Composition for preventing conversion from acute pain to chronic pain

Abstract

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

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 375,113 filed on September 9, 2022, the disclosure of which is incorporated herein in its entirety and for all purposes. Background Art

[0003] More than 1.5 billion people worldwide suffer from chronic pain, which often begins after an acute pain episode. The sequence of molecular events that leads to the chronicity of pain remains largely unknown, but filling this gap is essential to identify control nodes that may be targeted by preventive or disease-modifying therapies. Solutions to these and other problems in the art are disclosed herein. Summary of the invention

[0004] In one aspect, a method for treating pain in a subject in need is provided, the method comprising administering to the patient a composition of an effective amount, the composition comprising at least one purified free amino acid, at least one purified fatty acid and purified fatty acid amide. In various aspects, the composition is administered orally. In various aspects, the purified fatty acid is oleic acid or erucic acid. In certain aspects, the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine ​​or tryptophan.

[0005] In one aspect, a method of preventing chronic pain in a subject suffering from 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 purified fatty acid amides.

[0006] 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 purified fatty acid amides.

[0007] In one aspect, a method of preventing chronic pain in a subject with diabetes 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 fatty acid amides.

[0008] In one aspect, a method of reducing pain hypersensitivity in a subject following a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides, wherein the subject's pain hypersensitivity is reduced.

[0009] In one aspect, a composition is provided, comprising at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides.

[0010] In one aspect, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The features of the present disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of the present disclosure may be obtained by referring to the following detailed description and accompanying drawings which set forth illustrative embodiments in which the principles of the present disclosure are utilized, in which:

[0012] Figures 1A-1I .Dietary intervention prevents formalin-induced acute nociception, long-term paresthesias, mood disturbances, and memory deficits. Mice were randomly assigned to receive either a standard rodent chow (SD) or an experimental diet (ED: ED-1, ED-2, or combination) for a period of 3 weeks. Then, the animals were tested with formalin (1% volume, intraplantar injection) or saline injection (sham injection) and maintained on the respective diet for one week. Formalin-induced nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR), and mood disturbances (elevated plus maze test, EPM) were evaluated at different time points after formalin injection (post-formalin days, PFD). To evaluate whether the dietary intervention could permanently prevent the long-term effects of formalin, the ED was withdrawn on PFD 7 and replaced with SD. ( Figure 1A ) Time course of acute antinociceptive response to 1% formalin. Figure 1B ) Cumulative scores of the first phase (Phase I: 0-10 min) and the second phase (Phase II: 15-60 min) of the acute anti-nociceptive response. Figure 1C ) Paw edema (thickness of injected paw minus thickness of uninjected paw, in mm). Figure 1D , F) and contralateral ( Figure 1E , G) claws ( Figure 1D -E) Mechanical and ( Figure 1F -G) Thermal sensitivity. Figure 1H ) Anxiety-like behavior of mice on PFD 7 assessed using EPM. The left graph is the time in the open arm (seconds); the right graph is the anxiety index. ( Fig. 1I) Long-term memory of mice that received sham injection or formalin, measured by the discrimination index of PFD 21. Results are presented as mean ± SEM (n = 4-8 per group).

[0013] Figure 2A –2C Dietary intervention prevents long-term sensory hypersensitivity and memory deficits induced by spared nerve injury (SNI). Mice were randomly assigned to receive either a standard rodent chow (SD) or an experimental diet (ED: ED-1, ED-2, or combination) for a period of 3 weeks. Then, the animals underwent sham injection or spared nerve injury (SNI) to the sciatic nerve and were maintained on their respective diets for two weeks. SNI-induced nociceptive behaviors and cognitive impairments (novel object recognition test, NOR) were evaluated at different time points after surgery (post-SNI). To evaluate whether the dietary intervention could permanently prevent the long-term effects of SNI, the ED was withdrawn and replaced with SD after SNI 14. ( Figure 2A ) Mechanical allodynia in the operated (ipsilateral) limb. Figure 2B )The ipsilateral paw showed thermal hyperalgesia. The contralateral limb served as a control. Figure 2C ) Long-term memory of mice that received sham injection or SNI and received SD or ED, measured as the discrimination index after SNI 24. Results are expressed as mean ± SEM (n = 7-8 per group).

[0014] Figures 3A-3C Shown are changes in the levels of various spinal cord (L4-L6) metabolites in mice fed a standard diet (form SD) or a medical diet (form MF) 72 hours after intraplantar formalin administration; intermediates of glycolysis ( Figure 3A ), intermediates of the tricarboxylic acid (TCA) cycle ( Figure 3B ) and purine derivatives (including ATP) ( Figure 3C ). Medical foods can counteract the shift from TCA to glycolysis and the energy crisis (low ATP levels) produced by formalin injection.

[0015] Figures 4A-4C Shown are changes in the levels of various spinal cord (L4-L6) metabolites in mice fed a standard diet (form SD) or a medical diet (form MF) 72 hours after intraplantar formalin administration; amino acids ( Figure 4A ), urea cycle intermediates ( Figure 4B ) and acylated amino acids ( Figure 4C ).

[0016] Figure 5A-5B Shown are changes in the levels of various spinal cord (L4-L6) metabolites of small fatty acids in mice fed a standard diet (form SD) or a medical diet (form MF) 72 hours after intraplantar formalin administration; fatty acids ( Figure 5A ) and phospholipids ( Figure 5B ).

[0017] Figure 6 Graph showing the effect of medical food on paw withdrawal latency after interleukin-6 (IL-6, 5 ng, intraplantar) administration in male mice fed a standard diet (SD) after 1, 6 and 24 hours. Data are presented as mean + / - SEM, n = 8. ***P < 0.001; ****P < 0.0001, two-way ANOVA.

[0018] Figure 7A-7B Figure 2 shows the expression of prostaglandin E at 1, 6 and 24 hours in male mice primed with IL-6 on day 7 or day 14 after IL-6 administration. 2 (PGE 2 Graph showing the effect of medical food on paw withdrawal latency after administration of (100 ng, 100 ng, intraplantar). Data are presented as mean ± SEM, n = 8. **P < 0.01; ***P < 0.001; ****P < 0.0001, two-way ANOVA. Ns, not significant.

[0019] Fig. 8A Figure showing the effect of medical food on morphine-induced antinociception in male mice. Morphine (mg / kg, subcutaneous) was administered to animals fed a standard diet or medical food. Responses are expressed as a percentage of the maximum possible effect (MPE). Also included is the median effective dose (ED 50 )value. Figure 8B Figure showing the effect of medical food on tolerance to the antinociceptive effects of morphine in male mice. The antinociceptive effects of morphine (15 mg / kg, subcutaneous) were assessed on day 1. Tolerance was induced by administering morphine (30 mg / kg) on ​​days 2-6. Tolerance to injections of 15 mg / kg morphine was assessed on day 7. DETAILED DESCRIPTION

[0020] I. Definitions

[0021] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.The chemical structures and formulae shown herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0022] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms in which amino acids can be defined as (R)- or (S)- or (D)- or (L)- according to absolute stereochemistry, and individual isomers are all included within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art that are too unstable to synthesize and / or separate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-isomers 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 geometric asymmetric centers, unless otherwise specified, it is expected that the compounds include both E and Z geometric isomers.

[0023] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement and configuration of the atoms.

[0024] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0025] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0026] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the disclosed compounds are within the scope of the present disclosure.

[0027] Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures disclosed herein but with one hydrogen replaced by deuterium or tritium or one carbon replaced by a 13C- or 14C-enriched carbon are within the scope of the disclosure.

[0028] The compounds of the present disclosure may also contain unnatural ratios of atomic isotopes at one or more atoms that make up such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variants of the compounds of the present disclosure (whether radioactive or not) are encompassed within the scope of the present disclosure.

[0029] "Analog" or "analogue" is used in chemistry and biology according to its plain ordinary meaning and refers to a compound that is structurally similar to another compound (i.e., the so-called "reference" compound) but differs in composition, for example, in the replacement of one atom by an atom of a different element, or in the case of the presence of a specific functional group, or in the replacement of one functional group by another functional group, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to the reference compound in function and appearance but differs from the reference compound in structure or origin.

[0030] As used herein, the term "a" or "a kind" means one or more. In addition, as used herein, the phrase "substituted with [n]" means replacing a particular group with one or more of any or all of the specified substituents. For example, when a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl group or an unsubstituted 2 to 20-membered heteroalkyl group," the group may contain one or more unsubstituted C1-C20 alkyl groups, and / or one or more unsubstituted 2 to 20-membered heteroalkyl groups.

[0031] A "detectable agent" or "detectable moiety" is a substance (e.g., a compound) or composition detectable by an appropriate means (such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means). For example, useful detectable agents 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 2. 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, 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32 P, fluorophores (e.g., fluorescent dyes), electron-dense reagents, enzymes (e.g., commonly used in ELISA), biotin, rehmannia aglycone, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, single crystalline iron oxide nanoparticles, single crystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, Positron-emitting radionuclides, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells containing albumin, galactose, lipids and / or polymers; microbubble gas cores containing air, heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perfluorohexane lipid microspheres, perfluoropropane, etc.), iodine-containing contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, iodixanate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities that can be made detectable (e.g., by incorporating a radiolabel into a peptide or antibody that specifically reacts with a target peptide). The detectable moiety is a monovalent detectable agent or a detectable agent that can form a bond with another composition.

[0032] Radioactive materials (e.g., radioisotopes) that can be used as imaging and / or labeling agents according to embodiments of the present disclosure include, but are not limited to: 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 2. 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 225Ac. Paramagnetic ions that can be used as additional imaging agents according to embodiments of the present disclosure include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals with atomic numbers 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.

[0033] The description of the disclosed compounds is limited to the principles of chemical bonding known to those skilled in the art. Therefore, in the case where a group may be substituted by one or more of a plurality of substituents, such substitutions are selected so as to follow the principles of chemical bonding and to obtain compounds that are not inherently unstable and / or those skilled in the art will be known as being potentially unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, according to the principles of chemical bonding known to those skilled in the art, a heterocycloalkyl or heteroaryl group is connected to the rest of the molecule via a ring heteroatom, thereby avoiding inherently unstable compounds.

[0034] As used herein, the term "salt" refers to an acid or base salt of a compound used in the invention of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

[0035] As used herein, the terms "binding" and "bound" are used according to their simple ordinary meaning and refer to an association between atoms or molecules. Such an association may be direct or indirect. For example, the bound atoms or molecules may be direct (e.g., bound by a covalent bond or a linker (e.g., a first linker or a second linker)) or indirect (e.g., bound by a non-covalent bond (e.g., electrostatic interaction (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interaction (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (π effect), hydrophobic interaction, etc.).

[0036] As used herein, the term "capable of binding" refers to a moiety (e.g., a compound as described herein) that is capable of measurably binding to a target (e.g., NF-κB (Toll-like receptor protein)). In embodiments, when a moiety is capable of binding to a target, the moiety is capable of binding 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.

[0037] As used herein, the term "conjugated" when referring to two parts means that the two parts are bonded, wherein the one or more bonds connecting the two parts can be covalent bonds or non-covalent bonds. In an embodiment, the two parts are covalently bonded to each other (e.g., directly bonded or bonded through a covalently bonded intermediate). In an embodiment, the two parts are non-covalently bonded (e.g., through ionic bonds, van der Waals bonds / interactions, hydrogen bonds, polar bonds, or combinations or mixed bonds thereof).

[0038] The term "amino acid" refers to naturally occurring and 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 modified later, for example, hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds having the same basic chemical structure as naturally occurring amino acids, i.e., α carbon, carboxyl, amino, and R groups bound to hydrogen, for example, homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to compounds having a structure that is different from the general chemical structure of amino acids, but that functions in a manner similar to naturally occurring amino acids. The terms "non-naturally occurring amino acids" and "non-natural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that do not exist in nature. In embodiments, the amino acid can 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.

[0039] 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. Likewise, nucleotides may be referred to by their commonly accepted single-letter codes.

[0040] The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein in embodiments the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of the corresponding naturally occurring amino acid, and to naturally occurring amino acid polymers and 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 a single moiety.

[0041] The term "fatty acid" is used herein according to its simple common meaning and refers 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 non-branched. In embodiments, the fatty chain has a plurality of (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) carbon atoms. In embodiments, the fatty acid is an ester. In embodiments, the ester is a triglyceride, a phospholipid, or a cholesterol ester. In embodiments, the fatty acid has biological activity (e.g., regulating a biological process).

[0042] The term "palmitoylethanolamide" or "PEA" is used herein according to its simple ordinary meaning and refers to any of the synthetic or naturally occurring forms of the fatty acid amide palmitoylethanolamide, or variants or homologs thereof that maintain the activity of PEA (e.g., activity at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% compared to PEA). In an embodiment, PEA is substantially the same as the compound identified by CASID No. 544-31-0 or a variant or homolog having substantial identity with the compound. In an embodiment, PEA targets peroxisome proliferator-activated receptor alpha (PPAR--α). In an embodiment, PEA has affinity for G protein-coupled receptors (e.g., GPR55 and GPR119). In an embodiment, PEA is an anti-inflammatory agent. In an embodiment, PEA is an analgesic. In an embodiment, PEA is an antimicrobial agent. In an embodiment, PEA is an immunomodulator. In an embodiment, PEA has a neuroprotective effect.

[0043] The terms "acetyl-L-carnitine", "ALCAR" or "ALC" are used herein according to their plain ordinary meaning and refer to any of the synthetic or naturally occurring forms of acetyl-L-carnitine, or variants or homologs thereof that maintain the activity of acetyl-L-carnitine (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity compared to acetyl-L-carnitine). In embodiments, 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.

[0044] The term "alpha-lipoic acid" is used herein according to its plain ordinary meaning and refers to any of the synthetic or naturally occurring forms of alpha-lipoic acid (also known as thioctic acid), or variants or homologs thereof that maintain the activity of alpha-lipoic acid (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity of alpha-lipoic acid). In embodiments, the alpha-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.

[0045] The term "olisoxime" is used herein according to its simple common meaning and refers to any of the forms of olisoxime (also known as TRO 19622), or variants or homologs thereof that maintain the activity of olisoxime (e.g., at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity compared to olisoxime). In an embodiment, olisoxime is substantially the same as the compound identified by CASID No. 22033-87-0 or a variant or homolog having substantial identity with the compound.

[0046] 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, but are not limited to, polymeric forms of nucleotides (deoxyribonucleotides or ribonucleotides) covalently linked together that can have various lengths, or their analogs, derivatives or modifications. Different polynucleotides can have different three-dimensional structures and can 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 of sequences, isolated RNA of sequences, nucleic acid probes and primers. The polynucleotides that can be used in the methods of the present disclosure can include natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or combinations of such sequences.

[0047] A polynucleotide is generally composed of a specific sequence of the following four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (when the polynucleotide is RNA, thymine (T) is replaced by uracil (U)). Therefore, the term "polynucleotide sequence" is an alphabetic representation of a polynucleotide molecule; alternatively, the term may also be applied to the polynucleotide molecule itself. The alphabetic representation can be entered into a database of a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searches. A polynucleotide may optionally include one or more non-standard nucleotides, nucleotide analogs and / or modified nucleotides.

[0048] The terms "N-acylethanolamine hydrolase," "N-acylethanolamine acid amide hydrolase," or "NAAA" are used herein according to their plain ordinary meaning and refer to any of the recombinant or naturally occurring forms of N-acylethanolamine acid amide hydrolase, or variants or homologs thereof that maintain NAAA activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to NAAA). 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 the naturally occurring NAAA protein. In embodiments, the NAAA protein is substantially identical to the protein identified by UniProt reference number Q02083, or a variant or homolog having substantial identity to that protein.

[0049] The term "fatty acid amide hydrolase" or "FAAH" is used herein according to its plain ordinary meaning and refers to any of the recombinant or naturally occurring forms of fatty acid amide hydrolase, or a variant or homolog that maintains FAAH activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the 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 the naturally occurring FAAH protein. In embodiments, the FAAH protein is substantially identical to the protein identified by UniProt reference number O00519, or a variant or homolog having substantial identity to that protein. In an embodiment, the FAAH protein is substantially identical to the protein identified by UniProt reference number Q6GMR7, or a variant or homolog having substantial identity to that protein.

[0050] The term "peroxisome proliferator-activated receptor alpha" or "PPARα" is used herein according to its plain ordinary meaning and refers to any of the recombinant or naturally occurring forms of peroxisome proliferator-activated receptor alpha (also known as nuclear receptor subfamily 1, group C, member 1 (NR1C1)), or variants or homologs thereof that maintain PPARα activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity compared to PPARα). 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 partial sequence (e.g., a 50, 100, 150 or 200 consecutive amino acid portion) compared to the naturally occurring PPARα protein. In an embodiment, the PPARα protein is substantially identical to the protein identified by UniProt reference number Q07869, or a variant or homologue having substantial identity to that protein.

[0051] "Contacting" is used according to its plain ordinary meaning and refers to the process of allowing at least two different substances (e.g., chemical compounds or cells including biomolecules) to become close enough to react, interact or physically touch. It should be recognized; however, that the resulting reaction product can be produced directly from the reaction between the added reagents or from intermediates from one or more of the added reagents that can be produced in the reaction mixture.

[0052] The term "contacting" may include allowing two substances to react, interact, or physically touch, wherein the two substances 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 signaling pathway.

[0053] As defined herein, the terms "activation", "activate", "activating", "activator", etc., when referring to protein inhibitor interactions, mean a positive effect (e.g., increase) on the activity or function of a protein relative to the activity or function of the protein in the absence of an activator. In an embodiment, activation means a positive effect (e.g., increase) on the concentration or level of a protein relative to the concentration or level of the protein in the absence of an activator. These terms may refer to activation, sensitization, or upregulation of the amount of a signal transduction or enzyme activity or protein that is reduced in a disease. Thus, activation may include at least partially, partially, or wholly increasing stimulation, increasing, or achieving activation, sensitization, or upregulation of the amount of a signal transduction or enzyme activity or protein associated with a disease (e.g., a protein reduced in a disease relative to a control that is not ill). Activation may include at least partially, partially, or wholly increasing stimulation, increasing, or achieving activation, sensitization, or upregulation of the amount of a signal transduction or enzyme activity or protein.

[0054] The terms "agonist", "activator", "up-regulator", etc. 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 some cases, the expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more higher than the expression or activity in the absence of the agonist.

[0055] An "inhibitor" refers to a compound (eg, a compound described herein) that reduces an activity compared to a control (such as the absence of the compound or a compound known to be inactive).

[0056] As defined herein, the term "inhibition (inhibition, inhibit, inhibiting)" and the like, when it comes to protein inhibitor interactions, means to negatively affect (e.g., reduce) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means to negatively affect (e.g., reduce) the concentration or level of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptom. In embodiments, inhibition refers to the reduction of the activity of a specific protein target. Therefore, inhibition includes at least partially, partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or downregulating the amount of signal transduction or enzyme activity or protein. In embodiments, inhibition refers to the reduction of the activity of the target protein produced by direct interaction (e.g., the inhibitor binds to the target protein). In embodiments, inhibition refers to the reduction of the activity of the target protein produced by indirect interaction (e.g., the inhibitor binds to the protein that activates the target protein, thereby preventing the target protein from activating).

[0057] The terms "inhibitor", "repressor" or "antagonist" or "down-regulator" are used interchangeably and refer to a substance that can detectably reduce 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 some cases, expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more lower than expression or activity in the absence of the antagonist.

[0058] 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 molecular target relative to the absence of the modulator.

[0059] The term "modulate" is used according to its plain ordinary meaning and refers to the act of changing or causing a change in one or more properties. "Modulate" refers to the process of changing or causing a change in one or more properties. For example, when applied to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0060] In the context of a substance or substance activity or function associated with a disease, the term "associated" or "associated with..." (e.g., protein-related disease, cancer (e.g., cancer, inflammatory disease, autoimmune disease or infectious disease)) means that the disease (e.g., cancer, inflammatory disease, autoimmune disease or infectious disease) is caused (in whole or in part) by the substance or substance activity or function, or that the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function. As used herein, if a pathogenic factor is described as being associated with a disease, the pathogenic factor can be a target for treatment of the disease.

[0061] As used herein, "therapeutic agent" or "pharmaceutical agent" refers to an agent (e.g., a compound or composition) that, when administered to a subject, will have a desired prophylactic effect, e.g., 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, or a desired therapeutic effect, e.g., treating or ameliorating an injury, disease, lesion, or condition, or their symptoms, including any objective or subjective therapeutic parameter: such as alleviation; relief; attenuation of symptoms or making an injury, lesion, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the degenerative endpoint less debilitating; or improving the patient's physical or mental health. The drug portion is a monovalent drug. The therapeutic portion is a monovalent therapeutic agent.

[0062] The term "disease" or "condition" refers to the state or health 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 some other cases, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphomas, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer and liver cancer, including liver cancer, lymphomas, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL and CML) or multiple myeloma.

[0063] The term "treating" or "treatment" refers to any successful phenomenon of treating or ameliorating an injury, disease, lesion or condition, including any objective or subjective parameter, such as alleviation; relief; weakening symptoms or making an injury, lesion or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the degenerative endpoint less debilitating; improving the patient's physical or mental health. The treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of physical examinations, neuropsychiatric tests, and / or psychiatric assessments. The term "treatment" and its variations can include preventing injuries, pathologies, conditions or diseases. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention.

[0064] "Treating" or "treatment" as used herein (and as well understood in the art) also broadly includes any approach to obtaining beneficial or desired results (including clinical results) for a patient's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization (i.e., not worsening) of the disease state, prevention of disease transmission or spread, delay or slowing of disease progression, improvement or alleviation of the disease state, reduction and alleviation of disease recurrence, whether the clinical result is partial or complete, detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the occurrence of a disease; inhibit the spread of a disease; alleviate symptoms of a disease, completely or partially eliminate the underlying cause of a disease, shorten the duration of a disease, or a combination of these things.

[0065] As used herein, "treatment" includes preventive treatment. Treatment methods include administering a therapeutically effective amount of an active agent to a subject. The administration step may consist of a single administration, or may include a series of administrations. The length of the treatment cycle depends on a variety of factors, such as the severity of the illness, 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 dose of the active agent used for treatment or prevention may increase or decrease during a specific treatment or prevention regimen. By standard diagnostic assays known in the art, changes in dosage may occur and become apparent. In some cases, long-term administration may be required. For example, the composition is administered to the subject in an amount and duration sufficient to treat the patient. In many aspects, "treating" or "treatment" is not a preventive treatment.

[0066] The term "prevention" refers to reducing the occurrence of disease symptoms in a patient. As indicated above, prevention can be complete (ie, no detectable symptoms) or partial, such that fewer symptoms are observed than would occur without treatment.

[0067] As used herein, "pathological state" refers to an inflammatory condition, a neurodegenerative disease, 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), neurogenic pain (including but not limited to neuropathic pain, central pain and deafferented pain), peripheral or polyneuropathic pain, toxic neuropathy, chronic neuropathy caused by chemotherapeutic agents and antiviral agents, nociceptive pain, or pruritus caused by uremia, cancer-related pain, malignancies of various origins, 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, especially 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 are often substantial stressors.

[0068] In embodiments, "neuropathic pain" may include pain caused by primary lesions or dysfunctions of the nervous system. This pain may be chronic and may involve an abnormal state of persistent pain enhancement, wherein pain threshold reduction and the like persist, due to persistent dysfunction caused by damage or degeneration of nerves, plexuses or perineurial soft tissues. This damage or degeneration may be caused by wounds, compression, infection, cancer, ischemia, or metabolic or nutritional disorders (such as diabetes). Neuropathic pain may include, but is not limited to, neuropathic allodynia (wherein pain is caused by mechanical, thermal or other stimuli that do not usually cause pain), neuropathic hyperalgesia (wherein excessive pain occurs in response to stimulation that is usually lighter than the pain experienced). Examples of neuropathic pain include diabetic polyneuropathy, compression neuropathy, phantom pain, thalamic pain after stroke, postherpetic neuralgia, atypical facial neuralgia after tooth extraction, spinal cord injury, trigeminal neuralgia, and cancer pain that is tolerant to narcotic analgesics (such as morphine). In embodiments, neuropathic pain includes pain caused by central or peripheral nerve damage. In embodiments, it includes pain caused by mononeuropathy or polyneuropathy (e.g., familial amyloid polyneuropathy). In embodiments, neuropathic pain is resistant to therapy with nonsteroidal anti-inflammatory agents and opioids (e.g., morphine) compared to inflammatory pain. Neuropathic pain can be bilateral at mirrored sites, or can be distributed roughly according to the innervation of the injured nerve, it can last for months or years, and is experienced as burning, tingling, throbbing, tingling electric shock, or other unpleasant sensations.

[0069] The term "acute pain" is used according to its plain ordinary meaning and refers to the physiological response and experience to noxious stimulation. In embodiments, acute pain comes on suddenly and is time-limited. As used herein, the term "acute pain state" is a state of acute pain.

[0070] The term "chronic pain" is used according to its plain ordinary meaning and refers to pain that persists and lasts for more than three months. In embodiments, the chronic pain lasts for more than six months. As used herein, the term "chronic pain state" is a state of chronic pain.

[0071] The term "hyperalgesia" is used interchangeably with "hyperalgesia" and "allodynia" and includes both abnormally increased sensitivity to normally painful stimuli (hyperalgesia) and abnormally increased sensitivity to normally non-painful stimuli (allodynia). Long-term use of opioids for the treatment of chronic pain may produce opioid-induced hyperalgesia.

[0072] As used herein, "inflammatory condition" refers to a disease or condition characterized by abnormal inflammation (e.g., an increased degree of inflammation compared to a control, such as a healthy person without the disease). Examples of inflammatory conditions include postoperative cognitive dysfunction, 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, Sjögren'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.

[0073] As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Schenck disease, and schizophrenia. syndrome, Huntington disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, myalgic encephalomyelitis, narcolepsy, neuroborreliosis, Parkinson disease, Pelizaeus- Merzbacher disease, Pick disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord due to pernicious anemia, schizophrenia, spinocerebellar ataxia (many types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or tabes dorsalis.

[0074] "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 administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0075] An "effective amount" is an amount sufficient to achieve the stated purpose of the compound (e.g., to achieve the effect of the composition being administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signal transduction pathway, or to alleviate one or more symptoms of a disease or disorder) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to facilitate the treatment, prevention, or alleviation of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Allowance" of one or more symptoms (and grammatical equivalents of the phrase) means a reduction in the severity or frequency of the one or more symptoms, or the elimination of the one or more symptoms. A "prophylactic effective amount" of a drug is an amount of the drug that will have the expected preventive effect when administered to a subject, such as preventing or delaying the onset (or recurrence) of damage, disease, lesions, or conditions, or reducing the likelihood of the onset (or recurrence) of damage, disease, lesions, or conditions or their symptoms. A complete preventive effect does not necessarily occur due to the administration of a single dose, but may only occur after a series of doses are administered. Therefore, a preventive effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce enzyme activity relative to the absence of an antagonist. As used herein, "function-destroying amount" refers to the amount of antagonist required to destroy the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment, and will be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 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).

[0076] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays.Target concentrations will be those concentrations of one or more active compounds that are capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0077] As is well known in the art, therapeutically effective amounts suitable for humans can also be determined by animal models. For example, dosages for humans can be formulated to achieve concentrations that have been found to be effective in animals. Dosages for humans can be adjusted by monitoring compound effectiveness and adjusting the dosage upward or downward, as described above. It is entirely within the capabilities of ordinary technicians to adjust the dosage based on the above-described methods and other methods to achieve maximum effectiveness in humans.

[0078] As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic agent sufficient to improve a condition as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0079] The dosage may vary according to the needs of the patient and the compound employed. In the context of the present disclosure, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature and extent of any adverse side effects. The determination of the appropriate dosage for a specific situation is within the skill of the practitioner. In general, treatment begins with a smaller dose that is lower than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved in a variety of situations. The amount and interval of the dosage can be adjusted individually to provide an effective level of the administered compound for the specific clinical indication being treated. This will provide a treatment regimen corresponding to the severity of the individual's disease state.

[0080] As used herein, the term "use" is used according to its simple common meaning and includes oral administration to the subject, use as suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intranasal administration or subcutaneous administration, or implantation of sustained-release device, for example, small osmotic pump.In embodiments, the term "use" means oral administration to the subject, use as suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or implantation of sustained-release device, for example, small osmotic pump.Use by any approach, including parenteral and transmucosal (for example, through cheek, through sublingual, through palate, through gums, through nose, through vagina, through rectum or transdermal).Parenteral administration includes, for example, intravenous administration, intramuscular administration, intraarteriole administration, intradermal administration, subcutaneous administration, intraperitoneal administration, indoor administration and intracranial administration.Other delivery modes include, but are not limited to, use liposome preparations, intravenous infusion, transdermal patch etc. In embodiments, administering does not include administering any active agent other than the listed active agents.

[0081] "Co-administration" means that the compositions described herein are administered at the same time, just before, or just after the administration of one or more additional therapies. The compounds provided herein can be administered alone or can be co-administered to the patient. Co-administration is intended to include administering the compounds individually or in combination (more than one compound) simultaneously or sequentially. Therefore, the formulations may also be combined with other active substances (e.g., to reduce metabolic degradation) when necessary. The compositions of the present disclosure may be delivered transdermally, by topical routes, or formulated as applicator sticks, solutions, suspensions, emulsions, sols, creams, ointments, pastes, gels, paints, powders, and aerosols.

[0082] The compounds described herein may be used in combination 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 aid in the efficacy of the active agents.

[0083] In some embodiments, co-administration includes administering an active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, that is, preparing a pharmaceutical composition including two active agents. In other embodiments, active agents can be prepared separately. In another embodiment, active agents and / or adjuvants can be bonded or conjugated to each other.

[0084] As non-limiting examples, the compounds described herein can be co-administered with anticancer agents or conventional chemotherapeutic agents, including alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.), antimetabolites (e.g., 5-fluorouracil, azathioprine, methotrexate, leucovorin, capecitabine, cytarabine, etc.), tarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, icin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin, etc.), etc.

[0085] In the therapeutic use of treating diseases, the compound used in the pharmaceutical composition of the present invention can be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. A daily dosage range 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 can be used. However, the dosage may vary according to the needs of the patient, the severity of the condition being treated, and the compound or drug being used. For example, the type and stage of cancer diagnosed in a particular patient may be considered to empirically determine the dosage. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects in a particular patient accompanying the administration of the compound. The determination of the appropriate dosage for a specific situation is within the skill range of the practitioner. In general, treatment begins with a smaller dose that is lower than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the best effect is achieved in a variety of situations. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0086] The compounds described herein may be used in combination with other active agents known to be useful in treating cancer, or with adjunct agents that may not be effective alone but may aid in the effectiveness of the active agents.

[0087] 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, yadenosine, 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 TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM)、afatinib / BIBW2992、CI-1033 / canertinib、neratinib / HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、dacomitinib / PF299804、OSI-420 / desmethylerolo tinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. The anticancer agent portion is a monovalent anticancer agent (e.g., a monovalent form of the agents listed above).

[0088]

[00136] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its plain ordinary meaning and refers to a chemical composition or compound that possesses anti-neoplastic properties or the ability to inhibit cell growth or proliferation.

[0089] "Anti-diabetic agent" or "antidiabetic agent" is used according to its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has the ability to reduce blood glucose levels in a subject. In some embodiments, an anti-diabetic agent is an agent identified herein as having utility in a method of treating diabetes. In some embodiments, an anti-diabetic agent is an agent approved by the FDA or similar regulatory agency in a country outside the United States for the treatment of diabetes. Examples of antidiabetic agents include, but are not limited to, 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, nateglitein, nateglinide), α-glucosidase inhibitors (e.g., miglitol, acarbose, voglibose), peptide analog antidiabetic agents (e.g., incretins (glucagon-like peptide-1, gastric inhibitory peptide), glucagon-like peptide agonists (e.g., exenatide, liraglutide, taspoglutide), gastric inhibitory peptide analogs or dipeptidyl peptidase-4 inhibitors (e.g., vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin, septagliptin), amylin agonist analogs (e.g., pramlintide).

[0090] The terms "N-acylethanolamine acid amidase", "NAAA" and "hNAAA" are used according to the plain common meaning of the art and refer to the 31 kDa enzyme of the same name that is 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., Entrez 27163, Uniprot Q02083, RefSeq NM_014435, or RefSeq NP_055250). The term "NAAA" includes both the wild-type form of the nucleotide sequence or protein and any mutant forms 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, wherein the Y-numbered amino acid of NAAA typically has an X amino acid in the wild type, but has a Z amino acid in the mutant. In an embodiment, NAAA is human NAAA. In an embodiment, NAAA has a nucleotide sequence corresponding to reference number GI: 109148549. In embodiments, NAAA has a nucleotide sequence corresponding to RefSeq NM_014435.3. In embodiments, NAAA has a protein sequence corresponding to reference number GI: 109148550. In embodiments, NAAA has a protein sequence corresponding to RefSeq NP_055250.2. In embodiments, NAAA functions under acidic conditions (e.g., pH about 4.5-5.0).

[0091] The term "FAAH" refers to mammalian fatty acid amide hydrolase, and includes, but is not limited to, human, rat and mouse forms of the enzyme. U.S. Pat. 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)) is an enzyme responsible for the degradation of lipid ethanolamines, (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)), oleoylethanolamide (Rodríguez ... deFonseca, F. et al., Nature (London) 414, 209-212 (2001); Fu, J. et 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 various and important physiological effects of fatty acid ethanolamines, the class of small molecule compounds that can block FAAH or FAAHs but not bind other enzymes that metabolize endocannabinoids, such as monoglyceride lipase (MGL) (Dinh, TP et al., Proc. Natl. Acad. Sci. USA 99, 10819-10824 (2002)) or cannabinoid receptors are 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)).

[0092] In the present disclosure, "comprises", "comprising", "containing", and "having" and the like may have the meanings ascribed to them in U.S. patent law, and may mean "includes", "including", etc. "Consisting essentially of" or "consists essentially of" also have the meanings prescribed in U.S. patent law, and the terms are open ended, allowing for the existence of more than those listed, as long as the basic or novel features of those listed are not altered by the existence of more than those listed, but excluding embodiments of the prior art.

[0093] II. Composition

[0094] Specifically provided herein are compositions for treating or preventing (e.g., treating) pain in a subject in need thereof, the compositions comprising at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides and / or pharmaceutically acceptable salts thereof.

[0095] In various aspects, the fatty acid amide is palmitoylethanolamide (PEA), oleoylethanolamide (OEA), erucylethanolamide, or stearoylethanolamide (SEA).

[0096] In various aspects, the purified fatty acid is oleic acid, palmitic acid, or erucic acid.

[0097] In certain aspects, the purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, or tryptophan.

[0098] In various aspects, 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.

[0099] In various aspects, the purified free amino acid is ornithine, citrulline or argininosuccinate.

[0100] In various aspects, the purified free amino acid is an acylated amino acid. In various aspects, the acylated amino acid is N-acetyl-L-phenylalanine, N-acetylhistidine, N-acetylthreonine, N-acetylasparagine, N-methyl-L-isoleucine or N-acetylornithine.

[0101] In various aspects, the composition comprises at least two fatty acids. In various aspects, the composition comprises at least three fatty acids.

[0102] In various aspects, the composition comprises at least two purified free amino acids. In various aspects, the composition comprises at least three purified free amino acids. In various aspects, the composition comprises at least four purified free amino acids. In various aspects, the composition comprises at least five purified free amino acids. In various aspects, the composition comprises at least six purified free amino acids. In various aspects, the composition comprises at least seven purified free amino acids. In various aspects, the composition comprises at least eight purified free amino acids. In various aspects, the composition comprises at least nine purified free amino acids. In various aspects, the composition comprises at least 10 purified free amino acids. In various aspects, the composition comprises at least 11 purified free amino acids. In various aspects, the composition comprises at least 12 purified free amino acids.

[0103] In one aspect, 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).

[0104] In one aspect, 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).

[0105] In one aspect, 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).

[0106] In one aspect, the composition has an amino acid to 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).

[0107] In one aspect, a composition for treating pain in a subject in need thereof comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA).

[0108] In one aspect, a composition for preventing pain in a subject in need thereof comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA).

[0109] In one aspect, the composition further comprises an agent, wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

[0110] 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 juice). In one aspect, the composition can have a suitable form, such as a solid stick, paste, gel, tablet, capsule or liquid.

[0111] In one aspect, the composition further comprises a pharmaceutically acceptable excipient, such as a binder (e.g., pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); a filler (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); a lubricant (e.g., magnesium stearate, talc, or silicon dioxide); a disintegrant (e.g., potato starch or sodium starch glycolate); or an inhibitor (e.g., sodium lauryl sulfate). In one aspect, tablets 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, solutions, syrups, or suspensions, or they can be in the form of lyophilized products that are reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or edible hydrogenated fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-paraben or sorbic acid).

[0112] In one aspect, the composition further comprises a sweetener (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).

[0113] In one aspect, the composition further comprises a flavoring agent.

[0114] In one aspect, a dosage form of a composition is provided. In one aspect, the dosage form is a liquid or solid. In one aspect, the dosage form is a beverage or a syrup. In one aspect, the dosage form is a tablet, a capsule, or a sachet. In one aspect, the dosage form comprises about 1 gram to about 150 grams of composition. In one aspect, the dosage form comprises about 1 gram to about 10 grams of composition. In one aspect, the dosage form comprises about 2 grams to about 9 grams of composition. In one aspect, the dosage form comprises about 3 grams to about 8 grams of composition. In one aspect, the dosage form comprises about 4 grams to about 7 grams of composition. In one aspect, the dosage form comprises about 5 grams to about 6 grams of composition. In one aspect, the dosage form comprises about 10 grams to about 20 grams of composition. In one aspect, the dosage form comprises about 20 grams to about 30 grams of composition. In one aspect, the dosage form comprises about 30 grams to about 40 grams of composition. In one aspect, the dosage form comprises about 40 grams to about 50 grams of composition. In one aspect, the dosage form comprises about 50 grams to about 60 grams of composition. In one aspect, the dosage form comprises about 60 grams to about 70 grams of composition. In one aspect, the dosage form comprises about 70 grams to about 80 grams of composition. In one aspect, the dosage form comprises about 80 grams to about 90 grams of composition. In one aspect, the dosage form comprises about 90 grams to about 100 grams of composition. In one aspect, the dosage form comprises about 100 grams to about 110 grams of composition. In one aspect, the dosage form comprises about 110 grams to about 120 grams of composition. In one aspect, the dosage form comprises about 120 grams to about 130 grams of composition. In one aspect, the dosage form comprises about 130 grams to about 140 grams of composition. In one aspect, the dosage form comprises about 140 grams to about 150 grams of composition. In one aspect, the dosage form comprises about 1 gram of composition. In one aspect, the dosage form comprises about 2 grams of composition. In one aspect, the dosage form comprises about 3 grams of composition. In one aspect, the dosage form comprises about 4 grams of composition. In one aspect, the dosage form comprises about 5 grams of composition. In one aspect, the dosage form comprises about 6 grams of composition. In one aspect, the dosage form comprises about 7 grams of composition. In one aspect, the dosage form comprises about 8 grams of composition. In one aspect, the dosage form comprises about 9 grams of composition. In one aspect, the dosage form comprises about 10 grams of composition. In one aspect, the dosage form comprises about 20 grams of composition. In one aspect, the dosage form comprises about 30 grams of composition. In one aspect, the dosage form comprises about 40 grams of composition. In one aspect, the dosage form comprises about 50 grams of composition. In one aspect, the dosage form comprises about 60 grams of composition. In one aspect, the dosage form comprises about 70 grams of composition. In one aspect, the dosage form comprises about 80 grams of composition. In one aspect, the dosage form comprises about 90 grams of composition. In one aspect, the dosage form comprises about 100 grams of composition. In one aspect, the dosage form comprises about 110 grams of composition. In one aspect, the dosage form comprises about 120 grams of composition. In one aspect, the dosage form comprises about 130 grams of composition. In one aspect, the dosage form comprises about 140 grams of composition.In one aspect, the dosage form comprises about 150 grams of the composition.

[0115] III. Methods

[0116] Specifically provided herein are methods for treating or preventing (eg, treating) pain in a subject in need thereof, the methods comprising administering to a patient in need thereof a composition described herein.

[0117] 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 fatty acid amides.

[0118] 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).

[0119] 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 purified fatty acid amides.

[0120] In one aspect, a method for preventing chronic pain in a subject following a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein the subject's chronic pain is prevented.

[0121] In one aspect, a method of preventing peripheral neuropathic pain in a subject having cancer is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides, wherein chronic pain in the subject is prevented.

[0122] In one aspect, a method of preventing peripheral neuropathic pain in a subject having cancer is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein chronic pain in the subject is prevented.

[0123] In one aspect, a method for preventing chronic pain in a subject with diabetes is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides, wherein the chronic pain in the subject is prevented.

[0124] In one aspect, a method for preventing chronic pain in a subject with diabetes is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein the subject's chronic pain is prevented.

[0125] In one aspect, a method of reducing pain hypersensitivity in a subject following a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides, wherein the subject's pain hypersensitivity is reduced.

[0126] In one aspect, a method of reducing pain hypersensitivity in a subject following a traumatic pain event is provided, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified palmitoylethanolamide (PEA), wherein the subject's pain hypersensitivity is reduced.

[0127] In various aspects, the hyperalgesia is caused by acute pain / inflammatory pain. In various aspects, the inflammatory pain is IL-6 mediated.

[0128] In various aspects, the composition is administered orally. In various aspects, the composition is provided as a supplement to food. In one aspect, the composition can be administered without food. In various aspects, the oral form is selected from the group consisting of tablets, capsules, granules, powders, oily pearls, solutions, suspensions, and aerosols.

[0129] In various aspects, the at least one purified fatty acid is oleic acid or erucic acid. In various aspects, the composition comprises oleic acid and erucic acid.

[0130] In various aspects, at least one purified free amino acid is alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine ​​or tryptophan. In various aspects, the composition comprises at least two purified free amino acids. In various aspects, the composition comprises at least three purified free amino acids. In various aspects, the composition comprises at least four purified free amino acids. In various aspects, the composition comprises at least five purified free amino acids. In various aspects, the composition comprises at least six purified free amino acids. In various aspects, the composition comprises at least seven purified free amino acids. In various aspects, the composition comprises at least eight purified free amino acids. In various aspects, the composition comprises at least nine purified free amino acids. In various aspects, the composition comprises at least 10 purified free amino acids. In various aspects, the composition comprises at least 11 purified free amino acids. In various aspects, the composition comprises at least 12 purified free amino acids.

[0131] In various aspects, the dosage of each of the one or more compounds is provided in Table 1.

[0132] Table 1

[0133]

[0134] In various aspects, dosage ranges for each of the one or more compounds are provided in Table 2.

[0135] Table 2

[0136]

[0137] In one aspect, the dosage of PEA is from about 0.8 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 0.9 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 1 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 2 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 3 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 4 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 5 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 6 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 7 mg / kg to about 9 mg / kg. In various aspects, the dosage of PEA is from about 8 mg / kg to about 9 mg / kg.

[0138] In various aspects, the dosage of PEA is from about 0.8 mg / kg to about 8 mg / kg. In various aspects,

[0140] The dosage of PEA is about 0.8 mg / kg to about 7 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 6 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 5 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 4 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 3 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 2 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 1 mg / kg. In various aspects, the dosage of PEA is about 0.8 mg / kg to about 0.9 mg / kg.

[0141] In various aspects, the dosage of PEA is 0.8 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 0.9 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 1 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 2 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 3 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 4 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 5 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 6 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 7 mg / kg to 9 mg / kg. In various aspects, the dosage of PEA is 8 mg / kg to 9 mg / kg.

[0142] In various aspects, the dosage of PEA is 0.8 mg / kg to 8 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to about 7 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 6 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 5 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 4 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 3 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 2 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 1 mg / kg. In various aspects, the dosage of PEA is 0.8 mg / kg to 0.9 mg / kg.

[0143] In one aspect, the dosage of oleic acid is from about 48mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 49mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 50mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 75mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 100mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 150mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 200mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 250mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 300mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 350mg / kg to about 496mg / kg. In various aspects, the dosage of oleic acid is from about 400 mg / kg to about 496 mg / kg. In various aspects, the dosage of oleic acid is from about 450 mg / kg to about 496 mg / kg. In various aspects, the dosage of oleic acid is from about 475 mg / kg to about 496 mg / kg. In various aspects, the dosage of oleic acid is from about 490 mg / kg to about 496 mg / kg. In various aspects, the dosage of oleic acid is from about 495 mg / kg to about 496 mg / kg.

[0144] In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 495 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 490 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 475 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 450 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 400 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 350 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 300 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 250 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 200 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 150 mg / kg. In various aspects, the dosage of oleic acid is from about 48 mg / kg to about 100 mg / kg. In various aspects, the dosage of oleic acid is about 48 mg / kg to about 75 mg / kg. In various aspects, the dosage of oleic acid is about 48 mg / kg to about 50 mg / kg. In various aspects, the dosage of oleic acid is about 48 mg / kg to about 49 mg / kg.

[0145] In various aspects, the dosage of oleic acid is 48 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 49 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 50 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 75 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 100 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 150 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 200 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 250 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 300 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 350 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 400 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 450 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 475 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 490 mg / kg to 496 mg / kg. In various aspects, the dosage of oleic acid is 495 mg / kg to 496 mg / kg.

[0146] In various aspects, the dosage of oleic acid is 48 mg / kg to 495 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 490 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 475 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 450 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 400 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 350 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 300 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 250 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 200 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 150 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 100 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 75 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 50 mg / kg. In various aspects, the dosage of oleic acid is 48 mg / kg to 49 mg / kg.

[0147] In one aspect, the dosage of erucic acid is from about 2 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 3 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 4 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 5 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 6 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 7 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 8 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 9 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 10 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 11 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 12 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is from about 13 mg / kg to about 25 mg / kg. In various aspects, the dosage of erucic acid is about 14mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 15mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 16mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 17mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 18mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 19mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 20mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 21mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 22mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 23mg / kg to about 25mg / kg. In various aspects, the dosage of erucic acid is about 24mg / kg to about 25mg / kg.

[0148] In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 24 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 23 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 22 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 21 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 20 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 19 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 18 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 17 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 16 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 15 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 14 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 13 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 12 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 11 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 10 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 9 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 8 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 7 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 6 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 5 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 4 mg / kg. In various aspects, the dosage of erucic acid is from about 2 mg / kg to about 3 mg / kg.

[0149] In various aspects, the dosage of erucic acid is 2 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 3 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 4 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 5 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 6 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 7 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 8 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 9 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 10 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 11 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 12 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 13 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 14 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 15 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 16 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 17 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 18 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 19 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 20 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 21 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 22 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 23 mg / kg to 25 mg / kg. In various aspects, the dosage of erucic acid is 24 mg / kg to 25 mg / kg.

[0150] In various aspects, the dosage of erucic acid is 2 mg / kg to 24 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 23 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 22 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 21 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 20 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 19 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 18 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 17 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 16 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 15 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 14 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 13 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 12 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 11 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 10 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 9 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 8 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 7 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 6 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 5 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 4 mg / kg. In various aspects, the dosage of erucic acid is 2 mg / kg to 3 mg / kg.

[0151] In one aspect, the dosage of alanine is from about 20 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 25 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 30 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 40 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 50 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 75 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 100 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 125 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 150 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is from about 175 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is about 180 mg / kg to about 189 mg / kg. In various aspects, the dosage of alanine is about 185 mg / kg to about 189 mg / kg.

[0152] In various aspects, the dosage of alanine is from about 20 mg / kg to about 185 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 180 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 175 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 150 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 125 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 100 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 75 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 50 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 40 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 30 mg / kg. In various aspects, the dosage of alanine is from about 20 mg / kg to about 25 mg / kg.

[0153] In various aspects, the dosage of alanine is 20 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 25 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 30 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 40 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 50 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 75 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 100 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 125 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 150 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 175 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 180 mg / kg to 189 mg / kg. In various aspects, the dosage of alanine is 185 mg / kg to 189 mg / kg.

[0154] In various aspects, the dosage of alanine is 20 mg / kg to 185 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 180 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 175 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 150 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 125 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 100 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 75 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 50 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 40 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 30 mg / kg. In various aspects, the dosage of alanine is 20 mg / kg to 25 mg / kg.

[0155] In one aspect, the dosage of threonine is from about 12 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 13 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 14 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 15 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 20 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 30 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 40 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 50 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 60 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 70 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is from about 80 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is about 90 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is about 100 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is about 110 mg / kg to about 130 mg / kg. In various aspects, the dosage of threonine is about 120 mg / kg to about 130 mg / kg.

[0156] In various aspects, the dosage of threonine is from about 12 mg / kg to about 120 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 110 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 100 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 90 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 80 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 70 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 60 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 50 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 40 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 30 mg / kg. In various aspects, the dosage of threonine is from about 12 mg / kg to about 20 mg / kg. In various aspects, the dosage of threonine is about 12 mg / kg to about 15 mg / kg. In various aspects, the dosage of threonine is about 12 mg / kg to about 14 mg / kg. In various aspects, the dosage of threonine is about 12 mg / kg to about 13 mg / kg.

[0157] In various aspects, the dosage of threonine is 12 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 13 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 14 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 15 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 20 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 30 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 40 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 50 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 60 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 70 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 80 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 90 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 100 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 110 mg / kg to 130 mg / kg. In various aspects, the dosage of threonine is 120 mg / kg to 130 mg / kg.

[0158] In various aspects, the dosage of threonine is 12 mg / kg to 120 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 110 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 100 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 90 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 80 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 70 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 60 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 50 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 40 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 30 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 20 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 15 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 14 mg / kg. In various aspects, the dosage of threonine is 12 mg / kg to 13 mg / kg.

[0159] In one aspect, the dosage of proline is from about 24 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 25 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 50 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 75 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 100 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 125 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 150 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 175 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 200 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is from about 225 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is about 230 mg / kg to about 240 mg / kg. In various aspects, the dosage of proline is about 235 mg / kg to about 240 mg / kg.

[0160] In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg. In various aspects, the dosage of proline is from about 24 mg / kg to about 235 mg / kg.

[0161] In various aspects, the dosage of proline is 24 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 25 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 50 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 75 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 100 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 125 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 150 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 175 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 200 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 225 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 230 mg / kg to 240 mg / kg. In various aspects, the dosage of proline is 235 mg / kg to 240 mg / kg.

[0162] In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg. In various aspects, the dosage of proline is 24 mg / kg to 235 mg / kg.

[0163] In one aspect, the dosage of serine is from about 10 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 20 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 30 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 40 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 50 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 60 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 70 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 80 mg / kg to about 100 mg / kg. In various aspects, the dosage of serine is from about 90 mg / kg to about 100 mg / kg.

[0164] In various aspects, the dosage of serine is from about 10mg / kg to about 90mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 80mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 70mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 60mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 50mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 40mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 30mg / kg. In various aspects, the dosage of serine is from about 10mg / kg to about 20mg / kg.

[0165] In various aspects, the dosage of serine is 10 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 20 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 30 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 40 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 50 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 60 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 70 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 80 mg / kg to 100 mg / kg. In various aspects, the dosage of serine is 90 mg / kg to 100 mg / kg.

[0166] In various aspects, the dosage of serine is 10 mg / kg to 90 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 80 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 70 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 60 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 50 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 40 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 30 mg / kg. In various aspects, the dosage of serine is 10 mg / kg to 20 mg / kg.

[0167] In one aspect, the dosage of leucine is from about 28 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 29 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 30 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 40 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 50 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 100 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 150 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 200 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 250 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 300 mg / kg to about 310 mg / kg. In various aspects, the dosage of leucine is from about 305 mg / kg to about 310 mg / kg.

[0168] In various aspects, the dosage of leucine is from about 28 mg / kg to about 305 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 300 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 250 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 200 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 150 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 100 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 50 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 40 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 30 mg / kg. In various aspects, the dosage of leucine is from about 28 mg / kg to about 29 mg / kg.

[0169] In various aspects, the dose of leucine is 28 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 29 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 30 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 40 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 50 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 100 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 150 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 200 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 250 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 300 mg / kg to 310 mg / kg. In various aspects, the dose of leucine is 305 mg / kg to 310 mg / kg.

[0170] In various aspects, the dosage of leucine is 28 mg / kg to 305 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 300 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 250 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 200 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 150 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 100 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 50 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 40 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 30 mg / kg. In various aspects, the dosage of leucine is 28 mg / kg to 29 mg / kg.

[0171] In one aspect, the dosage of isoleucine is from about 24 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 25 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 50 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 75 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 100 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 125 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 150 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 175 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 200 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 225 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is from about 240 mg / kg to about 245 mg / kg.

[0172] In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 240 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 225 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 200 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 175 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 150 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 125 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 100 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 75 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 50 mg / kg. In various aspects, the dosage of isoleucine is from about 24 mg / kg to about 25 mg / kg.

[0173] In various aspects, the dosage of isoleucine is 24 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 25 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 50 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 75 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 100 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 125 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 150 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 175 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 200 mg / kg to 245 mg / kg. In various aspects, the dosage of isoleucine is 225 mg / kg to about 245 mg / kg. In various aspects, the dosage of isoleucine is 240 mg / kg to 245 mg / kg.

[0174] In various aspects, the dosage of isoleucine is 24 mg / kg to 240 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 225 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 200 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 175 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 150 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 125 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 100 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 75 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 50 mg / kg. In various aspects, the dosage of isoleucine is 24 mg / kg to 25 mg / kg.

[0175] In one aspect, the dosage of valine is about 22 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 23 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 24 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 25 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 50 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 75 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 100 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 125 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 150 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 175 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 200 mg / kg to about 230 mg / kg. In various aspects, the dosage of valine is about 225 mg / kg to about 230 mg / kg.

[0176] In various aspects, the dosage of valine is from about 22 mg / kg to about 225 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 200 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 175 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 150 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 125 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 100 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 75 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 50 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 25 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 24 mg / kg. In various aspects, the dosage of valine is from about 22 mg / kg to about 23 mg / kg.

[0177] In various aspects, the dosage of valine is 22 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 23 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 24 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 25 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 50 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 75 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 100 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 125 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 150 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 175 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 200 mg / kg to 230 mg / kg. In various aspects, the dosage of valine is 225 mg / kg to 230 mg / kg.

[0178] In various aspects, the dosage of valine is 22 mg / kg to 225 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 200 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 175 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 150 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 125 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 100 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 75 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 50 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 25 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 24 mg / kg. In various aspects, the dosage of valine is 22 mg / kg to 23 mg / kg.

[0179] In one aspect, the dosage of phenylalanine is from about 15 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 20 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 30 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 40 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 50 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 60 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 70 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 80 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 90 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is from about 100 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is about 110 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is about 120 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is about 130 mg / kg to about 150 mg / kg. In various aspects, the dosage of phenylalanine is about 140 mg / kg to about 150 mg / kg.

[0180] In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 140 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 130 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 120 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 110 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 100 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 90 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 80 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 70 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 60 mg / kg. In various aspects, the dosage of phenylalanine is from about 15 mg / kg to about 50 mg / kg. In various aspects, the dosage of phenylalanine is about 15 mg / kg to about 40 mg / kg. In various aspects, the dosage of phenylalanine is about 15 mg / kg to about 30 mg / kg. In various aspects, the dosage of phenylalanine is about 15 mg / kg to about 20 mg / kg.

[0181] In one aspect, the dosage of phenylalanine is 15 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 20 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 30 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 40 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 50 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 60 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 70 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 80 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 90 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 100 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 110 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 120 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 130 mg / kg to 150 mg / kg. In various aspects, the dosage of phenylalanine is 140 mg / kg to 150 mg / kg.

[0182] In various aspects, the dosage of phenylalanine is from 15 mg / kg to 140 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 130 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 120 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 110 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 100 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 90 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 80 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 70 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 60 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 50 mg / kg. In various aspects, the dosage of phenylalanine is from 15 mg / kg to 40 mg / kg. In various aspects, the dosage of phenylalanine is 15 mg / kg to 30 mg / kg. In various aspects, the dosage of phenylalanine is 15 mg / kg to 20 mg / kg.

[0183] In one aspect, the dosage of tyrosine is from about 9 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 10 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 20 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 30 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 40 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 50 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 60 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 70 mg / kg to about 90 mg / kg. In various aspects, the dosage of tyrosine is from about 80 mg / kg to about 90 mg / kg.

[0184] In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 80 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 70 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 60 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 50 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 40 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 30 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 20 mg / kg. In various aspects, the dosage of tyrosine is from about 9 mg / kg to about 10 mg / kg.

[0185] In various aspects, the dosage of tyrosine is 9 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 10 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 20 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 30 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 40 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 50 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 60 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 70 mg / kg to 90 mg / kg. In various aspects, the dosage of tyrosine is 80 mg / kg to 90 mg / kg.

[0186] In various aspects, the dosage of tyrosine is 9 mg / kg to 80 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 70 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 60 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 50 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 40 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 30 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 20 mg / kg. In various aspects, the dosage of tyrosine is 9 mg / kg to 10 mg / kg.

[0187] In one aspect, the dosage of methionine is from about 6 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 7 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 8 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 9 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 10 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 20 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 30 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 40 mg / kg to about 60 mg / kg. In various aspects, the dosage of methionine is from about 50 mg / kg to about 60 mg / kg.

[0188] In various aspects, the dosage of methionine is from about 6 mg / kg to about 50 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 40 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 30 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 20 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 10 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 9 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 8 mg / kg. In various aspects, the dosage of methionine is from about 6 mg / kg to about 7 mg / kg.

[0189] In one aspect, the dosage of methionine is 6 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 7 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 8 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 9 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 10 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 20 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 30 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 40 mg / kg to 60 mg / kg. In various aspects, the dosage of methionine is 50 mg / kg to 60 mg / kg.

[0190] In various aspects, the dosage of methionine is 6 mg / kg to 50 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 40 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 30 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 20 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 10 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 9 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 8 mg / kg. In various aspects, the dosage of methionine is 6 mg / kg to 7 mg / kg.

[0191] In one aspect, the dosage of cysteine ​​is from about 4 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 5 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 10 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 15 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 20 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 25 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 30 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 35 mg / kg to about 45 mg / kg. In various aspects, the dosage of cysteine ​​is from about 40 mg / kg to about 45 mg / kg.

[0192] In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 40 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 35 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 30 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 25 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 20 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 15 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 10 mg / kg. In various aspects, the dosage of cysteine ​​is from about 4 mg / kg to about 5 mg / kg.

[0193] In various aspects, the dosage of cysteine ​​is 4 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 5 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 10 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 15 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 20 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 25 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 30 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 35 mg / kg to 45 mg / kg. In various aspects, the dosage of cysteine ​​is 40 mg / kg to 45 mg / kg.

[0194] In various aspects, the dosage of cysteine ​​is 4 mg / kg to 40 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 35 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 30 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 25 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 20 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 15 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 10 mg / kg. In various aspects, the dosage of cysteine ​​is 4 mg / kg to 5 mg / kg.

[0195] In one aspect, the dosage of tryptophan is from about 6 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 7 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 8 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 9 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 10 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 15 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 20 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 25 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 30 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 35 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is from about 40 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is about 45 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is about 50 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is about 55 mg / kg to about 61 mg / kg. In various aspects, the dosage of tryptophan is about 60 mg / kg to about 61 mg / kg.

[0196] In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 60 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 55 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 50 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 45 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 40 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 35 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 30 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 25 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 20 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 15 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 10 mg / kg. In various aspects, the dosage of tryptophan is from about 6 mg / kg to about 9 mg / kg. In various aspects, the dosage of tryptophan is about 6 mg / kg to about 8 mg / kg. In various aspects, the dosage of tryptophan is about 6 mg / kg to about 7 mg / kg.

[0197] In one aspect, the dosage of tryptophan is 6 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 7 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 8 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 9 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 10 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 15 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 20 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 25 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 30 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 35 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 40 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 45 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 50 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 55 mg / kg to 61 mg / kg. In various aspects, the dosage of tryptophan is 60 mg / kg to 61 mg / kg.

[0198] In various aspects, the dosage of tryptophan is 6 mg / kg to 60 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 55 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 50 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 45 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 40 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 35 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 30 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 25 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 20 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 15 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 10 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 9 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 8 mg / kg. In various aspects, the dosage of tryptophan is 6 mg / kg to 7 mg / kg.

[0199] In one aspect, the method further comprises administering to the subject an effective amount of an agent, wherein the agent is administered about 1 to 7 days after the traumatic pain event, and wherein the agent is a 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 embodiments, the agent is administered within about 24 hours to about 96 hours after the traumatic pain event. In embodiments, the agent is a NAAA (N-acylethanolamine acid amidase) inhibitor. In embodiments, the agent is a FAAH (fatty acid amide hydrolase) inhibitor. In embodiments, 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 α-lipoic acid. In embodiments, the agent is olesoxime. In embodiments, the agent is administered in a therapeutically effective amount.

[0200] In an embodiment, 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), neurogenic pain, peripheral pain, polyneuropathic pain, toxic neuropathy, chronic neuropathy or pruritus, or acute postoperative pain.

[0201] 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.

[0202] In embodiments, the subject is a cancer patient.In embodiments, the subject is a diabetic patient.

[0203] 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 prior to or perioperatively.

[0204] In embodiments, the method comprises administering the composition one to four times per day. In embodiments, the method comprises administering the composition once per day. In embodiments, the method comprises administering the composition twice per day. In embodiments, the method comprises administering the composition three times per day.

[0205] In embodiments, the method includes administering the composition within about 0 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 1 day to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 2 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 3 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 4 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 5 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 6 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 7 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 8 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 9 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 10 days to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 15 days to about 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition within about 20 days to about 30 days after the traumatic painful event. In embodiments, the method comprises administering the composition within about 25 days to about 30 days after the traumatic painful event.

[0206] In embodiments, the method includes administering the composition within about 0 days to about 25 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 20 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 15 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 10 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 9 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 8 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 7 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 6 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 5 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 4 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 3 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 0 days to about 2 days after the traumatic pain event. In embodiments, the method comprises administering the composition between about 0 days and about 1 day after the traumatic painful event.

[0207] In embodiments, the method includes administering the composition within 0 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 1 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 2 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 3 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 4 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 5 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 6 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 7 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within about 8 to about 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 9 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 10 to 30 days after the traumatic pain event. In embodiments, the method includes administering the composition within 15 to 30 days after the traumatic pain event. In embodiments, the method comprises administering the composition within 20 to 30 days after the traumatic painful event. In embodiments, the method comprises administering the composition within 25 to 30 days after the traumatic painful event.

[0208] In embodiments, the method includes administering the composition within 0 to 25 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 20 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 15 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 10 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 9 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 8 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 7 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 6 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 5 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 4 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 3 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 2 days after the traumatic pain event. In embodiments, the method includes administering the composition within 0 to 1 day after the traumatic pain event.

[0209] In embodiments, the method includes administering the composition within about 30 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 25 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 20 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 15 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 10 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 9 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 8 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 7 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 6 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 5 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 4 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 3 days to about 1 day before the traumatic pain event. In embodiments, the method comprises administering the composition from about 2 days to about 1 day prior to the traumatic painful event.

[0210] In embodiments, the method includes administering the composition within about 30 days to about 2 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 3 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 4 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 5 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 6 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 7 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 8 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 9 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 10 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 15 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 20 days before the traumatic pain event. In embodiments, the method includes administering the composition within about 30 days to about 25 days before the traumatic pain event.

[0211] In embodiments, the method includes administering the composition within 30 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 25 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 20 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 15 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 10 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 9 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within about 8 days to about 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 7 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 6 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 5 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 4 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 3 days to 1 day before the traumatic pain event. In embodiments, the method includes administering the composition within 2 days to 1 day before the traumatic pain event.

[0212] In embodiments, the method includes administering the composition within 30 days to 2 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 3 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 4 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 5 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 6 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 7 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 8 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 9 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 10 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 15 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 20 days before the traumatic pain event. In embodiments, the method includes administering the composition within 30 days to 25 days before the traumatic pain event.

[0213] In embodiments, the method includes applying the composition once a day within 30 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 29 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 28 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 27 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 26 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 25 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 24 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 23 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 22 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 21 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 20 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 19 days before the traumatic pain event. In embodiments, the method includes applying the composition once a day within 18 days before the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 17 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 16 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 15 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 14 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 13 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 12 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 11 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition once a day within 10 days prior to the traumatic pain event.

[0214] In embodiments, the method includes applying the composition twice a day within 30 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 29 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 28 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 27 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 26 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 25 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 24 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 23 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 22 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 21 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 20 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 19 days before the traumatic pain event. In embodiments, the method includes applying the composition twice a day within 18 days before the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 17 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 16 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 15 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 14 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 13 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 12 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 11 days prior to the traumatic pain event. In embodiments, the method comprises administering the composition twice a day within 10 days prior to the traumatic pain event.

[0215] In one aspect, the method further comprises administering to the subject an effective amount of an agent, wherein the agent is administered about 1 to 7 days after the traumatic pain event, and wherein the agent is a 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 embodiments, the method comprises preventing the subject from converting from an acute pain state to a chronic pain state. In embodiments, the agent is administered within about 24 hours to about 96 hours after the traumatic pain event. In embodiments, the agent is a NAAA (N-acylethanolamine acid amidase) inhibitor. In embodiments, the agent is a FAAH (fatty acid amide hydrolase) inhibitor. In embodiments, 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.

[0216] In embodiments, the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, or PEA. In embodiments, the agent is a NAAA inhibitor. In embodiments, the agent is a FAAH inhibitor. In embodiments, the agent is a PPARα agonist. In embodiments, the agent is PEA.

[0217] 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 J Med Chem. 2020 Jul 23; 63(14):7475-7490, which is incorporated herein by reference in its entirety and for all purposes. In embodiments, the NAAA inhibitors are described in WO 2013 / 078430, US2013 / 0281490, WO 2009 / 049238, US2014 / 0094508, WO 2014 / 144836, US2016 / 0068482, WO 2017 / 201103, or US2019 / 0177313, which are incorporated herein by reference in their entirety and for all purposes.

[0218] In embodiments, the FAAH inhibitor is URB597, URB937, an analog of URB 597, or an analog of URB 937. In embodiments, the FAAH inhibitor is URB597. In embodiments, the FAAH inhibitor is -URB937. In embodiments, the FAAH inhibitor is an analog of URB 597. In embodiments, the FAAH inhibitor is an analog of URB 937. In embodiments, the FAAH inhibitor is described in J Med Chem. 2017 Jan 12;60(1):4-46, which is incorporated herein by reference in its entirety and for all purposes. In embodiments, the FAAH inhibitor is described in WO 2015 / 157313, US 2017 / 0088510, WO 2012 / 015704, US 2013 / 0217764, WO 2013 / 028570, or US 2014 / 0288170, which are incorporated herein by reference in their entirety and for all purposes.

[0219] In an embodiment, the PPARα agonist is a natural or non-natural PPARα agonist.

[0220] In an embodiment, the PPARα agonist is GW7647, PEA (palmitoylethanolamide) or OEA (oleoylethanolamide). In an embodiment, the PPARα agonist is GW7647. In an embodiment, the PPARα agonist is PEA (palmitoylethanolamide). In an embodiment, the PPARα agonist is OEA (oleoylethanolamide). In an embodiment, the PPARα agonist is described in Expert OpinInvestig Drugs. 2017 May; 26(5): 593-60, which is incorporated herein by reference in its entirety.

[0221] In embodiments, the method further comprises administering the agent within about 8 to 30 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 8 to 10 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 8 to 14 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 8 to 21 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 8 to 28 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 10 to 14 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 10 to 21 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 10 to 28 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 15 to 20 days after the traumatic pain event. In embodiments, the method further comprises administering the agent within about 15 to 30 days after the traumatic pain event.

[0222] In embodiments, the method further comprises continuously administering the agent within about 8 to 30 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 8 to 10 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 8 to 14 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 8 to 21 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 8 to 28 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 10 to 14 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 10 to 21 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 10 to 28 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 15 to 20 days after the traumatic pain event. In embodiments, the method further comprises continuously administering the agent within about 15 to 30 days after the traumatic pain event.

[0223] In embodiments, the traumatic pain event is due to an accidental physical injury, an invasive procedure, or an acute illness. In embodiments, the traumatic pain event is due to an accidental physical injury. In embodiments, the traumatic pain event is due to an invasive procedure. In embodiments, the traumatic pain event is due to an acute illness.

[0224] 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.

[0225] 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 laparotomy cholecystectomy. 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 embodiments, the invasive surgery is laparotomy cholecystectomy.

[0226] In embodiments, the medicament is applied in the perioperative period. In embodiments, the medicament is applied before, during or after surgery for a period of time. The term "perioperative period (perio perative or perioperatively)" is used according to its simple common meaning and generally refers to the time period before, during and / or after a surgical operation. For example, "perioperative period" can refer to a period of time from the time when the patient arrives at a surgical facility (e.g., a hospital, a clinic, a doctor's office) for a surgical operation (e.g., admission) until the patient leaves the surgical operation (e.g., discharge). In embodiments, the perioperative period includes the inclusion of surgical facilities, anesthesia, surgery and post-surgical recovery.

[0227] In one aspect, a method for preventing chronic pain in a subject is provided, the method comprising administering an effective amount of an agent to the subject in the perioperative period, wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid or olesoxime. In embodiments, NAAA inhibitors are as described herein (included in embodiments). In embodiments, FAAH inhibitors are as described herein (included in embodiments). In embodiments, PPARα agonists are as described herein, including in the examples.

[0228] 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 purified fatty acid amides, wherein the subject's chronic pain is prevented.

[0229] 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 the subject's chronic pain is prevented.

[0230] In one aspect, the method further comprises administering an effective amount of an agent to a cancer patient, wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid or olesoxime. In embodiments, the NAAA inhibitor is as described herein (included in embodiments). In embodiments, the FAAH inhibitor is as described herein (included in embodiments). In embodiments, the PPARα agonist is as described herein, including in the examples.

[0231] In embodiments, the method further comprises administering an anticancer agent (e.g., as described herein). In embodiments, the chronic pain is caused by an anticancer 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 paresthesia. The term "paresthesia" is used according to its simple ordinary meaning and generally refers to an abnormal sensation, e.g., tingling or poking pain. In embodiments, the chronic pain is numbness.

[0232] In one aspect, a method for 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 purified fatty acid amides, wherein the subject's chronic pain is prevented.

[0233] In one aspect, a method for 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 the subject's chronic pain is prevented.

[0234] In one aspect, the method further comprises administering an effective amount of an agent to a diabetic patient, wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid or olesoxime. In embodiments, the NAAA inhibitor is as described herein (included in embodiments). In embodiments, the FAAH inhibitor is as described herein (included in embodiments). In embodiments, the PPARα agonist is as described herein, including in the examples.

[0235] In embodiments, chronic pain is chronic peripheral neuropathy. In embodiments, chronic pain is chronic polyneuropathy. In embodiments, chronic pain is hyperalgesia. In embodiments, chronic pain is paresthesia (e.g., tingling or poking pain). In embodiments, chronic pain is numbness.

[0236] In an embodiment, the agent is not morphine. In an embodiment, the agent is not gabapentin. In an embodiment, the agent is not ketamine. In an embodiment, the agent is not ketoprofen.

[0237] In embodiments, the method further comprises administering an opioid analgesic for treating acute postoperative pain. In embodiments, the opioid analgesic is morphine, and the composition enhances the analgesic effect of morphine.

[0238] The methods described herein may reduce postoperative opioid consumption, decrease postoperative hospital stay, reduce preoperative anxiety, and decrease the need for sedative medications.

[0239] IV. Kit

[0240] In one aspect, a kit is provided comprising any of the compositions or compounds described above. In various aspects, the compositions and compounds are combined. In various aspects, the kit also comprises any of the medicaments described above. In various aspects, one or more of the compounds or medicaments are in separate containers. The kit may also include preparation and use instructions.

[0241] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that those skilled in the art will recognize various modifications or variations according to the present invention, which are all included in the spirit and authority of the present application and within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0242] Example

[0243] These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0244] Example 1: Effects of diet on chronic pain in vivo

[0245] The applicant found that formalin can produce "acute" anti-injury reaction in mice, followed by local inflammation and continuous neuropathological state, and its multi-mode performance is surprisingly similar to the chronic pain of people. Not wishing to be bound by theory, the applicant found the critical period of transition from acute pain to chronic pain, which is briefly opened after tissue damage and consistent with a large number of metabolic changes in the local spinal cord. These changes include free amino acids (alanine, threonine, proline, serine, leucine, isoleucine, valine, phenylalanine, tyrosine, methionine, cysteine, tryptophan), non-esterified unsaturated fatty acids (oleic acid, erucic acid) and fatty acid amide palmitoylethanolamide (PEA) concentration reduction. Therefore, a study was conducted to test whether the pain chronicity of mice injected with formalin can be eliminated by providing these missing compounds to animals through enriched diet. Three different experimental diets (ED) were tested in the mouse formalin test. ED used herein is a modified form of standard rodent diet (STD), rich in free amino acids plus fatty acids (ED-1), PEA (ED-2) or a combination (COMBO) of the two. The results show that formalin injection can cause severe swelling of the injected paws, and is accompanied by persistent bilateral hypersensitivity to mild painful thermal stimulation (thermal hyperalgesia) and usually harmless mechanical stimulation (mechanical allodynia). Pain hypersensitivity is accompanied by emotional and cognitive disorders. Dietary intervention by ED-1 or ED-2 can alleviate the sensory hypersensitivity caused by formalin, but after stopping ED and replacing it with STD, the appearance of persistent pain state cannot be prevented. In contrast, the combination of the two can prevent the development of chronic pain, normalize paresthesia, anxiety-like behavior and memory deficits. Therefore, the dietary enrichment of the combination of free amino acids, fatty acids and PEA can eliminate the chronicity of pain after surgery or accidental tissue damage.

[0246] Example 2: Materials and Methods

[0247] animal

[0248] Briefly, CD-1 mice (7 weeks old when received; Charles River, Wilmington, MA) were maintained in a pathogen-free environment at a controlled temperature (22°C) and humidity (50% to 60%) with a 12-hour light / dark cycle. Food and water were freely available. Animals were randomly assigned to study groups and handled for three consecutive days before the start of the experiment (approximately 3 min per animal / day), and behavioral tests were performed during the light phase of the light / dark cycle. The number of animals used and the discomfort of the animals were minimized. This study complied with all ethical regulations recommended by the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and the International Association for the Study of Pain. The experimental procedures have been approved by the Animal Care and Use Committee of the University of California, Irvine (AUP-20-117).

[0249] Dietary intervention

[0250] Mice were randomly assigned to receive a standard rodent diet (SD) or an experimental diet (ED: ED-1, ED-2 or COMBO) for a period of 3 weeks. Then, the animals were tested with formalin (1% volume, plantar injection) or saline injection (sham injection) and maintained on their respective diets for one week. In a separate experiment, the sciatic nerve of these animals was sham injected or spared nerve injury (SNI) and maintained on their respective diets for two weeks. Nociceptive behavior, paw edema, cognitive deficits (novel object recognition test, NOR) and emotional disorders (elevated plus maze test, EPM) caused by formalin injection or SNI were evaluated at different time points after the challenge.

[0251] Diet composition

[0252] The experimental diet (ED) was a modified form of standard rodent chow (SD; Teklad Diets, Madison, WI, USA) enriched with free amino acids plus fatty acids (ED1), palmitoylethanolamide (PEA) (ED2), or a combination of free amino acids, fatty acids, and PEA (COMBO). Mice had free access to the respective diets.

[0253] Table 3 Composition of ED1

[0254] Active ingredients Animal dose (mg / kg) Oleic acid 6200 Erucic acid 310 Alanine 2362.5 Threonine 1625 Proline 3000 Serine 1250 Leucine 3875 Isoleucine 3062.5 Valine 2875 Phenylalanine 1875 Tyrosine 1125 Methionine 750 Cysteine 562.5 Tryptophan 762.5

[0255] Table 4 Composition of ED2

[0256] Active ingredients Animal dose (mg / kg) pea 103.75

[0257] Table 5 Composition of components

[0258] Active ingredients Animal dose (mg / kg) pea 103.75 Oleic acid 6200 Erucic acid 310 Alanine 2362.5 Threonine 1625 Proline 3000 Serine 1250 Leucine 3875 Isoleucine 3062.5 Valine 2875 Phenylalanine 1875 Tyrosine 1125 Methionine 750 Cysteine 562.5 Tryptophan 762.5

[0259] Behavioral testing

[0260] Formalin

[0261] Formalin (1% volume, 20 μl) or saline was injected into the plantar surface of the right hind paw of mice as previously reported (Mabou Tagne et al., 2021). Immediately after injection, mice were transferred to a transparent observation chamber, where anti-nociceptive behavior (time of licking or biting the injected paw and number of paw shaking) was video recorded for 60 min and quantified by a blinded observer. Mechanical allodynia, thermal hyperalgesia, and paw edema were measured in injected and uninjected paws on days 7 and 14 after formalin injection (PFD).

[0262] Avoid nerve damage

[0263] To determine the spared nerve injury, a previously described protocol was used (Guida et al., 2020). Mice were anesthetized with isoflurane, and the right common sciatic nerve was exposed at its trifurcation as the sural nerve, tibial nerve, and common peroneal nerve using a blunt scalpel under sterile conditions. The common peroneal and tibial nerves were then tied (for mice, non-absorbable 6.0 silk thread was used), and the distal end of the ligature was cut, and the 2-4 mm distal nerve stump was cut. The sural nerve remained intact. The wound was closed with a muscle suture and skin clips. In sham-operated animals, the sciatic nerve was exposed but not cut.

[0264] Mechanical allodynia

[0265] Mechanical allodynia was assessed using a dynamic plantar aesthesiometer (Ugo Basile, Comerio, Italy). After a 45-min adaptation period, mechanical stimulation was applied to the plantar surface of both hind paws by applying increasing forces (from 0 g to 5 g in 10 s) via an automated steel wire in a transparent cage placed on a wire mesh surface. Three withdrawal thresholds (in grams) were recorded and averaged.

[0266] Paw edema

[0267] Paw edema was measured with a digital caliper (Fisher Scientific, USA) and Δ was expressed as the difference between the ipsilateral and contralateral paws (paw thickness, mm).

[0268] Thermal sensitivity

[0269] Thermal sensitivity was measured using a Hargreaves plantar tester (San Diego Instruments, San Diego, USA). After a 45-min adaptation period, the plantar surfaces of both hind paws were exposed to a radiant heat beam through a glass floor. The cutoff time was set to 15 seconds. The stimulation was repeated three times with a 2-min interval between each stimulation, and the delay to retract the paw (in seconds) was recorded and averaged.

[0270] Elevated plus maze test

[0271] Each mouse was placed on the central platform of the maze, facing the open arm and away from the experimenter, and behavior was recorded using Debut video capture software (NCH Software, Canberra, Australia). The time spent in the open and closed arms, as well as the number of entries into the open and closed arms, was measured by a blinded observer. The open arms of the maze were illuminated at 150 to 170 lux, and the closed arms were illuminated at 40 to 50 lux. The anxiety index was calculated as follows

[0272]

[0273] Novel object recognition test

[0274] The test was conducted over 3 days. On day 1, mice were acclimated to an open field for 20 min. On day 2, they were returned to the field, which now contained two identical objects. On day 3, one of the objects was replaced by another object of different shape, color, and texture. The mice were allowed to explore the field for 10 min, and the total time spent exploring each object (i.e., sniffing and sniffing at a distance ≤ 2 cm) was recorded by a blinded observer. The discrimination index (DI) was calculated as follows:

[0275]

[0276] Example 3: Effects of diet on spinal cord energy crisis and metabolite levels

[0277] This example describes the determination of metabolic changes in the spinal cord of mice following formalin-induced transition to chronic pain and treatment with a medical food.

[0278] Briefly, mice were maintained on a standard diet (SD) or medical food (MF) composition as described in Example 2 and then treated with formalin three weeks later as described in Example 1. Mouse spinal cord samples were collected 24 hours, 48 ​​hours, and 72 hours after formalin treatment and subjected to metabolomics analysis. The levels of metabolites involved in glycolysis, TCA cycle, purine derivatives, amino acids, urea cycle, acylated amino acids, fatty acids, and phospholipids were measured (Figure 3).

[0279] The results showed that the metabolic changes were reduced or reversed in mice treated with the medical food. The medical food can prevent the metabolic shift from the TCA cycle to aerobic glycolysis that occurs during the transition to chronic pain. Figure 3A and 3B ). Energy crisis (low ATP, Figure 3C ) is also blocked. Amino acids ( Figure 4A ) and urea cycle intermediates ( Figure 4B ) levels decrease during the transition to chronic pain but can be normalized by medical foods. Changes in acylated amino acid levels are counteracted by ( Figure 4C ).fatty acid( Figure 5A ) and phospholipids ( Figure 5B ) levels are differentially altered during the transition to chronic pain and can be normalized by medical foods.

[0280] Example 4: Effect of diet in the hyperalgesia elicitation model

[0281] This example describes the determination of the effects of diet in mice following hyperalgesia induction and treatment with a medical food.

[0282] Briefly, male mice were maintained on a standard diet (SD) or medical food (MF) composition as described in Example 2 and treated with IL-6 (5 ng, intraplantar) or its vehicle three weeks later. 2 To challenge IL-6 primed mice, behavioral tests were then performed to measure pain hypersensitivity (hyperalgesia). The results showed that administration of interleukin-6 (IL-6) in male mice fed a standard diet (SD) produced localized heat sensitivity (assessed by withdrawal latency (in seconds)) that lasted for >6 h ( Figure 6 Mice fed the medical food (MF) did not show this reaction ( Figure 6 ). The results showed that the medicinal food could inhibit the acute hyperalgesia caused by IL-6.

[0283] On days 7 and 14 after IL-6 injection, mice were additionally injected with prostaglandin E 2 (PGE 2 , 100ng, intraplantar). The results showed that in IL-6-induced male mice, prostaglandin E 2 Administration of induced localized heat sensitivity in animals fed a standard diet (SD) but not in animals fed a medical food (MF) ( Fig. 7A and 7B ). In conclusion, the results suggest that MF prevents the induction of inflammatory hyperalgesia and is effective in alleviating postoperative pain in addition to preventing the transition to chronic pain.

[0284] Example 5: Effect of diet on the antinociceptive effect of morphine

[0285] This example describes the determination of the effects of diet in mice following morphine-induced antinociception and treatment with a medical food.

[0286] Briefly, morphine (mg / kg, subcutaneously) was administered to animals fed a standard diet or medical food. Responses were expressed as a percentage of the maximum possible effect (MPE) ( Fig. 8A The median effective dose (ED 50 ) values. The results showed that MF enhanced the analgesic effect of morphine, which is commonly used to treat postoperative pain.

[0287] In addition, the effect of medical foods on tolerance to the antinociceptive effects of morphine was measured in male mice. The antinociceptive effects of morphine (15 mg / kg, subcutaneously) were assessed on day 1. Tolerance was induced by administering morphine (30 mg / kg) on ​​days 2-6. Tolerance to injections of 15 mg / kg morphine ( Figure 8B ). The results suggest that MF does not affect morphine-induced tolerance, which could reduce postoperative analgesia.

[0288] References

[0289] 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 inspared nerve injury model of neuropathic pain. Intemational Journal of Molecular Sciences, 21(9), 1-21. https: / / doi.org / 10.3390 / ijms21093396

[0290] Mabou Tagne, A., Fotio.Y., Lin, L., Squire, E., Ahmed, F., Rashid, TI, Karimian Azari, E., & Piomelli, D. (2021). Palmitoylethanolamide and hemp oilextract 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

[0291] While the present disclosure has been particularly shown and described with reference to certain embodiments, some of which are preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

[0292] Patent Implementation

[0293] Patent embodiment 1. A method for preventing chronic pain in a subject following a traumatic pain event, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid and purified fatty acid amide, wherein the subject's chronic pain is prevented.

[0294] Patent embodiment 2. A method as described in embodiment 1, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0295] Patent embodiment 3. A method as described in embodiment 1 or embodiment 2, wherein the composition is administered orally.

[0296] Patent embodiment 4. A method as described in embodiment 1 or embodiment 3, wherein the purified fatty acid is oleic acid or erucic acid.

[0297] Patent embodiment 5. A method as described in embodiment 4, wherein the subject is a human and the dose range of oleic acid is between 48 and 496 mg / kg.

[0298] Patent embodiment 6. A method as described in embodiment 4 or embodiment 5, wherein the subject is a human and the dose range of erucic acid is 2 to 25 mg / kg.

[0299] Patent embodiment 7. A method as described in 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.

[0300] Patent embodiment 8. A method as described in embodiment 7, wherein the subject is a human and the dose range of alanine is 20 to 189 mg / kg.

[0301] Patent embodiment 9. A method as described in embodiment 7 or embodiment 8, wherein the subject is a human and the dose range of threonine is 12 to 130 mg / kg.

[0302] Patent embodiment 10. The method as described in any one of embodiments 7 to 9, wherein the subject is a human and the dosage range of proline is 24 to 240 mg / kg.

[0303] Patent embodiment 11. A method as described in any one of embodiments 7 to 10, wherein the subject is a human and the dose range of serine is 10 to 100 mg / kg.

[0304] Patent embodiment 12. A method as described in any one of embodiments 7 to 11, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

[0305] Patent embodiment 13. A method as described in any one of embodiments 7 to 12, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

[0306] Patent embodiment 14. The method as described in any one of embodiments 7 to 13, wherein the subject is a human and the dose range of valine is 22 to 230 mg / kg.

[0307] Patent embodiment 15. A method as described in any one of embodiments 7 to 14, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

[0308] Patent embodiment 16. A method as described in any one of embodiments 7 to 15, wherein the subject is a human and the dose of tyrosine ranges from 9 to 90 mg / kg.

[0309] Patent embodiment 17. A method as described in any one of embodiments 7 to 16, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

[0310] Patent embodiment 18. The method as described in any one of embodiments 7 to 17, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

[0311] Patent embodiment 19. A method as described in any one of embodiments 7 to 18, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

[0312] Patent embodiment 20. A method as described in any one of embodiments 1 to 19, wherein the subject is a human and the dose range of PEA is 0.8 to 9 mg / kg.

[0313] Patent embodiment 21. The method of any one of embodiments 1 to 20, wherein the composition is administered from about 0 days to about 30 days after the traumatic pain event.

[0314] Patent embodiment 22. The method of any one of embodiments 1 to 21, wherein the composition is administered from about 30 days to about 1 day prior to the traumatic pain event.

[0315] Patent embodiment 23. A method as described in any one of embodiments 1 to 22, wherein the traumatic pain event is caused by physical injury, invasive surgery, or acute illness.

[0316] Patent embodiment 24. A method as described in any of embodiments 1 to 23, wherein the physical injury is an accidental physical injury.

[0317] Patent embodiment 25. A method as described in embodiment 23, wherein the physical injury is an acute physical injury.

[0318] Patent embodiment 26. A method as described in embodiment 25, wherein the acute physical injury is a concussion, a fracture, or an internal injury.

[0319] Patent embodiment 27. A method as described in embodiment 23, wherein the invasive surgery is knee arthroplasty, hip replacement, mastectomy, open heart surgery, hernia repair, thoracotomy, cesarean section, amputation or laparotomy cholecystectomy.

[0320] Patent embodiment 28. A method as described in embodiment 27, wherein the composition is administered perioperatively.

[0321] Patent embodiment 29. A method as described in any one of embodiments 1 to 28, wherein the method further comprises administering an agent about 1 day to 7 days after the traumatic pain event, and wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, PEA, acetyl-L-carnitine, α-lipoic acid or olesoxime.

[0322] Patent embodiment 30. The method of embodiment 29, further comprising administering the agent about 8 to 30 days after the traumatic pain event.

[0323] Patent embodiment 31. The method of embodiment 29 further comprises continuously administering the agent for about 8 to 30 days after the traumatic pain event.

[0324] Patent embodiment 32. A method for preventing chronic pain in a subject following a traumatic pain event, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amide, wherein the subject's chronic pain is prevented.

[0325] Patent embodiment 33. A method as described in embodiment 32, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0326] Patent embodiment 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, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and a purified fatty acid amide, wherein the subject's chronic pain is prevented.

[0327] Patent embodiment 35. A method as described in embodiment 34, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0328] Patent embodiment 36. A method as described in embodiment 32 or embodiment 34, wherein the composition is administered orally.

[0329] Patent embodiment 37. A method as described in embodiment 32 or embodiment 36, wherein the purified fatty acid is oleic acid or erucic acid.

[0330] Patent embodiment 38. A method as described in embodiment 37, wherein the subject is a human and the dose range of oleic acid is between 48-496 mg / kg.

[0331] Patent embodiment 39. A method as described in embodiment 37 or embodiment 38, wherein the subject is a human and the dose range of erucic acid is 2 to 25 mg / kg.

[0332] Patent embodiment 40. A method as described in any one 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.

[0333] Patent embodiment 41. A method as described in embodiment 40, wherein the subject is a human and the dose range of alanine is 20 to 189 mg / kg.

[0334] Patent embodiment 42. A method as described in embodiment 40 or embodiment 41, wherein the subject is a human and the dose range of threonine is 12 to 130 mg / kg.

[0335] Patent embodiment 43. A method as described in any one of embodiments 40 to 42, wherein the subject is a human and the dose range of proline is 24 to 240 mg / kg.

[0336] Patent embodiment 44. A method as described in any one of embodiments 40 to 43, wherein the subject is a human and the dose range of serine is 10 to 100 mg / kg.

[0337] Patent embodiment 45. A method as described in any one of embodiments 40 to 44, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

[0338] Patent embodiment 46. A method as described in any one of embodiments 40 to 45, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

[0339] Patent embodiment 47. The method of any one of embodiments 40 to 46, wherein the subject is a human and the dose of valine ranges from 22 to 230 mg / kg.

[0340] Patent embodiment 48. A method as described in any one of embodiments 40 to 47, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

[0341] Patent embodiment 49. A method as described in any one of embodiments 40 to 48, wherein the subject is a human and the dose of tyrosine ranges from 9 to 90 mg / kg.

[0342] Patent embodiment 50. The method of any one of embodiments 40 to 49, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

[0343] Patent embodiment 51. A method as described in any one of embodiments 40 to 50, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

[0344] Patent embodiment 52. A method as described in any one of embodiments 40 to 51, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

[0345] Patent embodiment 53. A method as described in any one of embodiments 32 to 52, wherein the subject is a human and the dose range of PEA is 0.8 to 9 mg / kg.

[0346] Patent embodiment 54. A method as described in any of embodiments 32 to 53, wherein the subject has cancer or has previously had cancer.

[0347] Patent embodiment 55. The method of any one of embodiments 32 to 54, further comprising administering an anticancer agent.

[0348] Patent embodiment 56. A method as described in embodiment 55, wherein the chronic pain is caused by the anti-cancer agent.

[0349] Patent embodiment 57. The method of any one of embodiments 32 to 56, wherein the chronic pain is chronic peripheral neuropathy.

[0350] Patent embodiment 58. The method of any one of embodiments 32 to 56, wherein the chronic pain is allodynia.

[0351] Patent embodiment 59. A method for preventing chronic pain in a subject with diabetes, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid and purified fatty acid amide, wherein the chronic pain in the subject is prevented.

[0352] Patent embodiment 60. A method as described in embodiment 59, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0353] Patent embodiment 61. The method of embodiment 59, wherein the composition is administered orally.

[0354] Patent embodiment 62. A method as described in embodiment 59 or embodiment 61, wherein the purified fatty acid is oleic acid or erucic acid.

[0355] Patent embodiment 63. A method as described in embodiment 62, wherein the subject is a human and the dose range of oleic acid is between 48-496 mg / kg.

[0356] Patent embodiment 64. A method as described in embodiment 62 or embodiment 63, wherein the subject is a human and the dose range of erucic acid is 2 to 25 mg / kg.

[0357] Patent embodiment 65. A method as described in any one 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.

[0358] Patent embodiment 66. A method as described in embodiment 65, wherein the subject is a human and the dose range of alanine is 20 to 189 mg / kg.

[0359] Patent embodiment 67. A method as described in embodiment 65 or embodiment 66, wherein the subject is a human and the dose of threonine ranges from 12 to 130 mg / kg.

[0360] Patent embodiment 68. A method as described in any one of embodiments 65 to 67, wherein the subject is a human and the dose of proline ranges from 24 to 240 mg / kg.

[0361] Patent embodiment 69. A method as described in any one of embodiments 65 to 68, wherein the subject is a human and the dose of serine ranges from 10 to 100 mg / kg.

[0362] Patent embodiment 70. The method of any one of embodiments 65 to 69, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

[0363] Patent embodiment 71. A method as described in any one of embodiments 65 to 70, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

[0364] Patent embodiment 72. The method of any one of embodiments 65 to 71, wherein the subject is a human and the dose of valine ranges from 22 to 230 mg / kg.

[0365] Patent embodiment 73. A method as described in any one of embodiments 65 to 72, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

[0366] Patent embodiment 74. A method as described in any one of embodiments 65 to 73, wherein the subject is a human and the dose of tyrosine ranges from 9 to 90 mg / kg.

[0367] Patent embodiment 75. The method of any one of embodiments 65 to 74, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

[0368] Patent embodiment 76. The method of any one of embodiments 65 to 75, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

[0369] Patent embodiment 77. A method as described in any of embodiments 65 to 76, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

[0370] Patent embodiment 78. The method of any one of embodiments 59 to 77, wherein the subject is a human and the dose range of PEA is 0.8 to 9 mg / kg.

[0371] Patent embodiment 79. The method of any one of embodiments 59 to 78, wherein the chronic pain is chronic peripheral neuropathy.

[0372] Patent embodiment 80. The method of any one of embodiments 59 to 78, wherein the chronic peripheral neuropathy is chronic polyneuropathy.

[0373] Patent embodiment 81. A method as described in any of embodiments 1 to 80, further comprising administering to the subject an effective amount of an agent, wherein the agent is administered about 1 day to 7 days after the traumatic pain event, and wherein the agent is a NAAA inhibitor, a FAAH inhibitor, a PPARα agonist, acetyl-L-carnitine, α-lipoic acid, or olesoxime.

[0374] Patent embodiment 82. The method of embodiment 81, further comprising administering the agent about 8 to 30 days after the traumatic pain event.

[0375] Patent embodiment 83. The method of embodiment 81, further comprising continuously administering the agent for about 8 to 30 days after the traumatic pain event.

[0376] Patent embodiment 84. A method as described in any of embodiments 81 to 83, wherein the agent is a NAAA inhibitor, a FAAH inhibitor, or a PPARα agonist.

[0377] Patent embodiment 85. A method as described in any of embodiments 81 to 84, wherein the NAAA inhibitor is ARN16186, ARN077 or ARN19702.

[0378] Patent embodiment 86. The method of any one of embodiments 81 to 84, wherein the FAAH inhibitor is URB597 or an analog of URB 597.

[0379] Patent embodiment 87. The method of any one of embodiments 81 to 84, wherein the FAAH inhibitor is URB937 or an analog of URB 937.

[0380] Patent embodiment 88. The method of any one of embodiments 81 to 84, wherein the PPARα agonist is a natural PPARα agonist.

[0381] Patent embodiment 89. The method of any one of embodiments 81 to 84, wherein the PPARα agonist is a non-natural PPARα agonist.

[0382] Patent embodiment 90. A method as described in any one of embodiments 81 to 84, wherein the PPARα agonist is GW7647, PEA or OEA.

[0383] Patent embodiment 91. Provided is a method for reducing pain hypersensitivity in a subject following a traumatic pain event, the method comprising administering to the subject an effective amount of a composition, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid and purified fatty acid amide, wherein the subject's pain hypersensitivity is reduced.

[0384] Patent embodiment 92. A method as described in embodiment 91, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0385] Patent embodiment 93. A method as described in embodiment 91, wherein the pain hypersensitivity is caused by acute pain / inflammatory pain.

[0386] Patent embodiment 94. A method as described in embodiment 91, wherein the inflammatory pain is IL-6 mediated.

[0387] Patent embodiment 95. A composition comprising at least one purified free amino acid, at least one purified fatty acid and purified fatty acid amide.

[0388] Patent embodiment 96. A composition as described in embodiment 95, wherein the fatty acid amide is purified palmitoylethanolamide (PEA).

[0389] Patent embodiment 97. The composition of embodiment 95 or embodiment 96, further comprising an artificial sweetener.

[0390] Patent embodiment 98. A dosage form comprising the composition of any one of embodiments 95 to 97, wherein the dosage form is a powder.

[0391] Patent embodiment 99. A dosage form as described in embodiment 98, wherein the dosage form is about 100 grams per dose.

[0392] Incorporated by Reference

[0393] The entire disclosure of each of the patent and scientific documents mentioned herein is incorporated by reference for all purposes.

[0394] Equivalent solution

[0395] The present invention may be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the above embodiments should be considered in all respects as illustrative, rather than limiting, the present invention described herein. The scope of the present invention is therefore indicated by the appended claims rather than by the preceding description, and all changes within the meaning and equivalent range of the claims are covered in the claims.

Claims

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

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

5. The method of claim 4, wherein the subject is a human and the dose of oleic acid ranges from 48 to 496 mg / kg.

6. The method of claim 4, wherein the subject is a human and the dose of erucic acid ranges from 2 to 25 mg / kg.

7. 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. The method of claim 7, wherein the subject is a human and the dose of alanine ranges from 20 to 189 mg / kg.

9. The method of claim 7, wherein the subject is a human and the dose of threonine ranges from 12 to 130 mg / kg.

10. The method of claim 7, wherein the subject is a human and the dose of proline ranges from 24 to 240 mg / kg.

11. The method of claim 7, wherein the subject is a human and the dose of serine ranges from 10 to 100 mg / kg.

12. The method of claim 7, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

13. The method of claim 7, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

14. The method of claim 7, wherein the subject is a human and the dose of valine ranges from 22 to 230 mg / kg.

15. The method of claim 7, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

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

17. The method of claim 7, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

18. The method of claim 7, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

19. The method of claim 7, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

20. The method of claim 1, wherein the subject is a human and the dose of PEA ranges from 0.8 to 9 mg / kg.

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

22. The method of claim 1, wherein the composition is administered from about 30 days to about 1 day prior to the traumatic pain event.

23. The method of claim 1, wherein the traumatic pain event is due to a physical injury, an invasive procedure, or an acute illness.

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

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

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

27. 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 laparotomy cholecystectomy.

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

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

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

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

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

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

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, wherein the composition comprises at least one purified free amino acid, at least one purified fatty acid, and purified fatty acid amides, wherein the subject's chronic pain is prevented.

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

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

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

38. The method of claim 37, wherein the subject is a human and the dose of oleic acid ranges from 48-496 mg / kg.

39. The method of claim 37, wherein the subject is a human and the dose of erucic acid ranges from 2 to 25 mg / kg.

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

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

42. The method of claim 40, wherein the subject is a human and the dose of threonine ranges from 12 to 130 mg / kg.

43. The method of claim 40, wherein the subject is a human and the dose of proline ranges from 24 to 240 mg / kg.

44. The method of claim 40, wherein the subject is a human and the dose of serine ranges from 10 to 100 mg / kg.

45. The method of claim 40, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

46. ​​The method of claim 40, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

47. The method of claim 40, wherein the subject is a human and the dose of valine ranges from 22 to 230 mg / kg.

48. The method of claim 40, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

49. The method of claim 40, wherein the subject is a human and the dose of tyrosine ranges from 9 to 90 mg / kg.

50. The method of claim 40, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

51. The method of claim 40, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

52. The method of claim 40, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

53. The method of claim 32, wherein the subject is a human and the dose of PEA ranges from 0.8 to 9 mg / kg.

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

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

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

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

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

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

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

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

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

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

64. The method of claim 62, wherein the subject is a human and the dose of erucic acid ranges from 2 to 25 mg / kg.

65. 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. The method of claim 65, wherein the subject is a human and the dose of alanine ranges from 20 to 189 mg / kg.

67. The method of claim 65, wherein the subject is a human and the dose of threonine ranges from 12 to 130 mg / kg.

68. The method of claim 65, wherein the subject is a human and the dose of proline ranges from 24 to 240 mg / kg.

69. The method of claim 65, wherein the subject is a human and the dose of serine ranges from 10 to 100 mg / kg.

70. The method of claim 65, wherein the subject is a human and the dose of leucine ranges from 28 to 310 mg / kg.

71. The method of claim 65, wherein the subject is a human and the dose of isoleucine ranges from 24 to 245 mg / kg.

72. The method of claim 65, wherein the subject is a human and the dose of valine ranges from 22 to 230 mg / kg.

73. The method of claim 65, wherein the subject is a human and the dose of phenylalanine ranges from 15 to 150 / kg.

74. The method of claim 65, wherein the subject is a human and the dose of tyrosine ranges from 9 to 90 mg / kg.

75. The method of claim 65, wherein the subject is a human and the dose of methionine ranges from 6 to 60 mg / kg.

76. The method of claim 65, wherein the subject is a human and the dose of cysteine ​​ranges from 4 to 45 mg / kg.

77. The method of claim 65, wherein the subject is a human and the dose of tryptophan ranges from 6 to 61 mg / kg.

78. The method of claim 59, wherein the subject is a human and the dose of PEA ranges from 0.8 to 9 mg / kg.

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

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

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

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

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

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

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

86. The method of claim 81, wherein the FAAH inhibitor is URB597 or an analog of URB 597.

87. The method of claim 81, wherein the FAAH inhibitor is URB937 or an analog of URB 937.

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

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

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

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

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

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

94. 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 purified fatty acid amides.

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

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

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

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

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