Composition for preventing the transition from acute pain to chronic pain

Abstract

Disclosed herein are, inter alia, methods for treating pain by administering compositions comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, as well as related compositions and kits thereof.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 375,113, filed September 9, 2022, the entire disclosure of which is incorporated herein by reference for all purposes. [Background technology]

[0002] More than 1.5 billion people worldwide suffer from chronic pain, which often begins after the onset of acute pain.The sequence of molecular events that lead to the chronicization of pain remains largely unknown, and there is a need to fill this gap in order to identify control nodes that can be targeted for preventive or disease-modifying therapy.In particular, solutions to these problems and other problems in the art are disclosed herein. Summary of the Invention

[0003] In one embodiment, a method for treating pain in a subject in need thereof is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide. In one embodiment, the composition is orally administered. In one embodiment, the purified fatty acid is oleic acid or erucic acid. In one embodiment, the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0004] In one aspect, a method of preventing chronic pain in a subject with acute pain is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0005] In one aspect, a method of preventing peripheral painful neuropathy in a subject previously treated with an anti-cancer agent is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0006] In one aspect, a method of preventing chronic pain in a diabetic subject is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0007] In one aspect, a method of reducing pain hypersensitivity in a subject after a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein pain hypersensitivity is reduced in the subject.

[0008] In one aspect, a composition is provided that includes at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0009] In one embodiment, the method further comprises administering to the subject an effective amount of an agent, wherein the agent is an N-acylethanolamine acid amidase (NAAA) inhibitor, a fatty acid amide hydrolase (FAAH) inhibitor, a PPARα agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

[0010] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0011] [Figure 1A]Dietary intervention prevents formalin-induced acute nociception, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Time course of acute nociceptive responses to 1% formalin. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1B] Dietary intervention prevents formalin-induced acute nociception, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (postformalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. The cumulative scores of the first phase (Phase I: 0–10 min) and second phase (Phase II: 15–60 min) of the acute nociceptive defense response were measured. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1C]Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and fed the respective chow for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Paw edema (thickness of injected paw minus uninjected paw, in mm) was measured. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1D] Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Mechanical sensitivity to the ipsilateral paw was assessed. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1E]Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective chow for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Mechanical sensitivity to the contralateral paw was assessed. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1F] Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Thermal sensitivity of the ipsilateral paw was assessed. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1G]Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued and replaced with SD on PFD7. Thermal sensitivity of the contralateral paw was assessed. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1H] Dietary intervention prevents formalin-induced acute pain sensation, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and maintained on the respective diet for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention could permanently prevent the long-term effects of formalin, ED was withdrawn and replaced with SD on PFD7. Anxiety-like behavior in mice on PFD7 was assessed by EPM. Left: time spent in the open arms (seconds); Right: anxiety index. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 1I]Dietary intervention prevents formalin-induced acute nociception, persistent paresthesia, emotional disturbance, and memory deficits. Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and fed the respective chow for 1 week. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional disturbances (elevated plus maze test, EPM) induced by formalin injection were assessed at various time points after injection (post-formalin injection day, PFD). To assess whether dietary intervention permanently prevented the long-term effects of formalin, ED was discontinued on PFD7 and replaced with SD. Long-term memory in mice treated with sham or formalin was assessed as a discrimination index on PFD21. Results are expressed as mean ± SEM (n = 4–8 per group). [Figure 2A] Dietary intervention prevents persistent sensory hypersensitivity and memory deficits caused by spatial nerve injury (SNI). Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals underwent sham surgery or spatial nerve injury (SNI) of the sciatic nerve and were fed the respective chow for 2 weeks. SNI-induced nociceptive behavior and cognitive impairment (novel object recognition test, NOR) were assessed at various time points after surgery (post-SNI). To assess whether dietary intervention could permanently prevent the long-term effects of SNI, ED was discontinued and replaced with SD on day 14 after SNI. Mechanical allodynia in the operated (ipsilateral) paw was observed. The contralateral paw served as a control. Results are expressed as mean ± SEM (n = 7–8 per group). [Figure 2B]Dietary intervention prevents persistent sensory hypersensitivity and memory deficits caused by spatial nerve injury (SNI). Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals underwent sham surgery or spatial nerve injury (SNI) of the sciatic nerve and were fed the respective chow for 2 weeks. SNI-induced nociceptive behavior and cognitive impairment (novel object recognition test, NOR) were assessed at various time points after surgery (post-SNI). To assess whether dietary intervention could permanently prevent the long-term effects of SNI, ED was discontinued and replaced with SD on day 14 after SNI. Thermal hyperalgesia in the ipsilateral paw was observed. The contralateral paw served as a control. Results are expressed as mean ± SEM (n = 7–8 per group). [Figure 2C] Dietary intervention prevents persistent sensory hypersensitivity and memory deficits caused by spatial nerve injury (SNI). Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals underwent sham surgery or spatial nerve injury (SNI) of the sciatic nerve and were fed the respective diets for 2 weeks. SNI-induced nociceptive behavior and cognitive impairment (novel object recognition test, NOR) were assessed at various time points after surgery (post-SNI). To assess whether dietary intervention permanently prevented the long-term effects of SNI, ED was discontinued and replaced with SD on day 14 after SNI. Long-term memory in mice subjected to sham surgery or SNI and fed either SD or ED was assessed as a discrimination index 24 days after SNI. Results are expressed as mean ± SEM (n = 7–8 per group). [Figure 3] Changes in the levels of various metabolites in the spinal cord (L4-L6) 72 hours after intraplantar administration of formalin in mice fed a standard diet (SD) or medical food (MF). These metabolites include glycolytic intermediates (A), tricarboxylic acid (TCA) cycle intermediates (B), and purine derivatives, including ATP (C). The medical food reversed the shift from TCA to glycolysis and the energy crisis (low ATP levels) caused by formalin injection. [Figure 4]Changes in the levels of various spinal metabolites (L4-L6) after intraplantar administration of formalin in mice fed a standard diet (SD) or a medical food (MF) are shown. Amino acids (A), urea cycle intermediates (B), and acylated amino acids (C) were also shown. [Figure 5] Changes in the levels of various spinal metabolites (L4-L6) in mice fed a standard diet (SD) or a medical food (MF) 72 hours after intraplantar administration of formalin: fatty acids (A) and phospholipids (B). [Figure 6] Figure 1 shows a plot of the effect of medical foods on paw withdrawal latency 1, 6, and 24 hours after administration of interleukin-6 (IL-6, 5 ng, intraplantar) to male mice fed a standard diet (SD). Data are expressed as mean + / - SEM, n=8. ***P<0.001; ****P<0.0001, two-way ANOVA. [Figure 7] Figure 1 shows a plot of the effect of medical foods on paw withdrawal latency at 1, 6, and 24 hours after IL-6 administration following administration of prostaglandin E2 (PGE2, 100 ng, plantar) to male mice pre-stimulated with IL-6 on days 7 or 14. Data are expressed as mean + / - SEM, n=8. **P<0.01; ***P<0.001; ****P<0.0001, two-way ANOVA. ns, not significant. [Figure 8A] Figure 1 shows a plot of the effect of medical food on morphine-induced antinociception in male mice. Animals fed standard chow or medical food were administered morphine (mg / kg, subcutaneously). Responses are shown as a percentage of the maximum possible effect (MPE). Also included are the median effective dose (ED50) values ​​that produced antinociception in the two groups of mice. [Figure 8B] Figure 1 shows a plot of the effect of medical foods on tolerance to the antinociceptive effect of morphine in male mice. The antinociceptive effect of morphine (15 mg / kg, subcutaneous) was assessed on day 1. Tolerance was induced by administering morphine (30 mg / kg) on ​​days 2-6. Tolerance was assessed on day 7 by injecting 15 mg / kg of morphine. DETAILED DESCRIPTION OF THE INVENTION

[0012] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0013] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)- with respect to amino acids, or as (D)- or (L)-, and individual isomers, are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0014] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0015] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0016] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0017] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0018] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by deuterium or tritium, or the replacement of a carbon by a C- or C-enriched carbon are within the scope of this disclosure.

[0019] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as tritium (H), iodine-125 (I), or carbon-14 (C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0020] The term "analog" or "analogue" is used according to its plain and ordinary meaning in chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., one atom is replaced by an atom of a different element, or a particular functional group is present, or one functional group is replaced by another, or the absolute stereochemistry of one or more chiral centers of the reference compound is different. Thus, an analogue is a compound that is similar or equivalent to the reference compound in function and appearance, but not in structure or origin.

[0021] The terms "a" or "an," as used herein, mean one or more. Additionally, the phrase "substituted with a [noun]," as used herein, means that the specified group may be substituted with one or more of any or all of the specified substituents. For example, if a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or an unsubstituted 2-20 membered heteroalkyl," the group can contain one or more unsubstituted C1-C20 alkyls and / or one or more unsubstituted 2-20 membered heteroalkyls.

[0022] A "detectable substance" or "detectable moiety" is a substance (e.g., a compound) or composition that can be detected by appropriate means, such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable substances include: 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy,166 Ho 169 Err 175 sun 177 sun 186 Re 188 Re 189 Re 194 Ir 198 I 199 I 211 And 211 Pb、 212 Hello 212 Pb、 213 Hello 223 Ra 225 Ac、Cr、V、Mn、Fe、Co、Ni、Cu、La、Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb、Lu、 32P, fluorophore (e.g., fluorescent dye), electron-dense reagent, enzyme (e.g., those commonly used in ELISA), biotin, digoxigenin, paramagnetic molecule, paramagnetic nanoparticle, tiny superparamagnetic iron oxide ("USPIO") nanoparticle, USPIO nanoparticle aggregate, superparamagnetic iron oxide ("SPIO") nanoparticle, SPIO nanoparticle aggregate, single crystal iron oxide nanoparticle, single crystal iron oxide, nanoparticle contrast agent, liposome, or gadolinium chelate ("Gd chelate") molecule, gadolinium, radioisotope, radionuclide (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloid, microbubble (e.g., including microbubble shells comprising albumin, galactose, lipids, and / or polymers; microbubble gas cores comprising air, heavy gas(es), perfluorocarbons, nitrogen, octafluoropropane, perflexan lipid microspheres, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglic acid), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or other delivery vehicles and proteins, including haptens, or other entities that can be made detectable, for example, by incorporating a radiolabel into a peptide or antibody that specifically reacts with a target peptide. The detectable moiety is a monovalent detectable substance or a detectable substance that can form a bond with another composition.

[0023] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with embodiments of the present disclosure include: 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu,64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra and 225 Paramagnetic ions that may be used as additional imaging agents in accordance with embodiments of the present disclosure include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0024] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group may be substituted with one or more of many substituents, the substitution is selected in accordance with the principles of chemical bonding and to result in a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions (such as aqueous conditions, neutral conditions, and some known physiological conditions).For example, heterocycloalkyl or heteroaryl is attached to the rest of the molecule through a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0025] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Examples of acceptable salts include inorganic acid salts (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), organic acid salts (such as acetic acid, propionic acid, glutamic acid, and citric acid), and quaternary ammonium salts (such as methyl iodide and ethyl iodide).

[0026] The terms "bond" and "bonded," as used herein, are used according to their clear and ordinary meaning and refer to a bond between atoms or molecules. The bond may be direct or indirect. For example, the bonded atoms or molecules may be direct, e.g., through a covalent bond or linker (e.g., a first linker or a second linker), or indirect, e.g., through a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effect), hydrophobic interactions, etc.).

[0027] The term "capable of binding," as used herein, refers to a moiety (e.g., a compound described herein) that can measurably bind to a target (e.g., NF-κB, Toll-like receptor protein). In embodiments, if a moiety is capable of binding to a target, the moiety can bind with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

[0028] As used herein, the term "conjugate," when referring to two moieties, means that the two moieties are linked together, where the bond or bonds connecting the two moieties may be covalent or non-covalent. In embodiments, the two moieties are covalently linked to one another (e.g., directly or through a covalently linked intermediate). In embodiments, the two moieties are non-covalently linked (e.g., through ionic bond(s), van der Waals bond(s) / interaction, hydrogen bond(s), polar bond(s), or a combination or mixture thereof).

[0029] The term "amino acid" refers to naturally occurring amino acids, synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature. In embodiments, the amino acid may be a protein-bound amino acid (e.g., part of a peptide or protein) or a free amino acid (e.g., not part of a peptide or protein). In embodiments, the free amino acid is administered exogenously.

[0030] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides may likewise be referred to by their commonly accepted one-letter abbreviations.

[0031] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to a moiety not consisting of amino acids. These terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers and to non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as one part.

[0032] The term "fatty acid" is used herein according to its plain and ordinary meaning to refer to a lipid comprising a carboxylic acid having an aliphatic chain. In embodiments, the aliphatic chain is saturated or unsaturated. In embodiments, the aliphatic chain is unbranched. In embodiments, the aliphatic chain contains a number of carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). In embodiments, the fatty acid is an ester. In embodiments, the ester is a triglyceride, a phospholipid, or a cholesteryl ester. In embodiments, the fatty acid has biological activity (e.g., modulates a biological process).

[0033] The term "palmitoylethanolamide" or "PEA" is used herein according to its plain and ordinary meaning and refers to either a synthetic or naturally occurring form of the fatty acid amide palmitoylethanolamide, or a variant or homolog thereof that maintains PEA activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to PEA). In embodiments, the PEA is substantially identical to the compound identified by CAS ID No. 544-31-0, or a variant or homolog having substantial identity thereto. In embodiments, the PEA targets peroxisome proliferator-activated receptor alpha (PPAR-α). In embodiments, the PEA has affinity for G protein-coupled receptors (e.g., GPR55 and GPR119). In embodiments, the PEA is an anti-inflammatory agent. In embodiments, the PEA is an analgesic agent. In embodiments, the PEA is an antibacterial agent. In embodiments, the PEA is an immunomodulatory agent. In embodiments, PEA has neuroprotective effects.

[0034] The terms "acetyl-L-carnitine," "ALCAR," or "ALC" are used herein according to their plain and ordinary meaning to refer to any synthetic or naturally occurring form of acetyl-L-carnitine, or a variant or homolog thereof that maintains acetyl-L-carnitine activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to acetyl-L-carnitine). In embodiments, the acetyl-L-carnitine is substantially identical to the compound identified by CAS ID No. 14992-62-2, or a variant or homolog having substantial identity thereto.

[0035] The terms "alpha lipoic acid" or "α-lipoic acid" are used herein according to their plain and ordinary meaning and refer to any synthetic or naturally occurring form of α-lipoic acid, also known as thioctic acid, or a variant or homolog thereof that maintains α-lipoic acid activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to α-lipoic acid). In embodiments, the α-lipoic acid is substantially identical to the compound identified by CAS ID No. 1077-28-7, or a variant or homolog having substantial identity thereto.

[0036] The term "olesoxime" is used herein according to its plain and ordinary meaning and refers to any form of olesoxime, also known as TRO19622, or any variant or homolog thereof that maintains olesoxime activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to olesoxime). In embodiments, olesoxime is substantially identical to the compound identified by CAS ID No. 22033-87-0, or a variant or homolog having substantial identity thereto.

[0037] As used herein, the terms "nucleic acid," "nucleic acid molecule," "nucleic acid oligomer," "oligonucleotide," "nucleic acid sequence," "nucleic acid fragment," and "polynucleotide" are used interchangeably and are intended to include polymeric forms of covalently linked nucleotides that can be of various lengths, including, but not limited to, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives, or modifications thereof. Different polynucleotides may have different three-dimensional structures and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include genes, gene fragments, exons, introns, intergenic DNA (including, but not limited to, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA sequences, isolated RNA sequences, nucleic acid probes, and primers. Polynucleotides useful in the methods of the present disclosure include naturally occurring nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or combinations of such sequences.

[0038] A polynucleotide is typically composed of a specific sequence of the four nucleotide bases adenine (A), cytosine (C), guanine (G), and thymine (T) (or uracil (U) instead of thymine (T) if the polynucleotide is RNA). Thus, the term "polynucleotide sequence" refers to the alphabetical representation of a polynucleotide molecule, or the term may apply to the polynucleotide molecule itself. This alphabetical representation can be entered into a database on a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. A polynucleotide may optionally contain one or more non-standard nucleotide(s), nucleotide analog(s), and / or modified nucleotides.

[0039] The term "N-acylethanolamine hydrolyzing acid amidase," "N-acylethanolamine acid amidohydrolase," or "NAAA" is used herein according to its plain ordinary meaning to refer to either a recombinant or naturally occurring form of N-acylethanolamine acid amidohydrolase, or a variant or homolog thereof that maintains NAAA activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to NAAA). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring NAAA protein. In an embodiment, the NAAA protein is substantially identical to the protein identified by UniProt reference number Q02083, or a variant or homologue having substantial identity thereto.

[0040] The term "fatty acid amide hydrolase" or "FAAH" is used herein according to its plain ordinary meaning and refers to either a recombinant or naturally occurring form of fatty acid amide hydrolase, or a variant or homolog thereof that maintains FAAH activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to FAAH). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring FAAH protein. In embodiments, the FAAH protein is substantially identical to a protein identified by UniProt reference number O00519, or a variant or homolog having substantial identity thereto. In embodiments, the FAAH protein is substantially identical to the protein identified by UniProt reference number Q6GMR7, or a variant or homologue having substantial identity thereto.

[0041] The term "peroxisome proliferator-activated receptor alpha," or "PPARα," is used herein according to its plain and ordinary meaning and refers to either a recombinant or naturally occurring form of peroxisome proliferator-activated receptor alpha, also known as nuclear receptor subfamily 1, group C, member 1 (NR1C1), or a variant or homolog thereof that maintains PPARα activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to PPARα). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring PPARα protein. In embodiments, the PPARα protein is substantially identical to the protein identified by UniProt reference number Q07869, or a variant or homologue having substantial identity thereto.

[0042] "Contacting" is used according to its plain and ordinary meaning to refer to the process of bringing at least two distinct species (e.g., chemical compounds, including biological molecules or cells) into sufficient proximity to react, interact, or physically touch, although it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.

[0043] The term "contacting" includes allowing two species to react, interact, or come into physical contact, where the two species may be a compound described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway.

[0044] As defined herein, the terms "activation," "activate," "activating," "activator," and the like, with respect to protein-inhibitor interactions, refer to positively affecting (e.g., increasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator. In embodiments, activation refers to positively affecting (e.g., increasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the activator. These terms can refer to activating, activating, sensitizing, or upregulating signaling or enzymatic activity, or the amount of a protein that is decreased in a disease. Thus, activation can include, at least in part, partially or fully, increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signaling or enzymatic activity or the amount of a protein associated with a disease (e.g., a protein that is decreased in a disease compared to a disease-free control). Activation can include, at least in part, partially or fully, increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signaling or enzymatic activity or the amount of a protein.

[0045] The terms "agonist," "activator," "upregulator," and the like refer to a substance that can detectably increase the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In certain examples, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more higher than the expression or activity in the absence of the agonist.

[0046] An "inhibitor" refers to a compound (e.g., a compound described herein) that reduces activity when compared to a control, such as the absence of the compound or a compound known to be inactive.

[0047] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to protein-inhibitor interactions, refer to negatively affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptom. In embodiments, inhibition refers to a decrease in the activity of a specific protein target. Thus, inhibition includes, at least in part, partially, or fully, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a decrease in the activity of a target protein that occurs as a result of a direct interaction (e.g., an inhibitor binding to a target protein). In embodiments, inhibition refers to a decrease in the activity of a target protein due to an indirect interaction (e.g., an inhibitor binding to a protein that activates the target protein, thereby preventing activation of the target protein).

[0048] The terms "inhibitor," "repressor," "antagonist," or "downregulator" refer synonymously to a substance capable of detectably reducing the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more lower than the expression or activity in the absence of the antagonist.

[0049] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a target of the molecule compared to the absence of the modulator.

[0050] The term "modulate" is used according to its plain and ordinary meaning and refers to the act of altering or changing one or more properties. "Modulation" refers to the process of altering or changing one or more properties. For example, when applied to the effect of a modulator on a target protein, modulating means altering the property or function of the target molecule, or the amount of the target molecule, by increasing or decreasing it.

[0051] The term "associated with" or "associated with" in reference to a substance or the activity or function of a substance associated with a disease (e.g., a protein-related disease, cancer (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease)) means that the disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) is caused (in whole or in part) by the substance or the activity or function of the substance, or the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance. As used herein, something described as associated with a disease, if it is a causative agent, can be a target for the treatment of the disease.

[0052] As used herein, a "therapeutic agent" or "drug" refers to an agent (e.g., a compound or composition) that, when administered to a subject, has an intended preventative effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition, or a symptom thereof, or an intended therapeutic effect, such as treating or ameliorating (including any objective or subjective parameter of treatment, such as alleviating; remission; reducing symptoms or making the injury, lesion, or condition more tolerable to the patient; slowing the rate of degeneration or wasting; reducing the wasting of the final stage of degeneration; or improving the patient's physical or mental health) an injury, disease, lesion, or condition, or a symptom thereof. The drug moiety is a monovalent drug. The therapeutic moiety is a monovalent therapeutic agent.

[0053] The term "disease" or "condition" refers to a state or condition of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In yet some other examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid cancers and cancers of the lymphatic system, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer (including hepatocellular carcinoma), lymphomas (including acute B lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma, large cell lymphoma), Hodgkin's lymphoma), leukemias (including AML, ALL, and CML), or multiple myeloma.

[0054] The term "treating" or "treatment" refers to an indication of success in therapy or improvement of an injury, disease, lesion, or condition, and includes objective or subjective parameters. Objective or subjective parameters include palliation, remission, reduction of symptoms or making the injury, lesion, or condition more tolerable to the patient, slowing the rate of degeneration or decline, making the final stage of degeneration less debilitating, and improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on subjective or objective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, medical condition, state, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0055] As used herein, "treating" or "treatment" (as well understood in the art) broadly includes any approach to obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or pathology, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of the spread or spread of disease, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission, whether partial or total, and whether detectable or undetectable. In other words, as used herein, "treatment" includes any cure, amelioration, or prevention of disease. Treatment can prevent the onset of disease, inhibit the spread of disease, alleviate symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0056] As used herein, "treating" and "treatment" include prophylactic treatment. A method of treatment involves administering a therapeutically effective amount of an active agent to a subject. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dosage of an agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Dosage changes may occur and be evident using standard diagnostic assays known in the art. In some cases, long-term administration may be required. For example, a composition is administered to a subject in an amount and for a period sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0057] The term "preventing" refers to reducing the occurrence of disease symptoms in a patient. As noted above, prevention may be complete (no detectable symptoms) or partial, with milder symptoms observed than would occur in the absence of treatment.

[0058] As used herein, a "pathological condition" includes inflammatory conditions, neurodegenerative diseases, pain, corneal neovascularization, diabetic retinopathy, dry macular degeneration, migraine, neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, diabetic neuropathy, chronic pain, nociceptive pain, complex regional pain syndrome (CRPS), neuropathic pain (including, but not limited to, neuropathic pain, central pain, and deafferentation pain), peripheral or polyneuropathic pain, toxic neuropathy, and the like. The term "pain" refers to pain caused by chronic pain, including neuropathies, chronic neuropathy caused by chemotherapy and antiviral agents, nociceptive pain, or pruritus caused by uremia, pain associated with cancer, malignancies of various etiologies, polycythemia, jaundice or cholestasis, iron deficiency, tinea pedis, xerosis, wound healing, thyroid disease, hyperparathyroidism, or menopause, glossopharyngeal neuralgia, occipital neuralgia, pain, postherpetic neuralgia, retinopathy of prematurity, sinus headache, trigeminal neuralgia, or wet macular degeneration. In embodiments, pain, particularly severe pain, can be a stressor. In embodiments, provided herein are methods of treating chronic pain conditions, including neuropathic pain and chronic or intermittent pain associated with chronic health conditions, as such conditions often result in significant stressors.

[0059] In embodiments, "neuropathic pain" may include pain caused by a primary lesion or dysfunction of the nervous system. Such pain may be chronic, with persistent dysfunction resulting from damage or degeneration of nerves, plexuses, or perineural soft tissues, maintaining an abnormal state of increased pain sensation with a continuing, e.g., decreased pain threshold. Such damage or degeneration may be caused by wounds, pressure, infection, cancer, ischemia, or metabolic or nutritional disorders such as diabetes. Neuropathic pain may include, but is not limited to, neuropathic allodynia, in which pain sensations are induced by mechanical, thermal, or other stimuli that do not normally cause pain, and neuropathic hyperalgesia, in which excessive pain occurs in response to stimuli that are less painful than normally experienced. Examples of neuropathic pain include diabetic polyneuropathy, entrapment neuropathy, phantom limb pain, thalamic pain after stroke, postherpetic neuralgia, atypical facial neuralgia such as after tooth extraction, spinal cord injury, trigeminal neuralgia, and cancer pain resistant to narcotic analgesics such as morphine. In embodiments, neuropathic pain includes pain caused by damage to either central or peripheral nerves. In embodiments, it includes pain caused by either mononeuropathy or polyneuropathy (e.g., familial amyloid polyneuropathy). In embodiments, compared to inflammatory pain, neuropathic pain is resistant to treatment with nonsteroidal anti-inflammatory drugs and opioid substances (e.g., morphine). Neuropathic pain may be bilateral at mirror-image sites or distributed roughly according to the distribution of the injured nerve, may persist for months to years, and may be experienced as burning, tingling, shooting, throbbing, stabbing, electric shock, or other unpleasant sensations.

[0060] The term "acute pain" is used according to its plain and ordinary meaning and refers to a physiological response and experience to a noxious stimulus. In embodiments, acute pain is of sudden onset and limited duration. As used herein, the term "acute pain state" is a state of acute pain.

[0061] The term "chronic pain" is used according to its plain and ordinary meaning and refers to pain that lasts for three or more consecutive months. In embodiments, chronic pain lasts for six or more months. As used herein, the term "chronic pain condition" refers to a chronic pain condition.

[0062] The term "pain hypersensitivity" is used interchangeably with "hyperalgesia" and "allodynia" and includes an abnormal increase in sensitivity to stimuli that are normally painful (hyperalgesia) and an abnormal increase in sensitivity to stimuli that are normally not painful (allodynia). Opioid-induced hyperalgesia can develop as a result of the long-term use of opioids in the treatment of chronic pain.

[0063] As used herein, the term "inflammatory condition" refers to a disease or condition characterized by abnormal inflammation (e.g., elevated levels of inflammation compared to a control, such as a healthy person not afflicted with the disease). Examples of inflammatory conditions include postoperative cognitive impairment, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0064] As used herein, the term "neurodegenerative disorder" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative disorders that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voght-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstoma disease, and others. These include: Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, dementia with Lewy bodies, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, myalgic encephalomyelitis, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various variants with features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, and spinal cord fistula.

[0065] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0066] An "effective amount" is an amount of a compound sufficient to achieve a stated purpose (e.g., achieve the effect for which the compound is administered, treat a disease, reduce enzyme activity, increase enzyme activity, attenuate a signaling pathway, or alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "reduction" of one or more symptoms (and grammatical equivalents of this phrase) means that the severity or frequency of the symptom(s) is reduced, or the symptom(s) disappears. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended preventative effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition, or their symptoms. A complete preventative effect does not necessarily occur by administering a single dose, but may occur only after administering a series of doses. Thus, a prophylactically effective amount can be administered in one or more doses. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, "function-perturbing amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist. The exact amount will depend on the purpose of treatment and can be ascertained by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0067] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound(s) that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0068] As is well known in the art, the therapeutically effective amount for use in humans can also be determined from animal models.For example, the dosage for humans can be formulated to achieve the concentration found to be effective in animals.The dosage for humans can be adjusted by observing the effectiveness of the compound and adjusting the dosage upward or downward as described above.Adjusting the dosage to achieve maximum efficacy in humans based on the above-mentioned method and other methods is well within the capabilities of those skilled in the art.

[0069] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to improve a disorder, as described above. For example, for a given parameter, a therapeutically effective amount may exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness may also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount may be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more than the control.

[0070] Dosage may vary depending on the requirements of the patient and the compound used. The dose administered to a patient, in the context of the present disclosure, should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of a physician. Generally, treatment is initiated with small dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments, depending on the situation, until the optimum effect is achieved. Dosage amount and interval can be individually adjusted to provide a level of the administered compound that is effective for the particular clinical indication being treated. This provides a treatment regimen commensurate with the severity of the individual's disease state.

[0071] As used herein, the term "administering" is used according to its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. In embodiments, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In embodiments, administering does not include administering any active agents other than the listed active agents.

[0072] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies. The compounds provided herein may be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (two or more compounds). Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation). The compositions of the present disclosure may be delivered topically, transdermally, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0073] The compounds described herein can be used in combination with each other, with other active agents known to be useful in treating diseases associated with cells expressing disease-associated cellular components, or with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0074] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-administration, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunct agents may be linked or conjugated to each other.

[0075] By way of non-limiting example, the compounds described herein include alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.), antimetabolites (e.g., 5-fluorouracil, azathioprine, methotrexate, leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllum, etc.), and the like. The compound may be co-administered with anti-cancer or conventional chemotherapeutic agents, including but not limited to, toxins, paclitaxel, docetaxel, etc., topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), anti-tumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin, etc.), etc.

[0076] In therapeutic applications for the treatment of disease, the compounds utilized in the pharmaceutical compositions of the present invention may be administered at an initial dosage of about 0.001 mg / kg to about 1000 mg / kg per day. Daily dosage ranges of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg may also be used. However, dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug being utilized. For example, dosages can be empirically determined, taking into account the type and stage of cancer diagnosed in a particular patient. The dosage administered to a patient, in the context of the present invention, should be sufficient to provide the patient with a beneficial therapeutic response over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that may accompany the administration of the compound in a particular patient. Determining the appropriate dosage for a particular situation is within the skill of the physician. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments, depending on the circumstances, until the optimum effect is reached. For convenience, the total daily dosage may be divided and administered in multiple doses during the day, if desired.

[0077] The compounds described herein can be used in combination with each other, with other active agents known to be useful in the treatment of cancer, or with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0078] University), H16 (Kansas State University), oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), noscapine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (e.g., desmethyleleutherobin, desacetyleleutherobin, isoeluterobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylhistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institute) Institutes, and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to I, triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitum Mab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OS Anticancer drug moieties include, but are not limited to, I-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. The anticancer drug moiety is a monovalent anticancer drug (e.g., a monovalent form of the drugs listed above).

[0079] "Chemotherapeutic drug" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0080] "Anti-diabetic agent" or "antidiabetic agent" is used according to its plain and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) capable of lowering blood glucose levels in a subject. In some embodiments, an antidiabetic agent is an agent identified herein that has utility in methods for treating diabetes. In some embodiments, an antidiabetic agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of diabetes. Examples of antidiabetic agents include insulin, insulin sensitizers (e.g., biguanides (e.g., metformin, phenformin, or buformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone)), secretagogues (e.g., sulfonylureas (e.g., tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glibenclamide, glimepiride, gliclazide, glycopyramide, gliquidone), meglitinides (e.g., repaglinide, nateglinide)), α-glucosidase inhibitors (e.g., miglitol, acarbose, voglibose), peptide analogue antidiabetic agents (e.g., incretins (glucagon-like peptide-1, gastric inhibitory peptide), glucagon-like peptide agonists (e.g., exenatide, liraglutide, taspoglutide), gastric inhibitory peptide analogues, or dipeptidyl peptidase-4 inhibitors (e.g., vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin), amylin agonist analogues (e.g., pramlintide).

[0081] The terms "N-acylethanolamine acid amidase," "NAAA," and "hNAAA" are used according to their clear and ordinary meaning in the art to refer to the 31 kDa enzyme of the same name involved in the hydrolysis of non-peptide amides. The term "NAAA" may refer to the nucleotide sequence or protein sequence of human NAAA (e.g., Entrez27163, Uniprot Q02083, RefSeq NM_014435, or RefSeq NP_055250). The term "NAAA" includes both the wild-type form of the nucleotide sequence or protein, as well as any mutants thereof. In some embodiments, "NAAA" is a wild-type NAAA receptor. In some embodiments, "NAAA" is one or more mutant forms. The term "NAAA"XYZ refers to the nucleotide sequence or protein of a mutant NAAA, where the wild-type NAAA normally has the X amino acid, but the mutant has the Z amino acid instead. In embodiments, the NAAA is human NAAA. In embodiments, the NAAA has a nucleotide sequence corresponding to reference number GI:109148549. In embodiments, the NAAA has a nucleotide sequence corresponding to RefSeq NM_014435.3. In embodiments, the NAAA has a protein sequence corresponding to reference number GI:109148550. In embodiments, the NAAA has a protein sequence corresponding to RefSeq NP_055250.2. In embodiments, the NAAA functions under acidic conditions (e.g., pH about 4.5-5.0).

[0082] The term "FAAH" refers to mammalian fatty acid amide hydrolase, including, but not limited to, human, rat, and mouse forms of the enzyme. U.S. Patent No. 6,271,015 discloses isolated and purified forms of FAAH. Fatty amide hydrolase (FAAH) (Deutsch, DG, et al., Prostaglandins Leukot. Essent. Fatty Acid, 66, 201-210 (2002)) catalyzes the synthesis of lipid ethanolamides (Fowler, CJ, et al., Biochem. Pharmacol. 62, 517-526 (2001); Patricelli, MP, et al., Vitam. Horm., 62, 663-674 (2001)), such as anandamide (Devane, WA, et al., Science 258, 1946-1949 (1992)), oleoylethanolamine (Rodriguez de Fonseca, F., et al., Nature (London) 414, 209-212 (2001); Fu, J., et al. al., Nature (London) 425, 90-93 (2003)), and palmitoylethanolamide (Calignano, A., et al., Nature (London) 394, 277-281 (1998); Lambert, DM, et al., Curr. Med. Chem. 9, 663-674 (2002)).Due to the diverse and important physiological roles of fatty acid ethanolamides, a class of small molecules that can block FAAH(s) but do not bind to other endocannabinoid metabolic enzymes such as monoglyceride lipase (MGL) (Dinh, T. P. et al., Proc. Natl. Acad. Sci. USA 99, 10819-10824 (2002)), or cannabinoid receptors, would be advantageous both as pharmacological tools and as prototypes for drug development projects (Piomelli, D., et al., Trends Pharmacol. Sci. 21, 218-224 (2000); Bisogno, T., et al., Curr. Pharm. Des. 8, 533-547 (2002); Yarnell, A., Chem. Eng. News 80(49), 32 (2002); Smith, A., Nat. Rev. Drug Discov.2,92(2003);Wendeler,M.,et al.,Angew.Chem.Int.Ed.42,2938-2941(2003)).

[0083] In this disclosure, "comprises," "comprising," "containing," and "having," etc., may have the meanings ascribed to them in U.S. patent law and may also mean "includes," "including," etc. "Consisting essentially of" or "consists essentially" also have the meanings ascribed to them in U.S. patent law, except that the terms are open-ended and permit the presence of more than what is recited, but exclude prior art embodiments, so long as the basic or novel characteristics of what is recited are not altered by the presence of more than what is recited.

[0084] II. Composition Provided herein, inter alia, are compositions for treating or preventing (e.g., treating) pain in a subject in need thereof, comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide and / or a pharmaceutically acceptable salt thereof.

[0085] In embodiments, the fatty acid amide is palmitoylethanolamide (PEA), oleoylethanolamide (OEA), erucylethanolamide, or stearoylethanolamide (SEA).

[0086] In embodiments, the purified fatty acid is oleic acid, palmitic acid, or erucic acid.

[0087] In embodiments, the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0088] In embodiments, the purified free amino acid is L-arginine, L-asparagine, L-isoleucine, L-leucine, L-methionine, L-proline, L-serine, L-threonine, or L-tyrosine.

[0089] In embodiments, the purified free amino acid is ornithine, citrulline, or argininosuccinic acid.

[0090] In embodiments, the purified free amino acid is an acylated amino acid, in embodiments, the acetylated amino acid is N-acetyl-L-phenylalanine, N-acetylhistidine, N-acetylthreonine, N-acetylasparagine, N-methyl-L-isoleucine, or N-acetylornithine.

[0091] In embodiments, the composition comprises at least two fatty acids. In embodiments, the composition comprises at least three fatty acids.

[0092] In embodiments, the composition comprises at least two purified free amino acids. In embodiments, the composition comprises at least three purified free amino acids. In embodiments, the composition comprises at least four purified free amino acids. In embodiments, the composition comprises at least five purified free amino acids. In embodiments, the composition comprises at least six purified free amino acids. In embodiments, the composition comprises at least seven purified free amino acids. In embodiments, the composition comprises at least eight purified free amino acids. In embodiments, the composition comprises at least nine purified free amino acids. In embodiments, the composition comprises at least ten purified free amino acids. In embodiments, the composition comprises at least eleven purified free amino acids. In embodiments, the composition comprises at least twelve purified free amino acids.

[0093] In one embodiment, the composition has an amino acid to fatty acid amide ratio of 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 70:1, 80:1, 90:1, or 100:1 weight / weight (w / w).

[0094] In one embodiment, the composition has a fatty acid / fatty acid amide ratio of 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 70:1, 80:1, 90:1, or 100:1 weight / weight (w / w).

[0095] In one embodiment, the composition has an amino acid to fatty acid amide ratio of 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 70:1, 80:1, 90:1, or 100:1 weight / weight (w / w).

[0096] In one embodiment, the composition has an amino acid / fatty acid ratio of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, or 20:1 weight / weight (w / w).

[0097] In one aspect, a composition for treating pain in a subject in need thereof, comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA).

[0098] In one aspect, a composition for preventing pain in a subject in need thereof, comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA).

[0099] In one embodiment, the composition further comprises a pharmaceutical agent, wherein the pharmaceutical agent is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

[0100] In one aspect, the composition is a liquid. In one aspect, the composition is a solid. In one aspect, the composition is a powder. In one aspect, the powder can be dissolved in a liquid suitable for human consumption, such as water or fruit juice. In one aspect, the composition may be in a suitable form, such as a solid bar, a paste, a gel, a tablet, a capsule, or a liquid.

[0101] In one aspect, the composition further comprises a pharmaceutically acceptable excipient, such as a binder (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), a filler (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), a lubricant (e.g., magnesium stearate, talc, or silica), a disintegrant (e.g., potato starch or sodium starch glycolate), or an inhibitor (e.g., sodium lauryl sulfate). In one aspect, the tablet can be coated by methods well known in the art. In one aspect, liquid preparations for oral administration can be in the form of, for example, a solution, syrup, or suspension, or can be in the form of a lyophilized product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).

[0102] In one embodiment, the composition further comprises a sweetening agent (e.g., sucrose, fructose, honey, or molasses) or a sweetener, such as an artificial sweetener (e.g., lactitol, maltitol, cyclamate, aspartame, isomalt, mannitol, sorbitol, xylitol, or erythritol).

[0103] In one embodiment, the composition further comprises a flavoring agent.

[0104] In one embodiment, a dosage form of the composition is provided. In one embodiment, the dosage form is a liquid or solid. In one embodiment, the dosage form is a beverage or syrup. In one embodiment, the dosage form is a tablet, capsule, or sachet. In one embodiment, the dosage form comprises about 1 gram to about 150 grams of the composition. In one embodiment, the dosage form comprises about 1 gram to about 10 grams of the composition. In one embodiment, the dosage form comprises about 2 grams to about 9 grams of the composition. In one embodiment, the dosage form comprises about 3 grams to about 8 grams of the composition. In one embodiment, the dosage form comprises about 4 grams to about 7 grams of the composition. In one embodiment, the dosage form comprises about 5 grams to about 6 grams of the composition. In one embodiment, the dosage form comprises about 10 grams to about 20 grams of the composition. In one embodiment, the dosage form comprises about 20 grams to about 30 grams of the composition. In one embodiment, the dosage form comprises about 30 grams to about 40 grams of the composition. In one embodiment, the dosage form comprises about 40 grams to about 50 grams of the composition. In one embodiment, the dosage form comprises about 50 grams to about 60 grams of the composition. In one embodiment, the dosage form comprises about 60 grams to about 70 grams of the composition. In one embodiment, the dosage form comprises about 70 grams to about 80 grams of the composition. In one embodiment, the dosage form comprises about 80 grams to about 90 grams of the composition. In one embodiment, the dosage form comprises about 90 grams to about 100 grams of the composition. In one embodiment, the dosage form comprises about 100 grams to about 110 grams of the composition. In one embodiment, the dosage form comprises about 110 grams to about 120 grams of the composition. In one embodiment, the dosage form comprises about 120 grams to about 130 grams of the composition. In one embodiment, the dosage form comprises about 130 grams to about 140 grams of the composition. In one embodiment, the dosage form comprises about 140 grams to about 150 grams of the composition. In one embodiment, the dosage form comprises about 1 gram of the composition. In one embodiment, the dosage form comprises about 2 grams of the composition. In one embodiment, the dosage form comprises about 3 grams of the composition. In one embodiment, the dosage form comprises about 4 grams of the composition. In one embodiment, the dosage form comprises about 5 grams of the composition. In one embodiment, the dosage form comprises about 6 grams of the composition. In one embodiment, the dosage form comprises about 7 grams of the composition. In one embodiment, the dosage form comprises about 8 grams of the composition. In one embodiment, the dosage form comprises about 9 grams of the composition. In one embodiment, the dosage form comprises about 10 grams of the composition. In one embodiment, the dosage form comprises about 20 grams of the composition. In one embodiment, the dosage form comprises about 30 grams of the composition.In one embodiment, the dosage form comprises about 40 grams of the composition. In one embodiment, the dosage form comprises about 50 grams of the composition. In one embodiment, the dosage form comprises about 60 grams of the composition. In one embodiment, the dosage form comprises about 70 grams of the composition. In one embodiment, the dosage form comprises about 80 grams of the composition. In one embodiment, the dosage form comprises about 90 grams of the composition. In one embodiment, the dosage form comprises about 100 grams of the composition. In one embodiment, the dosage form comprises about 110 grams of the composition. In one embodiment, the dosage form comprises about 120 grams of the composition. In one embodiment, the dosage form comprises about 130 grams of the composition. In one embodiment, the dosage form comprises about 140 grams of the composition. In one embodiment, the dosage form comprises about 150 grams of the composition.

[0105] III. Method Provided herein, inter alia, are methods for treating or preventing (e.g., treating) pain in a subject in need thereof, comprising administering to a patient in need thereof a composition described herein.

[0106] In one aspect, a method of treating pain in a subject in need thereof is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0107] In one aspect, a method of treating pain in a subject in need thereof is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA).

[0108] In one aspect, a method of preventing chronic pain in a subject in need thereof is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0109] In one aspect, a method of preventing chronic pain in a subject after a traumatic painful event is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein chronic pain is prevented in the subject.

[0110] In one aspect, a method of preventing peripheral neuropathic pain in a subject with cancer is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0111] In one aspect, a method of preventing peripheral neuropathic pain in a subject with cancer is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein chronic pain is prevented in the subject.

[0112] In one aspect, a method of preventing chronic pain in a diabetic subject is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0113] In one aspect, a method of preventing chronic pain in a diabetic subject is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein chronic pain is prevented in the subject.

[0114] In one aspect, a method of reducing pain hypersensitivity in a subject after a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein pain hypersensitivity is reduced in the subject.

[0115] In one aspect, a method of reducing pain hypersensitivity in a subject after a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein pain hypersensitivity is reduced in the subject.

[0116] In embodiments, the pain hypersensitivity is caused by acute / inflammatory pain. In embodiments, the inflammatory pain involves IL-6.

[0117] In an aspect, the composition is administered orally. In an aspect, the composition is provided as a food supplement. In one aspect, the composition is administered without food. In an aspect, the oral dosage form is selected from the group consisting of tablets, capsules, granules, powders, oily pearls, solutions, suspensions, and aerosols.

[0118] In an embodiment, the at least one purified fatty acid is oleic acid or erucic acid. In an embodiment, the composition comprises oleic acid and erucic acid.

[0119] In embodiments, the at least one purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan. In embodiments, the composition comprises at least two purified free amino acids. In embodiments, the composition comprises at least three purified free amino acids. In embodiments, the composition comprises at least four purified free amino acids. In embodiments, the composition comprises at least five purified free amino acids. In embodiments, the composition comprises at least six purified free amino acids. In embodiments, the composition comprises at least seven purified free amino acids. In embodiments, the composition comprises at least eight purified free amino acids. In embodiments, the composition comprises at least nine purified free amino acids. In embodiments, the composition comprises at least ten purified free amino acids. In embodiments, the composition comprises at least eleven purified free amino acids. In embodiments, the composition comprises at least twelve purified free amino acids.

[0120] In embodiments, the dosage of each of the one or more compounds is shown in Table 1. [Table 1]

[0121] In embodiments, dosage ranges for each of the one or more compounds are provided in Table 2. [Table 2]

[0122] In one embodiment, the dosage of PEA is about 0.8 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 0.9 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 1 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 2 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 3 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 4 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 5 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 6 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 7 mg / kg to about 9 mg / kg. In another embodiment, the dosage of PEA is about 8 mg / kg to about 9 mg / kg.

[0123] In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 8 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 7 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 6 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 5 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 4 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 3 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 2 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 1 mg / kg. In an embodiment, the dosage of PEA is about 0.8 mg / kg to about 0.9 mg / kg.

[0124] In an embodiment, the dosage of PEA is 0.8 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 0.9 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 1 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 2 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 3 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 4 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 5 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 6 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 7 mg / kg to 9 mg / kg. In an embodiment, the dosage of PEA is 8 mg / kg to 9 mg / kg.

[0125] In an embodiment, the dosage of PEA is 0.8 mg / kg to 8 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to about 7 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 6 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 5 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 4 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 3 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 2 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 1 mg / kg. In an embodiment, the dosage of PEA is 0.8 mg / kg to 0.9 mg / kg.

[0126] In one embodiment, the dosage of oleic acid is about 48 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 49 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 50 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 75 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 100 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 150 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 200 mg / kg to about 496 mg / kg. In another embodiment, the dosage of oleic acid is about 250 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 300 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 350 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 400 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 450 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 475 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 490 mg / kg to about 496 mg / kg. In an embodiment, the dosage of oleic acid is about 495 mg / kg to about 496 mg / kg.

[0127] In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 495 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 490 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 475 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 450 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 400 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 350 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 300 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 250 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 200 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 150 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 100 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 75 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 50 mg / kg. In an embodiment, the dosage of oleic acid is about 48 mg / kg to about 49 mg / kg.

[0128] In an embodiment, the dosage of oleic acid is 48 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 49 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 50 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 75 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 100 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 150 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 200 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 250 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 300 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 350 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 400 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 450 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 475 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 490 mg / kg to 496 mg / kg. In an embodiment, the dosage of oleic acid is 495 mg / kg to 496 mg / kg.

[0129] In an embodiment, the dosage of oleic acid is 48 mg / kg to 495 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 490 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 475 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 450 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 400 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 350 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 300 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 250 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 200 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 150 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 100 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 75 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 50 mg / kg. In an embodiment, the dosage of oleic acid is 48 mg / kg to 49 mg / kg.

[0130] In one embodiment, the dosage of erucic acid is about 2 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 3 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 4 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 5 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 6 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 7 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 8 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 9 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 10 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 11 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 12 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 13 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 14 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 15 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 16 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 17 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 18 mg / kg to about 25 mg / kg. In an embodiment, the dosage of erucic acid is about 19 mg / kg to about 25 mg / kg. In one embodiment, the dosage of erucic acid is about 20 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 21 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 22 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 23 mg / kg to about 25 mg / kg. In another embodiment, the dosage of erucic acid is about 24 mg / kg to about 25 mg / kg.

[0131] In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 24 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 23 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 22 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 21 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 20 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 19 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 18 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 17 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 16 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 15 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 14 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 13 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 12 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 11 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 10 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 9 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 8 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 7 mg / kg. In an embodiment, the dosage of erucic acid is about 2 mg / kg to about 6 mg / kg. In one embodiment, the dosage of erucic acid is about 2 mg / kg to about 5 mg / kg. In another embodiment, the dosage of erucic acid is about 2 mg / kg to about 4 mg / kg. In another embodiment, the dosage of erucic acid is about 2 mg / kg to about 3 mg / kg.

[0132] In one embodiment, the dosage of erucic acid is 2 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 3 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 4 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 5 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 6 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 7 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 8 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 9 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 10 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 11 mg / kg to 25 mg / kg. In one embodiment, the dosage of erucic acid is 12 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 13 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 14 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 15 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 16 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 17 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 18 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 19 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 20 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 21 mg / kg to 25 mg / kg. In one embodiment, the dosage of erucic acid is 22 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 23 mg / kg to 25 mg / kg. In another embodiment, the dosage of erucic acid is 24 mg / kg to 25 mg / kg.

[0133] In an embodiment, the dosage of erucic acid is 2 mg / kg to 24 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 23 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 22 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 21 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 20 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 19 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 18 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 17 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 16 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 15 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 14 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 13 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 12 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 11 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 10 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 9 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 8 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 7 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 6 mg / kg. In an embodiment, the dosage of erucic acid is 2 mg / kg to 5 mg / kg. In one embodiment, the dosage of erucic acid is 2 mg / kg to 4 mg / kg.In one embodiment, the dosage of erucic acid is 2 mg / kg to 3 mg / kg.

[0134] In one embodiment, the dosage of alanine is about 20 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 25 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 30 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 40 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 50 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 75 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 100 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 125 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 150 mg / kg to about 189 mg / kg. In one embodiment, the dosage of alanine is about 175 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 180 mg / kg to about 189 mg / kg. In another embodiment, the dosage of alanine is about 185 mg / kg to about 189 mg / kg.

[0135] In an embodiment, the dosage of alanine is about 20 mg / kg to about 185 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 180 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 175 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 150 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 125 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 100 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 75 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 50 mg / kg. In an embodiment, the dosage of alanine is about 20 mg / kg to about 40 mg / kg. In one embodiment, the dosage of alanine is about 20 mg / kg to about 30 mg / kg, and in another embodiment, the dosage of alanine is about 20 mg / kg to about 25 mg / kg.

[0136] In an embodiment, the dosage of alanine is 20 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 25 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 30 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 40 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 50 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 75 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 100 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 125 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 150 mg / kg to 189 mg / kg. In an embodiment, the dosage of alanine is 175 mg / kg to 189 mg / kg. In one embodiment, the dosage of alanine is 180 mg / kg to 189 mg / kg. In another embodiment, the dosage of alanine is 185 mg / kg to 189 mg / kg.

[0137] In an embodiment, the dosage of alanine is 20 mg / kg to 185 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 180 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 175 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 150 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 125 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 100 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 75 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 50 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 40 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 30 mg / kg. In an embodiment, the dosage of alanine is 20 mg / kg to 25 mg / kg.

[0138] In one embodiment, the dose of threonine is about 12 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 13 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 14 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 15 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 20 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 30 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 40 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 50 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 60 mg / kg to about 130 mg / kg. In one embodiment, the dose of threonine is about 70 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 80 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 90 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 100 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 110 mg / kg to about 130 mg / kg. In another embodiment, the dose of threonine is about 120 mg / kg to about 130 mg / kg.

[0139] In an embodiment, the dose of threonine is about 12 mg / kg to about 120 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 110 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 100 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 90 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 80 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 70 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 60 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 50 mg / kg. In an embodiment, the dose of threonine is about 12 mg / kg to about 40 mg / kg. In one embodiment, the dose of threonine is about 12 mg / kg to about 30 mg / kg. In another embodiment, the dose of threonine is about 12 mg / kg to about 20 mg / kg. In another embodiment, the dose of threonine is about 12 mg / kg to about 15 mg / kg. In another embodiment, the dose of threonine is about 12 mg / kg to about 14 mg / kg. In another embodiment, the dose of threonine is about 12 mg / kg to about 13 mg / kg.

[0140] In an embodiment, the dosage of threonine is 12 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 13 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is about 14 mg / kg to about 30 mg / kg. In an embodiment, the dosage of threonine is 15 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 20 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 30 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 40 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 50 mg / kg to 130 mg / kg. In an embodiment, the dosage of threonine is 60 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 70 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 80 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 90 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 100 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 110 mg / kg to 130 mg / kg. In one embodiment, the dosage of threonine is 120 mg / kg to 130 mg / kg.

[0141] In an embodiment, the dosage of threonine is 12 mg / kg to 120 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 110 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 100 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 90 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 80 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 70 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 60 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 50 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 40 mg / kg. In an embodiment, the dosage of threonine is 12 mg / kg to 30 mg / kg. In one embodiment, the dosage of threonine is 12 mg / kg to 20 mg / kg. In another embodiment, the dosage of threonine is 12 mg / kg to 15 mg / kg. In another embodiment, the dosage of threonine is 12 mg / kg to 14 mg / kg. In another embodiment, the dosage of threonine is 12 mg / kg to 13 mg / kg.

[0142] In one embodiment, the dosage of proline is about 24 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 25 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 50 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 75 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 100 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 125 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 150 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 175 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 200 mg / kg to about 240 mg / kg. In one embodiment, the dosage of proline is about 225 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 230 mg / kg to about 240 mg / kg. In another embodiment, the dosage of proline is about 235 mg / kg to about 240 mg / kg.

[0143] In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg. In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg.In an embodiment, the dosage of proline is about 24 mg / kg to about 235 mg / kg.

[0144] In an embodiment, the dosage of proline is 24 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 25 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 50 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 75 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 100 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 125 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 150 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 175 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 200 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 225 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 230 mg / kg to 240 mg / kg. In an embodiment, the dosage of proline is 235 mg / kg to 240 mg / kg.

[0145] In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg. In an embodiment, the dosage of proline is 24 mg / kg to 235 mg / kg.

[0146] In one embodiment, the dosage of serine is about 10 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 20 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 30 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 40 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 50 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 60 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 70 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 80 mg / kg to about 100 mg / kg. In another embodiment, the dosage of serine is about 90 mg / kg to about 100 mg / kg.

[0147] In an embodiment, the dosage of serine is about 10 mg / kg to about 90 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 80 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 70 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 60 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 50 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 40 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 30 mg / kg. In an embodiment, the dosage of serine is about 10 mg / kg to about 20 mg / kg.

[0148] In an embodiment, the dosage of serine is 10 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 20 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 30 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 40 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 50 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 60 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 70 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 80 mg / kg to 100 mg / kg. In an embodiment, the dosage of serine is 90 mg / kg to 100 mg / kg.

[0149] In an embodiment, the dosage of serine is 10 mg / kg to 90 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 80 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 70 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 60 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 50 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 40 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 30 mg / kg. In an embodiment, the dosage of serine is 10 mg / kg to 20 mg / kg.

[0150] In one embodiment, the dosage of leucine is about 28 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 29 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 30 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 40 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 50 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 100 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 150 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 200 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 250 mg / kg to about 310 mg / kg. In one embodiment, the dosage of leucine is about 300 mg / kg to about 310 mg / kg. In another embodiment, the dosage of leucine is about 305 mg / kg to about 310 mg / kg.

[0151] In an embodiment, the dosage of leucine is about 28 mg / kg to about 305 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 300 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 250 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 200 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 150 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 100 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 50 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 40 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 30 mg / kg. In an embodiment, the dosage of leucine is about 28 mg / kg to about 29 mg / kg.

[0152] In an embodiment, the dosage of leucine is 28 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 29 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 30 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 40 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 50 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 100 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 150 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 200 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 250 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 300 mg / kg to 310 mg / kg. In an embodiment, the dosage of leucine is 305 mg / kg to 310 mg / kg.

[0153] In an embodiment, the dosage of leucine is 28 mg / kg to 305 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 300 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 250 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 200 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 150 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 100 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 50 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 40 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 30 mg / kg. In an embodiment, the dosage of leucine is 28 mg / kg to 29 mg / kg.

[0154] In one embodiment, the dosage of isoleucine is about 24 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 25 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 50 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 75 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 100 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 125 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 150 mg / kg to about 245 mg / kg. In another embodiment, the dosage of isoleucine is about 175 mg / kg to about 245 mg / kg. In one embodiment, the dose of isoleucine is about 200 mg / kg to about 245 mg / kg. In another embodiment, the dose of isoleucine is about 225 mg / kg to about 245 mg / kg. In another embodiment, the dose of isoleucine is about 240 mg / kg to about 245 mg / kg.

[0155] In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 240 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 225 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 200 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 175 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 150 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 125 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 100 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 75 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 50 mg / kg. In an embodiment, the dosage of isoleucine is about 24 mg / kg to about 25 mg / kg.

[0156] In an embodiment, the dosage of isoleucine is 24 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 25 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 50 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 75 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 100 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 125 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 150 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 175 mg / kg to 245 mg / kg. In an embodiment, the dosage of isoleucine is 200 mg / kg to 245 mg / kg. In one embodiment, the dosage of isoleucine is 225 mg / kg to 245 mg / kg. In another embodiment, the dosage of isoleucine is 240 mg / kg to 245 mg / kg.

[0157] In an embodiment, the dosage of isoleucine is 24 mg / kg to 240 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 225 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 200 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 175 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 150 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 125 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 100 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 75 mg / kg. In an embodiment, the dosage of isoleucine is 24 mg / kg to 50 mg / kg. In one embodiment, the dosage of isoleucine is 24 mg / kg to 25 mg / kg.

[0158] In one embodiment, the dosage of valine is about 22 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 23 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 24 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 25 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 50 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 75 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 100 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 125 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 150 mg / kg to about 230 mg / kg. In one embodiment, the dosage of valine is about 175 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 200 mg / kg to about 230 mg / kg. In another embodiment, the dosage of valine is about 225 mg / kg to about 230 mg / kg.

[0159] In an embodiment, the dosage of valine is about 22 mg / kg to about 225 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 200 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 175 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 150 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 125 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 100 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 75 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 50 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 25 mg / kg. In an embodiment, the dosage of valine is about 22 mg / kg to about 24 mg / kg. In an embodiment, the dosage of valine is from about 22 mg / kg to about 23 mg / kg.

[0160] In an embodiment, the dosage of valine is 22 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 23 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 24 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 25 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 50 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 75 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 100 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 125 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 150 mg / kg to 230 mg / kg. In an embodiment, the dosage of valine is 175 mg / kg to 230 mg / kg. In one embodiment, the dosage of valine is 200 mg / kg to 230 mg / kg. In another embodiment, the dosage of valine is 225 mg / kg to 230 mg / kg.

[0161] In an embodiment, the dosage of valine is 22 mg / kg to 225 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 200 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 175 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 150 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 125 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 100 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 75 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 50 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 25 mg / kg. In an embodiment, the dosage of valine is 22 mg / kg to 24 mg / kg. In one embodiment, the dosage of valine is 22 mg / kg to 23 mg / kg.

[0162] In one embodiment, the dose of phenylalanine is about 15 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 20 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 30 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 40 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 50 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 60 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 70 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 80 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 90 mg / kg to about 150 mg / kg. In one embodiment, the dose of phenylalanine is about 100 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 110 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 120 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 130 mg / kg to about 150 mg / kg. In another embodiment, the dose of phenylalanine is about 140 mg / kg to about 150 mg / kg.

[0163] In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 140 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 130 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 120 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 110 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 100 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 90 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 80 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 70 mg / kg. In an embodiment, the dose of phenylalanine is about 15 mg / kg to about 60 mg / kg. In one embodiment, the dose of phenylalanine is about 15 mg / kg to about 50 mg / kg. In another embodiment, the dose of phenylalanine is about 15 mg / kg to about 40 mg / kg. In another embodiment, the dose of phenylalanine is about 15 mg / kg to about 30 mg / kg. In another embodiment, the dose of phenylalanine is about 15 mg / kg to about 20 mg / kg.

[0164] In one embodiment, the dosage of phenylalanine is 15 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 20 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 30 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 40 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 50 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 60 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 70 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 80 mg / kg to 150 mg / kg. In another embodiment, the dosage of phenylalanine is 90 mg / kg to 150 mg / kg. In an embodiment, the dosage of phenylalanine is 100 mg / kg to 150 mg / kg. In an embodiment, the dosage of phenylalanine is 110 mg / kg to 150 mg / kg. In an embodiment, the dosage of phenylalanine is 120 mg / kg to 150 mg / kg. In an embodiment, the dosage of phenylalanine is 130 mg / kg to 150 mg / kg. In an embodiment, the dosage of phenylalanine is 140 mg / kg to 150 mg / kg.

[0165] In an embodiment, the dosage of phenylalanine is 15 mg / kg to 140 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 130 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 120 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 110 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 100 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 90 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 80 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 70 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 60 mg / kg. In an embodiment, the dosage of phenylalanine is 15 mg / kg to 50 mg / kg. In one embodiment, the dosage of phenylalanine is 15 mg / kg to 40 mg / kg. In another embodiment, the dosage of phenylalanine is 15 mg / kg to 30 mg / kg. In another embodiment, the dosage of phenylalanine is 15 mg / kg to 20 mg / kg.

[0166] In one embodiment, the dosage of tyrosine is about 9 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 10 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 20 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 30 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 40 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 50 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 60 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 70 mg / kg to about 90 mg / kg. In another embodiment, the dosage of tyrosine is about 80 mg / kg to about 90 mg / kg.

[0167] In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 80 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 70 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 60 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 50 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 40 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 30 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 20 mg / kg. In an embodiment, the dosage of tyrosine is about 9 mg / kg to about 10 mg / kg.

[0168] In an embodiment, the dosage of tyrosine is 9 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 10 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 20 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 30 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 40 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 50 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 60 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 70 mg / kg to 90 mg / kg. In an embodiment, the dosage of tyrosine is 80 mg / kg to 90 mg / kg.

[0169] In an embodiment, the dosage of tyrosine is 9 mg / kg to 80 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 70 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 60 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 50 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 40 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 30 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 20 mg / kg. In an embodiment, the dosage of tyrosine is 9 mg / kg to 10 mg / kg.

[0170] In one embodiment, the dose of methionine is about 6 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 7 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 8 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 9 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 10 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 20 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 30 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 40 mg / kg to about 60 mg / kg. In another embodiment, the dose of methionine is about 50 mg / kg to about 60 mg / kg.

[0171] In an embodiment, the dose of methionine is about 6 mg / kg to about 50 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 40 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 30 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 20 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 10 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 9 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 8 mg / kg. In an embodiment, the dose of methionine is about 6 mg / kg to about 7 mg / kg.

[0172] In one embodiment, the dosage of methionine is 6 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 7 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 8 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 9 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 10 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 20 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 30 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 40 mg / kg to 60 mg / kg. In another embodiment, the dosage of methionine is 50 mg / kg to 60 mg / kg.

[0173] In an embodiment, the dosage of methionine is 6 mg / kg to 50 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 40 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 30 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 20 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 10 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 9 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 8 mg / kg. In an embodiment, the dosage of methionine is 6 mg / kg to 7 mg / kg.

[0174] In one embodiment, the dose of cysteine ​​is about 4 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 5 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 10 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 15 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 20 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 25 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 30 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 35 mg / kg to about 45 mg / kg. In another embodiment, the dose of cysteine ​​is about 40 mg / kg to about 45 mg / kg.

[0175] In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 40 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 35 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 30 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 25 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 20 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 15 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 10 mg / kg. In an embodiment, the dosage of cysteine ​​is about 4 mg / kg to about 5 mg / kg.

[0176] In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 5 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 10 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 15 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 20 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 25 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 30 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 35 mg / kg to 45 mg / kg. In an embodiment, the dosage of cysteine ​​is 40 mg / kg to 45 mg / kg.

[0177] In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 40 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 35 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 30 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 25 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 20 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 15 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 10 mg / kg. In an embodiment, the dosage of cysteine ​​is 4 mg / kg to 5 mg / kg.

[0178] In one embodiment, the tryptophan dosage is about 6 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 7 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 8 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 9 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 10 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 15 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 20 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 25 mg / kg to about 61 mg / kg. In another embodiment, the tryptophan dosage is about 30 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 35 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 40 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 45 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 50 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 55 mg / kg to about 61 mg / kg. In one embodiment, the tryptophan dosage is about 60 mg / kg to about 61 mg / kg.

[0179] In an embodiment, the tryptophan dosage is about 6 mg / kg to about 60 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 55 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 50 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 45 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 40 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 35 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 30 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 25 mg / kg. In an embodiment, the tryptophan dosage is about 6 mg / kg to about 20 mg / kg. In one embodiment, the tryptophan dosage is about 6 mg / kg to about 15 mg / kg. In another embodiment, the tryptophan dosage is about 6 mg / kg to about 10 mg / kg. In another embodiment, the tryptophan dosage is about 6 mg / kg to about 9 mg / kg. In another embodiment, the tryptophan dosage is about 6 mg / kg to about 8 mg / kg. In another embodiment, the tryptophan dosage is about 6 mg / kg to about 7 mg / kg.

[0180] In one embodiment, the tryptophan dosage is 6 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 7 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 8 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 9 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 10 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 15 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 20 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 25 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 30 mg / kg to 61 mg / kg. In another embodiment, the tryptophan dosage is 35 mg / kg to 61 mg / kg. In an embodiment, the tryptophan dosage is 40 mg / kg to 61 mg / kg. In an embodiment, the tryptophan dosage is 45 mg / kg to 61 mg / kg. In an embodiment, the tryptophan dosage is 50 mg / kg to 61 mg / kg. In an embodiment, the tryptophan dosage is 55 mg / kg to 61 mg / kg. In an embodiment, the tryptophan dosage is 60 mg / kg to 61 mg / kg.

[0181] In an embodiment, the tryptophan dosage is 6 mg / kg to 60 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 55 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 50 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 45 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 40 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 35 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 30 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 25 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 20 mg / kg. In an embodiment, the tryptophan dosage is 6 mg / kg to 15 mg / kg. In one embodiment, the dosage of tryptophan is 6 mg / kg to 10 mg / kg. In one embodiment, the dosage of tryptophan is 6 mg / kg to 9 mg / kg. In one embodiment, the dosage of tryptophan is 6 mg / kg to 8 mg / kg. In one embodiment, the dosage of tryptophan is 6 mg / kg to 7 mg / kg.

[0182] In one aspect, the method further comprises administering to the subject an effective amount of an agent, wherein the agent is administered between about 1 and 7 days after the traumatic pain event, and the agent is an NAAA (N-acylethanolamine acid amidase) inhibitor, a FAAH (fatty acid amide hydrolase) inhibitor, a PPARα (peroxisome proliferator-activated receptor-α) agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime. In an embodiment, the agent is administered between about 24 and about 96 hours after the traumatic pain event. In an embodiment, the agent is an NAAA (N-acylethanolamine acid amidase) inhibitor. In an embodiment, the agent is a FAAH (fatty acid amide hydrolase) inhibitor. In an embodiment, the agent is a PPARα (peroxisome proliferator-activated receptor-α) agonist. In an embodiment, the agent is PEA (palmitoylethanolamide). In an embodiment, the agent is acetyl-L-carnitine. In embodiments, the agent is alpha-lipoic acid. In embodiments, the agent is olesoxime. In embodiments, the agent is administered in a therapeutically effective amount.

[0183] In embodiments, the pain is neuropathic pain, nociceptive pain, chronic pain, neuropathic glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia, trigeminal neuralgia, postherpetic neuralgia, trigeminal neuralgia, causalgia, diabetic neuropathy, complex regional pain syndrome (CRPS), neuropathic pain, peripheral pain, polyneuropathic pain, toxic neuropathy, chronic neuropathy or pruritus, or acute post-operative pain.

[0184] In embodiments, the composition prevents the transition from an acute pain state to a chronic pain state. In embodiments, the composition prevents chronic pain in a subject with acute pain.

[0185] In embodiments, the subject is a cancer patient. In embodiments, the subject is a diabetes patient.

[0186] In one aspect, a method of preventing chronic pain in a subject is provided, the method comprising administering to the subject an effective amount of a composition pre- or peri-operatively.

[0187] In embodiments, the method comprises administering the composition 1 to 4 times daily. In embodiments, the method comprises administering the composition once daily. In embodiments, the method comprises administering the composition twice daily. In embodiments, the method comprises administering the composition three times daily.

[0188] In embodiments, the method comprises administering the composition between about 0 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 1 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 2 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 3 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 4 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 5 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 6 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 7 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 8 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 9 days and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 10 days and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 15 days and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 20 days and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 25 days and about 30 days after the traumatic pain event.

[0189] In embodiments, the method comprises administering the composition between about 0 and about 25 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 20 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 15 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 10 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 9 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 8 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 7 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 6 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 5 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 4 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 3 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 2 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 and about 1 day after the traumatic pain event.

[0190] In embodiments, the method comprises administering the composition between 0 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 1 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 2 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 3 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 4 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 5 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 6 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 7 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 8 and about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 9 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 10 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 15 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 20 and 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 25 and 30 days after the traumatic pain event.

[0191] In embodiments, the method comprises administering the composition between 0 and 25 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 20 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 15 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 10 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 9 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 8 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 7 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 6 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 5 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 4 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 3 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 2 days after the traumatic pain event. In embodiments, the method comprises administering the composition between 0 and 1 day after the traumatic pain event.

[0192] In embodiments, the method comprises administering the composition between about 30 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 25 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 20 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 15 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 10 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 9 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 8 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 7 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 6 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 5 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 4 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 3 days and about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 2 days and about 1 day before the traumatic pain event.

[0193] In embodiments, the method comprises administering the composition between about 30 days and about 2 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 3 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 4 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 5 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 6 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 7 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 8 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 9 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 10 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 15 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 20 days before the traumatic pain event. In embodiments, the method comprises administering the composition between about 30 days and about 25 days before the traumatic pain event.

[0194] In embodiments, the method comprises administering the composition between 30 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 25 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 20 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 15 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 10 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 9 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between about 8 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 7 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 6 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 5 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 4 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 3 days and 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition between 2 days and 1 day before the traumatic pain event.

[0195] In embodiments, the method comprises administering the composition between 30 days and 2 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 3 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 4 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 5 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 6 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 7 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 8 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 9 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 days and 10 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 and 15 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 and 20 days before the traumatic pain event. In embodiments, the method comprises administering the composition between 30 and 25 days before the traumatic pain event.

[0196] In embodiments, the method comprises administering the composition once daily for 30 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 29 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 28 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 27 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 26 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 25 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 24 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 23 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 22 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 21 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 20 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 19 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 18 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 17 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 16 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 15 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 14 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 13 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 12 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 11 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once daily for 10 days prior to the traumatic pain event.

[0197] In embodiments, the method comprises administering the composition twice daily for 30 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 29 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 28 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 27 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 26 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 25 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 24 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 23 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 22 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 21 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 20 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 19 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 18 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 17 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 16 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 15 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 14 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 13 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 12 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 11 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice daily for 10 days prior to the traumatic pain event.

[0198] In one aspect, the method further comprises administering to the subject an effective amount of an agent, wherein the agent is administered between about 1 and 7 days after the traumatic pain event, and the agent is an NAAA (N-acylethanolamine acid amidase) inhibitor, a FAAH (fatty acid amide hydrolase) inhibitor, a PPARα (peroxisome proliferator-activated receptor-α) agonist, PEA (palmitoylethanolamide), acetyl-L-carnitine, α-lipoic acid, or olesoxime. In an embodiment, the method comprises preventing the transition from an acute pain state to a chronic pain state in the subject. In an embodiment, the agent is administered between about 24 and about 96 hours after the traumatic pain event. In an embodiment, the agent is an NAAA (N-acylethanolamine acid amidase) inhibitor. In an embodiment, the agent is a FAAH (fatty acid amide hydrolase) inhibitor. In an embodiment, the agent is a PPARα (peroxisome proliferator-activated receptor-α) agonist. In embodiments, the agent is PEA (palmitoylethanolamide). In embodiments, the agent is acetyl-L-carnitine. In embodiments, the agent is alpha-lipoic acid. In embodiments, the agent is olesoxime. In embodiments, the agent is administered in a therapeutically effective amount.

[0199] In embodiments, the agent is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, or a PEA. In embodiments, the agent is an NAAA inhibitor. In embodiments, the agent is a FAAH inhibitor. In embodiments, the agent is a PPARα agonist. In embodiments, the agent is PEA.

[0200] In embodiments, the NAAA inhibitor is ARN16186, ARN077, or ARN19702. In embodiments, the NAAA inhibitor is ARN16186. In embodiments, the NAAA inhibitor is ARN077. In embodiments, the NAAA inhibitor is ARN19702. In embodiments, the NAAA inhibitor is described in Med Chem. 2020 Jul 23;63(14):7475-7490, the entire contents of which are incorporated herein by reference for all purposes. In embodiments, the NAAA inhibitor is described in WO2013 / 078430, US2013 / 0281490, WO2009 / 049238, US2014 / 0094508, WO2014 / 144836, US2016 / 0068482, WO2017 / 201103, or US2019 / 0177313, which are incorporated by reference in their entirety for all purposes.

[0201] In embodiments, the FAAH inhibitor is URB597, URB937, an analog of URB597, or an analog of URB937. In embodiments, the FAAH inhibitor is URB597. In embodiments, the FAAH inhibitor is URB937. In embodiments, the FAAH inhibitor is an analog of URB597. In embodiments, the FAAH inhibitor is an analog of URB937. In embodiments, the FAAH inhibitor is described in J Med Chem. 2017 Jan 12;60(1):4-46, the entire contents of which are incorporated herein by reference for all purposes. In embodiments, the FAAH inhibitor is described in WO2015 / 157313, US2017 / 0088510, WO2012 / 015704, US2013 / 0217764, WO2013 / 028570, or US2014 / 0288170, which are incorporated by reference in their entirety for all purposes.

[0202] In embodiments, the PPARα agonist is a naturally occurring or non-naturally occurring PPARα agonist.

[0203] In embodiments, the PPARα agonist is GW7647, PEA (palmitoylethanolamide), or OEA (oleoylethanolamine). In embodiments, the PPARα agonist is GW7647. In embodiments, the PPARα agonist is PEA (palmitoylethanolamide). In embodiments, the PPARα agonist is OEA (oleoylethanolamine). In embodiments, the PPARα agonist is described in Expert Opin Investig Drugs. 2017 May;26(5):593-60, the entire contents of which are incorporated herein by reference.

[0204] In embodiments, the method further comprises administering the agent between about 8 and 30 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 8 and 10 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 8 and 14 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 8 and 21 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 8 and 28 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 10 and 14 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 10 and 21 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 10 and 28 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 15 and 20 days after the traumatic pain event. In embodiments, the method further comprises administering the agent between about 15 and 30 days after the traumatic pain event.

[0205] In embodiments, the method further comprises continuously administering the agent for about 8 to 30 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 8 to 10 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 8 to 14 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 8 to 21 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 8 to 28 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 10 to 14 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 10 to 21 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 10 to 28 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 15 to 20 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent for about 15 to 30 days after the traumatic pain event.

[0206] In embodiments, the traumatic pain event results from accidental physical injury, invasive surgery, or acute illness. In embodiments, the traumatic pain event results from accidental physical injury. In embodiments, the traumatic pain event results from invasive surgery. In embodiments, the traumatic pain event results from acute illness.

[0207] In embodiments, the acute physical injury is a concussion, a fracture, or an internal injury. In embodiments, the acute physical injury is a concussion. In embodiments, the acute physical injury is a fracture. In embodiments, the acute physical injury is an internal injury.

[0208] In embodiments, the invasive surgery is cardiac surgery, breast surgery, or orthopedic surgery. In embodiments, the invasive surgery is cardiac surgery. In embodiments, the invasive surgery is breast surgery. In embodiments, the invasive surgery is orthopedic surgery. In embodiments, the invasive surgery is knee arthroplasty, hip replacement, mastectomy, open heart surgery, hernia repair, thoracotomy, Cesarean section, amputation, or open cholecystoctomy. In embodiments, the invasive surgery is knee arthroplasty. In embodiments, the invasive surgery is hip replacement. In embodiments, the invasive surgery is mastectomy. In embodiments, the invasive surgery is open heart surgery. In embodiments, the invasive surgery is hernia repair. In embodiments, the invasive surgery is thoracotomy. In embodiments, the invasive surgery is Cesarean section. In embodiments, the invasive surgery is amputation. In an embodiment, the invasive surgery is an open cholecystectomy.

[0209] In embodiments, the agent is administered perioperatively. In embodiments, the agent is administered before surgery, during surgery, or during the post-operative period. The term "perioperative" or "perioperatively" is used according to its plain and ordinary meaning and generally refers to the period approximately before, during, and / or approximately after a surgical procedure. For example, "perioperative" or "perioperatively" can refer to the period from when a patient arrives (e.g., is admitted) at a surgical facility (e.g., a hospital, clinic, or doctor's office) for surgery to when the patient completes the surgical procedure and is discharged (e.g., discharged from the hospital). In embodiments, the perioperative period includes admission to the surgical facility, anesthesia, surgery, and recovery from surgery.

[0210] In one aspect, a method for preventing chronic pain in a subject is provided, the method comprising administering an effective amount of a drug to the subject during perioperative period, wherein the drug is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid, or olesoxime.In an embodiment, the NAAA inhibitor is as described herein, including embodiments.In an embodiment, the FAAH inhibitor is as described herein, including embodiments.In an embodiment, the PPARα agonist is as described herein, including embodiments.

[0211] In one aspect, a method of preventing peripheral neuropathic pain in a subject previously treated with an anti-cancer agent is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0212] In one aspect, a method of preventing peripheral neuropathic pain in a subject previously treated with an anti-cancer agent is provided, the method comprising administering to the patient an effective amount of a composition comprising purified palmitoylethanolamide (PEA), at least one purified free amino acid, and at least one purified fatty acid, wherein chronic pain is prevented in the subject.

[0213] In one aspect, the method further comprises administering to the cancer patient an effective amount of a drug, wherein the drug is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid, or olesoxime.In an embodiment, the NAAA inhibitor is as described herein, including embodiments.In an embodiment, the FAAH inhibitor is as described herein, including embodiments.In an embodiment, the PPARα agonist is as described herein, including embodiments.

[0214] In embodiments, the method further comprises administering an anti-cancer agent (e.g., as described herein). In embodiments, the chronic pain is caused by the anti-cancer agent. In embodiments, the chronic pain is peripheral neuropathy. In embodiments, the chronic pain is allodynia. In embodiments, the chronic pain is hyperalgesia. In embodiments, the chronic pain is dysesthesia. The term "dysesthesia" is used according to its plain and ordinary meaning and generally refers to abnormal sensations such as tingling or pricking. In embodiments, the chronic pain is numbness.

[0215] In one aspect, a method of preventing chronic pain in a diabetic patient is provided, the method comprising administering to the patient an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0216] In one aspect, a method of preventing chronic pain in a diabetic patient is provided, the method comprising administering to the patient an effective amount of a composition comprising purified palmitoylethanolamide (PEA), at least one purified free amino acid, and at least one purified fatty acid, wherein chronic pain is prevented in the subject.

[0217] In one aspect, the method further comprises administering to the diabetic patient an effective amount of a drug, wherein the drug is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid, or olesoxime.In an embodiment, the NAAA inhibitor is as described herein, including embodiments.In an embodiment, the FAAH inhibitor is as described herein, including embodiments.In an embodiment, the PPARα agonist is as described herein, including embodiments.

[0218] In embodiments, the chronic pain is chronic peripheral neuropathy. In embodiments, the chronic pain is chronic polyneuropathy. In embodiments, the chronic pain is hyperalgesia. In embodiments, the chronic pain is abnormal sensations (e.g., tingling or stabbing). In embodiments, the chronic pain is numbness.

[0219] In embodiments, the drug is not morphine. In embodiments, the drug is not gabapentin. In embodiments, the drug is not ketamine. In embodiments, the drug is not ketoprofen.

[0220] In embodiments, the method further comprises administering an opioid analgesic for acute post-operative pain. In embodiments, the opioid analgesic is morphine and the composition enhances the analgesic effect of morphine.

[0221] The methods described herein can result in reduced postoperative opioid consumption, shorter postoperative hospital stays, reduced preoperative anxiety, and reduced sedative requirements.

[0222] IV. Kit In one embodiment, a kit is provided that includes any of the compositions or compounds described above. In an embodiment, the composition and the compound are combined. In an embodiment, the kit further includes any of the agents described above. In an embodiment, one or more compounds or agents are contained in separate containers. The kit may further include instructions for preparation and use.

[0223] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will occur to those skilled in the art in light of this, which are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. [Example]

[0224] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0225] Example 1: Effect of diet on chronic pain in vivo Applicant has found that formalin induces an "acute" nocifensive response in mice, followed by local inflammation and persistent neuropathological conditions, the various symptoms of which are strikingly similar to chronic pain in humans. While not wishing to be bound by theory, Applicant has discovered a critical period for the transition from acute to chronic pain, which begins temporally after tissue injury and coincides with major metabolic changes in the local spinal cord. These changes include decreases in the concentrations of free amino acids (alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, and tryptophan), non-esterified unsaturated fatty acids (oleic acid and erucic acid), and the fatty acid amide palmitoylethanolamide (PEA). Therefore, a study was conducted to test whether providing animals with these deficient compounds through a nutrient-enriched diet would prevent the chronicization of pain in formalin-injected mice. For the formalin study in mice, three different experimental diets (EDs) were tested. The ED used here was a modified version of standard rodent chow (STD) enriched with free amino acids and fatty acids (ED-1), PEA (ED-2), or a combination of both (COMBO). Results show that formalin injection produces significant swelling in the injected paw accompanied by persistent bilateral hypersensitivity to slightly painful thermal stimuli (thermal hyperalgesia) and normally innocuous mechanical stimuli (mechanical allodynia). Pain hypersensitivity was accompanied by emotional and cognitive impairment. Dietary intervention with either ED-1 or ED-2 attenuated formalin-induced sensory hypersensitivity but failed to prevent the emergence of persistent pain states when ED was discontinued and replaced with STD. In contrast, both combinations abrogated the development of chronic pain and normalized paresthesia, anxiety-like behavior, and memory deficits. Thus, dietary enrichment with a combination of free amino acids, fatty acids, and PEA prevents the chronicization of pain after surgery or accidental tissue injury.

[0226] Example 2: Materials and Methods animal Briefly, CD-1 mice (7 weeks old upon arrival, Charles River, Wilmington, MA) were housed in a pathogen-free environment under a 12-h light / dark cycle with controlled temperature (22°C) and humidity (50-60%). Food and water were available ad libitum. Animals were randomly assigned to experimental groups and handled manually (approximately 3 min per animal per day) for 3 consecutive days prior to the start of the experiment. Behavioral testing was performed during the light phase of the light / dark cycle. Efforts were made to minimize the number of animals used and their discomfort. This study complied with all ethical regulations of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and the recommendations of the International Association for the Study of Pain. Experimental procedures were approved by the Animal Care and Use Committee of the University of California, Irvine (AUP-20-117).

[0227] Dietary intervention Mice were randomly assigned to receive either standard rodent chow (SD) or experimental chow (ED: ED-1, ED-2, or COMBO) for 3 weeks. Subsequently, animals were exposed to formalin (1% volume, intraplantar injection) or saline injection (sham) and fed the respective chow for 1 week. In separate experiments, animals underwent sham surgery or spatial nerve injury (SNI) of the sciatic nerve and were fed the respective chow for 2 weeks. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and emotional impairments (elevated plus maze test, EPM) induced by formalin injection or SNI were assessed at various time points after exposure.

[0228] Feed composition The experimental diets (ED) were modified versions of standard rodent chow (SD, Teklad Diets, Madison, WI, USA) enriched with either free amino acids and fatty acids (ED1), palmitoylethanolamide (PEA) (ED2), or a combination of free amino acids, fatty acids, and PEA (COMBO). Mice were fed the respective diets ad libitum.

[0229] [Table 3]

[0230] [Table 4]

[0231] [Table 5]

[0232] Behavioral testing formalin Mice were injected intraplantarly with formalin (1% volume, 20 μl) or saline into the right hind paw, as previously reported (Mabou Tagne et al., 2021). After injection, mice were immediately transferred to a transparent observation chamber, where nocifensive behavior (time spent licking or biting the injected paw and number of paw shakes) was videotaped for 60 min and quantified by a blinded observer. Mechanical allodynia, thermal hyperalgesia, and paw edema were assessed in both the injected and uninjected paws on days 7 and 14 postformalin injection (PFD).

[0233] Partial nerve damage To assess nerve segment injury, we used a previously described protocol (Guida et al., 2020). Mice were anesthetized with isoflurane, and under sterile conditions, the right common sciatic nerve was exposed by blunt dissection at the level of its bifurcation into the sural, tibial, and common peroneal nerves. The common peroneal and tibial nerves were then tightly ligated (with non-absorbable mouse silk 6.0) and transected distally, removing 2–4 mm of the distal nerve stump. The sural nerve was left intact. The wound was closed with a single muscle suture and skin clips. In sham-operated animals, the sciatic nerve was exposed but not transected.

[0234] Mechanical allodynia Mechanical allodynia was assessed using a dynamic plantar esthesiometer (Ugo Basile, Comerio, Italy). After 45 min of habituation in a transparent cage placed on a wire mesh surface, mechanical stimulation was delivered to the plantar surface of both hind paws by an automated steel filament with increasing force ranging from 0 to 5 g over a 10-second period. Three withdrawal thresholds (in grams) were recorded and averaged.

[0235] Foot edema Paw edema was measured with a digital caliper (Fisher Scientific, USA) and expressed as the difference between the ipsilateral and contralateral paws (Δ paw thickness, mm).

[0236] Sensitivity to heat Heat sensitivity was measured using a Hargreaves plantar testing apparatus (San Diego Instruments, San Diego, USA). After a 45-minute habituation period, the plantar surfaces of both hind paws were exposed to a radiant heat beam through a glass floor. The cutoff time was set at 15 seconds. Stimulation was repeated three times with a 2-minute interval between stimuli, and paw withdrawal latencies (in seconds) were recorded and averaged.

[0237] Elevated plus maze test Each mouse was placed on the central platform of the maze facing the open arm opposite the experimenter, and behavior was recorded using Debut video capture software (NCH Software, Canberra, Australia). A blinded observer measured the time spent in the open and closed arms, as well as the number of entries into the open and closed arms. The open arms of the maze were illuminated at 150–170 lux, and the closed arms at 40–50 lux. Anxiety index was calculated as follows:

number

[0238] Novel object recognition test The test was conducted over three days. On day 1, mice were allowed to habituate to an empty arena for 20 minutes. On day 2, mice were returned to the arena, this time containing two identical objects. On day 3, one of the objects was replaced with another object that differed in shape, color, and texture. Mice were allowed to explore the arena for 10 minutes, and the total time spent exploring each object (i.e., poking or sniffing within a distance of 2 cm) was recorded by a blinded observer. The discrimination index (DI) was calculated as follows:

number

[0239] Example 3: Effect of diet on spinal energy crisis and metabolite levels This example describes the transition to formalin-induced pain chronification and the determination of metabolic changes in the spinal cord of mice following treatment with a medical food.

[0240] Briefly, mice were fed a standard diet (SD) or medical food (MF) composition as described in Example 2, and then treated with formalin after 3 weeks as described in Example 1. Spinal cord samples were collected from the mice 24, 48, and 72 hours after formalin treatment and subjected to metabolomics analysis. The levels of metabolites involved in glycolysis, the TCA cycle, purine derivatives, amino acids, the urea cycle, acetylated amino acids, fatty acids, and phospholipids were measured (Figure 3).

[0241] The results show that metabolic changes were attenuated or reversed in mice treated with the medical food. The metabolic shift from the TCA cycle to aerobic glycolysis (Figures 3A and 3B), which occurs during the transition to chronic pain, is prevented by the medical food. The energy crisis (low ATP, Figure 3C) is also blocked. The levels of amino acids (Figure 4A) and urea cycle intermediates (Figure 4B), which decrease during the transition to chronic pain, are normalized by the medical food. The changes in acetylated amino acid levels are reversed (Figure 4C). The levels of fatty acids (Figure 5A) and phospholipids (Figure 5B), which show different changes during the transition to chronic pain, are normalized by the medical food.

[0242] Example 4: Effect of diet on hyperalgesic stimulation model This example describes the determination of the effect of diet in mice following hyperalgesic stimulation and treatment with a medical food.

[0243] Briefly, male mice were fed a standard diet (SD) or a medical food (MF) composition as described in Example 2 and then treated with IL-6 (5 ng, intraplantar) or its vehicle after 3 weeks. The IL-6-stimulated mice were exposed to prostaglandin E2, a pain-inducing compound, and then subjected to behavioral testing to assess pain hypersensitivity (hyperalgesia). The results show that administration of interleukin-6 (IL-6) to male mice fed a standard diet (SD) induced localized heat hypersensitivity (assessed as withdrawal latency in seconds) lasting for more than 6 hours (Figure 6). This response was absent in mice fed a medical food (MF) (Figure 6). The results indicate that the medical food suppresses acute hyperalgesia induced by IL-6.

[0244] On days 7 and 14 after IL-6 injection, mice were further injected with prostaglandin E2 (PGE2, 100 ng, plantar). The results show that administration of prostaglandin E2 to male mice pre-primed with IL-6 induced localized heat hypersensitivity in animals fed a standard chow diet (SD) but not in animals fed a medical food (MF) (Figures 7A and 7B). Collectively, these results suggest that MF not only prevents the induction of inflammatory hyperalgesia and the progression to chronic pain, but may also be effective in alleviating postoperative pain. Example 5: Effect of food on morphine antinociception

[0245] This example describes the determination of morphine-induced antinociception and dietary effects in mice following treatment with medical foods.

[0246] Briefly, animals fed standard chow or medical chow were administered morphine (mg / kg, subcutaneously). Responses are shown as a percentage of the maximum possible effect (MPE) (Figure 8A). The median effective dose (ED) that produced antinociception in the two groups of mice was also calculated. 50 The results suggest that MF enhances the analgesic effects of morphine, which is often used to treat postoperative pain.

[0247] We also evaluated the effect of medical foods on tolerance to the antinociceptive effects of morphine in male mice. The antinociceptive effects of morphine (15 mg / kg, subcutaneous) were evaluated on day 1. Tolerance was induced by administering morphine (30 mg / kg) on ​​days 2–6. Tolerance was assessed on day 7 by injecting 15 mg / kg of morphine (Figure 8B). The results suggest that MF does not affect morphine-induced tolerance, which may suppress postoperative analgesia.

[0248] References Guida, F., De Gregorio, D., Palazzo, E., Ricciardi, F., Boccella, S., Belardo, C., Iannotta, M., Infantino, R., Formato, F., Marabese, I., Luongo, L., de Novellis, V., & Maione, S. (2020). Behavioral, biochemical and electrophysiological changes in spared nerve. injury model of neuropathic pain.International Journal of Molecular Sciences.21(9),1-21.https: / / doi.org / 10.3390 / ijms21093396 Mabou Tagne, A., Fotio, Y., Lin, L., Squire, E., Ahmed, F., Rashid, TI, Karimian Azari, E., & Piomelli, D. (2021).Palmitoylethanolamide and hemp oil extract exert synergistic anti-nociceptive effects in mouse models of acute and chronic pain.Pharmacological Research,167,105545.https: / / doi.org / 10.1016 / j.phrs.2021.105545

[0249] While the present disclosure has been shown and described in detail with reference to specific embodiments, some of which are preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the disclosure disclosed herein.

[0250] P embodiment Embodiment 1. A method of preventing chronic pain in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0251] Embodiment 2. The method of embodiment 1, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0252] P Embodiment 3. The method of embodiment 1 or 2, wherein the composition is administered orally.

[0253] Embodiment 4. The method of embodiment 1 or 3, wherein the purified fatty acid is oleic acid or erucic acid.

[0254] Embodiment 5. The method of embodiment 4, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

[0255] Embodiment 6. The method of embodiment 4 or 5, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

[0256] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0257] Embodiment 8. The method of embodiment 7, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

[0258] Embodiment 9. The method of embodiment 7 or 8, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

[0259] P Embodiment 10. The method of any of embodiments 7 to 9, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

[0260] P Embodiment 11. The method of any of embodiments 7 to 10, wherein the subject is a human and the dosage range of serine is 10 to 100 mg / kg.

[0261] Embodiment 12. The method of any one of embodiments 7 to 11, wherein the subject is a human and the dosage range of leucine is 28 to 310 mg / kg.

[0262] Embodiment 13. The method of any of embodiments 7 to 12, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

[0263] Embodiment 14. The method of any of embodiments 7 to 13, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

[0264] Embodiment 15. The method of any one of embodiments 7 to 14, wherein the subject is a human and the dosage range of phenylalanine is 15 to 150 mg / kg.

[0265] Embodiment 16. The method of any of embodiments 7 to 15, wherein the subject is a human and the dosage range of tyrosine is 9 to 90 mg / kg.

[0266] Embodiment 17. The method of any of embodiments 7 to 16, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

[0267] Embodiment 18. The method of any of embodiments 7 to 17, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

[0268] Embodiment 19. The method of any of embodiments 7 to 18, wherein the subject is a human and the dosage range of tryptophan is 6 to 61 mg / kg.

[0269] P Embodiment 20. The method of any one of embodiments 1 to 19, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

[0270] P Embodiment 21. The method of any of embodiments 1 to 20, wherein the composition is administered between about 0 and about 30 days after the traumatic pain event.

[0271] P Embodiment 22. The method of any one of embodiments 1 to 21, wherein the composition is administered between about 30 days and about 1 day before the traumatic pain event.

[0272] Embodiment 23. The method of any of embodiments 1 to 22, wherein the traumatic pain event results from physical injury, invasive surgery, or acute illness.

[0273] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the physical injury is an accidental physical injury.

[0274] Embodiment 25. The method of embodiment 23, wherein the physical injury is an acute physical injury.

[0275] Embodiment 26. The method of embodiment 25, wherein the acute physical injury is a concussion, a fracture, or an internal injury.

[0276] Embodiment 27. The method of embodiment 23, wherein the invasive surgery is knee arthroplasty, hip replacement, mastectomy, open heart surgery, hernia repair, thoracotomy, cesarean section, amputation, or open cholecystectomy.

[0277] Embodiment 28. The method of embodiment 27, wherein the composition is administered perioperatively.

[0278] Embodiment 29. The method of any preceding embodiment, further comprising administering an agent between about 1 and 7 days after the traumatic pain event, wherein the agent is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, alpha-lipoic acid, or olesoxime.

[0279] P Embodiment 30. The method of embodiment 29, further comprising administering the agent between about 8 and 30 days after the traumatic pain event.

[0280] Embodiment 31. The method of embodiment 29, further comprising continuously administering the agent for about 8 to 30 days after the traumatic pain event.

[0281] Embodiment 32. A method of preventing chronic pain in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0282] Embodiment 33. The method of embodiment 32, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0283] Embodiment 34. A method of preventing peripheral neuropathic pain in a subject previously treated with an anti-cancer agent, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0284] Embodiment 35. The method of embodiment 34, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0285] Embodiment 36. The method of embodiment 32 or 34, wherein the composition is administered orally.

[0286] Embodiment 37. The method of embodiment 32 or 36, wherein the purified fatty acid is oleic acid or erucic acid.

[0287] Embodiment 38. The method of embodiment 37, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

[0288] Embodiment 39. The method of embodiment 37 or 38, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

[0289] Embodiment 40. The method of any of embodiments 32 to 39, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0290] Embodiment 41. The method of embodiment 40, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

[0291] Embodiment 42. The method of embodiment 40 or 41, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

[0292] Embodiment 43. The method of any of embodiments 40 to 42, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

[0293] Embodiment 44. The method of any of embodiments 40 to 43, wherein the subject is a human and the dosage range of serine is 10 to 100 mg / kg.

[0294] P Embodiment 45. The method of any of embodiments 40 to 44, wherein the subject is a human and the dosage range of leucine is 28 to 310 mg / kg.

[0295] Embodiment 46. The method of any of embodiments 40 to 45, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

[0296] P Embodiment 47. The method of any of embodiments 40 to 46, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

[0297] Embodiment 48. The method of any of embodiments 40 to 47, wherein the subject is a human and the dosage range of phenylalanine is 15 to 150 mg / kg.

[0298] P Embodiment 49. The method of any of embodiments 40 to 48, wherein the subject is a human and the dosage range of tyrosine is 9 to 90 mg / kg.

[0299] P Embodiment 50. The method of any of embodiments 40 to 49, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

[0300] P Embodiment 51. The method of any of embodiments 40 to 50, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

[0301] P Embodiment 52. The method of any of embodiments 40 to 51, wherein the subject is a human and the dosage range of tryptophan is 6 to 61 mg / kg.

[0302] P Embodiment 53. The method of any of embodiments 32 to 52, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

[0303] P Embodiment 54. The method of any of embodiments 32 to 53, wherein the subject has or previously had cancer.

[0304] Embodiment 55. The method of any of embodiments 32 to 54, further comprising administering an anti-cancer agent.

[0305] P Embodiment 56. The method of embodiment 55, wherein the chronic pain is caused by an anti-cancer drug.

[0306] P embodiment 57. The method of any of embodiments 32 to 56, wherein the chronic pain is chronic peripheral neuropathy.

[0307] P embodiment 58. The method of any of embodiments 32 to 56, wherein the chronic pain is allodynia.

[0308] Embodiment 59. A method of preventing chronic pain in a diabetic subject, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

[0309] P Embodiment 60. The method of embodiment 59, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0310] Embodiment 61. The method of embodiment 59, wherein the composition is administered orally.

[0311] Embodiment 62. The method of embodiment 59 or 61, wherein the purified fatty acid is oleic acid or erucic acid.

[0312] Embodiment 63. The method of embodiment 62, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

[0313] Embodiment 64. The method of embodiment 62 or 63, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

[0314] Embodiment 65. The method of any of embodiments 59 to 64, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0315] Embodiment 66. The method of embodiment 65, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

[0316] P embodiment 67. The method of embodiment 65 or 66, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

[0317] P embodiment 68. The method of any of embodiments 65 to 67, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

[0318] P embodiment 69. The method of any of embodiments 65 to 68, wherein the subject is a human and the dosage range of serine is 10 to 100 mg / kg.

[0319] P Embodiment 70. The method of any of embodiments 65 to 69, wherein the subject is a human and the dosage range of leucine is 28 to 310 mg / kg.

[0320] P Embodiment 71. The method of any of embodiments 65 to 70, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

[0321] P embodiment 72. The method of any of embodiments 65 to 71, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

[0322] Embodiment 73. The method of any of embodiments 65 to 72, wherein the subject is a human and the dosage range of phenylalanine is 15 to 150 mg / kg.

[0323] P Embodiment 74. The method of any of embodiments 65 to 73, wherein the subject is a human and the dosage range of tyrosine is 9 to 90 mg / kg.

[0324] P Embodiment 75. The method of any of embodiments 65 to 74, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

[0325] P embodiment 76. The method of any of embodiments 65 to 75, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

[0326] P Embodiment 77. The method of any of embodiments 65 to 76, wherein the subject is a human and the dosage range of tryptophan is 6 to 61 mg / kg.

[0327] P embodiment 78. The method of any of embodiments 59 to 77, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

[0328] P embodiment 79. The method of any of embodiments 59 to 78, wherein the chronic pain is chronic peripheral neuropathy.

[0329] P embodiment 80. The method of any of embodiments 59 to 78, wherein the chronic peripheral neuropathy is chronic polyneuropathy.

[0330] Embodiment 81. The method of any preceding embodiment, further comprising administering to the subject an effective amount of an agent, wherein the agent is administered between about 1 and 7 days after the traumatic pain event, and the agent is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, acetyl-L-carnitine, alpha-lipoic acid, or olesoxime.

[0331] P Embodiment 82. The method of embodiment 81, further comprising administering the agent between about 8 and 30 days after the traumatic pain event.

[0332] P Embodiment 83. The method of embodiment 81, further comprising continuously administering the agent for about 8 to 30 days after the traumatic pain event.

[0333] Embodiment 84. The method of any one of embodiments 81 to 83, wherein the agent is an NAAA inhibitor, a FAAH inhibitor, or a PPARα agonist.

[0334] P embodiment 85. The method of any one of embodiments 81 to 84, wherein the NAAA inhibitor is ARN16186, ARN077, or ARN19702.

[0335] Embodiment 86. The method of any one of embodiments 81 to 84, wherein the FAAH inhibitor is URB597 or an analog of URB597.

[0336] Embodiment 87. The method of any one of embodiments 81 to 84, wherein the FAAH inhibitor is URB937 or an analog of URB937.

[0337] Embodiment 88. The method of any one of embodiments 81 to 84, wherein the PPARα agonist is a natural PPARα agonist.

[0338] Embodiment 89. The method of any one of embodiments 81 to 84, wherein the PPARα agonist is a non-naturally occurring PPARα agonist.

[0339] Embodiment 90. The method of any one of embodiments 81 to 84, wherein the PPARα agonist is GW7647, PEA, or OEA.

[0340] Embodiment 91. A method of reducing pain hypersensitivity in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein pain hypersensitivity is reduced in the subject.

[0341] Embodiment 92. The method of embodiment 91, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0342] P embodiment 93. The method of embodiment 91, wherein the pain hypersensitivity is caused by acute / inflammatory pain.

[0343] P embodiment 94. The method of embodiment 91, wherein the inflammatory pain is IL-6 mediated.

[0344] P Embodiment 95. A composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

[0345] P Embodiment 96. The composition of embodiment 95, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0346] P Embodiment 97. The composition of embodiment 95 or embodiment 96, further comprising an artificial sweetener.

[0347] P Embodiment 98. A dosage form comprising the composition of any one of embodiments 95 to 97, wherein the dosage form is a powder.

[0348] P Embodiment 99. The dosage form of embodiment 98, wherein the dosage form is about 100 grams per dose.

[0349] Incorporation by Reference The entire disclosure of each of the patent and scientific literature referenced herein is incorporated by reference for all purposes.

[0350] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A method for preventing chronic pain in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

2. 2. The method of claim 1, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

3. The method of claim 1 , wherein the composition is administered orally.

4. 2. The method of claim 1, wherein the purified fatty acid is oleic acid or erucic acid.

5. 5. The method of claim 4, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

6. 5. The method of claim 4, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

7. 2. The method of claim 1, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

8. 8. The method of claim 7, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

9. 8. The method of claim 7, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

10. 8. The method of claim 7, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

11. 8. The method of claim 7, wherein the subject is a human and the dosage range of serine is 10 to 100 mg / kg.

12. 8. The method of claim 7, wherein the subject is a human and the dosage range of leucine is 28 to 310 mg / kg.

13. 8. The method of claim 7, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

14. 8. The method of claim 7, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

15. 8. The method of claim 7, wherein the subject is a human and the dosage range of phenylalanine is 15-150 / kg.

16. 16. The method of any one of claims 7 to 15, wherein the subject is a human and the dosage range of tyrosine is 9 to 90 mg / kg.

17. 8. The method of claim 7, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

18. 8. The method of claim 7, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

19. 8. The method of claim 7, wherein the subject is a human and the dosage range of tryptophan is 6 to 61 mg / kg.

20. 2. The method of claim 1, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

21. 10. The method of claim 1, wherein the composition is administered between about 0 and about 30 days after the traumatic pain event.

22. 10. The method of claim 1, wherein the composition is administered between about 30 days and about 1 day before the traumatic pain event.

23. 10. The method of claim 1, wherein the traumatic pain event results from a physical injury, invasive surgery, or acute illness.

24. The method of claim 1 , wherein the physical injury is an accidental physical injury.

25. 24. The method of claim 23, wherein the physical injury is an acute physical injury.

26. 26. The method of claim 25, wherein the acute physical injury is a concussion, a fracture, or an internal injury.

27. 24. The method of claim 23, wherein the invasive surgery is knee arthroplasty, hip replacement, mastectomy, open heart surgery, hernia repair, thoracotomy, cesarean section, amputation, or open cholecystectomy.

28. 28. The method of claim 27, wherein the composition is administered perioperatively.

29. 10. The method of claim 1, further comprising administering a drug between about 1 and 7 days after the traumatic pain event, wherein the drug is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

30. 30. The method of claim 29, further comprising administering the agent between about 8 and 30 days after the traumatic pain event.

31. 30. The method of claim 29, further comprising administering the agent continuously for about 8 to 30 days after the traumatic pain event.

32. A method for preventing chronic pain in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

33. 33. The method of claim 32, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

34. A method for preventing peripheral neuropathic pain in a subject previously treated with an anti-cancer agent, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

35. 35. The method of claim 34, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

36. 33. The method of claim 32, wherein the composition is administered orally.

37. 33. The method of claim 32, wherein the purified fatty acid is oleic acid or erucic acid.

38. 38. The method of claim 37, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

39. 38. The method of claim 37, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

40. 33. The method of any of claims 32, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

41. 41. The method of claim 40, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

42. 41. The method of claim 40, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

43. 41. The method of claim 40, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

44. 41. The method of claim 40, wherein the subject is a human and the dosage range of serine is 10 to 100 mg / kg.

45. 41. The method of claim 40, wherein the subject is a human and the dosage range of leucine is 28-310 mg / kg.

46. 41. The method of claim 40, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

47. 41. The method of claim 40, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

48. 41. The method of claim 40, wherein the subject is a human and the dosage range of phenylalanine is 15-150 / kg.

49. 41. The method of claim 40, wherein the subject is a human and the dosage range of tyrosine is 9-90 mg / kg.

50. 41. The method of claim 40, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

51. 41. The method of claim 40, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

52. 41. The method of claim 40, wherein the subject is a human and the dosage range of tryptophan is 6-61 mg / kg.

53. 33. The method of claim 32, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

54. 33. The method of claim 32, wherein the subject has or previously had cancer.

55. 33. The method of claim 32, further comprising administering an anti-cancer agent.

56. 56. The method of claim 55, wherein the chronic pain is caused by an anti-cancer drug.

57. 33. The method of claim 32, wherein the chronic pain is chronic peripheral neuropathy.

58. 33. The method of claim 32, wherein the chronic pain is allodynia.

59. A method for preventing chronic pain in a diabetic subject, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein chronic pain is prevented in the subject.

60. 60. The method of claim 59, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

61. 60. The method of claim 59, wherein the composition is administered orally.

62. 60. The method of claim 59, wherein the purified fatty acid is oleic acid or erucic acid.

63. 63. The method of claim 62, wherein the subject is a human and the dosage range of oleic acid is between 48 and 496 mg / kg.

64. 63. The method of claim 62, wherein the subject is a human and the dosage range of erucic acid is 2 to 25 mg / kg.

65. 60. The method of claim 59, wherein the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

66. 66. The method of claim 65, wherein the subject is a human and the dosage range of alanine is 20 to 189 mg / kg.

67. 66. The method of claim 65, wherein the subject is a human and the dosage range of threonine is 12 to 130 mg / kg.

68. 66. The method of claim 65, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

69. 66. The method of claim 65, wherein the subject is a human and the dosage range of serine is 10-100 mg / kg.

70. 66. The method of claim 65, wherein the subject is a human and the dosage range of leucine is 28-310 mg / kg.

71. 66. The method of claim 65, wherein the subject is a human and the dosage range of isoleucine is 24 to 245 mg / kg.

72. 66. The method of claim 65, wherein the subject is a human and the dosage range of valine is 22 to 230 mg / kg.

73. 66. The method of claim 65, wherein the subject is a human and the dosage range of phenylalanine is 15-150 / kg.

74. 66. The method of claim 65, wherein the subject is a human and the dosage range of tyrosine is 9-90 mg / kg.

75. 66. The method of claim 65, wherein the subject is a human and the dosage range of methionine is 6 to 60 mg / kg.

76. 66. The method of claim 65, wherein the subject is a human and the dosage range of cysteine ​​is 4 to 45 mg / kg.

77. 66. The method of claim 65, wherein the subject is a human and the dosage range of tryptophan is 6-61 mg / kg.

78. 60. The method of claim 59, wherein the subject is a human and the dosage range of PEA is 0.8 to 9 mg / kg.

79. 60. The method of claim 59, wherein the chronic pain is chronic peripheral neuropathy.

80. 60. The method of claim 59, wherein the chronic peripheral neuropathy is chronic polyneuropathy.

81. 10. The method of claim 1, further comprising administering to the subject an effective amount of an agent, wherein the agent is administered between about 1 and 7 days after the traumatic pain event, and the agent is an NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

82. 82. The method of claim 81, further comprising administering the agent between about 8 and 30 days after the traumatic pain event.

83. 82. The method of claim 81, further comprising administering the agent continuously for about 8 to 30 days after the traumatic pain event.

84. 82. The method of claim 81, wherein the agent is an NAAA inhibitor, a FAAH inhibitor, or a PPARα agonist.

85. 82. The method of claim 81, wherein the NAAA inhibitor is ARN16186, ARN077, or ARN19702.

86. 82. The method of claim 81, wherein the FAAH inhibitor is URB597 or an analog of URB597.

87. 82. The method of claim 81, wherein the FAAH inhibitor is URB937 or an analog of URB937.

88. 82. The method of claim 81, wherein the PPARα agonist is a natural PPARα agonist.

89. 82. The method of claim 81, wherein the PPARα agonist is a non-naturally occurring PPARα agonist.

90. 82. The method of claim 81, wherein the PPARα agonist is GW7647, PEA, or OEA.

91. A method for reducing pain hypersensitivity in a subject after a traumatic pain event, the method comprising administering to the subject an effective amount of a composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein pain hypersensitivity is reduced in the subject.

92. 92. The method of claim 91, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

93. 92. The method of claim 91, wherein the pain hypersensitivity is caused by acute / inflammatory pain.

94. 92. The method of claim 91, wherein the inflammatory pain is IL-6 mediated.

95. A composition comprising at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide.

96. 96. The composition of claim 95, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

97. 96. The composition of claim 95, further comprising an artificial sweetener.

98. 96. A dosage form comprising the composition of claim 95, wherein the dosage form is a powder.

99. 99. The dosage form of claim 98, wherein the dosage form is about 100 grams per dose.

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