the FDA as a treatment for postherpetic neuralgia (PHN) and is also used in the treatment of diseases including but not limited to trigeminal neuralgia. Pregabalin is also approved in the United States as a treatment for painful diabetic peripheral neuropathy and neuropathic pain associated with spinal cord injury, and in the EU as a treatment for peripheral neuropathic pain and central neuropathic pain. It binds to calcium channels and affects the release of neurotransmitters, showing a similar effect to gabapentin but being more potent and used at lower doses. Side effects include dizziness, fluid retention, visual disturbances, somnolence, ataxia, euphoria, dizziness, etc. In Japanese studies, the analgesic effect of pregabalin in PHN has been reported to be six times that of gabapentin. Dose increases should be done gradually and carefully so as not to cause side effects despite pain reduction.

[0129] Baclofen can be administered at an initial dose of about 15 mg, for example, three times a day. The dosage range is from about 15 mg to about 90 mg, and it is gradually increased by about 15 mg every three days. The increase is done every seven days by 15 mg. Possible side effects include confusion, dizziness, drowsiness, gastrointestinal symptoms, a sense of well-being, hallucinations, etc. Baclofen may be used in the treatment of diseases including but not limited to trigeminal neuralgia. Baclofen may act through a complex mechanism of action such as GABAergic modulation, blockade of sodium channels, and blockade of glutamatergic (NMDA) receptors.

[0130] Botulinum toxin type A can be administered at an initial dose of about 25 - 195 units, for example, every 12 weeks. The dosage range can be from about 25 to about 195 units. Potential side effects include transient facial asymmetry, transient rash at the injection site, transient salivation, and difficulty chewing. Botulinum toxin type A is used in the treatment of trigeminal neuralgia and others, but is not limited to this. Botulinum toxin type A (BTX-A) is a toxin produced by Clostridium botulinum and is used in the treatment of various diseases such as dystonia, spasm, cerebral palsy, strabismus, and chronic pain of various origins including postherpetic neuralgia (PHN). Its mechanism of action has not been fully elucidated. It mainly acts by suppressing the release of pain mediators from nerve endings and dorsal root ganglia, suppressing inflammation around nerve endings, inactivating sodium channels, and demonstrating axonal transport. BTX-A was effective in reducing pain in 18 cases (31%) and showed significant results in 27 cases (46.6%) of PHN symptoms in a study conducted on 58 patients. The side effects of BTX-A treatment were mild, such as pain at the injection site, but disappeared within one week without treatment.

[0131] Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) that increases the levels of these neurotransmitters in the brain and spinal cord and helps regulate pain transmission. Duloxetine starts at 30 mg per day and is gradually increased up to a maximum dose of 60 mg / day. Representative doses are about 60 mg to about 120 mg per day. Side effects include nausea, dry mouth, dizziness, fatigue, constipation, dry mouth, decreased appetite, drowsiness, sweating, gastrointestinal discomfort, insomnia, etc. Duloxetine is used in the treatment of diseases including, but not limited to, PHN, DNP, and CIPN. Duloxetine potently inhibits the reuptake of serotonin and norepinephrine in nerve cells and does not inhibit dopamine reuptake much. Duloxetine does not show significant affinity for dopaminergic receptors, adrenergic receptors, cholinergic receptors, histaminergic receptors, opioid receptors, glutamate receptors, and GABA receptors. Also, in relation to the action of duloxetine in the spinal cord, it has a pain-regulating effect. Increasing the concentrations of serotonin and norepinephrine in the posterior horn of the spinal cord increases the descending inhibition of pain through the activation of 5-HT 1A 、5-HT 1B 、5-HT 1D 、5-HT 2 、5-HT 3 、α 1 -adrenergic receptors, and α 2 -adrenergic receptors.

[0132] Venlafaxine can be used in the treatment of diseases including, but not limited to, DNP and CIPN. Representative doses are about 75 mg to about 225 mg per day. Possible side effects include drowsiness, dizziness, and mild gastrointestinal disorders. The exact mechanism of action of venlafaxine in the treatment of various mental disorders is not fully understood, but it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibit the reuptake of serotonin and norepinephrine at the presynaptic terminal.

[0133] Lidocaine is a local anesthetic that is used topically to provide surface analgesia for chronic pain, including but not limited to postherpetic neuralgia (PHN) and diabetic neuropathic pain (DNP). It is prescribed as a patch containing 5% lidocaine and applied once daily for 12 hours to intact skin. Up to three 5% lidocaine patches can be applied once daily for 12 hours to intact skin. Lidocaine acts as a mechanical barrier at the site of allodynia, preventing irritation. Lidocaine is released continuously after application, and only 3% reaches the systemic circulation, which is far below toxic concentrations. Lidocaine is extensively metabolized in the liver and excreted by the kidneys. The side effects observed after lidocaine patch treatment are local skin reactions such as pruritus, erythema, rash, burning sensation, and edema. Lidocaine has a high tolerance regardless of age, with minimal side effects and a higher tolerance than systemic treatment with pregabalin. Lidocaine is approved in the EU and the US for PHN. Lidocaine acts by partially inhibiting voltage-dependent calcium channels (blocking abnormally functioning (sensitized) Nav1.7 and Nav1.8 sodium channels in cutaneous nociceptors) and reducing the discharge of ectopic activity in damaged afferent nociceptors, and may have anti-inflammatory properties through modulation of T-cell activity and suppression of nitric oxide production.

[0134] Capsaicin is a selective agonist of the TRPV1 channel present in cutaneous nociceptors. When exposed to capsaicin, TRPV1 is activated, causing an influx of calcium and inhibiting electron transport chain, resulting in the loss of cell integrity, long-term dysfunction of the nerve fibers of nociceptors, and pain relief. High-concentration 8% capsaicin transdermal patches are used for the treatment of neuropathic pain and can be used for up to 3 months with a single application. The patch contains 8% capsaicin (640 mcg / cm2), and a total of 179 mg of capsaicin is contained in one patch. Side effects such as burning sensation, erythema, pain, dryness, edema, and pruritus can be treated with topical analgesics such as lidocaine. Capsaicin cream can also be used, for example, at a concentration of 0.075% four times a day. Skin site side reactions may occur. Capsaicin can be used for the treatment of symptoms including but not limited to DNP. In the EU, capsaicin is approved as a topical treatment for peripheral neuropathic pain, either as monotherapy or in combination with other pharmaceuticals for pain treatment. In the United States, capsaicin is approved as a treatment for postherpetic neuralgia (PHN) and painful diabetic neuropathy (DNP). Capsaicin cream formulations may selectively activate TRPM8, which is also activated after cold sensation and sensory nerve injury.

[0135] Clonidine gel can be used for the treatment of symptoms including but not limited to DNP. A single dose of 0.65 g of the gel can be applied three times a day. Skin site reactions may occur. Topical clonidine is a presynaptic α-2 adrenergic receptor agonist with anti-nociceptive activity and has been associated with pain relief in DNP in a small number of studies of low to moderate quality.

[0136] Alpha-lipoic acid gel can be used for the treatment of conditions including but not limited to DNP. Typical dosages are approximately 600 - 1800 mg orally or 600 mg / day by intravenous injection for 3 weeks excluding weekends. Alpha-lipoic acid is a natural thiol with strong antioxidant properties and is used as a dietary supplement.

[0137] Opioids such as oxycodone, hydrocodone, and morphine have excellent analgesic effects, but their use in PHN is controversial due to concerns about toxicity and dependence. Opioids regulate pain by interacting with various opioid receptors of the mu, kappa, and delta classes present in both the central and peripheral nervous systems during the inflammatory response. These receptors bind to inhibitory G proteins and, when activated, cause the closure of voltage-dependent calcium channels, lead to potassium efflux and hyperpolarization, and reduce the production of cyclic adenosine monophosphate. Through these mechanisms, the excitability of nerve cells decreases, the transmission of nociceptive impulses decreases, and the response to pain changes. Some clinical studies have demonstrated the effectiveness of opioids in the management of neuropathic pain, including PHN. Side effects of opioids include nausea, itching, drowsiness, constipation, and sedation, and they should be used with caution in patients with a history of drug abuse. Opioids are usually used as second- or third-line drugs and are used at low doses as adjuvant therapy to provide immediate analgesia while other first-line drugs are titrated up to therapeutic doses. The maximum dose of oxycodone is about 120 mg per day taken in two divided doses. Chronic use can cause tolerance, frequent dose escalation, and hyperalgesia. Oxycodone and its active metabolites selectively bind not only to central and peripheral mu opioid receptors but also to kappa and delta opioid receptors and induce G protein-coupled receptor signaling pathways. Activation of the mu opioid receptor inhibits N-type voltage-operated calcium channels and suppresses the response to pain. Some opioids also act on the descending inhibitory system of the nervous system (pain suppression) through inhibition of noradrenergic and serotonergic reuptake. Opioids are approved in the United States and the EU for moderate to severe pain.

[0138] Cannabinoids can be used for the off-label treatment of pain as described herein. Cannabinoids are agonists of CB1 receptors present in the central nervous system, spinal cord, and peripheral nerves and may act through the inhibition of neuronal excitability. Some cannabinoid compounds have psychoactive effects, and synthetic cannabinoid receptor agonists may be more psychotomimetic than natural cannabis and should be considered carefully.

[0139] Tapentadol can be used for the treatment of diseases including, but not limited to, those containing DNP. Representative dosages are from about 100 mg to about 500 mg per day. Possible side effects include dizziness, drowsiness, headache, fatigue, gastrointestinal disorders, etc. Tapentadol is a centrally acting synthetic analgesic, and its binding affinity to the mu-opioid receptor is 18 times that of morphine. In addition, by inhibiting the reuptake of norepinephrine, it increases the norepinephrine concentration in the rat brain.

[0140] Tramadol is a weak opioid that acts on the mu receptor and inhibits the reuptake of serotonin and norepinephrine. The maximum daily dose is 400 mg, and it is gradually increased by 50 - 100 mg each time. Tramadol is considered a mild opioid, and although its analgesic effect in PHN has been proven to be inferior to other opioids, it has a high tolerance and is a safer alternative. It may be a better option for patients with a history of drug abuse or heart problems. Side effects include nausea, drowsiness, constipation, dizziness, headache, dizziness, and an increased risk of seizure attacks at high doses. Caution is recommended when using tramadol in patients with a history of seizures or those taking drugs that lower the seizure threshold.

[0141] Other drugs may also be used as standard treatments for TN or other conditions that cause pain, as described herein. For example, pimozide is a dopamine receptor antagonist and is mainly used for the treatment of Tourette syndrome. Efficacy was recognized in a randomized double-blind crossover trial involving 40 out of 48 patients with refractory TN. In this trial, pimozide achieved pain management in all 48 patients.

[0142] Topiramate is also a drug that may be used for the treatment of TN. The exact mechanism of action of topiramate is unknown. However, the pain-relieving effect of topiramate may be related to its blocking effect on voltage-dependent sodium channels and its enhancing effect on GABA activity by binding to the non-benzodiazepine site of the GABAA receptor. Topiramate (100 - 400 mg / day) was effective in 75% of patients in a certain study involving 8 classical TN patients.

[0143] Levetiracetam has been tried in TN. Its exact mechanism of action is unknown, but it is thought to target high-voltage N-type calcium channels and synaptic vesicle protein 2A (SV2A), thereby inhibiting impulse conduction via synapses. The evidence in TN is scarce. Recently, the efficacy and tolerability of levetiracetam in TN patients were examined in two open-label trials. In one study involving 10 patients, an improvement of 50 - 90% was reported. In another study involving 23 patients, it was reported that the number of seizures per day decreased by 62% in patients who received levetiracetam as an adjunctive therapy.

[0144] Other agents that show limited effects in the treatment of TN are also disclosed. For example, phenytoin and intravenous administration of phenytoin are anticonvulsants used for the prevention and control of various types of seizures.

[0145] Phosphenytoin is a water-soluble phenytoin prodrug that is used only in hospitals for the treatment of epileptic seizures. It acts by slowing down the impulses in the brain that cause seizures. Its main mechanism is to block frequency-dependent, use-dependent, and voltage-dependent neuronal sodium channels and limit the repetitive firing of action potentials. Phosphenytoin may be used in the treatment of diseases including but not limited to trigeminal neuralgia.

[0146] Clonazepam is an intermediate-acting long-duration benzodiazepine commonly used in the treatment of panic disorder, severe anxiety, and seizures. Clonazepam may be used in the treatment of diseases including but not limited to trigeminal neuralgia.

[0147] Valproic acid is an antiepileptic drug used to control complex partial seizures and both simple and complex absence seizures. Valproic acid may be used in the treatment of diseases including but not limited to trigeminal neuralgia.

[0148] Misoprostol is a prostaglandin E1 analogue used to reduce the risk of NSAID-induced gastric ulcers and to terminate pregnancy. Misoprostol may be used in the treatment of symptoms including but not limited to trigeminal neuralgia.

[0149] Tocainide is an orally active class 1b antiarrhythmic drug that interferes with cardiac sodium channels and is typically used in the treatment of ventricular arrhythmias. Tocainide may be used in the treatment of diseases including but not limited to trigeminal neuralgia.

[0150] Topical capsaicin cream is a topical analgesic used to relieve neuropathic pain associated with postherpetic neuralgia and other muscle and joint pain symptoms.

[0151] Lidocaine nasal administration is a local anesthetic used in various superficial and invasive treatments. Lidocaine ultimately exerts a paralytic effect by blocking sodium channels, and the neurons in the local tissue where the drug is applied are transiently unable to transmit signals related to sensation to the brain. Lidocaine nasal administration may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia.

[0152] Tizanidine is an α2 - adrenergic agonist used for the short - term treatment of muscle spasm. Tizanidine may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia.

[0153] Sumatriptan is a serotonin receptor agonist used for the treatment of migraine and cluster headache. Sumatriptan may be used in the treatment of diseases including, but not limited to, trigeminal neuralgia.

[0154] Amitriptyline is a tricyclic antidepressant (TCA) with analgesic effects and is widely used in the treatment of depression and neuropathic pain. Amitriptyline, nortriptyline, and desipramine are often used off - label in the treatment of PHN and CIPN. These bring about analgesia by inhibiting the reuptake of serotonin and norepinephrine at presynaptic nerve terminals and reduce perception between the brainstem and spinal cord. TCA is started at a low dose of 10 - 25 mg at bedtime and gradually increased by 10 - 25 mg every 3 - 7 days according to the patient's tolerance, with a maximum dose of 150 mg per day. TCA is accompanied by side effects such as sedation, dry mouth, blurred vision, constipation, urinary retention, QT interval prolongation, sexual dysfunction, dry mouth, fluid retention, increased appetite, weight gain, constipation, dizziness, and postural hypotension. Caution is required when prescribing TCA to patients at risk of suicide or overdose. Amitriptyline is the most widely prescribed but has strong anticholinergic effects. Nortriptyline and desipramine have higher tolerance and are more effective than amitriptyline. The mechanism of action of TCA has not been fully elucidated. Amitriptyline is suggested to inhibit the membrane pump mechanism responsible for the reuptake of neurotransmitter amines such as norepinephrine and serotonin, increasing their concentration in the synaptic cleft of the brain.

[0155] Other pain states that can be treated by the compositions and methods described herein include complex regional pain syndrome and phantom limb pain. Complex regional pain syndrome can be treated by non-steroidal anti-inflammatory drugs, anti-convulsants, tricyclic antidepressants, opioids, nerve stimulation, psychological support, and combinations thereof. Such treatments may be replaced by or used in combination with the compositions and methods of the present disclosure. Phantom limb pain can be treated by tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, opioids and opioid-like drugs, anti-convulsants, NMDA receptor agonists, local anesthetics, and combinations thereof. Such treatments may be replaced by or used in combination with the compositions and methods of the present disclosure.

[0156] Various formulations of the active agent for the treatment of trigeminal neuralgia in the methods of the present disclosure are contemplated. For example, oral, sublingual, topical, and injectable formulations can be employed in the methods of the present disclosure.

[0157] Liquid formulations are also contemplated. A typical liquid formulation contains 6 mg / ml of the active substance, but other dosages reflecting the dosage of the tablets, such as 2.5 mg / ml or 5 mg / ml, can also be used. If necessary, the exact dosage can be set in a Phase III trial for a specific indication. Other concentrations of the active substance can also be used to facilitate administration or reduce the amount of inactive substances. Other inactive components include sucrose, apricot flavor (No.1NS), ethanol 96%, anhydrous citric acid, sodium citrate, sodium benzoate, anhydrous sodium sulfite (E221), sodium metabisulfite (E223), ascorbic acid, and purified water, which are commonly used in syrups. Substitutions and modifications of the formulation, such as reducing or removing sucrose, can also be considered. For example, the liquid formulation can contain 1 mg / mL of trimipramine tartrate in methanol.

[0158] Nasal spray formulations are also conceivable. When the CNS / brain region is the target of treatment, nasal administration is a very useful route of administration. Therapeutic agents for nasal decongestion, rhinitis, and migraine have been successfully administered via the intranasal route. First-generation antihistamines such as trimethoprim pass through the blood-brain barrier (BBB) and are not substrates for the P-glycoprotein efflux pump present in the brain endothelial cells of the blood-brain barrier, unlike second-generation antihistamines.

[0159] Other first-generation antihistamines include ethylenediamine antihistamines (such as mepyramine, chloropyramine, antazoline, and tripelennamine), which are clinically effective H 1 The first group developed as antihistamines.

[0160] Mepyramine or pyrilamine targets the H1 receptor. It is a first-generation antihistamine. However, because it rapidly penetrates the brain, it often causes drowsiness as a side effect. It is included in over-the-counter formulations for colds and menstrual symptoms, but is considered an unapproved prescription drug for use in coughs, colds, and allergic symptoms.

[0161] Chloropyramine is a first-generation antihistamine and is used in Eastern European countries for the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, and other allergic reactions. It is also indicated for Quincke's edema, allergic reactions due to insect stings, food and drug allergies, and anaphylactic shock.

[0162] Antazoline is a first-generation antihistamine with an anticholinergic effect. It is used to relieve nasal congestion. It is also prescribed as an eye drop together with naphazoline to relieve allergic conjunctivitis.

[0163] Tripelennamine is a histamine H1 antagonist with a low sedative effect but a high gastrointestinal irritation. It is used for the treatment of asthma, hay fever, urticaria, and rhinitis, and is also used for veterinary purposes. Tripelennamine is administered via various routes including topical administration.

[0164] Other first-generation antihistamines include ethanolamine derivatives (such as diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromodiphenhydramine, clemastine, and dimenhydrinate).

[0165] Diphenhydramine was a representative agent of this group. In this group, significant side effects due to anticholinergic effects, as well as sedative effects, are recognized, but the incidence of side effects in the digestive system is relatively low. Diphenhydramine (perhaps best known under the trade name Benadryl) is a first-generation H1 receptor antihistamine and is widely used in the treatment of seasonal allergies, insect bites or stings, and rashes. However, it also has antiemetic, antitussive, hypnotic, and antiparkinsonian effects. Since histamine receptors are present in both the peripheral and central nervous systems, diphenhydramine has been shown to cause sedation by competitively antagonizing histamine H1 receptors within the central nervous system. The use of diphenhydramine in allergy treatment may be less preferred due to its sedative effects, but diphenhydramine is repurposed in many over-the-counter sleep aids, cough suppressants, and cold medications sold for "nighttime" use. Diphenhydramine is also used in combination with 8-chlorotheophylline as the antiemetic dimenhydrinate, which is mainly utilized for its antagonistic effect on H1 histamine receptors in the vestibular system. Diphenhydramine has also been shown to be involved in many neurotransmitter systems that affect behavior, such as dopamine, norepinephrine, serotonin, acetylcholine, and opioids. As a result, the anxiolytic and antidepressant effects of diphenhydramine are being studied.

[0166] Carbinoxamine is a first-generation antihistamine drug that competes with free histamine for binding at the HA receptor site. It antagonizes the action of histamine on the HA receptor, leading to the alleviation of negative symptoms caused by histamine-HA receptor binding. Since many unapproved carbinoxamine-containing formulations contain inappropriate labeling, promote unapproved uses (such as nasal congestion, cough, management of colds, use in children under 2 years old, etc.), and may cause serious health risks, to prevent and reduce misuse, the product labels of carbinoxamine as over-the-counter cough and cold medicines have been changed to state "do not use" for children under 4 years old.

[0167] Doxylamine is a histamine H1 antagonist with significant sedative effects. It is used as an anti-allergy, antitussive, antiemetic, and hypnotic drug. Doxylamine is also administered in veterinary medicine and was previously used for Parkinson's disease.

[0168] Orphenadrine is a muscarinic antagonist used for the treatment of drug-induced parkinsonism and the relief of pain due to muscle spasms. Orphenadrine antagonizes the H1 receptor, N-methyl-D-aspartic acid (NMDA) receptor, and non-selectively antagonizes the muscarinic acetylcholine receptor (therefore, it is used as an anticholinergic drug). It also blocks the human ether-à-go-go related gene (HERG) potassium channel together with Nav1.7, Nav1.8, and Nav1.9 sodium channels and is also an inhibitor of norepinephrine and dopamine reuptake.

[0169] Bromazine (also called bromodiphenhydramine) is an ethanolamine-based antihistamine drug with antibacterial effects. Bromodiphenhydramine is used for the treatment of skin allergies. Ethanolamine-based antihistamine drugs produce significant sedative effects in most patients. Bromodiphenhydramine competes with free histamine and binds to the HA receptor site. This antagonizes the action of histamine on the HA receptor, leading to the alleviation of negative symptoms caused by histamine-HA receptor binding.

[0170] Chlorpheniramine is a first-generation histamine H1 antagonist of ethanolamine derivatives and is used for allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis, and skin pruritus. It causes drowsiness. Chlorpheniramine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This inhibits the action of endogenous histamine and temporarily alleviates the negative symptoms caused by histamine.

[0171] Dimenhydrinate is a drug used for the prevention and treatment of nausea, vomiting, dizziness, and motion sickness. Initial research on dimenhydrinate focused on its role as an antihistamine for urticaria, and the treatment of motion sickness was an accidental discovery. Dimenhydrinate is a theoclate salt that dissociates into diphenhydramine and 8-chlorotheophylline. The exact mechanism of action is unknown, but diphenhydramine is theorized to reduce balance disorders by its antimuscarinic or histamine H1 antagonist action. 8-Chlorotheophylline is thought to cause excitation by blocking adenosine receptors and reduce the drowsiness caused by diphenhydramine.

[0172] Other first-generation antihistamines include alkylamines (such as pheniramine, chlorpheniramine, dexchlorpheniramine, dexbrompheniramine, brompheniramine, triprolidine, dimethindene, acrivastine, etc.). Isomers are an important factor in the activity of drugs in this group. For example, E-triprolidine is 1000 times more active than Z-triprolidine. This difference is related to the position and compatibility of the molecule at the histamine H1 receptor binding site. Alkylamines are thought to have relatively few sedative effects and gastrointestinal side effects, but a relatively high incidence of paradoxical stimulation of the central nervous system (CNS).

[0173] Pheniramine is a first-generation antihistamine of the alkylamine type, similar to brompheniramine and chlorpheniramine. In combination with other agents, it is used in over-the-counter allergy, cold, and influenza medications. The use of pheniramine as an anti-allergy medication has been supplanted by second-generation antihistamines such as cetirizine and loratadine. Pheniramine competes with histamine for the histamine H1 receptor and acts as an inverse agonist after binding. When the activity of the H1 receptor is reduced, not only is itching reduced, but vasodilation and capillary leakage are suppressed, and erythema and edema are reduced. This is seen in the suppression of the wheal (swelling) and flare (vasodilation) reactions induced by histamine. The sedative effect of first-generation antihistamines such as pheniramine is due to inverse agonism of the H1 receptor in the central nervous system. The binding of pheniramine to the H4 receptor and subsequent inverse agonism may also contribute to the reduction of itching by antagonizing inflammation.

[0174] Chlorpheniramine is a histamine H1 antagonist used for allergic reactions, hay fever, rhinitis, urticaria, and asthma. It is also used in veterinary medicine. It is one of the most widely used classical antihistamines and generally has less drowsiness and sedative effects than promethazine. Chlorpheniramine binds to the histamine H1 receptor. This inhibits the action of endogenous histamine and temporarily alleviates the negative symptoms brought about by histamine.

[0175] Dexchlorpheniramine is an antihistamine of the chlorpheniramine enantiomer and is indicated for the treatment of sunburn, insect bites, and skin allergic reactions. Dexchlorpheniramine is the potent S-enantiomer of chlorpheniramine. The salt form of the active ingredient, dexchlorpheniramine maleate, is available as a prescription drug indicated for adjuvant therapy of allergic and anaphylactic reactions. It is an antihistamine and has anticholinergic (drying) and sedative effects. It inhibits histamine signaling by competing with histamine at the cell receptor site on effector cells.

[0176] Dexbrompheniramine maleate is an antihistamine used in the treatment of allergic diseases such as hay fever and urticaria. Dexbrompheniramine competitively binds to the histamine H1 receptor. Dexbrompheniramine competes with histamine to acquire the normal H 1 receptor sites in effector cells of the gastrointestinal tract, blood vessels, and airways. This inhibits the action of endogenous histamine and temporarily alleviates the negative symptoms caused by histamine.

[0177] Brompheniramine is a histamine H1 antagonist and is used in the treatment of cough, upper respiratory tract inflammation symptoms, and nasal congestion associated with allergies and colds. Brompheniramine is an antagonist of the H1 histamine receptor and has a moderate antimuscarinic effect similar to common antihistamines such as diphenhydramine. Brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate due to its anticholinergic effect.

[0178] Triprolidine is a first-generation histamine H1 antagonist used in allergic rhinitis, asthma, and urticaria. It is also a component of cough suppressants and cold medications. Triprolidine is a histamine H1 antagonist that competes with histamine at the normal H1 receptor sites in effector cells of the gastrointestinal tract, blood vessels, and airways. It temporarily and effectively alleviates sneezing, watering eyes, itching, and runny nose due to hay fever and other upper respiratory allergies. Triprolidine has anticholinergic and sedative effects.

[0179] Dimethindene is an antihistamine / anticholinergic drug used orally and topically as an antipruritic. Dimethindene exists as a racemic mixture. (S)-(+)-Dimethindene is a potent M2-selective muscarinic receptor antagonist (with low affinity for M1, M3, and M4 muscarinic receptors). The (R)-(-)-enantiomer is the isomer responsible for histamine H1 receptor binding (for biological activity). Dimethindene is a selective histamine H1 antagonist that binds to the histamine H1 receptor. This inhibits the action of endogenous histamine and temporarily alleviates the negative symptoms caused by histamine.

[0180] Acrivastine is an antihistamine of the triprolidine analogue with indications for the treatment of allergies and hay fever. As an H1 receptor antagonist, it inhibits the action of histamine at this receptor, thereby preventing symptoms associated with histamine release such as pruritus, vasodilation, hypotension, edema, bronchoconstriction, and tachycardia.

[0181] Other first-generation antihistamines include piperazine-based (such as cyclizine, buclizine, chlorcyclizine, hydroxyzine, meclizine, ketotifen, etc.). These compounds are structurally related to ethylenediamine and ethanolamine, and except for hydroxyzine, they produce significant anticholinergic side effects. However, hydroxyzine has low or no affinity for muscarinic acetylcholine receptors, so the anticholinergic side effects can be ignored. Compounds in this group are commonly used for motion sickness, dizziness, nausea, and vomiting. Cetirizine, a second-generation H1-antihistamine, also belongs to this chemical group.

[0182] Cyclizine is a histamine H1 antagonist and is administered orally or parenterally for the suppression of postoperative and drug-induced vomiting and the suppression of motion sickness. Cyclizine is an antihistamine of the piperazine derivative and is used as an anti-dizziness / antiemetic agent. Cyclizine is used for the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it is also used for the management of dizziness in diseases affecting the vestibular organ. The mechanism by which cyclizine exerts its antiemetic and anti-dizziness effects has not been fully elucidated, but a central anticholinergic effect is partially involved. This drug may suppress the excitability of the labyrinth and vestibular stimulation and affect the chemoreceptor trigger zone in the medulla. It also has anticholinergic, antihistamine, central nervous system depressant, and local anesthetic effects. Cyclizine blocks the histamine receptors in the vomiting center, thereby reducing the activity of these pathways. Furthermore, since cyclizine also has an anticholinergic effect, the muscarinic receptors are similarly blocked.

[0183] Bucrilazine is an antihistamine drug with both antiemetic and anticholinergic effects. When administered to children in syrup form, it was advertised as effective as an appetite enhancer, but this indication has not been verified. In addition to the above symptoms, Bucrilazine has also been studied for the treatment of migraine attacks and nausea and vomiting during pregnancy. Bucrilazine acts by blocking histamine receptors in the vomiting center, thus suppressing activities along these pathways. Furthermore, since Bucrilazine also has an anticholinergic effect, muscarinic receptors are similarly blocked.

[0184] Chlorcyclizine is a first-generation phenylpiperazine antihistamine drug used in the treatment of urticaria, rhinitis, pruritus, and other allergic symptoms. Chlorcyclizine also has local anesthetic, anticholinergic, and antiserotonergic effects and can also be used as an antiemetic.

[0185] Hydroxyzine is a first-generation histamine H1 receptor antagonist of the diphenylmethane and piperazine classes, showing sedative, anxiolytic, and antiemetic effects. Hydroxyzine inhibits the activity of histamine and alleviates allergic symptoms such as pruritus. Also, due to off-target activity, it is used as a sedative anxiolytic and antiemetic in certain disease states. Hydroxyzine is a potent inverse agonist of the histamine H1-receptor. An inverse agonist is a drug considered to have "negative efficacy," which not only inhibits the activity of the receptor but actively attenuates it. This inverse agonism at these receptors is the cause of the effectiveness of hydroxyzine against histaminic edema, erythema, and pruritus. Since hydroxyzine is not a corticostatic drug, its sedative properties probably occur at the subcortical level of the CNS. These sedative properties enable its activity as an anxiolytic. The antiemetic effect is probably secondary due to off-target activity. It is also an inhibitor of the potassium voltage-gated channel subfamily H member 2.

[0186] Meclizine is a histamine H1 antagonist with antiemetic and antivertigo effects. It is used for the symptomatic treatment of motion sickness and the suppression of vertigo associated with vestibular system disorders. It also exhibits anticholinergic, central nervous system depressant, and local anesthetic effects. Through its antagonistic effect on the H1 receptor, meclizine acts mainly by inhibiting the transmission of the signal transduction pathway mediated by histaminergic neurotransmission from the vestibular nucleus and NTS to the CTZ and the medullary vomiting center. In addition to the histamine H1 receptor, it is also an inverse agonist of nuclear receptor subfamily 1 group I member 3.

[0187] Ketotifen is a benzocycloheptathiophene derivative with potent antihistamine and mast cell stabilizing effects. It has a structure similar to that of other first-generation antihistamines such as cyproheptadine and azatadine. The exact mechanism by which ketotifen exerts its therapeutic effect is unknown. Ketotifen is a potent and non-competitive antagonist of the H1 histamine receptor, which is thought to contribute significantly to its anti-allergic activity. Furthermore, ketotifen has been demonstrated in vitro to have the ability to stabilize mast cells and inhibit the release of allergic and inflammatory mediators such as histamine, leukotriene C 4 and D 4 (i.e., SRS-A), platelet-activating factor (PAF), etc.

[0188] Other first-generation antihistamines include tricyclic and tetracyclic ones (such as promethazine, alimemazine, cyproheptadine, mequitazine, etc.). These compounds differ from phenothiazine antipsychotics in terms of ring substitution and chain characteristics. They are also structurally related to tricyclic antidepressants (and tetracyclic antidepressants), which explains the side effects due to their H1-antihistamine effects and the low tolerance profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine is derived from compounds in this group.

[0189] Promethazine is a first-generation antihistamine drug. Since promethazine antagonizes various receptors, it is used in many indications such as allergic reactions, pain, sedation, nausea, and vomiting. Promethazine is an antagonist of histamine H1 receptor, postsynaptic mesolimbic dopamine receptor, α-adrenergic receptor, muscarinic receptor, and N-methyl-D-aspartic acid receptor (NMDA) receptor. The antagonistic effects on muscarinic receptor and NMDA receptor also contribute to its use as a sleep aid in addition to relieving anxiety and tension. Due to its antagonistic effects on histamine H1, muscarinic receptor, and dopamine receptor in the vomiting center, promethazine is useful for the treatment of nausea and vomiting.

[0190] Alimemazine, also known as trimeprazine, is an antihistamine drug used to prevent and relieve skin pruritus such as urticaria and other allergic symptoms. Trimeprazine competes with free histamine and binds to the HA receptor site. This antagonizes the action of histamine on the HA receptor and leads to the reduction of negative symptoms caused by histamine HA receptor binding.

[0191] Cyproheptadine is a potent competitive antagonist against both serotonin and histamine receptors. It is mainly used for the treatment of allergic symptoms, but its off-label use in appetite promotion and the treatment of serotonin syndrome may attract more attention. Cyproheptadine seems to exert antihistamine and antiserotonin effects by competing with free histamine and serotonin when they bind to their respective receptors. The antagonistic effect of serotonin in the appetite center of the hypothalamus is considered to explain the appetite-stimulating effect of cyproheptadine. Cyproheptadine is also an antagonist of histamine H1 receptor, 5-hydroxytryptamine receptor 2A, 5-hydroxytryptamine receptor 2C, histamine H2 receptor, 5-hydroxytryptamine receptor 2B, muscarinic acetylcholine receptor M1, muscarinic acetylcholine receptor M2, muscarinic acetylcholine receptor M3, and 5-hydroxytryptamine receptor 7.

[0192] Mekitazine is a histamine H1 antagonist (antihistamine). It competes with histamine and acts on the normal H1 receptor sites on effector cells in the gastrointestinal tract, blood vessels, and airways. It temporarily and effectively relieves sneezing, watering eyes, itching, and runny nose caused by hay fever and other upper respiratory allergies.

[0193] By formulating a compound such as trimeprazine into a nasal spray, drugs can be delivered directly to the brain, and the brain regions (dorsal root ganglion and Gasserian ganglion) involved in the perception of neuropathic pain in the target indications can be targeted more efficiently. This also has the potential advantage of reducing the dosage required for the therapeutic response against drowsiness, which is a side effect of compounds such as trimeprazine on the central nervous system. Compounds such as trimeprazine would be suitable for formulation into nasal sprays. In some embodiments, the LogP of trimeprazine is 4.71, and this compound is lipophilic. Although it is not desired to be bound by theory according to Lipinski's rule of five, compounds with LogP > 5 can cross the BBB. Formulations containing a compound such as trimeprazine in a vehicle similar to azelastine (benzalkonium chloride, disodium edetate, hypromellose, citric acid, dibasic sodium phosphate, sodium chloride, and purified water) can be used.

[0194] Sublingual dissolving film formulations are also considered. Such films disintegrate instantaneously when placed on the tongue and release the drug dissolved in saliva. Some drugs are absorbed from the mouth, pharynx, and esophagus when saliva flows into the stomach. In such cases, the bioavailability of the drug is much higher than that observed with conventional tablets. For the treatment of TN, ODF formulations of compounds such as trimeprazine are possible, and they have useful advantages such as being easy / convenient to administer, especially for elderly patients, not requiring water, having the potential for rapid absorption, and potentially requiring a lower dosage to obtain a therapeutic effect, and being less prone to side effects. Oral soluble film formulations of compounds such as trimeprazine may be useful for the pain attacks characteristic of TN.

[0195] Conventional tablet formulations are also conceivable. An exemplary amount of the active agent would be from about 2.5 mg to about 10 mg per tablet. Such tablets can be administered once, twice, or three times a day, or according to other dosing regimens as needed. Other inactive ingredients can include microcrystalline cellulose, lactose, colloidal anhydrous silica, magnesium stearate, sodium starch glycolate, hypromellose, macrogol 200, indigo carmine E132, and titanium dioxide E171. For example, the tablets can contain 5 mg of trimipramine (as trimipramine tartrate) and other active agents such as about 2 mg of prednisolone.

[0196] Topical formulations such as creams, lotions, and liquid drops are also contemplated. Compounds such as trimipramine can be formulated into lotions or creams for topical application to the skin, for example, for the treatment of pain in postherpetic neuralgia (PHN), trigeminal neuralgia (TN), diabetic neuropathic pain (DNP), and chemotherapy-induced neuropathic pain (CIPN). Standard methods for formulating creams, lotions, and solutions can be used, as is common with antihistamines and capsaicin creams. Other topical delivery systems such as patches are further contemplated. Patches generally consist of an adhesive material containing the active substance (in an aqueous or other form of base), which is applied to a non-woven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner. Patches generally contain inactive ingredients (but are not limited to) such as dihydroxyaluminum aminoacetate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea. Compounds such as trimipramine can be incorporated into patches for topical application to the skin, for example, for the treatment of pain in PHN, TN, DNP, CIPN. Compounds absorbed from the skin can have not only a local effect on pain but also a systemic effect.

[0197] Subcutaneous and intrathecal injections are also conceivable. Compounds such as trimipramine can be formulated for subcutaneous injection to treat the pain of PHN, DNP, TN, and CIPN. Standard formulations and syringes / needles suitable for subcutaneous injection can be used. There is evidence that injecting drugs such as methylprednisolone and lidocaine into the intrathecal space can suppress the pain of PHN. Compounds such as trimipramine can be formulated for intrathecal administration using common formulations and delivery techniques (pumps, needles, etc.). Preclinical and clinical formulation, efficacy, and dosing studies will be required to demonstrate therapeutic value (pain reduction).

[0198] Without wishing to be bound by theory, the mechanism of action of the compositions of the present disclosure is contemplated and disclosed herein. Pain is a multifaceted pathological condition, and therefore a combinatorial therapeutic approach that modulates the signaling, perception, and inflammatory processes involved in pain (as is common in other therapeutic areas, such as oncology) would be beneficial. What is proposed herein is a putative mechanism of action for using trimipramine to modulate multiple pain mechanisms in both the peripheral nervous system (PNS) and the central nervous system (CNS) for the treatment of trigeminal neuralgia and other neuropathic pain states, and a combination therapy approach for using trimipramine in combination with one or more first-generation antihistamines and / or one or more of the current standard treatments for trigeminal neuralgia to modulate multiple pain mechanisms in both the peripheral nervous system (PNS) and the central nervous system (CNS). The present disclosure is not intended to exclude other mechanisms of action.

[0199] Trimeprazine has been confirmed to treat the pain of postherpetic neuralgia and trigeminal neuralgia. The dorsal root ganglion (DRG) is involved in postherpetic pain, and the trigeminal ganglion (TG) is involved in trigeminal neuralgia. Both DRG and TG are involved in the perception of itch and pain. Chronic neuropathic pain is a hypersensitive state caused by peripheral and central sensitization. Chronic itch and chronic cough are also gradually being understood to be part of the hypersensitivity syndrome.

[0200] Trimeprazine is used as an anti-itch drug that exerts its therapeutic effect via the histamine H1 receptor (H1R). Trimeprazine is an inverse agonist of H1R and shows an action opposite to that of histamine binding at H1R. When histamine binds to H1R, a signal transduction cascade occurs with the activation of phospholipase C β3 (PLCβ3), and phosphatidylinositol-4,5-bisphosphate (PIP2) is cleaved into the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase Cε (PKCε), and PKCε phosphorylates and opens the transient receptor potential vanilloid receptor 1 (TRPV1) in DRG and probably TG. When TRPV1 is activated, the channel opens, allowing the passage of positively charged sodium, potassium, and calcium, resulting in depolarization. As a result, voltage-dependent sodium channels are activated, action potentials are generated along the nerve fibers, and itching is felt. As a result of the inflammatory process caused by tissue damage, injury, or infection (such as herpes zoster), resident cells (mast cells) and recruited (polymorphonuclear leukocytes, PMNL) immune cells, epithelial cells, Schwann cells, fibroblasts, and sympathetic postganglionic neurons (SPGN) are activated. Some of these cells (mainly mast cells) release histamine, which binds to H1R in the peripheral afferent nerves and DRG and TG, and then activates TRPV1, causing itching and pain.

[0201] TRPV1 is involved in neuropathic pain (such as postherpetic neuralgia, diabetic neuropathic pain, chemotherapy-induced pain, etc.) and may also be involved in trigeminal neuropathic pain. Both DRG and TG express the H1 receptor and are thought to be activated as a result of the inflammatory processes (e.g., histamine release by mast cells) underlying neuropathic pain and trigeminal neuralgia. The role of TRPV1 in nociception involves many of the same signal transduction cascades as histamine-induced itch. TRPV1 is activated or sensitized by the release of inositol trisphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2) via phospholipase C, and the combined action of diacylglycerol (DAG) and the release of Ca 2+ from intracellular stores activates classical PKC isozymes such as PKCδ. The increase in intracellular Ca 2+ also results in the activation of Ca 2+ -calmodulin-dependent protein kinase II (CaMKII), which may sensitize TRPV1.

[0202] Therefore, without wishing to be bound by theory, the therapeutic effect of trimipramine on pain reduction in trigeminal neuralgia and other neuropathic pain states reduces the excessive stimulation by histamine on the PNS afferent and CNS (DRG, TG, posterior horn of the spinal cord, thalamus) via the PLCβ3, PIP2, DAG, IP3 signal cascade. TRPV1 may also be activated or sensitized by indirect (non-histamine) means, in which case trimipramine may have a therapeutic effect of regulating the activity of TRPV1 by binding to H1R in the PNS afferent nerves and / or CNS and reducing pain. As the basis for this hypothesis, the side effects (drowsiness, sleep disorders) of first-generation antihistamines such as trimipramine are the result of the ability to bind to H1R in the CNS (such as DRG and TG) and cross the BBB, independent of the increase in histamine levels due to inflammation.

[0203] Furthermore, the hypothesis is proposed that other first-generation antihistamines capable of crossing the BBB, or other antihistamines capable of crossing the BBB, alone or in combination with trimipramine or other first-generation antihistamines, may have a therapeutic effect on pain reduction through the regulation of TRPV1 activation or sensitization via H1R binding. Without wishing to be bound by theory, by evaluating the individual antihistamine properties of first-generation antihistamines, it may be possible to design combination therapies that maximize TRPV1 activity via H1R binding, resulting in a greater therapeutic effect or reduction of side effects.

[0204] In light of these hypotheses, it is thought possible to combine trimipramine and other first-generation or other antihistamines capable of crossing the BBB with current SOC therapies for neuropathic pain that exert their main effects locally in the PNS to produce therapeutic effects in both the peripheral (e.g., neuronal signaling) and central (pain perception) aspects. Furthermore, current SOC therapies that cross the BBB and are likely to be associated with undesirable side effects can be replaced in a combinatorial approach with first-generation or other antihistamines capable of crossing the BBB, providing a therapeutic effect with an improved side effect profile. Trimipramine and other first-generation H1-antihistamines may also modulate pain by reducing the activity of the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) immune response transcription factor via the phospholipase C and phosphatidylinositol (PIP2) signaling pathways, resulting in a decrease in antigen presentation and the expression of inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Additionally, lowering the calcium ion concentration increases the stability of mast cells and further reduces histamine release.

[0205] Like other first-generation antihistamines, trimipramine has many off-target effects such as antimuscarinic, anti-α-adrenergic, and serotonergic effects. The therapeutic effect of reducing pain in peripheral neuropathy and trigeminal neuralgia may be mediated by any one, any combination, or all of these off-target effects. For example, several studies have revealed that the cholinergic system is involved in neuropathic pain. Muscarinic receptors are G protein-coupled receptors (GPCRs) involved in the parasympathetic nervous system. Muscarinic M1, M3, and M5 are excitatory receptors, while muscarinic M2 and M4 receptors are inhibitory receptors. The central muscarinic M2 receptor has been reported to regulate neuropathic pain induced by traumatic nerve injury, and activation of the muscarinic M2 receptor in the insular cortex can reduce oxaliplatin-induced neuropathic pain in male rats. Presynaptic muscarinic receptors expressed in the DRG and trigeminal ganglia regulate primary afferent inputs to spinal dorsal horn neurons and medullary dorsal horn neurons, respectively. Therefore, first-generation antihistamines such as trimipramine are not limited to M2 and M4 inhibitory receptors present in the PNS and CNS in peripheral neuropathic pain and trigeminal neuralgia, but it is proposed that they may have a therapeutic effect on reducing pain in peripheral neuropathic pain and trigeminal neuralgia through the regulation of muscarinic receptor activity.

[0206] Furthermore, it is contemplated that other first-generation antihistamines that can cross the BBB, or trimethoprim or other first-generation antihistamines alone or in combination, may have a therapeutic effect of pain reduction through the regulation of central muscarinic receptors (such as, but not limited to, M2 and M4). Furthermore, by evaluating the individual antimuscarinic properties of first-generation antihistamines, combination therapies can be designed that maximize antimuscarinic activity and lead to greater therapeutic effects or reduction of side effects. For example, cyproheptadine (a first-generation antihistamine in the same class as trimethoprim (phenothiazine)) is a potent antagonist of the M2 muscarinic receptor. Such combinations may also include trimethoprim and other SOC drugs for neuropathic pain.

[0207] As further examples of off-target effects and side effects, the sedating effects of trimipramine and other first-generation antihistamines are cited, and for this reason, they have come to be used as sleep aids (e.g., diphenhydramine in cough suppressants) and pediatric sedatives (trimipramine) before surgery. Sedation by first-generation antihistamines is probably the result of modulating H1-receptors in the CNS, and as a result, pain perception would be reduced (through modulation of TRPV1). However, there is also evidence that at least one first-generation antihistamine (orphenadrine) can block Nav1.7, Nav1.8, and Nav1.9 sodium channels involved in neuropathic pain and trigeminal neuralgia. Thus, first-generation antihistamines such as trimipramine may have a therapeutic effect on reducing pain in peripheral neuropathic pain and trigeminal neuralgia by indirectly or directly modulating any, any combination, or all of the Nav1.7, Nav1.8, and Nav1.9 sodium channels in the PNS and CNS. Evaluating the individual sodium channel blocking properties of first-generation antihistamines can be used to maximize the indirect or direct modulation of these channels and thus design combinatorial therapies that lead to greater therapeutic effects or reduction of side effects. Such combinations may include trimipramine and other SOC drugs for neuropathic pain.

[0208] Trimipramine and other first-generation antihistamines are also thought to be able to exert an indirect or direct therapeutic effect, alone or in combination, on reducing pain in peripheral neuropathy and trigeminal neuralgia, on any, any combination, or all of the following mechanisms in the PNS and / or CNS: Toll-like receptor (TLR), protease-activated receptor (PAR), G-protein coupled receptor (GPCR) MrgprA3 (MAS-related GPR, member A3), thymic stromal lymphopoietin (TSLP) receptor, reactive oxygen species, purinergic receptor (P 2 X) subunit, PX 22 and PX 23, transient receptor potential cation channel ankyrin 1 (TRPA1), calcitonin gene-related peptide (CGRP), substance P (SP), galanin, somatostatin, endothelin-1 (ET1), angiotensin II, neurotrophic factors (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), and neurotrophic factor-4 / 5 (NT-4 / 5)), nitric oxide synthase (NOS), γ-aminobutyric acid (GABA), phospholipase (PLC), N-methyl-D-aspartic acid receptor (NMDA), cyclin-dependent kinase 5 (Cdk5).

[0209] Example The present invention has been described in considerable detail with reference to its specific embodiments, but other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the descriptions and versions illustrated herein. Various aspects of the present invention will be described with reference to the following non-limiting examples.

[0210] Example 1

[0211] A certain middle-aged male patient suffers from typical trigeminal neuralgia, and sharp, syphilitic severe pain appears on the left face when taking a shower, eating, making facial movements, touching the facial skin or nose, brushing teeth, etc. The pain episode starts with the above stimuli and immediately stops all other activities until it subsides within a few seconds. His behavior is modified to avoid the above stimuli, which even affects his way of speaking and eating. He had an MRI examination in the past, but there was no vascular compression as a basis for diagnosis. His daily life is also dominated by the fear of whether an attack will occur.

[0212] He is afraid that carbamazepine (Tegretol) will deprive him of his pilot's license and thus does not take it. He also does not take analgesics. Before treatment with trimipramine, there was no treatment for such severe pain.

[0213] The patient started treatment with 5 mg of trimipramine taken in the morning and evening. On the second day of taking the drug, the intensity and frequency of the seizures decreased. Four days after starting the medication, all pain had disappeared. Since then, there has been some discomfort in the face, but no sharp, intolerable pain as before. This was successfully alleviated by taking half to one 5 mg tablet once or twice a day. Currently, the patient takes the drug on very few days. There are no side effects other than drowsiness after dosing. The patient points out that this is a common side effect experienced by patients in the case of drugs that may cause drowsiness.

[0214] Example 2

[0215] A typical clinical protocol for trigeminal neuralgia is outlined here.

[0216] Number of patients: 80 - 100.

[0217] Study period: 12 - 18 months (12 - week treatment period).

[0218] Study design: Randomized double - blind (DB) withdrawal trial, comparison with placebo. The study may include a screening period, a 7 - day run - in period, a 4 - or 6 - week single - dose optimization period, or a screening period, a 7 - day run - in period, a 4 - week open - label period, and a 14 - week double - blind period. There may be the possibility of long - term extension for patients who complete the double - blind period as needed.

[0219] Primary endpoint: The proportion of participants classified as responders at week 12 of the double - blind period.

[0220] Secondary endpoints: Measurement of safety, quality of life, and evaluation of the pharmacokinetics of the drug in the drug population.

[0221] Number of sites: 10 (in the United States only).

[0222] Primary endpoint: Patient Global Impression of Change (PGIC) score.

[0223] Secondary evaluation items: Number of seizures, measurement of quality of life by Penn-FPS-R, number of times the patient used "emergency drugs" (existing SOC drugs, opioids, etc.).

[0224] Inclusion criteria: 18 years of age or older who were diagnosed with classical, purely episodic TN more than 3 months before participating in the trial and experienced episodic pain more than 3 times a day.

[0225] Endpoints of the trial: Based on the change in the patient's overall impression (PGIC) score, Penn-Facial-Pain-Score-Revised score, EuroQoL 5-dimension 5-level (EQ-5D-5L) score, and patient-reported outcome measurement using work productivity and activity impairment (WPAI). Changes in the use of "emergency drugs" before and after the treatment period in each group.

[0226] Formulation of trimipramine: 5 mg BID of trimipramine sulfate or trimipramine tartrate. Most patients are administered 1 tablet of 5 mg once a day, twice a day, in the morning and evening. Elderly patients (especially those with symptoms of dizziness) may start with 1 tablet of 1x2.5 mg or 1 tablet of 5 mg once a day in the evening and gradually increase the dose to manage the potential side effects of dizziness.

[0227] Treatment may be discontinued based on the reduction in the intensity and frequency of pain. For example, in the case of TN, if the frequency and intensity of pain become zero, the treatment is discontinued, and if seizures recur, the treatment is restarted. However, in the case of other diseases that present as more continuous pain, such as PHN, the treatment may be continued over a long period. This is especially because it may act on the sensory ganglia involved in the perception of pain in the dorsal root ganglia (PHN, CIPN, DNP), or the trigeminal ganglia (TN).

[0228] Example 3

[0229] A typical clinical protocol for the treatment of postherpetic neuralgia is outlined here.

[0230] Postherpetic neuralgia (PHN) is the most common long-term complication of reactivation of varicella-zoster virus (VZV), also known as human herpesvirus-3 (HHV-3). This reactivation of latent VZV is known as herpes zoster or shingles. VZV is the causative agent of chickenpox, a childhood disease colloquially known as chickenpox.

[0231] The characteristics of PHN are stabbing / burning pain in a unilateral dermatomal pattern that persists for more than 3 months after the onset of herpes zoster (HZ).

[0232] Postherpetic neuralgia occurs in a subset of the population who have had an episode of acute HZ. Risk factors for progression of an acute HZ episode to PHN include age, severe immunosuppression, the presence of a prodrome, severe pain at the time of herpes zoster onset, allodynia, ocular disorders, and diabetes.

[0233] It is characteristic of PHN that persistent (more than 3 months) stabbing pain / burning pain, allodynia, sensory abnormalities, pruritus, paresthesia, and / or hyperalgesia are seen at or near the rash site. PHN also affects the quality of life of patients, and sleep disturbances are a common complaint. Sleep disturbances associated with pain enhance pain or reduce pain tolerance.

[0234] Treatment endpoints are reduction and / or disappearance of the overall intensity of PHN pain and improvement in sleep (reduction of sleep disturbances associated with PHN pain). Pain is manifested as stabbing pain / burning pain, allodynia, sensory abnormalities, pruritus, paresthesia, hyperalgesia at or near the HZ rash site. Sleep is also affected.

[0235] Number of patients: 100 - 120.

[0236] Study period: 12 - 18 months (12-week treatment period).

[0237] Study Design: Randomized, double-blind, placebo-controlled, efficacy trial. Treatment Group: During the treatment period, a 5 mg dose of the drug twice a day. Placebo Comparison Group: During the treatment period, placebo (sugar-coated tablets) twice a day.

[0238] Primary Outcome Measure: Change from baseline in the average daily pain intensity score over the past 7 days (at week 8 or the final visit).

[0239] Secondary Outcome Measures: Pain scale, sleep score, quality of life, mood profile.

[0240] Number of Sites: 20.

[0241] Country: United States only.

[0242] Primary Outcome Measure: Brief Pain Inventory (BPI) (PHN version).

[0243] Secondary Outcome Measures: BPI, McGill Short Pain Questionnaire, change in overall impression of clinician and patient, EuroQoL 5-Dimension 5-Level (EQ-5D-5L) score, sleep diary, mood, number of times the patient used "rescue medication" (existing SOC medications, opioids, etc.).

[0244] Inclusion Criteria: Subjects are men and women aged 50 and older with postherpetic neuralgia and pain persisting for more than 3 months after the healing of herpes zoster rash. Female subjects are not of childbearing potential (e.g., those who have undergone sterilization surgery, postmenopausal).

[0245] The primary endpoint of the trial is pain reduction (based on the BPI score) compared to baseline at week 8 or the final visit. Additional secondary endpoints are pain reduction compared to baseline at each visit, based on the following improvements compared to baseline: change in overall impression score of clinician and patient, EuroQoL 5-Dimension 5-Level (EQ-5D-5L) score, mood score, and sleep score. Change in the use of "rescue medication" before and after the treatment period in each group.

[0246] Example 4

[0247] Here is a general overview of the typical clinical protocols for the treatment of painful diabetic neuropathy.

[0248] Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting 50% of patients with type 1 and type 2 DM. Painful diabetic neuropathy (DNP) is clinically defined as pain resulting from damage to the peripheral, autonomic, local, or proximal nerves in patients with diabetes. DNP most commonly presents distally in the hands and feet and occurs in patients diagnosed with type 1 diabetes (T1D) or type 2 diabetes (T2D). The prevalence of painful neuropathy in type 2 diabetes is more than twice that in type 1 diabetes.

[0249] Most patients experience moderate to severe pain, and it is difficult to characterize this pain. General neuropathic pain expressions such as "burning," "electric shock," "stabbing pain in the legs," "prickling pain," "tingling" may be elicited during the interview. Also, features of evoked pain such as allodynia (pain in response to a non-painful stimulus) or hyperalgesia (enhanced pain in response to a stimulus that normally causes pain) may be present, which can have a significant impact on daily life. The pain is usually seen in the feet and may spread to the lower limbs and sometimes to both hands. The pain usually worsens at night, causing sleep disturbances and fatigue.

[0250] When pain occurs in combination with physical disabilities due to other long-term complications of diabetes, the quality of life is significantly reduced. Patients with neuropathic pain show significantly lower scores in areas of quality of life, including enjoyment of life, sleep, physical mobility, self-care, and energy levels.

[0251] Treatment endpoints are reduction of total pain in DNP, reduction of sleep disturbances, and improvement of quality of life and mood scores.

[0252] Number of patients: 200+.

[0253] Study period: 12 - 18 months (12-week treatment period).

[0254] Trial Design: Randomized, double-blind, placebo-controlled, parallel-group, efficacy trial.

[0255] Treatment Group: A drug with a dose of 5 mg, twice a day during the treatment period.

[0256] Comparison with Placebo: Placebo (sugar-coated tablets) twice a day during the treatment period.

[0257] Primary Evaluation Item: Comparison of the change in the average daily pain intensity score from baseline (days 7 to 1) and the average pain intensity score in the final week (week 12).

[0258] Secondary Evaluation Items: Pain scale, sleep score, quality of life, mood state profile.

[0259] Number of Sites: 20.

[0260] Country: United States only.

[0261] Primary Evaluation Item: 11-point Numerical Rating Scale for Pain Intensity (PI-NRS).

[0262] Secondary Evaluation Items: PI-NRS, overall impression of changes by clinicians and patients, EuroQoL 5-Dimension 5-Level (EQ-5D-5L) score, sleep diary, mood.

[0263] Inclusion Criteria: Subjects of both male and female, aged 18 or above and under 80, having optimized and stable blood glucose control in the 3 months before screening, with type 1 or type 2 diabetes for at least 6 months. Douleur Neuropathique4 (DN4) score of 4 or above, the number of times the patient used "rescue medications" (existing SOC drugs, opioids, etc.).

[0264] The endpoint of the trial shall be pain reduction (based on PI-NRS) compared to the baseline at week 8 or the final hospital visit. Additional secondary evaluation items are based on pain reduction compared to the baseline at each examination (or patient self-report), and the following improvements compared to the baseline: the change score of the overall impression of the clinician and the patient, the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) score, the mood score, and the sleep score. The change in the use of "rescue medications" before and after the treatment period in each group.

[0265] Example 5

[0266] A typical clinical protocol for chemotherapy-induced neuropathic pain is outlined here.

[0267] Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer drugs such as agents derived from platinum and taxane-based formulations (oxaliplatin, cisplatin, carboplatin, paclitaxel), and is essentially caused by damage to the somatosensory nervous system after anticancer treatment, and is one of the main causes of neuropathic pain in the cancer clinical setting.

[0268] Sensory symptoms usually present as abnormal sensations such as paresthesia, dysesthesia, tingling, burning, stabbing, or shock-like sensations, either spontaneously or induced, similar to allodynia or hyperalgesia induced by mechanical or thermal stimuli. The symptoms usually affect the extremities of the upper and lower limbs ("stocking and glove" distribution) and progress to the proximal regions of the body.

[0269] Neuropathic pain induced by chemotherapy initially appears as an acute pain syndrome with sensory symptoms occurring during or immediately after drug administration, and progresses to chronic neuropathy during repeated treatment cycles.

[0270] However, acute neuropathy generally resolves between treatments, while chronic neuropathy can persist for months or years, and 47% of patients receiving cancer treatment experience symptoms of peripheral neuropathy six years after treatment ends. The chronic pain of CINP significantly impairs the quality of life of cancer patients.

[0271] Patients with CINP report paresthesia, dysesthesia, numbness, burning, stabbing or electric shock-like sensations, and allodynia or hyperalgesia induced by mechanical or thermal stimuli, which affect the extremities of the upper and lower limbs ("stocking and glove" distribution) and progress to proximal regions of the body.

[0272] Treatment endpoints are the reduction of total pain in CINP and the measurement of quality of life.

[0273] Number of patients: 25 - 30.

[0274] Trial design: randomized, double-blind, placebo-controlled, parallel-group, efficacy trial.

[0275] Treatment group: During the treatment period, a drug with a dose of 5 mg twice a day.

[0276] Comparison with placebo: During the treatment period, placebo (sugar-coated tablets) twice a day.

[0277] Primary endpoint: Compare the pain intensity scores reported by patients after the treatment period (12 weeks) in the two groups of the trial.

[0278] Secondary endpoints: Pain scale (NPSI), measurement of cancer-related symptoms (e.g., FACT-taxane), change in users of "rescue medications".

[0279] Number of sites: Up to 10.

[0280] Country: United States only.

[0281] Primary assessment management: Basic Pain Inventory (BPI).

[0282] Secondary evaluation items: Neuropathic Pain Symptom Inventory (NPSI), FACT-Taxane, FACT-GOG-NTX, or FACT indicators appropriate for the chemotherapy used, and the number of times the patient used "rescue medications" (existing SOC medications, opioids, etc.).

[0283] Inclusion criteria: The patient is 18 years of age or older. The patient has experienced moderate to severe peripheral neuropathic pain. The patient must have chronic peripheral neuropathic pain, which is defined as pain lasting for more than 3 months that started in relation to chemotherapy. The patient must have bilateral peripheral neuropathic pain symptoms mainly related to the feet. The patient must have cancer (regardless of stage).

[0284] The endpoint of the trial is based on the reduction of pain (based on the BPI score) at the end of treatment (week 12). Additional secondary evaluation items are based on the reduction of pain (using NPSI, FACT-XXX) compared to the baseline at the end of the treatment period in each group of the trial. The change in the use of "rescue medications" in each group before and after the treatment period.

[0285] This disclosure is not limited to the specific systems, devices, and methods described, as these can vary. The terms used herein are for the purpose of describing particular versions or embodiments only and are not intended to limit the scope.

[0286] This disclosure is not limited in terms of the specific embodiments described in this application, and these are intended as examples of various aspects. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent methods and apparatuses within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be included within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims, and such claims are limited together with the full scope of equivalents to which such claims are entitled. It should be understood that this disclosure is not limited to a particular method, reagent, compound, composition or biological system. Also, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0287] Regarding the use of substantially any plural and / or singular terms herein, one of ordinary skill in the art can translate from plural to singular and / or from singular to plural, depending on the context and / or application. Various singular / plural permutations may be explicitly defined herein for clarity.

[0288] In general, it will be understood by those skilled in the art that the terms used in this specification, particularly in the appended claims (e.g., the body of the appended claims), are generally intended to be open terms (e.g., the term "including" should be construed as "including but not limited to", the term "having" should be construed as "having at least", the term "includes" should be construed as "including but not limited to", etc.). Various compositions, methods, and apparatuses are described from the perspective of "comprising" various components or steps (interpreted as meaning "including but not limited to these"), but the compositions, methods, and apparatuses may also "consist essentially of" or "consist of" various compositions and steps, and such terms should be construed as defining a group of essentially closed members. It will further be understood by those skilled in the art that where a specific number of introductions of a claim is intended, such intention is explicitly stated in the claim, and where there is no such statement, such intention does not exist.

[0289] For example, for the sake of understanding, the following appended claims may include the use of introductory phrases "at least one" and "one or more" for introducing the description of the claims. However, the use of such phrases should not be construed to mean that the repeated introduction of a claim by the indefinite article "a" or "an" limits a particular claim that includes the repetition of such introduced claims to embodiments that include only one such repetition, even if the same claim includes both an introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"), a particular claim that includes the repetition of such introduced claims should not be construed to mean that it is limited to embodiments that include only one such repetition. The same also applies to the use of definite articles used in the introduction of the description of the claims.

[0290] In addition, even if a specific number of introductions of a claim is explicitly recited, one of ordinary skill in the art would recognize that such a recitation should be construed to mean at least the recited number (e.g., a bare recitation of "two iterations" without other qualifying language means at least two iterations, or two or more iterations). Further, when a phrase similar to "at least one of A, B, and C, etc." is used, generally, such a construction is intended in the sense that one of ordinary skill in the art would understand the phrase (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, a system having A alone, B alone, C alone, a system having A and B together, a system having A and C together, a system having B and C together, and / or a system having A, B, and C together, etc.). When a phrase similar to "at least one of A, B, or C, etc." is used, generally, such a construction is intended in the sense that one of ordinary skill in the art would understand the phrase (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, a system having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). One of ordinary skill in the art would further understand that substantially any conjunctive word and / or phrase presenting two or more alternative terms, in any of the description, claims, or drawings, is intended to contemplate the possibility of including one of the terms, any of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B", or "A and B".

[0291] In addition, when a feature or aspect of the present disclosure is described from the perspective of a Markush group, one of ordinary skill in the art would recognize that the present disclosure is also described from the perspective of any individual member or subgroup of members of the Markush group.

[0292] As will be understood by those skilled in the art, all ranges disclosed herein include any and all possible sub-ranges and combinations thereof for any purpose, such as for the purpose of providing a written description. Any recited range can be readily recognized as being fully described and enabled to be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily decomposed into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all language such as "up to," "at least," etc. includes the recited number and refers to a range that can be subsequently decomposed into sub-ranges as described above. Finally, as will be understood by those skilled in the art, a range includes individual members. Thus, for example, a group having 1 to 3 compounds refers to a group having 1, 2, or 3 compounds. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 compounds, etc.

[0293] The various features and functions described above, or alternatives thereof, may be combined in many other different systems or applications. Various alternatives, modifications, variations, or improvements not presently foreseen or expected may subsequently be made by those skilled in the art, but each of these is also intended to be encompassed by the disclosed embodiments.

Claims

1. A method for treating trigeminal neuralgia, said method comprising the step of administering a therapeutically effective amount of trimipramine to a patient in need thereof, thereby treating the trigeminal neuralgia of said patient.

2. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is administered once a day.

3. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is administered twice a day.

4. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is administered by oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, topical administration, transdermal administration, nasal administration, or a combination thereof.

5. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is administered by oral administration.

6. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is administered by sublingual administration.

7. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is about 0.5 mg to about 20 mg.

8. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is about 5 mg.

9. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is about 0.05 mg / kg to about 20 mg / kg.

10. The method according to claim 1, wherein the therapeutically effective amount of trimipramine is about 0.1 mg / kg to about 10 mg / kg.

11. The method according to claim 1, wherein treating the trigeminal neuralgia comprises reducing the pain of said patient.

12. The method according to claim 10, wherein reducing the pain of said patient comprises improving the pain of said patient as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

13. The method according to claim 10, wherein reducing the pain of said patient comprises preventing an increase in the pain of said patient as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

14. The method according to claim 1, wherein treating the trigeminal neuralgia comprises improving the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, WPAI score, or a combination thereof.

15. The method according to claim 1, wherein treating the trigeminal neuralgia comprises preventing an increase in the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, or WPAI score, preventing a decrease in the PGIC score, or a combination thereof.

16. A method of reducing pain in a patient due to trigeminal neuralgia, the method comprising administering to a patient in need thereof a therapeutically effective amount of trimipramine, whereby the pain of the patient is reduced.

17. The method according to claim 16, wherein reducing the pain of the patient comprises improving the pain of the patient as measured by the Penn-FPS score as compared to the pain of the patient as measured by the Penn-FPS score before treatment.

18. The method according to claim 16, wherein reducing the pain of the patient comprises preventing an increase in the pain of the patient as measured by the Penn-FPS score as compared to the pain of the patient as measured by the Penn-FPS score before treatment.

19. The method according to claim 16, wherein reducing the pain of the patient comprises improving the pain of the patient as measured by the Penn-FPS-R score as compared to the pain of the patient as measured by the Penn-FPS-R score before treatment.

20. The method according to claim 16, wherein reducing the pain of the patient comprises preventing an increase in the pain of the patient as measured by the Penn-FPS-R score as compared to the pain of the patient as measured by the Penn-FPS-R score before treatment.

21. The method according to claim 16, wherein reducing the pain of the patient comprises improving the PGIC score of the patient at the end of the treatment period.

22. The method according to claim 16, wherein reducing the pain of the patient comprises preventing a decrease in the PGIC score at the end of the treatment period.

23. The method according to claim 16, wherein the therapeutically effective amount of trimipramine is from about 0.5 mg to about 20 mg.

24. The method according to claim 16, wherein the therapeutically effective amount of trimipramine is from about 0.05 mg / kg to about 20 mg / kg.

25. The method according to claim 16, wherein the therapeutically effective amount of trimipramine is from about 0.1 mg / kg to about 10 mg / kg.

26. The method according to claim 16, wherein the therapeutically effective amount of trimipramine is administered by oral administration.

27. The method according to claim 16, wherein the therapeutically effective amount of trimipramine is administered by sublingual administration.

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