Method of treating neuropathic pain using an Anti-CGRP inhibitor

Abstract

Methods of systemically treating neuropathic pain in a spinal cord injured patient by administering a calcitonin gene-related peptide (CGRP) inhibitor are provided. In some variations, pain-producing tissues correlated with sympathetically mediated central neuropathic pain in spinal cord injured (SCI) patients, were acquired.

Description

METHOD OF TREATING NEUROPATHIC PAIN USING AN ANTI-CGRP INHIBITOR PRIORITY

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 564,846, entitled “METHOD OF TREATING NEUROPATHIC PAIN USING AN ANTI-CGRP INHIBITOR”, filed on March 13, 2024, which is incorporated herein by reference in its entirety. FIELD

[0002] The disclosure is directed to methods of treating neuropathic pain in spinal cord injured patients. BACKGROUND

[0003] Spinal cord injury (SCI) frequently results in severe or disabling pain. Individuals with a SCI suffer anywhere from between 20 and 77% incidence of some level of severe or disabling chronic pain. Davis et al., Clin Orthop 112:76-80 (1975); Richards et al., Pain 8:355-366 (1980); Siddall et al., Spinal Cord 39:63-73 (2001); Stormer et al., Spinal Cord 446-455 (1997); Woolsey, J Am Paraplegia 9:39-41 (1986). Patients suffering from at least some level of severe or disabling chronic pain show reduced rehabilitation potential and tend to have a significant overall reduction in quality of life.

[0004] Pharmacological treatment of centrally mediated neuropathic pain in spinal cord injured patients requires pharmaceutical agents to cross the blood brain barrier (BBB) or the blood spinal cord barrier (BSCB). The BBB and BSCB isolate the central nervous system from the systemic circulation. The BBB and BSCB have several common structures. The meninges separate the cerebrospinal fluid (CSF) from both the brain and spinal cord. The meninges include the dura mater, arachnoid and pia mater, dural border cells, arachnoid cells, pial cells, basement membrane, and glial limitans and has a common structure in both the BBB and BSCB. The arachnoid cell layer contains tight junctions that prevent molecules from exiting the fenestrated blood vessels in the dural layers and accessing the CSF. Tight junctions between the blood vessels and pial cell layer prevent paracellular transfer into the arachnoid CSF. Endothelial cells of blood vessels are held together by tight junctions preventing paracellular transfer in both the BBB and BSCB. The central canal of the spinal cord is lined with ependymal cells that separate the CSF from spinal tissue. Koehn, L., Neural Regen. Res.2020 Jul; 15(7): 1235–1242. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC7047801 / .

[0005] Neither small molecule nor therapeutic antibody molecule that target CGRP or the CGRP receptor (CGRP-r) are believed to cross the blood brain barrier in therapeutically effective amounts. Members of the gepants, a class of small molecule CGRP-r antagonists, are thought to exert anti-migraine effects outside the BBB. Altamura et al., Neurol Sci.2022; 43(9): 5697–5708, Br J Clin Pharmacol.2015 Aug; 80(2): 193-199. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC9159895 / . The trigeminal ganglion located outside of the BBB is impacted by CGRP-antagonists. Eftekhari et al., Brain Res 1600:93–. primates suggests that therapeutic amounts of gepants do not cross the BBB. Additional studies have concluded that CGRP receptor antagonists do not cross the blood–brain barrier and therefore are not found in brain tissue. Joshi et al. Headache: The Journal of Head and Face Pain, 61(6) 2021, 803. https: / / headachejournal.onlinelibrary.wiley.com / doi / full / 10.1111 / head.14135.

[0006] Likewise, known FDA approved gepants have been measured not to cross the BBB. Nurtec (rimegepant) is an FDA approved orally administered pharmaceutical approved for acute treatment of migraine with or without aura and preventative treatment of episodic migraine. Nurtec antagonistically binds CGRP receptors located on the trigeminovascular system outside of the BBB. Ubrelvy (ubrogepant), an FDA approved pharmaceutical for acute treatment of migraine with or without aura in adults, does not readily cross the BBB, further supported by data showing low central CGRP receptor occupancy. J. Pharmacol. And Exper. Therap. April 2020, 373 (1) 160-166. Qulipta (atogepant), a gepant developed exclusively for migraine prevention, is limited to passive diffusion through the BBB. Hay et al., Trends in Pharmaceutical Sciences, 43(8) 701-702 (2022). https: / / www.cell.com / trends / pharmacological-sciences / fulltext / S0165-6147(22)00063-3.SUMMARY

[0007] In a first aspect, the disclosure is directed to a method of treating neuropathic pain in a spinal cord injured (SCI) patient comprising systemically administering a therapeutically effective amount of a calcitonin gene-related peptide (CGRP) inhibitor to the patient in need thereof.

[0008] In some variations, neuropathic pain is reduced in the patient by at least 1 point on the 10-point pain scale. In some variations, the neuropathic pain is reduced in the patient by at least 3 points on the 10-point pain scale.

[0009] In another aspect, the disclosure is directed to reducing opioid dependency. In one variation, an existing opioid dose is reduced without increasing pain to a patient in need 2 4897-2147-5622.1thereof. A combination therapy comprising a CGRP inhibitor and an opioid at a dose at least 10% lower than a baseline dose in the absence of the CGRP inhibitor, resulting in no increase in pain on a 0-10 pain scale. Alternatively, the opioid dose can be at least 20% lower than the baseline does in the absence of CGRP inhibitor. Alternatively, the dose can be at least 30% lower than the baseline does in the absence of CGRP inhibitor.

[0010] In a further variation, the disclosure is directed to a method of treating pain in a patient comprising administering to the patient a combination therapy comprising CGRP inhibitor and an opioid. Subsequently, the combination therapy comprising CGRP inhibitor and the opioid at a maintenance dose of the opioid at least 10% lower than the dose administered to the patient in the absence of CGRP inhibitor, wherein the patient has no increase in pain on a 0-10 pain scale.

[0011] In some variations, the disclosure is directed to reducing pain in conjunction with providing an opioid. In some instances, the opioid alone has no effect but in combination with CGRP inhibitor it decreases pain. In some instances, the pain is decreased more than the CGRP inhibitor alone. In some instances, the reduction in pain of the combined CGRP inhibitor and opioid is synergistic. In some instances, the opioid load will decrease with no change in pain. In some instances, the same opioid load will be administered with a decrease in pain. In some instances, the individual will both decrease opioid load and experience a decrease in pain.

[0012] In another aspect, the disclosure is directed to a method of treating spinal cord injury in a spinal cord injured patient comprising administering to the patient CGRP inhibitor intramedullary, including at a border of injured spinal cord tissue and non-injured spinal cord tissue. In some variations, the CGRP inhibitor is administered intrathecally at the site of spinal cord injury. In some variations, the CGRP inhibitor is administered on the dura mater corresponding to the site of spinal cord injury. In some variations the CGRP inhibitor is administered systemically.

[0013] In certain variations, the method, the neuropathic pain is centrally mediated. In further variations, the CGRP inhibitor is a CGRP antagonist. The CGRP inhibitor can be a CGRP receptor (CGRP-r) antagonist.

[0014] In some variations, the CGRP inhibitor is selected from the group consisting of Formula (I), Formula (V), and Formula (VII), or a salt, solvate, hydrate, ester, or combination thereof, as described herein. In some variations, the CGRP inhibitor is selected from the group consisting of Formula (III), Formula (IV), Formula (VI), Formula (VIII), and Formula (IX) , or a salt, solvate, hydrate, ester, or combination thereof, as described herein. 3 4897-2147-5622.1

[0015] In some variations, the CGRP inhibitor is an antibody. In various aspects, the antibody can be:

[0016] a heavy chain sequence of SEQ ID NO: 1 and a light chain sequence of SEQ ID NO:2;

[0017] a heavy chain sequence of SEQ ID NO: 3 and a light chain sequence of SEQ ID NO:4;

[0018] a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO:6; and

[0019] a heavy chain sequence of SEQ ID NO: 7 and a light chain sequence of SEQ ID NO:8. DETAILED DESCRIPTION

[0020] The following detailed description is provided to aid those skilled in the art in practicing the present disclosure. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0021] The disclosure is directed to the use of a calcitonin gene-related peptide (CGRP) inhibitor to treat neuropathic pain. In some variations, the neuropathic pain is in spinal cord injured individuals.

[0022] Pain-producing tissues correlated with sympathetically mediated central neuropathic pain in spinal cord injured (SCI) patients were acquired. Comparative analysis of molecular markers between electrically hyperactive pain-producing tissue and electrically normal non-pain producing tissue showed an increased abundance of CGRP in the pain- producing tissue implicated in central pain. Definitions

[0023] The term “administer” refers to the physical introduction of a composition comprising a therapeutic agent to a patient, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods and can be a therapeutically effective dose or a subtherapeutic dose. 4 4897-2147-5622.1

[0024] The term "antibody" means monoclonal antibodies, including any isotype, such as, IgG, IgM, IgA, IgD and IgE. An IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called "complementarity-determining regions" ("CDRs") or "hypervariable regions", which are primarily responsible for binding an epitope of an antigen. They are referred to as CDR1 , CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions outside of the CDRs are called the "framework regions". An "antibody fragment" means an Fv, scFv, dsFv, Fab, Fab' F(ab')2 fragment, or other fragment, which contains at least one variable heavy or variable light chain, each containing CDRs and framework regions.

[0025] "CDRs" are defined by either Chothia et al or Kabat et al. See Chothia C, Lesk AM. (1987) Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol., 196(4):901 -17, which is incorporated by reference in its entirety. See Kabat E.A, Wu T.T., Perry H.M., Gottesman K.S. and Foeller C. (1991 ). Sequences of Proteins of Immunological Interest.5th edit., NIH Publication no.91 -3242, US Dept. of Health and Human Services, Washington, DC, which is incorporated by reference in its entirety.

[0026] The term “CGRP inhibitor”, also referred to herein as “CGRP inhibitor compound”, “CGRP inhibitor agent”, or “CGRP inhibitor drug”, refers to a compound that reduces binding of a CGRP to a CGRP receptor (CGRP-r). The compound can be a CGRP antagonist or a CGRP-r antagonist. The CGRP inhibitor” includes any compounds encompassed by chemical formulae or amino acid sequences described herein.

[0027] CGRP inhibitors include, by way of example but not limitation, rimegepant (Nurtec) (Biohaven Pharmaceutical Holding Company Ltd. / Pfizer), zavegepant (Zavzpret) (Pfizer), atogepant (Qulipta) (AbbVie), ubrogepant (Ubrelvy) (Abbvie), galcanezumab (Emgality) Eli Lilly and Company, Ajovy (fremanezumab) (Teva Pharmaceutical Industries), erenumab (Aimovig) (Amgen, Inc.) eptinezumab (Vyepti) (Lundbeck).

[0028] CGRP inhibitor compounds may be identified either by their chemical structure, amino acid sequence, therapeutic name, and / or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated 5 4897-2147-5622.1compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.

[0029] Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. Compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof.

[0030] Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds described herein also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to,2H,3H,πC,13C,14C,I5N,180,17O, etc. In general, the compounds can include pharmaceutically acceptable salts, hydrates, solvates, esters, N-oxides, or combinations thereof. Certain compounds may exist in multiple crystalline or amorphous forms. All physical forms are equivalent for the uses contemplated herein. Further, when partial structures of the compounds are illustrated, that brackets indicate the point of attachment of the partial structure to the rest of the molecule.

[0031] The term “decrease severity of pain” refers to reducing pain by at least 1 point on the 0 to 10-point scale, with 0 being “no pain” and 10 “pain as bad as it could be” or “the worst pain imaginable,” as described by Farrar et al., Clinical importance of changes in chronic pain intensity measured on an 11 -point numerical pain rating scale, Pain 94 (2001 ) 149 - 158, and Hawker et al., Measures of Adult Pain, Arthritis Care & Research Vol.63 No. S11, November 2011 (S240 - S252), incorporated herein by reference in its entirety.

[0032] The term “dosing frequency” refers to the number of times a dose can be given in a specific period of time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a week or once in two weeks.

[0033] The term “fast-dispersing dosage form” refers to compositions that disintegrate or disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, after being placed in contact with a fluid. The fluid is preferably that found in the oral cavity, i.e., saliva, as with oral administration.

[0034] The term “neuropathic pain” refers to pain caused by a lesion or disease of the somatosensory nervous system, as defined by International Association for the Study of Pain (IASP) on March 13, 2024. 6 4897-2147-5622.1

[0035] The term “patient” refers to a mammal. The patient can be a human mammal. The terms, “subject”, “patient”, and “individual” are used interchangeably herein.

[0036] The term “pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- aphfhalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc. These salts can be made according to common organic techniques employing commercially available reagents.

[0037] The term “pharmaceutically acceptable vehicle” refers to a diluent, an adjuvant, an excipient, a carrier, or a combination of any of the foregoing with which a compound provided by the disclosure may be administered to a patient and which does not destroy the pharmacological activity thereof and which is non-toxic when administered in doses sufficient to provide a therapeutically effective amount of the compound. 7 4897-2147-5622.1

[0038] The term “pharmaceutical composition” refers to the combination of therapeutic amount of a compound and at least one pharmaceutically acceptable vehicle with which the compound is administered to a patient. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate processing of the compounds and one or more pharmaceutically acceptable vehicles into formulations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Pharmaceutical compositions provided by the disclosure may take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for administration to an individual.

[0039] Pharmaceutical compositions provided by the disclosure may be formulated in a unit dosage form. A unit dosage form refers to a physically discrete unit suitable as a unitary dose for individuals undergoing treatment, with each unit containing a predetermined quantity of the compound calculated to produce an intended therapeutic effect. For example, a unit dosage form may be for a single daily dose, for administration 2 times per day, or one of multiple daily doses, e.g., 3 or more times per day. When multiple daily doses are used, an example unit dosage form may be the same or different for each dose. One or more dosage forms may comprise a dose, which may be administered to an individual at a single point in time or during a time interval.

[0040] In some variations, the pharmaceutical compositions can be administered as recommended by FDA guidance.

[0041] The term “systemic administration” refers to administration by any method excluding intrathecal administration. System administration includes any methods of administration including p.o. (by mouth), IV (intravenously), SC (subcutaneously), intranasally, sublingually, and PR (per rectum).

[0042] The term “therapeutically effective amount” refers to the amount of a compound that, when administered to a patient for treating neuropathic pain or symptom of neuropathic pain, is sufficient to reduce neuropathic pain or the symptom of neuropathic pain.

[0043] The term “therapeutically effective dose” refers to a dose that provides an effective treatment of neuropathic pain or a symptom thereof in a patient. A therapeutically effective dose may vary based on compound or patient, and may depend upon factors such as the condition of the patient and the route of delivery. A therapeutically effective dose may be determined in accordance with routine pharmacological procedures known to those skilled in 8 4897-2147-5622.1the art. Such as in human patients during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. In various aspects, a therapeutically effective does excludes amounts that do not cross the blood brain barrier or blood spinal cord barrier in sufficient quantities to have a therapeutic effect (e.g., Moreno-Ajona et al., J Clin Med.2022 Mar; 11(6): 1656 and Altamura et al., Neurol Sci. 2022; 43(9): 5697–5708, incorporated herein by reference in their entirety).

[0044] The terms “treat”, “treatment”, or “therapy” refers to reduction in neuropathic pain in an SCI patient and may include decreasing severity of pain (based on the 11 point scale), decreasing frequency of pain, decreasing duration of pain, and increasing frequency and / or duration of pain-free periods. Spinal Cord and Spinal Cord Injury

[0045] All vertebrate animals have a central axis of the body that consists of the spinal or vertebral column. The vertebral column consists of a number of connected irregular bones, termed the vertebrae, which surround and thereby protect a spinal cord. The vertebrae are grouped according to the region in which they lie — cervical, thoracic, lumbar, sacral, and coccygeal or caudal. Each vertebra has a ventral and dorsal side. In series with each vertebra are a number of spinal nerves. Each nerve is formed by the union of an anterior (motor) and posterior (sensory) nerve-root. The posterior or dorsal nerve-roots are the central branches of the axons of the pseudounipolar cells of the spinal ganglia. There are thirty-one pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 1 coccygeal.

[0046] Central pain, as used herein, refers to persistent or chronic pain caused by injury to nervous tissue within the CNS. Often central pain is described as severe, diffuse, and / or continuous, with periods of exacerbation. Injury to nervous tissue within the CNS often results in the abnormal up-regulation of neuronal activity, and this plays a key role in central pain associated with the injury. Several electrophysiological studies have suggested that neurons in injured CNS tissue show abnormal changes in their firing patterns, including spontaneous activity, reduced thresholds and increased responsiveness to peripheral stimulation. Eide, Spinal Cord, 36:601-612 (1998).

[0047] Central pain has proven notoriously difficult to treat, often proving recalcitrant to modern medical and surgical pain treatment procedures. Of particular therapeutic significance is the surgical treatment of specific dorsal root entry zone(s) (DREZ(s)) of the spinal cord. Surgical destruction of a central pain-generating DREZ is believed to disrupt the neural (i.e., electrical) communication and / or generation of aberrant pain signals that result 9 4897-2147-5622.1from the injury. Initially, empiric techniques have been used to target DREZ sites for surgical treatment, resulting in modest outcomes for the patient, i.e., DREZ sites at the site of injury targeted for treatment. Friedman et al., J Neurosurg 65:465-469 (1986); Ishijima et al., Appl Neurophysiol 51:2-5, 175-187 (1988); Rath et al., Acta Neurochir 138:4, 364-369 (1996); Rath et al., Sterotact Funct Neurosurg 68:1-4, Pt 1, 161-167 (1997). One of the more relevant patient studies using this empirical technique suggests that approximately 50% of patients so treated achieve good relief from SCI associated central pain. Friedman et al., J Neurosurg 65:465-469 (1986). In that series, at-level pain, i.e., pain at the immediate vicinity of the injury, responded best (74% “good results”) and below-level pain, i.e., pain below the level of injury, responded poorly (20% “good results”). These results suggest that empiric DREZ lesioning techniques can provide satisfactory relief for about half the number of patients treated, especially if the patient is suffering from pain in the vicinity of the injury. However, the results also suggest that a significant number of patients do not receive benefit from the technique, especially where the patient is suffering from pain perceived below the level of the injury.

[0048] The correlation between DREZs with spontaneous hyperactivity and perceived regions of pain in SCI patients does not follow traditional dermatomal mapping (Falci et al., J. Neurosurg. (Spine 2), 97:193-200, 2002). Rather, there appears to be a correspondence in part between the spatial layout of sympathetic innervation, spinal segments of DREZ hyperactivity and regions of perceived pain. That is, the relationship between the location of sympathetic neurons within the intermediolateral cell columns of the spinal cord and their target territory roughly corresponds to the mapping of perceived regions of below-level pain to specific DREZs. Neuroanatomical dissection and clinical study have suggested that the sympathetic supply to ‘end’ organs of the lower extremities originates in caudal thoracic and cephalad lumbar spinal cord segments, to the head and neck, cephalad thoracic spinal cord segments, and to regions in between, by the intervening spinal cord segments. See Pick, The Autonomic Nervous System: Morphological, Comparative, Clinical and Surgical Aspects, Philadelphia: J. B. Lippincott, 1970; Yokota et al., Brain 114:1381-1394 (1991). Afferent sympathetic supply may follow the efferent supply. Browder, Am J Surg 18:100-102 (1932); Echlin, J Neurosurg 530-533 (1949); Harris, Brit Med J 2:112-115 (1936); Pick, The Autonomic Nervous System: Morphological, Comparative, Clinical and Surgical Aspects, Philadelphia: J. B. Lippincott, 1970; Shields, J Clin Neurophysiol 10:2-13 (1993). A somatotopic map of specific DREZs to perceived regions of pain may be found in Falci et al., J. Neurosurg. Spine 2), 97:193-200, 2002, expressly incorporated herein by reference in its 10 4897-2147-5622.1entirety, and a somatotopic map for neuropathic pain is provided by US 2007 / 0016264, which is expressly incorporated herein by reference in its entirety. Using data provided by the illustrative somatotopic map, it is believed that pain occurring distal from an injury site (below-level pain) is mediated significantly by the sympathetic nervous system. It is also believed that anatomic regions of perceived pain are somatotopically mapped to specific DREZ segments of the spinal cord. Specifically, lumbar segments (L1 in particular) mediate pain from the feet, T11 and T12 segments, the leg, and T8-T10 segments, the gluteal, rectal and perirectal regions. More cephalad segments would mediate pain in the truncal region. It is also believed that cephalad segments could mediate pain subtended by those in more caudal segments by way of the sympathetic chain or interneuronal pathways. CGRP Antagonist Compounds treating Neuropathic Pain in SCI Patients

[0049] CGRP2 is seen in markedly greater abundance in electrically hyperactive spinal cord tissue. The electrically hyperactive spinal cord tissue can be caudal to the level of injury and / or cephalad to the level of injury. Eradication of the hyperactive spinal cord tissue can result in complete pain relief, even if the spinal cord had been completely transected prior. As such, CGRP2 with its increase in abundance in spinal cord injured tissue, may be a generator of neuropathic pain in the spinal cord issued patient.

[0050] CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA. CGRP is widely distributed in the central nervous system and peripheral nervous system. CGRP is a potent vasodilatory neurotransmitter believed to play a key role in migraine pathophysiology.

[0051] The CGRP receptor (CGRP-r), is a heteromeric receptor complex of three subunits: calcitonin receptor-like receptor (CLR), receptor activity modifying protein 1 (RAMP-1), and receptor component protein (RCP). CLR is a type B, G protein-coupled receptor. The CLR receptor (class B GPCR) includes an N-terminal extracellular domain (ECD) or ectodomain, a seven helix transmembrane (7-TM) domain, and an intracellular carboxyl terminus. Without wishing to be limited to a particular mechanism or mode of action, ECD can function as a receptor for the CGRP molecule. RAMP-1 is a member of the single transmembrane RAMP family. RAMP-1 presents CLR to the plasma membrane as a mature glycoprotein. RAMP-1 may also serve as an antagonist binding site, but its role as a ligand for binding of CGRP or its antagonists remains unclear. Receptor component protein (RCP) is important in intracellular G protein signaling. As described herein, anti-migraine 11 4897-2147-5622.1CGRP and CGRP-r antagonists do not cross the BBB, instead acting on the peripheral nervous system for both acute and preventative migraine. Manghi, R.A., A. Calcitonin Gene- Related Peptide Receptor, Updated 2022 Jul 12, StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-, https: / / www.ncbi.nlm.nih.gov / books / NBK560648 / , which is incorporated herein by reference in its entirety.

[0052] CGRP inhibitors used to treat migraine are inaccessible to centrally expressed CGRP and CGRP-r due to the BBB. Neuropathic pain in spinal cord injured patients originates in the central nervous system (CNS). Surprisingly, however, the CGRP inhibitors of the disclosure can be used to treat neuropathic pain in SCI patients. Treating Neuropathic Pain in Spinal Cord Injured Patients by Systemic Administration of a CGRP Inhibitor Compounds

[0053] CGRP inhibitor compounds and pharmaceutical compositions described herein can be administered to treat neuropathic pain in SCI patients. In some variations, the neuropathic pain is perceived to be below (caudal to) the level of SCI. In some variations, the neuropathic pain is perceived to be at (at-level) or above (cephalad to) the level of SCI. In some variations, pain can be perceived to be below and at the level the neurological level of spinal cord injury. For example, in a complete spinal cord injury at the neurological level of T10, a patient should not feel painful stimuli lower (caudal) pain) from the umbilicus. However, the patient can nevertheless perceive non-evoked neuropathic pain in these regions.

[0054] In some variations, neuropathic pain in spinal cord individuals can be mediated by the sympathetic nervous system. Specifically, hyperactive electrical neuronal signals originating below the level of spinal cord injury can be routed around the injury site by way of the sympathetic chain to reach brain pain centers and / or ascend the spinal cord via intact afferent pathways, inclusive of sympathetic afferent pathways. If DREZ pain generators originate above the level of injury, signals can ascend via the sympathetic chain and / or ascend via spinal cord sensory tracts, inclusive of sympathetic afferent tracts. Sympathetically mediated spinal cord injury pain is perceived by the patient to be below the neurological level of spinal cord injury (referred to herein as “below-level pain”).

[0055] Administration of CGRP inhibitor can be as described herein for each CGRP inhibitor. Neuroprotection 12 4897-2147-5622.1

[0056] CGRP inhibitor compounds and pharmaceutical compositions described herein can be administered to provide neuroprotection and / or regeneration in SCI patients to preserve or restore function.

[0057] Electrically hyperactive areas as described herein are found at the borders of spinal cord contusions two weeks after spinal cord injury. The hyperactive tissue can be identified within weeks of the injury. The front of hyperactivity ascends and descends the cord over years as cord function is lost.

[0058] In one variation, the CGRP inhibitor compounds or pharmaceutical compositions can be administered soon after injury. For example, a CGRP inhibitor compound or pharmaceutical composition can be administered immediately after injury or in the ensuing hours or days following injury. In some variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within one hour after injury. In some variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within six hours after injury. In some variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within 12 hours after injury. In further variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within a day after injury. In further variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within three days after injury. In still further variations, a CGRP inhibitor compound or pharmaceutical composition can be administered within one week after injury.

[0059] In the case of administration can be systemic administration, or can be non- systemic administration (e.g., by intrathecal administration). Administration of a CGRP inhibitor can proceed at hourly, daily, or weekly intervals following injury. In one variation, the CGRP inhibitor is administered each hour, every two hours, every three hours, or every four hours to the site of injury. In another variation, the CGRP inhibitor is administered each day to the site of injury. The CGRP inhibitor can be administered daily, every other day, every three days, or every four days to the site of injury. In another variation, the CGRP inhibitor can be administered weekly. In some variations, the CGRP inhibitor is administered every week, every other week, ever three weeks, or every four weeks to the site of injury. CGRP inhibitor administration can terminate after a period of time, or can continue indefinitely. CGRP Inhibitors 13 4897-2147-5622.1

[0060] In variations, the CGRP inhibitor includes any molecular or biological agent that binds CGRP or the CGRP receptor thereby inhibiting binding of CGRP to the CGRP receptor. The compound includes any compounds encompassed by chemical formulae or amino acid sequences described herein. In some variations, the methods encompass reducing the pain level as described herein. The patient is a mammal, and in many variations a human. The patient may be female or male of any age. The patient has pain at a level.

[0061] Examples of CGRP inhibitor compounds are described in more detail below. Rimegepant (Nurtec)

[0062] In one variation, the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of formula (I), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment.

[0063] The compound can be any compound described in U.S. Patent Nos.8,314,117, 8,759,372, and 11,083,724, all of which are hereby incorporated by reference in their entirety.

[0064] In one variation, the compound is a compound of Formula (I)

[0066] R1is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;

[0067] R2is piperidinyl substituted with 1 substituent selected from the group consisting of 14 4897-2147-5622.1

[0068]

[0069] or R2is

[0070]

[0071] R3is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

[0072] R4is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

[0073] R5is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0074] R6is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0075] R7is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0076] R8is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0077] R9is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; 15 4897-2147-5622.1

[0078] R10is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0079] R11is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl;

[0080] or R10and R11taken together is O or N—OH;

[0081] provided that at least one of R5, R6, R7, R8, R9, R10, or R11is not hydrogen;

[0082] Ar1is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO2;

[0083] X is O, CH2, or NH; and

[0084] Y is a bond, O, CH2, or NH;

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In another variation, the CGRP inhibitor is a compound of Formula (I) where:

[0087] R1is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;

[0088] R2is piperidinyl substituted with 1 substituent selected from the group consisting of 16 4897-2147-5622.1

[0089] or R2is

[0090]

[0091] alkoxy, or haloalkoxy;

[0092] R4is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

[0093] R5is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; 17 4897-2147-5622.1

[0094] R6is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0095] R7is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0096] R8is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0097] R9is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0098] R10is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

[0099] R11is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; [000100] or R10and R11taken together is oxo; [000101] provided that at least one of R5, R6, R7, R8, R9, R10, or R11is not hydrogen; [000102] Ar1is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO2; [000103] X is O, CH2, or NH; and [000104] Y is a bond, O, CH2, or NH; [000105] or a pharmaceutically acceptable salt thereof [000106] In another variation, the CGRP inhibitor is a compound of Formula (II) with the designated stereochemistry.is a compound of Formula (I) or (II) wherein [000109] R1is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino; [000110] R2is piperidinyl substituted with 1 substituent selected from the group consisting of 18 4897-2147-5622.1[000111] [000112] [000113] R3is hydrogen or halo; [000114] R4is hydrogen or halo; [000115] R5is hydrogen or hydroxy; [000116] R6is hydrogen; [000117] R7is hydrogen; [000118] R8is hydrogen; [000119] R9is hydrogen or hydroxy; [000120] R10is hydrogen, hydroxy, azido, amino, alkylamino, or dialkylamino; [000121] R11is hydrogen; [000122] or R10and R11taken together is oxo; [000123] provided that at least one of R5, R6, R7, R8, R9, R10, or R11is not hydrogen; [000124] Ar1is phenyl substituted with 0-2 halo substituents; [000125] X is O, CH2, or NH; and [000126] Y is O; [000127] or a pharmaceutically acceptable salt thereof. [000128] In another variation, the CGRP inhibitor is a compound of formula I where R1is hydrogen; R2is piperidinyl substituted with 1 substituent selected from the group consisting of 19 4897-2147-5622.1[000129] R5is hydrogen or hydroxy; R6is hydrogen; R7is hydrogen; R8is hydrogen; R9is hydrogen or hydroxy; R10is hydroxy, azido, or amino; R11is hydrogen; or R10and R11taken together is oxo; provided that at least one of R5, R6, R7, R8, R9, R10, or R11is not hydrogen; Ar1is phenyl or difluorophenyl; X is O, CH2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. [000130] In another variation, the CGRP inhibitor is a compound of formula I where R1is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl. [000131] In another variation, the CGRP inhibitor is a compound of formula I where R2is N-piperidinyl and is 4-substituted. In another variation, the CGRP inhibitor is a compound of formula I where the substituent is [000132] [000133] In another variation, the CGRP inhibitor is a compound of formula I where R5is hydrogen, R6is hydrogen, R7is hydrogen, R8is hydrogen, R9is hydrogen, R10is hydroxy, azido, or amino, and R11is hydrogen; or where R5is hydrogen, R6is hydrogen, R7is hydrogen, R8is hydrogen, R9is hydrogen or hydroxy, and R10and R11taken together is oxo; or where R5is hydrogen, R6is hydrogen, R7is hydrogen, R8is hydrogen, R9is hydroxy, R10is hydrogen or hydroxy, and R11is hydrogen; or where R5is hydroxy, R6is hydrogen, R7is hydrogen, R8is hydrogen, R9is hydrogen, R10is hydrogen, and R11is hydrogen. [000134] In another variation, the CGRP inhibitor is a compound of formula I where Ar1is phenyl substituted with 2 halo substituents. [000135] In another variation, the CGRP inhibitor is a compound of formula I where Ar1is 2,3-difluorophenyl. 20 4897-2147-5622.1[000136] In another variation, the CGRP inhibitor is a compound of formula I where X is O. [000137] The scope of any instance of a variable, including R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, Ar1, X and Y, can be used independently with the scope of any other instance of a variable substituent. As such, the disclosure includes combinations of the different aspects. [000138] Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons, preferably 1 to 3 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,” “alkoxy” and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. “Aryl” includes carbocyclic and heterocyclic aromatic ring systems. “Amino” includes primary, secondary, and tertiary amine moieties. “Carbonyl” means CO. “Oxy” means —O—. “Aminocarbonyl” means —N(R)C(═O)—. “Oxycarbonyl” means —OC(═O)—. “Methylenecarbonyl” means —CHYDROGENC(═O)—. “Amino(cyano)iminomethyl” means —NHC(═NCN)—. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. [000139] In some variations, the compound is rimegepant. Rimegepant has the chemical structure of Formula (III), and is described, for example, in WO 2011 / 046997 published Apr. 21, 2011 or WO 2013 / 130402 published Sep.6, 2013, both of which are incorporated herein by reference in their entirety.21 4897-2147-5622.1[000140] In another variation, the compound has rimegepant hemisulfate sesquihydrate is (5S,6S,9R)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- yl 4-(2-oxo-2,3-dihydro-1Himidazo[4,5-b]pyridin-1-yl)-1-piperidinecarbxylate hemisulfate sesquihydrate and has the chemical structure of Formula (IV): [000141][000142] The pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.8,314,117, 8,759,372, or 11,083,724, incorporated by reference herein in its entirety. [000143] Alternatively, the pharmaceutical composition is described in the prescribing information for NURTEC, revised 5 / 2021, and incorporated herein by reference in its entirety. For example, the pharmaceutical composition can be administered as described therein at 75 mg taken orally every other day. Zavegepant (Zavzpret) [000144] In another variation, the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of Formula (V), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment. [000145] The compound can be a compound disclosed in U.S. Patent Nos.7,220,862, 7,314,883, or 8,481,546, each of which is incorporated by reference in its entirety. In one variation, the compound can be a compound formula ((V): 22 4897-2147-5622.1(V) [000146] or a pharmaceutically acceptable salt and / or solvate thereof [000147] wherein [000148] V is —N(R1)(R2) or OR4;[000149]R4is H, C1-6alkyl, C1-4haloalkyl or (C1-4alkylene)0-1R4′R4′is C3-7cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and [000151] R4′is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C1-3alkylamino, C1-3dialkylamino, (C1-3alkyl)0-2ureido, phenyl and benzyl; and [000152] R4′optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure of R4′; [000153] R1and R2are each independently L1, wherein L1is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —C1-6alkylene-amino(C1-3alkyl)2, C3- 7cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuiranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and [000154] R1and R2are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C1-3alkylamino, C1-3dialkylamino, (C1-3alkyl)0-2ureido, phenyl and benzyl; 23 4897-2147-5622.1[000155] R1and R2optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising R1and R2; [000156] wherein L1is optionally and independently interrupted from the nitrogen to which it is attached by L2, wherein L2is independently C1-3alkylene or C1-3alkylidene; or [000157] R1and R2together with the nitrogen to which they are attached form X, [000158] wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; [000159] wherein X is optionally substituted with Y, wherein Y is dioxolanyl, C1-9alkyl, C2-9alkenyl, C2-9alkynyl, C1-4alkylamino, C1-4dialkylamino, C1-4alkoxy, C3-7cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is —NHC(O)O—, — NHC(O)NH—, NC(O)NH2, —NH—, —C1-3alkylene-, —C1-3alkylene-, —C1-3alkenylene- NHC(O)O—C1-3alkylene-; and optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C1-4alkyl, amino, C1-3alkylamino, —C1-6alkylene-amino(C1-3alkyl)2, (C1-3alkyl)0-2ureido, phenyl and benzyl; [000160] X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; [000161] provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon atom and together form a spirocyclic moiety; [000162] Q is Q′ or Q″; [000163] wherein [000164] Q′ is (Sy)sR3; and[000168] U is CH2 or NH; [000169] provided that if Q is Q″, then U is CH2; [000170] R3is R3aor R3b24 4897-2147-5622.1[000171] Wherein [000172] R3ais [000173] (i) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings; [000174] (ii) a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; [000175] (iii) C3-7 cycloalkyl; [000176] (iv) carbazolyl, fluorenyl, phenyl, —O-phenyl, —O—C1-4alkylene-phenyl, or napthyl; or [000177] (v) C1-8alkyl, C2-7alkenyl, —C(O)R3′, CHC(O)O—R3′, CH(CH3)C(O)O— R3′,—C(O)O—R3′or C2-7 alkynyl; and [000178] wherein R3ais optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, —O-phenyl, —O—C1- 3alkylenephenyl, —C1-3alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C1-6alkyl, C1- 3mono-bi-tri-haloalkyl, C1-3mono-bi-tri-haloalkyloxy, (C1-3alkyl)1-2amine, —OR3′, —C(O)R3′, C(O)O—R3′, —O—C(O)R3′, —N(R3′)2, —C(O)N(R3′)2, —N(R3′)C(O)(R3′)2, — 2or —C(O)O—R3′, then said —C(O)R3′, CHC(O)O—R3′, CH(CH3)C(O)O—R3′or —C(O)O— R3′are unsubstituted; [000180] R3bis R3abut is not phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1- naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, formyl-1H-indol-3-yl, 1-(1,1- dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3- thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, 25 4897-2147-5622.1acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups; [000181] wherein said substituents may be the same or different and the above- mentioned benzoyl, benzoylamino- and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group; [000182] D is O, NCN or NSO2C1-3alkyl; [000183] A is C, N or CH; [000184] m and n are independently 0, 1 or 2; [000185] provided that [000186] if m and n are 0, then A is not N; [000187] if m is 2, then n is not 2; or [000188] if n is 2, then m is not 2; [000189] E is N, CH or C; [000190] p is 0 or 1; [000191] if p is 1, then G, J and E together form Axor Ay; [000192] Axis a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and [000193] optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle; [000194] Ayis a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and [000195] optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; [000196] wherein Axand Ayare optionally substituted with C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, C3-7cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or [000197] if p is 0 such that G and J are each attached to A, then A is C, and G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA′ or GJA″; 26 4897-2147-5622.1[000198] wherein [000199] GJA′ is Axor Ay; and [000200] GJA″ is Axor Ay; [000201] provided that [000202] Axis not a 1,3-diaza-fused heterocycle; and [000203] Ayis not a 1,3-diaza-heterocycle; [000204] and further provided that [000205] if Q is Q″, then R3is R3a; and [000206] if Q is Q′, then [000207] R3is R3b; or [000208] R3is R3a, p is 0 and G, J and A together form GJA″. [000209] In another variation, the compound is a compound disclosed in U.S. Patent No.7,314,883, which is incorporated herein by reference in its entirety. The compound can be a compound formula (VI): (VI).[000210] The pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.7,220,862, 7,314,883, or 8,481,546, incorporated by reference herein in its entirety. [000211] Alternatively, the pharmaceutical composition is described in the prescribing information for the Zavegepant (Zavzpret) product insert published by the FDA, revised 3 / 2023, and incorporated herein by reference in its entirety. For example, the pharmaceutical composition can be administered as described therein administered 10 mg nasally in a single dose per day. Qulipta (Atogepant) 27 4897-2147-5622.1[000212] In another variation, the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of Formula (VII), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment. [000213] The compound can be a compound disclosed in U.S. Patent Nos. USPN 8,754,096 USPN 9,499,545, 9,850,246, and 10,117,836, each of which is incorporated by reference in its entirety. In one variation, the compound can be a compound Formula (VII):[000214] or a pharmaceutically acceptable salt thereof, wherein: [000215] X is selected from —C(R8)═ or —N═, wherein R8is hydrogen, F or CN; [000216] R1is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000217] R2is selected from hydrogen and methyl; [000218] when R2is hydrogen then [000219] R3is selected from hydrogen, F or Cl; [000220] R4is selected from hydrogen, F or Cl; [000221] R5is hydrogen; [000222] R6is selected from hydrogen or F; and [000223] R7is selected from hydrogen, F or Cl; [000224] except that at least two of R3, R4, R6and R7must be F or Cl unless R3is F in which case R4, R6and R7may all be hydrogen; and if R4is Cl then R7cannot be Cl; [000225] when R2is methyl then 28 4897-2147-5622.1[000226] R3is selected from hydrogen, methyl, F, Cl, or Br; [000227] R4is selected from hydrogen, methyl, F or Cl; [000228] R5is selected from hydrogen or F; R6is selected from hydrogen or F; and [000229] R7is selected from hydrogen, methyl, F or Cl; [000230] except that if R5is F then at least three of R3, R4, R6and R7must be F; and if R4is methyl or Cl then R7cannot be methyl or Cl. [000231] In a further variation, the compound can be a compound of Formula (VII), wherein [000232] X is selected from —C(R8)═ or —N═, wherein R8is hydrogen, F or CN; [000233] R1is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000234] R2is selected from hydrogen and methyl; [000235] when R2is hydrogen then [000236] R3is selected from hydrogen, F or Cl; [000237] R4is selected from hydrogen, F or Cl; [000238] R5is hydrogen; [000239] R6is selected from hydrogen or F; and [000240] R7is selected from hydrogen, F or Cl; [000241] except that at least two of R3, R4, R6and R7must be F or Cl unless R3is F in which case R4, R6and R7may all be hydrogen; and if R4is Cl then R7cannot be Cl; [000242] when R2is methyl then [000243] R3is selected from hydrogen, methyl, F, Cl, or Br; [000244] R4is selected from hydrogen, methyl, F or Cl; [000245] R5is selected from hydrogen or F; [000246] R6is selected from hydrogen or F; and [000247] R7is selected from hydrogen, methyl, F or Cl; [000248] except that if R5is F then at least three of R3, R4, R6and R7must be F; and if R4is methyl or Cl then R7cannot be methyl or Cl. [000249] In a further variation, the compound is a compound of Formula (VII), wherein [000250] X is —C(R8)═, wherein R8 is hydrogen, F or CN; 29 4897-2147-5622.1[000251] R1 is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000252] R2 is selected from hydrogen and methyl; [000253] and wherein: [000254] when R2 is hydrogen then [000255] R3 is selected from hydrogen, F or Cl; [000256] R4 is selected from hydrogen, F or Cl; [000257] R5 is hydrogen; [000258] R6 is selected from hydrogen or F; and [000259] R7 is selected from hydrogen, F or Cl; [000260] except that at least two of R3, R4, R6 and R7 must be F or Cl unless R3 is F in [000261] which case R4, R6 and R7 may all be hydrogen; and with the proviso that if R4 is [000262] Cl then R7 cannot be Cl; [000263] when R2 is methyl then [000264] R3 is selected from hydrogen, methyl, F, Cl, or Br; [000265] R4 is selected from hydrogen, methyl, F or Cl; [000266] R5 is selected from hydrogen or F; [000267] R6 is selected from hydrogen or F; and [000268] R7 is selected from hydrogen, methyl, F or Cl; [000269] except that if R5 is F then at least three of R3, R4, R6 and R7 must be F; and with the proviso that if R4 is methyl or Cl then R7 cannot be methyl or Cl. [000270] In a still further variation, the compound is selected from a compound according to Formula (VII), wherein: [000271] X is selected from —C(R8)═ or —N═, wherein R8 is hydrogen, F or CN; [000272] R1 is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000273] R2 is selected from hydrogen and methyl; [000274] when R2 is hydrogen then [000275] R3 is selected from hydrogen, F or Cl; 30 4897-2147-5622.1[000276] R4 is selected from hydrogen, F or Cl; [000277] R5 is hydrogen; [000278] R6 is selected from hydrogen or F; and [000279] R7 is selected from hydrogen, F or Cl; [000280] except that at least two of R3, R4, R6 and R7 must be F or Cl unless R3 is F in [000281] which case R4, R6 and R7 may all be hydrogen; and if R4 is Cl then R7 cannot be Cl; [000282] when R2 is methyl then [000283] R3 is selected from hydrogen, methyl, F, Cl, or Br; [000284] R4 is selected from hydrogen, methyl, F or Cl; [000285] R5 is selected from hydrogen or F; [000286] R6 is selected from hydrogen or F; and [000287] R7 is selected from hydrogen, methyl, F or Cl; [000288] except that if R5 is F then at least three of R3, R4, R6 and R7 must be F; and if [000289] R4 is methyl or Cl then R7 cannot be methyl or Cl. In some variations, the compound is the compound of Formula (VIII)[000290] The pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.8,754,096, 9,499,545, 9,850,246, or 10,117,836, each of which are incorporated by reference herein in its entirety. [000291] Alternatively, the pharmaceutical composition is described in the prescribing information for the QULIPTA (atogepant) product insert published by the FDA, revised 9 / 2021, and incorporated herein by reference in its entirety. For example, the pharmaceutical composition can be administered as described therein orally administered in 10 mg, 30 mg, or 60 mg. UBRELVY (Ubrogepant) 31 4897-2147-5622.1[000292] The compound can be a compound disclosed in U.S. Patent Nos. USPN 8,754,096, 8,912,210, 9,499,545, 9,833,448 and 10,117,836, each of which is incorporated by reference in its entirety. [000293] In some variations, the compound is a compound according to Formula (IX)[000294] In a further variation, the compound has a structure of Formula (X):32 4897-2147-5622.1(XI) [000297] whereinthe compound has the structure of Formula (XII)[000299] wherein [000300] A is a 5 - 7 membered saturated or unsaturated cycloalkyl or heterocarbocyclic with a single carbon replaced with N; [000301] R3 and R4 can be combined to form a fused, optionally substituted, heteroaryl ring; [000302] R1 and R2 together on the same carbon can form C=O [000303] X is NH or O 33 4897-2147-5622.1[000304] B is a 6 membered saturated or unsaturated heterocarbocyclic ring containing at least one N including at the point of attachment to C=O, and [000305] R8 are optionally substituted on the same carbon together to form a 5- membered spirocyclic lactam, optionally substituted with a fused heteroaryl ring; [000306] Substituents R1 - R8 are chosen to cover the broad genuses described in US 8,754,096, US 9,499,545, and US 8,314,117. [000307] The pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.. USPN 8,754,096, 8,912,210, 9,499,545, 9,833,448 and 10,117,836, each of which is incorporated by reference herein in its entirety. [000308] Alternatively, the pharmaceutical composition is described in the prescribing information for the UBRELVY (Ubrogepant) product insert published by the FDA, revised 9 / 2021, and incorporated herein by reference in its entirety. For example, the pharmaceutical composition can be administered as described therein orally administered in 50 mg or 100 mg, additional doses after the first dose, to a maximum of 200mg. Therapeutic Antibodies [000309] In some variations, the CGRP inhibitor is an antibody. In some variations, the antibody is selected from Emgality (galcanezumab), Anjovy (fremanezumab), Vyepti (eptinezumab), and Aimovig (erenumab). Emgality (galcanezumab) [000310] In some variations, the antibody is Emgality. Emgality includes a heavy chain and a light chain amino acid sequence of the Fc regions of Emgality. In some variations, the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:1 and the light chain amino acid sequence of SEQ ID NO: 2. In some variations, the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO: 1 and light chain amino acid sequence of SEQ ID NO: 2. QVQLVQSGAE VKKPGSSVKV SCKASGYTFG NYWMQWVRQA PGQGLEWMGA IYEGTGKTVY  IQKFADRVTI TADKSTSTAY MELSSLRSED TAVYYCARLS DYVSGFGYWG QGTTVTVSSA  STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG  LYSLSSVVTV PSSSLGTKTY TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEAAGGPSVF  LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR  VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN  QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN  VFSCSVMHEA LHNHYTQKSL SLSLG (SEQ ID NO: 1) 34 4897-2147-5622.1DIQMTQSPSS LSASVGDRVT ITCRASKDIS KYLNWYQQKP GKAPKLLIYY TSGYHSGVPS  RFSGSGSGTD FTLTISSLQP EDFATYYCQQ GDALPPTFGG GTKVEIKRTV AAPSVFIFPP  SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT  LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC   (SEQ ID NO: 2) (Disulfide bridge: H22‐H96, H133‐L214, H146‐H202, H225‐H'225, H228‐ H'228, H260‐H320, H366‐H424, H'22‐H'96, H'133‐L'214, H'146‐H'202, Ajovy (Fremanezumab) [000311] In some variations, the antibody is Ajovy. Ajovy includes a heavy chain and a light chain amino acid sequence of the Fc regions of Ajovy. In some variations, the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:3 and the light chain amino acid sequence of SEQ ID NO: 4. EVQLVESGGG LVQPGGSLRL SCAASGFTFS NYWISWVRQA PGKGLEWVAE IRSESDASAT  HYAEAVKGRF TISRDNAKNS LYLQMNSLRA EDTAVYYCLA YFDYGLAIQN YWGQGTLVTV  SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ  SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS  VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVQFNWYV DGVEVHNAKT KPREEQFNST  FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP SSIEKTISKT KGQPREPQVY TLPPSREEMT  KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD SDGSFFLYSK LTVDKSRWQQ  GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ ID NO: 3)   EIVLTQSPAT LSLSPGERAT LSCKASKRVT TYVSWYQQKP GQAPRLLIYG ASNRYLGIPA  RFSGSGSGTD FTLTISSLEP EDFAVYYCSQ SYNYPYTFGQ GTKLEIKRTV AAPSVFIFPP  SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT  LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC    (SEQ ID NO: 4) (Disulfide bridge: H22‐H98, H136‐L214, H149‐H205, H224‐H'224, H225‐ H'225, H228‐H'228, H231‐H'231, H262‐H322, H368‐H426, H'22‐H'98, H'136‐ L'214, H'149‐H'205, H'262‐H'322, H'368‐H'426, L23‐L88, L134‐L194, L'23‐ L'88, L'134‐L'194) Erenumab (Aimovig) [000312] In some variations, the antibody is Aimovig. Aimovig includes a heavy chain and a light chain amino acid sequence of the Fc regions of Aimovig. In some variations, the 35 4897-2147-5622.1antibody comprises the heavy chain amino acid sequence of SEQ ID NO:5 and the light chain amino acid sequence of SEQ ID NO: 6. QVQLVESGGG VVQPGRSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAV ISFDGSIKYS  VDSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCARDR LNYYDSSGYY HYKYYGMAVW  GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV  HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP  APPVAGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVQFNWYVDG VEVHNAKTKP  REEQFNSTFR VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL  PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD GSFFLYSKLT  VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK   (SEQ ID NO:5)    QSVLTQPPSV SAAPGQKVTI SCSGSSSNIG NNYVSWYQQL PGTAPKLLIY DNNKRPSGIP  DRFSGSKSGT STTLGITGLQ TGDEADYYCG TWDSRLSAVV FGGGTKLTVL GQPKANPTVT  LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK AGVETTKPSK QSNNKYAASS  YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS   (SEQ ID NO:6)  (Disulfide bridge: H22‐H96, H144‐L215, H157‐H213, H232‐H'232, H233‐ H'233, H236‐H'236, H239‐H'239, H270‐H330, H376‐H434, H'22‐H'96, H'144‐ L'215, H'157‐H'213, H'270‐H'330, H'376‐H'434, L22‐L89, L138‐L197, L'22‐[000313] Eptinezumab (Vyepti) [000314] In some variations, the antibody is Vyepti. Vyepti includes a heavy chain and a light chain amino acid sequence of the Fc regions of Vyepti. In some variations, the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:7 and the light chain amino acid sequence of SEQ ID NO: 8. EVQLVESGGG LVQPGGSLRL SCAVSGIDLS GYYMNWVRQA PGKGLEWVGV IGINGATYYA  SWAKGRFTIS RDNSKTTVYL QMNSLRAEDT AVYFCARGDI WGQGTLVTVS SASTKGPSVF  PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV  TVPSSSLGTQ TYICNVNHKP SNTKVDARVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK  PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY ASTYRVVSVL  TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE EMTKNQVSLT  CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS  VMHEALHNHY TQKSLSLSPG K   (SEQ ID NO:7)   36 4897-2147-5622.1QVLTQSPSSL SASVGDRVTI NCQASQSVYH NTYLAWYQQK PGKVPKQLIY DASTLASGVP  SRFSGSGSGT DFTLTISSLQ PEDVATYYCL GSYDCTNGDC FVFGGGTKVE IKRTVAAPSV  FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL  SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC   (SEQ ID NO:8)  (Disulfide bridge: H22‐H95, H138‐H194, H214‐L219, H220‐H'220, H223‐H'223,  H255‐H315, H361‐H419, H'22‐H'95, H'138‐H'194, H'214‐L'219, H'255‐H'315, H'361‐ H'419, L22‐L89, L139‐L199, L'22‐L'89, L'139‐L'199) Coadministration of a CGRP Inhibitor and Opioid and Methods of Opioid Withdrawal [000315] In further variations, the disclosure is directed to treating neuropathic pain in SCI patients by administering to a patient in need thereof a combination therapy of a CGRP inhibitor and an opioid. In some instances, CGRP inhibitor is administered at a lower daily dosage, reduced dosage schedule, and / or lower reduced dosage over a time course. [000316] The combination therapy of CGRP inhibitor and opioid results in reduced dose requirements for the opioid. [000317] Opioids are relatively ineffective at relieving neuropathic pain. These same opioid receptors, which normally decrease the hyperexcitability of the pain producing neurons in the dorsal horn Rexed Layers 1 -3 in normal pain states, fail to do so in neuropathic pain states. This effect is observed in both clinical data and the ineffectiveness of opioids in having an effect on hyperactive DREZ recordings in patients taking high doses of narcotics or with opioid administration during general anesthesia. [000318] The opioid can be any opioid known in the art. The opioid can be used to treat acute pain or chronic pain, and more specifically neuropathic pain. In some variations, the opioid is administered at a lower daily dosage, reduced dosage schedule, and / or lower reduced dosage over a time course. The combination therapy surprisingly results in a reduced drug load to the patient. [000319] Further, the CGRP inhibitor can be administered to reduce opioid addiction by administering to a patient in need thereof. The CGRP inhibitor can be administered alone to a patient to whom opioid has been administered, or the opioid can be administered at a lower 37 4897-2147-5622.1dose than when administered alone. Alternatively, the dose of the opioid can be reduced over a period of time until a lower dosage plateau is reached. [000320] CGRP inhibitors can be used to reduce neuropathic pain in a patient on an opioid therapeutic regimen. The regimen adapted to treat chronic pain. Due to the chronic nature of pain treatment, the amount of opioid administered to such patients can in some cases be substantially greater than the amounts approved for administration on various product labels. The CGRP inhibitor is administered, and an opioid is also administered. [000321] The patient has a decrease in pain of at least 1 on a 0-10 pain scale as compared to administration of the opioid in the absence of the CGRP inhibitor. In various aspects, the opioid dose is maintained. The pain scale is generally known in the art, for example as described by Farrar et al., Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale, Pain 94 (2001 ) 149 - 158, and Hawker et al., Measures of Adult Pain, Arthritis Care & Research Vol.63 No. S11, November 2011 (S240 - S252). [000322] Without wishing to be limited to a particular mechanism or mode of action, the CGRP inhibitor may potentiate the effect of narcotics, allowing a substantial reduction in opioid dose and a substantial decrease in neuronal excitability. CGRP inhibitors may potentiate the effect of narcotics, resulting in a decrease in required narcotic dose. This can be true for any kind of pain, including acute pain, chronic pain, neuropathic pain, pain resulting from SCI, and post-surgical pain. [000323] Central pain can result from spontaneous neuronal hyperexcitability in the dorsal grey matter of the spinal cord. In normal pain states, opioids can act on the opioid receptors of hyperexcitable neurons in the dorsal grey matter to relieve pain (e.g., post- surgical pain, broken leg, etc.) by decreasing neuronal hyperexcitability. Hyperexcitable neurons in the dorsal grey matter layers are caused by the firing of injured peripheral neurons (e.g., from a broken leg) in these normal pain states. [000324] Different opioids can be administered in different doses depending on the opioid, mode of administration, and whether the patient is opioid-exposed. The dose of opioid can depend on the specific opioid used. In some variations, the opioid dose of a particular opioid can be determined relative to morphine equivalent. Table 1 depicts conversion of representative opioids in terms of morphine equivalents. Table 1 38 4897-2147-5622.1Opioid Morphine Potency Equivalent Codeine 0.15 iveconventional dosages for different administration and formulations. Table 239 4897-2147-5622.1[000326] The CGRP inhibitor alone, or when combined with opioid, can be used to reduce the dose of opioid administered to a patient, while retaining the same or better decrease in the severity of pain. In some variations, when a CGRP inhibitor is administered, the initial opioid dose can be reduced by a percentage compared to the recommended dose. For example, the initial opioid dose can be reduced by at least 10% of the conventional initial dose described in Table 2. Other variations are possible. In some variations, the initial opioid dose can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2. [000327] In some variations, the method is directed to reducing the maintenance dose of opioid by administering the CGRP inhibitor. In some variations, the maintenance dose of opioid can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2. The reduced dose is relative to morphine as described in Table 1. [000328] In some variations, combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale. In some variations, the combination therapy that included a reduced opioid dose results in reduced pain on a 0-10 pain scale. In some instances, the reduced pain is at least 1 point. In some instances, the reduced pain is at least 2 points. In some instances, the reduced pain is at least 3 points. In some instances, the reduced pain is at least 4 points. In some instances, the reduced pain is at least 5 points. In some instances, the reduced pain is at least 6. In some variations, the reduction can be by a percent. In some variations, the pain can be reduced by a percentage. In some variations, the reduction of pain is at least 10%. In some variations, the reduction of pain is at least 20%. In some variations, the reduction of pain is at least 30%. In some variations, the reduction of pain is at least 40%. In some variations, the reduction of pain is at least 50%. In some variations, the reduction of pain is at least 60%. [000329] In some variations, the dose of opioid administered can be reduced from the conventionally administered dose by a particular percentage per given time period following the beginning of CGRP inhibitor administration. In some instances, the opioid dose is reduced by at least 10% per month. In some instances, the dose of opioid is reduced by at least 20% per month. Additional variations are possible. In some further variations, the opioid dose administered to the patient is reduced by at least 30%. In some further variations, the opioid dose administered to the patient is reduced by at least 40%. In some further variations, the opioid dose administered to the patient is reduced by at least 50%. In some further variations, the opioid dose administered to the patient is reduced by at least 60%. In some 40 4897-2147-5622.1further variations, the opioid dose administered to the patient is reduced by at least 70%. In some further variations, the opioid dose administered to the patient is reduced by at least 80% per month. In some variations, combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale. In some variations, such as when a patient is treated for chronic pain, the initial dose of opioid is far above initial and maintenance doses for opioids. In such instances, the reductions in dose of opioid as described herein can be relative to the elevated dose for chronic pain. EXAMPLES [000330] The following examples provide support for aspects of the disclosure. Reference is now made to the following examples that provide support for aspects of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope thereof. The examples are not intended to be limiting. To the contrary, the examples can be varied in keeping with the spirit of the disclosure. Example 1: Tissues from Spinal Cord Injured Individuals [000331] Tissue was acquired both from hyperactive (i.e., pain generating) and non- hyperactive (i.e., non-pain generating) DREZ sites to determine the in the abundance of specific proteins. Differentially abundant proteins may be markers of spinal cord injury pain and / or targets for drug discovery and development. [000332] Tissues implicated in spinal cord injury central pain were acquired and fast frozen. Methods of acquiring tissues that exhibit spinal cord injury central pain have been described, for example, in U.S. Patent No.8,694,107, incorporated herein by reference in its entirety. [000333] DREZ tissue generating CNS pain was acquired surgically. First, the DREZs that are potentially implicated in perceived pain were determined by comparing the anatomical location of perceived pain to a somatotopic map. [000334] Areas of specific DREZ tissue displaying hyperactive electrical signals were then identified by measuring their electrical hyperactivity. Non-electrically hyperactive, non- pain generating DREZ sites were identified in the same individual. Samples of both the hyperactive, pain generating DREZ spinal cord tissue and non-hyperactive, non-pain generating DREZ spinal cord tissue were surgically excised from the individual. 41 4897-2147-5622.1[000335] Tissues were obtained surgically exposing the DREZ tissue inclusive of the substantia gelatinosa tissue above (cephalad), below (caudal), and at the level of injury. A recording electrode was inserted approximately 2 mm deep into the dorsal grey matter of the spinal cord, entering at the dorsal root entry zone (DREZ). Recordings of spontaneous electrical activity were recorded for one second. DREZ tissue was removed to a 2mm depth. [000336] Recordings were performed bilaterally along the DREZs cephalad at and caudal to the level of the injury approximately 1 mm apart. The recordings were analyzed using fast Fourier transform (FFT) root Mean Square analysis and "spindle" analysis (as disclosed in U.S. Patent Publication Nos.2010 / 0203022 and 2007 / 0016264, both of which are incorporated herein by reference) to identify regions of neuroelectrical hyperactivity. The regions recorded correspond to at least Rexed layers 1, 2, and 3 within the dorsal grey matter. [000337] The recordings were guided by a somatotopic map and made both cephalad and caudal to the level of injury as well as at the level of the injury until no additional electrical hyperactivity was detected. A small cut in the pia was made and a micro-pituitary rongeur was inserted to remove an approximate 1x1x2 mm piece of dorsal grey matter. The tissue was identified as pain-producing "hyperactive" or non-pain producing non-hyperactive "normoelectric" based on the electrical recordings. The tissue was snap-frozen within 10 minutes of excision and stored at - 81 °C. Example 2: CGRP Expression [000338] Tissues from hyperactive and non-hyperactive DREZ in Example 1 were then tested against a 4,000 marker panel, including CGRP2 according to methods at SomaLogic. [000339] “Hot” and “cold” DREZ tissues were obtained from 10 patients (107 samples) and analyzed on the SomaScan 5K plex, which measures 4981 human proteins. [000340] Hyperactive tissue was extracted from spinal cord injured patients. Per tissue protein extraction agent (Thermo Scientific) per the manufacturer's recommendation, 200 μL of buffer plus Halt protease inhibitor cocktail (Pierce Part# 78430) was added. The tissue was homogenized in a tube on ice with a rotary pestle for 30 seconds until no tissue fragments were visible. The sample was centrifuged at >14,000x g for 10 minutes while at 4°C. The supernatant was filtered through a 0.2 micron filter into a sterile tube or plate while at 0°C Millipore Multiscreen GV filter plate, 0.22 μηι, sterile, Part # MSGV2210 or similar). The amount of total protein was determined using Micro BCA Protein Assay Kit (Thermo Scientific). Aliquots were stored at - 81 °C. 42 4897-2147-5622.1[000341] Of the approximate ninety proteins having increased abundance in the hyperactive DREZ tissue, twenty-one found literature support for relevance in neuronal and glial function in the DREZ leading to neuronal depolarization, and relevance in epilepsy and / or neuropathic pain rodent models. CGRP was chosen from these twenty-one based on high hot / cold ratio of protein abundance, strong neurobiological relevance to neuronal and glial causation of DREZ neuronal hyperactivity involving multiple pathways, and strong rodent model validation. [000342] The tissues were tested by SOMAscan®analysis. SOMAscan tests tissue against a protein panel (including CGRP2), and a range of concentrations. SOMAscan®and related methods and reagents are described, for example, at U.S. Patent Nos.5,843,653; 5,853,984; 5,989,823; 6,261 ,783; 6,329, 145; 6,531 ,286; 6,670, 132; 6,673,553; 6,706,482; 7,709, 192; 7,855,054; 7,964,356; 8,975,026 and 8,945,830, which are incorporated by reference in their entirety. [000343] Hyperactive pain producing DREZ tissue was compared to non-pain producing DREZ tissue. Targets that were found in greater abundance in hyperactive (pain producing) DREZ tissue as compared to non-pain producing DREZ tissue were identified as pain targets. These pain targets were analyzed for drugs effective against the target. [000344] Electrically hyperactive neuropathic pain-producing DREZ spinal cord tissues and electrically normal non neuropathic pain-producing DREZ spinal cord tissues were collected from each of 10 patients experiencing severe below-level neuropathic pain and were analyzed for abundance of protein X. The ratio of abundance of protein X found in the electrically hyperactive tissue compared to the electrically normal tissue was 4.89, FDR 1.23 x 10-4. [000345] Based on the compared CGRP2 abundance, CGRP2 shows a 6.9 fold increase in abundance in the pain-producing tissue. The ratio of CGRP2 abundance in hyperactive dorsal grey matter tissue compared to normo-active dorsal grey matter tissue was 6.9. The FDR of the RFU analysis was 0.035. [000346] The hyperactive DREZ tissue showed an increase in CGRP2 abundance over non-hyperactive DREZ tissue. Surgical destruction of this hyperactive DREZ tissue resulted in complete or near-complete relief of below-level neuropathic pain. CGRP is therefore a target for treating neuropathic pain in spinal cord injured individuals. Example 3. [000347] A compound of one of Formulae (I), (II), (III), or (IV), or a pharmaceutical salt, hydrate, solvate, ester, N-oxide, or combination thereof, is administered to a male patient 43 4897-2147-5622.1having severe below-level neuropathic pain. The patient experiences severe pain continuously, or with bursts in intensity occurring at least once daily. The patient rates his pain as a 10 on a scale of 0 to 10, 10 considered near suicidal-level pain. [000348] The compound is administered as directed in the product label of the compound, as described and incorporated herein by reference. [000349] Administering the compound as described herein results in a reduction of central pain in the patient. Example 4. Opioid Dosing [000350] A patient is treated with a combination of opioid and rimegepant. During administration, the patient voluntarily lowered the opioid dose. The patient further had increased opioid efficacy with absence of withdrawal symptoms. The combination therapy demonstrated the effectiveness of combination therapy as well as the effectiveness of rimegepant in opioid withdrawal. [000351] The patient additionally begins a course of rimegepant at 25mg once a day (qD) for two weeks. This is increased to 50mg / day BID, i.e., 100mg / day and remains at this dose for a six month period. [000352] By one to two months after the initial rimegepant administration, the patient voluntarily decreases his breakthrough dosing of oxycodone to 20 mg / day. Pain decreases from 9-10 (near suicidal) to 6, without severe episodes. By 4-5 months the patient’s breakthrough dosing continued to decrease to at times not needing it at all. [000353] By five months, the breakthrough dose is completely eliminated. The complete elimination of opioid was coupled with a substantial decrease in pain from 10 to 6, or a 40% reduction. [000354] Having described several embodiments, it will be recognized by those skilled in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the disclosure. Additionally, a number of well-known processes and elements have not been described in order to avoid unnecessarily obscuring the disclosure. Accordingly, the above description should not be taken as limiting the scope of the disclosure. [000355] It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of this disclosure. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, 44 4897-2147-5622.1and the disclosure is not to be limited to the details given herein, but may be modified within the scope and equivalents of the allowed claims. [000356] All publications and patents cited herein are incorporated by reference in their entirety. 45 4897-2147-5622.1

Claims

Claims 1. A method of treating neuropathic pain in a spinal cord injured (SCI) patient comprising: systemically administering a therapeutically effective amount of a calcitonin gene- related peptide (CGRP) inhibitor to the patient in need thereof.

2. The method of claim 1, wherein the neuropathic pain is centrally mediated.

3. The method of any one preceding claim, wherein the CGRP inhibitor is a CGRP antagonist.

4. The method of one of claim 1 or claim 2, wherein the CGRP inhibitor is a CGRP receptor (CGRP-r) antagonist.

5. The method of any one preceding claim, wherein the CGRP inhibitor is selected from the group consisting of Formula (I), Formula (V), and Formula (VII).

6. The method of claim 1, wherein the CGRP inhibitor is selected from the group consisting of Formula (III), Formula (IV), Formula (VI), Formula (VIII), and Formula (IX).

7. The method of any one of claims 1-4, wherein the CGRP inhibitor is an antibody.

8. The method of claim 1, wherein the CGRP inhibitor is an antibody selected from the group consisting of: a heavy chain sequence of SEQ ID NO: 1 and a light chain sequence of SEQ ID NO:2; a heavy chain sequence of SEQ ID NO: 3 and a light chain sequence of SEQ ID NO:4; a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO:6; and a heavy chain sequence of SEQ ID NO: 7 and a light chain sequence of SEQ ID NO:

8. 46 4897-2147-5622.

19. The method of any one preceding claim, wherein the neuropathic pain is reduced in the patient by at least 1 point on the 10-point pain scale.

10. The method of any one preceding claim, wherein neuropathic pain is reduced in the patient by at least 3 points on the 10-point pain scale.

11. A method of reducing opioid dose without increasing pain to a patient in need thereof, the method comprising: administering to the patient a combination therapy comprising a CGRP inhibitor and an opioid at a dose at least 10% lower than the baseline dose in the absence of the CGRP inhibitor, wherein the patient has no increase in pain on a 0-10 pain scale.

12. The method of claim 12, wherein the CGRP inhibitor is selected from the group consisting of Formula (I), Formula (V), and Formula (VII), or a salt, solvate, hydrate, or combination thereof.

13. The method of claim 11, wherein the CGRP inhibitor is an antibody.

14. The method of claim 13, wherein the CGRP inhibitor is selected from the group consisting of Formula (III), Formula (IV), Formula (VI), Formula (VIII), and Formula (IX), or a , or a salt, solvate, hydrate, ester, or combination thereof..

15. The method of any one of claims 11-14, comprising administering the opioid at a dose at least 20% lower than the baseline does in the absence of CGRP inhibitor.

16. The method of any one of claims 11-14, comprising administering the opioid at a dose at least 30% lower than the baseline does in the absence of CGRP inhibitor.

17. The method of any one of claims 11-14, wherein the patient has a decrease in pain of at least 1 on a 0-10 pain scale.

18. The method of any one of claims 11-14, wherein the patient has a decrease in pain of at least 3 points on a 0-10 pain scale. 47 4897-2147-5622.

119. The method of any one of claims 11-14, further comprising reducing the opioid dose by an at least 20% per month.

20. The method of any one of claims 11 -19, wherein the opioid is selected from Codeine, Fentanyl, Hydrocodone, Hydromorphone, Methadone, Oxycodone, Oxymorphone, Buprenorphine, Methadone, Morphine, Naltrexone, Nalbuphine, Tramadol, and Tramadol.

21. A method of treating pain in a patient comprising: administering to the patient a combination therapy comprising CGRP inhibitor and an opioid; subsequently, administering to the patient the combination therapy comprising CGRP inhibitor and the opioid at a maintenance dose of the opioid at least 10% lower than the dose administered to the patient in the absence of CGRP inhibitor, wherein the patient has no increase in pain on a 0-10 pain scale.

21. The method of claim 21, wherein the CGRP inhibitor is a small molecule compound.

22. The method of claim 22, wherein the CGRP inhibitor is an antibody.

23. A method of treating spinal cord injury in a spinal cord injured patient comprising: administering to the patient CGRP inhibitor at a border of injured spinal cord tissue and non-injured spinal cord tissue.

24. The method of claim 23, where in the CGRP inhibitor is administered intrathecally at the site of spinal cord injury.

25. The method of claim 23, where in the CGRP inhibitor is administered on the dura mater corresponding to the site of spinal cord injury.

26. The method of claim 23, wherein the administration is systemic administration. 48 4897-2147-5622.1